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Sleep Apnea: Types, Mechanisms, and Clinical Cardiovascular Consequences.

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 JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 69, NO. 7, 2017

ª 2017 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION ISSN 0735-1097/$36.00

PUBLISHED BY ELSEVIER http://dx.doi.org/10.1016/j.jacc.2016.11.069

THE PRESENT AND FUTURE

STATE-OF-THE-ART REVIEW

Sleep Apnea
Types, Mechanisms, and Clinical Cardiovascular Consequences

Shahrokh Javaheri, MD,a Ferran Barbe, MD,b Francisco Campos-Rodriguez, MD,c Jerome A. Dempsey, PHD,d
Rami Khayat, MD,e Sogol Javaheri, MD,f Atul Malhotra, MD,g Miguel A. Martinez-Garcia, MD,h Reena Mehra, MD,i
Allan I. Pack, MBCHB, PHD,j Vsevolod Y. Polotsky, MD,k Susan Redline, MD,f,l Virend K. Somers, MD, PHDm

ABSTRACT

Sleep apnea is highly prevalent in patients with cardiovascular disease. These disordered breathing events are associated with
a profile of perturbations that include intermittent hypoxia, oxidative stress, sympathetic activation, and endothelial
dysfunction, all of which are critical mediators of cardiovascular disease. Evidence supports a causal association of sleep apnea
with the incidence and morbidity of hypertension, coronary heart disease, arrhythmia, heart failure, and stroke. Several
discoveries in the pathogenesis, along with developments in the treatment of sleep apnea, have accumulated in recent years.
In this review, we discuss the mechanisms of sleep apnea, the evidence that addresses the links between sleep apnea and
cardiovascular disease, and research that has addressed the effect of sleep apnea treatment on cardiovascular disease and
clinical endpoints. Finally, we review the recent development in sleep apnea treatment options, with special consideration of
treating patients with heart disease. Future directions for selective areas are suggested. (J Am Coll Cardiol 2017;69:841–58)
© 2017 by the American College of Cardiology Foundation.

C ardiovascular disease (CVD) accounted for

>800,000 deaths (31% of all deaths) in
2013 in the United States, with an estimated
155,000 deaths in Americans <65 years of age (1).
34% of men and 17% of women and is largely undi-
agnosed (2), is a modifiable CVD risk factor. OSA
is a cause of systemic hypertension (HTN) and is
associated with an increased incidence of stroke,
By 2030, total direct medical costs of CVD are heart failure (HF), atrial fibrillation (AF), and coro-
projected to be $920 billion. The high prevalence nary heart disease (CHD) (3). OSA, particularly
of obstructive sleep apnea (OSA), which affects when severe, is associated with increased all-cause

From the aPulmonary and Sleep Division, Bethesda North Hospital, Cincinnati, Ohio; bRespiratory Department, Institut Ricerca
Biomèdica de Lleida, Hospital Universitari Arnau de Vilanova, Lleida, Spain; cRespiratory Department, Hospital Universitario de
Valme, Sevilla, Spain; dDepartment of Population Health Sciences and John Rankin Laboratory of Pulmonary Medicine, University
of Wisconsin-Madison, Madison, Wisconsin; eSleep Heart Program, the Ohio State University, Columbus, Ohio; fHarvard Medical
School, Brigham and Women’s Hospital, Boston, Massachusetts; gPulmonary, Critical Care and Sleep Medicine, University of
California, San Diego, California; hRespiratory Department, Hospital Universitario de Politecnico La Fe, Valencia, Spain; iCleveland
Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio; jDivision of Sleep Medicine/Department of
Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; kDivision of Pulmonary and
Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; lBeth Israel Deaconess Medical Center,
m
Boston, Massachusetts; and the Department of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota. Dr. Shahrokh
Listen to this manuscript’s Javaheri is a consultant for Respicardia, Philips, and Leva Nova Group. Dr. Barbe has received research grants from ResMed and
audio summary by Oxigen Salus; and has received a speaker’s fee from Philips. Dr. Khayat has received research grants through The Ohio State
JACC Editor-in-Chief University from Philips Respironics. Dr. Mehra’s institution has received positive airway pressure machines and equipment from
Dr. Valentin Fuster. Philips Respironics and ResMed for research; and she has received royalties from Up to Date. Dr. Somers’ institution has received a
gift from the Phillips Respironics Foundation for the study of sleep and cardiovascular disease; he was a consultant for Respi-
cardia, ResMed, Sorin Inc., Biosense Webster, U-Health, Philips, Ronda Grey, Dane Garvin, and GlaxoSmithKline; and is working
with Mayo Health Solutions and their industry partners on intellectual property related to sleep and cardiovascular disease. All
other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Manuscript received July 29, 2016; revised manuscript received November 21, 2016, accepted November 22, 2016.
842 Javaheri et al. JACC VOL. 69, NO. 7, 2017

Sleep Apnea FEBRUARY 21, 2017:841–58

ABBREVIATIONS and cardiovascular (CV) mortality (Central prone to upper airway obstruction. Several anatomic
AND ACRONYMS Illustration). processes may compromise the patency of the upper
A sleep apnea subtype, central sleep apnea airway, including alterations in craniofacial struc-
AF = atrial fibrillation
(CSA) is rare in the general population, but tures, enlarged tonsils, upper airway edema,
AHI = apnea-hypopnea index
is common in patients with HF, stroke, and decreased lung volume, and most importantly,
CHD = coronary heart disease
AF (4,5). However, recent data suggest that obesity (9,10).
CPAP = continuous positive CSA is also a risk factor for incident AF (6) The mechanisms linking obesity to OSA (2,9) are
airway pressure
and HF (7). complex, although mostly due to direct mechanical
CSA = central sleep apnea
This review provides an update on sleep effects on the respiratory system. These include fat
CVD = cardiovascular disease
apnea and CVD. We hope to provide a cata- deposits within the upper airway and reduction in
HF = heart failure lyst for cardiologists to join with sleep phy- lung volume, resulting in a loss of caudal traction on
HTN = hypertension sicians to conduct research, particularly the upper airway (10).
OSA = obstructive sleep apnea clinical trials, that addresses the role of sleep Although obesity is the major risk factor for OSA,
TIA = transient ischemic attack apnea treatment in patients who are at high roughly 20% to 40% of OSA patients are not obese. In
risk of or have existing CVD. these individuals, nonanatomic factors (9,10), such
as upper airway dilator muscle dysfunction, height-
DEFINITIONS OF TYPES OF SLEEP APNEAS
ened chemosensitivity, and low arousal threshold
AND HYPOPNEAS
(i.e., waking up from sleep prematurely, causing
instability in ventilatory control), are important, and
An apnea is the absence of inspiratory airflow for at
define various phenotypes of OSA that may be
least 10 s. A hypopnea is a lesser decrease in airflow,
amenable to specific therapeutic options. Specif-
lasting 10 s or longer, and associated with a drop in
ically, dilator muscle dysfunction should best
arterial oxyhemoglobin saturation and or an electro-
respond to hypoglossal nerve stimulation, whereas
encephalographic arousal. Apneas and hypopneas are
heightened chemosensitivity and low arousal
classified as obstructive or central, but regardless,
threshold may be amenable to pharmacotherapy to
they result from an absence or reduction of brainstem
down-regulate ventilatory responses (nocturnal
neural output to upper airway muscles (e.g., genio-
oxygen-attenuating hypoxic response), and hyp-
glossus) and/or lower thoracic inspiratory pump
notics to increase the arousal threshold. With the
muscles (diaphragm and intercostal muscles). The
push toward personalized medicine, individualizing
pattern of neural output determines the phenotype:
therapy may be a viable approach for OSA, as the
OSA occurs when complete upper airway occlusion
mechanism(s) underlying disease are better defined
occurs (absent airflow, tongue falling backward) in
and consequently corrected. Much work is needed in
the face of continued activity of inspiratory thoracic
this area.
pump muscles (Figure 1) (8). In contrast, CSA
Another risk factor that has received recent atten-
(Figure 2) occurs when there is a transient reduction
tion is that of fluid around the upper airway (5,11). In
by the pontomedullary pacemaker in the generation
individuals with lower-extremity edema, excess fluid
of breathing rhythm, usually reflecting changes in the
may accumulate in the pharyngeal area with cephalad
partial pressure of CO 2 (PCO2 ), which can fall below
transposition of fluid from lower extremities to the
the apneic threshold, a level of PCO 2 below which
neck area when supine (5,11), rendering the upper
breathing ceases (4,5). The 2 most common causes in
airway susceptible to collapse during sleep. Redistri-
adults are HF and opioid use (4).
bution of fluid to the lungs also may potentiate CSA,
PATHOGENESIS OF OSA as discussed later in the text. Therapeutic ap-
proaches, such as diuretic agents, stockings, and
Sleep has multiple pronounced effects on the respi- exercise, have been shown to improve OSA and
ratory system and control of breathing. Experimental CSA (5,11).
studies in instrumented cats have shown decreased
electrical activity in medullary inspiratory neurons PATHOGENESIS OF CSA
with efferent output to the upper and lower respira-
tory muscles, reflected in decreased activity of dia- APNEIC THRESHOLD IN SLEEP AND INCREASED
phragm and dilator muscles of the upper airway (also LOOP GAIN. Apneic threshold is the arterial PCO 2
observed in human studies) (9). With reduction in the below which the ponto-medullary respiratory rhythm
activity of the genioglossus muscle at the onset of generator ceases, thereby silencing motor nerves
sleep, the tongue falls backward, and individuals with innervating inspiratory thoracic pump muscles. Con-
altered mechanical properties of the upper airway are sequently, ventilation ceases and CSA occurs. Sleep
JACC VOL. 69, NO. 7, 2017 Javaheri et al. 843
FEBRUARY 21, 2017:841–58 Sleep Apnea

