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

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.

Full text

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, PHD
m
ABSTRACT
Sleep apnea is highly prevalentin patients with cardiovascular disease. These disorderedbreathing events are associated with
aprofile of perturbations that include intermittent hypoxia, oxidative stress, sympathetic activation, and endothelial
dysfunction,all of which are critical mediators of cardiovasculardisease. Evidence supports a causal associationof 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, withspecial consideration of
treating patients with heart disease. Futuredirections for selective areas are suggested. (J Am Coll Cardiol 2017;69:841–58)
© 2017 by the American College of Cardiology Foundation.
Cardiovascular 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).
By 2030, total direct medical costs of CVD are
projected to be $920 billion. The high prevalence
of obstructive sleep apnea (OSA), which affects
34% of men and 17% of women and is largely undi-
agnosed (2),isamodifiable CVD risk factor. OSA
is a cause of systemic hypertension (HTN) and is
associated with an increased incidence of stroke,
heart failure (HF), atrial fibrillation (AF), and coro-
nary heart disease (CHD) (3).OSA,particularly
when severe, is associated with increased all-cause
From the
a
Pulmonary and Sleep Division, Bethesda North Hospital, Cincinnati, Ohio;
b
Respiratory Department, Institut Ricerca
Biomèdica de Lleida, Hospital Universitari Arnau de Vilanova, Lleida, Spain;
c
Respiratory Department, Hospital Universitario de
Valme, Sevilla, Spain;
d
Department of Population Health Sciences and John Rankin Laboratory of Pulmonary Medicine, University
of Wisconsin-Madison, Madison, Wisconsin;
e
Sleep Heart Program, the Ohio State University, Columbus, Ohio;
f
Harvard Medical
School, Brigham and Women’s Hospital, Boston, Massachusetts;
g
Pulmonary, Critical Care and Sleep Medicine, University of
California, San Diego, California;
h
Respiratory Department, Hospital Universitario de Politecnico La Fe, Valencia, Spain;
i
Cleveland
Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio;
j
Division of Sleep Medicine/Department of
Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania;
k
Division of Pulmonary and
Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland;
l
Beth Israel Deaconess Medical Center,
Boston, Massachusetts; and the
m
Department of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota. Dr. Shahrokh
Javaheri is a consultant for Respicardia, Philips, and Leva Nova Group. Dr. Barbe has received research grants from ResMed and
Oxigen Salus; and has received a speaker’s fee from Philips. Dr. Khayat has received research grants through The Ohio State
University from Philips Respironics. Dr. Mehra’s institution has received positive airway pressure machines and equipment from
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.
Listen to this manuscript’s
audio summary by
JACC Editor-in-Chief
Dr. Valentin Fuster.
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 69, NO. 7, 2017
ª2017 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
PUBLISHED BY ELSEVIER
ISSN 0735-1097/$36.00
http://dx.doi.org/10.1016/j.jacc.2016.11.069

and cardiovascular (CV) mortality (Central
Illustration).
A sleep apnea subtype, central sleep apnea
(CSA) is rare in the general population, but
iscommoninpatientswithHF,stroke,and
AF (4,5). However, recent data suggest that
CSA is also a risk factor for incident AF (6)
and HF (7).
This review provides an update on sleep
apnea and CVD. We hope to provide a cata-
lyst for cardiologists to join with sleep phy-
sicians to conduct research, particularly
clinical trials, that addresses the role of sleep
apnea treatment in patients who are at high
risk of or have existing CVD.
DEFINITIONS OF TYPES OF SLEEP APNEAS
AND HYPOPNEAS
An apnea is the absence of inspiratory airflow for at
least 10 s. A hypopnea is a lesser decrease in airflow,
lasting 10 s or longer, and associated with a drop in
arterial oxyhemoglobin saturation and or an electro-
encephalographic arousal. Apneas and hypopneas are
classified as obstructive or central, but regardless,
they result from an absence or reduction of brainstem
neural output to upper airway muscles (e.g., genio-
glossus) and/or lower thoracic inspiratory pump
muscles (diaphragm and intercostal muscles). The
pattern of neural output determines the phenotype:
OSA occurs when complete upper airway occlusion
occurs (absent airflow, tongue falling backward) in
the face of continued activity of inspiratory thoracic
pump muscles (Figure 1)(8).Incontrast,CSA
(Figure 2) occurs when there is a transient reduction
by the pontomedullary pacemaker in the generation
of breathing rhythm, usually reflecting changes in the
partial pressure of CO
2
(PCO
2
), which can fall below
the apneic threshold,alevelofPCO
2
below which
breathing ceases (4,5). The 2 most common causes in
adults are HF and opioid use (4).
PATHOGENESIS OF OSA
Sleep has multiple pronounced effects on the respi-
ratory system and control of breathing. Experimental
studies in instrumented cats have shown decreased
electrical activity in medullary inspiratory neurons
with efferent output to the upper and lower respira-
tory muscles, reflected in decreased activity of dia-
phragm and dilator muscles of the upper airway (also
observed in human studies) (9). With reduction in the
activity of the genioglossus muscle at the onset of
sleep, the tongue falls backward, and individuals with
altered mechanical properties of the upper airway are
prone to upper airway obstruction. Several anatomic
processes may compromise the patency of the upper
airway, including alterations in craniofacial struc-
tures, enlarged tonsils, upper airway edema,
decreased lung volume, and most importantly,
obesity (9,10).
The mechanisms linking obesity to OSA (2,9) are
complex, although mostly due to direct mechanical
effects on the respiratory system. These include fat
deposits within the upper airway and reduction in
lung volume, resulting in a loss of caudal traction on
the upper airway (10).
Although obesity is the major risk factor for OSA,
roughly 20% to 40% of OSA patients are not obese. In
these individuals, nonanatomic factors (9,10),such
as upper airway dilator muscle dysfunction, height-
ened chemosensitivity, and low arousal threshold
(i.e., waking up from sleep prematurely, causing
instability in ventilatory control), are important, and
define various phenotypes of OSA that may be
amenable to specific therapeutic options. Specif-
ically, dilator muscle dysfunction should best
respond to hypoglossal nerve stimulation, whereas
heightened chemosensitivity and low arousal
threshold may be amenable to pharmacotherapy to
down-regulate ventilatory responses (nocturnal
oxygen-attenuating hypoxic response), and hyp-
notics to increase the arousal threshold. With the
push toward personalized medicine, individualizing
therapy may be a viable approach for OSA, as the
mechanism(s) underlying disease are better defined
and consequently corrected. Much work is needed in
this area.
