Flaxseed

Physicians, scientists and savvy laypeople want reliable information on foods and
supplements that might improve the outcome in chronic diseases that otherwise
shorten our lives. These health conditions include type 2 diabetes, heart attacks, high
blood pressure, chronic kidney disease and others. Incorporating faxseed into one’s
diet can greatly improve outcomes in various health conditions. Thousands of peer-
reviewed articles have been published documenting the clinical effcacy of faxseed
as a whole or its individual components and reveal the mechanisms by which those
various components work.
Flaxseed: Evidence-Based Cardiovascular and Other Medicinal Benefts is an
encyclopedic and defnitive text describing the health benefts of this humble plant.
The book features exquisite detail on the three major components of the plant that are
responsible for most of the documented benefts, those components being omega-3
fatty acids and two compounds that increase endothelial production of nitric oxide,
those compounds being the amino acid L-arginine, and cyanogenic glycosides.
Attention Readers: If you are not already familiar with the health benefts of
omega-3 fatty acids and of the above-named nitric oxide donors, then this book opens
a vast world of scientifc discovery that one can immediately apply to improving
health. This book calls attention to a wealth of journal articles providing practical
information on consuming faxseed and its overall health benefts. Enjoy!
 Flaxseed
Evidence-Based Cardiovascular
and Other Medicinal Benefts

Robert Fried, PhD

Richard M. Carlton, MD
First edition published 2023
by CRC Press
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ISBN: 978-1-032-30274-4 (hbk)
ISBN: 978-1-032-30273-7 (pbk)
ISBN: 978-1-003-30428-9 (ebk)
DOI: 10.1201/b22986
Typeset in Times
by Apex CoVantage, LLC
Contents
Preface....................................................................................................................... xi
Acknowledgments ...................................................................................................xiii
Disclaimer ................................................................................................................ xv

Chapter 1 Introduction .......................................................................................... 1

1.1 Flax—Garment of Pharaohs and Health-Giving Seeds ............ 1
1.2 Flax—A Functional Food .......................................................... 2
1.3 Cyanogenic Glycosides (CNglcs)............................................... 3
1.4 How Safe Is It to Consume Flaxseed? ....................................... 3
1.5 Disclaimer ................................................................................. 6
1.5.1 CAVEAT........................................................................ 7
1.6 Supplement Dosages in Clinical and Research Trials ............... 7
1.6.1 Flaxseed......................................................................... 8
1.6.2 Omega-3 PUFAs—Alpha-Linolenic Acid
(ALA), Eicosapentaenoic Acid (EPA) and
Docosahexaenoic Acid (DHA) .....................................11
1.6.3 L-Arginine ....................................................................14
1.7 Ad Lib Supplementation ...........................................................18
1.7.1 Raw Flaxseed ...............................................................19
1.7.2 Including Flaxseed in Daily Diet .................................21
1.8 Summary ................................................................................. 22
1.9 References................................................................................ 22

Chapter 2 Flaxseed, a Functional Food—Constituents and Their

Health Benefts ................................................................................... 25
2.1 Introduction ............................................................................. 25
2.2 Constituents That Make Flaxseed a Functional Food ............. 25
2.3 Flaxseed Oil/Lipid Components ............................................. 26
2.4 Proteins .................................................................................... 27
2.5 Dietary Fiber ........................................................................... 28
2.6 Lignans .................................................................................... 29
2.7 Minerals ................................................................................... 29
2.8 The Health Benefts of Flaxseed ............................................. 29
2.9 CNglcs in Flaxseeds, NO-Donors ........................................... 34
2.10 Guidelines to Supplementation of Flaxseed and
Flaxseed Oil .............................................................................35
2.10.1 Recommended Flaxseed Supplement
Content of ALA ......................................................... 37

v
vi Contents

2.11 Potential Anti-Nutritional Aspects of Flaxseed ...................... 37

2.12 Health Benefts of Flax Proteins.............................................. 38
2.13 Summary ................................................................................. 39
2.14 References................................................................................ 39

Chapter 3 The Benefcial Effect of Omega-3 PUFA and L-Arginine

on Endothelial Nitric Oxide (NO) Bioavailability ............................. 45
3.1 The More You NO ................................................................... 45
3.2 Nitric Oxide: The 1992 Science “Molecule of the Year” .......... 46
3.3 Bottom Line . . . the Endothelium ........................................... 47
3.3.1 The Structure and Function of the
Endothelium ................................................................ 47
3.4 How Does the Body Form NO?............................................... 49
3.4.1 Footnote to History...................................................... 49
3.5 Reactive Oxygen Species (ROS) and Oxidative
Stress—A Major Cause of Endothelium Damage ................... 50
3.6 Endothelial NO from L-Arginine—Nitric Oxide
Synthase (eNOS)...................................................................... 51
3.7 How Endothelium-Derived Nitric Oxide (eNO)
Is Formed ................................................................................. 52
3.8 NO Formed from CNglcs ........................................................ 53
3.9 The Blood Vessels of the Blood Vessels
(Vasa Vasorum) Are Regulated by NO ................................... 54
3.9.1 Structure and Function of Vasa Vasorum ................... 55
3.9.2 Vasa Vasorum Depends Exclusively on
Endothelium-Derived (NO) Vasorelaxation ................ 56
3.10 The Endothelial Glycocalyx .................................................... 56
3.10.1 The Glycocalyx Regulates eNO Formation................. 58
3.11 The Endothelial Glycocalyx in Health and Disease ................ 59
3.11.1 Diabetes ....................................................................... 59
3.11.2 Atherosclerosis ............................................................60
3.11.3 Hypertension................................................................60
3.11.4 Kidney Function .......................................................... 61
3.12 Summary ................................................................................. 61
3.13 References................................................................................ 62

Chapter 4 The Role of Flaxseed Micronutrients and Nitric Oxide

(NO) in Blood Vessel and Heart Function ......................................... 67
4.1 Introduction ............................................................................. 67
4.2 What Propels Blood through the Circulatory System? ........... 68
4.2.1 Systole.......................................................................... 68
4.2.2 Flaxseed Increases NO Bioavailability ....................... 70
4.2.3 Flaxseed Omega-3 Fatty Acid, Alpha-Linolenic
Acid, Promotes eNO Formation .................................. 70
Contents vii

4.2.4 Flaxseed Improves the Ejection Fraction .................... 71

4.3 Arterial Vessel Compliance..................................................... 72
4.3.1 Flaxseed Oil Promotes Arterial Blood Vessel
Elasticity (Compliance) ............................................... 73
4.4 The Arterial Waveform ........................................................... 74
4.5 Measuring Blood Flow by Flow-Mediated
Dilation (FMD)........................................................................ 76
4.5.1 Flaxseed and L-Arginine Improve FMD .................... 77
4.6 Endothelial Nitric Oxide (eNO) and Control of Blood
Pressure ................................................................................... 79
4.6.1 Endothelium-Independent Control of
Blood Pressure ............................................................. 79
4.6.2 Endothelium-Dependent Control of
Blood Pressure ............................................................. 79
4.6.3 Interaction of Endothelium-Independent and
Endothelium-Dependent Blood Flow Control
Systems ........................................................................80
4.6.4 The Role of NO in Vascular Remodeling in
Hypertension................................................................ 80
4.6.5 Flaxseed Combats Hypertension ................................. 82
4.7 Flaxseed Combats Peripheral Artery Disease (PAD) ............. 83
4.8 Summary ................................................................................. 85
4.9 References................................................................................ 85

Chapter 5 Omega-3 Fatty Acids and NO from Flax Intervention in

Atherosclerosis and Chronic Systemic Infammation ........................ 89
5.1 Atherosclerosis ........................................................................ 89
5.1.1 The Causal Role of ROS in Atherosclerosis ................ 92
5.1.2 Omega-3 Fatty Acids, an Antioxidant Flaxseed
Constituent Can Prevent, Even Reverse,
Atherosclerosis ............................................................ 93
5.1.3 Omega-3 Fatty Acids from Flaxseed ........................... 93
5.1.4 Omega-3 Fatty Acids from Flaxseed and
Elevated Blood Cholesterol .........................................94
5.1.5 Omega-3 Fatty Acids from Flaxseed Lower
Triglycerides ................................................................ 96
5.1.6 L-Arginine (Abundant in Flaxseed) Prevents,
Even Reverses, Atherosclerosis ...................................97
5.2 Chronic Systemic Infammation..............................................99
5.2.1 C-Reactive Protein in Infammation............................99
5.2.2 Omega-3 ALA Reduces Infammation ...................... 101
5.2.3 L-Arginine, per se, and Infammation....................... 102
5.2.4 Flax/Omega-3 and Rheumatoid Arthritis.................. 102
5.3 Summary ............................................................................... 103
5.4 References.............................................................................. 104
viii Contents

Chapter 6 Flaxseed and L-Arginine, and Omega-3 Fatty Acids, per se, in
Treatment of Hypertension and Sickle Cell Disease .........................109
6.1 Hypertension...........................................................................109
6.1.1 Hypertension as Omega-3 Defciency ........................110
6.1.2 Flax/Omega-3 Fatty Acids Reduces Blood
Pressure—The Harris Omega-3 Index ....................... 111
6.1.3 The Safety of Cyanogenic Glycosides
in Flaxseed .................................................................113
6.1.4 L-Arginine Supplementation Reduces Blood
Pressure ...................................................................... 114
6.1.5 Studies Citing Flaxseed or Flax Oil, per se,
and Hypertension ........................................................ 117
6.1.6 Could It Be Due to Asymmetric
Dimethylarginine (ADMA) When
L-Arginine Fails? ....................................................... 117
6.1.6.1 Does ADMA Explain the Arginine
Paradox?...................................................... 118
6.2 Endothelial Dysfunction in Sickle Cell Disease
and L-Arginine Therapy.........................................................119
6.3 Summary ................................................................................120
6.4 References...............................................................................120

Chapter 7 L-Arginine and Omega-3 Fatty Acids in Adjuvant Treatment

for Type 2 Diabetes and Chronic Kidney Disease ............................125
7.1 The Contribution of Flaxseed Constituents in Type 2
Diabetes Mellitus ....................................................................125
7.1.1 Oxidative Stress in Type 2 Diabetes...........................126
7.1.2 Endothelial Dysfunction in Type 2 Diabetes..............128
7.2 Flaxseed as Adjuvant Treatment of Type 2 Diabetes .............129
7.2.1 Omega-3 Fatty Acids Reduce Triglycerides in
Type 2 Diabetes ..........................................................131
7.2.2 Type 2 Diabetes and Coronary Heart Disease ...........132
7.2.3 Omega-3 Fatty Acid as Adjuvant Treatment of
Type 2 Diabetes and Nonalcoholic Fatty Liver
Disease (NAFLD).......................................................132
7.2.4 Omega-3 Fatty Acid as Adjuvant Treatment of
Type 2 Diabetes with Diabetic Nephropathy .............133
7.2.5 Treatment Dosage Matters..........................................134
7.2.6 L-Arginine as Adjuvant Treatment of Type 2
Diabetes—Is Type 2 Diabetes Mellitus an NO
Defciency Disease? ....................................................134
7.3 Flax, Infammation and Endothelium Dysfunction
in CKD ...................................................................................138
7.3.1 Flaxseed as Adjuvant Treatment of CKD ..................138
Contents ix

7.3.2 Omega-3 Fatty Acids in Adjuvant Treatment of

Kidney Disease ...........................................................139
7.3.3 L-Arginine in Treatment of CKD...............................142
7.3.4 CKD, Hypertension and Chronic Heart Failure .........144
7.4 Summary ................................................................................145
7.5 References...............................................................................146

Chapter 8 NO from Flaxseed Enhances Sexual Function .................................151

8.1 Prologue ..................................................................................151
8.2 The Oyster and the Blue Pill: Sexual Desire vs. Sexual
Performance ...........................................................................151
8.2.1 What We Learn from The Perfumed Garden of
the Shaykh Nefzawi ....................................................152
8.3 The Most Common Cause of Erectile Dysfunction ...............153
8.4 Gas Fuels Performance...........................................................154
8.4.1 How a Simple “Blunder” Explains
Cardiovascular and Heart Disease .............................155
8.5 The Culprit: Oxidative Stress .................................................155
8.6 The Endothelium Forms Nitric Oxide (eNO) .........................156
8.6.1 The Glycocalyx: Sugar Coating the
Endothelium ...............................................................157
8.7 Sexual Performance Is about Shunting Blood Flow
in the Body .............................................................................157
8.7.1 The Penis Is Not a Muscle ..........................................158
8.8 The (Ach/NO/cGMP) Pathway to Penile Erection .................159
8.9 The Role of Aging in ED........................................................159
8.9.1 Do We Just Run Out of Gas as We Age? ....................161
8.10 Endothelium Dysfunction Is a Feature of ED ........................162
8.11 Enter Flaxseed ........................................................................162
8.11.1 Flaxseed Supplies L-Arginine, the
Substrate for NO .........................................................163
8.11.2 ROS Jeopardize Erectile Function .............................163
8.11.3 Flaxseed Supplies the Antioxidant Omega-3
Fatty Acids Promoting eNO Formation .....................164
8.12 Summary ................................................................................166
8.13 References...............................................................................166

Chapter 9 Omega-3 PUFA and L-Arginine for Longer Life Span with
a Longer Health Span ........................................................................169
9.1 One Way to Longer Life Is to Prevent Shortening It ..............169
9.2 How Can We Tell Whether People Who Consume
Flaxseed or Flax Oil Age More Slowly, Live Longer?...........171
9.2.1 Omega-3s Concentration Affects Cell Aging
via Telomere Length ...................................................171
x Contents

9.2.2 Omega-3 PUFAs Slow Aging by Lowering

Mitochondria Free Radical “Emissions” ....................172
9.2.3 Speaking of Cognitive Aging .....................................174
9.3 Criteria for Omega-3 Suffciency: The Omega-3 Index .........175
9.3.1 Availability vs. Absorbability .....................................178
9.4 Anti-Aging Action of L-Arginine ..........................................178
9.5 Summary ................................................................................179
9.6 References...............................................................................180

Index.......................................................................................................................183
Preface
In researching publications describing clinical trials or experimental (animal) stud-
ies of the effects of faxseed on medical conditions, we found that the titles of these
studies often did not specifcally come up with the key word “faxseed.” Given that
L-arginine, omega-3 fatty acids and cyanogenic glycosides are three of the main
benefcial constituents of faxseed, we chose to search the literature using those three
key words, in addition to the word “faxseed,” in order to detail the medicinal ben-
efts of this plant.
An evidence-based book like this is basically an extended research and clinical
studies review. To make it more readable without losing valuable information,

• we omitted the number of participants in treatment or controls groups in

any given study unless that information was absolutely vital to understand-
ing the study outcome, e.g., they were either very small or very large in
number;
• we substituted the word “signifcant” for signifcance levels, usually in the
form (P < 0.05, or P < 0.01);
• we usually left out the type or form of data analysis and the study design,
such as double-blind or prospective, unless it was of a special, uncommon
type;
• we substituted “participants” or “volunteers” for “subjects”;
• we numbered the references instead of citing author/date in the text, e.g., (1),
as opposed to (Fried & Carlton, 2018); and
• in some cases, we reproduced (with permission) a large excerpt from given
references in order to deepen the reader’s grasp of seminal fndings that are
of particularly key importance.

In addition, in the reference section,

• we list all the authors of a given study,

• we provide the full title of every journal publication, and
• wherever possible, we cited either a DOI or other identifer for ready access
to a reference.

xi
Acknowledgments
We express our deep appreciation to Ms. Randy Brehm, Senior Editor, Life Sciences
and Nutrition, CRC Press/Taylor & Francis, for, once again, supporting our work,
and to Dr. Jacqueline Perle for effciently carrying out the unenviable task of sorting
out and acquiring “permissions.”

xiii
Disclaimer
The information in this book is neither intended to diagnose nor treat any disease,
nor is it a substitute for medical guidance. The authors do not propose that anyone
who is undergoing treatment for any medical condition under the care of a physician,
or any other qualifed healthcare provider, should terminate such treatment in favor
of any treatment or substance described here.
Rather, where it may seem helpful to adopt a nutrition strategy based on foods or
supplements described here, the authors urge the reader to do so only with the advice,
and the supervision, of his or her physician or other qualifed healthcare provider.
The information provided here is intended only to educate the reader to what may
be available and not to suggest self-treatment. The authors shall not be held liable
or responsible for any misunderstanding or misuse of the information contained in
this book or for any loss, damage, or injury caused or alleged to be caused directly
or indirectly by any treatment, action, or application of any food or food source dis-
cussed in this book.
In writing a book that extols the virtues of consuming any given food product for
health purposes, there is the risk that others might wonder if the authors gain any
commercial beneft from sales of that food or any derivatives thereof. It is therefore
important for the reader to know that neither Dr. Fried nor Dr. Carlton, nor any of
their relatives or associates, stands to gain fnancially from sales of faxseed or any
of its derivatives. We are health professionals who have, for scores of years, been
seeking out pioneering information in the feld of health and nutrition, and have
“translated” that pioneering information into books, articles and lectures to make it
more accessible and understandable.

xv
 1 Introduction

FIGURE 1.1 Flax fowers. (From Nancea Whitham. https://jarviefora.com/pages/contact-

us. With permission.)

All that man needs for health and healing has been provided by God in nature,
the challenge of science is to fnd it.
—Paracelsus (1493–1541)

1.1 FLAX—GARMENT OF PHARAOHS AND

HEALTH-GIVING SEEDS
Most people driving down a country road probably pay scant attention to the little blue
fowers growing by the roadside. These fowers may not have meant much to them at the
time. They don’t mean much anymore to most people nowadays. In fact, they probably
did not even know what the fowers were. Well, they likely were fax fowers, and they
actually meant a great deal to our ancestors. Common fax (Linum usitatissimum L.) was
one of the frst domesticated crops. Parenthetically, usitatissimum means “most useful.”
The flaments in their stems were woven into linen (from the Latin word, linum); the
seeds from their fowers were used as medicine; it was an ingredient in embalming oils.
We use the word “faxseed” when we consume it as food, whereas we call
it “linseed” when it is used in industry or as animal fodder. Flaxseed oil, for
instance, is a consumable supplement, whereas linseed oil made from the same

DOI: 10.1201/b22986-1 1
2 Flaxseed

faxseeds is a principal component of commercially produced paint thinners and

wood sealers.
There are many claims about the origin and frst uses of the fax plant, but it was
most likely frst cultivated in Mesopotamia possibly as early as 3000 BCE. And
through the course of history, the fax plant enjoyed widespread use in ancient Greek
cuisine and in ancient Roman medicine, which used it as a laxative, as well as an
expectorant for coughs and for soothing irritated tissue.
The linen woven from fax is the world’s oldest known textile. The earliest frag-
ment of identifed cloth considered to be of linen is from eastern Turkey, carbon-
dated to ca. 9,000 years ago. Ancient Egyptian murals and papyri depict the growth
of fax, the spinning of fax thread, and the weaving of that thread into linen. And
3,000 to 4,000 years ago, mummifed remains of pharaohs were bound in delicate
fax linen woven with an expertise that is still diffcult to replicate today.
Linen is cited in a number of instances in the Old Testament of the Bible and also
in the Gospel of John in connection with the wrappings of the resurrected Lazarus
(John 11:1–44). And that use is also illustrated and immortalized in the folk-song
lyrics of Streets of Laredo, a traditional American Western ballad previously called
A Cowboy’s Lament. Here is the frst stanza:

As I walked out on the streets of Laredo.

As I walked out on Laredo one day,
I spied a poor cowboy wrapped in white linen,
Wrapped in white linen as cold as the clay.

In what is now the United States, fax was introduced by the colonists, and it four-
ished here. But, by the early 20th century, cheaper cotton and rising farm wages had
shifted production of fax to northern Russia, which came to provide 90% of the
world’s output. Since then, fax has lost ground as a commercial crop due to the easy
availability of more durable fbers.
Nevertheless, fax still has many uses: it is cultivated for its seeds, which can be
ground into meal or turned into faxseed oil, a nutrition supplement. Flaxseed oil as
linseed oil is an ingredient in many wood-fnishing products. But fax fbers are still
used to make linen, especially fne Belgian fax linen.
To the point, fax holds many constituents, some known as micronutrients that are
essential to health. It is often suspected that the defciency of these micronutrients con-
tributes much to the abundance of medical disorders that plague us now, including ath-
erosclerosis, heart failure and chronic kidney disease, type 2 diabetes and many more.
These micronutrients are vitamins, minerals and antioxidants needed for healthy living.
Micronutrients are ordinarily contained in common foods we consume, but unfor-
tunately, they are now routinely eliminated in the production of “processed foods”
that now constitute much of our food consumption. There is, therefore, a compelling
need for supplementation of these micronutrients.

1.2 FLAX—A FUNCTIONAL FOOD

Because of the many health-giving constituents of fax, both in seeds and in oil, it
can rightly be considered a “functional food.” Functional foods are foods that have
Introduction 3

a potentially positive effect on health beyond basic nutrition. Proponents of func-

tional foods say they promote optimal health and help reduce the risk of disease.
Functional foods differ from nutraceuticals. “Nutraceuticals” is a broad umbrella
term that is used to describe any products derived from food sources with extra
medicinal benefts.
A food that holds one or more nutraceuticals would be considered a functional
food. Flax fts that to a “t.”
This book emphasizes constituents in fax currently considered to be nutraceu-
ticals. The compounds are mainly L-arginine, omega-3 polyunsaturated fatty acids
(PUFAs), and cyanogenic glycosides (CNglcs), of which there are three: linamarin,
linustatin and neolinustatin.

1.3 CYANOGENIC GLYCOSIDES (CNglcs)

CNglcs are a group of plant nitrate-derived secondary compounds that can yield
cyanide (cyanogenesis) following their breakdown by digestive acids and enzymes.
They constitute an essential component of plant defense against predatory microbes,
fungi and viruses. We know of at least 2,000 plant species that hold CNglcs. Simply
put, CNglcs are a combination of cyanide and sugar present in many edible plants
(1) including corn, paddy rice, barley, wheat, rye, sugar cane, mango, cassava, lima
beans, bamboo shoots, sorghum, fax; common fruits such as apples; and stone fruits
like peaches, plums, cherries and apricots. Other sources of dietary cyanide include
vitamin B12.
While “cyanogenic glycoside” is a rather daunting, off-putting, unfriendly term
that conjures up concerns for safe consumption, these concerns, as you will see, are
largely unwarranted.

1.4 HOW SAFE IS IT TO CONSUME FLAXSEED?

Cyanide is a poison, but even so, its toxicity depends entirely on how much of it is
consumed. It certainly is not poison when it is formed from CNglcs in the minute
quantities found in certain quite common foods. When CNglcs are simply part of the
foods consumed, or in the quantity ordinarily contained in recommended servings
of faxseeds or faxseed oil as nutrient supplements, it is generally considered quite
safe to consume.
In fact, faxseeds have been termed a “functional food” in a report titled “Flax
and Flaxseed Oil: An Ancient Medicine and Modern Functional Food” published in
the Journal of Food Science and Technology in 2014. (2) Countless, perhaps millions
of people consume faxseeds or faxseed oil every day . . . and live to tell about it—in
fact, to acclaim its health benefts.
Although the CNglcs in faxseeds are essentially the same compound as found
in amygdalin typically extracted from apricot kernels or the synthetic form, lae-
trile, alleged in the 1950s to cure cancer (and now banned by the Food and Drug
Administration [FDA]), its presence in food does not reach the amounts of it con-
sumed in reported attempted cancer “cures” which, in some cases were reported to
result in poisoning. (3) But not so CNglcs from faxseed.
4 Flaxseed

According to a report published in 2017 in the journal Archives in Cancer

Research, when amygdalin was orally administered to people, the toxic dose was
found to be 4 grams per day, for 15 days. (4)
That is far greater than the amount in a serving of faxseed. Estimates of the amount
of ground faxseed in a tablespoon vary somewhat from source to source, but 6 to 7
grams is the consensus. (5) A report in the journal Nutrients tells us that no increase
in plasma cyanide levels above baseline has been observed with the consumption of
15 to 100 grams of faxseeds, which would be about 2 to 16 tablespoons. (6)
The linustatin and neolinustatin found in faxseed are thought to be the lowest
cyanide producers compared to other cyanogenic glycosides. This is because fax-
seed glycosides have a molecular structure that resists any spontaneous decomposi-
tion to hydrogen cyanide. Theoretically, 1 to 2 tablespoons of faxseed will produce
only approximately 5 to 10 mg of hydrogen cyanide after ingestion. This is highly
unlikely to cause toxicity for three reasons:

a) A 50 to 60 mg dose of cyanide is required to cause acute toxicity

b) The human body can routinely detoxify up to 100 mg/day of cyanide (7, 8)
c) By the way, cyanide is heat labile in cooked foods; cooking destroys it (9)

In one study, people given 50 grams/day of faxseeds did not show increased urinary
levels of thiocyanate, a signature metabolite of cyanide. (7) Based on these data,
people would need to consume the unrealistic amount of 1 kg of faxseeds daily for
cyanide toxicity to ever manifest itself. (10)
The recommendation of daily dietary supplementation of 9 grams of faxseed was
reported in the Journal of Food Science and Technology in connection with its high
content of alpha-linolenic acid (ALA; faxseeds holds about 23 grams/100 grams of
ALA). (2) However, Healthline stipulates that supplementation should be kept below
5 tablespoons per day. (11)
The Flax Council of Canada reports that consumption of moderate amounts of
fax (1 to 2 tbsp) daily is not likely to pose a health problem for North Americans who
have adequate intakes of protein and iodine. (12) In several clinical studies, volun-
teers ate muffns containing 50 grams (5 to 6 tbsp) of milled fax daily for up to six
weeks without ill effects. However, it should be noted that muffns made with milled
fax showed no trace of the CNglcs, confrming that cooking destroyed the enzyme
that metabolizes CNglcs. (13)
The Flax Council of Canada also noted that there are other sources of dietary
cyanide, including a metabolic by-product, thiocyanates, which can be found natu-
rally in milk, beer and green vegetables. Thiocyanate is a breakdown product of the
CNglcs and of glucosinolates found in millet and in cruciferous vegetables like cab-
bage, broccoli, caulifower, kale, mustard, turnip, radish and horseradish.
Thiocyanate can act as a goitrogen, meaning that it blocks the uptake of iodine
by the thyroid gland. When the diet is overly rich in goitrogens, the thyroid gland
swells to trap as much iodine as possible forming a goiter or lump in the neck. The
Council notes, however, that there is no evidence that consuming faxseed produces
symptoms of goiter. In fact, goiter is not a health problem where iodine intake is
adequate, and it is rare in North America. Goiter occurs mainly in Asia and Africa,
Introduction 5

and in 96% of cases, it is due to iodine defciency or consumption of cassava and not
to the overconsumption of known plant goitrogens. (12)
The Council also noted that fax contains two compounds, phytic acid and oxa-
late, that bind calcium, copper, iron, magnesium and zinc to form insoluble com-
plexes in the intestine. This may pose a problem for individuals prone to kidney
stones. However, fax contains less than 10 mg of oxalate/kgram and about 0.8% to
1.5% phytic acid by seed weight. The amount of phytic acid in fax is comparable to
that found in peanuts and soybeans. (14)
To sum up:

The acute lethal oral dose of cyanide in humans is reported to be between 0.5 and
3.5 mg/kg body weight. The toxic threshold value for cyanide in blood is considered
to be between 0.5 (ca. 20 μmol) and 1.0 mg/L (ca. 40 μmol), the lethal threshold
value ranges between 2.5 (ca. 100 μmol) and 3.0 mg/L (ca. 120 μmol). 120 grams
of crushed/ground faxseed can be consumed before a toxic threshold of 40 μmol/L
is reached. (15)

A tablespoon of milled faxseed weighs about 10 grams. Thus, to reach the toxic
threshold of 40 μmol/L, one would have to consume about 12 tablespoons of milled
faxseed at a sitting.
Furthermore, the safety and benefts of faxseed are so well-known that it is
recommended for heart health and other health reasons by numerous conventional
medicine-based websites:
American Heart Association News. “Know the Flax (and the Chia): A Little Seed
May Be What Your Diet Needs” (July 19, 2019):

“Flaxseeds or chia seeds offer good sources of alpha-linolenic acid (ALA), which are
unsaturated fatty acids that convert to omega-3 fatty acids typically found in fsh,” said
Linda Van Horn, a registered dietitian and professor in the department of preventive
medicine at Northwestern University in Chicago. “But they also offer a good plant-
based supply of plant-based proteins, fber, minerals and other nutrients.”

Specifcally, faxseeds contain lignans, a natural chemical compound that along with
fber, antioxidants and healthy fats can help reduce blood cholesterol and may also
help lower blood pressure. Some studies suggest lignans may have the potential to
reduce tumor growth in women with breast cancer and may protect against prostate
cancer.” (16)
Mayo Clinic (by Mayo Clinic Staff): “Overview—Polyunsaturated Fat”:

Flaxseed (Linum usitatissimum) and faxseed oil, which comes from faxseed, are rich
sources of the essential fatty acid alpha-linolenic acid—a heart-healthy omega-3 fatty
acid. Flaxseed is high in soluble fber and in lignans, which contain phytoestrogens.
Similar to the hormone estrogen, phytoestrogens might have anti-cancer properties.
Flaxseed oil doesn’t have these phytoestrogens.

Flaxseed can be used whole or crushed, or in a powder form as meal or four.

Flaxseed oil is available in liquid and capsule forms.
6 Flaxseed

Numerous health experts from leading academic centers have made strong rec-
ommendations that people use faxseed and faxseed oil to reduce cholesterol and
blood sugar and to treat diseases of the heart, kidneys and digestive system. A num-
ber of these experts also recommend taking faxseed to treat infammatory diseases
(such as arthritis). (17)
The American Heart Association (AHA) website:

Polyunsaturated fats can have a benefcial effect on your heart when eaten in moderation
and when used to replace saturated fat and trans fat in your diet.

Which foods are high in polyunsaturated fats? Foods high in polyunsaturated fat
include a number of plant-based oils, including the following:

• Soybean oil
• Corn oil
• Sunfower oil
• Flaxseed oil

Other sources include some nuts and seeds, such as walnuts and sunfower seeds;
tofu; and soybeans. The American Heart Association also recommends eating tofu
and other forms of soybeans, canola, walnut and faxseed and their oils. These foods
contain ALA, another omega-3 fatty acid. (18) And, fnally:
The Cleveland Clinic. “Flaxseed: Little Seed, Big Benefts. How and Why You
Should Be Adding Flax to Your Diet”:

Flaxseed benefts. Why do dietitians love faxseed? Let us count the ways:
. . . Flaxseed is a good source of high-quality plant protein, comparable to soy-
beans. Potassium. Potassium is a mineral that’s important for cell and muscle function
and helps maintain normal blood pressure. But many Americans don’t get enough.

Enter faxseed, which has more potassium than (the famously potassium-rich)
bananas. (19)

1.5 DISCLAIMER
Flaxseed, faxseed oil and their individual constituents (omega-3 alpha-linolenic
acid, L-arginine and trace amounts of cyanogenic glycosides [CNglcs]), with the
exception of CNglcs, per se, are commonly independent variables in the clinical and
experimental (animal-model) studies cited in the following chapters. In many cases,
they are cited as adjuvant treatment for conditions ranging from heart failure, to dia-
betes, to chronic kidney disease.
We will list the dosages that are recommended in these studies. But for obvious
professional and ethical reasons, we cite these dosages here for information purposes
only. We can make no specifc recommendations that anyone supplement either a
fax product or one of its constituents described in this book without competent med-
ical or other qualifed health provider supervision.
Introduction 7

While faxseed and its constituents are generally considered safe as food, not every-
one tolerates certain foods, and anaphylaxis is always a possibility. There are also other
cases where generally well-tolerated foods or substances can have an unpredicted para-
doxical effect. In addition, faxseed or its constituents supplemented as adjuvant treat-
ment for a serious medical condition cannot be undertaken without exact knowledge of
its safety in that setting. This requires on-site medical expertise. We cannot provide that.
L-Arginine, for instance: A clinical study cited in this book found that supple-
menting L-arginine in a certain kind of kidney transplant signifcantly improved
the treatment outcome except in the case of severe infammation when, unexpect-
edly, it had the opposite effect. Furthermore, each of the benefts of faxseed or its
constituents as adjuvant treatment can also constitute a hazard.

1.5.1 CAVEAT
• Flaxseeds or faxseed oil may result in lowered blood sugar. This may be of
concern for individuals with diabetes controlling their blood glucose levels
with prescription meds.
• Consuming faxseed oil may lower blood pressure. This may be of concern
for persons who are concurrently taking antihypertensives and/or diuretics.
• The use of faxseeds may increase the chances of bleeding. This may be of
concern for persons concurrently taking certain medications such as antico-
agulants (“blood thinners”), including but not limited to aspirin, Coumadin
and Plavix.
• Flaxseed and its constituents can affect hormones. This may be of concern
for pregnant or lactating women.
• Some people may be allergic to faxseed or its constituents.
• There is conficting information about whether ALA in faxseeds and
faxseed oil causes prostate cancer to become more aggressive. However,
faxseed oil has the nutrient lignan which has been linked to slowing the
growth of prostate cancers.

Because faxseed or its constituents can interfere with the absorption or function of other
medications, therefore consultation with a qualifed healthcare provider is essential.

1.6 SUPPLEMENT DOSAGES IN CLINICAL AND RESEARCH TRIALS

The 1998 Nobel Prize in Physiology and Medicine was awarded to three American
scientists, Drs. Robert F. Furchgott, Louis J. Ignarro and Ferid Murad, who described
a physiological phenomenon that no one could have imagined: blood fow through-
out the body and the brain is controlled in part by a gas, nitric oxide (NO). NO
is an intrinsic vasodilator, formed in and by the endothelial lining of blood ves-
sels. Triggered by the neurotransmitter acetylcholine (Ach), NO formation depends
largely on the action of an enzyme, nitric oxide synthase (NOS) on the amino acid
L-arginine. More about that in Chapter 8.
When the endothelium is damaged, as is the case, for instance, in hypertension
and in atherosclerosis, NO formation may be inadequate, and systemic as well as
8 Flaxseed

regional blood fow may be jeopardized. Impaired endothelium NO formation is now

seen as the common denominator in most cardiovascular diseases. Thus, restoring
that function is now also seen as the key to maintaining or restoring function and,
therefore, health. The focus on faxseed supplementation, then, is that it supports
endothelium viability and NO formation and bioavailability:

First, faxseed contains omega-3 polyunsaturated fatty acids (PUFAs) that support
endothelial function and promote NO formation. In fact, a study titled “Impact of n-3
[omega-3] fatty acids on endothelial function: results from human interventions stud-
ies,” appeared in the journal Current Opinion in Clinical Nutrition and Metabolic
Care in 2011. The investigators concluded that “In individuals with CVD risk factors
including overweight, dyslipidemia and Type 2 diabetes n-3 [omega-3] PUFAs may
improve endothelial function.” (20)

One tablespoon of ground fax contains 2 g of omega-3s.

Second, faxseed contains the amino acid L-arginine from which the endothelium
derives NO. There is about 2 g of L-arginine per 100 g of basic faxseed. That’s about
1 tablespoon.
Third, faxseed also contains (very) small amounts of cyanogenic glycosides that
likewise contribute to nitric oxide bioavailability.
In sum, there is strong evidence that the constituents of faxseed, individually,
as well as all together, promote cardiovascular health by supporting endothelium
viability and supplying the substrate, L-arginine, for nitric oxide formation.
So, the three main relevant ingredients in faxseed and faxseed oil supple-
mentation are the omega-3 fatty acid alpha-linoleic acid (ALA) (which the body
can convert to eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]),
L-arginine and cyanogenic glycosides. In the following section, we list the
published dosages recommended for omega-3 and L-arginine reported in clini-
cal trials of sole treatment and/or adjuvant treatment of various cardiovascular
disorders. There are no published dosages for the use of cyanogenic glycosides
(CNglcs) in adjuvant treatment of any conventional medical condition. However,
we know that it is present in faxseed (but not its oil) and that it is a nitric oxide
donor (see Chapter 2).
Here are some of the dosages recommended in published clinical reports:

1.6.1 FLAXSEED
• “1–2 tablespoons a day is considered a healthy amount.” Mar 31, 2015.
“Flaxseed Is Nutritionally Powerful”—Mayo Clinic Health System. (www.
mayoclinichealthsystem.org; accessed 11/15/21)
• “30 grams (3 tablespoons equival.) of roasted faxseed powder for 3
months” Saxena and Katare. 2014. Biomedical Journal, Nov–Dec; 37(6):
386–390. DOI:10.4103/2319–4170.126447.
• “The amount of faxseed ingested daily over an extended period of time
has been as much as 40 to 50 grams.” Dodin, Lemay, Jacques et al. 2005.
Journal of Clinical Endocrinology and Metabolism, Mar; 90(3): 1390–1397.
DOI:10.1210/ jc.2004–1148.
Introduction 9

• “Human studies with 50 g/day faxseed did not increase urinary thiocya-
nate levels.” Parikh, Netticadan, and Pierce. 2018. American Journal of
Physiology. Heart and Circulatory Physiology, Feb 1; 314(2): H146-H159.
DOI:10.1152/ ajpheart.00400.2017.
• “Clinical benefts of the n-3 fatty acids were not apparent until they were
consumed for > or =12 wk. It appears that a minimum daily dose of 3 g
eicosapentaenoic and docosahexaenoic acids is necessary to derive the
expected benefts.” Kremer. 2000. American Journal of Clinical Nutrition,
Jan; 71(1 Suppl): 349S3–51S. DOI : 10.1093/ajcn/71.1.349s.
• “Only 10 g of faxseed in the daily diet increases the daily fber intake by
1 g of soluble fber and by 3 g of insoluble fber.” Goyal, Sharma, Upadhyay
et al. 2014. Journal of Food Science and Technology, Sep; 51(9): 1633–1653.
DOI:10.1007/ s13197-013-1247-9.
• “Flaxseed supplementation (30 g/day) on hormonal levels in a 31-year old
woman.” Nowak, Snyder, and Brown. 2007. Current Topics in Nutraceutical
Research, 5(4): 177–181. PMCID: PMC2752973.

The previous listings are intended to illustrate the range of dosages that clinical inves-
tigators consider safe and potentially benefcial in a sample of differing applications.
There is no published recommended dietary allowance for faxseed or faxseed
oil. But, according to A. Wergin on the Mayo Clinic website, “While there are no
specifc recommendations for faxseed intake, 1–2 tablespoons a day is considered
a healthy amount.” (21) Here are examples of faxseed dosages in specifc clinical
applications:

• In treatment of infammatory biomarkers in patients with coronary artery

disease (read endothelial dysfunction): “12 weeks consumption of faxseed
(30 g/day) or usual care control.” Khandouzi, Zahedmehr, Mohammadzadeh
et al. 2019. Effect of faxseed consumption on fow-mediated dilation and
infammatory biomarkers in patients with coronary artery disease: a ran-
domized controlled trial. European Journal of Clinical Nutrition, Feb;
73(2): 258–265. DOI:10.1038/s41430–018–0268-x.
• In treatment of infammation in Metabolic Syndrome (read endothe-
lial dysfunction): “One group received 25 mL/day faxseed oil.” Akrami,
Makiabadi, Askarpour et al. 2020. A comparative study of the effect of
faxseed oil and sunfower oil on the coagulation score selected oxidative
and infammatory parameters in Metabolic Syndrome patients. Clinical
Nutrition Research, Jan; 9(1): 63–72. DOI:10.7762/cnr.2020.9.1.63.
• In treatment of dyslipidemia and hypertension: “The intervention group
received 36 g of faxseed sachet.” Haghighatsiar, Askari, Saraf-Bank et al.
2019. Effect of faxseed powder on cardiovascular risk factor in dyslipidemic
and hypertensive patients. International Journal of Preventive Medicine, 10:
218. DOI:10.4103 /ijpvm.IJPVM_563_17.
• In treatment of dyslipidemia: “Flaxseed in whole, ground, or defatted
form (generically called whole faxseed) was tested in 10 of 28 trials with
doses from 20.0 to 50.0 g (median: 38.0 g; 10 g ≈ 1 tablespoon).” Pan, Yu,
10 Flaxseed

Demark-Wahnefried et al. 2009. Meta-analysis of the effects of faxseed

interventions on blood lipids. American Journal of Clinical Nutrition, Aug;
90(2): 288–297. DOI:10.3945/ajcn.2009.27469.
• In treatment of Type 2 diabetes: “Type 2 diabetic patients with mild hyper-
cholesterolemia were enrolled into the study. Patients were randomized
to supplementation with faxseed-derived lignan capsules (360 mg lig-
nan per day) or placebo for 12 weeks, separated by an 8-week wash-out
period.” Pan, Sun, Chen et al. 2007. Effects of a faxseed-derived lig-
nan supplement in type 2 diabetic patients: a randomized, double-blind,
crossover trial. PLoS One, Nov 7; 2(11): e1148. DOI:10.1371/journal.pone.
0001148.
• In treatment of metabolic syndrome: “A total of 100 subjects (>or=50
years) were randomized to receive faxseed lignan (543 mg.day-1 in a 4050
mg complex) or placebo while completing a 6 month walking program
(30–60 min.day-1, 5–6 days.week-1).” Cornish, Chilibeck, Paus-Jennsen
et al. 2009. A randomized controlled trial of the effects of faxseed lignan
complex on metabolic syndrome composite score and bone mineral in older
adults. Applied Physiology, Nutrition and Metabolism, Apr; 34(2): 89–98.
DOI:10.1139/H08–142.
• In treatment of blood pressure: “Hypertriglyceridemic subjects with
untreated normal-high blood pressure were prescribed a 2 grams PUFA
supplementation.” Cicero, Derosa, Di Gregori et al. 2010. Omega 3 poly-
unsaturated fatty acids supplementation and blood pressure levels in hyper-
triglyceridemic patients with untreated normal-high blood pressure and
with or without metabolic syndrome: A retrospective study. Clinical and
Experimental Hypertension, Jan; 32(2): 137–144. DOI:10.3109/106419609
03254448.
• In prevention of cardiovascular risk factors. “Men and post-menopausal
women with pre-study low density lipoprotein cholesterol (LDL-C)
between 130 and 200 mg/dL were randomized to 40 g/day of ground fax-
seed-containing baked products or matching wheat bran products for 10
weeks while following a low fat, low cholesterol diet.” Bloedon, Balikai,
Chittams et al. 2008. Flaxseed and cardiovascular risk factors: Results
from a double-blind, randomized, controlled clinical trial. Journal of the
American College of Nutrition, Feb; 27(1): 65–74. DOI:10.1080/07315724.2008.
10719676.
• In treatment of obesity and insulin resistance: “Nine obese glucose intoler-
ant people consumed 40 g ground faxseed or 40 g wheat bran daily for
12 weeks with a 4-week washout period.” Rhee and Brunt. 2011. Flaxseed
supplementation improved insulin resistance in obese glucose intoler-
ant people: A randomized crossover design. Nutrition Journal, 10: 44.
DOI:10.1186/1475-2891-10-44.

According to V. Tan on the Healthline website, “Health benefts . . . were observed

with just 1 tablespoon (10 grams) of ground faxseeds per day. However, it’s
recommended to keep serving sizes to less than 5 tablespoons (50 grams) of fax
seeds per day.” (22)
Introduction 11

CAVEATS
Flaxseed can

• Cause allergy and worsen infammation

• Be unsafe during pregnancy or lactation
• Cause loose bowels or intestinal blockage
• Interact with medications including those for managing high blood pres-
sure, for thinning the blood and for maintaining healthy blood sugar levels

1.6.2 OMEGA-3 PUFAS—ALPHA-LINOLENIC ACID (ALA), EICOSAPENTAENOIC

ACID (EPA) AND DOCOSAHEXAENOIC ACID (DHA)
Table 1.1 provides information about our understanding of adequate intake of
omega-3 fatty acids according to the National Institutes of Health (NIH), Offce of
Dietary Supplements.
Here is a sample of published clinical and research dosage recommendations:

• “Current dietary recommendations for adults suggest a daily intake of

2.22 g of ALA based on a 2000 kcal diet.” Rodriguez-Leyva, Bassett,
McCullough et al. 2010. Canadian Journal of Cardiology, Nov; 26(9):
489–496. DOI:10. 1016/s0828–282x(10)70455–4.
• “For adults between 25 and 49 years old, Health Canada suggests 1500
mg of omega-3 and 9000 mg of omega-6 polyunsaturates daily for men
and 1100 mg of omega-3 and 7000 mg of omega-6 fatty acids daily
for women. This results in an omega-6—to—omega-3 ratio of 6:1.”
Schwalfenberg. 2006. Canadian Family Physician, Jun 10; 52(6): 734–740.
PMCID: PMC1780156.

TABLE 1.1
Adequate intake of omega-3 fatty acids
Adequate Intakes (AIs) for Omega-3s
Age Male Female Pregnancy Lactation
Birth to 6 months * 0.5 g 0.5 g
7–12 months* 0.5 g 0.5 g
1–3 years** 0.7 g 0.7 g
4–8 years** 0.9 g 0.9 g
9–13 years** 1.2 g 1.0 g
14–18 years** 1.6 g 1.1 g 1.4 g 1.3 g
19–50 years** 1.6 g 1.1 g 1.4 g 1.3 g
51+ years** 1.6 g 1.1 g
Source: NIH, Offce of Dietary Supplements. https://ods.od.nih.gov/factsheets/Omega3 FattyAcids-Health
Professional/#h2; accessed 12/1/21.
*As total omega-3s.

**As ALA.
12 Flaxseed

• “The effects of eicosapentaenoic acid (EPA) 600 and 1800 mg/day and
docosahexaenoic acid (DHA) 600 mg/day versus olive oil placebo.”
Schaefer, Asztalos, Gleason et al. 2016. Metabolism, Nov; 65(11): 1636–
1645. DOI:10.1016/j.metabol.2016.07.010.
• “An Adequate Intake for alpha-linolenic acid, based on the average daily intake
by apparently healthy people . . . has been set at 1.6 g/day for adult men and 1.1
g/day for adult women.” Erdman, Oria, and Pillsbury (eds.) 2011. Nutrition and
traumatic brain injury. Improving acute and subacute health outcomes in mili-
tary personnel. Chapter 13. Eicosapentaenoic Acid (EPA) and Docosahexaenoic
Acid (DHA). Washington DC: National Academies Press. ISBN-13: 978-0-309-
21008-9;ISBN-10: 0-309-21008-9. www.ncbi.nlm.nih.gov/books/NBK209320/
• “In a review of marketed fsh oil supplements (110 non-liquid and 14 liquid),
the median amount of EPA/DHA in non-liquid and liquid products was 0.216
g/0.2 g and 0.46 g/0.4 g, respectively.* Therefore, in order to achieve a dose of
3.36 g/day omega-3 fatty acids, it was found that a median intake of 11.2 serv-
ings/day would be required at a median monthly cost of $63.49 for non-liquid
formulations, and a median 3.6 teaspoons/day would be required at a median
monthly cost of $13.60 for liquid formulations.” Bradberry, and Hilleman. 2013.
Pharmacy and Therapeutics, Nov; 38(11): 681–691. PMCID: PMC3875260.

The preceding listing is intended to illustrate the range of dosages that are considered
safe and potentially effective in a sample of differing clinical applications.
Table 1.2 lists ALA, EPA and DHA content of selected foods according to the US
Department of Agriculture, Agricultural Research Service, FoodData Central, 2019.
Here are some examples of omega-3 PUFA dosage in specifc applications:

• Example of omega-3 dosage in treatment of endothelial dysfunction: “Healthy

volunteers . . . were given supplementation at 4g/day omega-3 fatty acids (or
were not treated) for 4 weeks.” Miyoshi, Noda, and Ohno. 2014. Omega-3
fatty acids improve postprandial lipemia and associated endothelial dys-
function in healthy individuals—a randomized crossover trial. BioMed
Pharmacotherapy, Oct; 68(8): 1071–1077. DOI:10.1016/j.biopha.2014.10.008.
• Example of omega-3 dosage in treatment of heart disease: “Patients surviv-
ing recent (< or = 3 months) myocardial infarction were randomly assigned
supplements of n-3 PUFA 1 g daily . . .” No authors listed. 1999. Dietary
supplementation with n-3 polyunsaturated fatty acids and vitamin E after
myocardial infarction: Results of the GISSI-Prevenzione Trial. Gruppo
Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico. Lancet,
Aug 7; 354(9177):4 47–455. PMID: 10465168.
• Example of omega-3 dosage in treatment of coronary heart disease: “In
patients with coronary heart disease the guidelines recommend 1 g daily
supplements and in hypertriglyceridaemic patients up to 4 g per day.”
Mori. 2014. Omega-3 fatty acids and cardiovascular disease: Epidemiology
and effects on cardiometabolic risk factors. Food and Function, Sep; 5(9):
2004–2019. DOI:10.1039/c4fo 00393d.

* It is not obvious to us what the authors mean by “0.216 g/0.2 g and 0.46 g/0.4 g.” We are
quoting them directly.
Introduction 13

TABLE 1.2
ALA, EPA and DHA content of selected foods
Food Grams per Serving
ALA DHA EPA
Flaxseed oil, 1 tbsp 7.26
Chia seeds, 1 ounce 5.06
English walnuts, 1 ounce 2.57
Flaxseed, whole, 1 tbsp 2.35
Salmon, Atlantic, farmed cooked, 3 ounces 1.24 0.59
Salmon, Atlantic, wild, cooked, 3 ounces 1.22 0.35
Herring, Atlantic, cooked, 3 ounces* 0.94 0.77
Canola oil, 1 tbsp 1.28
Sardines, canned in tomato sauce, drained, 3 ounces* 0.74 0.45
Mackerel, Atlantic, cooked, 3 ounces* 0.59 0.43
Salmon, pink, canned, drained, 3 ounces* 0.04 0.63 0.28
Soybean oil, 1 tbsp 0.92
Trout, rainbow, wild, cooked, 3 ounces 0.44 0.40
Black walnuts, 1 ounce 0.76
Mayonnaise, 1 tbsp 0.74
Oysters, eastern, wild, cooked, 3 ounces 0.14 0.23 0.30
Sea bass, cooked, 3 ounces* 0.47 0.18
Edamame, frozen, prepared, ½ cup 0.28
Shrimp, cooked, 3 ounces* 0.12 0.12
Refried beans, canned, vegetarian, ½ cup 0.21
Lobster, cooked, 3 ounces* 0.04 0.07 0.10
Tuna, light, canned in water, drained, 3 ounces* 0.17 0.02
Tilapia, cooked, 3 ounces* 0.04 0.11
Scallops, cooked, 3 ounces* 0.09 0.06
Cod, Pacifc, cooked, 3 ounces* 0.10 0.04
Tuna, yellowfn, cooked 3 ounces* 0.09 0.01
Kidney beans, canned ½ cup 0.10
Baked beans, canned, vegetarian, ½ cup 0.07
Ground beef, 85% lean, cooked, 3 ounces** 0.04
Bread, whole wheat, 1 slice 0.04
Egg, cooked, 1 egg 0.03
Chicken, breast, roasted, 3 ounces 0.02 0.01
Milk, low-fat (1%), 1 cup 0.01

Source: US Department of Agriculture (USDA), Agricultural Research Service. FoodData Central, 2019.
*Except as noted, the USDA database does not specify whether fsh are farmed or wild caught.
**The USDA database does not specify whether beef is grass fed or grain fed.

• Example of omega-3 dosage in treatment of type 2 diabetes: “Group II received

metformin 500 mg twice daily and omega-3 fatty acids (1 gram) once daily.”
Chauhan, Kodali, Noor et al. 2017. Role of omega-3 fatty acids on lipid profle
in diabetic dyslipidaemia: Single blind, randomized clinical trial. Journal of
14 Flaxseed

Clinical and Diagnostic Research, Mar; 11(3): OC13—OC16. DOI:10.7860/

JCDR/2017/20628.9449.
• Example of omega-3 dosage in treatment of kidney function and myocardial
infarction: “The patients received an additional targeted amount of 400
mg/d eicosapentaenoic acid and docosahexaenoic acid, 2 g/d α-linolenic
acid, eicosapentaenoic acid—docosahexaenoic acid plus α-linolenic acid.”
Hoogeveen, and Geleijnse. 2014. Effect of omega-3 fatty acids on kidney
function after myocardial infarction: The Alpha Omega trial. Clinical Journal
of the American Society of Nephrology, Oct 7; 9(10): 1676–1683. DOI:10.
2215/CJN.10441013.
• Example of omega-3 dosage in treatment of infammation in chronic kid-
ney disease (CKD): “Six-month supplementation with omega-3 acids (2 g/
day) was administered to 87 CKD patients.” Pluta, Stróżecki, and Kęsy.
2017. Benefcial effects of 6-month supplementation with omega-3 acids
on selected infammatory markers in patients with chronic kidney disease
stages 1–3. BioMed Research International, 2017: 1680985. Published
online 2017 Nov 19. DOI:10.1155/2017/1680985.
• In treatment of metabolic syndrome: “Were administered 1.7 g of [Long-
chain omega-3 fatty acids from fsh oils] O3 per day . . . or saffower oil
placebo.” Root, Collier, Zwetsloot et al. 2013. A randomized trial of fsh oil
omega-3 fatty acids on arterial health, infammation, and metabolic syn-
drome in a young healthy population. Nutrition Journal, 2013 Apr 8; 12:
40. DOI:10.1186/1475-2891-12-40. There are, in addition, FDA-approved
omega-3 PUFAs supplements for adults 18 years old or older with hypertri-
glyceridemia (≥ 500 mg/dL) as an adjunct to diet and exercise.
• Icosapent ethyl is administered as capsules with a daily dose of 4 g/day
taken as two, 2-gram capsules twice a day with meals.
• Omega-3-acid ethyl esters are administered as capsules with a daily dose of
4 g/day taken as four capsules once a day with meals or two capsules twice
a day with meals.
• Omega-3-carboxylic acids are administered as capsules with a daily
dose of 2 g/day taken as two capsules once per day or 4 g/day taken
as four capsules once a day. Clinical trial administration was without
regard to meals.
• Omega-3-acid ethyl esters A are administered as capsules with a daily dose
of 4 g/day taken as four capsules once a day with meals or two capsules
twice a day with meals. (23)

Parenthetically, Vascepa and Lovaza are two prescription brand-name omega-3 fatty
acid medications that treat high triglyceride levels. Both medicines are approved by
the US FDA.

