JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 78, NO.

6, 2021

ª 2021 PUBLISHED BY ELSEVIER ON BEHALF OF THE

AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

THE PRESENT AND FUTURE

JACC STATE-OF-THE-ART REVIEW

Sleep Disordered Breathing and

Cardiovascular Disease
JACC State-of-the-Art Review

Martin R. Cowie, MD, MSC,a Dominik Linz, MD, PHD,b Susan Redline, MD, MPH,c Virend K. Somers, MD, PHD,d
Anita K. Simonds, MDe

ABSTRACT

Sleep disordered breathing causes repetitive episodes of nocturnal hypoxemia, sympathetic nervous activation, and
cortical arousal, often associated with excessive daytime sleepiness. Sleep disordered breathing is common in people
with, or at risk of, cardiovascular (CV) disease including those who are obese or have hypertension, coronary disease,
heart failure, or atrial fibrillation. Current therapy of obstructive sleep apnea includes weight loss (if obese), exercise, and
positive airway pressure (PAP) therapy. This improves daytime sleepiness. Obstructive sleep apnea is associated with
increased CV risk, but treatment with PAP in randomized trials has not been shown to improve CV outcome. Central sleep
apnea (CSA) is not usually associated with daytime sleepiness in heart failure or atrial fibrillation and is a marker of
increased CV risk, but PAP has been shown to be harmful in 1 randomized trial. The benefits of better phenotyping,
targeting of higher-risk patients, and a more personalized approach to therapy are being explored in ongoing trials.
(J Am Coll Cardiol 2021;78:608–624) © 2021 Published by Elsevier on behalf of the American College of Cardiology
Foundation.

S leep disordered breathing (SDB) is a spectrum of

sleep-related breathing disorders, including
those that are characterized predominantly by
obstructive features (repetitive narrowing and closure
of the upper airway during sleep) or by abnormalities
in neuromuscular output without prominent airway
collapse (Figure 1). Obstructive sleep apnea (OSA) and
central sleep apnea (CSA) can co-occur in the same in-
dividual, complicating diagnosis and treatment.
DEFINITION
OBSTRUCTIVE SLEEP APNEA. OSA occurs in more
than 40% of patients with cardiovascular (CV) disease
(CVD) (1). Diagnosis of OSA requires objective evi-
dence of an elevated number of apneas or hypopneas
(Figure 1) (2). OSA is a heterogenous disorder, but key
pathophysiological causes may include a variable
combination of an anatomically compromised or
collapsible upper airway, inadequate upper airway
dilator muscles (genioglossus) responsiveness during
sleep, low respiratory arousal threshold, and a high
“loop gain” with an oversensitive ventilatory control
system (3). An approach to phenotypic classification
of OSA is shown in Figure 2 (4).
Many of the acute pathophysiological conse-
quences of obstructive and central apneas are similar
and relate to intermittent hypoxemia and

Listen to this manuscript’s

audio summary by
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From the aDepartment of Cardiology, Royal Brompton Hospital (Guy’s & St Thomas’s NHS Foundation Trust), London, United
Kingdom; bDepartment of Cardiology, Maastricht University Medical Centre & Cardiovascular Research Institute, Maastricht, the
Netherlands; cDepartment of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA;
d
Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota, USA; and the eDepartment of Sleep and Ventilation,
Royal Brompton Hospital (Guy’s & St Thomas’s NHS Foundation Trust), London, United Kingdom.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’
institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information,
visit the Author Center.

Manuscript received April 12, 2021; accepted May 11, 2021.

ISSN 0735-1097/$36.00 https://doi.org/10.1016/j.jacc.2021.05.048

JACC VOL. 78, NO. 6, 2021
AUGUST 10, 2021:608–624
HIGHLIGHTS

SDB is common and associated with an
increased risk of cardiovascular disease.

Weight loss, exercise, and positive airway
pressure therapy improve daytime
drowsiness and quality of life in patients
with OSA, but positive airway pressure
has not been proven to improve cardio-
vascular outcomes, possibly because of
potentially adverse effects in patients
with heart failure.