Anotherriskfactorthathasreceivedrecentatten-
tion is that of fluidaroundtheupperairway(5,11).In
individuals with lower-extremity edema, excess fluid
may accumulate in the pharyngeal area with cephalad
transposition of fluid from lower extremities to the
neck area when supine (5,11), rendering the upper
airway susceptible to collapse during sleep. Redistri-
bution of fluid to the lungs also may potentiate CSA,
as discussed later in the text. Therapeutic ap-
proaches, such as diuretic agents, stockings, and
exercise, have been shown to improve OSA and
CSA (5,11).
PATHOGENESIS OF CSA
APNEIC THRESHOLD IN SLEEP AND INCREASED
LOOP GAIN. Apneic threshold is the arterial PCO
2
below which the ponto-medullary respiratory rhythm
generator ceases, thereby silencing motor nerves
innervating inspiratory thoracic pump muscles. Con-
sequently, ventilation ceases and CSA occurs. Sleep
ABBREVIATIONS
AND ACRONYMS
AF =atrial fibrillation
AHI =apnea-hypopnea index
CHD =coronary heart disease
CPAP =continuous positive
airway pressure
CSA =central sleep apnea
CVD =cardiovascular disease
HF =heart failure
HTN =hypertension
OSA =obstructive sleep apnea
TIA =transient ischemic attack
Javaheri et al.JACC VOL. 69, NO. 7, 2017
Sleep Apnea FEBRUARY 21, 2017:841–58
842

unmasks a highly sensitive hypocapneic-induced
apneic threshold, which in health at sea level,
approximates the waking eupneic partial arterial
pressure of carbon dioxide (PaCO
2
)(4).When
ventilation increases in response to a transient
spontaneous arousal or sigh, the subsequent venti-
latory overshoot often elicits sufficient hypocapnia
(i.e., in the 1to4mmHgPaCO
2
range) to cause
apneas. Once the central respiratory drive is with-
drawn, apnea persists until PaCO
2
rises above the
apneic threshold.
Susceptibility to ventilatory instabilities depends
critically on the “loop gain”of the respiratory control
system. Loop gain defines the magnitude of a
response (increased ventilation) to a disturbance
(reduced breathing [4]). The higher the gain, the
greater the ventilatory overshoot and undershoot,
and the more likely the occurrence of continued
ventilatory cycling and repeated apneas. The role of
loop gain in mediating periodic breathing in HF has
been reviewed elsewhere (4).
OVERNIGHT CONSEQUENCES OF SLEEP
APNEA
Normal sleep provides a time of low physiological
stress, which is advantageous to the CV system. In
particular, during non–rapid-eye-movement sleep
(approximately 80% of total sleep time), sympathetic
activity decreases and parasympathetic activity in-
creases, with lowering of blood pressure (BP) and heart
rate (Figure 3). However, sleep-disordered breathing
(SDB) disrupts normal sleep. Apneas and hypopneas,
and the consequent compensatory hyperpneas, are
associated with 4 acute adverse CV consequences (12):
1) arterial blood gas abnormalities, with intermittent
hypoxemia–reoxygenation and fluctuations in PCO
2
;
2) excessive arousals; 3) decreased parasympathetic
and increased sympathetic activity (9,12);and4)large
negative intrathoracic pressure swings (12) (Figure 4).
These consequences are qualitatively similar for OSA
and CSA, but more pronounced in OSA. The adverse
consequences of SDB have been reviewed elsewhere
CENTRAL ILLUSTRATION Potential Etiological Risk Factors for Sleep Apnea and the Downstream Consequences
Sleep apnea
End-stage
cardiovascular disease
Increased
sympathetic
nerve activity
Heart disease Hypertension Atrial brillation
Metabolic
dysregulation Inammation Oxidative
stress
Vascular
endothelial
dysfunction
Intermittent
hypoxia
Upper airway dysfunctionRespiratory control instability Obesity
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.
JACCVOL.69,NO.7,2017 Javaheri et al.
FEBRUARY 21, 2017:841–58 Sleep Apnea
843

(4,5,9,12). We emphasize, however, that the large
negative pressure swings due to inspiratory effort
against a closed upper airway are reflected in juxta-
cardiac pressure increasing the transmural pressure of
all intrathoracic structures, including atria, ventricles,
intrathoracic aorta, and pulmonary vascular beds,
with adverse effects on these structures. The nega-
tive pressure increases left ventricular afterload,
increasing myocardial oxygen consumption, and im-
pedes stroke volume. Thin-walled atria are vulnerable
to surrounding negative pressure, stretching easily,
stimulating mechanoreceptors with activation of ion
channels that facilitate development of atrial ar-
rhythmias, specifically AF. These effects are most
prominent in association with other apnea-related
consequences, such as tissue hypoxia and increased
sympathetic activity. Atrial stretch also results in
secretion of atrial natriuretic peptide, causing noctu-
ria, a symptom of OSA.
MOLECULAR SIGNATURES OF SLEEP APNEA
IN R E LAT I ON TO CARDIOCEREBROVASCULAR
DISORDERS
OSA is a disorder associated with oxidative stress,
up-regulation of redox-sensitive genes, and inflam-
matory cascade (13,14). Multiple studies of bio-
markers related to CVD in patients with OSA assess
how they change with treatment (13–17).Muchofthis
work has focused on nuclear factor (NF)-kappaB–
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
body mass index. Obesity may magnify the effects of
OSA because macrophages in fat are likely the target
cells for the effects of chronic intermittent hypoxia,
leading to increases in inflammatory biomarkers; thus,
OSA and obesity may have synergistic effects. The re-
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
therapy alone; however, C-reactive protein levels were
only reduced in association with weight loss. The Ice-
landic Sleep Apnea Cohort (16) reported that intercel-
lular adhesion molecule levels increase over 2 years in
the most obese individuals with untreated OSA,
whereas levels decrease in regular CPAP users. Thus,
OSA may result in a progressive inflammatory state,
which may be 1 mechanism of the vasculardamage that
occurs from OSA. Inflammatory consequences of OSA
may vary with degree of obesity.