1.6.3 L-ARGININE
L-arginine, the substrate for endothelial nitric oxide (eNO) formation, is a conditionally
essential amino acid, which means that it is usually not essential except in times of
Introduction 15

illness and stress. Conditionally essential amino acids include also cysteine, gluta-
mine, tyrosine, glycine, ornithine, proline and serine.
Mean dietary L-arginine intake by US adults is reported to be 4.40 g/day, with
25% of people consuming less than 2.6 g/day. (24) Median L-arginine intake in
the adult population, participants of the National Health Nutrition and Examination
Survey, was also estimated to be 3.8 g/day. The highest level (90th percentile) of
intake of L-arginine in our population (6.7 g/day) was also within the range of previ-
ous reports (4.5–7.5 g/day). (25)
Here is a sample of published clinical and research dosage recommendations:

• “Healthy men received L-arginine supplementation (2000 mg daily) in the

intervention group . . . for 45 days.” Pahlavani, Jafari, Sadeghi et al. 2014.
F1000 Research, 3: 306. DOI:10.12688/f1000research.5877.2.
• “Patients . . . receive[d] either L-arginine (3 or 6 g thrice daily) or placebo
for 8 weeks.” Dashtabi, Mazloom, Fararouei et al. 2015. Research in Cardio-
vascular Medicine, Dec 29; 5(1): e29419. DOI:10.5812/cardiovascmed.
29419.
• “Athletes received daily either 2 g per day l-arginine supplement or the same
amount of placebo (maltodextrin) for 45 days.” Pahlavani N, Entezari MH,
Nasiri M, Miri A, Rezaie M, Bagheri-Bidakhavidi M, and O Sadeghi. 2017.
European Journal of Clinical Nutrition, Apr; 71(4):544–548. DOI:10.1038/
ejcn.2016.266.
• “Intravenous infusion of 30 g and 6 g l-arginine.” Bode-Böger, Böger,
Galland et al. 1998. British Journal of Clinical Pharmacology, Nov; 46(5):
489–497. DOI:10.1046/j.1365–2125.1998.00803.x.
• “Healthy young men 27 to 37 years old took L-arginine (7 g three times
daily) or placebo for 3 days each.” Adams, Forsyth, Jessup et al. 1995.
Journal of the American College of Cardiology, Oct; 26(4): 1054–1061.
DOI:10.1016/0735–1097 (95)00257–9.
• “Each subject was studied before and after 4 wk of L-arginine (7 grams x
3/day) or placebo powder.” Clarkson, Adams, Powe et al. 1996. Journal of
Clinical Investigation, Apr 15; 97(8): 1989–1994. DOI:10.1172/JCI118632.
DOI:10.1172 /JCI118632.

Here are published examples of L-arginine dosage in specifc applications:

• In treatment of endothelial dysfunction: “L-arginine (8 g p.o. two times

daily) or placebo for 14 days each.” Bode-Böger, Muke, Surdacki et al.
2003. Oral L-arginine improves endothelial function in healthy individuals
older than 70 years. Vascular Medicine, May; 8(2): 77–81. DOI:10.1191/13
58863x03vm474oa.
• In treatment of heart disease: “Healthy men received L-arginine supple-
mentation (2000 mg daily) in the intervention group.” Pahlavani, Jafari,
Sadeghi et al. 2017. L-Arginine supplementation and risk factors of cardio-
vascular diseases in healthy men: A double-blind randomized clinical trial.
F1000Res, 3: 306. DOI:10.12688/f1000research.5877.2.
16 Flaxseed

• As an antioxidant in treatment of patients with angina or following myo-

cardial infarction: “L-arginine administration (three grams per day for 15
days) resulted in increased activity of free radical scavenging enzyme super-
oxide dismutase (SOD) and increase in the levels of total thiols (T-SH) and
ascorbic acid with concomitant decrease in lipid per-oxidation, carbonyl
content, serum cholesterol and the activity of proxidant enzyme, xanthine
oxidase (XO).” Tripathi, Chandra, and Misra. 2009. Oral administration
of L-arginine in patients with angina or following myocardial infarction
may be protective by increasing plasma superoxide dismutase and total thi-
ols with reduction in serum cholesterol and xanthine oxidase. Oxidative
Medicine and Cell Longevity, Sep–Oct; 2(4): 231–237. DOI:10.4161/oxim.
2.4.9233.
• In treatment of obese, insulin-resistant type 2 diabetic patients: “The
frst group was also treated with L-arginine (8.3 g/day).” Lucotti, Setola,
and Monti. 2006. Benefcial effects of a long-term oral L-arginine treat-
ment added to a hypocaloric diet and exercise training program in obese,
insulin-resistant type 2 diabetic patients. American Journal of Physiology,
Endocrinology and Metabolism, Nov; 291(5): E906–12. DOI:10.1152/
ajpendo.00002.2006.
• In treatment of chronic renal failure (CRF): “Patients received either
L-arginine (300 mg/kg) or placebo.” Miller, Dascalu, and Rassin. 2003.
Effects of an acute dose of L-arginine during coronary angiography in
patients with chronic renal failure. A randomized, parallel, double-blind
clinical trial. American Journal of Nephrology, 23: 91–95. DOI: https://doi.
org/10.1159/000068036.
• In treatment of sickle cell disease with vaso-occlusive pain episodes:
“Patients received L-arginine (100 mg/kg tid) or placebo for 5 days or until
discharge.” Morris, Kuypers, and Lavrisha. 2013. A randomized, placebo-
controlled trial of arginine therapy for the treatment of children with sickle
cell disease hospitalized with vaso-occlusive pain episodes. Haematologica,
Sep; 98(9): 1375–1382. DOI:10.3324/haematol.2013.086637.
• In treatment of Peripheral Artery Disease (PAD): “Patients were randomly
assigned to oral doses of 0, 3, 6 or 9 g of L-arginine daily in three divided
doses for 12 weeks.” Oka, Szuba, and Giacomini. 2005. A pilot study of
L-arginine supplementation on functional capacity in peripheral arterial
disease. Vascular Medicine, Nov; 10(4): 265–274. DOI:10.1191/1358863x05
vm637oa.
• In treatment of intermittent claudication: “Thirty-nine patients with inter-
mittent claudication were randomly assigned to receive 2 x 8 g L-arginine/
day.” Böger, Bode-Böger, Thiele et al. 1998. Restoring vascular nitric oxide
formation by L-arginine improves the symptoms of intermittent claudica-
tion in patients with peripheral arterial occlusive disease. Journal of the
American College of Cardiology, Nov; 32(5): 1336–1344. DOI:10.1016/
s0735–1097(98)00375–1.
• In treatment of erectile dysfunction (ED): “The analysis demonstrated that
arginine supplements with dosage ranging from 1,500 to 5,000 mg sig-
nifcantly improved ED compared with placebo or no treatment.” Rhim,
Introduction 17

Kim, Park et al. 2019. The potential role of arginine supplements on erec-
tile dysfunction: A systemic review and meta-analysis. Journal of Sexual
Medicine, Feb; 16(2): 223–234. DOI:10.1016/j.jsxm. 2018.12.002.

CAVEAT
Possible interactions of L-arginine with medications include the following:

• Anticoagulants and anti-platelet drugs, herbs and supplements. Some

examples of these types of products (drugs, herbs and supplements) can
reduce blood clotting. Taking L-arginine with them might potentiate them,
thereby increasing the risk of bleeding.
• Blood pressure drugs, herbs and supplements. L-Arginine might lower
blood pressure in people who have high blood pressure. Therefore combin-
ing L-arginine with a blood pressure-lowering drug, herb or supplement
might increase the risk of blood pressure becoming too low.
• Diabetes drugs, herbs and supplements. L-Arginine might decrease blood
sugar levels in people with diabetes. Taking anti-diabetes drugs, herbs or
supplements may require adjusting the dosage of meds.
• Isoproterenol (Isuprel). Use of this heart medication with L-arginine might
cause low blood pressure.
• Nitrates. Use of this chest pain medication with L-arginine might cause low
blood pressure. Diuretics (potassium-sparing diuretics). One should not take
L-arginine with amiloride (Midamor), spironolactone (Aldactone, Carospir)
or triamterene (Dyrenium). These medications can increase potassium levels,
raising the risk of developing a higher than normal blood levels of potassium.
• Sildenafl (Revatio, Viagra) and tadafl. Use of this erectile dysfunction
medication with L-arginine might cause a precipitous fall in blood pressure.

There is no standard dose of arginine. Studies have used different amounts for dif-
ferent conditions. One common dosage is 2 to 3 grams three times a day, although
lower and higher doses have also been studied. The safety of long-term L-arginine
supplement use is not clear. (26)
Although higher doses are often used in research and clinical settings, it is recom-
mended by some authorities that daily dosing of L-arginine be kept under 9 grams
per day to avoid potential gastrointestinal side effects. (27)
In 2018, the journal Amino Acids published a report titled “Safety of Dietary
Supplementation with Arginine in Adult Humans.” The investigators reported that
previous studies have shown benefcial effects of dietary supplementation with
L-arginine (Arg) on reducing white fat and improving health but that long-term safe
levels administered to people are unknown. Therefore, the aim of their study was
to evaluate the safety and tolerability of oral L-arginine in overweight or obese but
otherwise healthy adults with a body mass index of ≥ 25 kg/m2.
A total of 142 participants completed a 7-day wash-in period using a 12 g Arg/day
dose. All the remaining eligible participants who tolerated the wash-in dose were
then assigned to 0, 15 or 30 g Arg (as pharmaceutical-grade Arg-HCl) per day for
90 days. The L-arginine treatment was taken daily in at least two divided doses by
mixing it with a favored beverage.
18 Flaxseed

At Days 0 and 90, blood pressures of treatment participants were recorded, their
physical examinations were performed and their blood and 24-hour urine samples
were obtained to measure the serum concentrations of amino acids, glucose, fatty acids
and related metabolites; and the renal, hepatic, endocrine and metabolic parameters.
It was found that the serum concentration of Arg in men or women signifcantly
increased progressively with increasing oral Arg doses from 0 to 30 g/day. Dietary
supplementation with 30 g Arg/day signifcantly reduced systolic blood pressure and
serum glucose concentration in women, as well as serum concentrations of free fatty
acids in both men and women.
It seems that the treatment participants tolerated oral administration of 15 and 30 g
Arg/day without adverse events. And, it is concluded that a long-term safe level of
dietary Arg supplementation is at least 30 g/day in adults. (28)

1.7 AD LIB SUPPLEMENTATION

There is a difference between supplementation and adjuvant treatment. It is assumed
that the individual who wants to supplement is looking to harvest the health benefts
of a given supplement, whereas in adjuvant treatment, there is a medical prescription
treatment plan in place. As noted earlier, supplements may interact with prescrip-
tion meds, possibly with adverse consequences. That said, supplementation of fax-
seed and faxseed oil is popular. Here is a market review report from Grand View
Research, San Francisco, CA 94105:

The global faxseeds market size was valued at USD 423.3 million in 2018 and is
expected to expand at a CAGR of 12.7% over the forecast period. Growing awareness
related to the health benefts of linseed is the main factor anticipated to drive the mar-
ket over the forecast period. (29)

Should one buy organic or nonorganic faxseeds? According to the Flax Council of
Canada, all fax that is “clean and that comes from a reputable supplier” is consid-
ered to be safe for consumption.

• Whole faxseeds—Flaxseed eaten whole supplies the benefts of the fber

and the lignans. In order to beneft from the omega 3-fatty acid in the fax-
seeds, the seeds must be chewed well or ground. Whole faxseeds can be
stored at room temperature for up to 10 months.
• Ground faxseeds or fax meal—There are approximately 1.6 grams of
omega 3-fatty acids in 1 tbsp of ground faxseeds. When it is eaten ground,
all nutritional benefts, i.e., omega 3-fatty acids, fber, and lignans, in fax-
seeds are preserved. Ground faxseeds are best stored in the refrigerator or
freezer and for no longer than 3 months. If one grinds the seeds, it is best to
grind as needed to prevent spoilage.
• Flax oil—Flax oil is extracted from the whole fax seed. It is sold as oil or
in gel supplements. It is best to keep fax oil in a cool, dark place—ideally
in the refrigerator. Flax oil is an excellent source of omega 3-fatty acids, but
it contains neither the lignans nor the fber, as these are eliminated in the
Introduction 19

process of oil extraction. One can look at the manufacturer’s best-before

date to determine how long it can be stored. There are approximately 7.2
grams of omega 3-fatty acids in 1 tbsp of fax oil.

To obtain the benefts of the entire faxseed, the best way to consume it is in the form
of the ground (or milled) faxseed/fax meal. (30)

1.7.1 RAW FLAXSEED

According to the Healthline website, consuming whole or ground faxseed delivers
all three macronutrients: carbohydrates, protein and fat. When comparing golden
faxseed with brown faxseed, the exact amount of protein, fat and carbohydrates
will depend on the type chosen.
Most adults are likely to consume about an ounce (28 grams) of whole or ground
faxseeds per serving and, according to the US Department of Agriculture (USDA),
this amount of faxseed contains the following:

• 152 calories
• 12 grams of fat
• 8.2 grams of carbohydrates, 7.8 grams of which come from dietary fber
• 5.2 grams of protein
• 6% of the daily value (DV) for calcium
• 9% of the DV for iron
• 5% of the DV for potassium
• 27% of the DV for magnesium
• 15% of the DV for phosphorus
• 11% of the DV for zinc
• 38% of the DV for copper
• 31% of the DV manganese
• 13% of the DV for selenium
• 39% of the DV for thiamin (vitamin B1)
• 5 % of the DV for niacin (vitamin B3)
• 6% of the DV for vitamin B5
• 8% of the DV for vitamin B6
• 6% of the DV for folic acid (vitamin B9)

Flaxseeds are also rich in lutein and zeaxanthin, antioxidants like phenolic com-
pounds and favonoids and lignans, a type of polyphenol. You can also fnd small
amounts (between 1% and 4%) of B-complex vitamins, vitamin E, vitamin K and
choline in each ounce of faxseeds.
Parenthetically, most of these nutrients are not present in faxseed oil. Flaxseed
oil and capsules contain pure fat and lack most of the nutritional value that whole and
ground faxseed products contain. (31)
Golden faxseed vs. brown faxseed—the difference between golden and
brown faxseed is minimal and centers on their macronutrient and antioxidant
contents. Golden faxseed is made up of about 37.5% fat, 23% protein and 30%
20 Flaxseed

carbohydrates, while brown faxseed is made up of 38% fat, 24.5% protein and
28% carbohydrates. However, what is different between golden and brown faxseed
is the type of fat in each.
Golden faxseeds have more polyunsaturated fatty acids and less monounsatu-
rated fatty acids compared to brown faxseeds. They also have larger amounts of
the two essential fats, i.e., alpha-linolenic acid (ALA) and linoleic acid present in
different ratios in golden and brown faxseed. There is more ALA in golden faxseed
than linoleic acid.
Most people who follow a Western Diet typically consume too many omega-6 fats,
like linoleic acid, and not enough omega-3 fats, like ALA. For that reason, golden
faxseed is a better choice for supplementing the diet with healthy fats. However,
brown faxseed has a substantially higher concentration of antioxidants. In fact, com-
pared to other similar seeds, like chia seeds and perilla seeds, golden faxseeds are
always the lowest in antioxidants. (32) Perilla, by the way, is a kind of mint.
Flaxseed can readily be purchased in health food stores and online. For example*:

• Bob’s Red Mill Organic Flax Seed

• Spectrum Essentials Organic Ground Premium
• Premium Gold Whole Flax Seed
• FGO Whole Brown Flaxseed
• Anthony’s Organic Flaxseed Meal

What type of faxseed is healthiest? Most nutrition experts recommend ground over
whole faxseed because the ground form is easier to digest. Whole faxseed may pass
through your intestine undigested, which means you won’t get all the benefts.
Examples of ground faxseed:

• Premium Gold Organic Ground Flax Seed

• Spectrum Essentials Organic Ground Flaxseed
• Viva Naturals Organic Ground Flax Seed
• Anthony’s Organic Flaxseed Meal
• Terrasoul Superfoods Organic Ground Flax Seeds

Whole seeds can be ground at home using a coffee grinder or food processor. For
instance:

• COOL KNIGHT Herb Grinder Electric Spice Grinder (electric)

• Cuisinart SG-10 Electric Spice-and-Nut Grinder (electric)
• Mini Seed Mill & Coffee Grinder (electric)
• Glass Sesame Seed Grinder by Asvel (hand power)
• Staub Cast Iron Grinder (hand power)

* We have no fnancial interest in any commercial product(s) cited in this book, which are
offered simply as an example of what is available. Nor does any citation constitute an
endorsement. We cannot certify any representation by a product manufacturer as to quality,
purity or effcacy of the product(s).
Introduction 21

1.7.2 INCLUDING FLAXSEED IN DAILY DIET

• Add a tablespoon of ground faxseed to hot or cold breakfast cereal.
• Add a teaspoon of ground faxseed to mayonnaise or mustard when making
a sandwich.
• Mix a tablespoon of ground faxseed into an 8-ounce container of yogurt.
• Bake ground faxseed into cookies, muffns, breads and other baked goods.

Like other sources of fber, faxseed should be taken with plenty of water or other
fuids. Flaxseed shouldn’t be taken at the same time as oral medications. (33)
One can also fnd a number of recipes online for including faxseed in meals. For
instance: Flaxseed recipes—these faxseed-based recipes are a great place to help
weight loss and health goals. Start with one recipe each day to reap the benefts.
Adding faxseed to oatmeal, smoothies and yogurt bowls is a great way to add
protein, fber and texture to your dish. Get started with one of these easy recipes.

• Flaxseed and blueberry oatmeal

• High-protein strawberry fax smoothie
• Chia and fax seed breakfast bowl
• Apple pie overnight oats
• Low-carb yogurt parfait with strawberries, fax and chia seeds

Flaxseed breads, tortillas, muffns and loaf recipes:

• Chia and faxseed tortillas

• Flax, carrot, apple muffns
• Healthy oatmeal chocolate chip cookies
• Flaxseed meal pancakes
• Honey fax banana bread

Flaxseed snack recipes:

• No-bake energy bites

• Honey almond fax granola
• Easy crunch faxseed crackers
• Flaxseed apricot bars
• Power biscotti

Other faxseed recipes:

• Healthy baked turkey meatballs

• Flaxseed chicken tenders
• Almond fax crusted fsh
• Veggie-fax burgers
• Keto low-carb meatballs*

* Source: 25 Simple Flaxseed Recipes by noom | Sep 20, 2019.

22 Flaxseed

• TopTeenRecipes—16 Easy Flaxseed Recipes: https://topteenrecipes.com/

faxseed-recipes/
• EatingWell—Healthy Flax Seed Recipes: www.eatingwell.com/recipes/19239/
ingredients/nuts-seeds/fax-seed/
• CookingLight—15 Ways to Use Ground Flaxseed: www.cookinglight.com/
food/recipe-fnder/ground-faxseed-recipes
• Profusion Curry—Flaxseed Garlic Chutney—Superfoods Chutney: https://
profusioncurry.com/faxseed-garlic-chutney-superfoods-chutney/
• Flaxseed Bread: https://nutritionrefned.com/faxseed-bread/

There are also books with faxseed recipes:

• Michelle Bakema M. 2015. Flaxseed Recipes: Lose Weight, Gain Energy, &
Achieve Overall Wellness. CreateSpace Independent Publishing Platform.
• Gale Spratley G. 2021. The Ultimate Guide To Flaxseed: Making Recipes
for Breakfast, Smoothie, Soup, Desserts, and More: Ground Flaxseed
Recipes. Independently Published.
• Bloomfeld B, Judy Brown J, and S Gursche. 2000. Flax the Super Food!:
Over 80 Delicious Recipes Using Flax Oil and Ground Flaxseed (Over 80
Delicious Recipes Using Flax Oil & Ground Flaxseed). Kindle Edition.
Book Publishing Company (TN).
• Vincent E. 2013. Flaxseed Recipes: How to Use Flaxseed in Omega 3, Low
Carb, Wheat Free, Egg Free, Celiac Disease and Gluten Free Recipes.
Includes 36 Flax Seed Recipes. Kindle Edition. Sidewinder Media.
• Niles S. 2014. Flaxseed Recipes: 50 Delicious Recipes Using Flaxseed
to Reduce Weight and Firing Up Your Metabolism rate. Paperback.
CreateSpace Independent Publishing Platform.

1.8 SUMMARY
There is a long history of mankind’s use of fax in many different ways as food,
medicine, and in making fne cloth. Flaxseed is a functional food that supplies basic
health-giving nutrients: The omega-3 fatty acids it contains are antioxidants that
also help to control weight, blood pressure, cholesterol levels and protect the vas-
cular endothelium. It also contains the amino acid L-arginine, the substrate for the
formation of endothelial NO, an intrinsic vasodilator that helps regulate blood fow
throughout the body. In addition, faxseed contains very small quantities of CNglcs
that also contribute to the formation of NO. There are different varieties of faxseed
that differ from each other in small ways, and there are different ways of consum-
ing faxseed as a dietary supplement. We cite examples of websites and books that
supply recipes.

1.9 REFERENCES
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Introduction 23

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24 Flaxseed

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 2 Flaxseed, a Functional
Food—Constituents and
Their Health Benefits

2.1 INTRODUCTION
“Wherever faxseeds become a regular food item among the people, there will be
better health.” So said Mohandas (Mahatma) Gandhi (1869–1948). Now, there’s an
endorsement, if ever there was one. Indeed, faxseeds are emerging as an important
functional food and food ingredient. They rank among the top 100 of the world’s
healthiest foods. This is largely due to rich contents of alpha-linolenic acid (ALA,
omega-3 fatty acid), fber and lignans. The lignans are a large group of polyphenols,
dietary antioxidants found in plants that include the familiar quercetin in apples and
resveratrol in red wine.
Flaxseeds, faxseed oil, fbers and fax lignans are shown to reduce atherosclero-
sis, heart disease, type 2 diabetes, arthritis, osteoporosis, autoimmune and neurologi-
cal disorders and cancer. Flax protein helps in the prevention and treatment of heart
disease, and it supports the immune system.
Flaxseeds can be used as roasted and milled seeds, while faxseed oil can be used
in various food formulations in the form of neat oils and stable emulsions. Flax or
faxseed oil has been incorporated into baked foods, juices, milk and dairy products,
muffns, dry pasta products, macaroni and beef patties.

2.2 CONSTITUENTS THAT MAKE FLAXSEED A FUNCTIONAL

FOOD
Flaxseeds are available in two basic varieties: brown and yellow or golden. Both have
similar nutritional characteristics and equal numbers of short-chain omega-3 fatty acids.
Omega-3 fatty acids are important fats that the body needs that it must get from the diet
because the body cannot produce them. The three most important types are

• Alpha-linolenic acid (ALA)

• Docosahexaenoic acid (DHA)
• Eicosapentaenoic acid (EPA)

ALA is mainly found in plants, seeds and nuts, including faxseeds, chia seeds,
faxseed oil and walnuts. DHA and EPA occur mostly in animal foods, such as fatty
fsh, fsh oils and algae.

DOI: 10.1201/b22986-2 25
26 Flaxseed

TABLE 2.1
Composition of nutrient and phytochemicals in flaxseed
Nutrients/Bioactive Quantity/100 g of Nutrients/Bioactive Quantity/100 g
Compounds Seed Compounds of Seed
Carbohydrates 29.0 g Biotin 6 mg
Protein 20.0 g α-Tocopherolb 7 mg
Total fats 41.0 g δ-Tocopherolb 10 mg
Linolenic acid 23.0 g γ-Tocopherolb 552 mg
Dietary fber 28.0 g Calcium 236 mg
Lignans 10–2,600 mg Copper 1 mg
Ascorbic acid 0.50 mg Magnesium 431 mg
Thiamin 0.53 mg Manganese 3 mg
Ribofavin 0.23 mg Phosphorus 622 mg
Niacin 3.21 mg Potassium 831 mg
Pyridoxin 0.61 mg Sodium 27 mg
Pantothenic acid 0.57 mg Zinc 4 mg
Folic acid 112 mg
Source: With permission.
(2) Journal of Food Science and Technology. Goyal, Sharma, Upadhyay et al. 2014.

Parenthetically, in order to meet the fatty acid composition profle of the margarine
industry, mutation breeding efforts led to development of fax varieties with major
reductions in ALA levels (approximately 3%). These fax varieties were known as
Linola™ or solin and registered and produced in Canada. The fatty acid composition
of solin oil is similar to other premium polyunsaturated oils, such as sunfower oil.
Oils from such varieties have higher solidifcation temperatures that are suitable for
the margarine industry. (1)
Various edible forms of fax are available in food markets, including whole fax-
seeds, milled fax, roasted fax and fax oil. Flaxseed contains many bioactive plant
substances, such as oil, protein, dietary fber, soluble polysaccharides, vitamins (A,
C, F and E) and minerals (potassium, magnesium, phosphorus, sodium, iron, copper,
manganese and zinc), lignans and phenolic compounds.
Phenolic compounds are ubiquitous in plants. They are an essential part of our
diet and very important to us because of their antioxidant properties. Phenolic com-
pounds include favonoids found in foods and beverages of plant origin, such as
fruits, vegetables, tea, cocoa and wine. They account for more than half of the more
than 8,000 different phenolic compounds that we consume. Table 2.1 shows the com-
position of faxseed.

2.3 FLAXSEED OIL/LIPIDS COMPONENTS

Flaxseed is the richest known plant source of the omega-3 fatty acid ALA. It is low
in saturated fatty acids (9%), moderate in monosaturated fatty acids (18%) and rich
in polyunsaturated fatty acid (73%). Of all lipids in faxseed oil, ALA is the major
Flaxseed, a Functional Food 27

TABLE 2.2
Major fatty acids profile in flaxseed oil
Fatty Acids Percentage (%) (Range)
Palmitic acid (C16:0) 4.90–8.00
Stearic acid (C18:0) 2.24–4.59
Oleic acid (C18:1) 13.44–19.39
Linoleic acid (C18:2) (ω-6) 12.25–17.44
α-Linolenic acid (C18:3) (ω-3) 39.90–60.42
Source: With permission.
(2) Goyal, Sharma, Upadhyay et al. 2014. Journal of Food Science and Technology.

fatty acid ranging from 39.00 to 60.42% followed by oleic, linoleic, palmitic and
stearic acids (see Table 2.2). Flaxseed provides an excellent omega-6 to omega-3
fatty acid ratio (1:4).
Although faxseed oil is naturally high in antioxidants like tocopherols and beta-
carotene, traditional faxseed oil easily oxidizes after being extracted and purifed.
The bioavailability of ALA is dependent on the type of fax consumed. For
instance, ALA has greater bioavailability in oil than in milled seed, and it has greater
bioavailability in oil and milled seed than in whole seed. Table 2.2 shows the fatty
acid profle in faxseed oil.

2.4 PROTEINS
The protein content of faxseed varies from 20% to 30% and it has an amino acid
profle comparable to that of soybean, but it contains no gluten. Amino acids are
organic compounds (meaning they contain carbon), with at least one nitrogen group,
that combine to form proteins. Digestion breaks down amino acids just as the body
uses amino acids to rebuild proteins.
Amino acids are classifed into three groups:

• Essential amino acids cannot be made by the body, and so they must come
from food. There are nine essential amino acids: histidine, isoleucine, leu-
cine, lysine, methionine, phenylalanine, threonine, tryptophan and valine.
• Nonessential amino acids can be produced by the body. These are alanine,
asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, pro-
line, serine and tyrosine.
• Conditional amino acids are usually not essential, except in times of ill-
ness and stress. These are arginine, cysteine, glutamine, tyrosine, glycine,
ornithine, proline and serine.

One does not need essential and nonessential amino acids at every meal, but getting
a balance of them over the whole day is important. (3) Flax protein is not considered
to be a complete protein due to the presence of the limiting amino acid lysine.
Whole faxseed, faxseed meals and isolated proteins are rich sources of glutamic
acid/glutamine, L-arginine, branched-chain amino acids (valine and leucine) and
28 Flaxseed

aromatic amino acid (tyrosine and phenylalanine). The total nitrogen content in fax-
seed is 3.25 grams/100 grams of seed.

Some people may have been advised to restrict their intake of the amino acid
L-arginine. For instance, persons with active herpes infection, or those with
Multiple myeloma or early Mm-protein markers may (should, actually) have been
advised by their healthcare providers to limit their intake of L-arginine—even of
foods high in contents of that amino acid. Multiple myeloma is an auxotrophic
mast-cell mutation with a specifc nutrient requirement of L-arginine caused by
the loss of the ability to synthesize it. (4) In addition, persons with hyperactivated
immune system response would also be well advised to limit L-arginine intake.

The content of L-arginine is not the same in different types of faxseed. In the basic
type of faxseed, the amount of L-arginine in 100 grams is 1.925 grams. For a typical
serving size of 1 cup of whole fax seed (or 168 grams), the amount of L-arginine is 3.23
grams. (5) For persons with herpes who will be concerned, the equivalent lysine content
is 1.45 grams, so they may need to supplement with extra lysine to prevent an arginine-
triggered activation of the virus. By comparison, chickpeas, or garbanzo beans, contain
3.878 grams per cup, which is a much more favorable (approx. 1:1) ratio.

In connection with caveats concerning L-arginine, faxseed oil may be the

preferred supplement because it contains no L-arginine. However, faxseeds
are a whole food providing a host of benefts not available in faxseed oil, the
latter not being a whole food.

2.5 DIETARY FIBER

The total fax plant is approximately 25% seeds, and 75% stem and leaves. The stem or
nonseed parts are about 20% fber, which can be extracted by chemical or mechanical
retting. Retting is a process employing the action of micro-organisms and moisture
on plants to dissolve or rot away much of the cellular tissues and pectins surrounding
fber bundles and so facilitating separation of the fber from the stem.
Flax fber is soft, lustrous and fexible; bundles of fber have the appearance of blonde
hair, hence the description “faxen.” It is stronger than cotton fber but less elastic.
Flax fbers include both soluble and insoluble dietary fbers. The ratio of soluble
to insoluble fber varies between 20–80 and 40–60. The major insoluble fber frac-
tion consists of cellulose and lignin, and the soluble fber fractions are the mucilage
gums that can be extracted by water and have good foam-stabilizing properties.
Cellulose is an insoluble substance that is the main constituent of plant cell walls
and of vegetable fbers, such as cotton. Lignin is a complex organic material depos-
ited in the cell walls of many plants, making them rigid and woody.
Flaxseed, a Functional Food 29

Mucilage gums are polysaccharides that become viscous when mixed with water
or other fuids and have an important role in laxatives. Polysaccharides are carbohy-
drates, such as starch, cellulose or glycogen, whose molecules consist of a number of
sugar molecules bonded together as a polymer.
Just 10 grams of faxseed in the daily diet increases the daily fber intake by 1 gram
of soluble fber and by 3 grams of insoluble fber. Insoluble fber helps improve laxa-
tion and prevent constipation, mainly by increasing fecal bulk and reducing bowel
transit time. On the other hand, water-soluble fber helps in maintaining blood glu-
cose levels and lowering blood cholesterol levels.

2.6 LIGNANS
Plant lignans are phenolic compounds present in almost all plants. They act as both
antioxidants and phytoestrogens. Phytoestrogens can have weak estrogen activity in
animals and humans. Flax contains up to 800 times more lignans than other plant
foods (and their content in faxseed is principally composed of secoisolariciresinol
diglucoside (SDG) (294–700 mg/100 gram), matairesinol (0.55 mg/100 gram), larici-
resinol (3.04 mg/100 gram) and pinoresinol (3.32 mg/100 g).
One source reported SDG content in the range of 11.7 to 24.1 mg/gram and 6.1 to
13.3 mg/gram in defatted faxseed four and whole faxseed, respectively. (6)
Besides lignans, other phenolic compounds found in faxseed are p-coumaric
acid and ferulic acid. P-coumaric acid is a plant metabolic by-product that exhibits
antioxidant and anti-infammatory properties. It also shows bactericidal activity by
damaging bacterial cell membranes and by interacting with bacterial DNA. Ferulic
acid is an antioxidant that works to boost the effects of other antioxidants. It is com-
monly used in skin care products to protect overall skin integrity by reducing the
development of fne lines, spots and wrinkles.
SDG found in fax and other foods is converted by bacteria in the gut to the lignans
enterodiol and enterolactone, which can provide health benefts due to their weak
estrogenic or antiestrogenic, as well as antioxidant effects. Studies have shown that
largely due to its antioxidant properties, SDG offers health benefts, including protec-
tive effects against cardiovascular diseases, diabetes, cancer and mental stress. (7)

2.7 MINERALS
A 30-gram serving of faxseed holds 7% to 30% of the recommended dietary allow-
ances (RDAs) of calcium, magnesium and phosphorus. The approximate content of
different minerals is shown in Table 2.1. Potassium content is high and comparable
to those levels of recommended sources such as bananas. Potassium intake lowers
the incidence of stroke, and it reduces blood platelet aggregation—often a precursor
of stroke.

2.8 THE HEALTH BENEFITS OF FLAXSEED

Flaxseed bestows health benefts in addition to nutrition for fve main reasons:

• First, it is high in omega-3 α-linolenic acid

• Second, it is rich in dietary soluble and insoluble fbers
30 Flaxseed

• Third, due to its high content of lignans, acting as antioxidants and phy-
toestrogens. ALA can be metabolized in the body into DHA (omega-3)
and EPA (omega-3)
• Fourth, it contains L-arginine, a NO-donor
• Fifth, it contains cyanogenic glycosides (CNglcs), a NO-donor

The health benefts of all omega-3 fatty acids (ALA, EPA and DHA) have been widely
reported for several conditions, including cardiovascular disease, hypertension,
atherosclerosis, diabetes, cancer, arthritis, osteoporosis, autoimmune and neurological
disorders. Flaxseed has also been reported to be anti-arrhythmic, normalizing the
heartbeat; anti-atherogenic, lowering the tendency to form arterial plaque; and
anti-infammatory, thereby improving blood vessel function. These benefts are
schematized in Figure 2.1.
Let’s take a look at some of these benefts one by one.

Flaxseed Decreases the Level of Proinfammatory Cytokines: A proinfammatory

cytokine is a molecule formed by immune system cells like helper T cells and macro-
phages, and sent out throughout the body promoting infammation. A study reported
in the American Journal of Clinical Nutrition compared the effects of either fax-
seed-based diets high in ALC or high in linoleic acid or an average American diet
on infammation in participants with elevated serum lipids (hypercholesterolemia).
It was found that increased consumption of dietary ALA is markedly anti-infam-
matory and heart protective. (8)

Flaxseed Increases the Production of Serotonin: Neurotransmitters are often referred

to as the body’s chemical messengers. They are the molecules used by the nervous
system to transmit messages between nerves (neurons) or from nerves to muscles.
Communication between two nerves or between nerves and muscles takes place
in the small gap (synapse) between nerve fbers, or between nerve fbers and mus-
cles, beginning as a brief electrical signal rapidly converted into a chemical neu-
rotransmitter substance. This chemical reaction then causes a specifc response in
the receiving neuron or muscle downstream.
Neurotransmitters infuence neurons in one of three ways:

• Excitatory neurotransmitters turn things ON.

• Inhibitory transmitters prevent things from happening. In a sense, they turn
things OFF.
• Neuromodulator neurotransmitters operate over a slower time course than
excitatory and inhibitory transmitters.

These neurotransmitter chemical molecules and their interactions are involved in

countless functions of the nervous system, as well as controlling bodily functions.
Serotonin is a substance mainly found in the brain, the bowels and blood platelets.
It transmits messages between nerve cells throughout the body and in the brain.
Sometimes called the “happy chemical” because it contributes to our feeling of
well-being and happiness, it is the precursor for melatonin that helps the body’s
Flaxseed, a Functional Food 31

FIGURE 2.1 Health targets of the functional elements of faxseed including oil, fber and
lignans. [(2) Goyal, Sharma, Upadhyay et al. 2014. Journal of Food Science and Technology.
With permission.]

sleep-wake cycles and the internal clock. It also plays a role in appetite, emotions
and motor, cognitive and autonomic functions.
Serotonin appears to play a key role in maintaining mood balance: Low serotonin
levels have been linked to depression. In fact, a 2015 report in the journal Clinical
Psychopharmacology and Neuroscience tells us that there is substantial clinical evi-
dence that omega-3 polyunsaturated fatty acids (PUFAs) such as those in faxseed
may prevent mood and anxiety disorders. (9)

Flaxseed Raises the Production of “Memory Boosting” Acetylcholine: Acetylcholine

(Ach) is a neurotransmitter. One of its primary functions is to carry signals from
32 Flaxseed

motor neurons to the skeletal muscles. It can be excitatory or inhibitory depending

on the site of its action: It is excitatory at the neuromuscular junction in skeletal
muscle—voluntary striated muscle—causing the muscle to contract. In contrast, it is
inhibitory in blood vessels—involuntary smooth muscle—and the heart, an involun-
tary striated muscle—where it can lower blood pressure and slow heart rate.
The journal Genes and Nutrition reported in 2009 that dietary PUFAs improve
cognitive function in the “aging brain” because of improved acetylcholine availabil-
ity. (10) PUFAs are found in profusion in faxseed.

Flaxseed Decreases Blood Pressure and Improves Heart Function: According to the
American Heart Association (AHA): Consuming faxseed may help lower blood pressure
in people with hypertension. People who added 30 grams of milled faxseed to their diet
every day for 6 months saw their systolic blood pressure decline by an average of 15 mm
Hg, and their diastolic blood pressure dropped by an average of 8 mm Hg. By compari-
son, people on a placebo had slightly increased systolic blood pressure, while diastolic
pressure remained steady. The researchers said that the level of blood pressure decrease
from adding faxseed could result in 50% fewer strokes and 30% fewer heart attacks. (11)

Flaxseed Prevents Cardiovascular Disease: Alpha-linolenic acid (ALA), an omega-3

PUFA found in faxseed, may reduce cardiovascular risk by regulating platelet func-
tion, reducing infammation, enhancing endothelial cell function, raising arterial
compliance (blood vessel fexibility) and reducing the risk of arrhythmia.
Modest dietary consumption of ALA (2 to 3 grams per day) is recommended for
the primary and secondary prevention of cardiovascular and heart disease. (12, 13)

Flaxseed Increases Heart Muscle Lipid Fluidity: “Membrane fuidity” refers to the
viscosity of the lipid in the bilayer of a cell membrane. Increasing viscosity means
there is resistance to fow, causing rigidity in the membrane. Flaxseed increases the
lipid fuidity of the membranes of heart muscle cells (that is, decreases rigidity), thus
improving heart function. (14)

Flaxseed Reduces the Incidence of Heart Arrhythmias and the Risk of Cardiac
Arrest: There is strong scientifc evidence that omega-3 fatty acid supplements
EPA and DHA can signifcantly reduce risk factors for heart disease, such as reduc-
ing blood triglyceride levels, reducing the incidence of heart arrhythmias, (15)
reducing the risk of nonfatal and fatal myocardial infarctions, sudden death (13)
and, by the way, reducing the risk of all-cause mortality. It should be noted, how-
ever, that, as reported in the journal Circulation in 2021, Smidt Heart Institute
researchers have found that taking high doses of fsh oil supplements EPA and
DHA—specifcally one gram or more per day—may increase the risk of develop-
ing atrial fbrillation. (72)

Flaxseed Decreases Blood Viscosity: Blood viscosity is the thickness and stickiness
of blood affecting the ability of blood to fow. It determines the amount of work the
heart has to do and the quantity of oxygen delivered to the tissues and organs. Health
depends on blood fowing freely. A number of factors affect blood viscosity:
Flaxseed, a Functional Food 33

• Plasma viscosity is highly affected by hydration and by plasma proteins,

especially high-molecular-weight proteins such as immunoglobulins and
fbrinogen. Flaxseed was found to reduce blood plasma viscosity and fbrin-
ogen in an animal model. (16)
• Hematocrit is the ratio of the volume of red blood cells to the total volume
of blood. It is the most obvious determinant of viscosity. A higher percent-
age of red blood cells (RBCs) results in thicker blood. Hematocrit accounts
for about 50% of the difference between normal blood viscosity and high
blood viscosity. Omega-3 fatty acids in faxseed reduce hematocrit. (17)
• Red blood cell (erythrocyte) deformability is the ability of red blood cells
to change shape, i.e., to elongate and to bend and fold to pass through the
slender passageways of the capillaries. The more fexible the RBCs are, the
less will be the viscosity of blood, and young red blood cells are more fex-
ible than older RBCs. Erythrocyte deformability is the second most impor-
tant determinant of blood viscosity, after hematocrit. Flaxseed was found to
increase RBC deformability in an animal model. (16)
• Blood platelets are a type of blood cell that helps form blood clots by stick-
ing together (aggregation). A clot is what stops the bleeding when there
is a wound. Platelet aggregation contributes to blood viscosity. Flaxseed
reduces platelet aggregation. (18)

Flaxseed Promotes Healthy Bowel Function: Flaxseed’s high fber content promotes
“regularity.” Each one tablespoon serving of faxseeds (about 6 grams) contains 3 grams
of fber, including a mix of both soluble and insoluble fber. It was found to be especially
helpful in persons with constipation and in those with type 2 diabetes. (19)

Flaxseed Lowers the Risk of Benign Prostate Hypertrophy: Flaxseed has been found
to help maintain overall prostate health and reduce the risk of an enlarged prostate
(hypertrophy), as well as lower urinary tract symptoms (LUTS). (20)

Flaxseed and Flaxseed Oil Reduces Joint Pain and Arthritis: According to the
Arthritis Foundation, Living with Arthritis blog, just two tablespoons of ground
faxseed contain more than 140% of the daily value of the infammation-reducing
omega-3 fatty acids, and 50% of the total fatty acids in faxseed oil is ALA, one of
three omega-3 fatty acids. When consumed, ALA is converted into the other, more
powerful omega-3s, DHA and EPA acids. Ground faxseed has ALA, but faxseed oil
contains the highest amount. In a study where volunteers consumed faxseed oil for
four weeks, the ALAs signifcantly decreased proinfammatory compounds. (13, 21)

Flaxseed Increases Insulin Production and Reduces Blood Glucose Level:

Individuals with diabetes are at increased risk of developing blood vessel complica-
tions leading to retinopathy, nephropathy, and neuropathy, in addition to cardiovas-
cular disease (CVD). The Diabetes Control and Complications Trial (22) and UK
Prospective Diabetes Study showed that faxseed in treatment programs resulted in
improved blood glucose control, as measured by HbA1c, and reduced micro-blood
vessel complications of diabetes. (23)
34 Flaxseed

Consuming faxseed reduces blood sugar levels after a meal (postprandial) and
increases insulin levels in prediabetic individuals. (24)

Flaxseed Improves Liver Function: Nonalcoholic fatty liver disease (NAFLD) is

the buildup of extra fat in liver cells that is not caused by alcohol consumption. It
is normal for the liver to contain some fat. However, if more than 5% to 10% of
liver weight is fat, then it is called “fatty liver” or steatosis. It was reported in the
International Journal of Food Science and Nutrition, in 2016, that faxseed supple-
mentation is effective in alleviating NAFLD. (25)

Flaxseed Improves Kidney Function: Chronic kidney disease (CKD) is an important

health problem among older adults and can lead to end-stage renal disease with its
need for dialysis or transplantation for survival. (26, 27)
Due to the anti-infammatory properties of omega-3 fatty acids plentiful in fax-
seed and faxseed oil, it has been suggested that in adults, these nutrients may protect
the kidneys from damage. PUFAs supplementation was observed to reduce kidney
infammation and fbrosis in animal models. (28) Increased dietary intake of long-
chain omega-3 PUFA was inversely associated with the prevalence of CKD in the
Blue Mountains Eye Study (1997–1999) (29).

Flaxseed Improves Lipid Profle: The lipid profle or lipid panel is a set of screen-
ing blood test results used to describe obtained blood serum levels of lipids, such as
cholesterol, and triglycerides, in comparison to standard healthy values. It is used
to screen for abnormalities. Serum lipid profle is directly related to the risk factors
of cardiovascular diseases. It is the most intensely investigated effect studied after
dietary supplementation of faxseed or fax oil.
The journal Reviews on Recent Clinical Trials reported in 2015 that “faxseed
may be regarded as a useful therapeutic food for reducing hyperlipidemia,” the lat-
ter meaning elevated serum cholesterol. (30) Another study published in the journal
Current Pharmaceutical Design, in 2016, concluded that the secoisolariciresinol
diglucoside (SDG) in faxseed slows the progression of and even reverses atheroscle-
rosis, and that it could serve as an alternative medicine for the treatment of coronary
artery disease, stroke and peripheral arterial vascular diseases. (31)

Flaxseed Improves Health Hazards of Menopause: A study published in the

journal Holistic Nursing Practice, in 2015, reported on the effects of faxseed on
menopausal symptoms and quality of life throughout the menopausal period. The
empirical research was conducted in the obstetrics and gynecology outpatient
department of a university hospital in Izmir, Turkey. The menopausal symptoms
decreased, and the quality of life increased among the women who used faxseed
for three months. (32)

2.9 CNglcs IN FLAXSEEDS, NO-DONORS

According to a report in the Journal of Agricultural and Food Chemistry, CNglcs
are nitrogenous secondary metabolites derived from amino acids. There are several
major categories, including linustatin and neolinustatin, a β-gentiobioside of acetone
Flaxseed, a Functional Food 35

cyanohydrin and methyl ethyl ketone cyanohydrins. There are also minor components,
including linamarin (1-cyano-1-methylethyl β-D-glycopyranoside), along with diglucosides
linustatin and neolinustatin. The quantity of constituents found in various cultivars has,
however, been shown to vary from sample to sample tested, depending also on seasonal
effect and on the location where they were grown. (33)
In fact, the journal Food and Nutrition Sciences reported on the content of the
CNglcs (linamarin, linustatin and neolinustatin) in 21 varieties belonging to dif-
ferent groups producing oil, fber and intermediate products. The total content of
CNglcs ranged from 0.74 to 1.60 g • Kg–1 CN–1. As expected, linamarin was a minor
component, accounting for only about 2% of total glycosides.
Linustatin was signifcantly lower in the intermediate group than in the other
groups, and, in particular, it was the lowest in the Festival variety. Neolinustatin was
lower in the fber group, although the variety Ventimiglia (belonging to the oil group)
showed a negligible level of this compound. Neolinustatin was positively correlated
to total CNglcs and inversely correlated to linustatin. (34)

2.10 GUIDELINES TO SUPPLEMENTATION OF FLAXSEED

AND FLAXSEED OIL
According to SELFNutritionData, Nutrition Facts, a typical serving size of ground
faxseeds is 1 tablespoon (7 grams) and it contains the following:

• Calories: 37
• Total fat: 3 grams
• Saturated fat: 0.3 grams
• Cholesterol: 0 mg
• Sodium: 2 mg
• Total carbohydrates: 2 grams
• Dietary fber: 2 grams
• Sugar: 0 grams
• Protein: 1 gram
• Monounsaturated fat: 0.5 grams
• Polyunsaturated fat: 2.0 grams
• Omega-3 fatty acids: 1,597 mg
• Vitamin B1: 8% of the recommended daily intake (RDI)
• Vitamin B6: 2% of the RDI
• Folate: 2% of the RDI
• Calcium: 2% of the RDI
• Iron: 2% of the RDI
• Magnesium: 7% of the RDI
• Phosphorus: 4% of the RDI
• Potassium: 2% of the RDI (35)

The Mayo Clinic website reports the following:

Flaxseed can be used whole or crushed, or in a powder form as meal or four. Flaxseed
oil is available in liquid and capsule form. People use faxseed and faxseed oil to
36 Flaxseed

reduce cholesterol and blood sugar and treat digestive conditions. Some people also take
faxseed to treat infammatory diseases. When used in combination with daily exercise
and a low cholesterol diet, faxseed might help control cholesterol levels. Flaxseed might
also be helpful for managing diabetes and lowering the risk of heart disease.

The website of the Institut de Montreal features an article titled “The Positive
Effects of Flaxseed on Cardiovascular Health.” The author, Martin Juneau, MD,
reports the recommendation of an average daily intake of 2.2 g of linolenic acid.
This is said to correspond to 1 tablespoon (15 mL) of faxseed. He further recom-
mends grinding the seeds to raise the absorption of omega-3 fatty acids and allow
the transformation of lignans into active phytoestrogens by intestinal bacteria.
However, omega-3 fatty acids are very fragile and sensitive to degradation, and
one should buy whole seeds that can be ground when needed in a simple coffee
grinder and store the ground seeds for a maximum of two weeks in the refriger-
ator in an airtight container (https://observatoireprevention.org/en/2018/01/25/
the-positive-effects-of-faxseed-on-cardiovascular-health/).
When taken in recommended amounts, faxseed and faxseed oil are generally
safe to use. However, when taken in large amounts and with too little water, faxseed
can cause bloating, gas, even diarrhea. It is best to follow these guidelines:

• Avoid use of faxseed and faxseed oil during pregnancy.

• Occasionally, using faxseed or faxseed oil causes an allergic reaction.
• Don’t eat raw or unripe faxseeds.
• Because faxseed oil might decrease blood clotting, stop using faxseed oil
two weeks before having elective surgery.