C ENTR AL I LL U STRA T I ON Potential Etiological Risk Factors for Sleep Apnea and the Downstream Consequences

Respiratory control instability Obesity Upper airway dysfunction

Sleep apnea

Increased Vascular
Metabolic Oxidative Intermittent
sympathetic Inflammation endothelial
dysregulation stress hypoxia
nerve activity dysfunction

Heart disease Hypertension Atrial fibrillation

End-stage
cardiovascular disease

Javaheri, S. et al. J Am Coll Cardiol. 2017;69(7):841–58.

The illustration depicts the multietiological risk factors for sleep apnea and its downstream consequences, which include increased sympathetic nerve activity,
metabolic dysregulation, inflammation, oxidative stress, vascular endothelial dysfunction, and intermittent hypoxia. These mechanistic pathways are critical for the
pathogenesis of coronary heart disease, hypertension, and atrial fibrillation, all of which are etiological risk factors for end-stage cardiovascular disease. The figure is a
schematic representation to illustrate important concepts, but does not fully depict the complex interactions between the various key variables.

unmasks a highly sensitive hypocapneic-induced OVERNIGHT CONSEQUENCES OF SLEEP

apneic threshold, which in health at sea level, APNEA
approximates the waking eupneic partial arterial
pressure of carbon dioxide (PaCO 2) (4). When Normal sleep provides a time of low physiological
ventilation increases in response to a transient stress, which is advantageous to the CV system. In
spontaneous arousal or sigh, the subsequent venti- particular, during non–rapid-eye-movement sleep
latory overshoot often elicits sufficient hypocapnia (approximately 80% of total sleep time), sympathetic
(i.e., in the
1 to
4 mm Hg PaCO 2 range) to cause activity decreases and parasympathetic activity in-
apneas. Once the central respiratory drive is with- creases, with lowering of blood pressure (BP) and heart
drawn, apnea persists until PaCO2 rises above the rate (Figure 3). However, sleep-disordered breathing
apneic threshold. (SDB) disrupts normal sleep. Apneas and hypopneas,
Susceptibility to ventilatory instabilities depends and the consequent compensatory hyperpneas, are
critically on the “loop gain” of the respiratory control associated with 4 acute adverse CV consequences (12):
system. Loop gain defines the magnitude of a 1) arterial blood gas abnormalities, with intermittent
response (increased ventilation) to a disturbance hypoxemia–reoxygenation and fluctuations in PCO2 ;
(reduced breathing [4]). The higher the gain, the 2) excessive arousals; 3) decreased parasympathetic
greater the ventilatory overshoot and undershoot, and increased sympathetic activity (9,12); and 4) large
and the more likely the occurrence of continued negative intrathoracic pressure swings (12) (Figure 4).
ventilatory cycling and repeated apneas. The role of These consequences are qualitatively similar for OSA
loop gain in mediating periodic breathing in HF has and CSA, but more pronounced in OSA. The adverse
been reviewed elsewhere (4). consequences of SDB have been reviewed elsewhere
844 Javaheri et al. JACC VOL. 69, NO. 7, 2017