METABOLIC DYSFUNCTION AND OSA
OSA is independently associated with metabolic
syndrome and insulin resistance, with an associated
risk for incident CV events (20). Three randomized
controlled trials (RCTs) (21–23) have demonstrated
that treatment of OSA with CPAP improves insulin
sensitivity. In 1 RCT, supervised CPAP treatment for 8
h over 2 weeks nightly significantly improved insulin
sensitivity and glucose response in intravenous and
oral glucose tolerance tests (21).InanotherRCTof
pre-diabetic patients, the insulin sensitivity index
improved significantly in those with severe OSA
treatedwithCPAP(22), and there was a significant
correlation between hours of CPAP use and
improvement in insulin sensitivity, emphasizing the
critical importance of adherence (21). Thus, current
FIGURE 1 Polysomnographic Example of OSA
First tracing is chin electromyogram, second and third are electroencephalogram, fourth
is electrocardiogram, fifth and sixth are airflow measured by thermocouple (fifth) and
CO
2
(sixth), seventh and eighth are rib cage (RC, seventh) and abdominal (ABD, eighth),
ninth is oxyhemoglobin saturation measured by pulse oximetry, and tenth is esophageal
pressure. Please note that during obstructive apnea, airflow is absent while breathing
effort continues. Breathing resumes with the onset of arousal. Reprinted with permission
from Javaheri (8). OSA ¼obstructive sleep apnea.
Javaheri et al.JACC VOL. 69, NO. 7, 2017
Sleep Apnea FEBRUARY 21, 2017:841–58
844

evidence suggests that OSA is associated with insulin
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,myocardialischemia,myocar-
dial infarction (MI), and sudden death. The epidemi-
ology of these associations has been extensively
reviewed (3,5,13,14,20).Inthefollowingsections,we
discuss trials of CPAP, the most effective therapy of
OSA. We also discuss adjunct therapy of OSA.
CPAP AND SYSTEMIC HTN. The effect of CPAP on
HTN has been widely investigated, and the available
evidence from multiple RCTs and several recent
meta-analyses demonstrates that CPAP significantly
reduces BP in OSA patients. Studies using 24-h BP
monitoring (25–32) consistently report drops of 2 to
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-
servative treatment (Figure 6), with greater re-
ductions in patients with resistant HTN (between 4.7
to7.2mmHgand2.9to4.9mmHgforSBPandDBP,
respectively) (Figure 7)(33–39). CPAP has also been
demonstrated to reverse nondipper or riser nocturnal
BP patterns in OSA patients.
Because long-term reductions of 2 to 3 mm Hg in
SBP are associated with a 4% to 8% reduction in the
future risk of stroke and CHD, long-term treatment of
OSA in hypertensive patients could eventually reduce
incident CV burden.
There are multiple reasons why the antihyperten-
sive effect of CPAP is limited. First, essential HTN is
quite common in the general population, and should
be equally prevalent in OSA patients. CPAP may not
decrease BP if the underlying cause of HTN is unre-
lated. Second, CPAP therapy can only reverse certain
intermediate mechanisms associated with OSA. For
example, CPAP reduces sympathetic tone, thereby
decreasing BP (18). However, other pathophysiolog-
ical mechanisms underlying HTN, such as those
associated with obesity, salt intake, and volume
overload, may be unaffected by CPAP. Third, OSA and
HTN are chronic disorders, and if OSA-induced HTN
has been longstanding, with consequent remodeling
of the vascular bed and/or increased set point for BP
on the basis of prevailing BP regulatory mechanisms
(e.g., baroreflex), CPAP may not be able to reduce BP
much, certainly in the short term. Given this issue, for
ethical reasons, RCTs have a follow-up of <1year.
Therefore, it is unknown whether BP may fall further
in long-term follow-up.
Overall, highly variable BP improvement is ex-
pected with CPAP therapy, as the drop correlates with
OSA severity, baseline HTN, and hours of CPAP use.
Depending on these characteristics, some study pa-
tients might have greater antihypertensive benefits
from CPAP, whereas others—for example, those with
less severe OSA—might not. The level of adherence
needed to obtain a significant reduction in BP levels is
unknown, although a minimum threshold of 4 h, and
optimally >5 to 6 h/night, is needed. In resistant HTN,
a linear correlation has been observed between the
numberofhoursofCPAPuseanddropinBPmea-
sures(decreasesof1.9and1.0mmHginSBPandDBP,
respectively, for each additional hour of CPAP use)
(37), suggesting that greater CPAP adherence would
be associated with better BP control. This dose-
dependent relationship is similar to that for insulin
sensitivity (22,23) and other CV outcomes, as dis-
cussed later in the text.
FIGURE 2 Polysomnographic Example of Hunte r-Cheyne-Stokes Breathing
The first 2 tracings are electro-occulogram; otherwise tracings as in Figure 1. Note the
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,
absence of naso-oral airflow, and excursions in pleural pressure, thorax, and abdomen.
The arousal occurs at the peak of hyperventilation. Desaturation is delayed because of
long circulation time in heart failure. Reprinted with permission from Dowdell WT,
Javaheri S, McGinnis W. Cheyne-Stokes respiration presenting as sleep apnea syndrome:
clinical and polysomnographic features. Am Rev Respir Dis 1990;141:871-9.
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FEBRUARY 21, 2017:841–58 Sleep Apnea
845

A recent study (40) reported that BP response to
CPAP in OSA patients with resistant HTN can be pre-
dicted by measuring the plasma levels of 3 specific
microribonucleic acids, which may help to person-
alize this treatment in the future.
There is evidence that the combination of antihy-
pertensive drugs (41) or weight loss (19) with CPAP
therapy could have a synergistic effect in reducing BP
in OSA patients, supporting the multidimensional
pathophysiology of HTN in this population. When
hypertensive patients with and without OSA were
treatedwithlosartanfor6weeks,theBPdrop
(measuredby24-hambulatoryBPmonitoring)was
significantly less in those with OSA than without.
