Brief Review

Unusual Hypertensive Phenotypes

What Is Their Significance?
Stanley S. Franklin, Ian B. Wilkinson, Carmel M. McEniery

A ccording to Webster,1 the terms “spurious,” “artifac-

tual,” or “pseudo” denote false or deceptive resem-
blance. These terms when used specifically to hypertension
peak and a normal mean arterial pressure and concluded that
this was spurious (or pseudo-) hypertension secondary to
exaggerated amplification of a normal central BP.
refer to something that does not correspond with reality—a Mahmud and Feely5 identified ISH in 11 of 174 consecu-
false perception; implicit in this definition is normalcy or a tively studied medical students (equally divided by sex),
benign prognosis. Before discussion of the pros and cons of whose brachial BP averaged 147/70 mm Hg. All 11 of the
spurious, artifactual, or pseudohypertension, one should dis- subjects with ISH were tall men, nonsmokers, and active in
pose of faulty technique (systematic error, terminal digit sports. Using the SphygmoCor system, the difference be-
preference, or observer bias) in measuring blood pressure tween central and brachial SBPs was 31 mm Hg in those with
(BP), including cuff-inflation hypertension and failure to use ISH versus only 20 mm Hg in those with normotension.
the proper size cuff in obese arms as causes of erroneously Following O’Rourke et al,4 they attributed this hypertension
high BP values. In this review, we limit our focus to the use subtype to spurious systolic hypertension secondary to exag-
of the terms “spurious,” “artifactual,” or “pseudohyperten- gerated pressure amplification in healthy, athletically active
sion” in relation to 3 unusual hypertensive phenotypes: (1) men with slow heart rates and highly elastic central arteries.
spurious isolated systolic hypertension (ISH) in late teenagers Pickering,6 in reviewing the data on ISH in the young,
to young adults, defined as systolic BP (SBP) ⱖ140 mm Hg concluded that this was probably a benign condition and
and diastolic BP (DBP) ⬍90 mm Hg; (2) artifactual or perhaps in association with some degree of “athlete’s heart.”
benign isolated diastolic hypertension (IDH) in young to More recent investigations dispute the view that ISH in
early middle-aged adults defined as a SBP ⬍140 mm Hg young subjects is benign. McEniery et al3 studied 1008 young
and DBP ⱖ90 mm Hg; and (3) pseudohypertension in the adult university students (mean age: 20 years) in the Evalu-
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elderly, presenting rarely with noncompressible artery syn- ation of Nitrous Oxide in the Gas Mixture for Anaesthesia
drome and, more commonly, an elevated diastolic brachial Study. In keeping with previous investigations, they found
artery pressure assessed indirectly with a cuff and sphygmo- that ISH in young adults had ⬇90% male predominance.
manometer, in the context of a “normal” intra-arterial pres- However, in the Evaluation of Nitrous Oxide in the Gas
sure assessed invasively. Mixture for Anaesthesia Study, ISH was associated with
The purpose of this review is to present evidence for and normal pulse pressure amplification but elevated brachial and
against with regard to the validity of these 3 forms of unusual central SBP, measured using the SphygmoCor technique.
hypertensive phenotypes. Hulsen et al,7 studying a population-based Utrecht cohort of
750 young adults also with the SphygmoCor technique, found
ISH in Late Teenagers to Young Adults 57 young men with ISH (versus only 3 women) who had
Although ISH is usually associated with the elderly, ISH is higher brachial and central SBP and DBP than in their
also the majority hypertensive subtype in adolescents2 and normotensive counterparts.
young adults.3 The phenomenon of spurious systolic hyper- A key question in interpreting the findings of these studies
tension in young individuals was first described by O’Rourke is, what should be considered a normal central pressure?
et al4 in 6 young males, aged 14 to 23 years. The investigators Pulse pressure widens moving from central to peripheral
noted elevated brachial SBP (150 –176 mm Hg) but normal arteries because of a rise in systolic pressure. This so-called
brachial DBP (55– 85 mm Hg), and all of these young pressure amplification is attributed mainly to differences in
subjects were relatively tall for their age. Using pulse wave vessel stiffness and wave reflections within the arterial tree
analysis with the SphygmoCor system, a technique for and is present in all but the very oldest individuals. Because
measuring radial arterial waveforms and deriving central of this disparity between brachial and central pressure,
(aortic) pressure, they found a sharper-than-usual systolic applying brachial BP thresholds to define normal values of