Sleep Apnea FEBRUARY 21, 2017:841–58

work has focused on nuclear factor (NF)-kappaB–

F I G U R E 1 Polysomnographic Example of OSA
mediated pathways. Rapid reoxygenation at the end
of apneas/hypopneas leads to production of free
radicals, resulting in oxidative stress and up-
regulation of nuclear factor-kappaB. There is some
evidence that treatment of OSA with continuous
positive airway pressure (CPAP) can reduce levels of
inflammatory mediators, such as interleukin-6, tumor
necrosis factor- a , and C-reactive protein (17).
Another molecular signature of OSA is increased
catecholamines, consistent with perturbations in the
autonomic nervous system. With effective treatment
of OSA, catecholamine levels decline, with reversal
upon withdrawal of CPAP (18).
Many CVD-related biomarkers are also elevated in
obesity, and disentangling obesity from OSA-related
effects is a challenge, especially given the high corre-
lation between the apnea-hypopnea index (AHI) and
First tracing is chin electromyogram, second and third are electroencephalogram, fourth
is electrocardiogram, fifth and sixth are airflow measured by thermocouple (fifth) and body mass index. Obesity may magnify the effects of
CO2 (sixth), seventh and eighth are rib cage (RC, seventh) and abdominal (ABD, eighth), OSA because macrophages in fat are likely the target
ninth is oxyhemoglobin saturation measured by pulse oximetry, and tenth is esophageal cells for the effects of chronic intermittent hypoxia,
pressure. Please note that during obstructive apnea, airflow is absent while breathing
leading to increases in inflammatory biomarkers; thus,
effort continues. Breathing resumes with the onset of arousal. Reprinted with permission
OSA and obesity may have synergistic effects. The re-
from Javaheri (8). OSA ¼ obstructive sleep apnea.
sults of a randomized controlled study in obese pa-
tients (19) showed that combined treatment with
weight loss and CPAP reduced BP more than either
(4,5,9,12). We emphasize, however, that the large
therapy alone; however, C-reactive protein levels were
negative pressure swings due to inspiratory effort
only reduced in association with weight loss. The Ice-
against a closed upper airway are reflected in juxta-
landic Sleep Apnea Cohort (16) reported that intercel-
cardiac pressure increasing the transmural pressure of
lular adhesion molecule levels increase over 2 years in
all intrathoracic structures, including atria, ventricles,
the most obese individuals with untreated OSA,
intrathoracic aorta, and pulmonary vascular beds,
whereas levels decrease in regular CPAP users. Thus,
with adverse effects on these structures. The nega-
OSA may result in a progressive inflammatory state,
tive pressure increases left ventricular afterload,
which may be 1 mechanism of the vascular damage that
increasing myocardial oxygen consumption, and im-
occurs from OSA. Inflammatory consequences of OSA
pedes stroke volume. Thin-walled atria are vulnerable
may vary with degree of obesity.
to surrounding negative pressure, stretching easily,
stimulating mechanoreceptors with activation of ion
METABOLIC DYSFUNCTION AND OSA
channels that facilitate development of atrial ar-
rhythmias, specifically AF. These effects are most
OSA is independently associated with metabolic
prominent in association with other apnea-related
syndrome and insulin resistance, with an associated
consequences, such as tissue hypoxia and increased
risk for incident CV events (20). Three randomized
sympathetic activity. Atrial stretch also results in
controlled trials (RCTs) (21–23) have demonstrated
secretion of atrial natriuretic peptide, causing noctu-
that treatment of OSA with CPAP improves insulin
ria, a symptom of OSA.
sensitivity. In 1 RCT, supervised CPAP treatment for 8
MOLECULAR SIGNATURES OF SLEEP APNEA h over 2 weeks nightly significantly improved insulin
IN RELATION TO CARDIOCEREBROVASCULAR sensitivity and glucose response in intravenous and
DISORDERS oral glucose tolerance tests (21). In another RCT of
pre-diabetic patients, the insulin sensitivity index
OSA is a disorder associated with oxidative stress, improved significantly in those with severe OSA
up-regulation of redox-sensitive genes, and inflam- treated with CPAP (22), and there was a significant
matory cascade (13,14). Multiple studies of bio- correlation between hours of CPAP use and
markers related to CVD in patients with OSA assess improvement in insulin sensitivity, emphasizing the
how they change with treatment (13–17). Much of this critical importance of adherence (21). Thus, current
JACC VOL. 69, NO. 7, 2017 Javaheri et al. 845
FEBRUARY 21, 2017:841–58 Sleep Apnea

evidence suggests that OSA is associated with insulin

F I G U R E 2 Polysomnographic Example of Hunter-Cheyne-Stokes Breathing
resistance, and CPAP treatment may improve insulin
sensitivity in pre-diabetic patients.
The effects of CPAP therapy of OSA on full-blown
diabetes remain to be elucidated (24). Large-scale
RCTs of CPAP are needed to establish the role of
OSA in proatherogenic dyslipidemia.

OSA AND RELATED CVD:

EFFECT OF CPAP THERAPY

OSA is strongly associated with a number of CVDs

(Figure 5) including HTN, resistant HTN, transient
ischemic attack (TIA), stroke, pulmonary hypertension
(PHTN), HF, CHD, AF, myocardial ischemia, myocar-
dial infarction (MI), and sudden death. The epidemi-
ology of these associations has been extensively
reviewed (3,5,13,14,20). In the following sections, we
discuss trials of CPAP, the most effective therapy of
OSA. We also discuss adjunct therapy of OSA. The first 2 tracings are electro-occulogram; otherwise tracings as in Figure 1. Note the
CPAP AND SYSTEMIC HTN. The effect of CPAP on smooth and gradual changes in the thoracoabdominal excursions and esophageal pressure
in the crescendo and decrescendo arms of the cycle. There is an intervening central apnea,
HTN has been widely investigated, and the available
absence of naso-oral airflow, and excursions in pleural pressure, thorax, and abdomen.
evidence from multiple RCTs and several recent
The arousal occurs at the peak of hyperventilation. Desaturation is delayed because of
meta-analyses demonstrates that CPAP significantly long circulation time in heart failure. Reprinted with permission from Dowdell WT,
reduces BP in OSA patients. Studies using 24-h BP Javaheri S, McGinnis W. Cheyne-Stokes respiration presenting as sleep apnea syndrome:
monitoring (25–32) consistently report drops of 2 to clinical and polysomnographic features. Am Rev Respir Dis 1990;141:871-9.

2.5 mm Hg and 1.5 to 2 mm Hg in systolic blood

pressure (SBP) and diastolic blood pressure (DBP),
respectively, compared with subtherapeutic or con- of the vascular bed and/or increased set point for BP
servative treatment (Figure 6), with greater re- on the basis of prevailing BP regulatory mechanisms
ductions in patients with resistant HTN (between 4.7 (e.g., baroreflex), CPAP may not be able to reduce BP
to 7.2 mm Hg and 2.9 to 4.9 mm Hg for SBP and DBP, much, certainly in the short term. Given this issue, for
respectively) (Figure 7) (33–39). CPAP has also been ethical reasons, RCTs have a follow-up of <1 year.
demonstrated to reverse nondipper or riser nocturnal Therefore, it is unknown whether BP may fall further
BP patterns in OSA patients. in long-term follow-up.
Because long-term reductions of 2 to 3 mm Hg in Overall, highly variable BP improvement is ex-
SBP are associated with a 4% to 8% reduction in the pected with CPAP therapy, as the drop correlates with
future risk of stroke and CHD, long-term treatment of OSA severity, baseline HTN, and hours of CPAP use.
OSA in hypertensive patients could eventually reduce Depending on these characteristics, some study pa-
incident CV burden. tients might have greater antihypertensive benefits
There are multiple reasons why the antihyperten- from CPAP, whereas others—for example, those with
sive effect of CPAP is limited. First, essential HTN is less severe OSA—might not. The level of adherence
quite common in the general population, and should needed to obtain a significant reduction in BP levels is
be equally prevalent in OSA patients. CPAP may not unknown, although a minimum threshold of 4 h, and
decrease BP if the underlying cause of HTN is unre- optimally >5 to 6 h/night, is needed. In resistant HTN,
lated. Second, CPAP therapy can only reverse certain a linear correlation has been observed between the
intermediate mechanisms associated with OSA. For number of hours of CPAP use and drop in BP mea-
example, CPAP reduces sympathetic tone, thereby sures (decreases of 1.9 and 1.0 mm Hg in SBP and DBP,
decreasing BP (18). However, other pathophysiolog- respectively, for each additional hour of CPAP use)
ical mechanisms underlying HTN, such as those (37), suggesting that greater CPAP adherence would
associated with obesity, salt intake, and volume be associated with better BP control. This dose-
overload, may be unaffected by CPAP. Third, OSA and dependent relationship is similar to that for insulin
HTN are chronic disorders, and if OSA-induced HTN sensitivity (22,23) and other CV outcomes, as dis-
has been longstanding, with consequent remodeling cussed later in the text.
846 Javaheri et al. JACC VOL. 69, NO. 7, 2017