Importantly, when CPAP was added at the end of 6
weeks of losartan and used at least 4 h nightly for the
next 6 weeks, BP decreased markedly in those with
OSA (41). The combination of CPAP and weight loss
may also have a synergistic effect, leading to larger BP
reductions in OSA patients (19).
CPAP AND PHTN. About 10% of patients with OSA
have PHTN (defined as the mean pulmonary artery
pressure $25 mm Hg) (42,43), and multiple observa-
tional studies demonstrate that treating OSA with
CPAP improves PHTN (42,43). In the only small ran-
domized crossover study (therapeutic vs. sham CPAP)
(44), 12 weeks of treatment resulted in a significant
decrease in pulmonary artery systolic pressure (from
ameanof30to24mmHg).Thereductionwas
greatest (8.5 mm Hg) in patients with baseline PHTN
(pulmonary artery systolic pressure $30 mm Hg
by echocardiography). The American College of
Cardiology/American Heart Association expert
consensus document recommends polysomnography
to rule out OSA for all patients with PHTN (45).The
recommendation comes from the idea that targeted
therapyofOSAcouldeitherimproveorprevent
further deterioration in central hemodynamics.
CPAP AND STROKE/TIA. Sleep apnea is highly prev-
alent in patients with stroke or TIA, and OSA also is
associated with increased risk for incident stroke
(46–48). There is some evidence that early CPAP
therapy has positive effects on long-term survival in
ischemic stroke patients with moderate-to-severe OSA
(46–48). Additionally, consistent with observational
studies (46–48), in a recent large RCT (49),thoseOSA
patients who were adherent to CPAP therapy exhibited
reduced risk of incident cerebral events.
The American Heart Association/American Stroke
Association guideline states: “A sleep study might be
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-
dence that the treatment of sleep apnea improves
outcomes in the general population”(50).
CPAP AND ARRHYTHMIAS. Two small RCTs showed
that treatment of OSA with CPAP reduces the mean
24-h heart rate, as well as the frequency of premature
ventricular beats during sleep (51,52).Datafrom
observational studies show that CPAP treatment is
associated with a significantly decreased recurrence
rate of AF, even after electrical cardioversion or
ablative therapies, and that patients are less likely to
progress to more permanent forms of AF and have
significantly reduced occurrence of paroxysmal AF
compared with untreated patients (53–56).
In a meta-analysis (57) of 698 CPAP users and 549
non-CPAPusers,thosewithOSAtreatedwithCPAP
afterAFinterventionhada44%reducedAFrisk;
younger, more obese, and male patients benefited the
most. On the basis of this evidence, a recent expert
consensus document on AF identified OSA as a risk
factor for AF recurrence after surgical and catheter
ablation, and recommended its treatment (58).
Although the reproducibility of these findings from
observational studies is compelling, data from clinical
trials are needed.
CPAP,CHD,CVMORTALITY,ANDCOMPOSITECV
OUTCOMES. Multiple observational studies demon-
strate that untreated OSA is associated with CV
morbidity and mortality, and that treatment with
CPAP improves the need for revascularization, inci-
dent CHD, and survival (59–62).
FIGURE 3 Normal Cardiovascular Changes in NREM
and REM Sleep
Parasympathetic Activity
Sympathetic Activity
Sympathetic Activity
NREM sleep:
Phasic REM sleep:
BP, HR, COP
Ventilation
Metabolic rate
BP and HR
Cardiovascular
Quiescence
During NREM sleep sympathetic activity decreases whereas
parasympathetic activity increases with consequent decrease in
BP and HR. The reverse occurs in phasic REM sleep. BP ¼blood
pressure; COP ¼cardiac output; HR ¼heart rate; NREM ¼
non–rapid eye movement; REM ¼rapid eye movement.
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846

To date, 3 RCTs investigated the effect of CPAP on
CV outcomes (Figure 8), with the main endpoint a
composite outcome of different fatal and nonfatal CV
events. In the first RCT (63), 725 nonsleepy patients
(Epworth Sleepiness Scale [ESS] <11 of 24), free of
CVD and with moderate-to-severe OSA (AHI $20/h),
were randomized to CPAP (n ¼357) or conservative
treatment (n ¼366), and were followed for a median
of 4 years. CPAP did not result in a significant
reduction in the incidence of the primary composite
outcome. However, in an adherence analysis, pa-
tients who used CPAP for $4 h/night did achieve a CV
benefit (incidence density ratio 0.72; 95% confidence
interval [CI]: 0.52 to 0.98; p ¼0.04).
Peker et al. (64) randomized 244 nonsleepy
(ESS <10) patients with newly revascularized CHD
and moderate-to-severe OSA (AHI >15/h) to autoti-
trating positive airway pressure (PAP) (n ¼122) or no
PAP (n ¼122) for a median of 57 months. The inci-
dence of the primary composite CV endpoint did not
differ between the 2 groups. However, adjusted on-
treatment analysis showed a significant CV risk
reductioninthosewhousedCPAPfor>4 h, compared
with those who used the device <4 h/night or did not
receive treatment (adjusted hazard ratio: 0.29; 95%
CI: 0.10 to 0.86; p ¼0.026).
The SAVE (Continuous Positive Airway Pressure
Treatment of Obstructive Sleep Apnea to Prevent
Cardiovascular Disease) study (49) enrolled 2,717
nonsleepy or mildly sleepy (ESS <15) patients age 45
to 75 years, with prior history of coronary or cerebro-
vascular disease and OSA, defined by an oxygen
desaturation index $12/h, diagnosed by means of a
2-channel screening device. Patients were allocated to
CPAP or usual-care treatment for a mean of 3.7 years.
The incidence of a composite CV outcome was similar
in the CPAP and control groups (p ¼0.34). One-to-one
propensity-score matching was performed to compare
561 patients who were adherent to CPAP therapy with
561 patients in the usual-care group. In this sensitivity
analysis, a lower risk of a composite endpoint of ce-
rebral events was found in the group of patients who
used CPAP for at least 4 h/day (hazard ratio: 0.52; 95%
CI: 0.30 to 0.90; p ¼0.02).