Flaxseed supplementation may entail possible interactions, including the following:

• Anticoagulant and anti-platelet drugs, herbs and supplements: These types

of drugs, herbs and supplements reduce blood clotting. Flaxseed oil also
might decrease blood clotting. It’s possible that taking faxseed oil along
with those blood-thinning agents might increase the risk of bleeding.
• Blood pressure drugs, herbs and supplements: Flaxseed oil might lower
blood pressure. Taking faxseed oil with drugs, herbs and supplements that
lower blood pressure might lower blood pressure too much.
• Diabetes drugs: Flaxseed might lower blood sugar levels. Taking faxseed
with diabetes drugs or herbs or supplements with hypoglycemic potential
might lower blood sugar too much.
• Estrogens: Flaxseed might have an anti-estrogen effect. Taking faxseed
might decrease the effects of oral contraceptive drugs and estrogen replace-
ment therapy.
• Oral drugs: Taking faxseed might decrease absorption of oral drugs.
Consider taking oral drugs and faxseed an hour or two apart. (36)

The Mayo Clinic website does not report how much one should take each day for
effective supplementation, nor does it report how much is too much. There is no set
Flaxseed, a Functional Food 37

dose of faxseed. In studies of people with high cholesterol, 15 to 50 grams of faxseed

per day has been used; 40 grams/day has been used for mild menopause symptoms.
Flaxseed must be ground prior to consumption, or it won’t work for these condi-
tions. It can be mixed with liquid or food, such as muffns or bread. But to be better
absorbed, it must be ground before using it to allow the oils to be available. Some
people use a small coffee grinder to grind daily doses as needed. (37)
A number of such grinders are commercially available:

• Cool Knight brand (manual or electric): Herb Grinder Electric Spice

Grinder Spices and Herbs
• Turimon brand: Large Herbal Grinders/Mill/(electric): Crusher for Spice
and Herbs
• Cuisinart brand: Grinder—(Electric) Spice-and-Nut Grinder
• MotorGenic brand: Herb Grain Grinder 700 g Electric Mill Cereal Machine
• Prima Cucina brand: Electric Pepper Mill With Light and Rounded Top

2.10.1 RECOMMENDED FLAXSEED SUPPLEMENTS CONTENT OF ALA

The Journal of Food Science and Technology reported in 2014 that for optimal health,
many governments and public health authorities recommend increasing omega-3 fatty
acids in the diet. In fact, as early as 1990, Health Canada recommended an omega-6
to omega-3 fatty acid dietary ratio in the range of 4:1 to 10:1. (38)
A number of sources recommend that supplement products need to contain an
amount and type of faxseed that will signifcantly increase the levels of ALA in the
blood over and above the recommended daily amount of 1.6 grams/day for men and
1.1 grams/day for women. (39, 40) But according to the US Department of Agriculture
(USDA), faxseed contains approximately 23 grams of ALA per 100 grams (41), and
thus the recommended dietary amounts can be obtained by consuming about 9 grams
of faxseed per day. But supplement products for clinical trials need to contain suf-
fcient faxseed to signifcantly raise the levels of ALA in the blood above the rec-
ommended daily amount of 1.6 grams/day for men and 1.1 grams/day for women.
(42, 43)

2.11 POTENTIAL ANTI-NUTRITIONAL ASPECTS OF FLAXSEED

Despite its health benefts, faxseed is not totally free of constituents considered
anti-nutritional, such as CNglcs. Flaxseed contains CNglcs and linamarin (ace-
tone—cyanohydrin-beta—glucoside C10H17O6N) in small amounts. (44) Whole
faxseed contains 250 to 550 mg of CNglcs per 100 grams, (45) of which linustatin
and neolinustatin are the major components. There is reportedly about 174 to 207
mg/100 grams of linustatin and neolinustatin, respectively, in faxseed. (46)
Damaging the seeds causes the release of β-glucosidases, contributing to the for-
mation of hydrogen cyanide. However, adequate processing of foodstuffs containing
CNglcs helps in reducing the potential risks associated with poisoning. (47, 48) For
example, more than 85% of linustatin, neolinustatin, were removed when faxseed
was heated for more than two hours at 200 °C (392 °F). (46)
38 Flaxseed

Flaxseed meal also contains 2.3% to 3.3% phytic acid. Phytic acid is found in nuts,
edible seeds, and beans/legumes. It is the main storage form of phosphorous, and it
also binds to positively charged metals, thus binding avidly to the kinds of minerals
that are crucial for nutrition such as magnesium, iron and zinc, thus impairing the
absorption of these minerals in the digestive tract. (49) For this reason, some health
authorities advise restricting consumption of nuts, beans, grains and legumes, which
are high in phytic acid, because phytic acid binds with minerals thereby potentially
jeopardizing bone health. On the other hand, phytic acid has antioxidant, anticancer,
hypocholesterolemic and hypolipidemic properties. (45)
Flaxseed meal also contains 10 mg/100 gram Linatine (gammaglutamyl- 1-amino-
D-proline), a vitamin B6 antagonist that can induce defciency. (45) Pyridoxal
5′-phosphate (P-5-P), a cofactor of Vitamin B-6, has a crucial role in amino acid
metabolism. A prevalence of moderate vitamin B-6 defciency in the population has
been reported, and it is thought to result from the ingestion of 1-amino D-proline
(1ADP) (linatine) found in faxseed. (50) However, other investigators reported that
the linatine in faxseed did not affect vitamin B6 levels or metabolism in people fed
up to 50 grams of ground faxseed per day. (51, 52) It has also been reported that
large amounts of faxseed depressed vitamin E levels in an animal model. (51)

2.12 HEALTH BENEFITS OF FLAX PROTEINS

Flax is not commonly used as a source of food protein for humans but is used in
animal feed. However, recent reports have shown it to have a number of healthful
properties (53–56):

• Flaxseed proteins were shown to be benefcial in coronary heart disease, kid-

ney disease and cancer. (57–59) For example, peptides derived from enzymatic
hydrolysis of faxseed proteins inhibited angiotensin I—converting enzyme
(ACE) activities and also displayed in vitro antioxidant activities. (60, 61)
• Flax proteins contain signifcant amounts of L-arginine and glutamine (62),
which are very important in the prevention and treatment of heart disease. (63)
• Peptide mixture from faxseed with high levels of branched-chain amino acids,
and low levels of aromatic amino acids have shown antioxidant properties
by scavenging 2,2-diphenyl-1-picrylhydrazyl radical and antihypertensive
properties by inhibiting the ACE activity. (64)
• Flaxseed supports immune system function. (65) They contain bioactive
peptides such as cyclolinopeptide A, which support immune function and
antimalarial activities, inhibiting the human malarial parasite Plasmodium
falciparum in culture. (66)

Table 2.3 lists the principal biological/functional properties of faxseed proteins

and identifes the characteristics of faxseed that make it a functional food. In particu-
lar, faxseed supplies high levels of ALA and omega-3 fatty acids. These antioxidant
constituents are well-known to the health and nutrition professions for their role in
preventing—even treating—cardiovascular and heart disease, stroke, kidney failure
and the symptoms of diabetes complications.
Flaxseed, a Functional Food 39

TABLE 2.3
Principal biological/functional properties of flaxseed proteins
Function of Flax Protein Effects/Mechanism Reference
Antifungal Acts against food spoilage fungi 67, 68
Penicilliumchrysogenum,
Fusariumgraminearum and Aspergillusfavus
Antioxidant Hydrolyzed faxseed proteins exhibited 68, 69
antioxidant properties by scavenging 2,
2-diphenyl-1- picrylhydrazyl radical,
superoxide radical and hydroxyl radical
Antihypertensive Inhibits angiotensin I-converting enzyme 64
Cholesterol-lowering effect Due to their bile acid binding activity 61
Antidiabetic Because fax proteins can interact with fber 70
and mucilage and also by stimulating the
secretion of insulin
Anti-thrombic Flax proteins- hirudine and linusitin 71
Anti-tumor Due to presence of low lysine/arginine ratio 70
Source: With permission.
(2) Goyal, Sharma, Upadhyay et al. 2014. Journal of Food Science and Technology.

So far, CNglcs have only been briefy described as a constituent of faxseed, and
no detailed mention of it has been made in connection with its potential to ward off
health hazards. As previously noted, that potential rests in their being an excellent
and plentiful source of NO.

2.13 SUMMARY
Flaxseed, an excellent nutrient supplement, is the richest plant source of the omega-3
fatty acid ALA. It is low in saturated fatty acids (9%), moderate in monosaturated fatty
acids (18%) and rich in polyunsaturated fatty acids. It is also high in fber and in lignans,
phenolic compounds that act as both antioxidants and phytoestrogens. Flaxseed contrib-
utes minerals such as calcium, magnesium and phosphorus, and it contains CNglcs, pow-
erful NO-donors. Health benefts include reduced risk of hypertension, cardiovascular
disease, atherosclerosis, diabetes, kidney failure, cancer, arthritis joint pain, osteoporo-
sis, autoimmune and neurological disorders. Flaxseed has also been reported to be anti-
arrhythmic, normalizing the heartbeat; anti-atherogenic, lowering the tendency to form
arterial plaque; and anti-infammatory, thereby improving blood vessel function. Dietary
supplementation is described and very rare but potentially adverse side effects are cited.

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long-chain n-3 PUFA, a-linolenic acid and fsh is associated with the prevalence of chronic
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 3 The Beneficial Effect
of Omega-3 PUFA
and L-Arginine on
Endothelial Nitric Oxide
(NO) Bioavailability

3.1 THE MORE YOU NO

This chapter will frst review aspects of the basic structure and physiology of arte-
rial blood vessels and their control systems. Then it will detail the contribution of
constituents of faxseed, i.e., omega-3 PUFAs and L-arginine, to maintaining their
healthy function.
All our cells, tissues and organs depend on oxygen (O2) supplied by blood. And
the heart that helps keep blood fowing under pressure to our cells, tissues and
organs likewise depends on a reliable oxygen-rich blood supply. Blood fow is under
the control of a number of factors and principal among them is tonus—degree of
constriction—regulated to a signifcant extent by the biological formation of a gas,
endothelial nitric oxide (eNO).
We italicized “helps keep” to emphasize that the conventional notion that blood
circulates under the action of the heart as a pump within vessels that can only con-
strict or dilate is reductio ad absurdum. Blood actually fows under the active pump-
ing control of virtually all segments of the circulatory system once it leaves the heart.
As noted in previous chapters, fax contributes many of its constituents to main-
taining blood vessel and heart health, and two of the most important are L-arginine
and the cyanogenic glycosides (CNglcs) because both of these form that key com-
ponent of blood vessel modulation and heart function, the gas molecule nitric oxide
(NO), as you will see. It was also briefy noted previously that it was discovered in
the early 1980s that a substance essential to healthy blood circulation, the gas NO,
ordinarily formed in the body from the amino acid L-arginine, can also be formed by
digestive enzymes from the CNglcs in certain foodstuffs, notably faxseed.
CNglcs are considered natural plant “toxins” that are present in minute quanti-
ties in a number of plants, most of which we consume. It is thought that they are part
of the plant defenses against insects, microbes and certain other predators. Their
toxicity derives from the fact that when digested, they can release minute quantities
of cyanide, which, as noted in previous chapters, is harmless to people at low doses.
Cyanide can be chemically decomposed in the body to yield NO. In fact, sodium

DOI: 10.1201/b22986-3 45
46 Flaxseed

nitroprusside is a NO-based drug that is used for vasodilation in emergency settings

to treat acute hypertension. (46)
The body commonly forms NO from the amino acid L-arginine found in high
concentrations in meats, protein-rich legumes and nuts and in foods rich in nitrates.
Flaxseed holding CNglcs, a source of NO, therefore makes it a useful nutrient supple-
ment in general to enhance NO availability and a valuable alternative to the amino
acid L-arginine as a source of NO, especially where an arginine-deprivation diet is
recommended.
There is, by the way, no appreciable amounts of CNglcs in faxseed oil.
NO regulates blood fow by triggering a cascade of events that result in relaxation
of arterial vessel smooth muscle. Absent NO, blood vessels, the heart and the kidneys
falter. And, as will be shown, by the way, so do the nervous system and the immune
system falter.
It is very important, therefore, to know what NO is, how it is formed and especially
what it does in the body to appreciate the contribution of faxseed as a NO-donor
supplement. This chapter will address these issues, and the following chapters will
then detail the role of NO, the consequences of NO unavailability and the effcacy of
increasing NO availability in a number of our unfortunately all too common health
hazards.

3.2 NITRIC OXIDE: THE 1992 SCIENCE “MOLECULE

OF THE YEAR”
In 1992, the prestigious journal Science took the very unusual step of declaring nitric
oxide (NO) the Molecule of the Year. Biological and medical scientists were at frst
in utter disbelief that a gas could play a crucial biological regulatory role in the body.
But today, searching “nitric oxide” on the US National Library of Medicine website
(PubMed) would result in more than 226,939 medical science journal title entries
linking it to virtually every known health condition, including asthma, cardiovascu-
lar and heart disease, diabetes, kidney failure, toxemia of pregnancy, cancer, sickle
cell disease, erectile dysfunction and many more. Here is a small sample:

• NO lowers blood pressure (Bode-Böger, Böger, Creutzig et al. 1994:

Clinical Science, 87; 303–310).
• NO reduces the workload of the heart (Rector, Bank, Mullen et al. 1996:
Circulation, 93; 2135–2141).
• NO is antioxidant at low concentrations (Wolf, Zalpour, Theilmeier et al.
1997: Journal of the American College of Cardiology, 29; 479–485).
• NO regulates kidney function (Mount and Power. 2006. Acta Physiologica
(Oxf), Aug; 187(4): 433–446).
• NO reduces insulin resistance in type-2 diabetes (Piatti, Monti, Valsecchi
et al. 2001. Diabetes Care, 24; 875–880).
• NO ameliorates sickle cell disease (Reiter and Gladwin. 2003. Current
Opinion in Hematology, Mar; 10(2): 99–107).
• NO strengthens penile erection (Zorgniotti and Lizza 1994: International
Journal of Impotence Research, 6; 33–35).
The Beneficial Effect of Omega-3 PUFA and L-Arginine 47

Clearly, it is highly desirable to maintain NO availability throughout our life span,

but unfortunately, we normally gradually lose the ability to form it as we age. (1)
However, we can increase NO availability by supplying its principal NO-donor
sources in the diet, typically L-arginine or vegetable-based nitrates, and now we can
also add faxseed to the list of NO-donor supplements.

3.3 BOTTOM LINE . . . THE ENDOTHELIUM

It is important to understand the contribution to vascular physiology made by the
discovery of the biological role of NO. But, it is largely left unsaid that this discovery
simultaneously led to an even more important “discovery”—namely, the biological
role of the endothelium, a single cell layer that lines the inside of blood vessels, lym-
phatic ducts, the heart (where it is termed the endocardium), the penis cavernosae
(likewise in the clitoris) and other vascular structures. The word “discovery” is in
quotes here because the cell structure of the endothelium was known, but it was
thought to have no particular function other than a barrier “lining” the inner surface
of arterial blood vessels in the vessel lumen.
NO is said to be a “signaling molecule” formed by the endothelium lining the
arterial vascular system and the heart. Such molecules are released from the cells,
sending the signal, crossing the gap between cells by diffusion and interacting
with specifc receptors in the cells that gave rise to them or other cells, triggering a
response by activating a series of enzyme-controlled reactions that lead to changes
in target cells.
While there may be a minor overlap in defnition, signal molecule differs from
neurotransmitter molecule. Signaling molecules transmit information between cells,
some over short distances, while others transmit information over very long dis-
tances. Most neurotransmitters, on the other hand, are released at the end of a nerve
fber by the arrival of a nerve impulse and diffuse across the synapse or junction,
causing the transfer of the impulse to another nerve fber, a muscle fber or some
other structure.

3.3.1 THE STRUCTURE AND FUNCTION OF THE ENDOTHELIUM

Arterial blood vessels have three major structures: The innermost layer, the tunica
intima (also called tunica interna), is simple squamous epithelium surrounded
by a connective tissue basement membrane with elastic fbers. The middle layer,
the tunica media, is primarily smooth muscle and is usually the thickest layer. It
not only provides support for the vessel but also changes vessel diameter to regulate
blood fow and blood pressure. The outermost layer, which attaches the vessel to
the surrounding tissue, is the tunica externa or tunica adventitia. This layer is con-
nective tissue with varying amounts of elastic and collagenous fbers. The connec-
tive tissue in this layer is quite dense where it is adjacent to the tunica media, but it
changes to loose connective tissue near the periphery of the vessel.
In ordinary circumstances, the degree of constriction, or tonus, of arterial blood
vessels and, consequently, blood fow and pressure, is determined by activity level in
two control systems:
48 Flaxseed

• The endothelium-independent system of action-hormones (adrenaline, nor-

adrenalin, etc.) and diuresis, and
• The endothelium-dependent signal system based on the availability of NO,
produced by the endothelium.

Figure 3.1 is an electron micrograph of a cross-section of a blood vessel: The red

blood cells are shown in the lumen through which blood fows. The futed accordion-
like structure is the endothelium cell lining, surrounded by the blood vessel walls.
The folds, or futing, facilitate relaxation and thus enlargement of the vessel increas-
ing blood fow.
It should be noted that the availability of L-arginine is never the only limiting fac-
tor in delivering NO. Endothelium dysfunction is another cause, and it was reported
in a previous publication (4) that the limitations may also be due also to conditions
that unlink or otherwise disable the eNOS enzyme (see the following discussion) that
cleaves NO from L-arginine.
Many studies support the benefcial role of both omega-3 PUFAs and L-arginine
in treatments of conditions that damage the endothelium and impair NO formation,
including the following.

FIGURE 3.1 Colored scanning electron micrograph (SEM) of a sectioned artery containing
red blood cells (erythrocytes). The futing of the endothelium, the inner lining of the blood
vessel, like that in an accordion, permits it to expand. [From Steve Gschmeissner. Science
Photo Library. (3) With permission.]
The Beneficial Effect of Omega-3 PUFA and L-Arginine 49

A clinical study published in the journal Atherosclerosis in 2014 reported that

“Omega-3 PUFAs improved endothelial function and arterial stiffness with a parallel
anti-infammatory effect in adults with metabolic syndrome.” (47) And a clinical study
published in the International Journal of Cardiology in 2002 reported, “Oral L-arginine
improves endothelial dysfunction in patients with essential hypertension.” (48)
A clinical study published in the American Journal of Physiology. Heart and
Circulatory Physiology in 2018 titled “Flaxseed: Its Bioactive Components and Their
Cardiovascular Benefts” reported that impaired vascular reactivity that accompanies
atherosclerosis was also improved in both contraction and endothelium-dependent
vessel relaxation in the presence of a faxseed-supplemented diet. (49)

3.4 HOW DOES THE BODY FORM NO?

In the early 1900s, the Austrian pharmacologist Otto Loewi discovered a substance
made by cells in the nervous system that he termed “vagus material.” Some years
later, Sir Henry Dale, with whom he later collaborated at the University of London,
and with whom he shared the 1936 Nobel Prize in Medicine, named it “acetylcho-
line” (ACh). This was the beginning of neuropharmacology based on neurotrans-
mitter chemical signals by which cells in the nervous system and the brain are now
known to communicate.
ACh was found to relax arterial smooth muscles, and this seemed a promising
road to lower blood pressure to treat hypertension. However, it did so unreliably and
unpredictably. No one knew why. Then in 1980, Dr. Robert F. Furchgott, professor of
pharmacology at Downstate Medical Center in Brooklyn, New York, published his
fndings in the journal Nature that ACh relaxation of arterial smooth muscle depended
on the simultaneous presence of a mysterious substance formed by the endothelium. It
was termed “endothelium-derived relaxing factor” (EDRF): ACh relaxed the vessels
only when EDRF was also present. (5) The identity of EDRF was a mystery.
It did not take long to verify the fnding, and in 1993, Dr. Salvador Moncada
at Wellcome Research Labs, United Kingdom, who had previously frst identifed
EDRF as the gas NO, detailed its role in health and disease in the New England
Journal of Medicine (NEJM). (6)
In 1998, Dr. Furchgott and two colleagues, Louis J. Ignarro and Ferid Murad,
were awarded the Nobel Prize in Medicine for the discovery of the biological role of
NO in blood vessel relaxation. One of the three recipients, Dr. Louis J. Ignarro, later
detailed how, in sexual arousal, ACh caused increased and sustained production of
NO formed from the amino acid L-arginine by the endothelium lining the spongy
chambers of the penis cavernosa(e). Following sexual stimulation, this causes them
to relax (dilate), allowing increased blood infow and thus erection. This discovery
led to the development of Viagra®.

3.4.1 FOOTNOTE TO HISTORY

Why doesn’t ACh reliably cause vasodilation in human blood circulation or in blood
vessel strips in the laboratory? What Dr. Furchgott discovered in his strips of arterial
blood vessels washed with ACh that did not relax is that on closer examination, it
50 Flaxseed

was found that “careless” laboratory preparation had damaged the endothelium, and
it turns out that damaged endothelium impairs NO production.
The observation that damaged endothelium cannot produce NO in amounts suff-
cient to cause dilation and maintain adequate blood circulation is now the explanation
for how we come by cardiovascular disorders such as hypertension, atherosclerosis,
coronary heart disease, heart failure, kidney failure and the most common form of
erectile dysfunction (ED), i.e., vasculogenic ED.
NO defciency caused by damaged endothelium is at the core of most of the com-
mon health hazards, starting with hypertension, atherosclerosis and so on. And clearly,
the damage to the endothelium is caused by a form equivalent to “careless” handling,
our junk food diet poor in nutrients and antioxidants resulting often in oxidative stress.

3.5 REACTIVE OXYGEN SPECIES (ROS) AND OXIDATIVE

STRESS—A MAJOR CAUSE OF ENDOTHELIUM DAMAGE
All the previously listed blood vessel damage conditions, and then some, are now
said to be either due to or aggravated by oxidative stress. The principal damage is
done to the endothelium. Oxidative stress results from sustained exposure to ROS
that exceeds our antioxidant defense capability.
ROS are toxic compounds formed by oxygen free radicals, i.e., atoms, ions or
molecules that have at least one unpaired electron in their structure, in combination
with lipids, proteins or other substances. For instance, unpaired electrons reacting
chemically with lipids cause lipid peroxidation, a damaging ROS.
The body ordinarily aims to neutralize or eliminate ROS to control their damag-
ing effects. This ongoing battle that could ultimately deplete antioxidant defenses
causes oxidative stress. Oxidative stress is the cost to the body of waging that bat-
tle. Oxidative stress damages the endothelium, reducing its ability to form NO by
impairing endothelium function as surely as if it were mechanically damaged by
“carelessly” mishandling in the laboratory.
It should be noted, however, that “carelessly” is not really accurate since no one
had any idea then that the endothelium had any biological function, so why bother
to spare it? It was thought then to be not much more than a sort of lining between
the bloodstream and the blood vessel walls—a barrier, something like a bedsheet.
Flaxseed supplies antioxidant omega-3 PUFAs and L-arginine. In type 2 diabetes,
ROS play a signifcant role in damaging blood vessel endothelium, thus fostering the
development of conditions such a retinopathy. A study published in the International
Journal of Preventive Medicine, in 2013, titled “The Effect of Omega-3 Supplements
on Antioxidant Capacity in Patients with Type 2 Diabetes,” concluded that omega-3
supplements can increase antioxidant capacity and that consumption of omega-3
supplements is recommended as primary prevention and secondary prevention of
diabetes complications. (50)
Sickle cell disease entails endothelium activation and cell adhesion. (51) A report
in the Nutrition and Food Science International Journal in 2019 titled “Antisickling
and Antioxidant Properties of Omega-3 Fatty Acids EPA/DHA” concluded that
omega-3 fatty acids EPA/DHA have antisickling, anti-hemolytic and antioxidant
properties, reducing the number of crises in this disease. (52)
The Beneficial Effect of Omega-3 PUFA and L-Arginine 51

L-arginine is an antioxidant. The authors of a report titled “Arginine and

Endothelial Function,” published in the journal Biomedicines in 2020, contend that
impaired endothelial NO availability in “perturbed vasculature” is likely due to
diminished NO bioavailability or, indirectly, to increased ROS production that inac-
tivates NO formation. They hold that in addition to counteracting oxidative stress,
L-arginine supplementation represents an alternative potential therapeutic strategy
in many cardiovascular disorders. (53)
There are a number of studies that report benefcial effects of faxseed on endo-
thelial function, but they are mostly experimental animal-model studies.

3.6 ENDOTHELIAL NO FROM L-ARGININE—NITRIC

OXIDE SYNTHASE (eNOS)
The cells of the endothelium typically form NO from dietary L-arginine or nitrates
with the help of synthase enzymes. There are three known (iso-)forms of the enzyme
nitric oxide synthase (NOS): two are constitutive (cNOS) and the third is induc-
ible (iNOS). The cNOS forms have two functions, one is brain constitutive, and
the other is endothelial constitutive (eNOS). The third form is the inducible iNOS,
which supplies the immune system cells with NO. Figure 3.2 illustrates NOS form
and function.

FIGURE 3.2 Important functions of the three known NOS isoforms. [Förstermann and
Sessa. 2012. (7) European Heart Journal. With permission.]
52 Flaxseed

In the top panel of Figure 3.2, neuronal NOS is shown to be expressed in specifc
neurons of the central nervous system involved in learning and memory formation.
It also participates in the central control of blood pressure. In the peripheral nervous
system, neuronal NOS-derived NO acts as an atypical neurotransmitter mediating
relaxing components of gut peristalsis, and vasodilation.
In the middle panel of Figure 3.2, NOS expression can be induced by cytokines
and other agents in almost any cell type. This had initially been shown for macro-
phages M.
The M-type of macrophage is an essential cellular frst responder in the
innate immune system, sensing, alerting, removing and destroying intracellular
and extracellular pathogens. The induction of inducible NOS in M is essential
for the control of intracellular bacteria, such as Mycobacterium tuberculosis or
the parasite Leishmania. However, inducible NOS is also up-regulated in various
types of infammatory diseases, and the NO generated by the enzyme mediates
various symptoms of infammation. Finally, inducible NOS-derived NO is the pre-
dominant mediator of vasodilation and blood pressure drop seen in septic shock.
The bottom panel of Figure 3.2 shows that endothelial NOS-derived NO is a
physiological vasodilator but can also convey vasoprotection in several ways. NO
released toward the vascular lumen is a potent inhibitor of platelet aggregation and
adhesion to the vascular wall. Besides protection from thrombosis, this also prevents
the release of platelet-derived growth factors that stimulate smooth muscle prolifera-
tion and its production of matrix molecules.
Endothelial NO also controls the expression of genes involved in atherogenesis.
NO decreases the expression of chemoattractant protein MCP-1 and of a number
of surface adhesion molecules, thereby preventing leucocyte adhesion to vascular
endothelium and leucocyte migration into the vascular wall. This offers protection
against early phases of atherogenesis. Also, the decreased endothelial permeability,
the reduced infux of lipoproteins into the vascular wall and the inhibition of low-
density lipoprotein oxidation may contribute to the anti-atherogenic properties of
endothelial NOS-derived NO.
Finally, NO has been shown to inhibit DNA synthesis, mitogenesis and prolif-
eration of vascular smooth muscle cells, as well as smooth muscle cell migration,
thereby protecting against a later phase of atherogenesis. (7)
This description of the synthase enzymes clearly points to a key regulatory role
for NO in virtually all body functions. But while brain and nervous system func-
tions are of great interest, the focus of this book will be on cardiovascular, heart
and kidney function, and by the way, eNO regulates blood vessel function in the
cavernosa(e) of the penis and the clitoris in sexual arousal as well.

3.7 HOW ENDOTHELIUM-DERIVED NITRIC

OXIDE (eNO) IS FORMED
Specifcally, endothelium-derived NO forms in response to stimulation of the endo-
thelial cells by cholinergic nerves. Acetylcholine causes the production of inositol
triphosphate (IP3), a second messenger in many hormone signal transduction path-
ways. IP3 opens calcium channels in the endoplasmic membrane of the endothelial
The Beneficial Effect of Omega-3 PUFA and L-Arginine 53

cells; the liberated calcium then activates NO synthase (eNOS) and causes the pro-
duction of NO.
NO diffuses across the muscle cell membrane and binds to guanylyl cyclase.
Guanylyl cyclase in turn catalyzes the synthesis of cyclic guanosine monophos-
phate (cGMP) from guanosine triphosphate (GTP). cGMP then activates a cGMP-
dependent protein kinase, which stimulates the uptake of calcium by the endoplasmic
reticulum of the smooth muscle cell. The reduced levels of cytoplasmic calcium cause
the muscle cell to relax.
Vasodilation results from muscle cell relaxation, and, as is true of any signal-
ing pathway, there must be a way to terminate the action of the signal: cGMP is
converted into GMP by a specifc phosphodiesterase (PDE). There are ten families
of PDEs: PDE1–10. The major PDE in vascular smooth muscle is type 5. Viagra®
(Sildenafl) is a specifc inhibitor of PDE type 5. By blocking the breakdown of
cGMP, Viagra acts to prolong the effects of cGMP, thus slowing the degradation of
NO and so maintaining cavernosal blood infow.

3.8 NO FORMED FROM CNglcs

Endothelium-derived nitric oxide (eNO) is a key signaling molecule in human car-
diovascular physiology. It regulates blood circulation and the workload of the heart.
But NO, otherwise derived, also plays an important role in plant physiology. There
is now general agreement that NO is an important and almost universal signaling
molecule in plants as well.
The role of NO in plants appears even more multifaceted than that in animals.
Plant-borne NO seems involved in controlling cell differentiation and lignifcation,
root and shoot development, fowering, growth and reorientation of pollen tubes,
senescence and maturation, stomatal movement, plant-pathogen interactions and
programmed cell death and many others. (8–12) There is little doubt that NO is an
important second messenger. (13)
Flaxseeds, as do most plants to a lesser extent, hold CNglcs. Cyanide is formed
following the hydrolysis of CNglcs that occurs during the crushing of the edible
plant material (such as faxseeds) either during consumption or during processing of
the food crop. CNglcs can generate hydrocyanic acid (prussic acid, cyanide) when
hydrolyzed by the enzyme beta-glucosidase into cyanohydrin. This is unstable and
dissociates to hydrocyanic acid.
As previously noted, common CNglcs include amygdalin found in bitter almonds
and peach kernels (both used in Chinese medicine), and prunasin in wild cherry bark
(Prunus serotina). The small quantities of cyanide generated from this bark are said
to be responsible for its antitussive properties, although this has not been confrmed
in modern pharmacological experiments. In general, the effects of cyanide are dose
related: in minute quantities, it stimulates respiration; in larger doses, it inhibits res-
piration; in larger doses yet, it is fatal.
Both amygdalin and prunasin yield benzaldehyde on hydrolysis, which accounts
for the characteristic almond-like aroma of wild cherry bark. The CNglcs linus-
tatin, neolinustatin and linamarin (in trace amounts) are found in faxseeds (Linum
usitatissimum).
54 Flaxseed

Hydrolysis of the glycosides in the digestive tract or by the liver leads to a slow
release of hydrocyanic acid that is readily detoxifed by the body. In fact, amygdalin
given orally to humans at 500 mg three times per day produced no toxic effects and
only moderately raised blood cyanide levels. (14, 15)

3.9 THE BLOOD VESSELS OF THE BLOOD VESSELS

(VASA VASORUM) ARE REGULATED BY NO
In considering diagnosis and treatment of blood vessel and heart disease, many
clinical publications now focus on endothelial dysfunction. For instance, in 2014,
the journal Global Cardiology, Science, and Practice published a report titled
“Endothelial Dysfunction and Cardiovascular Disease.” The term “endothelium”
appeared 18 times in that article, and they tell us that the endothelium is a single
vessel layer between the bloodstream and the vascular supply to other tissues. The
endothelium is comprised of up to [a] trillion cells and it has the largest area in the
body, covering 3 sq. meters and weighing in at about 1kg. It interacts with nearly
every system in the body, and it is implicated in numerous disease including heart,
neurologic, kidney, liver, blood vessels, skin and immunology-related disorders,
but frst and foremost is the hemostasis between thrombosis and anticoagulation.
In addition, the endothelium regulates vascular tone by balancing vasoconstriction
and vasodilation to provide adequate perfusion pressure to target organs. (2) Other
functions include regulation of angiogenesis, wound healing, smooth muscle cell
proliferation, fbrosis, and infammation. The endothelium is adversely affected by
cardiovascular risk factors such as tobacco use, obesity, age, hypertension, hyper-
lipidemia, physical inactivity, and poor dietary habits. It is positively affected by
benefcial lifestyle habits such as increased physical activity, dietary habits which
include anti-infammatory and antioxidant foods, and some pharmaceutical agents
such as L-arginine. (16)
The assertion that “the endothelium is a single vessel layer standing as the ulti-
mate layer between blood and vascular supply to other tissues ” is not actually accu-
rate. If all goes well, the endothelium should not in fact come into contact with blood
in the lumen because there is an additional structure, the glycocalyx, that separates
the endothelium from blood in the vessel (see the following).
The authors of that paper (affliated with the Mayo Clinic) curiously refer to
L-arginine as a “pharmaceutical agent.” It should be noted that exogenous L-arginine
is not conventionally considered a pharmaceutical agent in the United States. Here,
it is usually a “supplement.” As will be shown later, its supplementation is repeatedly
shown to signifcantly improve blood pressure and heart health. (17)
Arterial blood vessels and the endothelium, in particular, derive O2 and nutrients
and eliminate CO2 and wastes only in small part by diffusion in and out of the blood
vessel via the endothelium into and out of the bloodstream. The endothelium is addi-
tionally separated from the bloodstream by the glycocalyx, a carbohydrate-rich layer
lining the vascular endothelium that forms a barrier to substance diffusion between
the cells of the endothelium and the bloodstream in the vessel lumen. It is also sub-
ject to oxidative damage. More about that later.
The Beneficial Effect of Omega-3 PUFA and L-Arginine 55

3.9.1 STRUCTURE AND FUNCTION OF VASA VASORUM

Arterial blood vessel walls and the endothelium are supplied by their own set of
blood vessels, the vasa vasorum, that draw blood from the bloodstream and deliver
it to the vessel wall both inside and outside the walls.
The vasa vasorum is a network of small blood vessels that supply the walls of
large blood vessels, such as elastic arteries (e.g., the aorta) and large veins (e.g., the
venae cavae). There are two sets of these vessels, one set outside, the other inside.
Figure 3.3 depicts a segment of normal (pig) coronary artery showing the origin and
spatial distribution of vasa vasorum.
Vasa vasorum are dead-end structures. Unlike other aspects of blood circulation,
there are no other means of return. Damaging atherogenic substances can enter blood
vessel walls via the vasa vasorum. In fact, that is now thought to be the principal basis
for atherosclerosis: attack from within. (19) The scenario goes something like this:

FIGURE 3.3 Micrographs showing voxel gradient shading of a normal coronary artery at
different angles. Two anatomically different vasa types can be seen. First-order vasa vasorum
(arrows) originate from branches of a coronary artery and run longitudinally to the main
lumen. Second-order vasa vasorum (arrowheads) originate from frst-order vasa and run
circumferentially around the lumen, forming arch arterioles. Voxel size, 28 mm. [(18) The
Journal of Clinical Investigation. With permission.]
56 Flaxseed

Gradually, enlarging plaque deposits in the muscle wall distance the endothelium
from the vasa vasorum and thus distances the endothelium from its source of O2
while at the same time forcing it to encroach into the lumen. Thus metabolically
jeopardized cells in the endothelium gradually lose their ability to form NO, and,
ultimately, it may weaken and rupture due to shear stress on the inward bulge.

3.9.2 VASA VASORUM DEPENDS EXCLUSIVELY ON ENDOTHELIUM-

DERIVED (NO) VASORELAXATION
Both hypertension and atherosclerosis are known to damage the endothelium. In a
study titled “On the Regulation of Tone in Vasa Vasorum” published in Cardiovascular
Research, it was shown that vasa vasorum relaxation was solely endothelium-
dependent—that is, NO-dependent—whereas the arterial vessel responded to both
endothelium-dependent and the endothelium-independent relaxation signals (20)
described next. In brief, the study also concluded that damage done by atherosclerosis
to the endothelium intimately involves frst changes in the vasa vasorum.
Writing in the journal Medical Hypotheses in 2009, researchers contend that
known risk factors for atherosclerosis, such as high blood pressure and nicotine,
reduce blood fow in the end branches of the vasa vasorum. Local impaired blood
fow affects the cells of the endothelium causing local infammation. This makes the
endothelium permeable to large particles, such as various bacteria and low-density
lipoproteins (LDL) and other fatty acids, which macrophages engulf transforming
them into the foam cells that invade arterial blood vessel walls and begin the forma-
tion of plaque. (21)
These and many such reports underscore the dependence of arterial blood vessels
on NO availability. While we understand that blood fow through a vessel depends
on the ability of the endothelium of the vessel to form NO, it is equally clear that it is
also dependent on the ability of the vasa vasorum that serves it to form NO.
NO unavailability in the vasa vasorum can be seen to begin a cascade of failures.
This condition can be expected when the supply of the principal substrate for NO,
L-arginine, is restricted due to a low protein diet (for reasons good or bad). These
fndings make a strong case for the importance of faxseed as a NO-donor.

3.10 THE ENDOTHELIAL GLYCOCALYX

The endothelial glycocalyx is a carbohydrate-rich layer forming a lining covering
the endothelium in the lumen and thus separating it from the bloodstream. It is con-
nected to the endothelium through several “backbone” molecules, mainly proteins
(proteoglycans), and glycoproteins, proteins forming a network in which soluble mol-
ecules, either plasma- or endothelium-derived, are incorporated. Figure 3.4 depicts
the structure of the glycocalix.
Glycocalyx/eSL (endothelial surface layer) thickness is substantially greater than
endothelial cell (eC) thickness, as demonstrated in a transmission electron micro-
graph of a goat coronary capillary (prepared using glycocalyx-sparing fxation tech-
niques). Scale bar: 0.2 μm. Source: Yang and Schmidt. 2013. Tissue Barriers. (23)
With permission.
The Beneficial Effect of Omega-3 PUFA and L-Arginine 57

FIGURE 3.4 Structure of the endothelial surface layer showing the glycocalyx. [(18) Journal
of Clinical Investigation. With permission.]

The endothelial glycocalyx is an intricate, self-assembling 3D mesh of various

polysaccharides. A dynamic equilibrium exists between this layer of soluble compo-
nents and the fowing blood continuously affecting composition and thickness of the
glycocalyx. Several of its specifc properties are worth mentioning.
The endothelial glycocalyx is the endothelial gatekeeper. Located in the lumen
between the bloodstream and the endothelium, it is an important determinant of
vascular permeability. It can limit access of certain molecules to the endothelial
cell membrane, and it has been shown that enzymatic (partial) removal and subse-
quent loss of permeability barrier function of the glycocalyx leads to myocardial
edema. (24)
The presence of a relatively thick endothelial glycocalyx in vivo has great conse-
quences for the deformation of blood vessels and blood fow characteristics (rheol-
ogy), especially in the microvasculature. In this part of the circulation, local blood
viscosity and hematocrit (density of red blood cells in the area) appear to be modu-
lated by the glycocalyx.
Besides its capacity to restrict molecules from reaching the endothelium, the gly-
cocalyx also infuences blood cell—vessel wall interactions. It repulses red blood
cells from the endothelium. In the microcirculation, a red blood cell exclusion
zone fanking the endothelium can be observed in vivo, which is decreased upon
breakdown of the glycocalyx. Similarly, platelets are not often observed interacting
with the endothelium in control conditions, whereas partial glycocalyx removal is
accompanied by an increase in platelet-vessel wall interactions, which are dangerous
because they favor clot formation.
Cells defective of glycosylation, having a thinner glycocalyx, showed increased
attachment of neutrophils. Hence, in normal conditions, the soluble components of
58 Flaxseed

the glycocalyx seem to shield adhesion molecules, thereby preventing interaction.

Stimuli that degrade the glycocalyx or induce a more open mesh, such as enzymes,
cytokines or ischemia and reperfusion, appear to uncover the adhesion molecules,
which, in turn, allows blood cells to interact with the endothelium, which, again, is
bad because it favors clot formation. (22)
The endothelial glycocalyx is a mechanotransducer. Endothelial cells exposed to
shear stress produce NO, an important determinant of vascular tone. Shear stress is
caused by the fow of fuid across a surface, and its value is directly proportional to
the velocity of the surrounding fuid.
Recently, the glycocalyx has been added to the list of possible candidates respon-
sible for the translation of biomechanical forces into biochemical signals. (5) It
appears that shear stress is transmitted to other regions of the endothelial cell as well,
such as intercellular junctions and basal adhesion plaques, which are responsible for
additional shear sensing, even in the absence of a glycocalyx. (26)
The endothelial glycocalyx also controls the microenvironment. Docking of plasma-
derived molecules can infuence the local environment in several ways: Binding of
receptors or enzymes and their ligands to the endothelial glycocalyx causes a localized
rise in the concentration of these substances. This enables proper signaling or enzy-
matic modifcation.
Several important anticoagulant mediators such as antithrombin III, heparin
cofactor II, thrombomodulin and tissue factor pathway inhibitor can bind to the gly-
cocalyx making it vasculoprotective. Antithrombin III is a strong inhibitor of pro-
coagulant enzymes like thrombin and activated factors X and IX (FXa and FIXa).
(27) All anticoagulant molecules present in the glycocalyx contribute to the throm-
boresistant nature of healthy endothelium. (28) The endothelial glycocalyx also
modulates infammatory responses by binding cytokines and attenuating binding of
cytokines to cell surface receptors.
Another aspect of the vasculoprotective role of the endothelial glycocalyx is that
it supports antioxidant activity by binding quenchers of oxygen radicals, such as
extracellular superoxide dismutase (SOD). (29) These enzymes help to reduce the
oxidative stress and keep up NO bioavailability, thus, preventing the endothelium
from becoming dysfunctional.

3.10.1 THE GLYCOCALYX REGULATES eNO FORMATION

It is hard to imagine that the glycocalyx, this ultrathin mushy layer, could have
so many and such varied endothelium-protective activities. As noted earlier, one
of these is mechanical, i.e., it protects the endothelium from the fuid shear stress
caused by blood fowing through the lumen. As noted previously, degradation of
the glycocalyx promotes atherogenesis and exposes the endothelium to shear stress
incurring the risk of rupture. This fnding links diabetes, for instance, to “coronary”
heart attack, an otherwise unclear connection. And, parenthetically, the glycocalyx
gradually becomes dysfunctional as the vasculature ages. That dysfunction contrib-
utes to impairment of endothelial NO formation. (30)
Investigators reporting in the Biophysical Journal concluded that the glycocalyx
is a signifcant mediator of NO production in endothelial cells; degradation of the
The Beneficial Effect of Omega-3 PUFA and L-Arginine 59

endothelial glycocalyx layer drastically reduces endothelial cells production of NO

in response to fuid shear stress. (31) And in the journal PLoS One, investigators
reported a study concluding that endothelial surface glycocalyx (ibid.) participates
in endothelial cell mechanosensing and transduction through its heparan sulfate to
activate eNOS. (25, 32)

3.11 THE ENDOTHELIAL GLYCOCALYX IN HEALTH

AND DISEASE
In healthy vessels, the endothelial glycocalyx determines vascular permeability,
attenuates blood cell–vessel wall interactions, mediates shear stress sensing, enables
balanced signaling and fulflls a vasculoprotective role. But when it is disrupted or
modifed, these properties are lost, as has been shown through direct targeting of
the glycocalyx in experimental settings. In the last few years, evidence has been
emerging that (damage to) the glycocalyx plays a pivotal role in several vascular
pathologies.

3.11.1 DIABETES
One of the hallmarks of diabetes is insulin insuffciency or resistance, and subse-
quent hyperglycemia, impairing the protective capacity of the vessel wall and result-
ing in enhanced endothelial permeability and impaired NO synthase function. (33)
However, a common pathway leading to these vascular dysfunctions has not been
identifed.
It was recently shown that the systemic glycocalyx volume of healthy volunteers,
as assessed by comparing the intravascular distribution volume of a glycocalyx-
permeable and a glycocalyx-impermeable tracer, declined to one-half the volume six
hours after induction of acute hyperglycemia. (34) Using the same methodology, the
systemic glycocalyx volume in Type 1 diabetes patients was found to be about half of
that of healthy controls; it was further reduced in those with microalbuminuria. (35)
In the same study, plasma levels of hyaluronan and hyaluronidase were found to
be elevated in patients with diabetes, refecting increased synthesis and shedding of
hyaluronan under hyperglycemic conditions.

Hyaluronan (hyaluronic acid) is a high-molecular-mass polysaccharide

found in the extracellular matrix, especially of soft connective tissues. It is
synthesized in the plasma membrane of fbroblasts and other cells by the addi-
tion of sugars to the reducing end of the polymer, whereas the nonreducing
end protrudes into the pericellular space. The polysaccharide is catabolized
locally or carried by lymph to lymph nodes or the general circulation from
where it is cleared by the endothelial cells of the liver sinusoids. Hyaluronan
has been assigned various physiological functions in the intercellular matrix,
e.g., in water and plasma protein homeostasis.
60 Flaxseed

Analysis of serum hyaluronan is promising in the diagnosis of liver disease and vari-
ous infammatory conditions, e.g., rheumatoid arthritis. Interstitial edema caused by
accumulation of hyaluronan may cause dysfunction in various organs. (36)
Both studies showed that acute and long-standing hyperglycemia is associated
with profound reduction of glycocalyx volume. It is tempting to speculate that this
damage to the glycocalyx contributes to endothelial dysfunction in hyperglycemic
conditions, which can be measured in nondiabetic individuals as well. In fact, post-
prandial hyperglycemia, induced by oral glucose loading, attenuates endothelial
function as measured by decreased fow-mediated dilation (FMD) in healthy indi-
viduals without diabetes. (37)

FMD refers to dilation of an artery when blood fow increases in that artery.
The primary mechanism of FMD is the release of NO by endothelial cells.

3.11.2 ATHEROSCLEROSIS
Atherosclerosis is a large artery disease marked by disturbed blood fow profles.
There is evidence that the endothelial glycocalyx is involved in atherogenesis. One
study reported that administration of clinically relevant doses of oxidized LDL leads
to a disruption of the glycocalyx in hamster cremaster muscle microcirculation and
evokes local platelet adhesion. However, co-infusion with the antioxidant enzymes
SOD and catalase, enzymes catalyzing the dismutation of superoxide anion and the
decomposition of hydrogen peroxide abolished this effect, implicating a role for
oxygen-derived free radicals in the genesis of atherosclerosis. (38)
Apparently, loss of glycocalyx results in loss of endogenous protective enzymes,
such as extracellular SOD, and that increases the oxidative stress on endothelial
cells. This was further illustrated in a recent study showing a reduction in glycocalyx
dimensions after a high-fat diet. (39)
In another study, an inverse relation between glycocalyx thickness and blood ves-
sel intima-media ratio was found, refecting a reduction of vasculoprotective capac-
ity of the endothelial glycocalyx at sites with higher atherogenic risk. (40) These
studies suggest the rather novel notion that the endothelial glycocalyx is involved in
the initiation and progression of the atherosclerotic process.

3.11.3 HYPERTENSION
It is reasonably well established that a high-salt diet is one of the major risk factors in
the development and maintenance of hypertension. Numerous experimental and obser-
vational studies have confrmed the association of sodium intake with blood pressure
levels. The effects of a high-salt diet are related to the function of the renin-angiotensin
system, which is normally suppressed by a high-salt diet. Endothelial dysfunction prob-
ably plays an important role in the infuence of high sodium intake on blood pressure.
The renin-angiotensin-aldosterone system (RAAS) is a critical regulator of blood
volume and systemic vascular resistance. While the baroreceptor refex responds in a
short-term manner to decreased arterial pressure, the RAAS is responsible for more
The Beneficial Effect of Omega-3 PUFA and L-Arginine 61

chronic alterations. It is composed of three major compounds: renin, angiotensin II

and aldosterone. These three act to elevate arterial pressure in response to decreased
renal blood pressure, decreased salt delivery to the distal convoluted tubule and/
or beta-adrenergic agonism. Through these mechanisms, the body can elevate the
blood pressure in a prolonged manner.
This is the common wisdom underlying management of hypertension. But recent
studies of the glycocalyx unearthed another source of cardiovascular damage attrib-
utable to excessive salt intake:
According to a report in the journal F1000 Reports Biology, salt entering the
vascular bed after a salty meal is bound to the endothelial glycocalyx. This barrier
protects the endothelium against salt overload. But a degraded glycocalyx increases
the salt permeability of the vascular system and the amount of salt being deposited
in the body, which affects organ function. (41)
These fndings may shed some light on why salt loading results in a decrease
in NO production in both salt-sensitive and salt-resistant normotensive individuals,
which is independent of changes in blood pressure. (42)
In connection with management of chronic hypertension, it should be noted that
increasing salt concentration by as little as 4 mM (about one four hundredths of a
teaspoon) immediately induces damage to glycocalyx leading to chronic Na+ and
Ca2+ overload and vascular smooth muscle cells hypertrophy. (43)

3.11.4 KIDNEY FUNCTION

NO has a key role in kidney function. It regulates renal haemodynamics, maintains
perfusion of the middle (medullary) part of the kidney, mediates pressure-natriuresis
(i.e., excretion of salt), inhibits tubular sodium reabsorption and modulates renal
sympathetic neural activity. Its principal effect is to promote natriuresis and diuresis.
Defcient renal NO synthesis is implicated in the pathogenesis of hypertension. All
three isoforms of nitric oxide synthase (NOS)—namely, neuronal NOS (nNOS or
NOS1), inducible NOS (iNOS or NOS2) and endothelial NOS (eNOS or NOS3)—are
reported to contribute to NO synthesis in the kidney. (44)
Finally, total NO production was found to be decreased in renal disease, likely
due to impaired endothelial and renal NO production. (45)
Numerous clinical studies support supplementation of omega-3 fatty acids and
L-arginine where defcient bioavailability of NO seems to be the principal culprit.
Sometimes these studies cite faxseed, per se, as the dependent variable. At other
times, it is either omega-3 or L-arginine. There is a more detailed look at faxseed
constituents in common cardiovascular disorders in subsequent chapters.

3.12 SUMMARY
NO is a signal molecule ordinarily derived in the body from the amino acid L-
arginine in common staple foods containing proteins and nitrates. And it is also avail-
able to body functions from both L-arginine and CNglcs (e.g. in faxseed). NO is both
formed by the vascular endothelium and acts on it to regulate blood fow. The vascular
endothelium, in turn, largely depends for its blood supply on the vasa vasorum, which
also both forms NO and depends on it for its vascular control activities.
62 Flaxseed

The luminal surface of the endothelium is lined by the glycocalyx, which

modulates endothelium NO formation and supplies antioxidant protection as
well. A number of common health hazards are now linked to the degradation
of the glycocalyx, which results in endothelium function impairment and due
to, and consequently jeopardizing, production of endothelial NO. These hazards
typically encompass the panoply of cardiovascular diseases involving blood ves-
sels, heart and kidney dysfunctions and metabolic disorders, including type 2
diabetes.
Clinical trials have shown that faxseed, per se omega-3 fatty acids and
L-arginine, are antioxidants and, as such, supplementation has been recommended
in support of endothelial NO synthesis commonly jeopardized by ROS in cardio-
vascular disorders.

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 4 The Role of Flaxseed
Micronutrients and
Nitric Oxide (NO)
in Blood Vessel and
Heart Function

It is ambition enough to be employed as an under-labourer in clearing the

ground a little, and removing some of the rubbish which lies in the way to
knowledge.
—John Locke (1689)

4.1 INTRODUCTION
The frst three chapters of this book detailed the panoply of health-giving microcon-
stituents in faxseed and fax oil—many as antioxidants and others as a source of
nitric oxide (NO), the latter derived from both L-arginine and cyanogenic glycosides
(CNglcs). In general, faxseed improves cardiovascular function:
A study published in the American Journal of Physiology—Heart and Circulation
Physiology reports that a number of preclinical and clinical studies have shown the
benefcial cardiovascular effects of dietary supplementation with faxseed. They include

• Antihypertensive action
• Anti-atherogenic effects
• Cholesterol lowering
• Anti-infammatory action
• Inhibition of arrhythmias

The investigators generally attribute these benefcial effects to enrichment with the
omega-3 fatty acid, alpha-linolenic acid and the antioxidant lignin, secoisolarici-
resinol diglucoside (SDG), as well as its high fber content. In addition, faxseed
holds other potential bioactive compounds, such as proteins, cyclolinopeptides, and
CNglcs, which have been shown to produce biological effects. These compounds
could also be responsible for the benefcial cardiovascular effects of faxseed. (1)
The benefts of faxseed supplementation derive in large part from increased
endothelial NO (eNO) availability. But evidence-based reports of the benefts of

DOI: 10.1201/b22986-4 67
68 Flaxseed

faxseed supplementation do not invariably identify these active constituents. More

often, they focus on antioxidant capacity. This will be quite evident in studies cited
throughout this book.
Maintaining viable eNO formation and availability in the cardiovascular system
is absolutely essential, and an “amino acid deprivation diet,” indicated in certain
medical disorders can, under certain circumstances, results in NO insuffciency.
An important example of an intentional amino acid deprivation diet is restricting
dietary intake of amino acids. Amino acid restriction plays a key role in cancer
interventions, including arginine starvation, glycine restriction, serine starvation,
leucine deprivation glutamine blockade, asparagine and methionine restriction. (43)
The consequences of such insuffciency to the viability of blood vessels and the
heart cannot be overstated. Therefore, to head off NO insuffciency, both CNglcs and
L-arginine from faxseed supplementation are proposed as benefcial NO-donors.
This chapter frst details the physiological components of blood circulation and
its assessment critical to understanding how NO is the key to heart and blood vessel
function. Then we will look at clinical reports of the benefts to eNO formation of
supplementing faxseed or its constituents, omega-3 fatty acids or L-arginine.

4.2 WHAT PROPELS BLOOD THROUGH

THE CIRCULATORY SYSTEM?
On the face of it, the question “what propels blood through the circulatory system”
must seem naïve. After all, it is well-known that it is the pumping action of the heart
that sees to that. That’s what Wm Harvey said in the mid-1600s. But in fact, not
exactly.