Future research should focus on identi-
fying high-risk patients with SDB and
developing individualized therapeutic
strategies that improve cardiovascular
outcomes.
sympathetic nervous system activation (Figure 3).
However, obstructive (but not central) events are
additionally associated with large swings in intra-
thoracic pressure due to breathing against
occluded airway (1). Within the different phenotypes
of OSA, some data suggest that those with excessive
daytime sleepiness (ESD) may be at particularly
elevated CV and mortality risk (5); however, insuffi-
cient sleep and other causes of sleepiness may have
confounded previous studies (6).
CENTRAL SDB. This complex group of disorders
(Figure 1) (2) is characterized by breathing instability
and recurrent central apneas/hypopneas, often with
some upper airway narrowing. CSA-Cheyne-Stokes
breathing (CSB) often occurs in association with car-
diac or cerebrovascular disease—particularly heart
failure (HF) or atrial fibrillation (AF), stroke, or brain
stem/high cervical cord injury. In HF, its pathogen-
esis reflects an exaggerated chemoreflex and a pro-
longed circulation delay between the pulmonary
capillaries and carotid chemoreceptors. Cyclic periods
of hyperventilation cause CO 2 levels to fall below the
apneic threshold, precipitating apneas and hypo-
pneas, with resumption of breathing (and hyperven-
tilation) as CO 2 levels rise (7). Characteristic cycles of
crescendo–decrescendo breathing typically have cy-
cle lengths of 30 to 60 s, with longer cycles in HF.
Recently, subtypes of CSB have been identified, with
lower end-expiratory lung volume in patients with
longer CSB cycle, worse functional class, and higher
plasma N-terminal pro–B-type natriuretic peptide
(NT-proBNP) concentrations. This may help maintain
stroke volume and cardiac output in those with worse
cardiac function, and may also unload
Cowie et al. 609
Sleep Disordered Breathing and CV Disease
inspiratory muscles, at least during the initial ABBREVIATIONS
AND ACRONYMS
part of inspiration (8).
During the day, fluid may accumulate in
AF = atrial fibrillation
the intravascular and interstitial spaces of the
ASV = adaptive
legs due to gravity, and on lying down at
servoventilation
night, this redistributes rostrally. Some of
BP = blood pressure
this fluid may accumulate in the neck,
CPAP = continuous positive
increasing tissue pressure and causing the airway pressure
upper airway to narrow, thereby increasing
CSA = central sleep apnea
its collapsibility, and predisposing to OSA. In
CSB = Cheyne-Stokes
HF patients, with increased rostral fluid shift, breathing
fluid may additionally accumulate in the CV = cardiovascular
lungs, provoking hyperventilation and
CVD = cardiovascular disease
hypocapnia, driving PCO2 below the apnea
EDS = excessive daytime
threshold, leading to CSB (9). sleepiness
HF = heart failure
RISK FACTORS
HFrEF = heart failure with
SDB and CVD commonly co-occur, reflecting
reduced ejection fraction
HSAT = home sleep apnea test
both causal relationships and shared risk
LV = left ventricular
factors, such as male sex, older age, and
MACE = major adverse
obesity. The risk factors for SDB are listed in
cardiovascular events
Table 1 (10-22).
an MAS = mandibular
PATHOPHYSIOLOGY advancements splint
MI = myocardial infarction
SDB is associated with a range of physiologic OSA = obstructive sleep apnea
and pathophysiologic responses (Central RCT = randomized controlled
Illustration) (1). trial
REI = Respiratory Event Index
DIAGNOSIS
SDB = sleep disordered
breathing
Attended in-hospital polysomnography is the T<90 = time spent with
gold standard test for sleep disorders, iden- arterial oxygen
tifying apneas and hypopneas, staging sleep, saturation <90%
quantifying sleep fragmentation, and identifying
other sleep-related phenomena such as arrhythmia
and periodic leg movements. This can be performed
out of hospital and without an attendant present
overnight, but more limited, multichannel sleep pol-
ygraphy or home sleep apnea test (HSAT) with oxygen
saturation and other respiratory measures is more
widely available and can be set up by the patient at
home (23). Figure 2 shows typical recordings from a
patient with OSA and a patient with CSA from a HSAT.
Reflecting the lack of precise sleep data, the AHI
cannot be calculated, and the main metric from a
HSAT is the Respiratory Event Index (REI), which is
the sum of apneas and hypopneas divided by the
estimated sleep time. In practice, this is often merely