Sleep Apnea FEBRUARY 21, 2017:841–58

by echocardiography). The American College of

F I G U R E 3 Normal Cardiovascular Changes in NREM
and REM Sleep
Cardiology/American Heart Association expert
consensus document recommends polysomnography
NREM sleep: to rule out OSA for all patients with PHTN (45). The
recommendation comes from the idea that targeted
Sympathetic Activity Parasympathetic Activity
therapy of OSA could either improve or prevent
further deterioration in central hemodynamics.
BP, HR, COP CPAP AND STROKE/TIA. Sleep apnea is highly prev-
Cardiovascular
Ventilation
Quiescence alent in patients with stroke or TIA, and OSA also is
Metabolic rate
associated with increased risk for incident stroke
Phasic REM sleep: (46–48). There is some evidence that early CPAP
therapy has positive effects on long-term survival in
Sympathetic Activity
ischemic stroke patients with moderate-to-severe OSA
BP and HR (46–48). Additionally, consistent with observational
studies (46–48), in a recent large RCT (49), those OSA
patients who were adherent to CPAP therapy exhibited
During NREM sleep sympathetic activity decreases whereas
reduced risk of incident cerebral events.
parasympathetic activity increases with consequent decrease in
BP and HR. The reverse occurs in phasic REM sleep. BP ¼ blood The American Heart Association/American Stroke
pressure; COP ¼ cardiac output; HR ¼ heart rate; NREM ¼ Association guideline states: “A sleep study might be
non–rapid eye movement; REM ¼ rapid eye movement. considered for patients with an ischemic stroke or TIA
on the basis of the very high prevalence of sleep ap-
nea in this population and the strength of the evi-
A recent study (40) reported that BP response to dence that the treatment of sleep apnea improves
CPAP in OSA patients with resistant HTN can be pre- outcomes in the general population” (50).
dicted by measuring the plasma levels of 3 specific
CPAP AND ARRHYTHMIAS. Two small RCTs showed
microribonucleic acids, which may help to person-
that treatment of OSA with CPAP reduces the mean
alize this treatment in the future.
24-h heart rate, as well as the frequency of premature
There is evidence that the combination of antihy-
ventricular beats during sleep (51,52). Data from
pertensive drugs (41) or weight loss (19) with CPAP
observational studies show that CPAP treatment is
therapy could have a synergistic effect in reducing BP
associated with a significantly decreased recurrence
in OSA patients, supporting the multidimensional
rate of AF, even after electrical cardioversion or
pathophysiology of HTN in this population. When
ablative therapies, and that patients are less likely to
hypertensive patients with and without OSA were
progress to more permanent forms of AF and have
treated with losartan for 6 weeks, the BP drop
significantly reduced occurrence of paroxysmal AF
(measured by 24-h ambulatory BP monitoring) was
compared with untreated patients (53–56).
significantly less in those with OSA than without.
In a meta-analysis (57) of 698 CPAP users and 549
Importantly, when CPAP was added at the end of 6
non-CPAP users, those with OSA treated with CPAP
weeks of losartan and used at least 4 h nightly for the
after AF intervention had a 44% reduced AF risk;
next 6 weeks, BP decreased markedly in those with
younger, more obese, and male patients benefited the
OSA (41). The combination of CPAP and weight loss
most. On the basis of this evidence, a recent expert
may also have a synergistic effect, leading to larger BP
consensus document on AF identified OSA as a risk
reductions in OSA patients (19).
factor for AF recurrence after surgical and catheter
CPAP AND PHTN. About 10% of patients with OSA ablation, and recommended its treatment (58).
have PHTN (defined as the mean pulmonary artery Although the reproducibility of these findings from
pressure $25 mm Hg) (42,43), and multiple observa- observational studies is compelling, data from clinical
tional studies demonstrate that treating OSA with trials are needed.
CPAP improves PHTN (42,43). In the only small ran-
domized crossover study (therapeutic vs. sham CPAP) CPAP, CHD, CV MORTALITY, AND COMPOSITE CV
(44), 12 weeks of treatment resulted in a significant OUTCOMES. Multiple observational studies demon-
decrease in pulmonary artery systolic pressure (from strate that untreated OSA is associated with CV
a mean of 30 to 24 mm Hg). The reduction was morbidity and mortality, and that treatment with
greatest (8.5 mm Hg) in patients with baseline PHTN CPAP improves the need for revascularization, inci-
(pulmonary artery systolic pressure $30 mm Hg dent CHD, and survival (59–62).
JACC VOL. 69, NO. 7, 2017 Javaheri et al. 847
FEBRUARY 21, 2017:841–58 Sleep Apnea

F I G U R E 4 Pathophysiological Consequences of Sleep Apnea and Hypopnea

⇓ O2 delivery Organ dysfunction

Oxidative stress
Endothelial dysfunction
Inflammation
⇓ PO2 /⇑ PCO2
⇑ PO2 /⇓ PCO2
Hypoxic and hypercapnic
⇑ Right ventricular afterload
pulmonary vasoconstriction

⇑ Blood pressure
Sympathetic activation Arrhythmias
Cycles of sleep Myocyte toxicity
apnea and recovery
Arousals
Parasympathetic
⇑ Heart rate
withdrawal

R and L ventricular afterload

Arrhythmias (atrial)
⇑ Transmural pressure of all
⇓ Pleural cardiac chambers and aorta
Aortic dilation
Pressure ⇑ Pulmonary capillary
hydrostatic pressure
Increased lung H2O

Pleural pressure (Ppl) is a surrogate of the pressure surrounding the heart and other vascular structures. [ ¼ increased; Y ¼ decreased. Reprinted with
permission from Javaheri (8). CV ¼ cardiovascular; H2O ¼ water; L ¼ left; O2 ¼ oxygen; PCO2 ¼ partial pressure of carbon dioxide in the blood;
PO2 ¼ partial pressure of oxygen in the blood; R ¼ right.

To date, 3 RCTs investigated the effect of CPAP on with those who used the device <4 h/night or did not
CV outcomes (Figure 8), with the main endpoint a receive treatment (adjusted hazard ratio: 0.29; 95%
composite outcome of different fatal and nonfatal CV CI: 0.10 to 0.86; p ¼ 0.026).
events. In the first RCT (63), 725 nonsleepy patients The SAVE (Continuous Positive Airway Pressure
(Epworth Sleepiness Scale [ESS] <11 of 24), free of Treatment of Obstructive Sleep Apnea to Prevent
CVD and with moderate-to-severe OSA (AHI $20/h), Cardiovascular Disease) study (49) enrolled 2,717
were randomized to CPAP (n ¼ 357) or conservative nonsleepy or mildly sleepy (ESS <15) patients age 45
treatment (n ¼ 366), and were followed for a median to 75 years, with prior history of coronary or cerebro-
of 4 years. CPAP did not result in a significant vascular disease and OSA, defined by an oxygen
reduction in the incidence of the primary composite desaturation index $12/h, diagnosed by means of a
outcome. However, in an adherence analysis, pa- 2-channel screening device. Patients were allocated to
tients who used CPAP for $4 h/night did achieve a CV CPAP or usual-care treatment for a mean of 3.7 years.
benefit (incidence density ratio 0.72; 95% confidence The incidence of a composite CV outcome was similar
interval [CI]: 0.52 to 0.98; p ¼ 0.04). in the CPAP and control groups (p ¼ 0.34). One-to-one
Peker et al. (64) randomized 244 nonsleepy propensity-score matching was performed to compare
(ESS <10) patients with newly revascularized CHD 561 patients who were adherent to CPAP therapy with
and moderate-to-severe OSA (AHI >15/h) to autoti- 561 patients in the usual-care group. In this sensitivity
trating positive airway pressure (PAP) (n ¼ 122) or no analysis, a lower risk of a composite endpoint of ce-
PAP (n ¼ 122) for a median of 57 months. The inci- rebral events was found in the group of patients who
dence of the primary composite CV endpoint did not used CPAP for at least 4 h/day (hazard ratio: 0.52; 95%
differ between the 2 groups. However, adjusted on- CI: 0.30 to 0.90; p ¼ 0.02).
treatment analysis showed a significant CV risk This study has several limitations. First, SDB was
reduction in those who used CPAP for >4 h, compared diagnosed by means of a screening device on the basis
848 Javaheri et al. JACC VOL. 69, NO. 7, 2017