Received September 12, 2011; first decision October 16, 2011; revision accepted November 22, 2011.
From the School of Medicine (S.S.F.), Heart Disease Prevention Program, University of California, Irvine, Irvine, CA; Clinical Pharmacology Unit
(I.B.W., C.M.M.), University of Cambridge, Addenbrooke’s Hospital, Cambridge, United Kingdom.
Correspondence to Stanley S. Franklin, Heart Disease Prevention Program, Sprague Hall 112, University of California, Irvine, Irvine, CA 92697-4101.
E-mail [email protected]
(Hypertension. 2012;59:173-178.)
© 2011 American Heart Association, Inc.
Hypertension is available at http://hyper.ahajournals.org DOI: 10.1161/HYPERTENSIONAHA.111.182956

173
 174 Hypertension February 2012

Optimal ISH
125
Central systolic BP (mmHg)

120

115
Figure 1. Comparison between central systolic
blood pressure (BP; SBP) associated with “opti-
110
mal” brachial BP (SBP ⬍120 and diastolic BP
[DBP] ⬍80 mm Hg) and central SBP reported in
published investigations of isolated systolic hyper-
105 tension (ISH) in adolescents and young adults.

100

95
McEniery et al.. O’Rourke et al. Mahmud McEniery et al. Hulsen et al.
J Hypertens. Vasc Med. Hypertens. Hypertens. J Hypertens.
2006;24:2316. 2000;5:141. 2003;16:229. 2005;46:221. 2006;24:1027.

central pressure is inappropriate and misleading. Indeed, pressure (by definition, isolated diastolic hypertension) had
McEniery et al,8 found that, for a healthy cohort of 4000 auscultatory BP measurements that overestimated the true,
individuals, the brachial pulse pressure was, on average, intra-arterial DBP.11 In support of these observations, Fang et
1.7-fold higher than aortic pressure in 20- to 30-year– old men al12 analyzed 1560 participants in a worksite hypertension
(95% CI⫽1.35 to 2.05). Using a brachial systolic pressure of control program and concluded that the relative risk of
⬍120 mm Hg as a reference, this would translate to a myocardial infarction was greater in those with systolic/dia-
corresponding central SBP of ⬇105⫾8 mm Hg for men and stolic hypertension than in those with IDH defined as SBP
⬇101⫾9 mm Hg for women with a 95% CI of ⬍110 mm Hg. ⬍160 and DBP ⱖ90 mm Hg (5.20 versus 2.21 per 1000
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In contrast, the mean central SBPs for subjects with ISH in person-years, respectively). When IDH was defined as SBP
the 4 studies mentioned above were 119,4 116,5 120,3 and ⬍140 mm Hg, there were no myocardial infarctions recorded.
117 mm Hg,7 respectively. Moreover, the corresponding val- However, the study was underpowered, with only 25 myo-
ues in the normotensive controls in 3 of these studies were cardial infarctions during a 4.5-year follow-up. However,
100,5 98,3 and 105 mm Hg,7 in keeping with the observations subsequently, there have been 4 additional longitudinal out-
described above. Therefore, there is clear evidence that come studies, which have largely concluded that IDH is
central SBP is elevated along with brachial SBP in young benign and of minimal clinical importance. The Honolulu
subjects with ISH (Figure 1), suggesting that these individu- Heart Program13 and the Copenhagen City Heart Study14
als may be at significantly increased cardiovascular risk. defined IDH as SBP ⬍160 and DBP ⱖ90 mm Hg, which
McEniery et al3 also observed that aortic stiffness and/or would include stage 1 IDH in the current classification. The
stroke volume was elevated in these young individuals, Japanese Ohasama Study15 used home BP monitoring, defin-
providing plausible physiological mechanisms underlying the ing IDH as SBP ⬍137 and DBP ⱖ84 mm Hg and with an 8.6
observed elevations in central pressure. Moreover, based on year follow-up, obtained a nonsignificant hazard ratio of 1.2
work by Lund-Johannson9 and Julius et al,10 an increased (95% CI: 0.16 – 8.96) for total cardiovascular disease events.
stroke volume associated with systolic hypertension in youth All 3 of these studies were largely in middle-aged subjects. In
is highly likely to transform into sustained hypertension in the contrast, in the Finnish Male Cohort Study,16 3267 initially
future, suggesting that these individuals are in the very early healthy individuals were evaluated at ages 30 to 45 years and
stages of developing “fixed” hypertension. Thus, the prepon- followed for up to 32 years. IDH subjects were subdivided
derance of evidence is strongly against the existence of into SBP ⬍160 mm Hg and SBP ⬍140 mm Hg. When SBP
spurious hypertension in young persons with significant ISH. was ⬍140 mm Hg, the hazard ratio was a nonsignificant 1.11
Nevertheless, future longitudinal studies will be necessary to compared with the reference of 1.00 for normotensives.
determine causative pathways in the development, evolution, However, normotension was defined as SBP ⬍160 and DBP
and ultimate prognosis of ISH in adolescents and very young ⬍90 mm Hg, which would include subjects with stage 1 ISH,
adults. and, therefore, may have unfairly reduced the risk in the IDH
group. Pickering17 reviewed all of the above studies and
Artifactual/Benign Isolated Diastolic Hypertension concluded that IDH, as currently defined, is either a measure-
in Young Adults ment artifact or a benign state.
The concept of artifactual or benign isolated diastolic hyper- However, a number of lines of evidence suggest that IDH
tension arose from previous observations that individuals is likely to be associated with increased cardiovascular risk.
presenting with raised diastolic pressure and a narrow pulse The Framingham Heart Study showed that new-onset IDH
 Franklin et al Unusual Hypertensive Phenotypes 175