the total recording time, although it can be better
estimated by using available information on heart
rate and breathing pattern (24). Hypopneas with
arousal, but without significant desaturation, can also
weak not be picked up without electroencephalogram
610 Cowie et al.
Sleep Disordered Breathing and CV Disease
F I G U R E 1 Simplified Classification of SDB in Adults
Classification of Sleep Disordered Breathing in Adults (simplified)
Obstructive
• Repetitive narrowing or closure of
upper airway during sleep
AHI ≥5/h + characteristic symptoms
OR AHI >15 with or without symptoms
Apnea: near absence of airflow for ≥10 s
Hypopnea: ≥30% reduction in airflow for
≥10 s PLUS either Pa02 drop ≥3% OR
cortical arousal
AHI: Apnea Hypopnea Index =
apnea or hypopnea events per hour
of sleep
The main subdivision is into obstructive sleep apnea (with repetitive narrowing or closure of the upper airway during sleep) or central sleep apnea (CSA),
with repetitive loss of respiratory drive. See text for a fuller explanation. AHI ¼ apnea hypopnea index; CSB ¼ Cheyne-Stokes breathing; PaO2 ¼ partial
pressure of arterial oxygen; SDB ¼ sleep disordered breathing.
monitoring, although recent studies support the
ability to identify sleep and arousal from the photo-
plethysmography available on some HSATs (25).
Although HSATs are commonly used due to their
lower cost and burden, in-laboratory
somnography is generally recommended to evaluate
patients with complex comorbidities, such as HF.
When interpreting the results of HSAT, the REI may
underestimate the AHI by 12% (26), with the potential
for larger misclassification in patients with poor sleep
quality, such as in HF.
Even simpler screening may be performed by
recording nocturnal oxygen saturation via a finger
probe, which has a high sensitivity for SDB, including
in HF (27). Further investigation is needed for those
who test negative but where clinical suspicion re-
mains high, as well as for those who test positive, to
characterize the SDB clinical phenotype (minimally
requiring recording of abdominal and chest move-
ment). Algorithms have been developed in cardiac
implantable electronic devices to detect and quantify
SDB (28), with reasonable sensitivity for moderate-to-
severe SDB (29).
Patients at risk for OSA are usually initially
identified by assessing characteristic symptoms and
associated risk factors. A sleep history ideally
JACC VOL. 78, NO. 6, 2021
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Central: repetitive loss of respiratory drive
• Central Sleep Apnea (CSA)
• CSA with Cheyne-Stokes breathing (CSA-CSB)
Central AHI ≥5 events/hr & central apnea/hypopnea ≥50% of total
(CSB has a crescendo/decrescendo breathing amplitude pattern
with a cycle length >40 s)
• Treatment-emergent CSA (CSA persisting or emerging
when predominantly OSA is treated with positive airway
pressure, and in the absence of co-morbidity or substance use
that might trigger CSA)
• High altitude periodic breathing
• Opioid (or other substance) related CSA
NB Phenotype and clinical presentation may overlap
should be elicited with input from a bedpartner.
Common nocturnal breathing disturbances are
snoring, snorting, gasping, and breathing pauses
during sleep. Daytime symptoms include EDS, fa-
poly- tigue, and difficulty concentrating. In particular, the
presence of EDS—identified by assessing difficulties
in maintaining alertness, involuntary periods of
dozing, or drowsy driving—should trigger prompt
referral for diagnosis and treatment, given that this
symptom is a marker of increased risk for vehicular
crashes (30), as well as associated with better
adherence with OSA treatment (31). Patients with
CSA-CSB may report nonspecific symptoms such as
poor sleep quality with frequent awakenings,
paroxysmal nocturnal dyspnea, and nocturia, but
often do not report EDS. The index of suspicion for
SDB should be high for those with relevant symp-
toms, or difficult-to-treat or nondipping hyperten-
sion, or AF (particularly if there is a predominance
of nocturnal AF episodes).
There are several screening questionnaires that
can be used to facilitate symptom identification;
these questionnaires include assessment of OSA
symptoms and risk factors such as obesity, increased
neck girth, and hypertension. The reported sensi-
tivity is 77%-89%, but with low specificity around
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AUGUST 10, 2021:608–624 Sleep Disordered Breathing and CV Disease