Sleep Apnea FEBRUARY 21, 2017:841–58

ischemia. OSA has been associated with onset of MI

F I G U R E 5 Prevalence (%) of OSA in CVD
during the night/early morning (66). It is reasonable
to consider that the increased likelihood of nocturnal
Hypertension 30 83 nonfatal MI may also be accompanied by an increased
risk of fatal MI and sudden death. In >10,000 in-
Coronary heart
38 65 dividuals, the presence of OSA and significant desa-
disease
turation was associated with an almost 2-fold
Stroke 57 75 increase in risk of sudden death, independent of
known risk factors (67). Comparing the time of death
Heart failure 12 55 of individuals with and without SDB, those with the
disorder died mostly between 12:00 AM and 6:00 AM
Arrhythmias 20 50 (68) suggesting that untreated OSA in patients with
established CHD would likely lead to a poorer
0 10 20 30 40 50 60 70 80 90 100 prognosis.
SUMMARY OF CPAP THERAPY AND CARDIOVASCULAR
The lower limit is invariably using an AHI of $15/h, indicating presence of moderate-to-
DISEASE. High-quality evidence recommends CPAP
severe OSA. The upper part of the range relates to a lower threshold of $5/h. CVD ¼
therapy in patients with HTN and OSA, especially in
cardiovascular disease; OSA ¼ obstructive sleep apnea.
patients with resistant HTN. For other CVD and ce-
rebral events, CPAP is not effective unless it is used
for $4 h of sleep. The available evidence for ar-
of oximetry and nasal pressure recordings. In-
rhythmias is consistent with adverse effects of OSA
vestigators excluded patients with a pattern of
and beneficial effects of CPAP, but these data come
Cheyne-Stokes respiration on the ApneaLink (ResMed
from observational studies.
Corporation, San Diego, California) nasal pressure
recording, but this device may not accurately detect
Cheyne-Stokes respiration. Furthermore, this device ADJUNCT THERAPY IN OSA
could not differentiate between central and obstruc-
tive events. It is likely that patients with CSA were Although CPAP therapy is very effective in the treat-
included, particularly considering that CSA is com- ment of OSA, by itself it has limited metabolic effects,
mon in patients with stroke and HF associated with and poor adherence further compromises its effec-
CHD. It is known that CSA is unlikely to respond to tiveness, as evidenced by recent RCTs (49,63,64).
CPAP, and that these patients have a poorer CV Incorporation of exercise and weight loss as adjunct
prognosis. Second, the low average CPAP use of 3.3 therapy has important health benefits beyond CPAP
h/day raises concern that the results were negative therapy, and could be potentially synergistic.
because of poor adherence. Third, patients with the EXERCISE. Exercise training and physical activity
most severe OSA were excluded (those with ESS >15 attenuate OSA (69). In a meta-analysis of 5 studies
and hypoxemia, defined as oxygen saturation <80% enrolling a total of 129 participants, the pooled es-
for >10% of recording time). In fact, the mean AHI timate of mean pre- to post-exercise reduction in
was 29/h, and the mean ODI was 28/h, values within AHI was –6.3 events/h (95% CI: –8.5 to –4.0;
the moderate OSA severity range. Hard CV outcomes p < 0.001) (about a 32% reduction), and occurred
have been associated with severe OSA, but are less without significant weight loss (69). Multifactorial
associated with mild or moderate OSA; thus, it can be mechanisms (69) could include decreased rostral
argued that many patients in this study with only fluid redistribution (5,11,70); stabilization of chemo-
mild-to-moderate OSA were not at an increased risk receptor sensitivity; and improved nasal resistance,
of CV outcomes. Fourth, 66% of the cohort was Asian sleep quality, weight loss, and strength of pharyn-
in under-resourced areas, with some concern as to geal dilator muscles (69). In regard to the latter, a
whether the findings can be generalized to other races meta-analysis involving 120 adults concluded that
in other settings that were less represented in the selective oropharyngeal exercises reduced snoring
study. There is 1 ongoing RCT (65) that will shed more and AHI by 50%, from about 25 to 12/h (71).
light on the true role of CPAP therapy in hard CV Oropharyngeal exercise may also decrease the
endpoints. amount of tongue fat.
NOCTURNAL MYOCARDIAL ISCHEMIA, MI, AND WEIGHT LOSS. Weight reduction, when applicable,
SUDDEN DEATH. OSA patients with severe SDB and should be a core element in OSA treatment. In a
marked hypoxemia are at risk for nocturnal cardiac randomized trial discussed earlier, weight loss
JACC VOL. 69, NO. 7, 2017 Javaheri et al. 849
FEBRUARY 21, 2017:841–58 Sleep Apnea

F I G U R E 6 Effect of CPAP Therapy on BP in Patients With Hypertension

5
*16 (818)

*10 (587) *8 (968)

4 *7 (471) *28 (1,948)
Net Reduction in Blood Pressure (mm Hg)

*12 (572)
*31 (1,820)
3
Mean (95% CI)

2
*§4 (1,206)

-1

-2
Bazzano AIjami Mo Heantjens Montesi Fava Bakker Bratton

24h-SBP (mm Hg) 24h-DBP (mm Hg)

Summary of different meta-analyses of RCTs. Positive figures mean improvement in BP level with CPAP (net changes) *Number of studies
included (number of patients included). §Patients without daytime hypersomnia. BP ¼ blood pressure; CI ¼ confidence interval; CPAP ¼
continuous positive airway pressure; DBP ¼ diastolic blood pressure; RCT ¼ randomized controlled trial; SBP ¼ systolic blood pressure.