4.2.1 SYSTOLE
The normal heart (Figure 4.1 is a “cutaway” illustration) has two upper and two lower
chambers. The upper chambers, the right and left atria, receive incoming blood,
shown in blue. Blue typically indicates that there is less than normal oxygen (O2)
content, whereas red indicates properly oxygenated blood. In fact, the veins in the
wrist appear blue because veins usually carry less oxygenated blood than arteries.
The lower chambers, the more muscular right and left ventricles, pump blood out
of the heart. The heart valves, which keep blood fowing in the right direction, are
gates at the entrance to the chambers, preventing blood from fowing back when the
ventricle chambers contract.
The action of the left ventricle (shown on the right in Figure 4.1) is of great
concern because it can malfunction for various reasons thus seriously affecting
blood circulation. One of those malfunctions is heart failure.
The adequacy of the pumping action of the heart is determined by what is known
as the “ejection fraction”—that is, the amount—percentage actually—of blood that
is pumped out (or ejected) by each contraction of the ventricle as a bolus into the
aorta and thus into the bloodstream. The left ventricle does not eject all the blood
it contains with each contraction and so the effciency of the heart is determined
by the percentage of the blood it contains that is actually “ejected” into the blood
The Role of Flaxseed Micronutrients in Blood Vessel and Heart Function 69

FIGURE 4.1 Chambers and valves of the heart. (From mayoclinic.org. With permission.)

circulation with each beat. A normal heart ejection fraction may be between 50%
and 70%. Ejection fraction under 40% may be evidence of “heart failure.”
Just as blood vessels have an endothelial lining that participates in the function of
the vessel, the heart has a parallel inner surface lining, the endocardium. The endo-
cardium consists of a layer of endothelial cells and an underlying layer of connective
tissue. Therefore, the action of the heart, just like that of arterial blood vessels, is
regulated not only by action-hormones but to a great extent by the activity of NO.
And, just like blood vessels, its function is jeopardized by anything that affects the
viability of endothelial cells and eNO formation. Reactive oxygen species (ROS)
come to mind. (2, 3)
70 Flaxseed

The adequacy of the pumping action of the heart also depends on the synchrony
of the sequence of the chamber contractions. One study showed that one form of
asynchrony (arrhythmia), the well-known and not so uncommon atrial fbrillation,
disrupts the formation of NO by the endocardium. Apparently, atrial fbrillation
reduces the ability of the endocardium to form NO as needed, and this can also lead
to stroke. (4)
Blood fowing to the heart proper is delivered by the two-branch (right and left)
coronary arteries encircling the surface of the heart.
When the heart contracts, i.e. systole, the aortic valve opens as it ejects a portion of
the contents of the left ventricle into the aorta. Then the valve closes. Understanding
what happens next is the key to understanding why NO is crucial to blood circula-
tion. But exactly how dependent is heart function on NO availability?
According to a report in Science Daily (May 14, 2018), “Heart disease sever-
ity may depend on nitric oxide levels: Study fnds nitric oxide may also determine
drug effcacy.” (5) The report informs us that not only is NO defciency a key fea-
ture of heart disease but also meds intended to treat it don’t work well when NO is
insuffciently available. The authors of the study on which the report is based state
unequivocally, “In addition, our results point to the possibility that heart failure may
represent different clinical conditions depending on NO bioavailability.” (6)
According to another report in the journal Life Sciences titled “Nitric Oxide and
Cardiac Function,” NO is a key element in the control of heart contractility. (7) In
fact, reduced NO bioavailability imposes an upper limit on myocardial blood fow
regulation and its transmural distribution. (8)

4.2.2 FLAXSEED INCREASES NO BIOAVAILABILITY

Increased NO bioavailability by faxseed supplementation was reported in the
journal Obesity Medicine (in the blood vessels of type 2 diabetes patients). The
investigators concluded that faxseeds may offer vasoprotection. (9) Another
study published in the American Journal of Physiology—Heart and Circulation
Physiology concluded that ground faxseed is rich in L-arginine, and since L-arginine
is converted in the vascular endothelium to NO and citrulline, it increases the bio-
availability of NO. (1)

4.2.3 FLAXSEED OMEGA-3 FATTY ACID, ALPHA-LINOLENIC ACID,

PROMOTES eNO FORMATION
It is not solely for antioxidant properties that we value omega-3 polyunsaturated fatty
acids, but in addition, a key contribution to cardiovascular function is their promo-
tion of eNO formation: alpha-linolenic acid (ALA) improves endothelial function
by increasing NO production by directly stimulating eNO synthase gene and protein
expression. (10)
Many investigators who tout omega-3 fatty acids for heart health seem unaware
of the NO-connection. For instance, in a study titled “The Cardiovascular Effects
of Flaxseed and Its Omega-3 Fatty Acid, Alpha-Linolenic Acid” reported in the
Canadian Journal of Cardiology (used here with permission), we are told,
The Role of Flaxseed Micronutrients in Blood Vessel and Heart Function 71

Preventing the occurrence of cardiovascular disease (CVD) with nutritional interventions

is a therapeutic strategy that may warrant greater research attention. The increased use
of omega (ω)-3 fatty acids is a powerful example of one such nutritional strategy that
may produce signifcant cardiovascular benefts. Marine food products have provided
the traditional dietary sources of ω-3 fatty acids. Flaxseed is an alternative to marine
products. It is one of the richest sources of the plant-based ω-3 fatty acid, alpha-lino-
lenic acid (ALA). Based on the results of clinical trials, epidemiological investigations
and experimental studies, ingestion of ALA has been suggested to have a positive
impact on CVD. Because of its high ALA content, the use of faxseed has been advo-
cated to combat CVD. (11)

No mention is made of the role of omega-3 in promoting NO synthesis.

The website of the Institut de Montreal features an article titled “The Positive
Effects of Flaxseed on Cardiovascular Health.” The author, Martin Juneau, MD,
reports that an average daily intake of 2.2 g of linolenic acid is recommended.
This corresponds to one spoon (15 mL) of faxseed. One needs to grind the seeds
to increase absorption of omega-3 fatty acids and allow lignans to transform into
active phytoestrogens by intestinal bacteria. However, omega-3 fatty acids are very
fragile and sensitive to degradation. Therefore, one should buy whole seeds that can
be ground when needed in a simple seed grinder and store the ground seeds in an
airtight container in the refrigerator for at least two weeks. He further tells us that
the ground seeds have a slightly nutty favor that goes well with cereals, yogurts and
smoothies and can even be used as a salad topping. (12)
Many other studies have reported that faxseed has recently gained attention in
connection with cardiovascular disease because it is the richest known source of
both ALA and the phytoestrogen, lignans, as well as being a good source of solu-
ble fber. Human studies have shown that faxseed can reduce serum total and low-
density lipoprotein cholesterol concentrations, reduce postprandial glucose absorption,
decrease some markers of infammation and raise serum levels of the omega-3 fatty
acids, ALA and eicosapentaenoic acid. (13)

4.2.4 FLAXSEED IMPROVES THE EJECTION FRACTION

In a study published in the Journal of Pharmacology and Experimental Therapeutics,
the investigators report that in the in vivo myocardial infarction model, secoisolarici-
resinol diglucoside (SDG) from faxseed increased capillary density and myocardial
function as evidenced by increased fractional shortening and ejection fraction. (14)
Fractional shortening is the percentage of size differences of the left ventricle as a
measure of how well it is contracting and therefore reducing in size during systole.
Values greater than 28% are considered to be normal. SDG is an antioxidant phy-
toestrogen present in fax, sunfower, sesame and pumpkin seeds.
A year later, these investigators reported in the Journal of Molecular and Cellular
Cardiology that they observed signifcant improvement in left ventricular func-
tions in a hypercholesterolemic patient group given SDG (HSDG) as evidenced by
increased ejection fraction (55% vs. 45%), fractional shortening (28% vs. 22%) and
decreased left ventricular inner diameter in systole (8 mm vs. 6 mm) as compared to
a control group (HC). (15)
72 Flaxseed

4.3 ARTERIAL VESSEL COMPLIANCE

During the systole phase of the heartbeat, the heart muscle contracts and pumps
blood from the left chamber into the aorta. But the aorta is not devoid of blood. And
so the volume of the bolus ejected into the aorta is added to the volume of blood
that is still there after the last systole. As a consequence, the vessel momentarily
distends—bulges outward, as it were—as shown in Figure 4.2A.
Shortly thereafter, and before the next systole, the wall of the aorta recoils return-
ing the vessel to its previous confguration, as shown in Figure 4.2B.
This successive peristalsic stretch/distention and subsequent recoil pumps blood
along in the circulatory system. The sole, albeit by no means lesser role of the heart in
blood circulation is the ejection of the bolus from the left ventricle into the blood vessel.
The key to how all this works, and therefore the key to blood pressure is “compliance,”
i.e. the fexibility or distensibility of the vessel wall, i.e. the capacity to distend as a result
of pressure from inside and then return to its original shape. Clearly, rigidity such as that
due to atherosclerosis and other factors such as those related to aging impair compliance.
Figure 4.3 illustrates the change in a blood vessel due to compliance in normal
elastic arteries vs. that in stiff/rigid arteries.
How dependent is arterial compliance on NO? The authors of a study published
in the journal Hypertension concluded that in human peripheral conduit arteries, the
adaptation of smooth muscle tone and arterial stiffness during blood fow variations
is regulated by the vascular endothelium through the release of eNO. (18) Here again,

FIGURE 4.2 Distention of the aorta following systole and recoil of the aorta during dias-
tole. [From Serino. (No date) Cardiovascular System: Circulation pathways and BP regula-
tion. https://slideplayer.com/slide/14264710/; accessed 12/15/21. (16) With permission.]
The Role of Flaxseed Micronutrients in Blood Vessel and Heart Function 73

FIGURE 4.3 Schematic representation of the role of arterial compliance (i.e., the inverse
of arterial stiffness) in dampening blood pressure pulsatility and assuring adapted blood
fow through the peripheral circulation. [(17) Briet, Boutouyrie, Laurent et al. 2012. Kidney
International. With permission.]

the importance of faxseed supplementation is emphasized because it is a known

NO-donor and without minimizing the antioxidant and other micronutrient constitu-
ents properties that beneft blood vessels.

4.3.1 FLAXSEED OIL PROMOTES ARTERIAL BLOOD VESSEL

ELASTICITY (COMPLIANCE)
Because the compliance or elasticity of arterial blood vessels diminishes with increas-
ing cardiovascular risk and, conversely, systemic arterial compliance improves through
the eating of fsh and fsh oil, investigators tested the value of high intake of ALA,
the plant precursor of fsh fatty acids.
Obese people with markers for insulin resistance ate, in turn, four diets of four
weeks duration each: saturated/high fat (SHF), alpha-linolenic acid/low fat (ALF),
oleic/low fat (OLF) and then SHF again. Daily intake of ALA was 20 grams from
margarine products based on fax oil. Systemic arterial compliance was calculated
from aortic fow velocity and aortic root driving pressure. Plasma lipids, glucose
tolerance and in vitro LDL oxidizability were also measured.
Systemic arterial compliance rose signifcantly with ALF; systemic arterial
compliance with OLF was lower than with ALF. Mean arterial blood pressures and
results of oral glucose tolerance tests were similar during ALF, OLF and second
SHF; total cholesterol levels were also not signifcantly different. However, insulin
sensitivity and high-density lipoprotein (HDL) cholesterol diminished and LDL
oxidizability increased with ALF. The marked rise in arterial compliance at least
with ALA refected rapid functional improvement in the systemic arterial circulation
despite a rise in LDL oxidizability.
74 Flaxseed

The investigators concluded that dietary omega-3 fatty acids in fax oil improve
arterial function. (19)
In the following study, investigators sought to determine the effect of L-arginine
on arterial stiffness and oxidative stress in people with chronic kidney disease (CKD):
Thirty patients with stage II to IV CKD were administered 9 grams of L-arginine per
day orally for a period of 12 weeks.
The parameters evaluated at baseline, at eight weeks, and at the end of 12 weeks
were serum nitric oxide (NO), carotid-femoral pulse wave velocity (cf PWV) and
radial artery pulse wave analysis, which included aortic augmentation pressure (AP),
aortic augmentation index (AIx) at a heart rate of 75 bpm, subendocardial viability
ratio, radial pressures and central aortic pressure. Serum levels of NO and malondi-
aldehyde (MDA) were estimated at baseline and at the end of 12 weeks. The control
group was composed of age- and sex-matched healthy individuals. Baseline NO levels
were low in all the participants.

• The carotid-femoral pulse wave velocity (cf PWV) is a measure of

arterial stiffness determined from the time taken for the arterial
pulse to propagate from the carotid to the femoral artery.
• The aortic augmentation pressure (AP) is the contribution that wave refec-
tion makes to systolic arterial pressure. It is an indirect measure of arterial
stiffness and is calculated as AG divided by pulse pressure (PP) ×100.
• The AIx is derived from the aortic pressure waveform and is calcu-
lated as aortic augmentation from the initial peak or shoulder to
peak pressure divided by pulse pressure.
• MDA: Free radicals generate the lipid peroxidation process in an
organism. MDA is one of the fnal products of polyunsaturated fatty
acids peroxidation in the cells.

Administration of L-arginine resulted in improvement in the carotid-radial pulse

wave velocity (crPWVr), cf PWV, AIx, AP, and NO. There was no signifcant change
in the levels of MDA.
The investigators concluded that PWV, an indicator of arterial stiffness, is greatly
increased even in the early stages of CKD. But supplementation of L-arginine is
a safe, well tolerated and effective way of improving endothelial dysfunction in
patients with CKD. (20)
Although L-arginine was not derived from faxseed in the aforementioned study,
it is cited in context—i.e., eNO improves arterial blood vessel compliance and other
pulse wave parameters. Compliance can be observed indirectly in the arterial wave-
form (see the following section).

4.4 THE ARTERIAL WAVEFORM

The arterial waveform results from the dynamic interactions between the volume
of blood ejected by the heart during each beat, the speed with which this volume is
ejected by the heart, the ability of the vascular tree to distend and accommodate this
The Role of Flaxseed Micronutrients in Blood Vessel and Heart Function 75

ejected volume and the rate at which the ejected volume of blood is able to fow away
from the central arterial compartment into the peripheral tissues. (21)
Compliance can be observed as the extent of the “dichrotic notch.” The dicrotic notch
is a prominent and distinctive feature of the pressure waveform in the central arteries.
It is universally used to demarcate the end of systole and the beginning of diastole in
these arteries. It is seen as a secondary upstroke in the descending part of a pulse tracing
corresponding to the transient increase in aortic pressure when the aortic valve closes.
The arterial pulse waveform can be separated into three distinct components:

• The systolic phase characterized by a rapid increase in pressure to a peak,

followed by a rapid decline. This phase begins with the opening of the
aortic valve and corresponds to the left ventricular ejection.
• The dicrotic notch, which is widely believed to represent the closure of the
aortic valve.
• The diastolic phase, which represents the runoff of blood into the peripheral
circulation.

FIGURE 4.4 Arterial pulse waveform over one cardiac cycle. The waveform can be sepa-
rated into anacrotic (upstroke) and dicrotic (downstroke) limbs. [(22) derangedphysiology.
com. With permission.]
76 Flaxseed

However, it is now generally believed that the peripheral dicrotic notch owes more of
its shape to the vascular resistance of peripheral vessels, i.e. compliance, than simply
as a marker of the closing of the aortic valve.
So we can assess the effectiveness of heart function by estimating the ejection
fraction. We can further determine the effectiveness of the arterial vascular system
by estimating compliance. In addition, we can assess the status of arterial blood
vessels by measuring blood fow. (23) All of these assessment means can be used
to evaluate endothelial/endocardial function and the impact of NO defciency on
systemic or regional blood fow. By the same token, they also refect the benefts of
faxseed supplementation or the benefts of supplementing its constituents singly.
The journal Physiological Reports published a clinical study in 2015 titled
“Effect of Omega-3 Polyunsaturated Fatty Acid Supplementation on Central Arterial
Stiffness and Arterial Wave Refections in Young and Older Healthy Adults.” Based
on changes in pulse waveform, the authors concluded that 12 weeks of daily omega-3
supplementation decreases central arterial stiffness (cf PWV) in older adults. (44)
In a clinical study titled “The Effect of L-Arginine on Arterial Stiffness and
Oxidative Stress in Chronic Kidney Disease,” published in the Indian Journal of
Nephrology in 2012, the investigators concluded that, based on PWV measures of
arterial stiffness, supplementation of L-arginine is a safe, well tolerated and effective
way of improving endothelial dysfunction in patients with CKD. (45)

4.5 MEASURING BLOOD FLOW BY FLOW-MEDIATED

DILATION (FMD)
One of the most common methods for assessing the effect of raising NO availability is
by examining its corresponding effects on regional blood fow. That effect is typically
observed in the brachial artery with the method known as fow-mediated dilation (FMD).
FMD is an indirect, noninvasive measure of blood vessel health. The primary
cause of FMD is the release of nitric oxide (eNO) by endothelial cells, and in clinical
application, there is ultrasound imaging to evaluate brachial artery dilation follow-
ing a transient period of forearm ischemia.
Here is how the method of observing FMD is described in a report in the British
Journal of Clinical Pharmacology. During reactive hyperaemia,* induced by cuff
infation and then defation, the diameter of the artery is measured by high-resolution
ultrasound in response to an increase in blood fow causing shear stress. Reactive hyper-
aemia leads to endothelium-dependent dilatation. The response of the blood vessel is
contrasted with the response to sublingual nitroglycerin, an endothelium-independent
dilator. The artery is scanned and the diameter measured during two conditions: (1) at
baseline, during reactive hyperaemia induced by infation and then defation of a sphyg-
momanometer cuff around the limb, distal to the scanned part of the artery; (2) after
administration of sublingual nitroglycerin using a normal antianginal dose of 400 μg,
which causes endothelium-independent smooth muscle mediated vasodilatation.

* Reactive hyperemia is the excess blood that fows through a blood vessel following the cir-
culation arrest and subsequent restoration of the blood supply. “Hyperaemia” is an archaic
form of the word.
The Role of Flaxseed Micronutrients in Blood Vessel and Heart Function 77

It can take between one and ten minutes to obtain a high-quality baseline scan.
The cuff infation period of fve minutes was initially decided to produce adequate
hyperaemia to allow fow-mediated dilatation, but not to compromise patient comfort.
Shorter infation periods do not seem to produce signifcant fow-mediated dilata-
tion. The usual scanning period used in their laboratory is 30 seconds before and 90
seconds after the cuff defation. (24)
FMD compares the response of the brachial artery, after compression to stem
blood fow, when given nitroglycerin, a vasodilator substance, and to endothelium-
derived NO. Nitroglycerin is a vasodilator because it is a NO-donor. So the test
basically asks the question, If I administer a NO-donor, what is the blood vessel
response? If I ask the endothelium to supply the NO, how well can it do that by com-
parison? The description of the previous method is pretty much conventional, but
there are published variations in application details.
A study published in the American Journal of Cardiology found FMD to be an excel-
lent predictor of long-term adverse cardiovascular events. Participants with below-mean
FMD were 278% more likely to experience cardiovascular “events” during the 4.6-year
average follow-up period than participants with above-mean FMD. (25) The importance
of this information is that it points to the fact that eNO formation is an important clue to
cardiovascular health insofar as low eNO availability is an indication of cardiovascular
pathophysiology. In addition, enhancing NO formation and availability is now a viable
treatment modality both pharmacologically and by nonprescription means.
Does FMD depend on NO? It does. At least to some extent according to a report
based on meta-analysis. (26)

4.5.1 FLAXSEED AND L-ARGININE IMPROVE FMD

A number of publications report that fax improves FMD. Keep in mind that FMD is
mediated by eNO and thus refects the patency of endothelial function.
The purpose of a study published in the European Journal of Clinical Nutrition
was to examine the effect of faxseed consumption on FMD and infammatory
markers in coronary artery disease (CAD) patients. Fifty patients of both genders
with CAD were randomly allocated to 12 weeks consumption of faxseed (30 grams/
day) or usual care control. Before and after the intervention, changes in brachial
FMD and plasma high-sensitivity C-reactive protein (hs-CRP),* interleukin-6 (IL-6)
and tumor necrosis factor-α (TNF-α) were measured.
It was found that though no signifcant weight changes were observed in either
group, faxseed consumption resulted in improved FMD. Furthermore, when com-
pared to control participants, faxseed consumption was associated with reduced
infammatory markers (signifcant mean change from baseline for hs-CRP, IL-6, and
TNF-α). The authors concluded that by adding faxseed to the diets of CAD patients, it
is possible to improve FMD and to lower plasma levels of infammatory markers. (27)

• The high-sensitivity C-reactive protein (hs-CRP) test detects lower

blood levels of C-reactive protein (CRP), a marker of infammation.
78 Flaxseed

• IL-6, Interleukin 6, is an interleukin that acts as both a proinfam-

matory cytokine and an anti-infammatory myokine. It is a multi-
functional cytokine that plays a central role in host defense due to
its wide range of immune and hematopoietic activities and its potent
ability to induce the acute-phase response.
• TNF-α, tumor necrosis factor-a, is a cytokine, a small protein used by
the immune system for cell signaling. If macrophages detect stressors
such as an infection, they release TNF to alert other immune system
cells as part of an infammatory response.

In a study published in the Journal of the American College of Nutrition, the investi-
gators aimed to determine the effects of ALA (from walnuts and faxseed) on cardio-
vascular responses to acute stress; FMD of the brachial artery; blood concentrations
of endothelin-1, a potent vasoconstrictor encoded by the EDN1 gene and produced by
vascular endothelial cells; and arginine-vasopressin (AVP) (an antidiuretic hormone).
The diets signifcantly reduced diastolic blood pressure and total peripheral resis-
tance, and this effect was evident at rest and during stress. FMD increased by 34%
in the diet containing additional ALA. (28) Walnuts, parenthetically, are very high
in L-arginine: dried walnuts contain 4.522 grams per cup. One cup of faxseeds con-
tains about 3.23 grams of L-arginine.
Aging is associated with normal progressive endothelial dysfunction as evidenced
by studies of impairment of FMD of the brachial artery. This is a hallmark in the
elderly with cardiovascular disease and reduced vascular NO bioavailability. The
aim of a study published in the journal Vascular Medicine, in 2003, was to determine
whether oral L-arginine can improve impaired FMD in healthy very old people.
Healthy participant 73.8 ± 2.7 years old took 8 g p.o. two times daily L-arginine
or placebo for 14 days each, separated by a wash-out period of 14 days. It was found
that L-arginine signifcantly improved FMD, whereas the placebo had no effect.
Because NO synthesis can be antagonized by its endogenous inhibitor asymmetric
dimethyl L-arginine (ADMA), ADMA plasma concentrations were determined and
shown to be elevated at baseline in comparison to healthy middle-aged individuals.
ADMA remained unchanged during treatment, but L-arginine supplementa-
tion signifcantly normalized the L-arginine/ADMA ratio. It was concluded that
in healthy very old age endothelial function is impaired and may be improved by
oral L-arginine supplementation, probably due to normalization of the L-arginine/
ADMA ratio. (46)

ADMA is a naturally occurring metabolic by-product of continual protein

modifcation processes in the cytoplasm of all human cells. Found in blood
plasma, it is closely related to L-arginine. ADMA levels rise with “poor” diet/
lifestyle, elevated LDL cholesterol, high blood sugar, high blood pressure or
smoking—the usual cardiovascular risk suspects.
The Role of Flaxseed Micronutrients in Blood Vessel and Heart Function 79

4.6 ENDOTHELIAL NITRIC OXIDE (eNO) AND CONTROL

OF BLOOD PRESSURE
Hypertension is a major risk factor for cardiovascular disease and kidney failure, and
reducing elevated blood pressure signifcantly reduces those risks. Dysfunctional
endothelium and reduced bioavailability of NO have been shown in hypertensive
individuals to be dependent on the duration and severity of arterial hypertension.
(29) Both endothelium-independent and endothelium (NO)-dependent systems con-
trol blood pressure and blood fow.

4.6.1 ENDOTHELIUM-INDEPENDENT CONTROL OF BLOOD PRESSURE

In brief, the renin-angiotensin-aldosterone system of the kidneys regulates blood vol-
ume. In response to rising blood pressure, the kidneys secrete renin into the blood.
Renin converts the plasma protein angiotensinogen into angiotensin I, which in turn
is converted into angiotensin II by enzymes from the lungs. Angiotensin II activates
two mechanisms that raise blood pressure:
Angiotensin II constricts blood vessels throughout the body, raising blood pres-
sure by increasing resistance to blood fow. Constricted blood vessels reduce the
amount of blood delivered to the kidneys, which decreases the kidneys’ potential to
excrete water, raising blood pressure by increasing blood volume.
Angiotensin II stimulates the adrenal cortex to secrete aldosterone, a hormone
that reduces urine output by increasing retention of water and sodium by the kidneys,
raising blood pressure by increasing blood volume.
Various substances infuence blood pressure: Epinephrine and norepinephrine, which
are hormones secreted by the adrenal medulla, raise blood pressure by increasing
heart rate and the contractility of the heart muscles and by causing vasoconstriction
of arteries and veins.
Antidiuretic hormone produced by the hypothalamus and released by the posterior
pituitary raises blood pressure by stimulating the kidneys to retain water, thus raising
blood pressure by increasing blood volume.
Atrial natriuretic peptide, a hormone secreted by the atria of the heart, lowers
blood pressure by causing vasodilation and by stimulating the kidneys to excrete
more water and sodium thus lowering blood pressure by reducing blood volume.

4.6.2 ENDOTHELIUM-DEPENDENT CONTROL OF BLOOD PRESSURE

It is now increasingly evident that endothelial dysfunction, which is characterized
by impairment of NO bioavailability, is an important risk factor for hypertension,
cardiovascular and kidney disease. NO is a vasodilator that controls blood fow in
response to regional blood fow and tissue oxygenation demands.
It has been shown that NO plays a major role in regulating blood pressure and
that impaired NO availability can lead to hypertension. Clinical studies have
shown that patients with hypertension show reduced arterial vasodilation response
to infusion of endothelium-dependent vasodilators such as nitroglycerin and that
inhibition of eNO formation raises blood pressure. Impaired NO formation and
80 Flaxseed

availability is also implicated in arterial stiffness, a major mechanism of systolic

hypertension. (30)
Clearly, NO also regulates resting blood vessel tone, adaptation of blood fow to
metabolic demand and adaptation of vessel diameter to volume of infow, i.e., FMD.

Vascular “tone” describes the degree of smooth muscle contraction of an

arterial blood vessel.

Arterial hypertension is associated with an increased vascular tone of resistance

vessels and a reduced compliance of conduit arteries, along with a thickening of the
intima-media leading to vascular “remodeling.”

4.6.3 INTERACTION OF ENDOTHELIUM-INDEPENDENT AND ENDOTHELIUM-

DEPENDENT BLOOD FLOW CONTROL SYSTEMS
A review appearing in the journal Pharmacology and Therapeutics concludes that
endothelium-dependent NO and the autonomic nervous system mechanisms interact
in the control of blood fow and in cardiovascular regulation, both in experimental
animals and in humans. In fact, NO interacts with the autonomic nervous system
both at the central level and peripherally.
The primary effect of NO in humans is a reduction of basal sympathetic vasocon-
strictor tone rather than inhibition of the excitability of this system. Impaired NO
synthesis in humans, therefore, promotes sustained vasoconstriction by two distinct
mechanisms. One is loss of vasodilator tone at vascular smooth muscle cells and the
other is by facilitating central neural vasoconstrictor outfow. Insulin resistance, essen-
tial hypertension and end-stage renal failure are examples of diseases, where impaired
NO buffering of neural outfow may contribute to sustained sympathetic activation.
In addition to the sympathetic nervous system, NO also interacts with the cholin-
ergic nervous system. Cholinergic mechanisms play a major hitherto unrecognized
role in offsetting the arterial hypertension and cardiac sympathetic activation caused
by inhibition of NO synthesis in normal humans. The investigators concluded that
there may be benefts in the use of therapeutic interventions that deliver NO and/or
modulate the bioavailability of endogenously produced NO to adjust the autonomic
control of the circulation in humans. (31)
Many journal publications conclude, as did the authors of the one cited earlier, that
“there may be benefts in the use of therapeutic interventions that deliver NO and/or
modulate the bioavailability of endogenously produced NO” to whatever ends. It is
becoming increasingly clear that faxseed per se, omega-3 fatty acids, and L-arginine
are precisely the interventions they are looking for. These interventions do exactly what
they are looking for, i.e., rectify endothelium damage and increase NO bioavailability.

4.6.4 THE ROLE OF NO IN VASCULAR REMODELING IN HYPERTENSION

Hypertension causes permanent changes in blood vessels, such as vascular remodeling,
changes in the structure of resistance vessels contributing to elevated systemic
The Role of Flaxseed Micronutrients in Blood Vessel and Heart Function 81

resistance and compliance. Vascular remodeling involves changes in at least four

cellular processes: cell growth, cell death, cell migration and the synthesis or deg-
radation of extracellular matrix. It occurs in response to long-standing changes in
hemodynamic conditions. (32)
Atherosclerotic narrowing of the arterial lumen is not simply due to enlarge-
ment of atherosclerotic lesions. (33) Instead of simply remodeling the narrowed
lumen, arteries undergo many changes, such as increasing the outside diameter, to
preserve blood fow. This adaptability of the arteries is essential in arterial diseases.
As with atherosclerotic coronary disease, peripheral vascular disease and hyperten-
sion may be considered a failure of the arterial wall to maintain a suitable mesh
size to allow normal blood fow. It has been proposed that the inability of vessels
to remodel is a “vascular insuffciency,” similar to that observed in the heart during
heart failure.
Hypertension elicits two different kinds of diffuse structural changes in the sys-
temic microcirculation. One, “rarefaction,” consists of an abnormally low spatial den-
sity of arterioles, capillaries and, possibly, venules. The other consists of structural
modifcations of resistance small arteries and arterioles, which lead to a reduction in
lumen diameter and are grouped under the generic name of “remodeling.” (34)
While it is well-known that the vascular endothelium mediates the ability of
blood vessels to alter their architecture in response to hemodynamic changes, the
specifc endothelial-derived factors that are responsible for vascular remodeling are
unknown. But it is emerging that eNO is a major endothelial-derived mediator con-
trolling vascular remodeling.
For instance, a study in the Journal of Clinical Investigation reported that in
response to external carotid artery ligation, mice with targeted disruption of the
endothelial nitric oxide synthase (eNOS) gene did not remodel their ipsilateral com-
mon carotid arteries, whereas wild-type mice did. The eNOS mutant mice displayed
a paradoxical increase in wall thickness accompanied by a hyperplastic response of
the arterial wall. These fndings demonstrate a critical role for endogenous NO as
a down regulator of vascular smooth muscle proliferation in response to a remodel-
ing stimulus. Furthermore, the data suggested that a primary defect in the NOS/NO
pathway can promote abnormal remodeling and may facilitate pathological changes
in vessel wall morphology associated with complex diseases such as hypertension
and atherosclerosis. (35)
Likewise, a study published in the journal Hypertension concluded that reduced
blood fow in hypertensive animals promotes hypertrophy by enhancing smooth
muscle cell (SMC) proliferation via mechanisms that reduce the inhibitory effects of
NO on SMC proliferation. (36)
NO as a critical regulator of vascular remodeling has also been reported in the
journal Human Genetics ’99: The Cardiovascular System. The authors contend that
pharmacologic studies using inhibitors of the enzyme, NOS, have implicated NO as
an important endothelial mediator of fow- or pressure-induced arterial remodeling.
Long-term treatment of rats with the NOS inhibitor, nitro-l-arginine methyl ester,
causes a sustained increase in systemic blood pressure accompanied by marked
microvascular remodeling, as judged by an increase in wall-to-lumen ratios of
coronary arteries. (37)
82 Flaxseed

In light of the desirability to avoid the notably adverse structural changes of blood
vessels in hypertension, maintaining NO bioavailability is of prime concern. That
can apparently also be accomplished by faxseed supplementation in order to sup-
ply the substrates L-arginine and cyanogenic glycosides, proven NO-donors. And
omega-3 PUFAs can also play a benefcial role:
A review titled “Omega-3 Polyunsaturated Fatty Acids: Structural and Functional
Effects on the Vascular Wall” was published in the journal BioMed Research
International in 2015. The authors contend that by targeting both arterial wall stiff-
ness and endothelial dysfunction, omega-3 PUFAs have the potential to benefcially
impact arterial wall remodeling and cardiovascular outcomes. Furthermore, their
effects on systemic infammation, modulation of lipid profle and platelet aggregation
are additionally thought to contribute to the reduction of cardiovascular risk. (47)

4.6.5 FLAXSEED COMBATS HYPERTENSION

The purpose of a meta-analysis titled “Flaxseed Consumption May Reduce Blood
Pressure: A Systematic Review and Meta-Analysis of Controlled Trials,” reported
in the Journal of Nutrition, was to clarify the effect of faxseed consumption on
blood pressure. The search centered on PubMed (Medline), Cumulative Index to
Nursing and Allied Health Literature, and Cochrane Library (Central) through July
2014 for studies in which humans supplemented their habitual diet with faxseed or
its extracts (i.e., oil, lignans, fber) for ≥ two weeks.
It was found that faxseed supplementation reduced systolic blood pressure and
diastolic blood pressure. These results were not infuenced by categorization of par-
ticipants into higher baseline blood pressure (≥130 mm Hg). An improvement in
diastolic blood pressure was observed in subgroup analysis for consuming whole
faxseed and duration of consumption ≥12 weeks.
It was concluded that consumption of faxseed may lower blood pressure some-
what. The benefcial potential of faxseed to reduce blood pressure (especially dia-
stolic blood pressure) may be greater when it is consumed as a whole seed and for a
duration of >12 weeks. (38)
The purpose of a subsequent study reported in the journal Hypertension was to
determine the effects of daily consumption of a variety of foods that contained 30
grams of milled faxseed, or placebo, each day over six months, on systolic blood pres-
sure (SBP) and diastolic blood pressure (DBP) in peripheral artery disease patients.
Plasma levels of the omega-3 fatty acid, ALA and enterolignans, increased 2- to 50-fold
in the faxseed-fed group but did not increase signifcantly in the placebo group.
Patients’ body weight was not signifcantly different between the two groups at
any time. After six months, SBP was ≈ 10 mm Hg lower and DBP was ≈ 7 mm Hg
lower in the faxseed group, compared to the placebo.
Patients who entered the trial with an SBP ≥ 140 mm Hg at baseline experienced a
signifcant reduction of 15 mm Hg in SBP, and 7 mm Hg in DBP from faxseed inges-
tion. The antihypertensive effect was achieved selectively in hypertensive patients.
Circulating ALA levels correlated with SBP and DBP, and lignan levels correlated
with changes in DBP.
In summary, faxseed induced one of the most potent antihypertensive effects
achieved by a dietary intervention. (39)
The Role of Flaxseed Micronutrients in Blood Vessel and Heart Function 83

The following meta-analysis published in the journal Clinical Nutrition aimed

to determine the effects of faxseed supplements on blood pressure. The search
included PUBMED, Cochrane Library, Scopus and Embase up to February 2015 to
identify randomized control trials (RCTs) investigating the effect of faxseed supple-
ments on plasma blood pressure.
It was found that there was a greater effect on both SBP and DBP in the subset of
trials with ≥12 weeks of duration vs. the subset lasting <12 weeks. Another subgroup
analysis was performed to assess the impact of faxseed supplement type on blood
pressure. Reduction of SBP was signifcant with faxseed powder but not oil and
lignan extract. However, DBP was signifcantly reduced with powder and oil prepa-
rations but not with lignan extract.
The investigators concluded that this meta-analysis showed signifcant reductions
in both SBP and DBP following supplementation with various faxseed products. (40)
In a 2020 review titled “The Effects of L-Arginine in Hypertensive Patients: A
Literature Review,” the authors report a modest decrease in blood pressure with
L-arginine supplementation but a greater decrease in blood pressure in hyperten-
sive patients or those with endothelial dysfunction. L-Arginine supplementation has
also shown benefts in renal hypertension where there is usually poor endothelial
function, a condition that can be recovered by the supplementation of L-arginine.
Furthermore, studies show that supplementation of L-arginine improves patients
with diabetes mellitus and those with congestive heart failure. (48)

4.7 FLAXSEED COMBATS PERIPHERAL ARTERY DISEASE (PAD)

Peripheral artery disease (PAD) in the legs or lower extremities is the narrowing or
blockage of the vessels that carry blood from the heart to the legs. It is primarily
caused by the buildup of fatty plaque in the arteries, i.e., atherosclerosis. It should not
be surprising to learn that faxseed is helpful in the treatment of PAD because it had
already been shown that so is L-arginine—because it is a NO-donor.
But frst, in a report in the journal Circulation, investigators tell us that asymmetric
dimethylarginine (ADMA) levels are increased in people with hypercholesterolemia,
atherosclerosis, hypertension, chronic heart failure, diabetes mellitus and chronic
renal failure. In a study published in the journal Circulation, investigators report
strong evidence for impaired NOS in patients with PAD. ADMA concentrations
were notably elevated in their PAD patients. (41) But in a subsequent clinical study, a
subgroup of these investigators found that the symptoms of intermittent claudication
in patients with PAD could be diminished by administration of L-arginine thus
improving the condition.

Intermittent claudication is pain affecting the calf, and less commonly the
thigh and buttock, that is induced by exercise and relieved by rest.

Patients with intermittent claudication were assigned to receive 2 × 8 grams of L-

arginine/day, or 2 × 40 micrograms of prostaglandin E1 (PGE1)/day or no
84 Flaxseed

hemodynamically active treatment, for three weeks. The pain-free and absolute
walking distances were assessed on a walking 12% slope treadmill at 3 km/h and
NO-mediated, FMD of the femoral artery was assessed by ultrasonography at base-
line, at one, two and three weeks of therapy and six weeks after the end of treatment.
L-Arginine increased the pain-free walking distance by 230 ± 63% and the abso-
lute walking distance by 155 ± 48%. Prostaglandin E1 improved both parameters
by 209 ± 63% and 144 ± 28%, respectively, whereas control patients experienced no
signifcant change. L-Arginine therapy also improved endothelium-dependent vaso-
dilation in the femoral artery (FMD), whereas PGE1 had no such effect.
There was a signifcant linear correlation between the L-arginine/ADMA ratio
and the pain-free walking distance at baseline. L-Arginine treatment elevated the
plasma L-arginine/ADMA ratio and increased urinary nitrate and cyclic GMP
excretion rates, indicating normalized endogenous NO formation. Prostaglandin
E1 therapy had no signifcant effect on any of these parameters. The investigators
concluded that restoring NO formation and endothelium-dependent vasodilation by
L-arginine improves the clinical symptoms of intermittent claudication in patients
with peripheral arterial disease. (42)

Prostaglandin E1, Alprostadil, a medication, is used as a smooth muscle

relaxant and vasodilator.

A number of clinical studies support the benefcial effects of faxseed and its con-
stituents in PAD. For instance, there is enough interest in its possible benefts in
PAD to even warrant an ongoing trial called FLAX-PAD reported in the journal
Contemporary Clinical Trials in 2011. However, so far we know only from that trial
that in PAD patients fed 30 g of milled faxseed every day for six months, blood pres-
sure dropped signifcantly. (49)
There is a school of thought that a number of cardiovascular disorders are in
fact omega-3 defciency diseases. A recent study reported that individuals diagnosed
with PAD have a lower Omega-3 Index compared to those who don’t have that dis-
ease. The study titled “Peripheral Artery Disease Is Associated with a Defciency
of Erythrocyte Membrane n-3 Polyunsaturated Fatty Acids” was published in the
journal Lipids in 2019. (50)
The omega index is a measure of erythrocyte (red blood cells) membrane omega-3
concentration as a percentage of total fatty acids. (51)
There are clinical studies on the effects of L-arginine supplementation in PAD.
Some support supplementation while others don’t. One of the “don’ts” is titled “Nitric
Oxide in Peripheral Arterial Insuffciency—NO-PAIN” (June 28, 2007). It appears
on the website of the American College of Cardiology (ACC) (www.acc.org/latest-
in-cardiology/clinical-trials/2010/02/23/19/12/nopain; accessed 1/19/22). It reports a
trial that aimed to determine the effect of long-term therapy with oral L-arginine on
vascular reactivity and functional capacity in patients with intermittent claudication
due to PAD. It was found that the patients actually got worse on 3 g per day of oral
L-arginine for six months.
The Role of Flaxseed Micronutrients in Blood Vessel and Heart Function 85

According to a report titled “Variations in L-arginine Intake According to Demo-

graphic Characteristics and Cardiovascular Risk,” published in the journal Nutrition
Research in 2008, the average dietary L-arginine intake for the US adult population
is 4.40 g/day. A daily dosage of oral L-arginine of 3 grams is less than the average
American consumes in meals daily. Typical clinical dosages hover around 9 g/day. (52)
The Mayo Clinic website recommends L-arginine for PAD (www.mayoclinic.org/
drugs-supplements-l-arginine/art-20364681; accessed 1/19/22). But it does not say
how much one should take.
Here is a study that seemed to have somewhat better success: In a pilot study of
L-arginine supplementation on functional capacity in peripheral arterial disease pub-
lished in the journal Vascular Medicine, in 2005, patients were assigned to oral doses
of 0, 3, 6 or 9 g of L-arginine daily in three divided doses for 12 weeks. No signifcant
differences were observed in absolute claudication distance between the treatment and
the control groups. However, a trend was observed for a greater increase in walking
distance in the group treated with 3 g L-arginine daily, and there was a trend for an
improvement in walking speed in patients treated with L-arginine. (53)

4.8 SUMMARY
Endothelium-derived nitric oxide (eNO), an intrinsic vasodilator, is essential to the
control of blood fow and heart function. It is ordinarily derived in the body from
the amino acid L-arginine. eNO defciency is implicated in blood vessel compliance
and heart and blood vessel diseases, including PAD. Supplementing L-arginine has
been clinically proven to correct defciency and restore function. But supplementing
faxseed has likewise proven clinically effective in treating blood vessel and heart
diseases because, like L-arginine, it is a NO-donor.

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 5 Omega-3 Fatty
Acids and NO from
Flax Intervention in
Atherosclerosis and
Chronic Systemic
Inflammation

5.1 ATHEROSCLEROSIS
Atherosclerosis is a life-threatening predominantly asymptomatic pandemic condi-
tion, a known health hazard that is responsible for more annual deaths in the United
States than COVID-19. It is the thickening, and therefore hardening, of the arteries
caused by a buildup of plaque in the blood vessel wall. A lipoprotein-driven dis-
ease, it leads to plaque formation at specifc sites of the arterial tree through intimal
infammation, necrosis, fbrosis and calcifcation. It is said to lead to hypertension,
heart disease and peripheral vascular disease.
Atherosclerosis is concerning because it causes clinical diseases by obstructing
blood fow to the heart (coronary heart disease), to the brain (stroke) or to lower
extremities.
After decades of relatively slow progression, atheromas (plaques) may suddenly
cause life-threatening thrombosis. Most often, the culprit is blood vessel wall rup-
ture with exposure of highly thrombogenic red cell–rich necrotic core material (see
Figure 5.1). What sets the stage for this to occur is an extremely thin fbrous cap, a
layer of fbrous connective tissue that is thicker and less cellular than the normal
intima, containing macrophages and smooth muscle cells.
However, the mechanisms involved in plaque erosion remain largely unknown,
although coronary artery spasm is suspected. (1) Figure 5.1 summarizes how medi-
cine generally understands the nature of atherosclerosis, and it forms the basis for
treatment recommendations. In the fgure, VSMCs stands for vascular smooth mus-
cle cells, and EC stands for endothelial cell.
Figure 5.1 illustrates atherosclerosis and unstable atherosclerotic plaque in aging.
The emphasis is on the rupture of the arterial wall leading to thrombosis. But
though there is no mention of it in that publication, and it is quite apparent in the
illustration, there is another very important aspect of atherosclerosis: Long before
it causes overt cardiovascular and related diseases, it progressively damages the

DOI: 10.1201/b22986-5 89
90 Flaxseed

FIGURE 5.1 Schematic of atherogenesis and an unstable atherosclerotic plaque. The

advanced atherosclerotic plaque consists of a fbrous cap rich in VSMCs and collagen,
surrounding a “necrotic” core comprising lipids, foam cells and debris. Plaque formation
involves a series of events initiated from (1) EC dysfunction and activation with increased
surface adhesion molecules on ECs, including ICAM-1 and VCAM-1, and augmented
vascular permeability promoting the (2) attachment and infltration of lipid and infammatory
cells into the subendothelial space. (3) Monocytes differentiate into macrophages, engulf lipid
to form foam cells and release proinfammatory cytokines (e.g., MCP1, IL-6, IL-1β) to create
an infammatory environment. (4) In early lesions, VSMCs proliferate/migrate in response
to mitogens such as platelet-derived growth factor (PDGF) and synthesize collagen to form
the fbrous cap that encloses the growing lipid core. At later stages, VSMCs undergo senes-
cence and release multiple cytokines as part of the senescence-associated secretory phenotype,
which augments the preexisting infammation. (5) The gradual loss of VSMCs by apoptosis,
in part mediated by engagement of death receptors on VSMCs with death ligands on macro-
phages and T lymphocytes, and increased activity of matrix-degrading enzymes in the cap
result in (6) plaque rupture, with subsequent platelet attachment and thrombosis. Each of the
processes involved in atherogenesis and plaque rupture indicated as (1) to (6) are promoted
by cellular senescence. (Illustration: Cosmocyte/Ben Smith.) [(2) Wang and Bennett. 2012.
Aging and atherosclerosis. Mechanisms, functional consequences, and potential therapeu-
tics for cellular senescence. Circulation Research, Jul 6; 111(2): 111:245–259. https://doi.
org/10.1161/CIRCRESAHA.111.261388.]
Omega-3 Fatty Acids and NO from Flax in Atherosclerosis and CSI 91

endothelium. The “necrotic core” distances the endothelium from its blood supply,
the internal longitudinal vasa vasorum (not shown), thus damaging it and impair-
ing regional eNO formation. What’s more, as plaque forms, atherosclerosis causes
infammation of the vasa vasorum. (3) Infammation impairs NO formation by the
vasa vasorum, on which both the arterial blood vessel and the vasa vasorum actu-
ally depend, and that also facilitates migration of monocytic cells to sites of early
disease. (4)
It is also generally understood that diet and lifestyle factors play a key role in
atherosclerosis. The emphasis is usually on saturated fats in the diet and on alcohol
use, smoking and physical inactivity. But there is now a common understanding
that atherosclerosis is an infammatory disease, and there is substantial scientifc
literature on the role of reactive oxygen species (ROS) in plaque formation, and these
arise largely from mitochondria metabolic activity. In fact, ROS have been shown to
promote atherosclerotic plaque formation. (5)
In fact, investigators contend, in an article published in the journal Molecular
Nutrition and Food Research in 2005, that diet-derived oxidized fatty acids in the
chylomicron remnants formed in the intestine that transport dietary triglyceride to
peripheral tissues and cholesterol to the liver, as well as LDL, accelerate athero-
sclerosis by increasing oxidized lipid levels in circulating LDL and chylomicron
remnants.
This hypothesis is supported by feeding experiments on animals. When rabbits
were fed oxidized fatty acids or oxidized cholesterol, the fatty streak lesions in the
aorta were increased by 100%. Moreover, dietary oxidized cholesterol signifcantly
increased aortic lesions in apo-E and LDL receptor-defcient mice.
A typical Western Diet is rich in oxidized fats and therefore could contribute to
the increased arterial atherosclerosis in our population. (6) In a 1997 animal-model
(rabbits) study titled “Dietary Flax Seed in Prevention of Hypercholesterolemic
Atherosclerosis,” published in the journal Atherosclerosis, the investigator con-
cluded that because of its antioxidant activity, “fax seed supplementation is effective
in reducing hypercholesterolemic atherosclerosis markedly without lowering serum
cholesterol.” (7)
The implication of this study is that concerning atherosclerosis, it is not simply a
matter of amassing serum cholesterol but whether it is or it is not oxidized. Flaxseed
and fax oil antioxidant constituents have been shown to even reverse atherosclerosis
progression (8) and that is now becoming increasingly well-known, albeit not yet
mainstream.
In part, this may be because some of the most convincing studies are conducted
on animal models—rabbits, usually. This, despite the fact that this animal model is
conventional in trials on prescription drugs—like statins—used to combat athero-
sclerosis. Rabbits are subject to diet-induced atherosclerosis just as we are, and they
respond to anti-atherosclerosis therapy in a way similar to the way that we do.
In a study published in the American Journal of Physiology. Heart and Circulatory
Physiology in 2013, investigators aimed to determine the therapeutic potential of
dietary faxseed on atherosclerotic plaque regression and vascular contractile func-
tion in a rabbit model. Rabbits received either a regular diet for 12 weeks (group I)
92 Flaxseed

or a 1% cholesterol-supplemented diet for four weeks, followed by a regular diet for

eight weeks (group II).
The remaining experimental animals were treated as in group II but were fed
for an additional 14 weeks with either a regular diet (group III) or a 10% faxseed-
supplemented diet (group IV).
Animals in group II showed clear evidence of plaque growth stabilization. Their
vessels also exhibited signifcantly lower norepinephrine-induced contraction and
an impaired relaxation response to acetylcholine compared with animals in group I.
Dietary faxseed supplementation resulted in a signifcant ≈40% reduction in plaque
formation. Animals in both groups III and IV displayed improved contraction and
endothelium-dependent vessel relaxation. (9)

5.1.1 THE CAUSAL ROLE OF ROS IN ATHEROSCLEROSIS

According to a report published in the journal Arteriosclerosis, Thrombosis, and
Vascular Biology in 2017, excessive concentrations of lipids result in free radical
formation, and interaction of these molecules with the endothelial wall of the arteries
leads to endothelial infammation. An infamed endothelium recruits infammatory
cells such as monocytes via the expression of various mediators and chemokines.
(10) This in addition to the imbalance of ROS generation leads to monocytes becom-
ing foam cells that consume dead cells and lipids.
This debris eventually develops into a sclerotic fbrofatty plaque, which decreases
the compliance of the vessel, increases the possibility of embolus or thrombus devel-
opment through plaque rupture and, fnally, increases the risk of multiple comor-
bidities. (11) In all of these processes, ROS play a signifcant role in homeostasis of
vascular cells and the pathogenesis of atherosclerosis. (12)
A review published in the journal Frontiers in Cardiovascular Medicine in 2019
concludes that subclinical nonatherosclerotic intimal lesions emerge before the
appearance of pathologic intimal thickening and advanced atherosclerotic plaques.
Intimal thickening is associated with several risk factors, including oxidative stress
due to ROS, infammatory cytokines and lipids. The main ROS producing system in
vivo is reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase
(Nox). (13)
The previous fnding was corroborated in a review published in the journal
Antioxidants in 2017 in which the investigators also report that the major source of
ROS generated within the vascular system is the NADPH oxidase family of enzymes
(Nox), of which seven members have been characterized.
The Nox family are critical determinants of the redox state within the vessel
wall that dictate, in part, the pathophysiology of several vascular phenotypes.* The
journal articles cited highlight the putative role of ROS in controlling what happens
to blood vessels by promoting endothelial dysfunction, altering vascular smooth
muscle phenotype and adversely altering vascular stem cells. (14)

* The phenotype is the observable traits, such as height, eye color and blood type. The genetic
contribution to the phenotype is called the genotype.
Omega-3 Fatty Acids and NO from Flax in Atherosclerosis and CSI 93

5.1.2 OMEGA-3 FATTY ACIDS, AN ANTIOXIDANT FLAXSEED CONSTITUENT

CAN PREVENT, EVEN REVERSE, ATHEROSCLEROSIS
Omega−3 fatty acids, also called omega-3 oils, −3 fatty acids or n−3 fatty acids,
are polyunsaturated fatty acids (PUFAs) found in foods, such as fsh and seeds, and
in dietary supplements, such as fsh oil. The three main omega-3 fatty acids are

• Alpha-linolenic acid (ALA)

• Eicosapentaenoic acid (EPA)
• Docosahexaenoic acid (DHA)

ALA is found mainly in plant oils such as faxseed, soybean, and canola oils. DHA
and EPA are found in fsh—oily fsh such as salmon and mackerel, in particular—
and other seafood. It is an essential fatty acid—the body can’t make it—and it must
be obtained from the foods and beverages we consume. The body can convert some
ALA into EPA and then to DHA, but only in very small amounts. Therefore, get-
ting EPA and DHA from foods and dietary supplements is the only practical way
to increase levels of these omega-3 fatty acids in the body. Omega-3s are important
components of cell membranes.
Consuming faxseed can provide ALA to the circulation and tissues of the body.
But what is the human requirement for omega-3 PUFAs? One source recommended
a daily intake of 2.22 grams of ALA based on a 2,000 kcal diet. (15) ALA levels rise
as soon as two weeks after the initiation of faxseed supplementation. (16)
The bioavailability of ALA is dependent on the type of fax. Golden faxseeds
have more PUFAs and less monounsaturated fatty acids compared to brown fax-
seeds. They also have larger amounts of the two essential fats that your body isn’t
able to produce: ALA and linoleic acid. ALA has greater bioavailability in oil than
in milled seed and has greater bioavailability in milled seed than in whole seed. (17)
Crushing and milling of faxseed substantially improve the bioavailability of
enterolignans (18) likely due to the improved accessibility of the colon bacteria to
crushed and ground faxseed, the dose of faxseed ingested (19) and the fat compo-
sition of the diet. Concurrent administration of linoleic acid (AKA omega-6, LA)
in the diet will reduce ALA accumulation (19) because of competition among the
enzymes involved in the elongation and desaturation of LA and ALA. EPA and DHA
are more rapidly incorporated into plasma and membrane lipids and produce more
rapid effects than ALA.
Average daily recommended amounts for ALA in grams (g) are listed in Table 5.1
A ratio of alpha-linoleic acid (LA) to ALA of 4:1 or lower is optimal for the elon-
gation of 11 grams of ALA to 1 gram of long-chain omega-3 PUFAs. (20) Age does
not appear to infuence ALA bioavailability or its conversion to DHA. (21)

5.1.3 OMEGA-3 FATTY ACIDS FROM FLAXSEED

Flaxseed is one of the richest plant sources of the omega-3 fatty ALA. The omega-3
fatty acids found in faxseed differ from those in fsh. The health benefts of fsh oil
are believed to derive principally from two omega-3 fats, eico-sapenta-enoic acid
94 Flaxseed

TABLE 5.1
Recommended amount of ALA by age and gender
Life Stage Recommended Amount of ALA
Birth to 12 months* 0.5 g
Children 1–3 years 0.7 g
Children 4–8 years 0.9 g
Boys 9–13 years 1.2 g
Girls 9–13 years 1.0 g
Teen boys 14–18 years 1.6 g
Teen girls 14–18 years 1.1 g

Pregnant teens and women 1.4 g

Breastfeeding teens and women 1.3 g

Source: ods.od.nih.gov.
*As total omega-3s. All other values are for ALA alone.