F I G U R E 2 Schematic of the Phenotypic Traits That Cause OSA

Narrow/crowded/
collapsible
upper-airway

Arousal

EEG EMGMTA

Poor muscle responsiveness

Epiglottic EMGraw
pressure
OSA Epiglottic
pressure
Low arousal threshold
Airflow

Ventilatory response
High loop gain

Required breathing level

Ventilatory disturbance

Some degree of abnormal upper airway anatomy is required (narrow/crowded/collapsible) but with variable contribution also from a low cortical arousal threshold, poor
muscle responsiveness, or high loop gain. Modified with permission from Carberry et al (4). EEG ¼ electroencephalogram; EMG ¼ genioglossus electromyogram;
MTA ¼ moving time average; OSA ¼ obstructive sleep apnea.

34% (32). The Epworth Sleepiness Scale, a tool for The implementation of sleep apnea testing
grading the propensity for dozing in 8 different sit- management requires close interdisciplinary
uations, has higher specificity (67%), but low sensi- collaboration between the cardiologist and sleep
tivity (42%) (33). OSA screening questionnaires specialists, ideally within an integrated care model
appear to have poorer diagnostic accuracy in certain (36).
groups, such as in women (who commonly report
fatigue and insomnia symptoms rather than sleepi- SEVERITY GRADING
ness [33]) and in patients with HF, AF, or resistant
hypertension, who may not report sleepiness despite OSA disease severity is categorized using AHI/REI
fragmented sleep (34), likely related to sympathetic cutoffs: <5 (normal), 5 # 15 (mild), 15-30 (moderate),
activation. Because of these limitations, overnight and >30 (severe), with further assessment based on
oximetry may be of value to screen patients with the severity of overnight hypoxemia, sleep fragmen-
multiple OSA risk factors who are at increased risk tation, and daytime sleepiness. Stronger associations
for CV consequences of untreated OSA, such as pa- with CVD incidence and morbidity have been
tients with AF (26,35). observed with an AHI >30 (37-39) and with more
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Study of middle-aged to older participants, an AHI

F I G U R E 3 Characteristic Home Sleep Apnea Testing Traces
>30 predicted a 46% increased rate of all-cause