This study has several limitations. First, SDB was
diagnosed by means of a screening device on the basis
FIGURE 4 Pathophysiological Consequences of Sleep Apnea and Hypopnea
Hypoxic and hypercapnic
pulmonary vasoconstriction
⇓ O2 delivery
Cycles of sleep
apnea and recovery Arousals
⇓ Pleural
Pressure
⇓ PO2 /⇑ PCO2
⇑ PO2 /⇓ PCO2
Organ dysfunction
Endothelial dysfunction
⇑ Right ventricular afterload
⇑ Blood pressure
Arrhythmias
Myocyte toxicity
⇑ Heart rate
R and L ventricular afterload
Arrhythmias (atrial)
Aortic dilation
Increased lung H2O
Oxidative stress
Inammation
Sympathetic activation
Parasympathetic
withdrawal
⇑ Transmural pressure of all
cardiac chambers and aorta
⇑ Pulmonary capillary
hydrostatic pressure
Pleural pressure (Ppl) is a surrogate of the pressure surrounding the heart and other vascular structures. [¼increased; Y¼decreased. Reprinted with
permission from Javaheri (8).CV¼cardiovascular; H
2
O¼water; L ¼left; O
2
¼oxygen; PCO
2
¼partial pressure of carbon dioxide in the blood;
PO
2
¼partial pressure of oxygen in the blood; R ¼right.
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847

of oximetry and nasal pressure recordings. In-
vestigators excluded patients with a pattern of
Cheyne-Stokes respiration on the ApneaLink (ResMed
Corporation, San Diego, California) nasal pressure
recording, but this device may not accurately detect
Cheyne-Stokes respiration. Furthermore, this device
could not differentiate between central and obstruc-
tive events. It is likely that patients with CSA were
included, particularly considering that CSA is com-
mon in patients with stroke and HF associated with
CHD. It is known that CSA is unlikely to respond to
CPAP, and that these patients have a poorer CV
prognosis. Second, the low average CPAP use of 3.3
h/day raises concern that the results were negative
because of poor adherence. Third, patients with the
most severe OSA were excluded (those with ESS >15
and hypoxemia, defined as oxygen saturation <80%
for >10% of recording time). In fact, the mean AHI
was 29/h, and the mean ODI was 28/h, values within
the moderate OSA severity range. Hard CV outcomes
have been associated with severe OSA, but are less
associated with mild or moderate OSA; thus, it can be
argued that many patients in this study with only
mild-to-moderate OSA were not at an increased risk
of CV outcomes. Fourth, 66% of the cohort was Asian
in under-resourced areas, with some concern as to
whether the findings can be generalized to other races
in other settings that were less represented in the
study. There is 1 ongoing RCT (65) that will shed more
lightonthetrueroleofCPAPtherapyinhardCV
endpoints.
NOCTURNAL MYOCARDIAL ISCHEMIA, MI, AND
SUDDEN DEATH. OSA patients with severe SDB and
marked hypoxemia are at risk for nocturnal cardiac
ischemia. OSA has been associated with onset of MI
during the night/early morning (66).Itisreasonable
to consider that the increased likelihood of nocturnal
nonfatal MI may also be accompanied by an increased
riskoffatalMIandsuddendeath.In>10,000 in-
dividuals,thepresenceofOSAandsignificant desa-
turation was associated with an almost 2-fold
increase in risk of sudden death, independent of
known risk factors (67).Comparingthetimeofdeath
of individuals with and without SDB, those with the
disorder died mostly between 12:00 AM and 6:00 AM
(68) suggesting that untreated OSA in patients with
established CHD would likely lead to a poorer
prognosis.
SUMMARY OF CPAP THERAPY AND CARDIOVASCULAR
DISEASE. High-quality evidence recommends CPAP
therapy in patients with HTN and OSA, especially in
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-
rhythmias is consistent with adverse effects of OSA
and beneficial effects of CPAP, but these data come
from observational studies.
ADJUNCT THERAPY IN OSA
Although CPAP therapy is very effective in the treat-
ment of OSA, by itself it has limited metabolic effects,
and poor adherence further compromises its effec-
tiveness, as evidenced by recent RCTs (49,63,64).
Incorporation of exercise and weight loss as adjunct
therapy has important health benefits beyond CPAP
therapy, and could be potentially synergistic.
EXERCISE. Exercise training and physical activity
attenuate OSA (69). In a meta-analysis of 5 studies
enrolling a total of 129 participants, the pooled es-
timate of mean pre- to post-exercise reduction in
AHI was –6.3 events/h (95% CI: –8.5 to –4.0;
p<0.001) (about a 32% reduction), and occurred
without significant weight loss (69).Multifactorial
mechanisms (69) could include decreased rostral
fluid redistribution (5,11,70); stabilization of chemo-
receptor sensitivity; and improved nasal resistance,
sleep quality, weight loss, and strength of pharyn-
geal dilator muscles (69). In regard to the latter, a
meta-analysis involving 120 adults concluded that
selective oropharyngeal exercises reduced snoring
and AHI by 50%, from about 25 to 12/h (71).
Oropharyngeal exercise may also decrease the
amount of tongue fat.
WEIGHT LOSS. Weight reduction, when applicable,
should be a core element in OSA treatment. In a
randomized trial discussed earlier, weight loss
FIGURE 5 Prevalence (%) of OSA in CVD
0102030405060708090100
Arrhythmias
Heart failure
Stroke
Coronary heart
disease
Hypertension
20 50
12 55
57 75
6538
30 83
The lower limit is invariably using an AHI of $15/h, indicating presence of moderate-to-
severe OSA. The upper part of the range relates to a lower threshold of $5/h. CVD ¼
cardiovascular disease; OSA ¼obstructive sleep apnea.
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provided an incremental BP reduction in CPAP-
adherent participants (19). In contrast, use of CPAP
often results in a small amount of weight gain, due in
part to a reduction in nocturnal metabolic rate related
to OSA work of breathing (eliminated by CPAP), with
dietary intake and eating behavior having the great-
est effects leading to a positive energy balance and
weight gain (72).Thesefindings highlight the impor-
tance of lifestyle modifications combined with CPAP
(19), and ongoing follow-up of patients after CPAP is
initiated to monitor weight and other health behav-
iors. Even though weight loss is an important
component of long-term management of OSA and has
significant respiratory and cardiometabolic effects,
weight loss does not necessarily cure OSA, even after
bariatric surgery, and requires follow-up sleep study
after weight stabilization.