(EPA) and doco-sahexa-enoic acid (DHA) [hyphens inserted here to help pronuncia-
tion]. Flaxseed, on the other hand, contains a third, plant-based omega-3 ALA. The
typical North American diet provides approximately 1.4 grams of ALA per day and
0.1 gram to 0.2 grams of EPA and DHA. (22)
A study published in the American Journal of Clinical Nutrition in 2006, con-
cerned plasma phospholipid omega-3 fatty acid concentrations after ALA supple-
mentation. It was reported that ALA supplementation with up to 14 grams/day
resulted in dose-dependent (but modest) increases in plasma ALA concentrations.
Some of the observed variability, especially at low ALA doses, was attributed to
differences in the amount of omega-6 linoleic acid (LA) concurrently in the diet.
The dose response appeared linear. There were small increases in EPA after ALA
supplementation; however, plasma phospholipid DHA, an essential omega-3 fatty
acid, concentrations were not observed to increase. (19)

5.1.4 OMEGA-3 FATTY ACIDS FROM FLAXSEED AND

ELEVATED BLOOD CHOLESTEROL
Many studies have reported the benefcial effects of faxseed on normalizing blood
total cholesterol (TC), on LDL cholesterol or on high-density lipoprotein (HDL) cho-
lesterol. For instance, in 1997, an article published in the journal Arteriosclerosis,
Thrombosis and Vascular Biology concluded, “The marked rise in arterial compli-
ance at least with -linolenic acid refected rapid functional improvement in the
systemic arterial circulation despite a rise in LDL oxidizability. Dietary n-3 fatty
acids in fax oil thus confer a novel approach to improving arterial function.” (23)
Investigators reported in 2008, in the Journal of Women’s Health, that Native
American postmenopausal women beneft from regular consumption of faxseed by
reducing their risk of cardiovascular disease, as observed by lowered LDL-C and
TC levels. (24)
Omega-3 Fatty Acids and NO from Flax in Atherosclerosis and CSI 95

In 2008, the British Journal of Nutrition reported a study of the phytoestrogen

properties of lignans derived from faxseed. The treatments consisted of a placebo, 300
or 600 mg/day of dietary secoisolariciresinol diglucoside (SDG) from faxseed extract.
It was intended to determine the effect on plasma lipids and fasting glucose levels.
Signifcant treatment effects were achieved for the decrease of TC, LDL choles-
terol (LDL-C) and glucose concentrations, as well as their percentage decrease from
baseline. At weeks six and eight in the 600 mg SDG group, the decreases of TC and
LDL-C concentrations were in the range of 22.0% to 24.38%, respectively compared
to placebo. For the 300 mg SDG group, signifcant differences from baseline were
observed only for decreases in TC and LDL-C.
Plasma glucose was found to be signifcantly lower in the 600 mg SDG group at
weeks six and eight, especially in the participants with baseline glucose concentra-
tions ≥ 5.83 mmol/l (lowered 25.56% and 24.96%) compared to placebo, respec-
tively. Plasma concentrations of secoisolariciresinol (SECO), enterodiol (ED) and
enterolactone were all signifcantly raised in the groups supplemented with faxseed
lignan. The observed cholesterol-lowering values were correlated with the concen-
trations of plasma SECO and ED. The investigators concluded that dietary faxseed
lignan extract decreased plasma cholesterol and glucose concentrations in a dose-
dependent manner. (25)
A publication in the journal Nutrition Reviews, in 2004, was titled “Flaxseed and
Cardiovascular risk.” The investigators report that human studies have shown that fax-
seed can reduce serum total and low-density lipoprotein cholesterol concentrations,
reduce postprandial glucose absorption, decrease some markers of infammation and
raise serum levels of the omega-3 fatty acids, ALA and eicosapentaenoic acid. (26)
We know that the omega-3 fatty acids—especially ALA—in faxseed and fax oil
lower blood triglycerides (TC) and lipoproteins because omega-3 derived from other
sources does it just as well. For instance:
A study published in the journal Arteriosclerosis, Thrombosis and Vascular
Biology reported comparing the effect in volunteer participants of ingestion of 7
grams/day of omega-3, omega-6 or omega-9 fatty acids (EPA 41.4%, DHA 23.6%,
providing a total of 4.55 grams of EPA/DHA) for four weeks versus no dietary inter-
vention, on platelet-derived growth factor (PDGF-A, PDGF-B), heparin-bound epi-
dermal growth factor (HB-EGF), monocyte chemoattractant protein-1 (MCP-1) and
interleukin-10 gene expression in unstimulated Mononuclear Cells (MNCs) and in
monocytes that were adherence-activated ex vivo.
These benefts were not found with omega-6 or omega-9 fatty acids. This demon-
strates that omega-3 fatty acids can modulate infammatory gene expression. MCP-1
induces monocyte activation and attraction and both MCP-1 and PDGF are thought
to promote atherosclerosis.
Omega-6 PUFA via corn oil (providing LA 50.1%, saturated fats 12.9%) tended to
increase PDGF-A and MCP-1 (although not signifcantly). (27)

PDGF is a platelet-derived growth factor. PDGFs are molecules released

from platelets. Forms of PDGF help to heal wounds and to repair damage to
blood vessel walls. They also help blood vessels grow.
96 Flaxseed

In 2021, the journal Current Problems in Cardiology reported a systematic review

and meta-analysis titled “Effects of Flaxseed on Blood Lipids in Healthy and
Dyslipidemic Subjects.” The study aimed to determine the effects of faxseed on lipid
profle in healthy and dyslipidemic individuals. The literature search was performed
based on English reports of randomized control trials (RCTs) up to April 2021. It was
found that faxseed signifcantly improves the lipid profle in dyslipidemic patients
comprising TC, LDL-C and triglyceride (TG) in comparison with the control group.
In healthy individuals, faxseed signifcantly increased HDL-C, LDL-C and TG.
Subgroup analysis on healthy subjects showed that faxseed increased LDL-C on
overweight subjects with BMI > 25. (28)
In a study published in the journal Lancet, patients awaiting carotid endarterec-
tomy were given either sunfower oil (providing 3.6 grams of linoleic acid), fsh oil or
control until surgery with a median duration of treatment being 42 days. Compared
to control and sunfower oil, EPA/DHA decreased the prevalence of thin fbrous
caps, increased thick fbrous caps, reduced signs of infammation and reduced the
number of macrophages within plaques.
The investigators concluded that atherosclerotic plaques readily incorporate
omega-3 PUFAs from fsh oil supplementation, inducing changes that can enhance
stability of atherosclerotic plaques. By contrast, increased consumption of omega-6
PUFAs does not affect carotid plaque fatty-acid composition or stability. (29)
Interestingly, it was also found in the aforementioned study that there were more
thin fbrous cap atheromas (29.6% vs. 22.8%), fewer thick fbrous cap atheromas
(53.7% vs. 56.1%) and a greater percentage of plaque rupture (5.6% vs. 3.5%) in the
sunfower oil group vs. control, respectively. Although none of these differences
were signifcant the numerical trend for worse plaque morphology with the intake
of omega-6 PUFAs is concerning. Additionally, what is generally considered stable
plaque tended to be lower in the sunfower group compared to the control group.
These clinical studies illustrate the benefts of omega-3 fatty acids, but they did
not derive them from faxseed or fax oil.

5.1.5 OMEGA-3 FATTY ACIDS FROM FLAXSEED LOWER TRIGLYCERIDES

Triglycerides are composed of glycerol and three fatty acids. They are the main con-
stituent of body fat. They are present in blood and enable the bidirectional transfer
of adipose fat and blood glucose from the liver. In most people who do not have a
genetic predisposition to hypertriglyceridemia, it is commonly associated with obe-
sity, type 2 diabetes and metabolic syndrome.
While the clinical emphasis is usually on cholesterol, recent evidence suggests
that triglyceride levels above normal raise risk of catastrophic cardiovascular dis-
ease. Here are the clinical ranges for triglycerides:

Clinical ranges of triglyceride levels (51)

Normal less than 150*
Borderline high 150–199
High 200–499
Very high 500 or higher
*All values in milligrams per deciliter.
Omega-3 Fatty Acids and NO from Flax in Atherosclerosis and CSI 97

In 2003, the American Journal of Clinical Nutrition reported that “Dietary lin-
olenic acid is inversely associated with plasma triacylglycerol” as part of the
National Heart, Lung, and Blood Institute, which showed that dietary ALA (high-
est quintile 1.24 grams/day) is associated with lower plasma triglycerides (TG)
concentrations. (30)

5.1.6 L-ARGININE (ABUNDANT IN FLAXSEED) PREVENTS,

EVEN REVERSES, ATHEROSCLEROSIS
L-arginine, a semi-essential -amino acid, part of the biosynthesis of proteins, is
naturally found in red meat, poultry, fsh, dairy, beans and nuts and seeds. It is a
precursor of NO essential to blood vessel and heart function, to brain and nervous
system function and to immune system function. Each of these functions has its
own dedicated form (isoforms) of catalyst synthase enzyme. These enzymes convert
L-arginine to citrulline, producing NO in the process. Oxygen and NADPH are nec-
essary cofactors.
A number of authorities hold that atherosclerosis is basically due to endothelial
dysfunction. For instance, investigators writing in the Journal of Molecular and
Cellular Medicine in 1999, conclude,

Endothelial dysfunction by aging, menopause and hypercholesterolemia is involved in

the development of atherosclerotic vascular lesions, and predisposes the blood vessel
to several vascular disorders, such as vasospasm and thrombosis. Multiple mecha-
nisms are apparently involved in the pathogenesis of the endothelial dysfunction in
atherosclerosis. The reduced production of nitric oxide by the endothelium is caused
by abnormalities in endothelial signal transduction, availability of L-arginine, cofac-
tors for endothelial nitric oxide synthase and expression of the enzyme. Other mecha-
nisms may also be involved in the impaired endothelium-dependent relaxations in
atherosclerosis, including increased destruction of nitric oxide by superoxide anion,
altered responsiveness of vascular smooth muscle, and concomitant release of vaso-
contracting factors. (31) With permission.

Even more directly, the author of a 1998 report in the Journal of Investigative
Medicine titled his publication “Is Atherosclerosis an Arginine Defciency Disease?”
To wit, “A reduction in NO synthesis and/or activity may contribute to the initia-
tion and progressive of atherosclerosis. Derangement of the NO synthase pathway
may occur by several mechanisms, including lipoproptein-induced alterations in
signal transduction; increases in superoxide anion elaboration (and degradation of
NO); reduced affnity of NOS for L-arginine; and/or elevated levels of circulating
antagonists.” (32)
The “reduced affnity of NOS for L-arginine” is unlikely due to what is known as
the arginine paradox: Exogenous L-arginine causes NO-mediated biological effects
even when nitric oxide synthases (NOS) are saturated with L-arginine. (33) None of
this is to discount the role of nutrition, oxidative stress and lifestyle factors that lead
to the endothelial dysfunction associated with atherosclerosis.
A good number of studies have supported supplementing L-arginine orally
or by infusion to control plaque formation. For instance, authors of a clinical
study published in 1997 in the journal Atherosclerosis titled their report “Oral
98 Flaxseed

L-Arginine Improves Endothelium-Dependent Dilatation and Reduces Monocyte

Adhesion to Endothelial Cells in Young Men with Coronary Artery Disease.”
In this study, men with angiographically proven coronary atherosclerosis took 7
grams of L-arginine three times per day, or placebo, for three days with a ten-day
wash-out period.
Following L-arginine, plasma levels of arginine rose signifcantly (318 ± 18 vs.
124 ± 9 mumol/l), and endothelium-dependent dilatation of the brachial artery mea-
sured as the change in diameter in response to reactive hyperaemia (FMD) using exter-
nal vascular ultrasound improved signifcantly (4.7 ± 1.1 vs. 1.8 ± 0.7%). No such
results were found in the placebo comparison. Serum from participants after L-arginine
and placebo was then added to confuent monolayers of human umbilical vein endothe-
lial cells for 24 hours before human monocytes obtained by countercurrent centrifugal
elutriation (34) were added and cell adhesion assessed by light microscopy.

Centrifugal elutriation is a liquid clarifcation technique that makes it pos-

sible to separate different cells with different sizes. Since cell size is correlated
with cell cycle stages this method also allows the separation of cells at differ-
ent stages of the cell cycle.

Adhesion was found to be signifcantly reduced following L-arginine compared to

placebo (42 ± 2 vs. 50 ± 1%). The investigators, therefore, concluded that in young
men with coronary artery disease, oral L-arginine improves endothelium-dependent
dilatation and reduces monocyte/endothelial cell adhesion. (35)
In connection with the arginine paradox, the authors of a report published in the
Journal of Nutrition in 2004 contend that the mechanism of beneft of L-arginine on
endothelial function is unclear because intracellular concentrations of L-arginine far
exceed that required by eNOS. One potential explanation of this “arginine paradox”
is that L-arginine restores endothelial function in atherosclerotic patients in whom
there are elevated levels of ADMA, an endogenous inhibitor of eNOS. (36)
A study conducted in Iran, published in 2014 in the journal F1000 Research aimed
to evaluate the effect of low-dose L-arginine supplementation on cardiovascular disease
(CVD) risk factors, including lipid profle, blood sugar and blood pressure in healthy
Iranian men. For 45 days, the intervention group received 2,000 mg daily L-arginine
supplementation. The control group received 2,000 mg of maltodextrin placebo daily.
At the end of study, fasting blood sugar and lipid profle, i.e, triglyceride (TG),
cholesterol, LDL, HDL, decreased signifcantly in the L-arginine group but no sig-
nifcant change in the placebo group were found. In addition, reductions in fasting
blood sugar and the lipid profle were signifcantly better than the control group.
However, no signifcant changes were found in systolic and diastolic blood pressure
either in L-arginine or placebo group. (37)
There are many more clinical and experimental (animal model) studies that
could be cited to show the benefts of L-arginine of relevance to faxseed or fax
Omega-3 Fatty Acids and NO from Flax in Atherosclerosis and CSI 99

oil–derived L-arginine in lowering or even in reversing atherosclerosis. These

studies go to the effect of enhancing eNO. As noted earlier, omega-3 enhances
endothelial function and L-arginine is the substrate for NO. Likewise, cyanogenic
glycosides (CNglcs) in faxseed are NO-donors–fax oil, which is extracted from
the seeds does not contain appreciable amounts of cyanogenic glycosides. No
creditable studies of CNglcs from any source concerning atherosclerosis could
be found.

5.2 CHRONIC SYSTEMIC INFLAMMATION

Chronic systemic infammation (CSI) is also referred to as slow, long-term infam-
mation lasting for prolonged periods of several months to years. It results from the
release of proinfammatory cytokines from immune-related cells and the chronic
activation of the innate immune system. Diseases in which infammation plays a
dominant pathological role have the suffx “-itis.”
Infammation comes in two forms—acute and chronic. Acute infammation helps
us with the healing process and is generally short-lived. In chronic infammation, the
effects linger. Over time, chronic infammation will have an adverse effect on tis-
sues and organs. CSI plays a role in the development of many diseases ranging from
autoimmune diseases to cancer.
Typical signs of CSI include fatigue, fever and joint and muscle pain. There are
also atypical symptoms, including balance issues, insulin resistance, muscle weak-
ness, eye problems, skin issues and more. More recently, atherosclerosis has been
added to the list.
A report in the journal Current Pharmaceutical Design appearing in 2012 con-
tends that

atherosclerosis starts with an innate immune response involving the recruitment and
activation of monocytes macrophages that respond to an excessive accumulation of
modifed lipids within the arterial wall, followed by an adaptive immune response
involving antigen-specifc T lymphocytes. Effector T cells recognize modifed auto-
antigens such as oxidized LDL and heat shock proteins (i.e. HSP-60) that are presented
by antigen-presenting cells such as macrophages or dendritic cells. The accumulation
of infammatory cells within the arterial wall leads to local production of chemokines,
interleukins and proteases that enhance the infux of monocytes and lymphocytes,
thereby promoting the progression of atherosclerotic lesions. (38)

The study was titled “Atherosclerosis as an Infammatory Disease.”

What is CSI? Is it a disease? Is it a process leading to disease? It is likely that it
is both. In any case, the evidence for CSI is in the test known as C-reactive protein
(CRP).

5.2.1 C-REACTIVE PROTEIN IN INFLAMMATION

C-Reactive protein (CRP) is an acute-phase protein of liver origin found in plasma
that increases following interleukin-6 secretion by macrophages and T cells. Its
100 Flaxseed

circulating concentrations rise in response to infammation. CRP is usually mea-

sured in milligrams of CRP per liter of blood (mg/L). Normal CRP levels are typi-
cally below 3.0 mg/L. But, the normal reference range often varies between labs.
The range of CRP in milligrams per liter of blood in adults and their clinical
signifcance are as follows (52):

• Below 3.0: Normal

• 3.0–10.0: Slightly elevated, which may signify a variety of condi-
tions, such as pregnancy, the common cold or gingivitis
• 10.0–100.0: Moderately elevated, which signifes infection or an infam-
matory condition such as rheumatoid arthritis, Crohn’s dis-
ease or lupus
• 100.0–500.0: Severely elevated, which signifes severe bacterial infection

A high-sensitivity CRP (hs-CRP) test can detect levels below 10.0 mg/L. This kind
of test is performed primarily to determine a person’s risk for heart disease. hs-CRP
ranges in milligrams per liter of blood and heart disease risk (52):

• Below 1.0: Low risk

• 1.0–3.0: Moderate risk
• 3.0–10.0: High risk

CRP, an acute infammatory protein that increases up to 1,000-fold at sites of infec-

tion or infammation, is synthesized primarily in liver hepatocytes but also by
smooth muscle cells, macrophages, endothelial cells, lymphocytes and adipocytes.
(39) Some reports fnd CRP useful in evaluating the benefts of faxseed and fax oil
as an outcome measure in faxseed or fax oil supplementation, while others fnd it
limited to specifc clinical populations. For instance:
In a meta-analysis titled “Effect of Flaxseed Intervention on Infammatory Marker
C-Reactive Protein,” published in the journal Nutrients in 2016, the investigators
reported that faxseed and its derivatives may have a benefcial effect on reducing
circulating CRP only in obese populations. (40)
The aim of a multicenter trial reported in the journal Nutrition Research, in 2012,
was to determine the effects of faxseed oil on infammation in patients with chronic
renal failure undergoing renal replacement therapy with hemodialysis (HD). It was
hypothesized that fax oil supplementation would lower CRP levels. Patients received
three dialysis sessions per week over a three-month period. They were given blind
doses of 1 gram fax oil twice a day, and the control group was given 1 gram mineral
oil placebo twice a day for a period of 120 days.
Infammation was observed in 89 patients (61%) at the beginning of the study.
There was a signifcant linear correlation between CRP and the body mass index and
HDL cholesterol, and the CRP levels decreased signifcantly over time in the group
that received fax oil compared to the control group. During the study period, 33.3%
of the fax oil group no longer had infammation whereas only 16.9% changed in the
mineral oil group. The investigators concluded that fax oil decreases the CRP levels
and that infammation in hemodialysis patients appears to be correlated to their body
mass index and reduced HDL cholesterol levels. (41)
Omega-3 Fatty Acids and NO from Flax in Atherosclerosis and CSI 101

In one clinical study (42), the intake of an ALA-rich diet of 6.5% of energy/day
from ALA has led to a large 75% decrease in CRP levels in blood samples from hyper-
cholesterolemic men and women. ALA appears to decrease CVD risk by inhibiting
vascular infammation and endothelial activation beyond its lipid-lowering effects.
In another independent study, ALA levels in a plasma cholesterol fraction have
also been negatively correlated with CRP concentrations. In this study on overweight
adolescents, published in the American Journal of Clinical Nutrition in 2005, eicos-
apentaenoic acid in phospholipids and cholesterol esters (CEs) and linolenic acid in
CEs were signifcantly inversely related to CRP. These fndings remained signifcant
after adjustment for the waist-to-hip ratio. No signifcant relation between fatty acids
composition and the homeostasis model assessment was observed.
The investigators concluded that a high intake of long-chain PUFAs, especially
omega-3 PUFAs may protect obese subjects against metabolic syndrome and low-
grade infammation as early as adolescence. (43)
In yet another study published in the journal Nutrition, Metabolism and
Cardiovascular Diseases in 2008, it was reported that secoisolariciresinol diglu-
coside (SDG) isolated from faxseed (500 mg/day) reduced CRP concentration by
approximately 15% in healthy postmenopausal women when they were compared
with a placebo group during a six-week intervention period. (44)
We should be careful not to be misled by the results of studies that report no
change in CRP consequent on faxseed or fax oil supplementation because there
may have been other clinically signifcant changes. However, it should be noted that
there are publications that report no detectable change in CRP as a consequence of
fax seed or fax oil supplementation. (45)

5.2.2 OMEGA-3 ALA REDUCES INFLAMMATION

A study published in the Journal of Nutrition in 2004 aimed to determine whether ALA
could reduce the risk of CVD by lowering vascular infammation and endothelial dys-
function. Infammatory markers and lipids and lipoproteins were assessed in hypercho-
lesterolemic participants fed two diets low in saturated fat and cholesterol and high in
PUFAs varying in ALA (ALA Diet) and linoleic acid (LA Diet—omega-6), compared
with an average American diet (AAD). The ALA Diet provided 17% energy from PUFA
(10.5% LA; 6.5% ALA), the LA Diet provided 16.4% energy from PUFA (12.6% LA;
3.6% ALA) and the AAD provided 8.7% energy from PUFA (7.7% LA; 0.8% ALA).
The ALA diet signifcantly decreased CRP, whereas the LA Diet only tended to
decrease CRP. Although the two high-PUFA diets similarly signifcantly decreased inter-
cellular cell adhesion molecule-1 vs. AAD (−19.1% by the ALA Diet; –11.0% by the LA
Diet), the ALA Diet signifcantly decreased vascular cell adhesion molecule-1 (VCAM-
1, −15.6% vs. −3.1% and E-selectin (−14.6% vs. −8.1%) more than the LA Diet.

E-Selectin is a glycoprotein only expressed on endothelial cells after acti-

vation by interleukin 1 (IL-1), tumor necrosis factor  (TNFα), or bacterial
lipopolysaccharides. Regulation of E-selectin expression might be crucial to
control leukocyte accumulation in infammatory responses. (50)
102 Flaxseed

Changes in CRP and VCAM-1 were inversely associated with signifcant changes
in serum eicosapentaenoic acid (EPA), or EPA plus docosahexaenoic (DHA)
after subjects consumed the ALA Diet. The two high-PUFA diets signifcantly
decreased serum total cholesterol, LDL cholesterol and triglycerides; the ALA
Diet signifcantly decreased HDL cholesterol and apolipoprotein AI compared
with the AAD. The investigators concluded that ALA appears to decrease CVD
risk by inhibiting vascular infammation and endothelial activation beyond its
lipid-lowering effects. (42)

5.2.3 L-ARGININE, PER SE, AND INFLAMMATION

An experimental study published in the International Journal of Molecular Sciences
in 2019 reported that L-arginine exerts anti-infammatory and antioxidant effects
to protect IPEC-J2 cells from an infammatory response and oxidative stress chal-
lenged by lipopolysaccharide at least partly via the Arg-1 signaling pathway. (46)

• IPEC-J2 cells are intestinal porcine enterocytes isolated from the

jejunum of a neonatal unsuckled piglet.
• The Arg-1 gene instructs the production of the enzyme arginase that
participates in the urea cycle, a series of reactions that occurs in liver
cells. The urea cycle processes excess nitrogen, which is generated when
proteins and their building blocks (amino acids) are used by the body.

We remind you that faxseeds are abundant in arginine.

A review and meta-analysis of clinical studies titled “Effect of L-arginine
Supplementation on C-Reactive Protein and Other Infammatory Biomarkers” pub-
lished in the journal Complementary Therapies in Medicine in 2019 concluded that
L-arginine supplementation increased the circulating concentrations of CRP in indi-
viduals older than 60, in those with higher levels of CRP, in patients with cancer and
when used in enteral formula. (47)

5.2.4 FLAX/OMEGA-3 AND RHEUMATOID ARTHRITIS

Rheumatoid arthritis is a chronic infammatory autoimmune disorder that can affect
joints, the skin, eyes, lungs, heart and blood vessels. Unlike osteoarthritis, it affects
the lining of joints, causing a painful swelling that can eventually result in bone
erosion, joint deformity and damage to other parts of the body as well. Signs and
symptoms may include the following:

• Tender, warm, swollen joints

• Joint stiffness that is usually worse in the mornings and after inactivity
• Fatigue, fever and loss of appetite
• Early rheumatoid arthritis tends to affect smaller joints frst—particularly
the joints that attach the fngers to the hands and the toes to the feet
Omega-3 Fatty Acids and NO from Flax in Atherosclerosis and CSI 103

• As the disease progresses, symptoms often spread to the wrists, knees,

ankles, elbows, hips and shoulders. In most cases, symptoms occur in the
same joints on both sides of the body

Signs and symptoms may vary in severity and may even come and go. Periods of
increased disease activity, called fares, alternate with periods of relative remission
when the swelling and pain fade or disappear. Over time, rheumatoid arthritis can
cause joints to deform and shift out of place.
A comprehensive literature search and meta-analysis published in the journal
Advances in Nutrition in 2019 showed signifcant effects of faxseed intake on cir-
culating high-sensitivity CRP (hs-CRP) and TNF. However, no signifcant changes
were found in IL-6 concentration and CRP. Moreover, by eliminating one of the
studies from the sensitivity analysis, changes in IL-6 concentration were signifcant.
The changes in infammatory biomarkers were dependent on study design (parallel
or crossover), supplement type (faxseed, faxseed oil, or lignan), study quality (high
or low) and participants’ age and body mass index (BMI).
According to this meta-analysis, faxseed signifcantly reduced circulating con-
centrations of hs-CRP and TNF, but did not affect IL-6 and CRP. (48)
There is a report in the American Journal of Clinical Nutrition in 2000 that
supplementation of omega-3 fatty acids has been consistently shown to reduce
both the number of tender joints on physical examination and the amount of
morning stiffness in patients with rheumatoid arthritis. In these cases, supple-
ments were consumed daily in addition to background medications and the
clinical benefts of the omega-3 fatty acids were not apparent until they were
consumed for ≥ 12 wk.
A minimum daily dose of 3 grams of eicosapentaenoic and docosahexaenoic
acids is necessary to derive the expected benefts. These doses of omega-3 fatty acids
are associated with signifcant reductions in the release of leukotriene B(4) from
stimulated neutrophils and of interleukin 1 from monocytes. Both of these mediators
of infammation are thought to contribute to the infammatory events that occur in
the rheumatoid arthritis disease process.
There have been a number of reports that rheumatoid arthritis patients con-
suming omega-3 dietary supplements were able to lower or discontinue their
background doses of nonsteroidal anti-infammatory drugs or disease-modifying
anti-rheumatic drugs. However, the investigators contend that because the methods
used to determine whether patients taking omega-3 supplements can discontinue
taking these agents are variable, confrming and defnitive studies are needed to
settle this issue.
Omega-3 fatty acids have virtually no reported serious toxicity in the dose range
used in rheumatoid arthritis and are generally very well tolerated. (49)

5.3 SUMMARY
Atherosclerosis and chronic systemic infammation are grouped in this chapter
because they are related, i.e., atherosclerosis is an infammatory disease that begins
with free radical oxidation of cholesterol. Studies have shown that both atherosclerosis
104 Flaxseed

and chronic systemic infammation respond to faxseed and fax oil supplementation
because fax supplies both omega-3 fatty acids and L-arginine, the substrate for nitric
oxide formation. Both are antioxidants and both support endothelium health.

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 6 Flaxseed and L-Arginine,
and Omega-3 Fatty Acids,
per se, in Treatment
of Hypertension and
Sickle Cell Disease

6.1 HYPERTENSION
This chapter makes the case for faxseed supplementation in controlling blood pres-
sure and in treating sickle cell disease because its two main active constituents,
L-arginine and omega-3 fatty acid, have demonstrated clinical effectiveness.
In 2017, the American College of Cardiology and the American Heart Association
(AHA) published new guidelines for hypertension management and defned hyper-
tension as having blood pressure at or above 130/80 mm Hg. Hypertension raises the
risk of heart disease, stroke, peripheral vascular disease, kidney disease and many
more medical disorders, which are leading causes of death in the United States. In
2019, more than half a million deaths in the United States had hypertension as a pri-
mary or contributing cause. (1) It cost the United States about $131 billion each year,
averaged over 12 years from 2003 to 2014.
Hypertension is largely a “silent” disease, but there are sometimes symptoms such
as the following:

• Severe headaches
• Nosebleeds
• Fatigue or confusion
• Vision problems
• Chest pain
• Diffculty breathing
• Irregular heartbeat
• Blood in the urine

It is often frst detected during a routine periodic medical checkup.

Common factors that can lead to high blood pressure are said to be a diet high
in salt, fat and/or cholesterol and a sedentary lifestyle. It is a primary risk factor for
cardiovascular disease, including stroke, heart attack, heart failure, kidney failure
and aneurysm. Keeping blood pressure under control is vital for preserving health

DOI: 10.1201/b22986-6 109

110 Flaxseed

and reducing the risk of these dangerous conditions. Clinical studies confrm that the
constituents of faxseed and fax oil, especially omega-3 fatty acids and L-arginine,
successfully combat these health risks.

6.1.1 HYPERTENSION AS OMEGA-3 DEFICIENCY

In a previous chapter, it was reported that atherosclerosis might be an L-arginine def-
ciency disease. (2) “Defciency” does not necessarily mean “lack of” in the conven-
tional sense, especially in light of the arginine paradox that the nitric oxide synthase
(NOS) enzyme is often supersaturated. It might just mean that something interferes
with or prevents its normal function, i.e., perhaps a dysfunctional or missing enzyme
or cofactor. We raise this issue here because a number of authorities make the parallel
suggestion that hypertension may, in many cases, be an omega-3 defciency disease.
There is considerable scientifc support for this notion.
We will revisit the question, “Could hypertension be a defciency disease?” in any
sense, later in this chapter—see ADMA.
But to the point, it was shown in an experimental animal-model study (Sprague–
Dawley rats) that omega-3 polyunsaturated fatty acid defciency, particularly dur-
ing the prenatal period, can cause hypertension in later life. (3) Additionally, when
defciency is reversed in later life, omega-3 fatty acid levels are essentially restored
while hypertension remains. (4) The issue is further confounded by the fact that, as
reported in the journal Hypertension in 2010, body fat and leptin may be factors
involved in omega-3 fatty acid defciency hypertension. (5)
Maternal deprivation of omega-3 fatty acids has been shown to result in (animal)
infants that develop hypertension. Dietary omega-3 fatty acid defciency can lead to
hypertension in later life. We can lower blood pressure in adults with hypertension
with omega-3. But what is the effect of altering the dietary protein level on blood
pressure in animals defcient or suffcient in omega-3 fatty acids?
In an experimental study reported in the American Journal of Hypertension in
2010, female rats were placed on one of four experimental diets one week prior
to mating. Diets were either defcient (10% saffower oil; DEF) or suffcient (7%
saffower oil, 3% faxseed oil; SUF) in omega-3 fatty acids and contained 20% or
30% casein (DEF20, SUF20, DEF30, SUF30). Offspring were maintained on the
maternal diet for the duration of the experiment. At 12, 18, 24 and 30 weeks, blood
pressure was assessed by tail-cuff plethysmography.
It was found that at both 12 and 18 weeks of age, no differences in blood pressure
were observed based on diet. However, by 24 weeks, hypertension was evident in
DEF30 animals; there were no signifcant blood pressure differences between the
other groups. This hypertension in DEF30 group was increased at 30 weeks, with
systolic, diastolic and mean arterial pressure all signifcantly elevated.
The investigators concluded that the hypertension previously attributed to omega-3
fatty acid defciency is also dependent on additional dietary factors, including protein
content of the diet. (6)
There is evidence also, as reported in the journal BMJ in 2003, that prenatal
omega-3 fatty acid supplementation may reduce diastolic blood pressure in human
infants as well. (7) It is consistent with these fndings that the Mediterranean Diet,
rich in omega-3, may be thought to help reduce blood pressure.
Flaxseed and L-Arginine in Treatment of Hypertension and Sickle Cell Disease 111

The Greek Mediterranean Diet prior to the 1960s provided adequate consumption
of the essential omega-3 fatty acids with the ratio omega-3/omega-6 of 2:1. (8) This,
parenthetically, is in contrast to the current diet of Greeks with the total omega- 6 to
omega-3 ratio of about 10:1, which is closer to the Western Diet of 15:1.
This increase in the ratio is unfortunate because, as reported in a study published
in the Journal of the American College of Nutrition in 2001, omega-6 fatty acids,
and especially linoleic acid (AL), in disproportionate amounts, cause endothelial cell
dysfunction most markedly as well, and it can potentiate TNF-mediated endothelial
cell injury and is, therefore, atherogenic. (9)
Reporting in the journal Current Vascular Pharmacology in 2012, the investigators
contend that there is considerable evidence that people with essential hypertension,
i.e., high blood pressure that doesn’t have a known primary cause, suffer endothelial
dysfunction caused by impaired nitric oxide (NO) availability secondary to oxidative
stress. (10, 11, 12) More about that next.
That given, there is also considerable evidence that faxseed and fax oil lower
blood pressure by their benefcial effect on endothelial health: Their omega-3 fatty
acids are antioxidants, and both L-arginine and cyanogenic glycosides are NO-donors.

6.1.2 FLAX/OMEGA-3 FATTY ACIDS REDUCES BLOOD PRESSURE—

THE HARRIS OMEGA-3 INDEX
In a study published in the Journal of Hypertension in 2018, investigators hypoth-
esized that the Omega-3 Index (defned next) would be inversely associated with
blood pressure (BP) levels in young healthy adults. Participants with cardiovascular
disease, known diabetes or a body mass index (BMI) higher than 35 kg/m2 were
excluded from the study. It was found that a higher Omega-3 Index is associated
with statistically signifcant, clinically relevant lower systolic and diastolic blood
pressure.
Based on the fndings, the investigators recommended diets rich in omega- 3 fatty
acids for primary prevention of hypertension. (13)

The Omega-3 Index test is a measure of the amount of EPA and DHA in the
blood, specifcally in the red blood cell membranes. The Omega-3 Index test
yields a percentage. For example, if there are 64 fatty acids in a cell mem-
brane and three are EPA and DHA, then the Omega-3 Index is 4.6%.

An Omega-3 Index of 8% or higher is ideal, the lowest risk zone. However, most
American consumers are at 4% or less, the highest risk zone. Being in the highest
risk zone translates to a 90% higher risk of sudden cardiac death. Here are the “risk
zones” for coronary heart disease developed by Dr. WS Harris and colleagues,
published in the American Journal of Clinical Nutrition in 2008 (14):

• Risk Zones: Omega-3 Index

• High Risk = <4%
112 Flaxseed

• Intermediate Risk = 4%–8%

• Low Risk = >8%

The following study is particularly noteworthy because the authors conclude, “In
summary, faxseed induced one of the most potent antihypertensive effects achieved
by a dietary intervention.” The clinical trial published in the journal Hypertension
in 2013 aimed to determine the effects of daily faxseed on systolic blood pres-
sure (SBP) and diastolic blood pressure (DBP) in peripheral artery disease patients.
Patients were given a variety of foods that contained 30 grams of milled faxseed, or
a placebo, each day for more than six months.
Plasma levels of the omega-3 fatty acid ALA and enterolignans rose signifcantly—
2- to 50-fold—in the faxseed-fed group but did not increase signifcantly in the pla-
cebo group. SBP was ≈ 10 mm Hg lower, and DBP was ≈ 7 mm Hg lower in the fax-
seed group compared with placebo after six months. Patients who entered the trial
with a SBP ≥ 140 mm Hg at baseline saw a signifcant reduction of 15 mm Hg in SBP
and 7 mm Hg in DBP from faxseed consumption. The antihypertensive effect was
achieved selectively in hypertensive patients: Circulating ALA levels correlated with
SBP and DBP and lignan levels correlated with changes in DBP.
As noted earlier the investigators concluded that “faxseed induced one of the
most potent antihypertensive effects achieved by a dietary intervention.” (15)
The purpose of the following review and meta-analysis, published in the Journal
of Nutrition in 2015, was to determine the effect of faxseed consumption on blood
pressure and also the infuence of baseline blood pressure, type of faxseed supple-
mentation and duration of faxseed supplementation on blood pressure.
The analysis comprised PubMed (Medline), Cumulative Index to Nursing and
Allied Health Literature and Cochrane Library (Central), through July 2014 for stud-
ies where people supplemented their habitual diet with faxseed or its extracts (i.e.,
oil, lignans, fber) for ≥2 weeks.
The investigators concluded that consumption of faxseed may somewhat lower
blood pressure, but the beneft is greater, especially for DBP, when it is consumed as
a whole seed and for more than 12 weeks. (16)
A study reported in the American Journal of Hypertension in 2011 aimed to
assess how modest variations in omega-3 fatty acid intake might affect blood pres-
sure (BP) in a healthy community sample. The participants included Pittsburgh-area
adults 30 to 54 years of age (11% black, 51% female) not taking omega-3 fatty acid
supplements or antihypertensive medications. Standardized assessments of clinic
and 24-hour ambulatory BP and pulse rate were obtained.
Docosahexanenoic acid (DHA) and eicosapentaenoic acid (EPA) in fasting serum
phospholipids were measured. Analyses controlled for age, gender, race, BMI, self-
reported sodium intake and physical activity.
It was found that DHA was inversely associated with clinic DBP, awake ambula-
tory DBP and 24-hour DBP. A signifcant increase in DHA was associated with 2.1
mm Hg lower in-clinic and 2.3 mm Hg lower awake ambulatory DBP. In addition,
DHA was inversely associated with pulse rate measured at rest in the clinic.
The investigators concluded that in this sample of American adults not on anti-
hypertensive medications, a modest albeit signifcant inverse association was found
between DHA exposure and both clinic and ambulatory DBP. Therefore, increasing
Flaxseed and L-Arginine in Treatment of Hypertension and Sickle Cell Disease 113

DHA consumption through diet modifcation, rather than large dose supplementa-
tion, might be an effective strategy for preventing hypertension. (17)
While omega-3 fatty acids may have blood pressure (BP)–lowering effects in
untreated hypertensive and elderly patients, their effect on BP in young, healthy
adults remains unknown. A study published in the Journal of Hypertension in 2018,
aimed to determine whether the omega-3 Index is inversely associated with BP in
young healthy adults. The study investigated the baseline characteristics of a cohort
that included healthy adults aged 25 to 41 years. Individuals with cardiovascular
disease, known diabetes or a BMI higher than 35 kg/m were excluded.
It was found that median Omega-3 Index was 4.58%. Compared to individu-
als in the lowest Omega-3 Index quartile, individuals in the highest had a SBP and
DBP that was signifcantly lower (4 and 2 mm Hg lower, respectively). A signifcant
linear inverse relationship of the Omega-3 Index with 24-hour and offce BP was
observed. These fndings are statistically signifcant. It was concluded that a higher
Omega-3 Index is associated with statistically signifcant, clinically relevant lower
SBP and DBP levels in normotensive young and healthy individuals. Furthermore,
diets rich in omega-3 fatty acids may be a strategy for the primary prevention of
hypertension. (13)

6.1.3 THE SAFETY OF CYANOGENIC GLYCOSIDES IN FLAXSEED

One tablespoon of ground faxseed weighs about 10 grams. It holds about 7 grams of
fatty acids of which 1,800 mg is omega-3. One tablespoon of fax oil holds about 14,000
mg of omega 3. One tablespoon of ground faxseed holds about 198 mg of L-arginine.
According to the Nutraceutical Alliance, regarding cyanogenic glycoside (CNglcs)
in faxseed, the main safety concern is with crushed or ground fresh faxseed, not
whole faxseed from which little cyanide is formed and released when consumed, nor
fax oil which is extracted from the seed and does not contain appreciable amounts
of CNglcs nor the enzymes needed to produce cyanide from cyanogenic glycosides.
The normal content of CNglcs precursors present in faxseed from many sources in
different continents ranges from less than 80 up to about 300 mg cyanide-equivalents/
kg seed. (18)
Based on data from a study by Abraham, Buhrke and Lampen (2016), consum-
ing 30 grams, ca. 3 tablespoons, of faxseed with a cyanogenic precursor content
of 200 mg/kg seed will result in an average peak blood cyanide concentration of
5 μmol/L. This is less than the toxic threshold value of 20 to 40 μmol/L favored by
the European Food Safety Authority.
Using their data as a guide, as much as 120 grams of crushed/ground faxseed
can be consumed before a toxic threshold of 40 μmol/L is reached. Given that a
tablespoon of ground faxseed weighs about 10 grams, this amounts to about 12
tablespoons.
Cyanogenic glycosides are cited here in connection with the treatment of hyper-
tension because, like L-arginine, they are NO-donors. But there are no studies in
conventional journals that address CNglcs in that connection. There is, however, an
intriguing review titled “Infammation, Its Regulation and Antiphlogistic Effect of
the CNglcs Amygdalin” (amygdalin, AKA cyanogenic glycoside), not drawn from
faxseed, that appeared in the journal Molecules in 2021. (19)
114 Flaxseed

6.1.4 L-ARGININE SUPPLEMENTATION REDUCES BLOOD PRESSURE

Given that the NO-donor L-arginine supplements reduce blood pressure, it is reason-
able to speculate that if that, therefore, faxseed would logically reduce blood pres-
sure since faxseed contains available L-arginine. Therefore, we present data here on
the benefts of L-arginine supplementation not necessarily obtained from faxseed.
This is due to the fact that clinical studies that cite faxseed or fax oil per se in con-
nection with blood pressure/hypertension typically do that on the basis of omega-3
content and, for unknown reasons, ignore the role of L-arginine. Here is what can be
expected from L-arginine supplementation via faxseed.
What actually happens in the body when L-arginine is administered either orally
or by intravenous infusion? This question is answered by a clinical study pub-
lished in the British Journal of Clinical Pharmacology in 1998 that addressed the
“pharmacokinetic-pharmacodynamic relationship” in L-arginine-induced vasodila-
tion in healthy people after a single intravenous infusion of 30 grams or 6 grams
of L-arginine, or after a single oral application of 6 grams, as compared with the
respective placebo. It was found that the vascular effects of L-arginine are closely
correlated with its plasma concentrations.
The investigators contend that “these data may provide a basis for the utilization
of L-arginine in cardiovascular diseases.” (20)
The Western(ized) Diet is characterized by a high content of proteins mostly
derived from fatty domesticated animals and processed meats. It stands to reason
that such a diet should provide an ample supply of L-arginine. Indeed, it does, and
L-arginine defciency is therefore rare. Yet, as shown in the sample of clinical studies
cited next, supplementing L-arginine has been shown in countless clinical reports to
lower blood pressure. How can we explain this?
For openers, endothelium dysfunction comes to mind: A clinical study published
in the Journal of the American College of Cardiology in 1992 titled “Abnormal
Endothelium-Dependent Coronary Vasomotion in Hypertensive Patients” aimed to
assess the integrity of endothelium-dependent vasodilation, the response of coro-
nary arteries to acetylcholine (an endothelium-dependent vasodilator) and nitro-
glycerin (an endothelium-independent vasodilator) in patients undergoing cardiac
catheterization.
Patients with essential hypertension were compared to normotensive patients.
None had obstructive disease detectable by coronary arteriography. Coronary artery
diameter was measured with digital-subtracted arteriography and coronary blood
fow velocity with a Doppler fow velocity catheter. At baseline, coronary artery
diameter was similar in the hypertensive and the normotensive control patients
(2.4 ± 0.3 vs. 2.8 ± 0.7 mm).
During intracoronary acetylcholine infusion (30 micrograms/min), coronary
artery diameter decreased signifcantly to 1.3 ± 0.7 mm in the hypertensive patients,
but it was unchanged (2.7 ± 0.8 mm) in the normotensive patients. With intracoro-
nary nitroglycerin (200 micrograms), coronary artery diameter increased signif-
cantly in both groups. Coronary blood fow decreased during acetylcholine infusion
by 59 ± 31% in the hypertensive patients but increased by 3 ± 3% in the normotensive
group. There was a signifcant negative correlation between the percent change in
Flaxseed and L-Arginine in Treatment of Hypertension and Sickle Cell Disease 115

estimated coronary blood fow during acetylcholine infusion and mean arterial pres-
sure measured at baseline.
Therefore, these hypertensive patients exhibited marked coronary vasoconstric-
tion in response to intracoronary acetylcholine but normal vasodilation in response
to nitroglycerin, suggesting abnormal endothelium-dependent vasodilation. (21)
Likewise, investigators reported a clinical study in the New England Journal of
Medicine in 1990. They aimed to determine if patients with essential hypertension
have an endothelium-dependent abnormality in vascular relaxation. They examined
the response of the forearm vasculature to acetylcholine (an endothelium-dependent
vasodilator) and sodium nitroprusside (a direct dilator of vascular smooth muscle)
in hypertensive patients averaging 50.7 years of age (±10 years), two weeks after the
withdrawal of antihypertensive medications.
The drugs were infused at increasing concentrations into the brachial artery and
the response in forearm blood fow was measured by strain-gauge plethysmogra-
phy. It was found that the basal forearm blood fow was similar in the patients and
controls. The responses of blood fow and vascular resistance to acetylcholine were
signifcantly reduced in the hypertensive patients. However, there were no signifcant
differences between groups in the responses of blood fow and vascular resistance to
sodium nitroprusside.
Because the effect of acetylcholine might also be due to presynaptic inhibition of
the release of norepinephrine by adrenergic nerve terminals, it was assessed during
phentolamine-induced, alpha-adrenergic blockade. Under these conditions, it was
also evident that the responses to acetylcholine were signifcantly blunted in hyper-
tensive patients. The investigators concluded that endothelium-mediated vasodila-
tion is impaired in patients with essential hypertension. (22)
The authors of a review titled “The Antihypertensive Effect of Arginine,” reported in
the International Journal of Angiology in 2008, that the blood pressure-lowering effect
of the Dietary Approaches to Stop Hypertension (DASH) study may be due to its higher
arginine-containing protein, higher antioxidants (and low salt content). (23)
The aim of a review published in the journal Nutrients in 2019 was to determine
whether oral administration of the amino acids L-arginine and L-citrulline, potential
substrates for eNO, could effectively reduce blood pressure (BP) by increasing NO
production. Both arginine and citrulline effectively increase plasma arginine.
The investigators report that oral arginine supplementation can lower BP by
5.39/2.66 mm Hg, which is an effect that is comparable to diet changes and exercise
implementation.
They contend that the exact mechanism by which citrulline and arginine exert their
effect is obscured because normal plasma arginine concentration greatly exceeds the
Michaelis constant (Km) of eNOS. Thus, elevated plasma arginine concentrations would
not be expected to increase endogenous NO production signifcantly, but have nonethe-
less been observed to do so. This phenomenon refects the “arginine paradox.” (24)

The Michaelis(–Menten) equation characterizes the enzymatic rate at differ-

ent substrate concentrations. (25)
116 Flaxseed

A clinical study reported in the International Journal of Cardiology in 2002 con-

ducted on patients with essential hypertension administered either 6 grams of
L-arginine or a placebo. Patients were examined for fow-mediated, endothelium-
dependent dilatation of the brachial artery (FMD) before and one-and-a-half hours
after administration of L-arginine or placebo.
The two groups of L-arginine and placebo were similar regarding age, sex, blood
lipids, smoking, diabetes, coronary artery disease, body mass index, intima-media
thickness of the common carotid artery, clinics blood pressure and baseline brachial
artery parameters. It was found that at the end of the trial, heart rate, blood pres-
sure, baseline diameter, blood fow or reactive hyperemia did not change signif-
cantly. However, L-arginine resulted in a signifcant improvement of fow-mediated
dilatation (FMD) while placebo did not signifcantly change this parameter. The
effect of L-arginine on FMD was signifcantly different from the effect of placebo.
L-Arginine did not signifcantly infuence nitrate-induced dilatation.
It was concluded that oral administration of L-arginine acutely improves
endothelium-dependent FMD of the brachial artery in patients with essential
hypertension. (26)
The Journal of Chiropractic Medicine published an “umbrella review,” i.e., a
review of previously published systematic reviews or meta-analyses that encom-
passed the literature from January 1, 1980, through December 31, 2015, of three
separate databases—PubMed, Cochrane Library and Cumulative Index to Nursing
and Allied Health Literature.
The seven meta-analyses that were included in this umbrella review reported sig-
nifcant positive benefts of L-arginine on reducing systolic and DBP in hyperten-
sive adults by 2.2 to 5.4 mm Hg and 2.7 to 3.1 mm Hg, respectively, reducing DBP
in pregnant women with gestational hypertension by 4.9 mm Hg and reducing the
length of stay in the hospital for surgical patients.
In addition, two of the three meta-analyses indicated a 40% reduction in the inci-
dence of hospital-acquired infections. However, these positive results should be con-
sidered with caution because statistically signifcant heterogeneity was observed in
fve of the seven meta-analyses.
The investigator concluded that there is evidence to support the beneft of
L-arginine supplementation for reducing systolic and diastolic blood pressure in
hypertensive adults and reducing the incidence of hospital-acquired infections and
the length of stay in the hospital for surgical patients. (27)
Simply put, the effectiveness of L-arginine in reducing blood pressure and con-
trolling hypertension is not in doubt—it works. Here follow some additional interest-
ing applications and fndings: For instance, as reported in a clinical trial published in
the journal Chest in 1996, healthy men were given a 30-minute infusion of 0.5 g/kg
L-arginine hydrochloride. They underwent continuous monitoring of BP and heart
rate (HR), as well as intermittent determination of mixed expired NO concentration
and plasma L-arginine and L-citrulline levels. Infusion of L-arginine produced a
signifcant fall in mean BP with a peak effect of −9.3 ± 0.9%.
The hemodynamic effects of L-arginine were associated with a signifcant
increase in mixed expired NO concentration (FeNO) and a signifcant increase
in the rate of pulmonary NO excretion of 118 ± 45%, as well as a rise in plasma
Flaxseed and L-Arginine in Treatment of Hypertension and Sickle Cell Disease 117

L-citrulline from 25 ± 4 to 46 ± 5 μmol/L. There was a signifcant correlation

between the hypotensive response to L-arginine and the increase in expired NO.
According to the investigators, the hypotensive effect of L-arginine in humans
appears to be mediated, at least in part, by NO synthase metabolism of L-arginine
and increased endogenous NO production as indicated both by increased plasma
L-citrulline and by increased expired NO. (28)
Based on these fndings, it should be possible to use expired NO as an indirect
measure of endothelium health. It is surprising that this is not routine because the
technology for measuring expired NO has existed for some time now.

6.1.5 STUDIES CITING FLAXSEED OR FLAX OIL, PER SE, AND HYPERTENSION
Most studies of the effects of faxseed or fax oil on blood pressure cite omega-3 as
the active constituent. We found no clinical studies that actually cited faxseed, per
se, in treatment of hypertension.

6.1.6 COULD IT BE DUE TO ASYMMETRIC DIMETHYLARGININE (ADMA)

WHEN L-ARGININE FAILS?
Asymmetric dimethylarginine (ADMA) is an analogue of L-arginine that is a natu-
rally occurring product of metabolism found in human circulation. Elevated levels
of ADMA inhibit NO formation, impairing endothelial function and thus promoting
atherosclerosis. ADMA levels are increased in people with hypercholesterolemia,
atherosclerosis, hypertension, chronic heart failure, diabetes mellitus and chronic
renal failure. A number of studies have reported ADMA as a novel risk marker of
cardiovascular disease.
Elevated levels of ADMA have been shown to be the strongest risk predictor,
beyond traditional risk factors, of cardiovascular events and all-cause and cardio-
vascular mortality in people with coronary artery disease. Interventions such as
treatment with L-arginine have been shown to improve endothelium-mediated vaso-
dilatation in people with high ADMA levels. (29)
According to Mayo Clinic Laboratories also, ADMA is an independent risk factor
for major adverse cardiovascular events. It inhibits NO synthesis and is elevated in
diseases related to endothelial dysfunction, including hypertension, hyperlipidemia,
and type 2 diabetes.
Elevation in ADMA and subsequent NO synthesis inhibition leads to vaso-
constriction, reduced peripheral blood fow and reduced cardiac output. Baseline
ADMA remained a signifcant risk factor for adverse, events even after adjusting for
low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol
(HDL-C), triglycerides, creatinine and high-sensitivity C-reactive protein. (39)
A number of studies, including one published in the journal Current Cardiology
Reviews in 2010, have reported increased levels of ADMA to be the strongest risk
predictor of cardiovascular events and all-cause and cardiovascular mortality in
people with coronary artery disease. Interventions such as treatment with L-arginine
have been shown to improve endothelium-mediated vasodilatation in people with
high ADMA levels. (29)
118 Flaxseed

The author of a report titled “Does ADMA Cause Endothelial Dysfunction?” pub-
lished in the journal Arteriosclerosis, Thrombosis, and Vascular Biology in 2000
contends that

Asymmetric dimethylarginine (ADMA) is an endogenous and competitive inhibitor of

nitric oxide synthase. Plasma levels of this inhibitor are elevated in patients with ath-
erosclerosis and in those with risk factors for atherosclerosis. In these patients, plasma
ADMA levels are correlated with the severity of endothelial dysfunction and athero-
sclerosis. By inhibiting the production of nitric oxide, ADMA may impair blood fow,
accelerate atherogenesis, and interfere with angiogenesis. ADMA may be a novel risk
factor for vascular disease. (30) With permission.