Obstructive apnea
mortality (38), with the association driven by find-
A ings in men aged <70 years, with no significant in-
Flow
crease observed in women.
Thorax P r o g n o s t i c m a r k e r s . Several studies have reported
that measures of overnight hypoxemia better predict
Abdomen
mortality than the AHI—findings consistent with a
SaO2 central role of cyclical changes in oxygen saturation
95 96 95 96 96 96
94 91 87 88
94 94 93 90 90 in contributing to inflammation, oxidative stress, and
sympathetic nervous system activation. In over
30 seconds
10,000 Canadian patients followed for a median of
Central apnea/CSB
B 68 months, AHI did not predict mortality; but by
contrast, a 58% increased mortality was associated
Flow
with T<90 of 9 min compared with 0 min (49). Mor-
Thorax tality was also associated with other indices of sleep
disruption, including periodic leg movements,
Abdomen
numbers of awakenings, and a short sleep time. In a
SaO2 94 91 93 95 94 91 94 95 93 prospective analysis of more than 10,000 individuals
86 88 85 88
84 84
in another cohort followed for an average of 5.3 years,
patients with significant nocturnal hypoxemia had a
(A) Patient with OSA; (B) a patient with CSA, showing airflow, thoracic and abdominal nearly 2-fold increase in the risk of sudden cardiac
wall movements, and Pa02 (partial pressure of arterial oxygen). Note: desaturation is
death after potential confounders had been consid-
delayed in CSA because of long circulation time in heart failure. Abbreviations as in
ered (50). Another large prospective study of older
Figures 1 and 2.
men demonstrated, not only that increased T<90
predicted mortality, but that this association was
partially mediated by an elevation in inflammatory
severe overnight hypoxemia, including percentage
mediators (51). Other indices of hypoxemia during
sleep time with PaO 2 <90% (T<90) (40). Further ad-
sleep also have been identified as potentially potent
vances in quantitative phenotyping, including longi-
predictors of mortality (52,53), supporting the use of
tudinal sleep monitoring, may better identify which
oximetry-based measures for risk stratification.
OSA patients are at highest CVD risk and which best
Although the aforementioned studies reported as-
respond to specific therapies (41-43).
sociations that were adjusted for multiple potential
ASSOCIATION WITH CVD AND OUTCOME confounders, it is possible that findings reflect resid-
ual biases. One approach for addressing causality
MORTALITY. Physician diagnosis of OSA predicted a between SDB and mortality is to identify appropriate
2.4 increase in mortality, and a higher CVD incidence, temporal associations. A large population study re-
over 7.5 years in more than 5,000 participants in the ported that sudden cardiac death occurred during
MESA study (Multi-Ethnic Study of Atherosclerosis) sleep in 46% of patients with OSA, compared with
who were free of known CVD at baseline (44). Asso- 23% of control patients (54). This pattern was attrib-
ciations are stronger for an AHI >30, with weaker or uted to the likelihood that OSA events directly trig-
inconsistent associations for milder OSA (45). Several gering arrhythmia, as was shown in a
observational studies from Spain followed patients polysomnography study demonstrating a 17-fold in-
for 5-10 years after referral to sleep centers. Among crease in atrial and ventricular arrhythmias occurring
men, untreated severe OSA was associated with a 2.9- immediately following an apnea or hypopnea
fold increased risk of fatal CVD events compared with compared with after a period of normal breathing (55).
untreated patients with mild or moderate OSA (46). In addition to SDB, there is increasing evidence
Among women, the mortality rate was 3.5-fold higher that short sleep duration, and fragmented sleep and
in severe untreated OSA than in female control pa- variable sleep–wake patterns, may contribute to
tients (47). In the Wisconsin Sleep Study, individuals increased risk of CV morbidity and mortality (56).
with severe OSA had a 3-fold increased HR for all- Conversely, HF and other cardiac disorders may
cause mortality compared with those with no OSA, negatively affect sleep quality. Research is required
with somewhat higher estimates for CVD mortality to elucidate the potential mechanisms of this likely
(48). In the community-based Sleep Heart Health bidirectional association (57).
JACC VOL. 78, NO. 6, 2021
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HYPERTENSION. Up to 50% of OSA patients may
have hypertension, and 30% of hypertensive patients
will likely have OSA (58). Patients with untreated OSA
followed over 4 years have a 2- to 3-fold increased
risk of developing incident hypertension (59). OSA
has been recognized as a particularly important likely
causal factor in resistant hypertension (60), and this
may be important in those of African ancestry, a
population with a high prevalence of unrecognized
OSA, poorly controlled hypertension, and hyperten-
sive complications (61).
However, in a randomized controlled trial (RCT)
evaluating incident hypertension and CVD events in
nonsleepy patients with OSA, continuous positive
airway pressure (CPAP) did not result in a significant
reduction in either of these endpoints over a median