provided an incremental BP reduction in CPAP- patient with HF who probably had AF (Figure 2). For
adherent participants (19). In contrast, use of CPAP this reason, we refer to this pattern of breathing as
often results in a small amount of weight gain, due in Hunter-Cheyne-Stokes breathing (HCSB). HCSB is
part to a reduction in nocturnal metabolic rate related unique to patients with HF, as it has a long cycle time
to OSA work of breathing (eliminated by CPAP), with (Figure 2), reflecting the prolonged circulation time, a
dietary intake and eating behavior having the great- pathological feature of heart failure with reduced
est effects leading to a positive energy balance and ejection fraction (HFrEF) (4,73).
weight gain (72). These findings highlight the impor- Although HCSB with central apneas or hypopneas
tance of lifestyle modifications combined with CPAP is common in HF, patients frequently experience
(19), and ongoing follow-up of patients after CPAP is the coexistence of both OSA and CSA; however,
initiated to monitor weight and other health behav- generally 1 variant predominates (73). Overall,
iors. Even though weight loss is an important moderate-to-severe SDB (AHI $15/h) is highly
component of long-term management of OSA and has prevalent in various pathological conditions associ-
significant respiratory and cardiometabolic effects, ated with symptomatic or asymptomatic left ven-
weight loss does not necessarily cure OSA, even after tricular dysfunction (Figure 9) discussed later in
bariatric surgery, and requires follow-up sleep study the text.
after weight stabilization.
PREVALENCE OF SLEEP APNEA IN ASYMPTOMATIC
HF COMORBID WITH SLEEP APNEA LEFT VENTRICULAR DYSFUNCTION. Using poly-
somnography, Lanfranchi et al. (74) showed that 66%
Both OSA and CSA are common in HF patients, and of individuals with asymptomatic left ventricular
could lead to progression and decompensation of HF, systolic dysfunction experience moderate-to-severe
as reviewed in detail elsewhere (4,5,73). Regarding sleep apnea: 55% with CSA and 11% with OSA
CSA, John Hunter first described the Cheyne-Stokes (Figure 9). The prevalence is lower in heart failure
breathing pattern. Hunter noted recurrent cycles of with preserved ejection fraction (HFpEF), at about
smooth and gradual crescendo–decrescendo changes 25% (4% CSA), although the prevalence of diastolic
in tidal volume with an intervening central apnea in a dysfunction increases with the severity of OSA (75).
850 Javaheri et al. JACC VOL. 69, NO. 7, 2017

Sleep Apnea FEBRUARY 21, 2017:841–58

F I G U R E 7 Effect of CPAP Therapy on BP in Patients With Resistant Hypertension

Randomized controlled trials Meta-analyses

(n=35) ∫ (n=40)
12 (n=41)
11
10 *4 (n=329)
Net Reduction in Blood Pressure (mm Hg)

9 (n=196) *5 (n=446)
8
7
6 (n=117)
Mean (95% CI)

5
4
3
2
1
0
-1
-2
-3
-4
Lozano Pedrosa Martinez-Garcia De Oliveira Muxfeldt Iftikhar Liu

24h-SBP (mm Hg) 24h-DBP (mm Hg)

The figure shows 5 randomized controlled trials and 2 meta-analyses. The differences between the 2 meta-analyses depend on the most
updated references included in the 2015 meta-analysis. Positive figures mean improvement in BP level with CPAP (net changes) *Number of
studies included (number of patients included). !Daytime BP values. Abbreviations as in Figure 6.

What is the clinical significance of a high preva- patients, showing that 58% had moderate-to-severe
lence of SDB in asymptomatic left ventricular SDB (AHI $15), with 46% classified as CSA and 16%
dysfunction? Because asymptomatic left ventricular OSA (78). However, there is considerable variation in
dysfunction is a predictor of incident symptomatic the reported prevalence of these 2 forms of sleep
HF, undiagnosed SDB may contribute to the pro- apnea (73), with underestimation of prevalence of
gression from an asymptomatic to a symptomatic OSA in some studies due to misclassification of
condition. In this context, 2 prospective longitudinal hypopneas (obstructive or central) as a component of
studies demonstrated that OSA was independently a AHI.
significant predictor of incident HF in men (76) and The prevalence of sleep apnea in HFpEF is similar
women (77). Similarly, the presence of CSA/HCSB has to that in HFrEF. Combining 2 studies (79,80) with a
been shown to predict incident HF in a prospective total of 263 consecutive patients, 47% had sleep
study of 2,865 participants (7). This suggests that apnea (AHI $15): 24% OSA and 23% CSA (Figure 9).
HCSB is not simply a marker of more severe HF, but However, with decompensation, the prevalence
may precede the onset of clinical HF, possibly by increases considerably. In 1,117 consecutive HFrEF
making those with subclinical ventricular dysfunc- patients hospitalized with acute HF who underwent
tion more likely to decompensate. in-hospital polygraphy, 334 patients were identified
with CSA (31%) and 525 with OSA (47%) (Figure 9) (81).
PREVALENCE OF SLEEP APNEA IN HFrEF, HFpEF,
AND ACUTE HF. Combining the results of several TREATMENT OF SDB IN HF
studies (4,8,73), 53% of 1,607 patients with HFrEF had
moderate-to-severe sleep apnea (defined as an Depending on the predominant phenotype of sleep
AHI $15), of whom an estimated 34% had CSA and apnea, treatment strategies are different. However, a
19% had OSA (Figure 9). These findings are consistent number of approaches are applicable to either type of
with a recent study of 963 well-treated HFrEF sleep apnea.
JACC VOL. 69, NO. 7, 2017 Javaheri et al. 851
FEBRUARY 21, 2017:841–58 Sleep Apnea

F I G U R E 8 Effect of CPAP Treatment on CV Risk

Barbe et al (CERCAS) 0.83 (0.63-1.1), p=0.20

(CPAP=358,
control=367) 0.72 (0.52-0.98), p=0.04
Follow-up: 4 yrs

Peker et al 0.80 (0.46-1.41 ), p=0.44

(RICCADSA)
(CPAP=122, 0.29 (0.1 0-0.86), p=0.026
control=122)
Follow-up: 4.7 yrs
McEvoy et al (SAVE) 1.10 (0.91-1.32), p=0.34
(CPAP=1359,
control=1358)
Follow-up: 3.7 yrs) 0.52 (0.30-0.90), p=0.02
*
0 0.5 1 1.5
In Favor of CPAP In Favor of Control

Intention-to-treat analysis Adherence analysis (patients with

CPAP adherence ≥4 hours/day)

The figure shows the incidence risk for the primary composite endpoints in 3 RCTs (49,63,64) in the CPAP compared with the control group
(hazard ratio or incidence density ratio, 95% CI) in the intention-to-treat analysis and in the adherence analysis (patients with CPAP
adherence $4 h/day). *In the McEvoy study (49), the significant CV improvement in patients who used CPAP $4 h/day was only achieved in
the risk of a cerebrovascular event, but not in the primary composite outcome. CV ¼ cardiovascular; other abbreviations as in Figure 6.

GENERAL BENEFICIAL MEASURES. O p t i m i z a t i o n One important issue is the augmentation of the