In a review published in the journal Alternative Medicine Review in 2005, the

authors concluded that the endothelium plays a crucial role in the maintenance of
vascular tone and structure via endothelium-derived NO formed in healthy vascular
endothelium from the amino acid L-arginine. Endothelial dysfunction is caused by
cardiovascular risk factors, metabolic diseases and systemic or local infammation.
One possible cause of endothelial dysfunction is elevated blood levels of ADMA,
an L-arginine analogue that inhibits NO formation and can, therefore, impair vas-
cular function. Supplementation with L-arginine can restore vascular function and
improve the clinical symptoms of diseases associated with vascular dysfunction. (31)
ADMA is of no small concern because, as noted earlier, it is a feature of hyper-
tension but in addition, it is considered an extremely high risk of coronary catastro-
phe. (32)

6.1.6.1 Does ADMA Explain the Arginine Paradox?

We asked previously whether the arginine paradox could result from a malfunction-
ing or missing enzyme or cofactor. The author of a report in the Journal of Nutrition
in 2004 proposes that elevated ADMA levels may explain the arginine paradox,
i.e., the observation that supplementation with exogenous L-arginine improves
NO-mediated vascular functions in vivo, although its baseline plasma concentration
is about 25-fold higher than the Michaelis-Menten constant (Km) of the isolated,
purifed endothelial NO synthase in vitro.
According to the author, the biochemical and physiological pathways related
to ADMA are well understood: Dimethylarginines are the result of degradation of
methylated proteins. The methyl group is derived from S-adenosylmethionine. Both
ADMA and its regioisomer, symmetric dimethylarginine, are eliminated from the body
by renal excretion, whereas only ADMA is metabolized via hydrolytic degradation to
citrulline and dimethylamine by the enzyme dimethylarginine dimethylaminohydro-
lase (DDAH). Decreases in DDAH activity and/or expression may therefore contribute
to the pathogenesis of endothelial dysfunction in various diseases. Administration of
L-arginine is suggested because it has been shown to improve endothelium-dependent
vascular functions in subjects with high ADMA levels. (33)
Parenthetically, not only does L-arginine reduce levels of ADMA, but there is
some evidence that polyunsaturated fatty acids (PUFAs) may do so also. But the
evidence consists mainly of a small number of experimental animal studies. (34)
Flaxseed and L-Arginine in Treatment of Hypertension and Sickle Cell Disease 119

6.2 ENDOTHELIAL DYSFUNCTION IN SICKLE CELL DISEASE

AND L-ARGININE THERAPY
Endothelial dysfunction is a known feature of sickle cell disease (SCD), which is
present both in crisis and in steady state in children and adults with that disorder.
Flaxseed delivers L-arginine, shown to be helpful in treatment of sickle cell disease
because that disease is characterized by endothelium dysfunction, and L-arginine
is a NO-donor. Flaxseed also delivers omega-3—alpha-linolenic acid and other
PUFAs. Omega-3 has also been shown to be benefcial in connection with treatment
of sickle cell disease.
The authors of a 2019 publication in the journal Expert Review of Hematology
contend that,

Considering the complex pathogenesis of the disease and the restricted access to cura-
tive therapies, the management of SCD must rely on a combination of therapies cov-
ering multiple pathways. Arginine supplementation, a low-cost approach, has shown
promising results, which is particularly important considering most of the affected
patients still live in unfavorable socioeconomic conditions. These fndings should
encourage further clinical trials, evaluating other outcomes and specifc subpopula-
tions, such as adult patients and compound heterozygotes. (35) With permission.

A study of Sudanese SCD patients, including children and adults aged 2 to 24

years, published in the American Journal of Clinical Nutrition in 2013, reported
that omega-3 fatty acids signifcantly reduced the frequency of pain episodes from
a median of 4.6 down to 2.7 per year, and of pain requiring hospitalization from a
median of one down to zero per year. It also signifcantly reduced the frequency of
severe anemia from 16.4% down to 3.2% per year and of transfusion from 16.4%
down to 4.5% per year. (36)
It has been shown that endothelium dysfunction is a key feature of SCD. In a
clinical study published in the journal, Kidney 360, investigators aimed to deter-
mine the relationship between endothelial dysfunction, biomarkers of renal dys-
function, and biomarkers of disease severity in asymptomatic SCD patients with
renal disease.
Patients with homozygous SCD in steady state and age- and sex-matched controls
were enrolled between 2013 and 2014 in a tropical tertiary hospital. Ultrasonographic
FMD of the right brachial artery, renal arterial Doppler, complete blood count, creat-
inine, fetal hemoglobin, soluble P-selectin and cystatin C (Cys-C) levels were deter-
mined. Using the median FMD value of the control group, the SCD subjects were
further classifed into two groups for comparison.
It was found that the median FMD in SCD patients (3.44) was signifcantly lower
than that of controls (5.35). There was a signifcant negative correlation between FMD
and Cys-C levels, along with renal artery resistivity index in SCD patients. Additionally,
Cys-C level was signifcantly higher in SCD subjects with FMD below 5.35.
The investigators concluded that brachial artery FMD is signifcantly lower in
SCD patients compared to the control group, Cys-C and Renal Artery Resistance
Index showing a negative correlation with FMD indicates that renal function is
related to endothelial dysfunction in SCD. (37) Given that a key feature of SCD is
120 Flaxseed

endothelial dysfunction, L-arginine might play a role in reducing this aspect of the
disease. In fact, that was shown in the following study:
The investigators of a clinical study published in the journal Haematologica in
2013 reiterate that low NO bioavailability contributes to vasculopathy in SCD. They
hypothesized that arginine may be a benefcial treatment for pain related to SCD
because L-arginine is the substrate for NO production, and an acute defciency is
associated with the pain of vaso-occlusive episodes.
Children with SCD hospitalized for at least 56 episodes of pain were enrolled in
the study. They received 100 mg/kg tid of L-arginine or placebo for fve days, or until
they were discharged. As a result, there was a signifcant reduction in total parenteral
opioid use of 54%, and lower pain scores at discharge were reported in the treatment
group, compared to the placebo group. There was no signifcant difference in the
length of stay in the hospital, although a trend favored the arginine group.
The investigators concluded that arginine therapy represents a novel intervention
for painful vaso-occlusive episodes because it resulted in a “remarkable” reduction
of narcotic use by more than 50%. (38)
Surprisingly, no studies on the effects of fax, per se, in the treatment of SCD
could be found.

6.3 SUMMARY
Clinical as well as experimental (animal) studies have shown that endothelium dys-
function and impaired bioavailability of NO are both principal features of hyper-
tension and SCD. Flaxseed delivers L-arginine and CNglcs, both NO-donors, to
lower blood pressure and to relieve pain episodes in sickling. In addition, it delivers
omega-3 fatty acid shown to improve endothelium dysfunction underlying both con-
ditions. Although evidence of clinical faxseed administration, per se, in hyperten-
sion and in SCD is limited, many studies confrm the benefcial effects of L-arginine
and omega-3 fatty acids, per se, in treatment of these medical conditions.

6.4 REFERENCES
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1679. DOI:10.3390/nu11071679.
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 7 L-Arginine and Omega-3
Fatty Acids in Adjuvant
Treatment for Type 2
Diabetes and Chronic
Kidney Disease

7.1 THE CONTRIBUTION OF FLAXSEED CONSTITUENTS

IN TYPE 2 DIABETES MELLITUS
Research and clinical studies label treatments based on faxseed in accordance with
what, in the faxseed, is thought to be the principal dependent variable. It could be
“faxseed,” per se, or its omega-3 polyunsaturated fatty acids (PUFAs). However, it is
almost never L-arginine and never CNglcs that are proposed as the active agent. For
that reason, this chapter details the treatment of type 2 diabetes and chronic kidney
disease (CKD) with L-arginine separate and apart from the omega-3 PUFAs because
supplementing or adjuvant treatment with faxseed must, of necessity, include the
ample L-arginine contained in faxseeds.
Both L-arginine and omega-3 fatty acids have shown success in clinical trials in
the adjuvant treatment of type 2 diabetes and in kidney failure when they were admin-
istered separately. Cyanogenic glycosides (CNglcs) in faxseed are also NO-donors
like L-arginine. However, their specifc contribution to diabetes and kidney disease
can only be surmised because there is no published clinical trial evidence. It is rea-
sonable to assume, however, that the contribution of CNglcs is imbedded in the out-
come of faxseed per se supplementation trials and in L-arginine from faxseed trials.
Type 2 diabetes is characterized by high levels of glucose in the blood. It is a
chronic impairment in the regulation of blood glucose caused either by insulin resis-
tance, where cells respond poorly to it, or where the pancreas does not produce suf-
fcient insulin. More than 34 million Americans have diabetes (about 1 in 10), and
approximately 90% to 95% have type 2 diabetes. Most often, type 2 diabetes devel-
ops in people over age 45, but more and more children, teens and young adults are
developing it.
Type 2 diabetes is an expanding global health problem closely linked to the
epidemic of obesity. Individuals with type 2 diabetes are at high risk for both micro-
vascular complications including retinopathy, nephropathy and neuropathy, and
micro- and macrovascular complications such as cardiovascular comorbidities due

DOI: 10.1201/b22986-7 125

126 Flaxseed

to hyperglycemia and individual components of the insulin resistance metabolic

syndrome.
Environmental factors, obesity, an unhealthy diet, physical inactivity and genetic
factors contribute to the multiple pathophysiological disturbances that are respon-
sible for impaired glucose homeostasis in type 2 diabetes. But insulin resistance and
impaired insulin secretion remain the core defects. (1)
While deranged glucose metabolism is certainly a prima facie feature of type 2
diabetes, the problems that the condition causes relate to the effects of reactive oxy-
gen species (ROS) it generates en masse and the resulting oxidative stress. Therefore,
the two features of type 2 diabetes that concern us are infammation and the resulting
endothelial dysfunction that leads to the well-known consequences of that disease.

7.1.1 OXIDATIVE STRESS IN TYPE 2 DIABETES

There are numerous reports of the damaging role played by ROS in diabetes in stud-
ies showing that oxygen radical damage greatly increases in type 2 diabetes and that
this condition is often characterized by abnormalities in antioxidant defenses.
For instance, the aim of a study published in the journal Acta Medica in 2005 was
to determine whether there is a relationship between the severity of type 2 diabetes
retinopathy and leukocyte superoxide dismutase (SOD), catalase (CAT) activities
and lipid peroxidation (LPO). Leukocyte malondialdehyde (MDA) levels, SOD and
CAT activities were measured in patients with type 2 diabetes mellitus and nondia-
betic healthy control participants.

• Superoxide dismutase(s) SODs form the front line of defense against ROS-
mediated injury.
• Catalase enzyme brings about (catalyzes) the reaction by which hydrogen
peroxide is decomposed to water and oxygen.

It was found that LPO, a natural component of the immune system, in the type 2
diabetic patients with retinopathy was signifcantly higher, whereas SOD and CAT
activities were signifcantly lower compared to those of controls. MDA concentra-
tions (see the following) rose, while SOD and CAT activities fell with increasing
severity of diabetic retinopathy.
The investigators concluded that leukocytes in patients with type 2 diabetic reti-
nopathy are affected by oxidative stress, which might contribute to the pathogenesis
of the retinopathy. (2)

Free radicals generate lipid peroxidation. MDA is one of the fnal products
of PUFA peroxidation in the cells. An increase in free radicals causes over-
production of MDA. MDA level is commonly known as a marker of oxidative
stress and antioxidant status. (3)

Just as oxidative stress is considered to be a damaging factor in type 2 diabetes so

too can antioxidants neutralize it. This was shown in a clinical study published in
L-Arginine and Omega-3 Fatty Acids for Type 2 Diabetes and CKD 127

the journal Diabetes Care in 2004. The aim of the study was to determine whether
antioxidant intake could predict type 2 diabetes. The study centered on a cohort of
men and women 40 to 69 years of age, free of diabetes at baseline. Food consump-
tion during the previous year was estimated using a dietary history interview, and
intake of vitamin C, four tocopherols, four tocotrienols and six carotenoids were
determined. Follow-up lasted 23 years.
It was found that vitamin E intake was signifcantly associated with a reduced
risk of type 2 diabetes. Intakes of α-tocopherol, γ-tocopherol, δ-tocopherol and
β-tocotrienol were inversely related to a risk of type 2 diabetes. Among single carot-
enoids, β-cryptoxanthin intake was signifcantly associated with a reduced risk of
type 2 diabetes. The investigators concluded that development of type 2 diabetes
may be reduced by the intake of antioxidants in the diet. (4)
Some prospective studies have shown that higher vegetable and fruit consumption
may lower the risk of developing diabetes, suggesting that antioxidants in the diet may
have a synergistic effect. For instance, a study published in Diabetes Care in 1995
investigated the role of diet as a predictor of glucose intolerance and type 2 diabetes.
At the 30-year follow-up survey of the Dutch and Finnish cohorts of the Seven
Countries Study (1989/1990), men were examined according to a standardized pro-
tocol, including a two-hour oral glucose tolerance test. Information on habitual
food consumption was obtained using the cross-check dietary history method, (5)
a dietary survey method to estimate the habitual food consumption of individuals.
Those men in whom information on habitual diet was also available 20 years earlier
were included in this study. Participants with known diabetes in 1989/1990 were
excluded from the analyses.
It was found that adjusting for age and cohort, the intake of total saturated
and monounsaturated fatty acids and dietary cholesterol 20 years before diagnosis
was higher in men with newly diagnosed diabetes in the survey than in men with
normal or impaired glucose tolerance. After adjustment for cohort, age, past
body mass index and past energy intake, the past intake of total fat was signif-
cantly positively associated with two-hour, post-load glucose level. There was a
signifcant inverse association with the past intake of vitamin C. These associa-
tions were independent of changes in the intake of fat and vitamin C during the
20-year follow-up. A greater consumption of vegetables and legumes, potatoes and
fsh during the 20-year follow-up was found to be signifcantly inversely related to
two-hour glucose level.
The investigators concluded that these results indicate that a high intake of fat,
especially that of saturated fatty acids, contributes to the risk of glucose intolerance
and type 2 diabetes, while foods such as fsh, potatoes, vegetables and legumes may
have a protective effect. Furthermore, the observed inverse association of vitamin C
and glucose intolerance suggests that antioxidants may also play a role in the devel-
opment of derangements in glucose metabolism. (6)

A prospective study watches for outcomes, such as the development of a dis-

ease, during the study period and relates this to other factors, such as sus-
pected risk.
128 Flaxseed

7.1.2 ENDOTHELIAL DYSFUNCTION IN TYPE 2 DIABETES

Having shown in the previous section that ROS plays an adverse role in type 2
diabetes, it remains now to show that its adverse impact is on the endothelium.
Endothelial dysfunction has received increasing attention as a potential contributor
to the pathogenesis of vascular disease in diabetes mellitus: the delicate balanced
release of endothelial-derived relaxing and contracting factors is altered in diabetes,
thereby contributing to further progression of vascular and end-organ damage. (7)
A clinical study published in the Journal of the American Medical Association
in 2004 aimed to assess the relationship between the biomarkers of endothelial dys-
function and the risk of type 2 diabetes. Elevated plasma levels of biomarkers refect-
ing endothelial dysfunction (E-selectin; intercellular adhesion molecule 1 [ICAM-1];
and vascular cell adhesion molecule 1 [VCAM-1]) were shown to predict develop-
ment of type 2 diabetes in initially nondiabetic women.
In a prospective study within the Nurses’ Health Study, an ongoing US study initi-
ated in 1976, women who were initially enrolled provided blood samples from 1989
to 1990. Controls were selected according to matching age, fasting status and race.
It was found that baseline median levels of the biomarkers E-selectin, 61.2 vs.
45.4 ng/mL; ICAM-1, 264.9 vs. 247.0 ng/mL; and VCAM-1, 545.4 vs. 526.0 ng/
mL were signifcantly higher among type 2 diabetes cases than among controls.
Elevated E-selectin and ICAM-1 levels predicted incident diabetes. The adjusted
relative risks for incident diabetes in the top quintile vs. the bottom quintiles were
5.43 for E-selectin, 3.56 for ICAM-1 and 1.12 for VCAM-1.

E-selectin (CD62E) is a glycoprotein expressed on endothelial cells only after

activation by interleukin 1 (IL-1), tumor necrosis factor α (TNFα) or bacte-
rial lipopolysaccharides. E-selectin expression might be crucial to control-
ling leukocyte accumulation in infammatory responses. ICAM-1 plays a role
in infammatory processes and in the T-cell mediated host defense system.
VCAM-1 protein mediates the adhesion of lymphocytes, monocytes, eosino-
phils and basophils to vascular endothelium. It also functions in leukocyte-
endothelial cell signal transduction, and it may play a role in the development
of atherosclerosis and rheumatoid arthritis.

Adjustment for waist circumference instead of body mass index (BMI) or further
adjustment for baseline levels of C-reactive protein (CRP), fasting insulin and hemo-
globin Hba1c or exclusion of cases diagnosed during the frst four years of follow-up
did not alter these fndings.
The investigators concluded that endothelial dysfunction predicts type 2 diabetes
in women independent of other known risk factors, including obesity and subclinical
infammation. (8) Given these fndings, one might reasonably expect that faxseed
taken as a whole, because it contains antioxidant omega-3 fatty acids as well as
the NO-donor L-arginine (and the NO-donor cyanogenic glycosides), should have a
signifcant benefcial effect on type 2 diabetes.
L-Arginine and Omega-3 Fatty Acids for Type 2 Diabetes and CKD 129

7.2 FLAXSEED AS ADJUVANT TREATMENT OF TYPE 2 DIABETES

A number of functional foods have been shown to possess hypoglycemic properties.
(9) Flaxseed is a functional food that is rich in omega-3 fatty acids and other
antioxidants and is low in carbohydrates. Flaxseed contains 32% to 45% of its mass
as oil of which 51% to 55% is alpha-linolenic acid (ALA).
Research titled “In Vivo and In Vitro Antidiabetic and Anti-Infammatory
Properties of Flax (Linum usitatissimum L.) Seed Polyphenols,” published in a report
in the journal Nutrients in 2021, was conducted on mice and Wistar rats. It found
18 active polyphenols and concluded that they may serve as dietary supplements or
novel phytomedicines to treat diabetes and its complications. (10)
A clinical open-label study on the effect of fax seed powder in the management of
diabetes—a trial where participants and investigators know which treatment/substance
each one is receiving—was published in the Journal of Dietary Supplements in 2011. The
study aimed to determine the effcacy of faxseed supplementation in type 2 diabetes.
The experimental group diet was supplemented daily with 10 grams of faxseed
powder for a period of one month. The control group received no supplementation or
placebo. During the study, diet and drug regimen of the participants were unaltered.
The effcacy of supplementation with faxseed was evaluated by a battery of clinico-
biochemical parameters.
Supplementation with faxseed signifcantly reduced fasting blood glucose by
19.7% and glycated hemoglobin (HbA1c) by 15.6%. A favorable signifcant reduction
in total cholesterol (14.3%), triglycerides (17.5%), low-density lipoprotein cholesterol
(21.8%), apolipoprotein B and a signifcant increase in high-density lipoprotein
cholesterol (11.9%) were also noticed.
These observations suggest the therapeutic potential of faxseed in the manage-
ment of diabetes mellitus. (11) There are in addition, many randomized blind-control
studies, reviews and meta-analyses with positive outcome reports. For example:
A clinical study published in the journal Nutrition Research in 2013 aimed to
determine whether, in overweight or obese individuals with pre-diabetes, fasting
glucose, insulin, fructosamine, CRP, interleukin-6 will decrease and adiponectin
will increase with daily faxseed consumption.

Serum fructosamine is a glycated protein.

Overweight or obese men and postmenopausal women with pre-diabetes consumed

0.0, 13 or 26 grams of ground faxseed for 12 weeks. Glucose, insulin, homeostatic
model assessment (HOMA-IR) and normalized percent of ALA were obtained.
Glucose decreased signifcantly on the 13 gram intervention compared to the 0.0
gram period [13 g = −2.10 ± 1.66 mg/L (mean ± SEM), 0 g = 9.22 ± 4.44 mg/L].
Insulin decreased signifcantly on the 13 gram intervention but not the 26 gram and 0.0
gram periods (13 g = −2.12 ± 1.00 mU/L, 26 g = 0.67 ± 0.84 mU/L, 0 g = 1.20 ± 1.16
mU/L). HOMA-IR decreased signifcantly on the 13 gram period but not on the 26
gram and 0.0 gram periods (13 g = −0.71 ± 0.31, 26 g = 0.27 ± 0.24, 0 g = 0.51 ± 0.35).
130 Flaxseed

The ALA increase for the 0.0 gram period was signifcantly different from the
13 gram and the 26 gram periods (13 g: 0.20 ± 0.04, 26 g: 0.35 ± 0.07, 0 g: −0.01 ±
0.07). Fructosamine, high-sensitivity C-reactive protein (hCRP), adiponectin and
high-sensitivity interleukin-6 showed no signifcant differences. Flaxseed intake
signifcantly decreased glucose and insulin and improved insulin sensitivity as
part of a habitual diet in overweight or obese pre-diabetes individuals. (12)
A meta-analysis published in the journal Nutrition Reviews in 2018 aimed to
systematically review and analyze randomized controlled trials to determine the
effects of faxseed consumption on glycemic control. The investigators searched
PubMed, Medline via Ovid, SCOPUS, Embase and ISI Web of Sciences databases
up to November 2016. They selected clinical trials where faxseed or its products
were administered as an intervention.
It was found that there is a signifcant association between faxseed supplementation
and a reduction in blood glucose, insulin levels and HOMA-IR index, as well as an
increase in QUICKI index (see the following). There was no signifcant impact on
HbA1c. In subgroup analysis, a signifcant reduction in blood glucose, insulin and
HOMA-IR and a signifcant increase in QUICKI were found only in studies using
whole faxseed but not faxseed oil and lignan extract. Furthermore, a signifcant
reduction was observed in insulin levels and insulin sensitivity indexes only in the
subset of trials lasting ≥12 weeks. It was concluded that whole faxseed, but not
faxseed oil and lignan extract, signifcantly improves glycemic control. (13)

• The QUICKI index is a quantitative insulin sensitivity check index,

a novel mathematical transformation of fasting blood glucose and
insulin levels. It is derived using the inverse of the sum of the loga-
rithms of the fasting insulin and fasting glucose:
• 1 / (log(fasting insulin μU/mL) + log(fasting glucose mg/dL))
• This index correlates well with glucose clamp studies, and it is useful for
measuring insulin sensitivity, which is the inverse of insulin resistance.
It has the advantage that it can be obtained from a fasting blood sample
and is the preferred method for certain types of clinical research. (14)

Another open-labeled clinical trial published in the journal Clinical Nutrition

Research in 2019 was conducted on patients with type 2 diabetes to investigate the
effect of faxseed-enriched yogurt on glycemic control, lipid profles and blood pres-
sure. Participants were given 200 grams of 2.5% fat yogurt containing 30 grams of
faxseed, or plain yogurt daily for eight weeks.
After eight weeks of supplementation, HbA1c decreased signifcantly in the inter-
vention group compared to that in controls. Also, at the end of the study, there were
signifcant differences between the faxseed-enriched yogurt group and the control
groups, in triglycerides and total cholesterol concentrations, systolic blood pressure
and diastolic blood pressure.
No signifcant differences were found between the two groups in low-density
lipoprotein, high-density lipoprotein, body weight and waist circumference, and it
L-Arginine and Omega-3 Fatty Acids for Type 2 Diabetes and CKD 131

was therefore concluded that the addition of faxseed to yogurt can be effective in the
management of type 2 diabetes. (15)
Omega-3 fatty acids reduce insulin resistance: A prospective study published in
the journal Annals of Medical Health Sciences Research in 2013 aimed to determine
the effects of antioxidants, e.g., AL, omega-3 fatty acid and vitamin E on parameters
of insulin sensitivity (blood glucose and HbA1c) in type 2 diabetes patients with
documented insulin resistance. Patients were given ALA, omega 3 fatty acid and
vitamin E or just a placebo. Fasting blood glucose and HbA1c were measured at frst
visit (Visit 1) and after 90 days (Visit 2).
It was found that analysis of baseline (Visit 1) vs. end of treatment period (Visit 2)
parameters, showed signifcant decrease in HbA1c in the three treatment groups. A
decrease in fasting blood glucose in the three treatment groups was observed, but it
was not statistically signifcant. The investigators concluded that ALA, omega-3 and
vitamin E can be used as “add-on” therapy in patients with type 2 diabetes mellitus
to improve insulin sensitivity and lipid metabolism. (23)
A clinical study published in the journal Scientifc Reports in 2014 aimed to determine
whether Omega-3 Index, i.e., red blood cell concentrations of eicosapentaenoic acid (EPA)
and docosahexaenoic acid (DHA), affects insulin sensitivity and other metabolic out-
comes. The study was conducted on overweight men aged, on average, 46.5 ± 5.1 years.
The participants were assessed twice, 16 weeks apart. Insulin sensitivity was
assessed by the Masuda method (55) (see the following) from an oral glucose toler-
ance test. The participants were separated according to their Omega-3 Index values,
e.g., lower tertiles (LOI) and highest tertile (HOI).
Increasing Omega-3 Index was signifcantly correlated with higher insulin sensi-
tivity, higher disposition index and lower CRP concentrations. Masuda Index insulin
sensitivity scores were 43% (signifcantly) higher in HOI than in LOI men. Similarly,
HOI men had a disposition index that was 70% (signifcantly) higher and fasting insu-
lin concentrations 25% (signifcantly) lower. HOI men displayed signifcantly lower
nocturnal systolic blood pressure and signifcantly greater systolic blood pressure
dip. Men in the HOI group also had signifcantly lower concentrations of CRP (41%
lower) and signifcantly lower concentrations of free fatty acids (21% lower).
The investigators concluded that a higher Omega-3 Index is associated with
increased insulin sensitivity and a more favorable metabolic profle in middle-aged
overweight men. (25)

• The Masuda Index indicates values that are comparable to the rate
of disappearance of plasma glucose measured by insulin clamp
(1mU/kg per min insulin infusion, corrected at the insulin concen-
tration of 100 microU/mL) with glucose tracer.
• The Disposition Index is the product of insulin sensitivity times the
amount of insulin secreted in response to blood glucose levels.

7.2.1 OMEGA-3 FATTY ACIDS REDUCE TRIGLYCERIDES IN TYPE 2 DIABETES

The aim of another prospective study published in the Journal of Clinical and
Diagnostic Research in 2017 was to determine the effects of omega-3 fatty acids
132 Flaxseed

(derived from fsh oil) on lipid profle in type 2 diabetes patients. Patients were
assigned to three groups: Group 1 received 500 mg of metformin twice daily and a
placebo; Group 2 received 500 mg of metformin twice daily plus 1 gram of omega-3
fatty acids once daily; Group 3 received 500 mg of metformin twice daily and 1 gram
of omega-3 fatty acids twice daily.
It was found that Group 2 signifcantly reduced the triglyceride level from 144.59 ±
14.18 mg/dL to 101 ± 13.31 mg/dL, compared to Group 1, which reduced triglyceride
level from 147.67 ± 18.57 mg/dL to 145.8 ± 19.86 mg/dL, respectively. Group 3 receiv-
ing 1 gram of omega-3 fatty acids twice daily showed a signifcant decrease from
144.83 ± 22.17 mg/dL to 86 ± 17.46 mg/dL and was more effective in reducing tri-
glyceride levels than Group 2 receiving only 1 gram of omega-3 fatty acids once daily.
The investigators concluded that omega-3 fatty acids can be given in conjunction
with metformin to reduce triglyceride levels in diabetic dyslipidemia without any
adverse drug effects or drug interactions. Omega-3 fatty acids were effective in reduc-
ing the triglyceride level signifcantly, as compared to placebo. Two grams of omega-3
fatty acids are, however, more effective than 1 gram in reducing triglyceride levels. (24)

7.2.2 TYPE 2 DIABETES AND CORONARY HEART DISEASE

Type 2 diabetes has been strongly linked to coronary heart disease. Patients with type
2 diabetes are at increased risk of myocardial infarction and stroke. (26) A study
published in the British Journal of Nutrition in 2019 was performed to determine
the effects of vitamin D and omega-3 fatty acids co-supplementation on markers of
cardiometabolic risk in diabetic patients with coronary heart disease (CHD). The
trial was conducted on vitamin D–defcient diabetic patients with CHD. At baseline,
the range of serum 25-hydroxyvitamin D levels in study participants was 6.3–19.9
ng/mL. The participants were assigned to two groups either taking 50,000 IU vitamin
D supplements every two weeks plus 1,000 mg omega-3 fatty acids from faxseed oil
or a placebo twice a day for six months.
Vitamin D and omega-3 fatty acids co-supplementation signifcantly reduced
mean and maximum levels of right and left carotid intima-media thickness, com-
pared to the placebo group. The effect of increases in intima-media thickness of the
carotid is a sign of cardiovascular disease.
In addition, co-supplementation led to a signifcant reduction in fasting plasma glu-
cose (β −0·40 mmol/l), insulin (β −1·66 μIU/mL), insulin resistance (β −0·49) and LDL
cholesterol (β −0·21 mmol/l), and a signifcant increase in insulin sensitivity (β + 0·008)
and HDL cholesterol (β + 0·09 mmol/L) compared to the placebo group. High-sensitivity
CRP (β −1·56 mg/L) was signifcantly reduced in the supplemented group compared to
the placebo group. The investigators concluded that vitamin D and omega-3 fatty acids
co-supplementation had benefcial effects on markers of cardiometabolic risk. (27)

7.2.3 OMEGA-3 FATTY ACID AS ADJUVANT TREATMENT OF TYPE 2

DIABETES AND NONALCOHOLIC FATTY LIVER DISEASE (NAFLD)
Nonalcoholic fatty liver disease (NAFLD; steatohepatitis) is rapidly becoming the
most common liver disease worldwide. It can progress to liver cirrhosis and, it is
L-Arginine and Omega-3 Fatty Acids for Type 2 Diabetes and CKD 133

thought, even to hepatocarcinoma. The prevalence of NAFLD is 80% to 90% in

obese adults, 30% to 50% in patients with diabetes and up to 90% in patients with
hyperlipidemia. (29)
The aim of a clinical trial published in the Chinese Journal of Internal Medicine
(Zhonghua Nei Ke Za Zhi) was to determine the relationship between serum omega-3
polyunsaturated fatty acid (omega-3 PUFA) levels and insulin resistance (IR) in patients
with type 2 diabetes mellitus and NAFLD. The trial was conducted on patients with
type 2 diabetes mellitus with NAFLD (Group 4), patients with type 2 diabetes alone
(Group 3), patients with only NAFLD (Group 2) and healthy control participants (Group
1). Serum omega-3 PUFA profle was analyzed with capillary gas chromatography.
Insulin resistance was assessed by homeostasis model assessment (HOMA-IR). ALT,
AST, gamma-glutamyltransferase (GGT) and serum lipids were measured.
It was found that the levels of HOMA-IR were signifcantly higher in patients
with type 2 diabetes mellitus with NAFLD (Group 4) than those in Group 3 (type
2 diabetes alone), Group 2 (patients with only NAFLD) and Group 1 (control). The
levels of ALT, AST, GGT, TC, TG, LDL-C were signifcantly higher in Group 4 than
those in Group 3, Group 2 or Group 1. The level of omega-3 PUFA was signifcantly
lower in Group 4 than those in Groups 3, 2 or 1. Omega-3 PUFA concentration was
signifcantly negatively correlated with HOMA-IR, TC, TG and LDL-C.
The investigators concluded that serum omega-3 PUFA is signifcantly lowered in
patients with type 2 diabetes mellitus and NAFLD. Serum omega-3 PUFA is signif-
cantly negatively correlated with insulin resistance. Thus, it can be said that omega-3
PUFA plays a very important role in blunting the development of diabetes mellitus
and NAFLD. (30)

7.2.4 OMEGA-3 FATTY ACID AS ADJUVANT TREATMENT OF

TYPE 2 DIABETES WITH DIABETIC NEPHROPATHY
The aim of a meta-analysis published in the journal PlosOne in 2020 was to eval-
uate the effects of omega-3 PUFA on proteinuria, estimated glomerular fltration
rate (eGFR) and metabolic biomarkers among patients with diabetes. The electronic
search included PubMed, Embase and Cochrane Central Register of Controlled
Trials from January 1960 to April 2019 to identify randomized control trials, which
examined the effects of omega-3 fatty acids on proteinuria, eGFR and metabolic
biomarkers among diabetic patients.
It was found that omega-3 fatty acids reduced the amount of proteinuria among
type 2 diabetes mellitus to a statistically signifcant extent. While they also tended to
lower proteinuria in type 1 diabetes mellitus patients, the effect was not statistically
signifcant. And only studies where the duration of intervention was 24 weeks or
longer demonstrated a signifcantly lower proteinuria in omega-3 fatty acids treated
patients compared to the control group.
There was a higher eGFR in both type 1 and type 2 diabetes groups in omega-3
fatty acids treated patients vs. the control group. However, the effect was not
statistically signifcant.
It was concluded that omega-3 fatty acids could help ameliorate proteinuria in
type 2 diabetes with supplementation lasting at least 24 weeks. (31)
134 Flaxseed

A study reported in the Iran Journal of Kidney Diseases in 2016 was performed
to determine the effects of omega-3 fatty acid supplementation on infammatory
cytokines and advanced glycation end products (AGEs) in patients with diabetic
nephropathy (DN). Patients with DN were randomly divided into two groups to receive
either 1,000 mg/d of omega-3 fatty acid from faxseed oil or a placebo for 12 weeks.
The primary outcome variables were tumor necrosis factor-α (TNF-α), receptor tumor
necrosis factor alpha and growth differentiation factor 15. Fasting blood samples were
taken at the onset and the end of the study to quantify the related markers.
It was found that, compared to placebo, omega-3 fatty acid supplementation resulted
in a signifcant decrease in serum AGEs (−2.3 ± 2.8 AU versus 0.2 ± 2.5 AU). Despite
a signifcant reduction in serum level of the receptor for AGEs (−0.1 ± 0.3 AU) in the
omega-3 fatty acid group, no signifcant difference was found between the two groups
in terms of their effects on the receptor for AGEs. Supplementation with omega-3
fatty acid had no signifcant effect on the infammatory cytokines as compared with
the placebo. The investigators concluded that omega-3 fatty acid supplementation in
patients with diabetic nephropathy had favorable effects on AGEs. (32)

AGEs are proteins or lipids that become glycated as a result of exposure to

sugars. They are a biomarker implicated in aging and the development, or
worsening, of many degenerative diseases, such as diabetes, atherosclerosis
and chronic kidney disease.

7.2.5 TREATMENT DOSAGE MATTERS

There is some disagreement about the possible benefcial effects of omega-3 PUFA
supplementation in patients with diabetes and cardiovascular disease. It is likely that
conficting results between different clinical studies and meta-analyses could be due
to variable dosage supplementation and supplementation duration, either of which
could alter the effects of omega-3 PUFA on cardiometabolic biomarkers.
The authors of a report in 2018, in the journal Cardiovascular Diabetology,
contend that meta-analyses are commonly limited by the inability to draw inferences
regarding dosage, duration and the interaction of dosage and duration of omega-3
PUFA intake. Even so, almost all end points in the so-called negative meta-analyses
leaned toward a trend for beneft with a near 10% reduction in cardiovascular
outcomes and a borderline statistical signifcance.
However, many trials included in these meta-analyses tested an insuffcient daily
dose of omega-3 PUFA of less than 1,000 mg. Probably, the consistent cardiovascular
effects of omega-3 PUFA supplements could be expected only with daily doses of
more than 2,000 mg. (28)

7.2.6 L-ARGININE AS ADJUVANT TREATMENT OF TYPE 2 DIABETES—IS TYPE 2

DIABETES MELLITUS AN NO DEFICIENCY DISEASE?
While omega-3 and other constituents of faxseed and fax oil deliver antioxidants
that protect the endothelium, L-arginine (which as we recall is abundant in fax seed)
L-Arginine and Omega-3 Fatty Acids for Type 2 Diabetes and CKD 135

delivers NO, which seems to play a key role in promoting insulin release and over-
coming insulin resistance. Recent studies have shown that reduced synthesis of NO
from L-arginine in endothelial cells is a major factor contributing to the impaired
action of insulin in the vasculature of obese and diabetic people. (51)
The decreased NO generation results from (1) a defciency of (6R)-5,6,7,8-
tetrahydrobiopterin (BH4), (33) an essential cofactor for NO synthase (NOS), and
(2) increased generation of glucosamine, an inhibitor of the pentose cycle for the
production of NADPH, another cofactor for NOS, from glucose and L-glutamine.

A superoxide dismutase-mimetic (tempol) reversed the diabetes mellitus–

induced reduction of GTPCH and BH4 and endothelial dysfunction in strepto-
zotocin-induced diabetes mellitus in an animal (rat) model. (33)

According to a report published in the journal Biofactors in 2009, endothelial dys-

function can be prevented by (1) enhancement of BH4 synthesis through supple-
mentation of its precursor (sepiapterin) via the salvage pathway, (2) transfer of the
gene for GTP cyclohydrolase-I (the frst and key regulatory enzyme for de novo syn-
thesis of BH4) or (3) dietary supplementation of L-arginine (which stimulates GTP
cyclohydrolase-I expression and inhibits hexosamine production). Modulation of the
arginine-NO pathway by BH4 and arginine is benefcial for ameliorating vascular
insulin resistance in obesity and diabetes. (34)
Chronic L-arginine supplementation has been shown to improve insulin sensitivity
and endothelial function in nonobese type 2 diabetic patients. The aim of a study
published in the American Journal of Physiology, Endocrinology and Metabolism
in 2006 was to determine the effects of a long-term oral L-arginine therapy on
adipose fat mass (FM) and muscle free-fat mass (FFM) distribution, daily glucose
levels, insulin sensitivity, endothelial function, oxidative stress and adipokine release
in obese type 2 diabetic patients with insulin resistance who were treated with a
combined regimen of hypocaloric diet and exercise training.
Type 2 diabetes patients who participated in a hypocaloric diet plus an exercise
training program for 21 days were divided into two groups: the frst group was also
treated with 8.3 g/day of L-arginine, and the second group was treated with a placebo.
It was found that body weight, waist circumference, daily glucose profles, fruc-
tosamine, insulin and homeostasis model assessment index signifcantly decreased
in both the diet plus exercise group that received placebo and the diet plus exercise
group that received L-arginine. In addition, L-arginine supplementation further sig-
nifcantly decreased FM and waist circumference preserving FFM and signifcantly
improved mean daily glucose profles and fructosamine.
Additional signifcant outcomes were a decrease in the area under the curve of
cGMP, second messenger of NO; superoxide dismutase, index of antioxidant capac-
ity; and increased adiponectin levels, whereas basal endothelin-1 levels and leptin-
to-adiponectin ratio decreased signifcantly in the L-arginine group.
The investigators concluded that long-term oral L-arginine treatment resulted
in an additive effect compared with a diet and exercise training program alone on
glucose metabolism and insulin sensitivity. Furthermore, it improved endothelial
136 Flaxseed

function, oxidative stress and adipokine release in obese type 2 diabetic patients
with insulin resistance. (35)
TNF-α is an infammatory cytokine produced by macrophages/monocytes during
acute infammation and is responsible for a diverse range of signaling events within
cells leading to necrosis or apoptosis. The protein is also important for helping the
body fght off infections and cancers.
Diabetes and obesity are very commonly associated metabolic disorders that are
linked to chronic infammation. Leptin is one of the important adipokines released
from adipocytes, and its level increases with increasing BMI. TNF-α is released
not only by immune cells (macrophages/monocytes) but by adipocytes as well in
response to chronic infammation. Type 2 diabetes mellitus is believed to be associ-
ated with low-grade chronic infammation. (36)
The aim of a study published in theEuropean Review for Medical and Pharmacological
Sciences journal in 2012 was to determine the infuence of L-arginine supplementa-
tion on TNF-α, insulin resistance and selected anthropometric and biochemical param-
eters in patients with visceral obesity. The patients with visceral obesity were randomly
assigned to either receive 9 grams of L-arginine or a placebo for three months. Healthy
lean participants were used as control. Selected anthropometrical measurements and
blood biochemical analyses were performed at baseline and after three months. TNF-α
and its soluble receptor 2 (sTNFR2) were assessed in both treated groups. Insulin resis-
tance in the participants was evaluated according to the HOMA-IR protocol.
It was found that the concentration of insulin, TNF-α and sTNFR2 and HOMA-IR
levels in obese patients signifcantly exceeded those observed in the control partici-
pants. Basal TNF-α and sTNFR2 concentrations were positively correlated with basal
BMI, waist circumference, percent of body fat and HOMA-IR. Furthermore, three-
month L-arginine supplementation resulted in a signifcant decrease in HOMA-IR
and insulin concentration. Only an insignifcant tendency to decrease TNF-α and
sTNFR2 was observed.
The investigators confrmed the role of TNF-α in the complex pathogenesis
of insulin resistance in patients with visceral obesity. The three-month, 9-gram
L-arginine dose supplementation improved insulin sensitivity in patients with vis-
ceral obesity. (37)
The aim of a study published in the journal Diabetes Care in 2001 was to deter-
mine whether long-term administration of L-arginine acting by normalizing the
cGMP pathway could ameliorate peripheral and hepatic insulin sensitivity in lean
type 2 diabetic patients.
The study was conducted over a period of three months. In the frst month, patients
remained on their usual diet; then they were randomly assigned to two groups. In
group 1, they were treated with diet plus oral placebo three times per day for two
months. In group 2, they were treated for one month with diet plus oral placebo
three times per day. Then for one month, they were treated with diet plus 3 grams of
L-arginine three times per day.
At the end of the frst and the second month, patients underwent a euglycemic-
hyperinsulinemic clamp combined with [6,6–2H2] glucose infusion.
It was found that in control group 1, there were no changes in basal cGMP lev-
els, systolic blood pressure, forearm blood fow, glucose disposal and endogenous
L-Arginine and Omega-3 Fatty Acids for Type 2 Diabetes and CKD 137

glucose production. In group 2, however, L-arginine normalized basal cGMP levels

and signifcantly increased forearm blood fow by 36% and glucose disposal during
the clamp by 34%, and it signifcantly decreased systolic blood pressure and endog-
enous glucose production by 14% and 29%, respectively. However, compared to that
in control participants, the L-arginine treatment did not completely overcome the
defect in glucose disposal.
The investigators concluded that L-arginine treatment signifcantly improves but
does not completely normalize peripheral and hepatic insulin sensitivity in type 2
diabetic patients. (38)
What makes these two studies particularly interesting is not only that they dem-
onstrated the benefts of L-arginine in correcting glucose metabolism but that they
tied it to the action of NO via the cGMP element of the NO/cGMP pathway.
There is considerable evidence that NO affects insulin release and metabolism, but
overall the evidence is controversial. On balance, eNOS-derived NO seems to stimulate
insulin release (eNOS is a constitutive NOS). On the other hand, inducible, i.e., iNOS-
derived NO, is said to inhibit insulin secretion. (39, 40) According to a report published
in the EXCLI Journal in 2020, NO increases insulin secretion. Decreased NO bioavail-
ability has been demonstrated in obesity and type 2 diabetes in both animal and human
studies and restoration of NO levels has many favorable metabolic effects in type 2
diabetes, suggesting that NO through modulation of insulin secretion and its signaling
pathways may be a potential target for the treatment of type 2 diabetes.
However, some studies have shown that inhibition of islet NO synthase (NOS)
activity is accompanied by an increase in glucose-stimulated insulin secretion
(GSIS). Moreover, GSIS has been shown to be suppressed by different concentra-
tions of NO-donors, indicating a negative role of NO in insulin secretion.
It is proposed in that report that the controversy over the role of NO in insu-
lin secretion may be artifactual, i.e., that it depends on the use of various β-cell
lines with different qualitative/quantitative secretory reaction patterns, incubation of
islets/β-cells in high or low glucose media, using different NOS inhibitors or differ-
ent types of extracellular/intracellular NO-donors. Also varying enzymatic activities
of the different isoforms of NOS may be of importance. (41)
Finally, a number of clinical studies have also established the effects of L-arginine
supplementation by administering it intravenously. The aim of such a clinical study
published in the European Journal of Clinical Investigation in 1997 was to deter-
mine the effect of a low-dose intravenous supplementation of L-arginine on insulin-
mediated vasodilatation and insulin sensitivity.
The study was conducted on healthy participants and on patients with obesity
and type 2 diabetes mellitus. Insulin-mediated vasodilatation was measured by
venous occlusion plethysmography during the insulin suppression test, evaluat-
ing insulin sensitivity. Measurements were obtained twice for each healthy par-
ticipant and each patient with or without a concomitant infusion of 0.52 mg/kg−1
min−1 of L-arginine.
L-Arginine signifcantly restored the impaired insulin-mediated vasodilatation
observed in obesity and type 2 diabetes. No signifcant effect on insulin-mediated
vasodilatation was observed in healthy participants. Insulin sensitivity was signif-
cantly improved in all groups by infusion of L-arginine. L-Arginine had no effect
138 Flaxseed

on insulin, insulin-like growth factor I (IGF-I), free fatty acids (FFAs) or C-peptide
levels during the insulin suppression test.
The data show that defective insulin-mediated vasodilatation in obesity and type
2 diabetes can be normalized by intravenous L-arginine: L-arginine improves insu-
lin sensitivity in obese and type 2 diabetes patients, as well as in healthy subjects,
suggesting a possible mechanism that is different from the restoration of insulin-
mediated vasodilatation. (42)

7.3 FLAX, INFLAMMATION AND ENDOTHELIUM

DYSFUNCTION IN CKD
Chronic kidney disease (CKD), also called chronic kidney failure, is the loss of
kidney fltration function. The advanced form causes dangerous levels of fuid, elec-
trolytes and wastes to build up in the body. In the early stages of CKD, there may be
few signs or symptoms, if any. Treatment centers on slowing the progression of kid-
ney damage, usually by controlling the cause. But even controlling the cause might
not keep kidney damage from progressing. CKD can progress to end-stage kidney
failure, which is fatal without artifcial fltering (dialysis) or a kidney transplant.
According to the Centers for Disease Control and Prevention in “Chronic Kidney
Disease in the United States, 2021,” 15% of US adults, or 37 million people, are estimated
to have CKD. As many as nine in ten adults with CKD do not know they have it, and
about two in fve adults with severe CKD do not know they have it. (52) Since there is
no cure for CKD, what contribution can faxseed, per se, or its relevant constituents,
omega-3 fatty acid, L-arginine or cyanogenic glycosides, make to favorably altering the
course of the disease? Simply put, CKD shares endothelium dysfunction with cardiovas-
cular diseases that likewise proft from restoring endothelial NO formation.

7.3.1 FLAXSEED AS ADJUVANT TREATMENT OF CKD

There are a number of reports of the benefcial effects of faxseed, per se, on kidney
dysfunction, but they are largely based on experimental (animal-model) studies. For
instance, a study published in the journal Kidney International in 2003 sought to deter-
mine whether changing the source of protein intake from animal protein, casein, to
plant protein in the form of either soy protein concentrate or faxseed protein in the diet
would have a different impact on renal function and nephropathy in male obese SHR/
N-cp rats model (which commonly, as a matter of course, tend to develop diabetes).
The subjects were assigned to one of three diets containing either 20% casein,
20% soy protein concentrate or 20% faxseed meal. Except for the protein source,
all three diets were identical and contained similar amounts of protein, fat, carbo-
hydrates, minerals and vitamins. All animals were maintained on these diets for
six months. At the end of the study period, blood sampling and 24-hour urine col-
lections were performed for renal functional measurements, and the kidneys were
harvested and examined for histologic evaluation.
It was found that all three groups had similar amounts of food intake and body
weight gain and exhibited fasting hyperglycemia and hyperinsulinemia. Plasma glu-
cose levels did not differ among the three groups, but plasma insulin concentration
L-Arginine and Omega-3 Fatty Acids for Type 2 Diabetes and CKD 139

was signifcantly lower in rats fed faxseed meal than those fed either casein or soy
protein concentrate. Mean plasma creatinine, creatinine clearance and urinary urea
excretion also did not differ signifcantly between the three groups. By contrast, uri-
nary protein excretion was signifcantly lower in subjects fed faxseed than in those
fed either casein or soy protein concentrate.
Morphologic analysis of renal structural lesions showed that the percentage of
abnormal glomeruli with mesangial expansion and the tubulointerstitial score (an
index of severity of tubulointerstitial damage) were signifcantly reduced in rats fed
faxseed meal compared to those fed casein or soy protein concentrate.
The investigators concluded that dietary protein substitution with faxseed meal
reduces proteinuria and glomerular and tubulointerstitial lesions in obese SHR/N-cp
rats and that faxseed meal is more effective than soy protein in reducing proteinuria
and renal histologic abnormalities in this model. The reduction in proteinuria and
renal injury was independent of the amount of protein intake and glycemic control.
But the investigators could not determine which dietary component(s) present in
faxseed meal is (are) responsible for the renal protective effects. (43)
In another experimental study, this one published in the Journal of Oleo Science
in 2013, the investigators report that faxseed-derived PUFAs, including the omega-3
and omega-6 essential fatty acids, have been shown to blunt the effects of hyperten-
sion. It is, however, unclear whether the faxseed, which is rich in these essential fatty
acids, could improve the liver and kidney dysfunctions observed in the hypertensive
condition. The aim of their study was to examine markers of the liver and kidney
function, including aspartate aminotransferase (AST), alanine aminotransferase
(ALT), blood urea nitrogen (BUN), uric acid (UA), creatinine and renin in hyperten-
sive male Wistar rats fed a faxseed diet.
Normotensive subjects maintained on a standard diet were made hypertensive
with a daily administration of 25 mg/kg of cyclosporin A (CYS) for four weeks.
Subsequently, they were either fed a standard diet alone or a faxseed-supplemented
standard diet (FLX; 10% W/W) for eight weeks.
It was found that compared to normotensive rats, standard diet-fed hypertensive
rats had signifcantly elevated blood pressure, altered lipid profles and increased
plasma levels of tissue markers measured immediately following the CYS treat-
ment and thereafter at four- and eight-week intervals. However, subjects fed the fax-
supplemented diet had signifcantly lower blood pressure and improved lipid profles
after four- and eight-week durations.
The investigators reported that the data demonstrated for the frst time the favorable
effects of fax in improving liver and kidney functions in the hypertensive condition, and
concluded that these effects are likely to result from the ALA contents of faxseed. (44)

7.3.2 OMEGA-3 FATTY ACIDS IN ADJUVANT TREATMENT OF KIDNEY DISEASE

A report titled “Polyunsaturated Fatty Acids and Renal Fibrosis: Pathophysiologic
Link and Potential Clinical Iimplications” was published in the Journal of
Nephrology in 2005. The authors contend that PUFA may play a key role in renal
infammation and fbrosis, crucial stages in CKD: benefcial effects of omega-3
PUFA on the course of experimental and human nephropathies have been reported.
140 Flaxseed

PUFAs can ameliorate chronic, progressive renal injury beyond the simple
reduction of serum lipid levels because they also interfere with the formation of
infammatory factors related both to the modulation of the balance of omega-6- and
omega-3-derived eicosanoids and to direct action on the cellular production of the
major cytokine mediators of infammation and on endothelium function.
The mechanisms by which PUFAs can improve some stages in renal fbrosis pro-
cesses, such as mesangial cell activation and proliferation and extracellular matrix
protein synthesis; include the downregulation of some proinfammatory cytokine
production, as well as regulation of renin and NO systems; and expression of peroxi-
some proliferator-activated receptor gene, involved in regulating glucose.
An optimal omega-6/omega-3 PUFA ratio or a high Omega Index dietary intake
could offer new therapeutic strategies aimed at interrupting the irreversible process
of renal fbrosis and ameliorating chronic renal injury. (16)
A study titled “Blood Omega-3 Fatty Acids Are Inversely Associated with
Albumin-Creatinine Ratio in Young and Healthy Adults (The Omega-Kid Study),”
published in the journal Frontiers in Cardiovascular Medicine in 2021, has important
implications for kidney health and disease because an elevated albumin-creatinine
ratio (ACR) is a risk factor for cardiovascular disease (CVD), all-cause mortality and
accelerated glomerular fltration rate (GFR) decline in the general population.
The investigators aimed to determine the relationship between omega-3 PUFAs
and the ACR in healthy individuals with preserved GFR.
The analysis is part of the GAPP study (genetic and phenotypic determinants
of blood pressure and other cardiovascular risk factors), a population-based cohort
of healthy adults aged 25–41 years. Individuals with known CVD, diabetes or a
BMI >35 kg/m2 were excluded. eGFR was calculated according to the combined
Creatinine/Cystatin C CKD-EPI formula. ACR was obtained from a fasting morning
urine sample. The Omega-3 Index (relative amount of EPA and DHA of total fatty
acids in percent) was obtained from whole blood aliquots.