developed primarily from normal and high-normal BP during common in elderly subjects, hence the term pseudohyperten-
a 10-year follow up.18 Furthermore, 82.5% of participants sion in the elderly.
with baseline IDH developed systolic/diastolic hypertension In an extreme form, there may be true incompressibility of
during the ensuing 10 years of follow-up, suggesting that IDH the brachial artery because of calcification. Ectopic calcifi-
was a frequent precursor for systolic/diastolic hypertension cation (also known as Monckeberg sclerosis) can specifically
and, therefore, potentially not a benign condition.18 Further affect the muscular arteries of both the upper and lower
compelling evidence comes from a large meta-analysis of BP extremities; rare involvement of the upper extremity results in
values from ⬎1 million middle-aged and older individuals a mechanical problem whereby BP cannot be measured by
(all aged ⬎40 years) demonstrating a continuous, positive sphygmomanometry because of severely calcified brachial
relationship between DBP and vascular and all-cause mortal- arterial walls rendering them noncompressible.24 Much more
ity.19 Interestingly, the authors could not detect any threshold commonly, medial artery calcification involves the lower
for risk down to DBP values of 75 mm Hg. Recently, these extremity arteries and is manifest by a decreased (⬍0.9) or
observations were extended in a large cohort study of incompressible increased ankle brachial index of ⱖ1.4.25
Swedish men in whom baseline examinations were under- Importantly, incompressible arteries, whether the rare form in
taken at a mean age of 18 years, with 24 years of follow-up.20 the upper extremities or the more common form in the lower
The authors noted a continuous and steep relationship be- extremities, are frequently associated with chronic renal
tween values of DBP ⬎90 mm Hg and cardiovascular and disease, with or without diabetes mellitus, and, hence, with
all-cause mortality, which was stronger than for SBP. In increased cardiovascular disease risk.24 –28 However, curi-
support of these observations, the Framingham Heart Study21 ously, individuals with ectopic medial calcification of the
showed that DBP was a better predictor of future coronary muscular arteries of the lower extremities with elevated ankle
heart disease events than SBP in adults ⬍50 years of age; the brachial indices (markedly elevated ankle and minimally
reverse was true after 50 years of age.21 Finally, the Chinese elevated brachial pressure) do not have the traditional risk
Stroke Prevention Project,22 a community-based cohort study factors associated with atherosclerosis; indeed, their age-
in 5 large cities across China, has provided a definitive adjusted prevalence of hypertension is generally no greater
than persons with normal or low ankle brachial index val-
answer to the importance of hypertension in general and IDH
ues.25–28 Thus, the incompressible artery syndrome is not a
in particular in predisposing to stroke risk. A total of 26 587
true representation of pseudohypertension.
subjects without a history of stroke were recruited in 1987
Perhaps more common is the situation of compressible but
and were followed for a mean duration of 9.5 years, during
stiffened arteries, which was thought to lead to an overesti-
which time 1107 stroke events occurred. Stroke etiology was
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mation of diastolic pressure by sphygmomanometer in com-