HF COMORBID WITH SLEEP APNEA
BothOSAandCSAarecommoninHFpatients,and
couldleadtoprogressionanddecompensationofHF,
as reviewed in detail elsewhere (4,5,73).Regarding
CSA, John Hunter first described the Cheyne-Stokes
breathing pattern. Hunter noted recurrent cycles of
smooth and gradual crescendo–decrescendo changes
in tidal volume with an intervening central apnea in a
patientwithHFwhoprobablyhadAF(Figure 2). For
this reason, we refer to this pattern of breathing as
Hunter-Cheyne-Stokes breathing (HCSB). HCSB is
unique to patients with HF, as it has a long cycle time
(Figure 2), reflecting the prolonged circulation time, a
pathological feature of heart failure with reduced
ejection fraction (HFrEF) (4,73).
Although HCSB with central apneas or hypopneas
is common in HF, patients frequently experience
the coexistence of both OSA and CSA; however,
generally 1 variant predominates (73).Overall,
moderate-to-severe SDB (AHI $15/h) is highly
prevalent in various pathological conditions associ-
ated with symptomatic or asymptomatic left ven-
tricular dysfunction (Figure 9) discussed later in
the text.
PREVALENCE OF SLEEP APNEA IN ASYMPTOMATIC
LEFT VENTRICULAR DYSFUNCTION. Using poly-
somnography, Lanfranchi et al. (74) showed that 66%
of individuals with asymptomatic left ventricular
systolic dysfunction experience moderate-to-severe
sleep apnea: 55% with CSA and 11% with OSA
(Figure 9).Theprevalenceislowerinheartfailure
with preserved ejection fraction (HFpEF), at about
25% (4% CSA), although the prevalence of diastolic
dysfunction increases with the severity of OSA (75).
FIGURE 6 Effect of CPAP Therapy on BP in Patients With Hypertension
-2
-1
0
1
2
3
4
5
*16 (818)
*10 (587) *7 (471)
24h-SBP (mm Hg) 24h-DBP (mm Hg)
*12 (572)
*28 (1,948)
*8 (968)
*§4 (1,206)
*31 (1,820)
Bazzano
Net Reduction in Blood Pressure (mm Hg)
Mean (95% CI)
AIjami Mo Heantjens Montesi Fava Bakker Bratton
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 ¼blood pressure; CI ¼confidence interval; CPAP ¼
continuous positive airway pressure; DBP ¼diastolic blood pressure; RCT ¼randomized controlled trial; SBP ¼systolic blood pressure.
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What is the clinical significance of a high preva-
lence of SDB in asymptomatic left ventricular
dysfunction? Because asymptomatic left ventricular
dysfunction is a predictor of incident symptomatic
HF, undiagnosed SDB may contribute to the pro-
gression from an asymptomatic to a symptomatic
condition. In this context, 2 prospective longitudinal
studies demonstrated that OSA was independently a
significant predictor of incident HF in men (76) and
women (77). Similarly, the presence of CSA/HCSB has
been shown to predict incident HF in a prospective
study of 2,865 participants (7).Thissuggeststhat
HCSB is not simply a marker of more severe HF, but
may precede the onset of clinical HF, possibly by
making those with subclinical ventricular dysfunc-
tion more likely to decompensate.
PREVALENCE OF SLEEP APNEA IN HFrEF, HFpEF,
AND ACUTE HF. Combining the results of several
studies (4,8,73), 53% of 1,607 patients with HFrEF had
moderate-to-severe sleep apnea (defined as an
AHI $15), of whom an estimated 34% had CSA and
19% had OSA (Figure 9). These findings are consistent
with a recent study of 963 well-treated HFrEF
patients, showing that 58% had moderate-to-severe
SDB (AHI $15), with 46% classified as CSA and 16%
OSA (78).However,thereisconsiderablevariationin
the reported prevalence of these 2 forms of sleep
apnea (73), with underestimation of prevalence of
OSA in some studies due to misclassification of
hypopneas (obstructive or central) as a component of
AHI.
The prevalence of sleep apnea in HFpEF is similar
to that in HFrEF. Combining 2 studies (79,80) with a
total of 263 consecutive patients, 47% had sleep
apnea (AHI $15): 24% OSA and 23% CSA (Figure 9).
However, with decompensation, the prevalence
increases considerably. In 1,117 consecutive HFrEF
patients hospitalized with acute HF who underwent
in-hospital polygraphy, 334 patients were identified
with CSA (31%) and 525 with OSA (47%) (Figure 9)(81).
TREATMENT OF SDB IN HF
Depending on the predominant phenotype of sleep
apnea, treatment strategies are different. However, a
number of approaches are applicable to either type of
sleep apnea.
FIGURE 7 Effect of CPAP Therapy on BP in Patients With Resistant Hypertension
12
11
10
9
8
7
6
5
4
3
2
1
0
-1
-2
-3
-4
(n=41) (n=35) ∫(n=40)
Randomized controlled trials Meta-analyses
(n=196)
(n=117)
*4 (n=329)
*5 (n=446)
24h-SBP (mm Hg) 24h-DBP (mm Hg)
Lozano
Net Reduction in Blood Pressure (mm Hg)
Mean (95% CI)
Pedrosa Martinez-Garcia De Oliveira Muxfeldt Iftikhar Liu
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.
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GENERAL BENEFICIAL MEASURES. Optimization
of cardiopulmonary function. Before obtaining
an outpatient sleep study, it is often beneficial to
use guided medical therapy of HF to improve
cardiopulmonary function and minimize volume
overload (5,11). Treatment of volume overload is
important because fluid from lower extremities
translocated cephalad can result in narrowing of the
upper airway and precipitates obstructive events
(5,11). In contrast, fluid translocation into the lungs
promotes CSA (5) by increasing pulmonary capillary
pressure (82).
Intensive HF therapy must be executed carefully,
otherwise adverse consequences, such as renal fail-
ure, may occur and improvement in quality of life and
reverse remodeling may not ensue (83).Regarding
device therapy, a meta-analysis (84) of cardiac
resynchronization therapy trials in patients with
HFrEF demonstrated improvement in CSA, but not
OSA.