The Omega-3 Index test is a measure of the amount of EPA and DHA in red
blood cell membranes. See https://omegaquant.com/omega-3-index-basic/fpr
test kit availability. (53)

A signifcant inverse relationship was found between the Omega-3 Index and the
ACR. No association was found between the Omega-3 Index and eGFR. The adjusted
difference in eGFR per 1-unit increase in Omega3-Index was signifcant (−0.21).
The investigators concluded that a higher Omega-3 Index is signifcantly associ-
ated with lower ACR in this young and healthy population with preserved eGFR.
Omega-3 fatty acids may exhibit cardio- and nephroprotective effects in healthy
individuals through modulation of the ACR. (17)
Omega-3 fatty acids are associated with a lower risk of CVD and with benefcial
effects on CV risk factors. (54) The ACR is a risk factor for CVD, all-cause mortality
and accelerated GFR declines in the general population.
L-Arginine and Omega-3 Fatty Acids for Type 2 Diabetes and CKD 141

The aim of a meta-analysis published in the journal Clinics (Sao Paulo) in 2017
was to determine the benefts and/or risks of omega-3 fatty acid supplementation in
patients with chronic kidney disease. A systematic search of articles in PubMed,
Embase, the Cochrane Library and reference lists was undertaken: all eligible stud-
ies assessed proteinuria, the serum creatinine clearance rate, the estimated glomeru-
lar fltration rate or the occurrence of end-stage renal disease.
Compared to no-dose or low-dose omega-3 fatty acid supplementation, any or high-
dose omega-3 fatty acid supplementation, respectively, was signifcantly associated
with a lower risk of proteinuria but had little or no effect on the serum creatinine clear-
ance rate or the estimated GFR. However, this supplementation was associated with a
signifcantly reduced risk of end-stage renal disease. The investigators concluded that
omega-3 fatty acid supplementation is associated with a signifcantly reduced risk of
end-stage renal disease and delays the progression of this disease. (18)
Supplementation of omega-3 fatty acid can ameliorate but not reverse CKD, but
such supplementation may be able to avoid it altogether:
Relatively few epidemiological studies have examined the anti-infammatory prop-
erties of PUFA protection against kidney damage in adults. A study published in the
British Journal of Nutrition in 2011 investigated the association between dietary intakes
of PUFA, i.e., omega-3, omega-6, ALA, and fsh and the prevalence of CKD. The study
examined 2,600 Blue Mountains Eye Study participants 50 years old or older.

The Blue Mountains Eye Study is a population-based survey of vision and

common eye diseases in residents of a defned area west of Sydney, Australia.

Dietary data were collected using a semi-quantitative Food Frequency (portion size)
Questionnaire (FFQ) and PUFA and fsh intakes were calculated. Baseline biochem-
istry including serum creatinine was measured. Moderate CKD was defned as an
estimated glomerular fltration rate of < 60 mL/min per 1.73 m2.
Participants in the highest quartile of long-chain omega-3 PUFA intake had a
signifcantly reduced likelihood of having CKD compared with those in the lowest
quartile of intake. The highest, compared with the lowest quartile of fsh consump-
tion, was associated with a reduced likelihood of CKD.
The authors concluded that an increased dietary intake of long-chain omega-3
PUFA and fsh reduces the prevalence of CKD. They hold that a diet rich in
omega-3 PUFA and fsh could have a role in maintaining healthy kidney function, in
addition to their role in preventing other diseases. (19)
Omega-3 PUFA supplementation may reduce cardiovascular mortality in patients
on hemodialysis: another meta-analysis published in the journal Clinical Nutrition
in 2020 aimed to determine the effects of omega-3 PUFA intake on patients with
CKD. The investigators searched Medline, Embase and Central through January 12,
2018. Eligible studies were randomized controlled trials evaluating n-3 PUFA intake
(supplementation or dietary) compared with placebo, standard care or other treat-
ment, on cardiovascular and all-cause mortality, end-stage kidney disease (ESKD),
acute transplant rejection and allograft loss.
142 Flaxseed

It was found that low to very low certainty evidence suggested that omega-3 PUFA
supplementation reduced cardiovascular death for participants on hemodialysis, and pre-
vented ESKD in participants with CKD not receiving renal replacement therapy, but made
little or no difference in all-cause mortality, acute transplant rejection or allograft loss.
It was concluded that omega-3 PUFA supplementation may reduce cardiovascular
mortality in patients on hemodialysis, but it is uncertain whether supplementation
prevents mortality or ESKD in patients with CKD. (20)
Because CKD is typically accompanied by infammation, a study published in
the journal BioMed Research International in 2017 aimed to determine the effect of
six-month supplementation with omega-3 fatty acids on selected markers of infam-
mation in patients with CKD stages 1–3: six-month supplementation with 2 grams/
day of omega-3 was given to CKD patients and to healthy individuals.
At baseline and after follow-up, blood was taken for CRP and monocyte chemo-
tactic protein-1 (MCP-1) concentration analysis and white blood cell (WBC) count.
Serum concentration of omega-3fatty acids—EPA, DHA and ALA—was determined
as well as 24-hour urinary collection was performed to measure MCP-1 excretion.
It was found that after six months of omega-3 supplementation, ALA concentra-
tion increased signifcantly in CKD patients and in the healthy control group, while
EPA and DHA did not change. At follow-up, a signifcant decrease in urinary MCP-1
excretion in CKD and in the reference group was found. CRP, serum MCP-1 and
WBC did not change signifcantly. The estimated glomerular fltration rate (eGFR)
did not change signifcantly in the CKD group.
It was concluded that the reduction in urinary MCP-1 excretion may suggest a
benefcial effect of omega-3 supplementation on tubular MCP-1 production. (21)

MCP-1 is a potent infammatory cytokine. It is one of the key chemokines that

regulate migration and infltration of monocytes/macrophages. Migration of
monocytes from the bloodstream across the vascular endothelium is required
for routine immunological surveillance of tissues, as well as in response to
infammation. (22)

7.3.3 L-ARGININE IN TREATMENT OF CKD

As noted earlier, there is considerable attention given to the benefts of omega-3 fatty
acids in adjuvant treatment of CKD. The benefts are mostly attributed to promoting
endothelium viability. Yet most, albeit not all of the research on L-arginine is con-
ducted on animal models—rats. Investigators are well aware that both diabetes and
chronic kidney disease are related insofar as both share endothelium dysfunction. In
a sense, then, both are “nitric oxide defciency diseases” and a number of investiga-
tors seem well aware of that.
In a report titled “Arginine, Arginine Analogs and Nitric Oxide Production
in Chronic Kidney Disease” published in the journal Nature Clinical Practice
Nephrology in 2006, the authors make a number of cogent points. They contend that
renal disease causes reduced NO production and that this contributes to cardiovas-
cular disease and worsening of kidney damage.
L-Arginine and Omega-3 Fatty Acids for Type 2 Diabetes and CKD 143

They hold that defciency of L-arginine and increased levels of circulating endog-
enous inhibitors of NO synthase (particularly ADMA) cause NO defciency. The
decreased L-arginine availability in CKD is due to perturbed renal biosynthesis of
this amino acid. In addition, elevated plasma and tissue levels of ADMA in CKD
are due to both reduced renal excretion and reduced catabolism by dimethylargi-
nine dimethylaminohydrolase (DDAH). The latter might be associated with loss-of-
function polymorphisms of a DDAH gene, functional inhibition of the enzyme by
oxidative stress in CKD and end-stage renal disease or both.
They also aver that there is support for novel therapies, including supplementa-
tion of dietary L-arginine or its precursor L-citrulline, the inhibition of non-NO-
producing pathways of L-arginine utilization or both. Increased ADMA is now
seen as a major independent risk factor in end-stage renal disease (and probably
also in CKD), so lowering ADMA concentration might be a major therapeutic
goal. (45)
We have raised the issue of excess ADMA formation in a previous section in con-
nection with the “arginine paradox” and also in connection with its excess formation
in oxidative stress.
Here is the Abstract of a report titled “L-Arginine as a Therapeutic Tool in Kidney
Disease” published in the journal Seminars in Nephrology in 2004:

Infusion of L-arginine in experimental animals increases renal plasma fow (RPF)

and glomerular fltration rate (GFR). It is likely that a component of these hemody-
namic changes are mediated by nitric oxide (NO) as suggested by studies with spe-
cifc antagonists of L-arginine metabolism. L-Arginine administration ameliorates
the infltration of the renal parenchyma by macrophages in rats with obstructive
nephropathy or rats with puromycin-induced nephrotic syndrome. L-Arginine admin-
istration also blunts the increase in interstitial volume, collagen IV, and alpha-smooth
muscle actin. Rats with a remnant kidney given 1% L-arginine in the drinking water
had a greater GFR and RPF. L-Arginine administration also decreased proteinuria.
Diabetic rats given L-arginine had signifcantly lower excretion of protein and cyclic
guanosine monophosphate than diabetic rats not receiving L-arginine. Despite per-
sistent hyperglycemia, the administration of L-arginine prevented the development of
hyperfltration and ameliorated proteinuria in diabetic rats. In the setting of ischemic
acute renal failure, the administration of L-arginine had a benefcial effect on GFR
and RPF, decreased O2- production, diminished up-regulation of soluble guanylate
cyclase, and prevented up-regulation of inducible NO synthase (iNOS). The pharma-
cokinetics of L-arginine indicate that side effects are rare and mostly mild and dose
dependent. (46) Seminars in Nephrology, with permission.

And, here is yet another example of the recognition of the role of endothelial dys-
function in CKD. It is the Abstract of a report titled “Endothelial Dysfunction in
Chronic Kidney Disease, from Biology to Clinical Outcomes: A 2020 Update” pub-
lished in the Journal of Clinical Medicine in 2020.

The vascular endothelium is a dynamic, functionally complex organ, modulating mul-

tiple biological processes, including vascular tone and permeability, infammatory
responses, thrombosis, and angiogenesis. Endothelial dysfunction is a threat to the
integrity of the vascular system, and it is pivotal in the pathogenesis of atherosclerosis
144 Flaxseed

and cardiovascular disease. Reduced nitric oxide (NO) bioavailability is a hallmark of

chronic kidney disease (CKD), with this disturbance being almost universal in patients
who reach the most advanced phase of CKD, end-stage kidney disease (ESKD). Low
NO bioavailability in CKD depends on several mechanisms affecting the expression
and the activity of endothelial NO synthase (eNOS). Accumulation of endogenous
inhibitors of eNOS, infammation and oxidative stress, advanced glycosylation prod-
ucts (AGEs), bone mineral balance disorders encompassing hyperphosphatemia, high
levels of the phosphaturic hormone fbroblast growth factor 23 (FGF23), and low lev-
els of the active form of vitamin D (1,25 vitamin D) and the anti-ageing vasculoprotec-
tive factor Klotho all impinge upon NO bioavailability and are critical to endothelial
dysfunction in CKD. Wide-ranging multivariate interventions are needed to counter
endothelial dysfunction in CKD, an alteration triggering arterial disease and cardio-
vascular complications in this high-risk population. (47) With permission.

It is clear that we are well aware of the NO-connection in CKD and yet arginine
supplementation with a proven track record of enhancing endothelium function is not
given the prominence it well deserves.
There are however specifc applications of benefcial L-arginine supplementa-
tion. For instance: Hypertension may develop in kidney transplant (KT) patients
because of reduced NO bioavailability resulting in abnormal NO-mediated vaso-
dilation. Therefore, raising NO bioavailability with L-arginine might restore the
NO-mediated vasodilation and lower blood pressure.
The benefcial effects of L-arginine on systemic blood fow have been reported in
patients with heart failure and are summarized in another section of this book. But
so far, no benefcial effects of L-arginine on systemic blood fow have been reported
in connection with those who also suffer from kidney failure. Thus, even if the cli-
nician declines to recommend that these patients take supplemental arginine, they
might consider recommending to them that they add faxseeds to their diet—for the
arginine, as well as for the PUFAs and the cyanogenic glycosides.

7.3.4 CKD, HYPERTENSION AND CHRONIC HEART FAILURE

A study published in the Journal of Hypertension in 2000 aimed to determine
the effects of oral administration of L-arginine on renal blood fow, sodium and
water handling, and various hormonal factors in patients with chronic heart fail-
ure. Patients with chronic congestive heart failure (New York Heart Association)
Functional Classifcation II–III, 56 ± 12 years of age) were assigned to receive 15
g/day of oral L-arginine and placebo, or placebo and arginine sequentially for fve
days each.
Twenty-four-hour creatinine clearance (Ccr), and 24-hour urinary cyclic guano-
sine 5-monophosphate (cGMP) excretion were determined. Saline loading was per-
formed on day fve of each treatment. Renal blood fow, GFR and urinary sodium
excretion rate (UNa) were assessed before and after saline loading.
It was found that 24-hour cGMP was signifcantly higher and plasma endothelin
level was signifcantly lower with L-arginine treatment compared to placebo treatment.
In addition, the relative increase of UNa and GFR after saline loading was signif-
cantly higher in L-arginine than in placebo treatment.
L-Arginine and Omega-3 Fatty Acids for Type 2 Diabetes and CKD 145

The investigators concluded that oral administration of L-arginine has benef-

cial effects on glomerular fltration rate, natriuresis and plasma endothelin level in
patients with chronic congestive heart failure. (48)
A prospective pilot study published in JPEN Journal of Parenteral and Enteral
Nutrition in 2001reported that normotensive volunteers and KT patients received 9
grams per day of oral L-arginine supplements for nine days; then 18.0 grams per day
for nine more days. A group of hemodialysis (HD) and a group of peritoneal dialysis
patients received the same dose for 14 days. Some KT patients also received 30 mL/d
of canola oil (CanO) in addition to L-arginine. Systolic (SBP) and diastolic (DBP)
blood pressure, creatinine clearance (CCr) and serum creatinine (Cr) were measured
at baseline, at day nine and at day 18.
In a subsequent study, a group of hypertensive KT patients with stable but abnor-
mal renal function were assigned to a study to start L-arginine-only, or L-arginine +
CanO supplements for two 2-month periods with an intervening month of no supple-
mentation. SBP, DBP, CCr and Cr were measured monthly for seven months.
It was found in this pilot study that L-arginine signifcantly lowered the SBP in HD
patients from 171.5 ± 7.5 mm Hg (baseline) to 142.8 ± 8.3 mm Hg. In the crossover
study, SBP was signifcantly reduced from baseline (155.9 ± 5.0 mm Hg), after the
frst two months (143.2 ± 3.2 mm Hg), and subsequent two months (143.3 ± 2.5 mm
Hg) of supplementation. DBP was also reduced after supplementation in both studies.
CanO had no effect on blood pressure. Renal function did not change.
The investigators concluded that oral L-arginine supplements and preparations
(L-arginine ± CanO) were well tolerated for up to 60 consecutive days and had favor-
able effects on systolic and diastolic blood pressure in hypertensive kidney transplant
and hemodialysis patients. (49)
Caveat: A study published in the Journal of the American Society of Nephrology
in 2001 aimed to determine the therapeutic benefts of L-arginine supplementa-
tion in allogeneic renal transplantation in Brown Norway rat kidneys transplanted
into Lewis rat recipients, with one native kidney remaining. Recipients received
2.5 mg/kg per d low-dose cyclosporin (subcutaneously) to obtain moderate vascular
and interstitial rejection, with or without 1% L-arginine in drinking water for
seven days post-transplantation.
Transplantation signifcantly increased renal vasoconstriction thereby reducing
GFR. It was found that treatment with L-arginine restored renal graft function to
levels found in normal donors. L-Arginine signifcantly reduced vascular occlusion
because of lesser infammation, endothelial disruption, and thrombosis. L-Arginine
also decreased tubulitis, interstitial injury and macrophage infltration. These pro-
tective effects suggest that L-arginine might be useful as additive therapy to conven-
tional immune suppression.
However, there is a downside: the investigators also reported their observation
that in a proinfammatory environment, L-arginine can worsen renal injury. (50)

7.4 SUMMARY
Flaxseed yields omega-3, L-arginine and cyanogenic glycosides. The administration
of faxseed per se, as well as omega-3 and L-arginine individually as adjuvant
146 Flaxseed

treatments have shown benefts in reducing chronic systemic infammation, pro-

moting insulin secretion in type 2 diabetes and enhancing glomerular fltration in
chronic kidney disease. It is the consensus that the benefcial effects of these con-
stituents is the restoration of endothelial function and of NO bioavailability.
There are no published reports of cyanogenic glycosides per se in treatment of
type 2 diabetes or CKD.

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43. Velasquez MT, Bhathena SJ, Ranich T, Schwartz AM, Kardon DE, Ali AA, Haudenschild
CC, and CT Hansen. 2003. Dietary faxseed meal reduces proteinuria and ameliorates
nephropathy in an animal model of type II diabetes mellitus. Kidney International, Dec;
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44. Al-Bishri WM. 2013. Favorable effects of faxseed supplemented diet on liver and kid-
ney functions in hypertensive Wistar rats. Journal of Oleo Science, 62(9): 709–715.
DOI:10.5650/jos.62.709.
45. Baylis C. 2006. Arginine, arginine analogs and nitric oxide production in chronic kidney dis-
ease. Nature Clinical Practice Nephrology, Apr; 2(4): 209–220. DOI:10.1038/ncpneph0143.
46. Klahr S, and J Morrissey. 2004. L-Arginine as a therapeutic tool in kidney disease.
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47. Roumeliotis S. Mallamaci F, and C Zoccali. 2020. Endothelial dysfunction in chronic
kidney disease, from biology to clinical outcomes: A 2020 update. Journal of Clinical
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L-arginine on renal function in patients with heart failure. Journal of Hypertension, Feb;
18(2): 229–234. DOI:10.1097/00004872-200018020-00015.
49. Kelly BS, Alexande JW, Dreyer D, Greenberg NA, Erickson A, Whiting JF, Ogle CK,
Babcock GF, and MR First. 2001. Oral arginine improves blood pressure in renal
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PMID: 9311257.
 8 NO from Flaxseed
Enhances Sexual
Function

8.1 PROLOGUE
Flaxseed has a number of important properties that directly lead to maintaining
sexual “health,” even enhancing sexual function throughout maturity. First, fax-
seed delivers L-arginine, a nitric oxide (NO)-donor. Why that is important will be
explained in the following sections of this chapter. Second, it delivers cyanogenic
glycosides (CNglcs), likewise NO-donors. Third, it contains high levels of the anti-
oxidant omega-3 fatty acid alpha-linolenic acid (ALA) that has been shown to protect
the endothelium, even enhancing endothelial nitric oxide (eNO) formation where and
when it is needed in the body.
For instance, faxseeds (and fax oil) contain a group of nutrients called lignans,
which have powerful antioxidant and estrogenic properties. (30) The lignans are
a large group of polyphenols found in plants, particularly seeds, whole grains and
vegetables. Lignans are precursors to phytoestrogens. Free radicals and the com-
monly resulting reactive oxygen species (ROS) are the very bane of eNO forma-
tion. The surest way to jeopardize eNO formation is an antioxidant-poor diet.
Flaxseed does not promote an increase in free testosterone levels; it reduces andro-
gen levels in both men and women. This reduction may possibly retard or slow down
the process of hair loss called pattern baldness (alopecia) because it prevents testos-
terone from converting to the more potent dihydrotestosterone, a powerful androgen
implicated in that process. (29)

8.2 THE OYSTER AND THE BLUE PILL: SEXUAL DESIRE VS.
SEXUAL PERFORMANCE
Contrary to everything that has been said about different kinds of aphrodisiacs
that one can take to increase sexual desire (libido), science tells us that, with few
exceptions, the only real biological fuel for sexual desire is the steroid hormone tes-
tosterone. The countless alleged aphrodisiacs, including foods—oysters come to
mind—beverages, salves and amulets that we hear and read about that are said to
increase desire usually fail because they don’t raise testosterone levels. Even the
expectation—the placebo effect, as it were—that these will improve performance by
increasing desire usually falls short of fulfllment.
We have been consistently led to confuse desire with performance, reasoning
that if performance is inadequate, it must be due to lacking desire. It’s the old

DOI: 10.1201/b22986-8 151

152 Flaxseed

adage, “You could if you wanted to.” And so, we have witnessed a search for
aphrodisiacs spanning recorded history. Sometimes that search comes with a
twist.

8.2.1 WHAT WE LEARN FROM THE PERFUMED GARDEN OF THE SHAYKH

NEFZAWI
Abou el Heidja has defowered in one night
Once eighty virgins, and he did not eat nor drink between
Because he’d surfeited himself frst with chick’peas
And had drunk camel’s milk with honey mixed.”
(ca. 15th Century) R. Burton Translation

In the translation by Sir Richard Burton of the 15th-century tome on sexuality, it is

reported that Abou el Heidja had defowered in one night once 80 virgins because
he’d surfeited himself frst with chick’peas [ibid.]. It so happens that while chickpeas
are not notably aphrodisiacs, they do proffer a considerable amount of L-arginine, a
key NO-donor necessary for satisfactory “performance”:
In a typical serving size of 1 cup of chickpeas (or 200 grams), there are 3.64
grams of L-arginine. That’s a lot and, by the way, enough to avoid if one has an
active herpes infection. For that reason, the previous book of the frst author,
Great Food/Great Sex. The Three Food Factors for Sexual Fitness (Time/Warner
Books, 2006) cites chickpeas among foods highly recommended to enhance sex-
ual performance.
Parenthetically, and much to the chagrin of those who mistakenly think that fat
is fattening, the only “food” that is reliably aphrodisiac, in a sense, is fat, of course.
Because testosterone is a steroid hormone derived from cholesterol, changes in fat
intake can alter testosterone levels.
In a study published in the Journal of Steroid Biochemistry and Molecular
Biology, in 2021, low-fat diets were reported to decrease testosterone levels in
men. Men with North American and European ancestry experienced a greater
decrease in testosterone in response to a low-fat diet. This study frst put men on
a high-fat diet (40% fat) and then transferred them to a low-fat diet (20% fat), and
found their testosterone levels decreased by 10%–15% on average. Vegetarian
low-fat diets caused decreases in testosterone levels up to 26%. Men on high-fat
diets had testosterone levels that were about 60 points higher, on average, than
men on low-fat diets. (31)
Modern science, however, does not support the reasoning that, ipso facto, low
performance means low desire. In fact, while sexual performance commonly fol-
lows desire, it can also be quite independent of desire, although it is true that we
commonly engage in sex when we desire to do so. But up to now, most people who
experience consistent failure of performance may attribute it, as psychoanalysts
falsely claim, to subconscious sabotage of desire. We know better now. Inadequate
performance is commonly a medical issue, although it may ultimately cause a psy-
chological problem.
NO from Flaxseed Enhances Sexual Function 153

8.3 THE MOST COMMON CAUSE OF ERECTILE

DYSFUNCTION
While a great many American men—said to exceed 30 million—suffer varying
degrees of erectile dysfunction (ED), their problem is rarely low or absent sexual
desire. American men would not resort to, and pay the high cost of prescription meds
such as Viagra® and Cialis® for instance, if they had no desire for sex. The millions
of such prescriptions flled by consumers tell us clearly that their problem is weak
or absent sexual performance—absent or unreliable penile erection—not lack of
desire: they want to do it . . . but somehow, they can’t.
In the past, ED in adult men was most often, and erroneously, blamed on weak
or absent desire (low or absent libido) due to subconscious psychological issues. The
emotional basis of ED was steeped in Freudian psychobabble about subconscious
oedipal confict and similar myths. This explanation had enjoyed great popularity in
the United States despite the lack of any shred of evidence to support it.
Men who think the secret to addressing ED is rooted in emotional problems might
consider the following: according to the National Institutes of Health (NIH), about
4% of men in their 50s, and nearly 17% of men in their 60s, experience a total
inability to achieve an erection. The incidence jumps to 47% for men older than
75 (see National Institutes of Health [NIH] Consensus Conference. NIH Consensus
Development Panel on Impotence. JAMA, 1993).
Judging from these statistics, one would have to conclude that in a fair number of
American men, subconscious emotional conficts lie in wait, hidden out of sight, until
their mid-50s and 60s when they suddenly surge as would an epidemic simultane-
ously now infecting almost half the population of men, and completing the infection
by the time they reach the age of 75. There is neither logic nor any scientifc basis for
concluding that subconscious psychological conficts develop and grow in severity as
we mature until, in our middle years, they fnally worsen and bring us down.
It could, of course, be that sexual desire declines with age because testosterone,
the “hormone of desire,” declines with advancing age. While that is certainly true, it
is not generally the case that serum available testosterone levels decline precipitously
in the middle years, as shown in a later section of this chapter.
In fact, age-related change causes an enzyme, 5α-reductase, to convert testoster-
one to an even more powerful form, dihydrotestosterone (DHT), that boosts desire
(libido) and, by the way, causes benign prostate hypertrophy (BPH), as well as pat-
tern baldness. We do however know now that there is an age-related decline in NO
production that would directly affect performance.
Conventional medical treatment for either BPH or pattern baldness, parentheti-
cally; or both, consists mainly of prescription meds that inhibit the action of the
enzyme, 5α-reductase (for instance, Dutasteride®). These are however not without
some risk of adverse impact on libido and erectile function: in 2012, the Journal
of Sexual Medicine reported that Finasteride (Propecia®) has been associated with
sexual side effects that may persist despite discontinuation of the medication. In a
clinical series, 20% of subjects with male pattern hair loss had persistent sexual
dysfunction for more than six years, suggesting the possibility that the dysfunction
may be permanent. (1)
154 Flaxseed

While libido in men and in women depends almost entirely on testosterone, it does
not fuel performance. The average testosterone level of men between the ages of 59
and 69 is somewhat lower than that in men between 19 and 29. The concentration of
plasma testosterone is quite variable (2) with the highest levels and least variability in
men between the ages of 32 and 51. But even by the age of 70, while more variable and
thus less predictable, testosterone levels are not all that low. (3) Free-form testosterone
does decline with age, but it is not dramatically lower until about age 80.
In 2009, Americans spent $807.7 million on erection-promoting prescription
meds. Why would they do that if they lacked sexual desire?

8.4 GAS FUELS PERFORMANCE

Testosterone fuels desire but the gas NO fuels performance. As you will see, bottom
line, no matter how much testosterone is there to fuel desire, if the body can’t come
up with an adequate supply of NO where and when needed, performance suffers. So,
to understand why a NO-donor like faxseed can improve—even restore—sexual
performance, it helps to know a little about what science calls the “ACh/NO/cGMP
pathway.”
In the early 1900s, the Austrian pharmacologist Otto Loewi discovered an inter-
esting substance made by nerve cells in the brain and in the body. Some years later,
Sir Henry Dale, with whom Loewi later collaborated at the University of London,
and with whom he shared the 1936 Nobel Prize in Medicine named it “acetylcho-
line” (ACh). This was the beginning of modern neuropharmacology based on chemi-
cal signals called neurotransmitters by which cells in the nervous system and brain
communicate.
ACh was found to relax the arterial smooth muscles all throughout the circulatory
system, and this seemed a promising road to lower blood pressure to treat hyperten-
sion. However, it did so unreliably and unpredictably. No one knew why.
In 1980, Dr. Robert F. Furchgott, professor of pharmacology at Downstate
Medical Center in Brooklyn, New York, published his fndings in the journal Nature
that ACh relaxation of arterial smooth muscle depended on the simultaneous pres-
ence of a mysterious substance actually made by the endothelium, the inner lining
of those blood vessels. The endothelium is an accordion-like structure lining the
inner surface of the arterial blood vessels. There is an illustration of the endothelium
in Chapter 3 (see Figure 3.2 colored scanning electron micrograph [SEM] of a sec-
tioned artery containing red blood cells).
The mysterious substance was initially termed “endothelium-derived relaxing
factor” (EDRF): ACh relaxed the blood vessels only when EDRF was also present
(4). No one had any idea what EDRF actually was.
It did not take long to verify the fnding, and in 1993, Dr. Salvador Moncada
at Wellcome Research Labs, United Kingdom, frst identifed EDRF as a gas, NO,
and detailed its role in health and disease in the New England Journal of Medicine
(NEJM) (5). NO is derived in the body principally from the food-borne amino acid
L-arginine and from dietary nitrates as well. At frst, this news was, of course, met
with disbelief—even derision. A gas, indeed! It was not known then that NO had a
biological role, much less in blood vessels.
NO from Flaxseed Enhances Sexual Function 155

Then, in 1998, Dr. Furchgott and two colleagues were awarded the Nobel Prize
in Medicine for the discovery of the biological role of NO in blood vessels and heart
function, and in the nervous system and the brain. The immune system was soon
added to the list of NO-dependent body systems.
One of the three recipients, Dr. Louis J. Ignaro, detailed how in sexual arousal,
ACh led to increased and sustained production of NO made from the amino acid
L-arginine by the endothelium lining the spongy chambers of the penis cavernosa(e)
(see the following section). This causes them to relax (dilate) allowing increase blood
infow and, thus, erection.

8.4.1 HOW A SIMPLE “BLUNDER” EXPLAINS CARDIOVASCULAR AND

HEART DISEASE
When the body forms Ach, it should invariably cause the formation of NO by the
endothelium of arterial blood vessels, causing them to relax and increase blood fow.
So why didn’t it do that reliably in Dr. Furgott’s laboratory?
What Dr. Furchgott discovered in strips of arterial blood vessels washed with Ach
is that the strips did not relax when, on closer examination, it was found that labora-
tory preparation had damaged the endothelium. A simple blunder, perhaps, but it was
soon learned that damaged endothelium can’t form NO. And this turned out to be a
very important lesson for medicine with far-reaching implications for cardiovascular
health and for the treatment of ED as well.
The observation that damaged endothelium can’t produce NO in amounts suf-
fcient to cause blood vessel dilation and maintain adequate blood circulation is the
explanation for how we come by cardiovascular disorders such as hypertension, ath-
erosclerosis, heart failure, kidney disease and metabolic syndrome, and now we can
add ED.
Each of these conditions is said to result from damage to the endothelium, and
each, in turn, causes further damage to the endothelium. But in the population at
risk, it is diet and lifestyle factors—especially a low antioxidants diet—that damage
the endothelium and not some laboratory blunder.

8.5 THE CULPRIT: OXIDATIVE STRESS

Although we are entirely dependent on oxygen for survival, our body limits how
much we absorb because in fact, in excess, we would actually burn up, i.e. oxidize.
But that’s not the worst of it. In its common form, O2 sustains life. But if you tamper
with its molecular structure, it can become an unstable “free radical” that destabi-
lizes everything it comes into contact with, creating new and toxic compounds that
we call reactive oxygen species (ROS). Oxidized lipoprotein and hydrogen peroxide
are examples of ROS formed in the body by oxygen free radicals formed, actually,
by our own metabolism.
There are also always oxygen free radicals in the surrounding air. So, if you
leave an apple exposed to air, for instance, it will shrivel and turn brown, resulting
in a new species of apple, rotten. Likewise, butter left exposed on the kitchen coun-
ter metamorphoses from fresh to a new species of butter, rancid. Lipids circulating
156 Flaxseed

in the bloodstream are typically safe until they combine with oxygen free radi-
cals forming new, reactive species. These are very appetizing to white blood cells
(macrophages) that readily gobble them up and infltrate blood vessel walls to form
atherosclerosis.
Oxidative stress is the cost to the body of an imbalance between ROS and the
ability of the body to detoxify with antioxidants and to repair the resulting damage.
What are the main precursors of oxidative stress? Recapitulating, factors that may
increase a person’s risk of long-term oxidative stress include

• Obesity
• Diets high in saturated fats, sugar and processed foods
• Exposure to radiation
• Smoking cigarettes or other tobacco products
• Alcohol consumption
• Certain medications
• Pollution
• Exposure to pesticides or industrial chemicals

Oxidative stress impairs endothelium function as surely as if it were mechanically

damaged by mishandling—as in Dr. Furchgott’s laboratory. And, by the way, high
on the list of contributors to oxidative stress is the high salt, high sugar, high satu-
rated fat, low antioxidant Standard American Diet (SAD).
It bears mention that while the damage to the endothelium in Dr. Furchgott’s lab
was thought due to “careless handling, “careless” is not really accurate because, at
that time, no one had any idea that the endothelium had any vital biological control
function, so why spare it? It was thought then to be not much more than a sort of inert
lining between the bloodstream and the blood vessel walls to keep undesirable stuff
in blood out of the vessel walls.
So, let’s look at the endothelium and the part it plays in translating sexual arousal
into sexual performance via the so-called Ach/NO/cGMP pathway.

8.6 THE ENDOTHELIUM FORMS NITRIC OXIDE (eNO)

Arterial blood vessels have three major structures: the outer wall composed of
smooth muscle rings that surround the blood vessels: these can constrict (narrow-
ing them) or relax (dilating them), a middle wall and the inner cell lining, or endo-
thelium. In ordinary circumstances, the degree of constriction, or tonus, of arterial
blood vessels, and consequently blood pressure, is principally determined by activity
level in two control signal systems:

• The endothelium-dependent signal system based on the availability of

L-arginine-derived NO, produced by the endothelium, and
• The endothelium-independent system of action-hormones (adrenaline, nor-
adrenalin, etc.) and by diuresis regulating body sodium levels.

There are others, but these dominate.

NO from Flaxseed Enhances Sexual Function 157

As previously noted, the endothelium is a thin layer of cells lining the interior
surface of blood vessels. It shields the vessel wall from circulating blood in the vessel
inner cavity through which blood fows called the lumen. Endothelial cells line the
entire circulatory system from the heart to the smallest capillary. They reduce the
turbulence of blood fowing through the vessel, allowing it to be pumped farther.
These cells also function in vasoconstriction and vasodilation, and hence they con-
trol blood fow and pressure.
The endothelium has a barrier function: it acts as a selective barrier between the
vessel lumen and surrounding tissue, controlling the passage of materials and the
passage of white blood cells into and out of the bloodstream.

8.6.1 THE GLYCOCALYX: SUGAR COATING THE ENDOTHELIUM

Most descriptions of blood vessels, including the endothelium, portray the endothe-
lium as lining the inner surface of the blood vessel so that blood coursing through the
lumen comes in direct contact with it. That is actually not the case. The surface of
the endothelium facing blood fow has a microscopic “sugar coating” called the gly-
cocalyx that insulates it and protects it from damaging substances such as bacteria
and viruses in the bloodstream. Damage to the glycocalyx typically results in dam-
age to the endothelium, impairing its ability to form NO where and when needed.
This is signifcant not only to our understanding of cardiovascular and heart disease
but also to erectile function, as well as ED.
For instance, excess salt in diet damages the glycocalyx (6), and so does diabe-
tes. (7) It is also thought to contribute to hypertension (8) and to lead to the forma-
tion of atherosclerosis. (9) These are all the well-known cardiovascular and heart
hazards that are also associated with ED. And it should come as no surprise that
the glycocalyx is often found to be damaged as a result of COVID-19 infection.
(10)
Damage to the glycocalyx subjects the endothelium to shear stress as blood
courses over it under pressure. This stress on the endothelium also contributes to
its impairment of NO formation. (11) That the damage to the glycocalyx leaves the
endothelium vulnerable to assault may go a long way to explain the “cardiovascular”
complications of both COVID-19 infection and those leading to ED.
The ability of the endothelium to deliver NO in sexual arousal is the key to erec-
tile function and thus satisfactory sexual performance because it is NO that is needed
in the “pathway” for the blood vessel to relax. The endothelium is the gateway to
sexual “performance” vitality, and the glycocalyx protects the endothelium and thus
protects NO formation where and when needed to assure that vitality.

8.7 SEXUAL PERFORMANCE IS ABOUT SHUNTING BLOOD

FLOW IN THE BODY
In old-fashioned railroad parlance, “shunting” meant to move a train from the main
line to a siding. Sexual performance requires the shunting of blood from the main
circulation in the body to the sex organs: the body is the main line, and the sex
organs are the siding. There is a good reason for that.
158 Flaxseed

In ordinary circumstances, most people are not consistently in a state of sexual

arousal: in men, the penis is faccid. That means that blood is fowing through it, but
not in suffcient volume to cause and maintain erection. In women, blood is likewise
fowing through the clitoris and the labia but not in suffcient volume to cause and
maintain engorgement. So, to begin with, sexual arousal can result in, at best, a tran-
sient physical state because nature intended it to be transient. Nature invested more
in supplying blood to the organs of the body that keep us alive and active than to
those that involve reproduction.
How does the shunting mechanism work? Let’s frst look at the parts and then at
how they work in sequence in sexual response.

8.7.1 THE PENIS IS NOT A MUSCLE

How NO affects blood vessels and what this has to do with erection makes sense
only if one understands that the penis is basically a bundle of blood vessels. There
are, of course, muscles at the base of the penis, those attached to the pelvis by means
of which most men can slightly raise an erect penis. But the penis is largely an
encased pair of spongy “cavernosa” chambers—side by side—that are, in fact, modi-
fed, spongy arterial blood vessels with blood-supplying arteries whose endothelium
controls blood infow.
Figure 8.1 shows a transverse section of the penis: The two large central spongy
corpora cavernosae, as well as a spongy chamber that encircles the urethra, the cor-
pora spongeosum. The blood infow cavernosal arteries are shown in the chambers.
These engorge with blood during sexual stimulation with increased NO signaling the
endothelium to relax the vessel.

FIGURE 8.1 Cross-section of the penis. (From https://en.wikipedia.org/wiki/Corpus_

cavernosum_penis#/media/File:Gray1155.png.)
NO from Flaxseed Enhances Sexual Function 159

As the penis erects, the bulging chambers constrict the veins under the relatively
inelastic outer tunica, thus causing less blood to fow out of the penis through the
veins than comes into it through the arteries: this is basically a pressure regulated
mechanical valve controlled by a biologically active gas.

8.8 THE (ACh/NO/cGMP) PATHWAY TO PENILE ERECTION

In sexual arousal, the brain sends signals via the nervous system and bloodstream to
the spongy expandable cavernosae of the penis:

1. Components of the central nervous system release the chemical neurotrans-

mitter messenger ACh that signals the cells of the endothelium to form
nitric oxide (eNO) from L-arginine by the action of the eNOS.
2. In the vascular smooth muscle penis cavernosae, eNO signals the release
of another enzyme sequence that helps to form cGMP (cyclic guanosine
monophosphate).
3. cGMP is the actual vasodilator that relaxes the cavernosae smooth muscle,
increasing blood infow. (12)
4. As blood infow rises in the cavernosae, the increased infow and pressure
cause shear stress on the endothelium that results in the additional release
of eNOS and further maintenance of NO formation.
5. As blood flls the cavernosae, they expand, exerting pressure on the veins
that lie between the albuginea and the tunica. This pressure constricts the
veins, thus limiting blood outfow.
6. However, at the same time, there is also the formation and buildup of the
enzyme phosphodiesterase type-5 (PDE5) that breaks down cGMP, causing
reabsorption of the constituents, thus ending erection.

What Dr. L. Ignarro discovered was that if one has endothelium damage caused
by health hazards such as atherosclerosis, or diabetes, but one can still form NO,
albeit in insuffcient amounts for satisfactory sexual “performance,” then one can be
helped by disabling the reabsorption enzyme PDE5. This led to the development of
agents such as Viagra® (Sildenafl) that protect NO formation. These are aptly called
PDE5 inhibitors. However, in the face of a seriously impaired endothelium, even
PDE5 inhibitors may not work.

8.9 THE ROLE OF AGING IN ED

Americans are living longer now than they did just a few decades ago. According to
the 2011 CIA World Book, average life expectancy in the United States was 78.37
years. Women live somewhat longer than men. There is little evidence of widespread
loss of interest in sexuality in our “maturing” population. As we age, issues of sexu-
ality for men and women diverge: while desire remains relatively high in older men,
it can drop precipitously in most women in menopause.
Common myths make a compelling case for dismissing the lack of interest of
seniors in lovemaking as there is still a residual attitude that sexuality as we reach
160 Flaxseed

the “golden years” is really not altogether proper. However, soaring sales of meds
like Viagra® tell a different story: it’s not all in the head, and it’s not all just about
age, but some of it is.
Seniors do face a challenge as the years pile up. There are anatomical changes in
the cavernosal endothelium in men as they age and in the comparable clitoral caver-
nosae in postmenopausal women in whom decreased hormones of desire reduce both
libido and the ability to maintain sexual intercourse comfortably.
ED is of great concern to many men especially as they age. A number of miscon-
ceptions cloud our understanding of the extent of ED in American men. For instance,
a press release dated August 5, 2003, from the Harvard School of Public Health,
titled “Prevalence of Erectile Dysfunction Increases With Age,” tells us that fewer
than 2% of the men in the study who reported that they had erection problems expe-
rienced them before the age of 40, and 4% had experienced problems between age
40 and 49. From age 50 upwards, the percentage of men reporting ED increased
dramatically with 26% between the ages of 50 to 59, 40% aged 60 to 69 years and
61% for men older than 70 having experienced ED. (13)
The Harvard press release avers that “61 percent [of] men older than 70 [have]
experienced ED,” but it does not defne “experienced.” In fact, in a Massachusetts
Male Aging Study (MMAS), it was shown that only about 15% of men in that age
group were totally impotent, while less than 30% of them experienced “moderate”
ED. Clearly, the manner of presenting data can give a different impression of the
facts.
The MMAS study shows the likelihood that someone may experience either
no dysfunction, minimal dysfunction, moderate or complete dysfunction. This is
a more meaningful way to describe sexuality in populations of men as they age.
In women, testosterone also is pretty much minimal by age 45, leading to loss of
estrogen from which they derive it. Whereas in men, both free testosterone and free
dihydrotestosterone remain relatively high well past that age. In fact, free dihy-
drotestosterone levels in men remain higher than free testosterone levels up to about
age 70. (14, 15)
Hormonal issues notwithstanding, the evidence clearly shows that the NO/
cGMP mechanism affects the response to sexual arousal in both men and women.
Much has been published about that response in men, and the research on the role
of that mechanism in women has been neglected. However, we know that there are
age-related changes in the clitoris cavernosae like those in the penis cavernosae
in aging men:
The Journal of Urology reported a strong link between increasing age and
decreased clitoral cavernosal smooth muscle fbers. In the post-mortem tissue sam-
ples studied, not only did those decreases in cavernosal smooth muscle fbers cor-
relate signifcantly with increase in age, but in the age group of 44 to 90 years,
clitoral cavernosal fbrosis was found to be signifcantly greater in the presence of
cardiovascular disease–related mortality compared with those without cardiovascu-
lar disease–related mortality. (16)
It’s only a small jump from these data to the conclusion that women’s physical
arousal problems may also be linked to regularly consuming the SAD and to a sed-
entary lifestyle accelerating endothelial impairment just as happens in men. The
NO from Flaxseed Enhances Sexual Function 161

authors did not pull their punches: “Vascular risk factors may adversely affect the
structure of clitoral cavernosal tissue.” In other words, it is impaired endothelium
and thus, impaired NO/cGMP formation.
Aging has a signifcant adverse impact on sexual response both in men and in
women, and medical authorities agree that it is due to progressive impairment of the
endothelium and its ability to serve us NO when and where needed. Parenthetically,
Sildenafl (Viagra®) increases clitoral and uterine blood fow in healthy postmeno-
pausal women, even without any erotic stimulation. (17) The question remains, does
NO production ipso facto decrease with age in men in parallel with declining erectile
function?

8.9.1 DO WE JUST RUN OUT OF GAS AS WE AGE?

Contrary to common belief, testosterone, the hormone of desire, does not decrease
much as we age, but NO production that fuels performance declines precipitously.
In 1996, a report in the journal Hypertension concluded that with age, eNO for-
mation is impaired. This decline is detailed below in Figure 8.4.

FIGURE 8.2 Endothelium-dependent NO/cGMP) blood vessel relaxation decreases with

age. [(18) Gerhard M, Roddy MA, Creager SJ, and MA Creager. 1996. Aging progressively
impairs endothelium-dependent vasodilation in forearm resistance vessels of humans.
Hypertension, Apr; 27(4): 849–853. DOI:10.1161/01.hyp.27.4.849.]
162 Flaxseed

The investigators found that in people ranging in age from 19 to 90, NO/cGMP
was progressively, and dramatically, impaired with increasing age. Furthermore, the
decline is already evident by the fourth decade (age 30 to 39 years). (18) The fuel
for performance declines in men just as they begin to produce a super testosterone
hormone of desire, DHT.
Parenthetically, in addition to age, total cholesterol and low-density lipoprotein
cholesterol were also predictors of NO/cGMP formation impairment. It seems that
we have found diet and lifestyle ways of replicating the blunder in Dr. Furgott’s lab.
The investigators concluded that age is the most signifcant predictor of NO/
cGMP formation impairment, even in healthy persons. It stands to reason that oxida-
tive stress lifestyle factors, including inactivity, damage our endothelium, thus caus-
ing our cardiovascular and health hazards to accumulate as we age.
Likewise, a clinical study published in the European Journal of Preventive
Cardiology in 2013 found that fow-mediated dilation* (FMD) decreases signif-
cantly with increasing age in both genders up to 70 years for men and 80 for women.
In women, age-related decline in FMD was steepest after age 45; in men, there is
a steady decline after age 30. Curiously, in men 80 years and older, FMD was higher
than in men aged 50–79 years. We suspect a curious bias here: it may be that the
men who survive to that age are endowed with a healthier cardiovascular system,
refected in less FMD impairment. (28)

8.10 ENDOTHELIUM DYSFUNCTION IS A FEATURE OF ED

According to a report published in the Journal of Andrology, the earliest detect-
able changes in vascular disease states associated with ED are abnormalities of the
endothelium causing a loss in its normal homeostatic mechanisms that convention-
ally protect against disease-related processes. Considering the crucial role of the
endothelium, it is not surprising that conditions that cause endothelial dysfunc-
tion, such as aging, diabetes, cardiovascular disease and hypercholesterolemia, are
closely associated with ED. Normal penile erection requires coordinated arterial
endothelium-dependent vasodilation, i.e., NO-dependent. (19)

8.11 ENTER FLAXSEED

Recapitulating the ACh/NO/cGMP pathway to sexual performance: the brain sends
out ACh when we are sexually stimulated. It does not ordinarily have any problem
doing that. ACh triggers NO formation by the endothelium of the blood vessel–like
spongy cavernosae chambers of the penis. NO then causes the formation of the ves-
sel-relaxing cGMP. If there is adequate NO formation, there will be adequate cGMP
formation to cause and sustain erection. If NO formation is poor, type-5PDE will
mop up what little there is of cGMP, and the result is little if any erection. The whole

* To measure FMD, the brachial artery is frst bound to stop blood fow. Then the ligature
is released and dilation is observed when blood fow is restored in the artery. The primary
mediator of FMD is a release of NO by endothelial cells. (32)
NO from Flaxseed Enhances Sexual Function 163

cycle depends on NO, and the NO-donors in faxseed and fax oil are an excellent
way of supplying it.
There are a number of ways that faxseed contributes to enhanced male performance.

8.11.1 FLAXSEED SUPPLIES L-ARGININE, THE SUBSTRATE FOR NO

First, faxseed supplies L-arginine. A number of publications support supplement-
ing L-arginine in treatment of ED. For instance, a meta-analysis published in the
Journal of Sexual Medicine encompassed studies published up to April 2018 that
evaluated the effcacy of arginine supplements identifed from multiple databases
such as Google Scholar, PubMed, Medline, Embase, Kiss, DBpia and Cochrane
databases. The studies in the meta-analysis compared arginine supplements to pla-
cebo or no treatment, focusing only on patients with mild to moderate severity of ED,
and presenting outcomes such as improvement rate, International Index of Erectile
Function (IIEF) score and adverse effects.
The analysis demonstrated that arginine supplements with a dosage ranging from
1,500 to 5,000 mg/day signifcantly improved ED compared with placebo or no
treatment. Arginine supplements also caused signifcant improvements in the IIEF
subdomain scores of overall satisfaction, intercourse satisfaction, orgasmic function
and erectile function, whereas the IIEF sexual desire scores remain unchanged. The
adverse effect rate in the arginine-treated group was 8.3% and that in the placebo
group was 2.3%, none of which were severe. (20)
A clinical study published in the journal Andrologia examined the effects of
L-arginine supplementation in medical (pharmacological) treatment of ED: the
study compared the clinical effcacy of daily use of L-arginine, tadalafl, and com-
bined L-arginine with tadalafl (Cialis), in the treatment of elderly patients with erec-
tile dysfunction. Daily oral L-arginine (5 grams), or tadalafl (5 mg), or L-arginine
(5 grams) combined with tadalafl (5 mg), or placebo were taken for 6 weeks in each
group of patients, respectively.
Patients were assessed before and after treatments using the Sexual Health
Inventory for Men (SHIM) questionnaire and total serum testosterone. The means of
Q1–5, total scores of SHIM and total testosterone in L-arginine, tadalafl and com-
bined L-arginine with tadalafl groups were signifcantly higher after treatments.
Combined L-arginine with tadalafl group had the highest SHIM scores and levels
of total tetosterone.
The investigators concluded that combining daily L-arginine with tadalafl ther-
apy for elderly male ED patients could signifcantly increase SHIM scores and levels
of total testosterone compared to L-arginine or tadalafl alone. (21) In other words,
increasing NO bioavailability by L-arginine supplementation enhances the effects of
tadalafl, a medical/pharmacological PDE5 inhibitor.

8.11.2 ROS JEOPARDIZE ERECTILE FUNCTION

The antioxidant properties of faxseed and fax oil, in addition to these substances
being NO-donors, cannot be overemphasized insofar as it has been shown that
164 Flaxseed

oxidative stress is a feature in both cardiovascular diseases (CVD) and ED involving

the overproduction of ROS, in particular, superoxide (O2•−) and hydrogen peroxide
(H2O2). (22)
Furthermore, in an article titled the “Role of Oxidative Stress in the Patho-
physiological Mechanism of Erectile Dysfunction,” published in the Journal of
Andrology, the investigators report that increased production of ROS is associated
with decreased normal erectile response, primarily because of reduced NO concen-
trations. Increased production of ROS in diseases such as diabetes and hypertension
might be an important cause of an increased risk of ED. (23)

8.11.3 FLAXSEED SUPPLIES THE ANTIOXIDANT OMEGA-3 FATTY ACIDS

PROMOTING eNO FORMATION
There are no conventional medical publications that address the potential role of cya-
nogenic glycosides in connection with ED. But fax supplies omega-3 fatty acids. and
a number of publications report that these enhance sexual function by various means.
For instance, it has been well established that oxidative stress and infammation
disrupt NO production directly or by, among other things, increasing resistance to
insulin. This action is a documented contribution to determinants of vascular dis-
eases, including ED. Men with ED have decreased vascular NO, as well as decreased
circulating and cellular antioxidants. Also, oxidative stress and infammatory mark-
ers are increased in men with ED, and these increase with age.
Potent antioxidants or high doses of weaker antioxidants increase vascular NO
and improve vascular and erectile function. Antioxidants may be particularly impor-
tant in men with ED who smoke, are obese or have diabetes.
It is reported in the International Journal of Impotence Research that omega-3
fatty acids reduce infammatory markers, decrease cardiac death and increase endo-
thelial NO production, and are therefore critical for men with ED who are under age
60 years and/or have diabetes, hypertension or coronary artery disease and are at
increased risk of serious or even fatal cardiac events. (24)
The link between ED and cardiovascular disease is now so well-known that a
subset of the authors of the aforementioned report called that link “the canary in the
coal mine” in a study published in the American Journal of Cardiology. (25)
The supplementation of omega-3 fatty acids from faxseed or fax oil in ED may
be particularly cogent since it was reported in a study published in the journal Lipids
in Health and Disease that fatty acid metabolism is “disturbed” in ED. The study
concerned ED in type 2 diabetes patients because vasculogenic erectile dysfunction
is considered a common complication in that population.
The study aimed to determine whether changes in fatty acid classes measured in
erythrocytes are associated with increased risk of diabetic vasculogenic erectile dys-
function (VED) along with related risk factors. The investigators assessed erythrocyte
(red blood cell) fatty acids composition, lipid peroxidation parameters and infammatory
cytokines in type 2 diabetes patients with VED compared to that in healthy volunteers.
It was found that diabetic patients had signifcantly lower indices of Δ6-desaturase
and elongase activities compared to the other studied groups. The same group of
NO from Flaxseed Enhances Sexual Function 165

participants displayed lower erythrocyte levels of dihomo-γ-linolenic acid precursor

of the messenger molecule PGE1 mainly involved in promoting erection. Moreover,
absolute saturated fatty acids (SFA)s concentration and HOMA-IR levels were higher
in type 2 diabetes patients with VED when compared to controls, and associated
with impaired NO concentration.
The results showed that IL-6 and TNF-α were signifcantly increased and posi-
tively correlated with malondialdehyde level (MDA, a marker of oxidative stress)
only in type 2 diabetes people with VED, suggesting a decrease in the relative avail-
ability of vasodilator mediators and activation of vasoconstrictors release.
The investigators concluded that the “deranged” fatty acids metabolism consti-
tutes a marker of vasculogenic erectile dysfunction in progress, or at least an indica-
tor of increased risk within men with type 2 diabetes. (26)

• Δ6-desaturase, or delta-6-desaturase enzyme, is one of two rate limiting

enzymes that convert the polyunsaturated fatty acid (PUFA) precursors
α-linolenic (omega-3) and linoleic acid (omega-6) to their respective
metabolites. Changes in the delta-6-desaturase enzyme activity alter
fatty acid profles and are associated with metabolic and infammatory
diseases including cardiovascular disease and type 2 diabetes.
• Elongase is a generic term for an enzyme that catalyzes carbon
chain extension of an organic molecule, especially a fatty acid.
Elongases play a variety of roles in mammalian organisms, account-
ing for changes in tissue function and lipid regulation.
• Dihomo-γ-linolenic acid is an omega-6 PUFA.
• HOMA-IR, homeostatic model assessment for insulin resistance is
an index of insulin resistance.
• PGE1 is a smooth muscle relaxant and is used as a vasodilator medi-
cation in the management of erectile dysfunction and ductus arterio-
sus in neonates.
• IL-6 is a cytokine with broad-ranging effects in the immune response.
One of the roles of IL-6 is to support immunocompetence, the ability
of a host to respond to infections.
• TNF-α: Tumor necrosis factor alpha is an infammatory cytokine pro-
duced by macrophages/monocytes during acute infammation.