follow-up of 4 years (62). In a randomized comparison
of 3 months of CPAP versus nocturnal oxygen on 24-h
systemic blood pressure (BP) in 281 patients with CVD
or multiple CV risk factors, CPAP was accompanied by
a modest fall in 24-h BP (around 2.5 mm Hg), with BP
reduction especially evident at night (63), which is
likely prognostically beneficial. Several meta-
analyses of randomized trials of CPAP in patients
with hypertension have reported similar BP decreases
(64,65). CPAP appeared most effective at lowering BP
at night compared with daytime, and in those pa-
tients who were sleepy, those who were more
adherent to CPAP therapy, and those with a higher
AHI (66). Two meta-analyses of trials of CPAP in
resistant hypertension have provided more encour-
aging results, with a drop in ambulatory BP of at least
5 mm Hg systolic/3 mm Hg diastolic, but with wide
interindividual variation (67,68).
CARDIAC ARRHYTHMIA. The complex and dynamic
substrate for arrhythmias induced by OSA, which is
characterized by structural remodeling as well as
transient apnea-associated electrophysiological
changes, is summarized in Figure 3 (69).
A t r i a l fi b r i l l a t i o n . Patients with OSA show marked
atrial structural changes and conduction abnormal-
ities, without any changes in atrial refractoriness
(70,71). OSA may also increase AF trigger formation in
the pulmonary veins and elsewhere (70,72). Addi-
tionally, obstructive respiratory events may result in
transient electrophysiological arrhythmogenic
changes, which may explain the increased risk of
nocturnal AF paroxysms temporally related to such
events (55,69,73). In the VARIOSA-AF (Night-to-Night
Variability in Severity of Sleep Apnea and Daily Dy-
namic Atrial Fibrillation Risk) study (Figure 4), the
nights with more severe sleep apnea conferred a 2.3-
fold increased risk of $1 h of AF during the same day
compared with the best sleep nights (74,75) (Figure 5).
Cowie et al. 613
Sleep Disordered Breathing and CV Disease
T A B L E 1 Risk Factors for SDB
Sex
2- to 4-fold more prevalent in men than in women (10)
More prevalent in women after menopause, unless hormone replacement therapy used (11)
Differences due to men having a longer pharynx and more upper airway fat deposition and
anatomic narrowing then women when obese
Ventilatory drive and cortical arousal also lower in women, with shorter respiratory events,
more hypopneas rather than apneas, and less oxygen desaturation with respiratory events
(12)
Age
Increased prevalence with age due to reducing airway stiffness and increasing cardiac/
metabolic/neurologic comorbidity
Obesity
40%-60% of people with OSA are obese (13)
4-fold increase in OSA in obese middle-aged individuals compared with normal weight
individuals due to increased fat in the tongue and parapharyngeal tissues, reduced chest
wall compliance and lung volumes, and increased work of breathing
Obesity-associated cytokine elevation also promotes daytime sleepiness
NB 20% of people with OSA are not obese
Craniofacial features
A narrower oropharyngeal airways increases risk of snoring and OSA (14)
Particularly relevant in people of Asian ancestry where OSA increases with only minor changes
in BMI (15)
Small or recessed jaw, brachycephalic head form, high-arched and narrow palate, large tongue
and excessive soft tissue in the throat promote OSA (16)
Systemic inflammation
Plasma CRP and IL-6, elevated insulin levels, and leptin resistance associated with changes in
central and peripheral ventilatory drive and fat deposition, increasing SDB risk (17-20)
Genetics
First degree relative of an individual with OSA has a 2-fold risk of OSA compared with someone
without an affected relative (21)
Association partly explained by obesity, but also craniofacial characteristics, ventilatory
control, and comorbidities such as cardiometabolic diseases (22)
BMI ¼ body mass index; CRP ¼ C-reactive protein; IL ¼ interleukin; OSA ¼ obstructive sleep apnea; SDB ¼ sleep
disordered breathing.
The prevalence of SDB in patients with AF is higher
(21%-74%) than in control subjects without AF (3%-
49%) (76-78). Also, severe OSA is associated with a
lower response rate to antiarrhythmic drug therapy
(79). Meta-analyses of observational studies show
that patients with OSA have a 31% greater AF-
recurrence rate after pulmonary vein isolation than
those without OSA (80,81). In nonrandomized,
observational studies, CPAP use was associated with
lower AF recurrences after cardioversion (82) and
lower AF recurrence rate after pulmonary vein isola-
tion (83,84). In meta-analyses of several non-
randomized studies, the use of CPAP was associated
with a 42% decreased risk of AF recurrence (85,86).
Randomized controlled trials are ongoing, including
SLEEP-AF (Sleep Apnoea and Atrial Fibrillation: The
Effect of Treatment of Sleep Apnoea on Atrial Fibril-
lation Burden; ACTRN12616000088448).
Non-CPAP interventions may also be effective in
reducing AF recurrence. Weight loss by behavioral
changes or bariatric surgery, as well as alcohol absti-
nence, have beneficial effects on OSA and have been
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C E NT R AL IL L U STR AT IO N Pathophysiological Abnormalities in Sleep Disordered Breathing