determined as follows: 55.5% ischemic, 40.7% hemorrhagic,
parison with true intra-arterial pressure.29,30 To fully appre-
and 3.8% unclassified. A major finding of this study was that
ciate how this became a clinical entity, one must understand
the IDH subtype (defined as SBP ⬍140 mm Hg and DBP
its historical context. This entity was defined by the simulta-
ⱖ90 mm Hg) was not an uncommon cause of stroke in the
neous measurement of brachial cuff and direct intra-arterial
Chinese population. Furthermore, IDH (hazard ratio: 2.35
measurement in the 1970s and 1980s at a time when hyper-
[95% CI: 1.91–2.90]) and ISH (hazard ratio: 2.16 [95% CI: tension was classified almost exclusively by elevation in
1.69 –2.76]) had similar predictive values for stroke inci- DBP; SBP was considered significantly elevated only with
dence. Thus, we now have definitive evidence in an Asian values of ⱖ160 mm Hg.31,32 Furthermore, observational stud-
population that the IDH subtype is an important predictor of ies had not yet proven that SBP was a more important
cardiovascular disease risk and should be treated vigorously. cardiovascular risk factor than DBP in the older-aged popu-
These findings are supported by ambulatory BP monitoring lation, with risk beginning at SBP values ⬎115 mm Hg.19
(ABM) findings that show pulse pressure is the dominant Therefore, pseudohypertension was defined as a diastolic cuff
predictor of cardiac events; in contrast, mean BP is the major pressure ⬎100 mm Hg and with an intra-arterial pressure
predictor of stroke risk.23 The failure of the previous IDH ⬍90 mm Hg.30 This entity was thought to occur as often as
outcome studies to predict risk may have resulted from 4% to 7% in elderly individuals who presented with hyper-
insufficient statistical power as a result of the following: (1) tension.30 It was often considered to have a benign prognosis
a small sample size; (2) poor precision of BP measurements; but was never tested for cardiovascular risk in a population
(3) a low IDH relative risk for future cardiovascular disease study.29,30 Although, described by Spence et al31,32 as diastolic
events; and (4) the manner in which the data were analyzed pseudohypertension in subjects suspected of having pseu-
statistically. In conclusion, the preponderance of evidence dohypertension, with DBP frequently increased by as high as
now strongly excludes IDH as an artifactual or benign form of 20 mm Hg above normal values, intra-arterial SBP measure-
hypertension. ments were consistently elevated (frequently as high as stage
2 or 3 hypertension). These observations regarding diastolic
Pseudohypertension in the Elderly pseudohypertension have been largely confirmed. As summa-
This is most commonly used to describe an elevated brachial rized by Smulyan and Safar,33 the Association for the
artery pressure assessed indirectly with a cuff and sphygmo- Advancement of Medical Instrumentation34 in 1993 evaluated
manometer, in the context of a normal intra-arterial pressure 5 studies that compared cuff auscultatory brachial artery with
assessed invasively. The underlying pathophysiology is often the gold standard intra-arterial brachial BP; for SBP (Figure
cited as stiffening of the brachial artery, which is much more 2A), intra-arterial was 3 to 4 mm Hg higher than cuff
 176 Hypertension February 2012

Figure 2. A and B, References used by

Association for the Advancement of Medical
Instrumentation33 to validate cuff auscultatory
vs intra-arterial systolic blood pressure (A)
and diastolic blood pressure (B) measure-
ments. Plotted values indicate average differ-
ences for each reference. Horizontal lines
with brackets indicate the SD of differences
(when available). Despite large standard devi-
ations, these findings show a small decrease
in auscultatory brachial systolic blood pres-
sure as compared with simultaneous intra-
arterial readings. In contrast, there was an
⬇10 mm Hg false elevation in auscultatory
brachial diastolic blood pressure as com-
pared with simultaneous intra-arterial read-
ings. Adapted with permission from Smulyan
and Safar.33
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auscultatory, whereas for DBP (Figure 2B), cuff auscultatory accepted as a risk factor for cardiovascular events. The term
was ⬇10 mm Hg higher than intra-arterial readings, thus pseudohypertension is, therefore, misleading in this context
confirming diastolic pseudohypertension and ruling out sys- and ignores the considerable excess risk associated with ISH
tolic pseudohypertension. in older individuals. Moreover, stiffening of the brachial
Interestingly, Messerli et al35 popularized the presence of artery rarely occurs in isolation, and we now appreciate that
pseudohypertension in older subjects by indicating that they aortic stiffening, which characterizes ISH in the elderly,36 is
could be identified on the basis of palpable thickening of the an independent predictor of cardiovascular events.37,38 There-
radial artery (Osler positive sign). Messerli et al35 identified fore, assessment of pulse wave velocity, the current gold
13 persons with palpable radial arteries and falsely elevated standard measure of arterial stiffness,39 may be a better
DBP by 16.4 and falsely elevated SBP by 15.8 mm Hg as diagnostic test in these individuals. Furthermore, medial
compared with intra-arterial measurements; however, with artery calcification of the elastic aorta and its branches may
correction, the mean intra-arterial BP was 181/78 mm Hg, play an important role in the development of ISH in older
indicating that these individuals actually had ISH. Subsequent persons. In this regard, quantitative high-resolution CT im-
studies have shown that the Osler sign is not a useful aging has disclosed medial vascular calcification in the
diagnostic test because of low sensitivity and selectivity.29 ascending, descending, and abdominal aortas in patients
Therefore, the available evidence suggests that most indi- with ISH who are otherwise apparently healthy.40 Interest-
viduals who have been labeled with the term pseudohyper- ingly, the quantity of aortic calcification correlated with
tension in the elderly actually have ISH, which is well both the severity of ISH and with the resistance to
 Franklin et al Unusual Hypertensive Phenotypes 177