o f c a r d i o p u l m o n a r y f u n c t i o n . Before obtaining adrenergic state imposed by SDB in patients with
an outpatient sleep study, it is often beneficial to HFrEF (Figure 10). Small RCTs have shown that CPAP
use guided medical therapy of HF to improve treatment decreases vascular (87) and myocardial
cardiopulmonary function and minimize volume sympathetic nerve function (88), improves myocar-
overload (5,11). Treatment of volume overload is dial energetics in the case of severe OSA (88), and
important because fluid from lower extremities increases left ventricular ejection fraction (LVEF)
translocated cephalad can result in narrowing of the (89,90), although not consistently (88). OSA is inde-
upper airway and precipitates obstructive events pendently associated with excess hospital read-
(5,11). In contrast, fluid translocation into the lungs mission and mortality (81,91). In the largest
promotes CSA (5) by increasing pulmonary capillary observational study of about 30,000 Medicare bene-
pressure (82). ficiaries newly diagnosed with HF (92), treatment of
Intensive HF therapy must be executed carefully, SDB was associated with decreased readmission,
otherwise adverse consequences, such as renal fail- health care cost, and mortality (Figure 11) (91,92).
ure, may occur and improvement in quality of life and With regard to OSA comorbid with HFpEF, there is
reverse remodeling may not ensue (83). Regarding 1 randomized trial (93) showing reversal of diastolic
device therapy, a meta-analysis (84) of cardiac dysfunction with CPAP.
resynchronization therapy trials in patients with TREATMENT OF CSA: IMPACT OF THERAPY ON
HFrEF demonstrated improvement in CSA, but not SYMPATHETIC ACTIVITY, LVEF, READMISSION, AND
OSA. MORTALITY. Intensive therapy of HF with pharma-
E x e r c i s e . As discussed earlier in the text, several cotherapy and cardiac resynchronization therapy can
studies indicate that supervised exercise attenuates improve cardiac function, periodic breathing, and
OSA. Exercise training of patients with HF also at- CSA (5,73,84).
tenuates SDB, particularly OSA (85). In contrast to OSA, CPAP is only partially effective
TREATMENT OF OSA: IMPACT OF THERAPY ON in CSA (about 50% of patients) (86,94), and may be
SYMPATHETIC ACTIVITY, LVEF, READMISSION, AND harmful in those whose CSA is not suppressed (94).
MORTALITY. CPAP has been successfully used to treat Medications including theophylline and acetazol-
OSA in patients with HF, both acutely (86) and amide have been used in small RCTs, and have
chronically (87–89), with beneficial CV benefits. been extensively reviewed previously (73). Cardiac
852 Javaheri et al. JACC VOL. 69, NO. 7, 2017

Sleep Apnea FEBRUARY 21, 2017:841–58

F I G U R E 9 Sleep Apnea is Prevalent in Left Ventricular Dysfunction

90%

80%

70%

60%

50%
%

40%

30%

20%

10%

0%
LVSD LVDD
HFrEF HFpEF ADHF
Asymptomatic Asymptomatic

AHI > 15/h 66% 25% 53% 47% 78%

OSA 55% 21% 20% 23% 47%
CSA 11% 4% 33% 24% 31%

AHI > 15/h OSA CSA

Prevalence (%) of moderate-to-severe sleep apnea (AHI $15) in asymptomatic left ventricular systolic dysfunction (LVSD) or left ventricular
diastolic dysfunction (LVDD), heart failure with preserved ejection fraction (HFpEF) or heart failure with reduced ejection fraction (HFrEF),
and acutely decompensated heart failure (ADHF). AHI ¼ apnea-hypopnea index; CSA ¼ central sleep apnea; OSA ¼ obstructive sleep apnea.

transplantation virtually eliminates CSA (95), but OSA (reviewed by Javaheri et al. [73]), in the largest and
develops in a large number of patients who gain most recent mortality study of 963 well-treated pa-
weight (Figure 12). We will discuss 3 therapeutic op- tients with HFrEF, those with CSA had the worst
tions: positive airway pressure, nasal oxygen, and survival after accounting for several cofounders (78).
phrenic nerve stimulation (PNS). These data are consistent with CSA as a negative
Similar to OSA, CSA also imposes an augmented prognostic indicator (104). Surprisingly, the recent
hyperadrenergic state in HFrEF (96) (Figure 10), as ASV trial, SERVE-HF (Treatment of Predominant
measured by overnight urinary and morning plasma Central Sleep Apnoea by Adaptive Servo Ventilation
norepinephrine levels (97), and microneurography in Patients With Heart Failure) (105), designed spe-
(98,99). Importantly, several randomized trials have cifically to treat CSA with ASV, not only did not show
demonstrated that attenuation of CSA by CPAP de- survival benefit, but was associated with excess CV
creases plasma and urinary norepinephrine and mortality. The ASV algorithm provides an anticyclical
nocturnal minute ventilation (surrogate of work of pressure support such that when the patient is
breathing), improving respiratory muscle strength hypoventilating the support is augmented, and vice
and fatigue (97,100,101). The decrease in urinary versa (106).
catecholamines has also been confirmed in random- The SERVE-HF investigators (105) cited 2 explana-
ized trials comparing therapeutic adaptive servo- tions for their findings: 1) increased PAP compro-
ventilation (ASV) to sham ASV (102) and nocturnal mised cardiac output; or 2) CSA serves as a
oxygen to sham (room air from a concentrator) (103). compensatory mechanism with protective effects, as
Consistent with a number of previous studies previously hypothesized (104). As detailed elsewhere
JACC VOL. 69, NO. 7, 2017 Javaheri et al. 853
FEBRUARY 21, 2017:841–58 Sleep Apnea

F I G U R E 1 0 Effects of Sleep Apnea and HF on Central Sympathetic Outflow

Baroreceptors; Peripheral arterial chemoreceptors

Heart failure
Sleep fragmentation; Periodic limb movement

Disinhibition of pulmonary stretch receptors

Apnea

Peripheral arterial chemoreceptors

Hypoxemia Central Sympathetic outflow

Medullary central chemoreceptors

Hypercapnia
Peripheral arterial chemoreceptors

Locus ceruleus
Arousal

Heart failure is a hyperadrenergic state. Sleep apnea further contributes to increased central sympathetic outflow. Locus ceruleus is the
brainstem arousal network, and norepinephrine is the neurotransmitter. HF ¼ heart failure.

(107), there are additional reasons that may account reduction in loop gain; and improvement in
for the observed increased mortality. One concern is hypoxemia-related effects. The use of oxygen in HF,
that the results may not be applicable to the modern particularly to overcome hypoxemia, is also sup-
generation of ASV devices. SERVE-HF tested an early- ported by data showing that degree of overnight
generation ASV device (106), which may have sub- hypoxemia is among the most significant de-
optimally treated CSA and OSA, and its application of terminants of HF-related mortality (78,109). How-
pressure may have caused excessive ventilation, as ever, it is important to note that use of high levels of
well as adverse hemodynamic responses in vulner- oxygen in normoxic HF patients (when awake) has
able subsets of patients (107). Given results of the been shown to cause unwanted hyperoxia, increased
SERVE-HF trial, ASV is contraindicated to treat CSA in systemic vascular resistance, and impaired ventricu-
patients with low ejection fraction. Research with lar function (110). RCTs are needed to determine the
new-generation ASV devices is needed, with one in role of oxygen in treating CSA in HFrEF (108).
progress (ADVENT-HF [Effect of Adaptive Servo TRANSVENOUS UNILATERAL PNS. Transvenous
Ventilation (ASV) on Survival and Hospital Admis- unilateral PNS has been used to treat CSA. The
sions in Heart Failure]; NCT01128816). phrenic nerve can be stimulated through the wall
SUPPLEMENTAL NASAL OXYGEN. The uncertainty of either the right brachiocephalic vein or the left
over use of pressure devices in patients with reduced pericardiophrenic vein (111,112). In the recently
ejection fraction has opened the door for other ther- completed RCT (112), 151 patients with CSA were
apeutic options devoid of increasing intrathoracic implanted and randomized to stimulation or no
pressure. We briefly review 2 options: nasal oxygen stimulation for 6 months. With stimulation, multiple
and PNS. measures of sleep apnea severity (AHI, central apnea
Systematic studies in patients with HFrEF (73,108) index, arousal index, and oxygen desaturation in-
have shown that nocturnal nasal oxygen improves dex), quality of life, and daytime sleepiness improved
CSA, with randomized studies showing that therapy significantly. The most common side effect was
improves maximal exercise capacity; decreases therapy-related discomfort that was resolved with
overnight urinary norepinephrine excretion and reprogramming in all but 1 patient. During the 6
muscle sympathetic nerve activity; and improves months of therapy, 2 deaths occurred in the treat-
ventricular arrhythmias, LVEF, and quality of life ment group during daytime when stimulation was
(reviewed by Javaheri [73,108]). The potential bene- off, and 2 deaths occurred in the control group. Local
fits of supplemental oxygen include: improvement in side effects, such as infection and dislodgment,
oxygen stores; stabilization of breathing pattern; occurred in 13 of 151 implanted patients.
854 Javaheri et al. JACC VOL. 69, NO. 7, 2017

Sleep Apnea FEBRUARY 21, 2017:841–58

statistically significant differences in event rates.