Cowie, M.R. et al. J Am Coll Cardiol. 2021;78(6):608–624.

Sleep disordered breathing is associated with several major pathophysiological abnormalities, including intrathoracic pressure swings (particularly in OSA), sleep
reduction and fragmentation, cyclical hypoxemia and reoxygenation, sympathetic system activation, endothelial dysfunction and increased thrombosis. Nocturnal
rostral fluid shifts may exacerbate both OSA and CSA. IV ¼ interventricular; CSA ¼ central sleep apnea; LA ¼ left atrium; LV ¼ left ventricle; NF-kB ¼ nuclear factor-kB;
OSA: ¼ obstructive sleep apnea; PAI-1 ¼ plasminogen activator inhibitor type-1; REM ¼ rapid eye movement; RV ¼ right ventricle; VEGF ¼ vascular endothelial
growth factor.

shown to also promote the maintenance of sinus
rhythm (87,88).
AF may predispose to CSB through mechanisms
similar to those in HF (with raised pulmonary
vascular pressure triggering hyperventilation and
hypocapnia through stimulation of pulmonary vagal
irritant receptors, leading to respiratory system
instability) (89), or CSB may increase the propensity
to AF by hypocapnia and increased electrical insta-
bility (90). Alternatively, autonomic dysfunction may
predispose to both CSB and AF, as can be found in
idiopathic CSB (91).
Ventricular a r r h y t h m i a . Intrathoracic pressure
swings during obstructive apneas contribute to
changes in ventricular repolarization, and this along
with sympathetic activation may represent mecha-
nisms for increased risk of sudden cardiac death in
OSA (92). An AHI of 20/h was an independent risk
factor for incident sudden cardiac death in a
study of more than 10,000 patients referred for
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F I G U R E 4 The Complex and Dynamic Substrate for Arrhythmia Induced by Sleep Apnea

• Negative intrathoracic pressure changes

• Cyclical desaturation/reoxygenation
• Sympatho-vagal activation

Acute (transient) electrophysiological Chronic (progressive) cardiac

changes remodeling

Atrium Atrium
- Refractoriness p - Atrial dilatation
- Conduction velocity p - Fibrosis/ connexin remodeling +
- Triggers n - Conduction disturbances Cardiovascular
Risk Factors
Ventricle Ventricle
- QT dispersion n - Hypertrophy
- Triggers n - Heart failure
Increasing Arrhythmia Risk

Arrhythmia risk
Transient apnea-associated peaks
in arrhythmia risk

Structural substrate
due to long-term sleep apnea &
cardiovascular risk factors

Time (Several Months to Years)

(Top) Sleep apnea–related pathophysiological changes resulting in acute transient electrophysiological changes (blue box) and chronic progressive cardiac
remodeling processes (red box). (Bottom) Individual acute sleep apnea episodes cause transient apnea-associated peaks in arrhythmia risk (blue lines),
but in the absence of an underlying structural substrate, the threshold necessary to trigger an arrhythmia (dashed black line) cannot be reached. However,
in the presence of structural remodeling due to long-term sleep apnea and cardiovascular risk factors (red line), acute sleep apnea episodes can trigger
arrhythmia.