Finally, in a meta-analysis published in the Iranian Journal of Basic Medical

Sciences, the investigators report that the main constituents of faxseed include lip-
ids, proteins, lignans, fbers and minerals, and faxseed contains antioxidants such as
tocopherols, beta-carotene, cysteine and methionine, which result in a decrease in
blood pressure; reduced risk of heart disease, as well as of hepatic and neurological
disorders; and increased insulin sensitivity, and because faxseed is commonly used
for its antidiabetic and anticancer activities, benefting also cardiovascular, gastroin-
testinal, hepatic, urological and reproductive disorders; therefore, it is recognized as
a medical plant. (27)
166 Flaxseed

8.12 SUMMARY
In most clinical cases, ED is not due to emotional inhibitions or lack of desire but to
organic dysfunction preventing sexual stimulation from leading to increased blood
fow to the genitals in both men and women. Recent research has shown that this
defcit commonly results from impaired NO formation in the endothelium thought
to be damaged by oxidative stress. Flaxseed supplies L-arginine, the substrate for
NO; and cyanogenic glycosides, a NO-donor; and the omega-3 fatty acids that supply
antioxidants to combat further free radical damage.

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 9 Omega-3 PUFA and
L-Arginine for Longer
Life Span with a
Longer Health Span

9.1 ONE WAY TO LONGER LIFE IS TO PREVENT

SHORTENING IT
The frst eight chapters of this book examined the basic benefts of faxseed con-
stituents, i.e., L-arginine, omega-3 polyunsaturated fatty acids (PUFAs) and cya-
nogenic glycosides. What this examination revealed at the level of the tissues and
organs is that these constituents seem to bestow their benefts principally on blood
vessels and the heart by supporting endothelial (and endocardial) function by their
antioxidant action and by setting the stage, as it were, for enhancing nitric oxide
(NO) formation.
We focused mainly on omega-3 PUFAs because they are far more plentiful in
faxseed and in fax oil than omega-6s. But keep in mind that faxseed contains
both omega-3 and omega-6 fatty acids, both of which promote good health. In fact,
omega-6 PUFAs were shown to reduce the risk of coronary heart disease. (1) So
both are benefcial, but it is not the ratio that really counts because you can have
a low 6:3 ratio and in the end still wind up with low absolute levels of omega-3 in
the tissues. What matters is the amount of omega-3s that one gets, not so much the
ratio.
Flaxseed oil is about 50% to 60% omega-3 fatty acids, mainly alpha-linolenic acid
(ALA). That is more than is contained in fsh oil. The omega-6 to omega-3 PUFAs
ratio is 1:4, which is ideal. Some researchers think faxseed oil might have some of
the same benefts as fsh oil. But the body is not very effcient at converting ALA into
EPA and DHA. The ALA that is so abundant in faxseed oil is not readily converted
by the body into EPA and DHA. So, in the frst eight chapters, we described preven-
tion and treatment of cardiovascular and related risk factors with these nutrients. But
here, we’ll focus also on forestalling catastrophe.
Omega-3 PUFAs prevent life span from being shortened because one pathway
to longevity is, to put it bluntly, avoiding death from cardiovascular disease. As WS
Harris put it in the title of his 2016 publication in the journal Atherosclerosis, “[low
levels of] RBC omega-3 predicts risk for death.” (2)
Think about this: according to the Centers for Disease Control and Prevention,
there are four major cardiovascular disease risk factors: high blood pressure,
unhealthy blood cholesterol levels, diabetes mellitus and obesity. (3) There are others,

DOI: 10.1201/b22986-9 169

170 Flaxseed

of course, including smoking, abusing alcohol and/or drugs, heredity and so on, but
these are said to be the major ones.
According to a report recently published in the American Journal of Clinical
Nutrition in 2021, fatty acids concentration was measured in red blood cells from
a cohort followed for 11 years. It was found that the information conveyed by tests
on the concentrations of fatty acids obtained from red blood cells was as useful
as the information conveyed by tests of lipid levels, blood pressure, smoking and
diabetic status in predicting total mortality. (4) In that study, the investigators
used levels of erythrocyte fatty acids (“fngerprint”) to predict risk of all-cause
mortality in the Framingham Offspring Cohort. Their report provides some addi-
tional gems:
The fatty acids most clearly associated with reduced risk for cardiovascular
disease (CVD) and for total mortality (i.e., death from any cause) are the omega-3
PUFAs, eicosapentaenoic (EPA) (20: 5n–3) and docosahexaenoic (DHA) (22: 6n–3).
Likewise, a report published in the journal Circulation: Cardiovascular Quality
and Outcomes in 2010, was titled “Blood Eicosapentaenoic and Docosahexaenoic
Acids Predict All-Cause Mortality in Patients with Stable Coronary Heart Disease:
The Heart and Soul Study.” (5)
In yet another study, published in the journal Annals of Internal Medicine, in
2013, the investigators send the very clear message that “higher circulating indi-
vidual and total ω3-PUFA levels are associated with lower total mortality, especially
CHD death, in older adults.” (6)
A report published in the Journal of Clinical Lipidology in 2018 describes a study
where participants in the Framingham Offspring Cohort were followed for a median
of 7.3 years (i.e., between ages ~66 and 73 y). It was found that the baseline red
blood cell (erythrocytes) EPA + DHA content (the Omega-3 Index) was signifcantly
inversely associated with risk for death from all causes. Individuals in the highest
quintile were 33% less likely to succumb during the follow-up years compared with
those in the lowest quintile. (7)
The investigators reported that “a higher omega-3 index was associated with
reduced risk of both CVD and all-cause mortality.” The Omega Index, developed
by Drs. WS Harris and C. Von Schacky in 2004 is described in greater detail in a
later section of this chapter. (27) Similar fndings were observed in the Women’s
Health Initiative Memory Study: the purpose of the prospective cohort study, also
published in the Journal of Clinical Lipidology, albeit earlier, in 2017, was to deter-
mine the associations between red blood cells (RBC) PUFA levels and risk for death.
The study centered on men and women aged 65 to 80 years who participated in the
Women’s Health Initiative Memory Study (enrollment began in 1996). The primary
“outcome” was total mortality through August 2014.
It was found that after a median of 14.9 years of follow-up, 1,851 women (28.5%)
had died. RBC levels of EPA and DHA were signifcantly higher in the survivors.
In the fully adjusted models, the hazard ratios* (99% confdence intervals) for
mortality associated with 1 standard deviation PUFA increase for total mortality

* The hazard ratio is an estimate of the ratio of the hazard rate in a treatment group versus that
in a control group.
Longer Life Span with a Longer Health Span 171

were 0.92 (0.85, 0.98) for the Omega-3 Index, 0.89 (0.82, 0.96) for EPA, 0.93 (0.87,
1.0) for DHA and 0.76 (0.64, 0.90) for the PUFA factor score. There was no sig-
nifcant specifc differentiation between ALA, arachidonic acid or linoleic acid
with total mortality. The investigators concluded that higher RBC levels of marine
omega-3 PUFAs predicted reduced risk for all-cause mortality. (8)
A study conducted in Germany, published in the journal Atherosclerosis, in 2016,
reported that EPA and DHA were associated with reduced mortality in patients
referred for coronary angiography in the Ludwigshafen Risk and Cardiovascular
Health Study, independent of other risk factors, with the association of EPA with
mortality being nonlinear. (9)
The message is unambiguous: omega-3 fatty acids promote health and in fact,
forestall death from cardiovascular disease. The good news: omega-3 fatty acids are
plentiful in faxseed.

9.2 HOW CAN WE TELL WHETHER PEOPLE WHO

CONSUME FLAXSEED OR FLAX OIL AGE
MORE SLOWLY, LIVE LONGER?
Most of our cells have a nucleus that contains chromosomes. The chromosomes
end in telomeres, special structures that provide protection from enzymatic end-
degradation and maintain chromosomal and genomic stability. For this reason,
adequate telomere structure (including the presence of telomere-binding proteins)
remains the key to avoiding cellular dysfunction.
With each cell replication, telomeres shorten. There is a consensus that not only
is their length reduced by aging as cells divide to replicate but also that the pro-
cess can be accelerated by metabolic stress, among other factors, and that shorter
telomeres can impair health and longevity. Thus, slowing telomere shortening or,
at least, not accelerating the process, is to our advantage in preserving our natural
life span.
You may recall the Greek myth of the three Fates who control the mother thread
of life from birth to death. Clotho spun the thread of life, Lachesis measured the
thread allotted to each person and Atropos was the cutter of the thread, choosing the
moment of each person’s passing. You can substitute “metabolic stress” for Atropos,
and “telomeres” for the “thread of life.”

9.2.1 OMEGA-3S CONCENTRATION AFFECTS CELL AGING VIA

TELOMERE LENGTH
Shorter telomeres have been associated with oxidative stress, poor health behaviors—
so-called lifestyle factors—age-related diseases, and early mortality. Telomere
length is regulated by the enzyme telomerase and is linked to exposure to proinfam-
matory cytokines and oxidative stress.
In a study titled “Omega-3 Fatty Acids, Oxidative Stress, and Leukocyte Telomere
Length: A Randomized Controlled Trial,” published in the journal Brain, Behavior
and Immunity, in 2013, omega-3 PUFA supplementation was found to lower the
172 Flaxseed

concentration of serum proinfammatory cytokines. The study aimed to determine

whether omega-3 PUFA supplementation also affected leukocyte telomere length,
telomerase and oxidative stress.
The study was conducted on healthy sedentary overweight middle-aged and older
adults who received (1) 2.5 g/day omega-3 PUFAs, (2) l.25 g/day omega-3 PUFAs
or (3) placebo capsules that mirrored the proportions of fatty acids in the typical
American diet.
It was found that the supplementation signifcantly lowered oxidative stress.
Changes in the omega-6/omega-3 PUFA plasma ratios refected in telomere length
signifcantly increased with decreasing ratios. A decreasing omega-6 to omega-3
ratio means that there are more omega-3s and that the increase in omega-3s (relative
to omega-6s) is associated with longer telomere length.
The investigators concluded that lower omega-6/omega-3 PUFA ratios can ben-
efcially impact cell aging. And, furthermore, “The triad of infammation, oxidative
stress, and immune cell aging represents important pre-disease mechanisms that
may be ameliorated through nutritional interventions.” (10)
Myocardial “remodeling” is a continuum of changes in the structure and function
of the myocardium. That commonly occurs as a result of aging or of pathological
processes. Adverse myocardial remodeling is associated with poor patient outcomes
in the context of ischemic heart disease and/or myocardial infarction, cardiac hyper-
trophy and cardiomyopathic disease states. (11)
Remodeling of myocardial cell membranes, then, is an aspect of advanced age.
Mitochondrial function, crucial to sustaining energy production and management of
myocardial metabolism, is impacted by age-dependent remodeling and ultimately
exhibits a diminished threshold for excess Ca2+ buffering during events that stimu-
late increased myocardial Ca2+, such as augmented cardiac work, oxidative stress or
post-ischemic refow.
In a study published in the journal Experimental Gerontology, in 2005, it was
reported that a diet rich in omega-3 PUFA reverses the age-associated membrane
omega-6:omega-3 PUFA imbalance, and dysfunctional Ca2+ metabolism, facilitating
increased effciency of mitochondrial energy production and improved tolerance of
ischemia and reperfusion. (12)

9.2.2 OMEGA-3 PUFAS SLOW AGING BY LOWERING MITOCHONDRIA

FREE RADICAL “EMISSIONS”
We derive energy by combining food-derived “fuel” with oxygen. We call this “oxi-
dative metabolism,” and the structures in our cells largely responsible for this pro-
cess are the mitochondria. Although we are exposed to a panoply of environmentally
produced oxygen free radicals, one by-product of oxidative metabolism is a large
outpouring of free radicals. These combine with other substances in our body to
form ROS.
A prominent theory of aging is the Harman theory, i.e., that aging is due, in large
part, to the corrosive action of ROS on DNA, i.e. metabolic stress. (26) Omega-3 poly-
unsaturated fatty acids (omega-3 PUFA) are known anti-infammatory antioxidants
Longer Life Span with a Longer Health Span 173

that may be benefcial in the treatment of loss of muscle tissue as a natural part of the
aging process (sarcopenia). A clinical study published in the journal Aging in 20127
aimed to determine the effects of omega-3 PUFA on muscle mitochondrial physiol-
ogy and protein metabolism in older adults.
Young men (18–35 years) and older men (65–85 years) and women were studied at
baseline. Older adults were then studied again following 3.9g/day of omega-3 PUFA
supplementation for 16 weeks. Muscle biopsies were used to evaluate respiratory
capacity (high-resolution respirometry) and oxidant emissions (spectrofuorometry)
in isolated mitochondria. It was found that maximal respiration was signifcantly
lower in older compared to young participants. Omega-3 PUFA supplements signif-
cantly reduced oxidant emissions.
Following omega-3 PUFA supplementation, mixed muscle, mitochondrial and
sarcoplasmic protein synthesis rates were increased in older adults before exercise.
Omega-3 PUFA increased post-exercise mitochondrial and myofbrillar protein syn-
thesis in older adults.
The investigators concluded that omega-3 PUFA supplements reduce mito-
chondrial oxidant emissions, increase postabsorptive muscle protein synthesis and
enhance anabolic responses to exercise in older adults. In other words, omega-3
PUFA supplementation reduced “mitochondrial oxidant emission” without adversely
affecting metabolism. (13) Only antioxidant action could have accomplished that.
An experimental animal-model (mice) study published in the journal
Prostaglandins, Leukotrienes and Essential Fatty Acids, in 2015, aimed to deter-
mine the effect of orally administered omega-3 (PUFA) on mitochondrial function
and processing of the amyloid precursor protein in brains of young (3 months old)
and aged (24 months old) Naval Medical Research Institute (NMRI)-mice.
The neuroprotective properties of 1.6 mL/kg p.o. of fsh oil were assessed ex vivo
after 21 days in dissociated brain cells and isolated mitochondria and it was found
that DHA levels were signifcantly lower in the blood and brains of aged mice, which
were not compensated by fsh oil administration. Isolated dissociated brain cells
and mitochondria from aged mice showed signifcantly lower adenosine triphosphate
(ATP) levels and reduced activity of complexes I+II and IV of the mitochondrial
respiration system, respectively. However, fsh oil restored the age-related decrease
in respiration and improved ATP production.
The investigators concluded that their fndings reveal new mechanisms underly-
ing the neuroprotective actions of omega-3 PUFA and identifed fsh oil as a promis-
ing nutraceutical to delay age-related mitochondrial dysfunction in the brain. (14) So,
aging is not simply a musculoskeletal issue; it also entails cognitive function.
To wit: In a review titled “Omega-3 Fatty Acids and Brain Resistance to Ageing
and Stress: Body of Evidence and Possible Mechanisms,” published in the journal
Ageing Research Reviews in 2013, the authors assert,

The increasing life expectancy in the populations of rich countries raises the pressing
question of how the elderly can maintain their cognitive function. Cognitive decline
is characterised by the loss of short-term memory due to a progressive impairment
of the underlying brain cell processes. Age-related brain damage has many causes,
some of which may be infuenced by diet. An optimal diet may therefore be a practical
174 Flaxseed

way of delaying the onset of age-related cognitive decline. Nutritional investigations

indicate that the ω-3 poyunsaturated fatty acid (PUFA) content of western diets is too
low to provide the brain with an optimal supply of docosahexaenoic acid (DHA), the
main ω-3 PUFA in cell membranes. Insuffcient brain DHA has been associated with
memory impairment, emotional disturbances and altered brain processes in rodents.
Human studies suggest that an adequate dietary intake of ω-3 PUFA can slow the
age-related cognitive decline and may also protect against the risk of senile dementia.
However, despite the many studies in this domain, the benefcial impact of ω-3 PUFA
on brain function has only recently been linked to specifc mechanisms. This review
examines the hypothesis that an optimal brain DHA status, conferred by an adequate
ω-3 PUFA intake, limits age-related brain damage by optimizing endogenous brain
repair mechanisms. Our analysis of the abundant literature indicates that an adequate
amount of DHA in the brain may limit the impact of stress, an important age-aggravating
factor, and infuences the neuronal and astroglial functions that govern and protect
synaptic transmission. This transmission, particularly glutamatergic neurotransmis-
sion in the hippocampus, underlies memory formation. The brain DHA status also
infuences neurogenesis, nested in the hippocampus, which helps maintain cognitive
function throughout life. Although there are still gaps in our knowledge of the way
ω-3 PUFA act, the mechanistic studies reviewed here indicate that ω-3 PUFA may be
a promising tool for preventing age-related brain deterioration. (15) With permission.

Their review aims to determine whether an optimal brain DHA status derived
from an adequate omega-3 PUFA intake, limits age-related brain damage by opti-
mizing endogenous brain repair mechanisms. Based on their analysis, the authors
conclude that an adequate amount of DHA in the brain may limit the impact of age-
aggravating stress, infuencing brain cell functions that govern and protect synaptic
transmission. They concluded that omega-3 PUFA may be helpful in preventing age-
related brain deterioration. (15)

9.2.3 SPEAKING OF COGNITIVE AGING

There is considerable evidence that cognitive decline results not only from changes
in brain health but also depends on nutritional status. Decline in the ability to think
and reason abstractly and solve problems, i.e., “fuid intelligence,” is one of the most
debilitating aspects of cognitive aging. That decline has been linked to omega-3
PUFA defciency. However, it is not known whether this phenomenon results from
specifc omega-3 PUFAs acting on particular aspects of brain function.
The aim of a clinical study published in the journal Nutritional Neuroscience (an
International Journal on Nutrition, Diet and Nervous System), in 2018, was to deter-
mine whether omega-3 PUFAs infuence fuid intelligence by supporting specifc
neural structures. The investigators measured six plasma phospholipid omega-3
PUFAs, fuid intelligence, and regional gray matter volume in the frontal and pari-
etal cortices in 100 cognitively intact older adults (65–75 years old).
It was found that one pattern of omega-3 PUFAs, consisting of ALA, stearidonic
acid and eicosatrienoic acid, was linked to fuid intelligence, and that total gray mat-
ter volume of the left frontoparietal cortex fully mediated the relationship between
this omega-3 PUFA pattern and fuid intelligence.
Longer Life Span with a Longer Health Span 175

The investigators concluded that fuid intelligence may be optimally supported by

specifc omega-3 PUFAs through the preservation of frontoparietal cortex gray mat-
ter structure in cognitively intact older adults. This report provides novel evidence
for the anti-aging benefts of particular omega-3 PUFA patterns on fuid intelligence
and underlying gray matter structure. (16)

9.3 CRITERIA FOR OMEGA-3 SUFFICIENCY: THE

OMEGA-3 INDEX
Despite the evident need for assessing individual body concentrations of benefcial
fatty acids, there is no simple home-testing means for doing so currently available to
the typical consumer. Home measurement kits are available at pharmacies to mea-
sure blood pressure, arterial blood O2 concentration, blood glucose and even blood
lipids. In fact, there are few guidelines as to what criteria one might use to establish
healthy vs. defciency levels. So, how can the average individual who wishes to attain
benefcial levels of omega-3s via diet or supplements know if s/he is successful? That
is now changing.
A number of commercial laboratories provide “home test” kits that evaluate a
small fnger prick sample of blood for fatty acids composition and return a report to
the purchaser with omega-3 concentration, the Omega Index. For instance, there are
the following:

Omegaquant
5009 W. 12th Street, Suite 8
Sioux Falls, SD 57106
Phone: 1-605-271-6917
Toll-free: 1-800-949-0632
Fax: 1-800-526-9873
Email: [email protected]
Website: https://omegaquant.com/what-is-the-omega-3-index/ (accessed 1/12/22)

If one contacts them, they will send the customer a test kit to be returned to
them with a drop of blood as instructed. They will then return a report indicating
the Omega Index, a percentage value. Parenthetically, the laboratory procedure for
determining the ratio of these fatty acids consists of determining their concentration
in red blood cells. (17) Omegaquant also supplies the following information about
cardiovascular “risk zones”:

• High risk = less than 4%

• Intermediate risk = 4% to 8%
• Low risk = more than 8%

The Omega-3 Index as a risk factor for heart disease was frst put forth in 2004 in
the journal Preventive Medicine by Dr. WS Harris, who co-invented the Omega-3
Index test. It provides a percentage which is a measure of the amount of omega-3
fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in one’s
176 Flaxseed

red blood cell membranes. An Omega-3 Index of 8% or higher is ideal, the lowest
risk zone. If one’s Omega-3 Index is in the optimal range, the omega-6 to omega-3
ratio should also be OK—it’s all about the denominator. However, most people hover
around 5% to 6% or less. And unfortunately in the United States, many people are at
4% or below—the highest risk zone.
As noted previously, in 2008, WS Harris published a report in the American
Journal of Clinical Nutrition, which points out that

Because blood concentrations of n-3 (or omega-3) fatty acids (FAs) (eicosapentaenoic
and docosahexaenoic acids) are a strong refection of dietary intake, it is proposed
that a n-3 FA biomarker, the omega-3 index (erythrocyte eicosapentaenoic acid plus
docosahexaenoic acid), be considered as a potential risk factor for coronary heart
disease mortality, especially sudden cardiac death. The omega-3 index fulflls many
of the requirements for a risk factor including consistent epidemiologic evidence, a
plausible mechanism of action, a reproducible assay, independence from classic risk
factors, modifability, and, most important, the demonstration that raising levels will
reduce risk for cardiac events. Measuring membrane concentrations of n-3 FAs is a
rational approach to biostatus assessment as these FAs appear to exert their benefcial
metabolic effects because of their actions in membranes. They alter membrane phys-
ical characteristics and the activity of membrane-bound proteins, and, once released
by intracellular phospholipases from membrane stores, they can interact with ion
channels, be converted into a wide variety of bioactive eicosanoids, and serve as
ligands for several nuclear transcription factors, thereby altering gene expression.
The omega-3 index compares very favorably with other risk factors for sudden car-
diac death. Proposed omega-3 index risk zones are (in percentages of erythrocyte
FAs): high risk, <4%; intermediate risk, 4–8%; and low risk, >8%. Before assessment
of n-3 FA biostatus can be used in routine clinical evaluation of patients, standard-
ized laboratory methods and quality control materials must become available. (18)
With permission.

There is a compelling need for routine evaluation of blood concentrations of ben-

efcial fatty acids in light of the fact that they may be as telling as the panoply of
other routine blood tests currently in vogue. There is however a recent delineation
of criteria and targets for optimal omega-3 concentrations. It was published in 2021
in the journal BMJ Open, in a report titled “Mean Serum LC Omega-3 Fatty Acid
Concentrations (% of Total Fatty Acids) by Age Group in NHANES 2011–2012.”
You can access it at https://bmjopen.bmj.com/content/11/5/e043301.
Go to the PDF version, and you will see their second table: “Comparisons
are *children 3–19 years vs adults 20+ years, †early childhood and middle
childhood vs adolescents, and ‡adults vs seniors. Sum LC omega-3 represents
EPA+DPA+DHA. BMI, body mass index; DHA, docosapentaenoic acid; EPA,
eicosapentaenoic acid; LC, long chain; NHANES, National Health and Nutrition
Examination Survey.”
The aim of their study was to determine reference ranges of circulating
omega-3 PUFAs, EPA, DPA and DHA in a nationally representative popula-
tion of Americans. Serum concentrations were compared with concentrations
associated with consuming the recommended amount of EPA and DHA by the
Dietary Guidelines for Americans and the Omega-3 Index (EPA + DHA). The
Longer Life Span with a Longer Health Span 177

setting was the National Health and Nutrition Examination Survey 2011–2012
cycle and the participants with fatty acids measured in serum were children aged
3–19 years and adults aged 20 years and older. The main measures were serum
EPA, DPA, DHA and sum of omega-3 fatty acids expressed as percent of total
fatty acids.
The fndings, summarized in that table, are essentially that fatty acids concen-
trations in adults were found to be higher than that in children; more than 95% of
children and 58% of adults had omega-3 concentrations below those recommended
by Dietary Guidelines for Americans*, and, not surprisingly, 89% of the adults had
an Omega-3 Index in the “high cardiovascular risk” category. (19)
The need for criteria is both timely and pressing particularly in light of a study
published in the journal Nutrients, in 2015, titled “Suboptimal Plasma Long Chain
n-3 Concentrations Are Common among Adults in the United States, NHANES
2003–2004.” The aim of the study was to describe plasma concentrations of
omega-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFA), mainly EPA (20:5
n-3) and DHA (22:6 n-3), and compare them to concentrations associated with
cardiovascular health and dietary recommendations for two weekly servings of
seafood.
Fasting plasma fatty acids were measured in participants 20 years old or older
drawn from the National Health and Nutrition Examination Survey, 2003–2004.
Fatty acids concentrations represent the sum of EPA, DHA and docosahexaenoic
acid relative to total fatty acids (expressed as a percentage).
It was found that overall, 80.6% of participants had omega-3 LC-PUFA levels
below concentrations recommended for cardiovascular health; nearly all partici-
pants (95.7%) had below-concentration levels associated with cardiovascular protec-
tion; participants 60 years or older had higher omega-3 PUFA concentrations than
those aged 20–39 years but not those aged 40–59 years. Omega-3 PUFA concentra-
tions were found to be lower in Hispanic participants relative to non-Hispanic black
participants.
It was concluded that suboptimal long-chain omega-3 concentrations are common
among US adults. And, the authors conclude that there is a need to increase intake
among Americans. (20) And, by the way, the aforementioned BMJ Open study
reported that approximately 89% of adults in their study had an Omega-3 Index in
the high cardiovascular risk category.
It should be noted that, in addition to Omegaquant, there are a number of other
“Omega-3 Index Home test” kits available online. Here is a sample of those:

• VitalChoice Omega-3 Index Home Test

• Dr. Guberman Omega-3 Index Plus Test

* The Dietary Guidelines for Americans provide nutritional advice for Americans who are
healthy or who are at risk for chronic disease but do not currently have a chronic dis-
ease. The guidelines are published every fve years by the US Department of Agriculture,
together with the US Department of Health and Human Services. Notably, the most recent
ninth edition for 2020–2025 includes dietary guidelines for children from birth to 23
months.
178 Flaxseed

• Carlson Labs Omega-3 Test Kit

• Omega-3 Plus Patch

They range in price from $20.00 to $500.00 each.

Supplementing faxseed or faxseed oil seems to be a good avenue of achieving
optimal omega-3 concentration given the published clinical evidence.
Disclaimer: First, we cannot vouch for the effcacy, reliability, validity or safety
of any products that we cite as “examples.” Second, we have no fnancial interest in
any products that we cite as “examples.”

9.3.1 AVAILABILITY VS. ABSORBABILITY

It should be kept in mind that availability is not invariably absorbability. This is
brought to our attention in a report in the International Journal for Vitamin
and Nutrition Research, in 1998, titled “Can Adults Adequately Convert Alpha-
Linolenic Acid (18:3n-3) to Eicosapentaenoic Acid (20:5n-3) and Docosahexaenoic
acid (22:6n-3)?”
The author points out that a certain though restricted conversion of high doses
of ALA to EPA occurs, but conversion to DHA is severely restricted. A background
diet high in saturated fat restricts conversion to long-chain metabolites to approxi-
mately 6% for EPA and 3.8% for DHA. With a diet rich in omega-6 PUFA, conver-
sion is nevertheless reduced by 40% to 50%.
The author further stipulates that we may need to focus on the adequate pro-
vision of DHA, which can reliably be achieved only with the supply of the pre-
formed long-chain metabolite. (21) Similarly, guidelines for absorbability are also
given in a report titled “Alpha-Linolenic Acid Supplementation and Conversion to
n-3 Long-Chain Polyunsaturated Fatty Acids in Humans,” published in the journal
Prostaglandins, Leukotrienes and Essential Fatty Acids in 2009. (22)

9.4 ANTI-AGING ACTION OF L-ARGININE

“Anti-aging” is in quotes here because the term presents us with a conundrum: meant
literally, one needs to be of advanced age to suffer from age-related diseases. But
that is not what is commonly meant here. What we mean is that there are diseases
that progress predictably as we age. This is the only meaning that validates the con-
cept of anti-aging. Thus, anti-aging can be applied to the slowing or halting of the
progression of what would otherwise be age-related diseases. In that sense, they are
anti-aging, and they prolong life.
The amino acid L-arginine, plentiful in faxseed, is said to be anti-aging.
In previous chapters, it was noted that supplementation of faxseed, therefore
L-arginine, increased NO formation, the “Arginine Paradox”* notwithstand-
ing. But as reported in many journal publications, enzymatic production of NO

* The Arginine Paradox: Exogenous L-arginine causes NO-mediated biological effects despite
the fact that nitric oxide synthases (NOS) are theoretically saturated with L-arginine. (23)
Longer Life Span with a Longer Health Span 179

declines steadily with increasing age, even in healthy people. Thus implementing
strategies to diagnose and treat NO insuffciency may provide enormous benefts
to the geriatric patient.
In a review published in the Journal of Advanced Research in 2010, titled “Anti-
Aging Effects of L-Arginine,” the author asserts that a number of clinical and
experimental animal studies show that exogenous L-arginine intake is benefcial in
doses larger than those in normal dietary consumption. Among the benefts cited
is the reduction in the risk of vascular and heart diseases, reduction in erectile
dysfunction, improvement in immune response and inhibition of gastric hyperacid-
ity. Many, if not all, body functions are debilitated by aging. Studies have shown
that L-arginine, through its versatile metabolic and physiological pathways, can
improve many of these functions.
The author recites that arginine (1) increases the production of a variety of
enzymes, hormones and structural proteins, (2) facilitates the release of growth hor-
mone, insulin, glucagon and prolactin; (3) is involved in the action of vasopressin,
produced by the pituitary gland; and (4) is a precursor of nitric oxide, polyamines,
proline, glutamate, creatine, agmatine and urea. What’s more, L-arginine boosts
immunity, stimulates the thymus and promotes lymphocyte production, the key to
promoting the healing of wounds and burns.
The author concludes from the review that “the demonstrated anti-aging ben-
efts of L-arginine show promises greater than any pharmaceutical or nutraceutical
agent ever previously discovered.” (24)
The authors of a study titled “Endothelial Cellular Senescence Is Inhibited by
Nitric Oxide: Implications in Atherosclerosis Associated with Menopause and
Diabetes,” published in the Proceedings of the National Academy of Sciences
USA, in 2006, report investigating the effect of NO bioavailability on high glucose-
promoted cellular senescence of umbilical vein endothelial cells.
They found that inhibition by eNOS transfection* of this cellular senescence
under high glucose conditions was less pronounced. Treatment with L-arginine
or L-citrulline of eNOS-transfected cells partially inhibited, and a combination
of L-arginine and L-citrulline with antioxidants strongly prevented high glucose-
induced cellular senescence. It was concluded that NO can prevent endothelial senes-
cence, thereby contributing to the anti-senile action of estrogen. And, the ingestion
of NO-boosting substances, including L-arginine, L-citrulline and antioxidants, can
delay endothelial senescence under high glucose. (25)
The authors proposed that the delay in endothelial senescence through NO and/
or eNOS activation may have clinical utility in the treatment of atherosclerosis in the
elderly.

9.5 SUMMARY
Flaxseed and fax oil contain high amounts of omega-3 fatty acids. Clinical stud-
ies show that an ample supply of these constituents in body tissues slows cell aging

* Transfection is a procedure that introduces foreign nucleic acids into cells to produce genet-
ically modifed cells.
180 Flaxseed

and reduces the risk of cardiovascular disease and premature death. There are now
nonprescription blood tests, such as the Omegaquant Omega-3 Index, available to
the public for assessing omega-3 body levels. Flaxseed also contains L-arginine, the
precursor of nitric oxide that protects and enhances endothelial function.

9.6 REFERENCES
1. Harris WS, Mozaffarian D, Rimm E, Kris-Etherton P, Rudel LL, Appel LJ, Engler MM,
Engler MB, and F Sacks. 2009. Omega-6 fatty acids and risk for cardiovascular disease.
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Index
Note: Page numbers in italics indicate a fgure and page numbers in bold indicate a table on the corres-
ponding page.

A diastolic phase, 75
dicrotic notch, 75
acetylcholine (ACh), 7, 31–32, 49, 154–155 systolic phase, 75
adjuvant treatment of type 2 diabetes, faxseed in, asymmetric dimethyl L-arginine (ADMA), 78,
129–138, see also type 2 diabetes 83, 117
treatment dosage matters, 134 Arginine Paradox and, 118
L-arginine as, 134–138 as L-arginine’s analogue, 117–118
ad lib supplementation, 18–22 atherosclerosis, 49, 89–104
fax oil, 18–19 atherosclerotic plaque, 89, 90
golden faxseed vs. brown faxseed, 19–20 endothelial glycocalyx in, 60
ground faxseeds, 18 L-arginine in preventing/reversing, 97–99
macronutrients, 19 omega-3 fatty acids and NO from fax
raw faxseed, 19–20 intervention in, 89–104
whole faxseeds, 18 polyunsaturated fatty acids (PUFAs) in
aging effect, in erectile dysfunction (ED), preventing/reversing, 93
159–162 rheumatoid arthritis, 102–103
alanine aminotransferase (ALT), 139 ROS role in, 92
albuginea, 159
albumin-creatinine ratio (ACR), 140 B
alpha-linoleic acid (ALA), 4–5, 8, 11–14, 20, 25,
70, 93, 129, 151 benign prostate hypertrophy (BPH), 153
content of selected foods, 12, 13 blood fow control systems, 80
in eNO formation, 70–71 blood platelets, 33
alpha-linolenic acid/low fat (ALF), 70, 73 blood pressure
American Heart Association (AHA), 6, 32, 109 drugs, 36
amino acid L-arginine, 8 endothelium-dependent control of, 79–80
amino acids, 27 endothelium-independent control of, 79
1-amino D-proline (1ADP), 38 eNO in controlling, 79–83
aminotransferase (AST), 139 L-arginine supplementation reducing, 114–117
amygdalin, 3, 53 reduction, by fax/omega-3 fatty acids,
anti-aging action of L-arginine, 178–179 111–113
anticoagulant drugs, 36 treatment, 10
antidiabetic beneft, 38, 39 blood through the circulatory system, 68–71
antifungal beneft, 38, 39 blood urea nitrogen (BUN), 139
antihypertensive beneft, 38, 39 blood vessel and heart function, 67–85
anti-nutritional aspects of faxseed, 37–38 arterial vessel compliance, 72–74
CNglcs, 34–35 arterial waveform, 74–76
hydrogen cyanide, 37 faxseed micronutrients role in, 67–85
linamarin, 35 nitric oxide (NO) role in, 67–85
neolinustatin, 37 peripheral artery disease (PAD) combating,
phytic acid, 38 83–85
antioxidants, 19, 38, 39 blood vessels (Vasa Vasorum), 54–56
anti-platelet drugs, 36 depends on endothelium derived NO
anti-thrombic beneft, 38, 39 vasorelaxation, 56
anti-tumor beneft, 38, 39 NO regulating, 54–56
arginine paradox, 118, 143 structure and function of, 55–56
arterial vessel compliance, 72–74 bread recipe, 21
arterial waveform, 74–76 brown faxseed, 19–20

183
184 Index

C diastolic phase, 75
dicrotic notch, 75
canola oil (CanO), 145 Dietary Approaches to Stop Hypertension
cardiovascular disease (CVD), 10, 155, 170 (DASH), 115
Carlson Labs Omega-3 test kit, 178 dietary fber, 28–29
catalase (CAT), 126 digital-subtracted arteriography, 114
cellulose, 28 dihydrotestosterone (DHT), 153
cholesterol esters (CEs), 101 dimethylarginine dimethylaminohydrolase
cholesterol-lowering beneft of fax proteins, (DDAH), 118
38, 39 docosahexaenoic acid (DHA), 8, 11–14, 12, 13,
chronic heart failure, 144–145 25, 93–94, 102, 112–113, 131, 170, 175
chronic kidney disease (CKD), 34, 138–145 Dr. Guberman Omega-3 index plus test, 177
fax, infammation, and endothelium dyslipidemia treatment, 9
dysfunction in, 138–145
faxseed as adjuvant treatment of, 138–139
hypertension and chronic heart failure and, E
144–145 eicosapentaenoic acid (EPA), 8, 11–14, 12, 13, 25,
L-arginine in treatment of, 142–144 93–94, 102, 112, 131, 170, 175
omega-3 fatty acids in adjuvant treatment of, ejection fraction, 71
14, 139–142 endocardium, 69
chronic renal failure (CRF) treatment, endothelial dysfunction
L-arginine in, 16 in L-arginine therapy, 119–120
chronic systemic infammation (CSI), 99–103 in sickle cell disease therapy, 119–120
C-reactive protein (CRP) in, 99 treatment, L-arginine in, 15
L-arginine reducing, 102 treatment, omega-3 PUFAs in, 12
omega-3 ALA reducing, 101–102 in type 2 diabetes, 128
omega-3 fatty acids intervention in, 89–104 endothelial glycocalyx, 56–59
Cialis®, 153 in atherosclerosis, 60
cognitive aging, 174–175 in diabetes, 59–60
common fax (Linum usitatissimum L.), 1 glycocalyx regulate eNO formation, 58–59
conditional amino acids, 27 in health and disease, 59–61
constitutive nitric oxide synthase (cNOS), in hypertension, 60–61
51–52 endothelial nitric oxide (eNO) bioavailability, 14,
Cool Knight brand grinder, 37 45–62, 81, 151, 156–157
coronary heart disease, 9, 132 in blood pressure control, 79–83
omega-3 PUFAs in treatment of, 12 blood vessels regulated by NO, 54–56
type 2 diabetes and, 132 endothelial glycocalyx, 56–59
corpora cavernosae, 158, 158 endothelial NO from L-Arginine, 51–52
corpora spongeosum, 158, 158 endothelium, 47–49
C-reactive protein (CRP), 99–103 formation, 52–53
creatinine clearance (Ccr), 144–145 L-arginine benefcial effect on, 45–62
cross-check dietary history method, 127 NO from CNglcs, 53–54
Cuisinart brand grinder, 37 omega-3 PUFA benefcial effect on, 45–62
cyanogenic glycosides (CNglcs) in faxseeds, oxidative stress in endothelium damage,
3–4, 6, 8, 34–35, 99, 113, 125, 151 50–51
cyclic guanosine monophosphate (cGMP), 53, reactive oxygen species (ROS) in endothelium
159 damage, 50–51
cyclosporin A (CYS), 139 endothelial nitric oxide synthase (eNOS),
51–52, 81
D endothelium, structure and function of,
47–49, 154
daily diet, faxseed in, 21–22 endothelium-derived relaxing factor (EDRF),
diabetes, see also type 2 diabetes 49, 154
drugs, 36 endothelium dysfunction, erectile dysfunction
endothelial glycocalyx in, 59–60 (ED) and, 162
diabetic nephropathy, type 2 diabetes with, enterodiol (ED), 95
133–134 epinephrine, 79
Index 185

erectile dysfunction (ED), 50, 153 fow-mediated dilation (FMD), 60, 76–78, 116
aging role in, 159–162 faxseed improving, 77–78
causes of, 153–154 L-arginine improving, 77–78
endothelium dysfunction as a feature of, 162 measuring blood fow by, 76–78
faxseed in, 162–165 foam cells, 56
L-arginine in treating, 16, 163 Food and Drug Administration (FDA), 3
omega-3 fatty acids in treating, 164–165 free-fat mass (FFM), 135
reactive oxygen species (ROS) jeopardizing, functional food, faxseed as, 2–3, 25–39
155–156 constituents, 25–26
sexual performance and, 161–162 dietary fber, 28–29
erythrocyte deformability, 33 fatty acids profle in faxseed oil, 26–27, 27
essential amino acids, 27 faxseed oil/lipids components, 26–27
essential fats, 20 health benefts, 25–39
estimated glomerular fltration rate (eGFR), 133 lignans, 29
minerals, 29
F nutrient and phytochemicals, composition,
26, 26
fat mass (FM), 135 proteins, 27–28
fatty acids profle in faxseed oil, 26–27, 27
Finasteride (Propecia®), 153 G
Flax Council of Canada, 4
fax fbers, 28 gamma-glutamyltransferase (GGT), 133
fax/fax plant gas fuels performance, 154–155
bleeding chances increased, 7 β-gentiobioside of acetone cyanohydrin, 34–35
in blood pressure lowering, 7 glomerular fltration rate (GFR), 140
in blood sugar lowering, 7 glucose-stimulated insulin secretion (GSIS), 137
consumption, safety, 3–6 glycocalyx, 157
as a functional food, 2–3 eNO formation regulation, 58–59
in garment of pharaohs, 1–2 glycocalyx/eSL (endothelial surface layer), 56
health uses, 1–2 goitrogens, 4–5
on hormones, 7 golden faxseed, 19–20
supplement dosages, 7–18 Greek Mediterranean diet, 111
uses, 1–2 ground faxseeds, 18
faxseed, 8–11 guanosine triphosphate (GTP), 53
as adjuvant treatment of CKD, guanylyl cyclase, 53
138–139
as adjuvant treatment of type 2 diabetes, H
129–138
in blood pressure reduction, 10, 111–113 Harman theory, 172
in cardiovascular risk factors prevention, 10 health benefts of faxseed, 29–34
CNglcs safety in, 113 acetylcholine (Ach) production increase, 31–32
constituents contribution in type 2 diabetes, benign prostate hypertrophy risk lowering, 33
125–128 blood glucose level reduction, 33
in coronary artery disease treatment, 9 blood pressure decrease, 32
dosages, 8–9 blood viscosity decrease, 32–33
dyslipidemia, 9 cardiac arrest risk reduction, 32
in erectile dysfunction (ED) treatment, cardiovascular disease prevention, 32
162–165 fax proteins, 38–39
in hypertension treatment, 9, 109–120 health hazards of menopause improvement, 34
fow-mediated dilation (FMD) improved by, healthy bowel function promotion, 33
77–78 heart arrhythmias incidence reduction, 32
in metabolic syndrome treatment, 9–10 heart function improvement, 32
micronutrients, in blood vessel and heart heart muscle lipid fuidity increase, 32
function, 67–85 insulin production increase, 33
in obesity and insulin resistance treatment, 10 joint pain and arthritis reduction, 33
oil, 18–19, 26–27 kidney function improvement, 34
type 2 diabetes, 10 lipid profle improvement, 34
186 Index

liver function improvement, 34 asymmetric dimethylarginine (ADMA) as an

proinfammatory cytokines level decrease, 30 analogue of, 117
serotonin production increase, 30–31 in atherosclerosis prevention/reversing, 93
health span benefcial effect on eNO, 45–62
cognitive aging, 174–175 in chronic kidney disease treatment, 142–144
L-arginine increasing, 169–180 in chronic renal failure (CRF) treatment, 16
omega-3 PUFA increasing, 169–180 in chronic systemic infammation (CSI)
health targets of functional elements of faxseed, reduction, 102
30, 31 dosage recommendations, 15
heart disease, 155 in endothelial dysfunction treatment, 15,
treatment, L-arginine in, 15 119–120
treatment, omega-3 PUFAs in, 12 in erectile dysfunction (ED) treatment,
heart function, 67–85 16–17, 163
chambers and valves, 68, 69 fow-mediated dilation (FMD) improved by,
systole, 68–70 77–78
hematocrit, 33 health span increase by, 169–180
hemodialysis (HD), 100, 145 in heart disease treatment, 15
high-density lipoprotein (HDL), 94 in hypertension treatment 109–120
high-sensitivity C-reactive protein (hs-CRP) intermittent claudication treatment, 16
test, 77 life span increase by, 169–180
HOMA-IR index, 130 in myocardial infarction treatment, 16
homeostasis model assessment (HOMA-IR), 133 in peripheral artery disease (PAD)
hydrogen cyanide, 37 treatment, 16
hypertension, 109–120, 144–145 in sickle cell disease treatment, 16
endothelial glycocalyx in, 60–61 supplementation, in blood pressure reduction,
faxseed combating, 82–83 114–117
faxseed in treatment of, 109–120 in type 2 diabetes treatment, 17, 125–146
L-arginine in treatment of, 109–120 lariciresinol, 29
as omega-3 defciency, 110–111 life span
omega-3 fatty acids in treatment of, 109–120 availability vs. absorbability, 178
reduction, by fax/omega-3 fatty acids, cognitive aging, 174–175
111–113 faxseed consumers, 171–175
treatment, 9 L-arginine increasing, 169–180
hypocaloric diet, 135 omega-3 PUFA increasing, 169–180
preventing the shortening of, 169–171
I lignans, 29
linamarin, 35, 53
icosapent ethyl, 14 linatine, 38
inducible nitric oxide synthase (iNOS), 51–52 linen textiles from fax, 2
inositol triphosphate (IP3), 52 linoleic acid, 20
insulin resistance, omega-3 fatty acids reducing, linustatin, 4, 34–35, 53
131 lipid peroxidation (LPO), 126
interleukin 6, 78 loaf recipe, 21
intermittent claudication, L-arginine in, 16 lower urinary tract symptoms (LUTS), 33
International Index of Erectile Function (IIEF) lumen, 157
score, 163 lutein, 19
isoproterenol (isuprel), 17
M
K
macronutrients, 19
kidney function, omega-3 PUFAs in, 14, see also malondialdehyde (MDA), 74, 126
chronic kidney disease matairesinol, 29
metabolic syndrome treatment, 9–10, 14
L methyl ethyl ketone cyanohydrins, 35
Michaelis-Menten constant (Km), 118
L-arginine (Arg), 3, 7, 14–18 micronutrients, 2
anti-aging action of, 178–179 mitochondria free radical “emissions,” 172–174
Index 187

Molecule of the Year, 1992, 46, see nitric Omega-3 Index, 111–113, 131, 175–178
oxide Omega-3 Index Home test, 177
mononuclear cells (MNCs), 95 Omega-3 plus patch, 178
5-monophosphate (cGMP), 144 omega-3 polyunsaturated fatty acids (PUFAs),
MotorGenic brand grinder, 37 3, 11–14
mucilage gums, 28 aging slowed down by, 172–174
muffns recipe, 21 cell aging and, 171–172
myocardial infarction treatment, L-arginine in chronic kidney disease (CKD)
in, 16 treatment, 14
content of selected foods, 12, 13
N in coronary heart disease treatment, 12
in endothelial dysfunction treatment, 12
neolinustatin, 4, 34–35, 37, 53 eNO effect on, 45–62
neurotransmitters, 47, 154 health span increase by, 169–180
nicotinamide adenine dinucleotide phosphate in heart disease treatment, 12
(NADPH), 92 icosapent ethyl, 14
nitrates, 17 intake of, 11, 11
nitric oxide (NO), 7–8, 45–46, 151; see also in kidney function and myocardial infarction
sexual function treatment, 14
in atherosclerosis, 89–104 life span increase by, 169–180
bioavailability, faxseed increasing, 70 in metabolic syndrome treatment, 14
in blood vessel and heart function, 67–85 in type 2 diabetes treatment, 13
in chronic systemic infammation, 89–104 omega-3-acid ethyl esters, 14
from CNglcs, 53–54 omega-3-carboxylic acids, 14
from faxseed enhancing sexual function, oral drugs, 36
151–166 oral glucose tolerance test, 127
formation in body, 49–50 oxidative stress, 155–156
nitric oxide synthases (NOS), 7, 97, 137 in endothelium damage, 50–51
nonalcoholic fatty liver disease (NAFLD), 34, in type 2 diabetes, 126–127
132–133
nonessential amino acids, 27 P
norepinephrine, 79
nutraceuticals, 3 p-coumaric acid, 29
penis, 158–159, see also sexual function
O corpora cavernosae, 158
corpora spongeosum, 158
obesity and insulin resistance treatment, 10 cross-section of, 158, 158
oleic/low fat (OLF), 73 penile erection, ACH/NO/CGMP pathway
omega-3 ALA, in CSI reduction, 101–102 to, 159
omega-3 fatty acids, 70–71, 111–113 Perfumed Garden of the Shaykh Nefzawi, The,
in adjuvant treatment of kidney disease, 152
139–142 peripheral artery disease (PAD)
as adjuvant treatment of NAFLD, 132–133 faxseed combating, 83–85
in atherosclerosis, 89–104 treatment, 16
blood pressure reduction by, 111–113 phosphodiesterase (PDE), 53
in chronic kidney disease treatment, 125–146 phosphodiesterase type-5 (PDE5), 159
in chronic systemic infammation, 89–104 phospholipids, 101
from elevated blood cholesterol, 94–96 phytic acid, 5, 38
in eNO formation, 70–71 pinoresinol, 29
in erectile dysfunction (ED) treatment, placebo effect, 151
164–165 plasma viscosity, 32–33
from faxseed, 93–94, 96–97 polyphenol, 19
in hypertension treatment, 109–120 polyunsaturated fatty acids (PUFAs), 93
insulin resistance reduction by, 131 Prima Cucina brand grinder, 37
in triglycerides reduction in Type 2 diabetes, proteins, 27–28
131–132 prunasin, 53
in type 2 diabetes treatment, 125–146 pyridoxal 5´-phosphate (P-5-P), 38
188 Index

Q guidelines, 35–37
interactions involved, 36
QUICKI index, 130 systole, 68–70, 75

R T
raw faxseed, 19–20 testosterone, 151
reactive oxygen species (ROS), 91, 151, 155–156 thiocyanates, 4
in atherosclerosis, 91 tortillas recipe, 21
in endothelium damage, 50–51 total cholesterol (TC), 94
jeopardizing erectile function, 155–156 triglycerides (TG), 95, 98
red blood cell (erythrocyte) deformability, 33 tumor necrosis factor-α (TNF-α), 77–78
renin-angiotensin-aldosterone system (RAAS), tunica, 159
60–61 Turimon brand grinder, 37
rheumatoid arthritis, 102–103 type 2 diabetes, 125–146
coronary heart disease and, 132
S endothelial dysfunction in, 128
faxseed as adjuvant treatment of, 129–138
S-adenosylmethionine, 118 faxseed constituents contribution in,
saturated fatty acids (SFAs), 165 125–128
saturated/high fat (SHF), 73 L-arginine in treatment of, 125–146
secoisolariciresinol (SECO), 95 no defciency disease, question of, 134–138
secoisolariciresinol diglucoside (SDG), 29, 34, omega-3 fatty acids in treatment of, 125–146
67, 71, 95 omega-3 fatty acids reduce triglycerides in,
SELFNutritionData, 35 131–132
serum creatinine (Cr), 145 oxidative stress in, 126–127
sexual desire vs. sexual performance, 151–152 treatment, L-arginine in, 17
sexual function, 151–166, see also erectile treatment, omega-3 PUFAs in, 13
dysfunction; penis
gas fuels performance, 154–155
U
NO from faxseed enhancing, 151–166
oyster and the blue pill, 151–152 uric acid (UA), 139
penis, 158–159 urinary sodium excretion rate (UNa), 144
Perfumed Garden of the Shaykh Nefzawi,
The, 152
V
as shunting blood fow in the body, 157–159
shunting blood fow in the body, 157–159 vagus material, 49
sickle cell disease (SCD), 109–120 vascular remodeling in hypertension, 80–82
endothelial dysfunction in, 119–120 vasculogenic erectile dysfunction (VED), 164
faxseed in treatment of, 109–120 Viagra® (Sildenafl), 53, 153, 159
L-arginine in treatment of, 16, 109–120
omega-3 fatty acids in treatment of, 109–120 W
signal molecule, 47
Sildenafl (Viagra), 17 Western(ized) Diet, 114
snack recipe, 21 whole faxseeds 18, 28
superoxide dismutase (SOD), 58, 126
supplementation, faxseed, 7–18 Z
ALA, recommended content, 37
in clinical and research trials, 7–18 zeaxanthin, 19