achieving adequate control with antihypertensive ther- scientific reports of pseudohypertension in the elderly during
apy.40 Similar associations of calcification of thoracic the past 2 decades despite the continued inclusion of this
aorta and ISH were noted in a study that evaluated large entity as a hypertension phenotype in the medical literature.
arteries for calcium content during routine health mainte- The myth lives on. Is it not time to give it a proper burial?
nance screening.41 Thus, it appears that vascular calcifica-
tion, out of proportion to the normal aging process, may Perspectives
play an important role in the development of ISH. All 3 of the hypertensive phenotypic syndromes described in
During the past decade, validated devices for 24-hour this review show mild-to-severe cardiovascular risk, and,
ABM using the oscillometric method have become the gold therefore, cannot be described as having a benign cardiovas-
standard for assessing and classifying hypertensive cardio- cular prognosis. In young individuals, spurious systolic hy-
vascular risk because of excellent correlation with target pertension is actually associated with increased central and
organ damage and with morbidity and mortality outcomes.42 brachial SBP, rather than exaggerated central-to-peripheral
Importantly, the use of ABM has identified the new hyper- BP amplification. Similarly, so-called artifactual isolated
tensive phenotypes of white-coat hypertension and white-coat diastolic hypertension in young individuals is typically asso-
effect,42 both of which are very common in the elderly and ciated with additional cardiovascular risk factors and often
can simulate pseudohypertension. Indeed, white-coat hyper- precedes the development of systolic/diastolic hypertension
tension is more likely to be observed in individuals with in later life. In older individuals, the noncompressibility
increased large artery stiffness, because the influence of the artery syndrome, predominately involving the lower extrem-
“alerting” or white-coat response on the measured BP is ities, is associated with severe medial calcification of mus-
likely to be greater in individuals with stiffened arteries and cular arteries, frequently an elevated ankle-brachial index,
a concomitant reduction in arterial buffering capacity. ABM and typically no significant increase in age-adjusted BP. In
is the ideal method of diagnosing both white-coat hyperten- contrast, diastolic pseudohypertension, representing wide
sion and white-coat effect, but other options are available that pulse pressure ISH, is associated with calcification of the
are less expensive and more easily repeatable for the addi- aorta and is accompanied by significantly increased cardio-
tional assessment of the response to treatment, including vascular risk. Indeed, using ABM as the new gold standard
home BP monitoring.42 for assessing cardiovascular risk in the elderly, we conclude
Despite these new developments in assessing hypertensive that white-coat hypertension and white-coat effect, in the
cardiovascular risk, the concept of pseudohypertension in the absence of target organ damage, have been masquerading as
elderly has been perpetuated in textbooks, journals,43 and pseudohypertension. In summary, there are no legitimate
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even in a recent consensus statement for hypertension in the elevated BP phenotypes that should be labeled as spurious,
elderly,44 suggesting that it should be suspected if measured artifactual, or as pseudohypertension.
SBP values are inappropriately high in the absence of target
organ damage or if antihypertensive drugs provoke symptoms Disclosures
of hypotension despite the persistence of elevated SBP; in None.
retrospect, these clinical states should raise the likely possibility
of white-coat hypertension, white-coat effect in the absence of
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