Exercise. As discussed earlier in the text, several
studies indicate that supervised exercise attenuates
OSA. Exercise training of patients with HF also at-
tenuates SDB, particularly OSA (85).
TREATMENTOFOSA:IMPACTOFTHERAPYON
SY MP ATH ET I C ACTIVITY, LVEF, READMISSION, AND
MORTALITY. CPAP has been successfully used to treat
OSA in patients with HF, both acutely (86) and
chronically (87–89),withbeneficial CV benefits.
One important issue is the augmentation of the
adrenergic state imposed by SDB in patients with
HFrEF (Figure 10). Small RCTs have shown that CPAP
treatment decreases vascular (87) and myocardial
sympathetic nerve function (88), improves myocar-
dial energetics in the case of severe OSA (88),and
increases left ventricular ejection fraction (LVEF)
(89,90), although not consistently (88). OSA is inde-
pendently associated with excess hospital read-
mission and mortality (81,91).Inthelargest
observational study of about 30,000 Medicare bene-
ficiaries newly diagnosed with HF (92),treatmentof
SDB was associated with decreased readmission,
health care cost, and mortality (Figure 11)(91,92).
With regard to OSA comorbid with HFpEF, there is
1randomizedtrial(93) showing reversal of diastolic
dysfunction with CPAP.
TREATMENTOFCSA:IMPACTOFTHERAPYON
SYMPATHETIC ACTIVITY, LVEF, READMISSION, AND
MORTALITY. Intensive therapy of HF with pharma-
cotherapy and cardiac resynchronization therapy can
improve cardiac function, periodic breathing, and
CSA (5,73,84).
In contrast to OSA, CPAP is only partially effective
in CSA (about 50% of patients) (86,94),andmaybe
harmful in those whose CSA is not suppressed (94).
Medications including theophylline and acetazol-
amide have been used in small RCTs, and have
been extensively reviewed previously (73).Cardiac
FIGURE 8 Effect of CPAP Treatment on CV Risk
Barbe et al (CERCAS)
(CPAP=358,
control=367)
Follow-up: 4 yrs
0.83 (0.63-1.1), p=0.20
0.72 (0.52-0.98), p=0.04
0.80 (0.46-1.41 ), p=0.44
1.10 (0.91-1.32), p=0.34
0.29 (0.1 0-0.86), p=0.026
0.52 (0.30-0.90), p=0.02
*
00.5
Intention-to-treat analysis Adherence analysis (patients with
CPAP adherence ≥4 hours/day)
In Favor of CPAP In Favor of Control
1.51
Peker et al
(RICCADSA)
(CPAP=122,
control=122)
Follow-up: 4.7 yrs
McEvoy et al (SAVE)
(CPAP=1359,
control=1358)
Follow-up: 3.7 yrs)
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 ¼cardiovascular; other abbreviations as in Figure 6.
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transplantation virtually eliminates CSA (95),butOSA
develops in a large number of patients who gain
weight (Figure 12). We will discuss 3 therapeutic op-
tions: positive airway pressure, nasal oxygen, and
phrenic nerve stimulation (PNS).
Similar to OSA, CSA also imposes an augmented
hyperadrenergic state in HFrEF (96) (Figure 10), as
measured by overnight urinary and morning plasma
norepinephrine levels (97),andmicroneurography
(98,99).Importantly,severalrandomizedtrialshave
demonstrated that attenuation of CSA by CPAP de-
creases plasma and urinary norepinephrine and
nocturnal minute ventilation (surrogate of work of
breathing), improving respiratory muscle strength
and fatigue (97,100,101). The decrease in urinary
catecholamines has also been confirmed in random-
ized trials comparing therapeutic adaptive servo-
ventilation (ASV) to sham ASV (102) and nocturnal
oxygen to sham (room air from a concentrator) (103).
Consistent with a number of previous studies
(reviewed by Javaheri et al. [73]), in the largest and
most recent mortality study of 963 well-treated pa-
tients with HFrEF, those with CSA had the worst
survival after accounting for several cofounders (78).
These data are consistent with CSA as a negative
prognostic indicator (104). Surprisingly, the recent
ASV trial, SERVE-HF (Treatment of Predominant
Central Sleep Apnoea by Adaptive Servo Ventilation
in Patients With Heart Failure) (105),designedspe-
cifically to treat CSA with ASV, not only did not show
survival benefit, but was associated with excess CV
mortality. The ASV algorithm provides an anticyclical
pressure support such that when the patient is
hypoventilating the support is augmented, and vice
versa (106).
The SERVE-HF investigators (105) cited 2 explana-
tions for their findings: 1) increased PAP compro-
mised cardiac output; or 2) CSA serves as a
compensatory mechanism with protective effects, as
previously hypothesized (104). As detailed elsewhere
FIGURE 9 Sleep Apnea is Pre valent in Left Ventricular Dysf unction
90%
80%
70%
60%
50%
40%
%
30%
20%
10%
0%
66%
55%
11%
AHI > 15/h
OSA
CSA
AHI > 15/h OSA CSA
25%
21%
4%
53%
20%
33%
47%
23%
24%
78%
47%
31%
LVSD
Asymptomatic
LVDD
Asymptomatic HFrEF HFpEF ADHF
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 ¼apnea-hypopnea index; CSA ¼central sleep apnea; OSA ¼obstructive sleep apnea.
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(107), there are additional reasons that may account
for the observed increased mortality. One concern is
that the results may not be applicable to the modern
generation of ASV devices. SERVE-HF tested an early-
generation ASV device (106),whichmayhavesub-
optimally treated CSA and OSA, and its application of
pressure may have caused excessive ventilation, as
well as adverse hemodynamic responses in vulner-
able subsets of patients (107). Given results of the
SERVE-HF trial, ASV is contraindicated to treat CSA in
patients with low ejection fraction. Research with
new-generation ASV devices is needed, with one in
progress (ADVENT-HF [Effect of Adaptive Servo
Ventilation (ASV) on Survival and Hospital Admis-
sions in Heart Failure]; NCT01128816).
SUPPLEMENTAL NASAL OXYGEN. The uncertainty
over use of pressure devices in patients with reduced
ejection fraction has opened the door for other ther-
apeutic options devoid of increasing intrathoracic
pressure. We briefly review 2 options: nasal oxygen
and PNS.