F I G U R E 1 1 Comparative Survival of 258 HF Patients Treated for Sleep Apnea and
30,000 Patients Not Tested for Sleep Apnea
Because there are no optimal control conditions for
CPAP, outcomes should be objectively collected and
100% prospectively ascertained to minimize bias. Trials
Diagnosed with sleep apnea and
treated N=258 require careful implementation of methods for opti-
mizing treatment adherence across the duration of
Percent of Cohort Alive

90%
interventions, aiming to treat sleep apnea every night
Not tested or treated for sleep and all night. Low adherence to CPAP has been a
80% apnea N=30,065
major limitation of the 3 major trials (49,63,64) dis-
cussed earlier in the text. Moreover, conventional
70% methods for assessing adherence only consider
average hours of use per night. For CVD, it may be
Hazard ratio = .33 (95% CI: .21-.51 ), P <0.0001 that selective nonuse during early morning hours,
60%
Baseline 1 2 3 4 5 6 7 8
when rapid-eye-movement sleep dominates and
Quarters After HF Onset hypoxemia may be most profound, may contribute to
specific CVD-related stress (113). Failure to treat sleep

Adapted with permission from Javaheri et al. (92). HF ¼ heart failure.

apnea during these critical periods may account for
reduced treatment efficacy.
Future trials may benefit from more comprehen-
sive approaches to CPAP adherence that account for
FUTURE DIRECTIONS both mechanical issues and behavior change. Careful
attention to mask and pressure comfort, claustro-
CARDIOVASCULAR DISEASE. RCTs are needed to
phobia, nasal clogging, naso-oral dryness, and oral
provide unbiased assessments of the role of sleep leak are critical. However, social and behavioral fac-
apnea intervention on incident CVD, and CVD- tors also are important, including bed partner support
associated morbidity and mortality. RCTs are and self-efficacy. Motivational education, patient
designed to overcome potential biases in observa- engagement using real-time electronic feedback, and
tional studies, ensuring that groups who are treated peer support are promising strategies for improving
are otherwise comparable to control groups. How- adherence.
ever, RCTs present several challenges in design and As alternatives to CPAP, such as nocturnal sup-
implementation that need to be addressed in future plemental oxygen, oral appliances, or hypoglossal
trials. Studies need to be sufficiently large, and of nerve stimulation, are identified, there is also
sufficient duration to detect clinically and opportunity to conduct comparative effectiveness
trials. These trials may more easily be conducted
in “real-world” settings, and may allow for broader
F I G U R E 1 2 Prevalence of OSA in 45 of 60 Consecutive Cardiac Transplant Recipients patient enrollment, such as patients with
sleepiness, who generally have been excluded from
Apnea hypopnea index studies with “no treatment” arms (49,63,64). Symp-
47% 53% tomatic patients may better adhere to therapy,
51% and also are a group who may be at high risk for
36% moderate to severe OSA adverse outcomes.
21
20 36% RCTs are necessary across a number of other CV
Number of Subjects

24% severe OSA disorders. Current studies show a high prevalence of

15 SDB in asymptomatic left ventricular systolic and
16%
diastolic dysfunction. It remains to be established in
10 7
7 RCTs if treatment of OSA or CSA aborts or delays
5
5 4 incident HF in subjects with preclinical left ventric-
1 0 ular dysfunction or, conversely, if treatment of left
0-< 5 5-< 10 10-< 15 15-< 20 20-< 30 30-< 40 ≥40 ventricular dysfunction improves SDB, breaking a
vicious cycle.

Those who developed sleep apnea had gained the most weight after transplantation.
In patients with HFrEF, studies have demonstrated
Adapted with permission from Javaheri et al. (95). CI ¼ confidence interval; HF ¼ heart reversal of adverse consequences of OSA, including
failure; OSA ¼ obstructive sleep apnea. diastolic dysfunction, with CPAP. Randomized,
adequately-powered trials are needed to confirm the
JACC VOL. 69, NO. 7, 2017 Javaheri et al. 855
FEBRUARY 21, 2017:841–58 Sleep Apnea

results of largely observational studies showing that underlying disease can be defined and corrected. For
treatment with CPAP lowers hospital readmission and example, in patients with dysfunction in the upper
improves survival in such patients. With regard to airway dilator muscles, if well-defined, hypoglossal
HFpEF, a small RCT showed improvement in left nerve stimulation of the upper airway muscles could
ventricular diastolic dysfunction with CPAP treat- be effective. Elevated loop gain can be effectively
ment of OSA (93). This is an important observation minimized using oxygen or acetazolamide. If certain
that should lead to a large randomized trial, as so far sedative/hypnotic agents could raise the arousal
there has not been a therapy for HFpEF showing threshold, they would be predicted to stabilize
reverse cardiac remodeling. breathing in carefully selected individuals with low
Results of the SERVE-HF trial suggest that arousal threshold. An elevated arousal threshold can
treatment of CSA with ASV could be harmful. How- allow the accumulation of respiratory stimuli (carbon
ever, the ASV used in the trial was an older- dioxide, negative intrathoracic pressure) that acti-
generation device with algorithm shortcomings vate upper airway dilator muscles, and thus stabilize
(106). Another trial using state-of-the-art ASV is in breathing. In individuals in whom fluid accumula-
progress. Nocturnal oxygen therapy and PNS are 2 tion around the upper airway is playing an important
treatment options devoid of increasing intrathoracic role in compromising the upper airway, diuretic
pressure. The pivotal study on PNS has been pub- therapy can be helpful to improve apnea, albeit to a
lished (112). Time has passed for an RCT with oxygen modest extent. In certain individuals, multiple ab-
therapy (108). These RCTs with PNS and oxygen normalities likely underlie OSA pathogenesis, and
should be powered to determine important cardio- thus, combination therapy may be required to elim-
vascular outcomes. inate SDB.
Many studies implicate untreated SDB in the ACKNOWLEDGMENT The authors thank Mr. Alex
development and recurrence of AF; the field is ripe for Mackey for his excellent technical contribution in
the conduct of RCTs with well-phenotyped partici- preparing the figures.
pants, followed closely for intervention adherence, to
examine the effect of SDB treatment on AF outcomes. ADDRESS FOR CORRESPONDENCE: Dr. Shahrokh
PHENOTYPING. Pathogenesis underlying OSA is Javaheri, Pulmonary and Sleep Division, Bethesda
variable. With the recent push toward personalized Sleep Laboratory, Bethesda North Hospital, 10535
medicine, individualizing therapy may be a viable Montgomery Road, Suite 200, Cincinnati, Ohio 45242.
approach for OSA if the exact mechanism(s) E-mail: [email protected].

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