Systematic studies in patients with HFrEF (73,108)
have shown that nocturnal nasal oxygen improves
CSA, with randomized studies showing that therapy
improves maximal exercise capacity; decreases
overnight urinary norepinephrine excretion and
muscle sympathetic nerve activity; and improves
ventricular arrhythmias, LVEF, and quality of life
(reviewed by Javaheri [73,108]). The potential bene-
fits of supplemental oxygen include: improvement in
oxygen stores; stabilization of breathing pattern;
reduction in loop gain; and improvement in
hypoxemia-related effects. The use of oxygen in HF,
particularly to overcome hypoxemia, is also sup-
ported by data showing that degree of overnight
hypoxemia is among the most significant de-
terminants of HF-related mortality (78,109).How-
ever,itisimportanttonotethatuseofhighlevelsof
oxygen in normoxic HF patients (when awake) has
been shown to cause unwanted hyperoxia, increased
systemic vascular resistance, and impaired ventricu-
lar function (110). RCTs are needed to determine the
role of oxygen in treating CSA in HFrEF (108).
TRANSVENOUS UNILATERAL PNS. Transvenous
unilateral PNS has been used to treat CSA. The
phrenic nerve can be stimulated through the wall
of either the right brachiocephalic vein or the left
pericardiophrenic vein (111,112).Intherecently
completed RCT (112), 151 patients with CSA were
implanted and randomized to stimulation or no
stimulation for 6 months. With stimulation, multiple
measures of sleep apnea severity (AHI, central apnea
index, arousal index, and oxygen desaturation in-
dex), quality of life, and daytime sleepiness improved
significantly. The most common side effect was
therapy-related discomfort that was resolved with
reprogramming in all but 1 patient. During the 6
months of therapy, 2 deaths occurred in the treat-
ment group during daytime when stimulation was
off, and 2 deaths occurred in the control group. Local
side effects, such as infection and dislodgment,
occurred in 13 of 151 implanted patients.
FIGURE 10 Effects of Sleep Apnea and HF on Central Sympath etic Outflow
Heart failure
Apnea
Hypoxemia
Hypercapnia
Arousal
Baroreceptors; Peripheral arterial chemoreceptors
Sleep fragmentation; Periodic limb movement
Disinhibition of pulmonary stretch receptors
Peripheral arterial chemoreceptors Central Sympathetic outow
Medullary central chemoreceptors
Peripheral arterial chemoreceptors
Locus ceruleus
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 ¼heart failure.
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FUTURE DIRECTIONS
CARDIOVASCULAR DISEASE. RCTs are needed to
provide unbiased assessments of the role of sleep
apnea intervention on incident CVD, and CVD-
associated morbidity and mortality. RCTs are
designed to overcome potential biases in observa-
tional studies, ensuring that groups who are treated
are otherwise comparable to control groups. How-
ever, RCTs present several challenges in design and
implementation that need to be addressed in future
trials. Studies need to be sufficiently large, and of
sufficient duration to detect clinically and
statistically significant differences in event rates.
Becausetherearenooptimalcontrolconditionsfor
CPAP, outcomes should be objectively collected and
prospectively ascertained to minimize bias. Trials
require careful implementation of methods for opti-
mizing treatment adherence across the duration of
interventions, aiming to treat sleep apnea every night
and all night. Low adherence to CPAP has been a
major limitation of the 3 major trials (49,63,64) dis-
cussed earlier in the text. Moreover, conventional
methods for assessing adherence only consider
average hours of use per night. For CVD, it may be
that selective nonuse during early morning hours,
when rapid-eye-movement sleep dominates and
hypoxemia may be most profound, may contribute to
specific CVD-related stress (113). Failure to treat sleep
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
both mechanical issues and behavior change. Careful
attention to mask and pressure comfort, claustro-
phobia, nasal clogging, naso-oral dryness, and oral
leak are critical. However, social and behavioral fac-
tors also are important, including bed partner support
and self-efficacy.Motivationaleducation,patient
engagement using real-time electronic feedback, and
peer support are promising strategies for improving
adherence.
As alternatives to CPAP,suchasnocturnalsup-
plemental oxygen, oral appliances, or hypoglossal
nerve stimulation, are identified, there is also
opportunity to conduct comparative effectiveness
trials. These trials may more easily be conducted
in “real-world”settings, and may allow for broader
patient enrollment, such as patients with
sleepiness, who generally have been excluded from
studies with “no treatment”arms (49,63,64). Symp-
tomatic patients may better adhere to therapy,
and also are a group who may be at high risk for
adverse outcomes.
RCTs are necessary across a number of other CV
disorders. Current studies show a high prevalence of
SDB in asymptomatic left ventricular systolic and
diastolic dysfunction. It remains to be established in
RCTs if treatment of OSA or CSA aborts or delays
incident HF in subjects with preclinical left ventric-
ular dysfunction or, conversely, if treatment of left
ventricular dysfunction improves SDB, breaking a
vicious cycle.
In patients with HFrEF, studies have demonstrated
reversal of adverse consequences of OSA, including
diastolic dysfunction, with CPAP. Randomized,
adequately-powered trials are needed to confirm the
FIGURE 12 Prevalence of OSA in 45 of 60 Consecutive Cardiac Transplant Recipients
20
15
10
5
0-< 5 5-< 10 10-< 15 15-< 20 20-< 30 30-< 40 40
21
1
7
0
54
7
16%
24% severe OSA
36% moderate to severe OSA
36%
51%
53%47%
Number of Subjects
Apnea hypopnea index
Those who developed sleep apnea had gained the most weight after transplantation.
Adapted with permission from Javaheri et al. (95).CI¼confidence interval; HF ¼heart
failure; OSA ¼obstructive sleep apnea.
FIGURE 11 Comparative Survival of 258 HF Patients Treated for Sleep Apnea and
30,000 Patients Not Tested for Sleep Apnea
100%
90%
80%
70%
60%
Baseline 1 2
Quarters After HF Onset
Percent of Cohort Alive
Not tested or treated for sleep
apnea N=30,065
Hazard ratio = .33 (95% CI: .21-.51 ), P <0.0001
Diagnosed with sleep apnea and
treated N=258
345678
Adapted with permission from Javaheri et al. (92).HF¼heart failure.
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854

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