polysomnography (50,93). Coexisting HF and sleep
apnea increase the risk of developing malignant
ventricular arrhythmia (29). Severe OSA also in-
creases the risk of ventricular premature beats and
nonsustained ventricular tachycardia, and nocturnal
sudden cardiac death (55,67). Registry data show that
treatment of CSB with servoassisted ventilation in HF
patients with implantable cardioverter defibrillator
devices decreases the
dioverter- defibrillator therapies (94), although CVD
(and all-cause) mortality was increased in a large
randomized trial of this therapy (95).
CORONARY ARTERY DISEASE. OSA is associated
with increased risk of coronary events. In an
observational cohort of more than 1,400 patients,
and after adjustment for traditional risk factors, OSA
was associated with a 2-fold increase in risk of CVD
events or death (96). The prevalence of undiagnosed
severe OSA in patients with ST-segment elevation
myocardial infarction (MI) was about 40% (97). In
patients admitted with an MI without a prior diag-
nosis of OSA, those with OSA were far more likely to
use of implantable car- have had their MI during the nighttime, presumably
because of the acute nocturnal hypoxic, adrenergic,
and hemodynamic stress induced by obstructive
apneas (98). In a 4-year follow-up of patients after
MI, independent predictors of major adverse car-
diovascular events (MACE) included severity of
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F I G U R E 5 Simultaneous Long-Term Day-by-Day Variation in Sleep Apnea and Episodes of AF

25
Nightly RDI (Events/h)

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6 lat ive
cumu
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24% days AF >1 h 20% days AF >1 h 21% days AF >1 h 39% days AF >1 h

AF AF AF
AF

Q2 Q3
Least Severe SDB (Q1) Most Severe SDB (Q4)
Nightly RDI (Events/h)

25.0 25.0 25.0 25.0

20.0 20.0 20.0 20.0
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Day Number Day Number Day Number Day Number

Least Severe SDB (Q1) Q2 Q3 Most Severe SDB (Q4)

Patients with implanted pacemakers showed considerable night-to-night variation in sleep apnea severity, with a higher respiratory disturbance index (RDI) associated
with an increasing risk of atrial fibrillation (AF) during the same day. Modified with permission from Linz et al (74).

nocturnal hypoxemia (99) and EDS (100). Patients was increased in those with moderate-to-severe
with OSA have evidence of increased arterial stiff- OSA, independent of other risk factors (105). Acute
ness, early atherosclerosis (101), coronary artery pressor surges, hypoxemia, and adrenergic activa-
calcification (102), coronary plaque instability (103), tion during apneic events (1) may be implicated as
and increased plaque vulnerability (104). In a retro- triggers of cardiac ischemia or plaque rupture.
spective analysis of patients who underwent coro- Franklin et al reported a close temporal relationship
nary angiography, severity of coronary artery disease between the hypoxemia of an obstructive apnea and
JACC VOL. 78, NO. 6, 2021
AUGUST 10, 2021:608–624
the development of ST-segment changes and chest
pain waking a patient from sleep (99). Rather than
the AHI, it is the severity of nocturnal oxygen
desaturation that appears to most strongly predict
the development of nocturnal ST-segment depres-
sion in OSA patients (106).
OSA is associated with increased mortality after an
MI (107) and with heightened CVD risk after coronary
intervention. In more than 1,300 patients who un-
derwent polysomnography, more than 45% had an
AHI $15/h. OSA was independently associated with
an increased risk of MACE (108). In a subsequent
meta-analysis of effects of OSA after percutaneous
coronary intervention, OSA was found to increase the
risk of MACE, but not of readmission for HF or of
stroke (109).
HEART FAILURE. SDB is common in HF, with preva-
lence rates of 50%-75% (110,111) in HF with reduced
ejection fraction (HFrEF) and HF with preserved
ejection fraction (112,113). In acute decompensated
HF, the prevalence is between 44% and 97% (114,115).
A study of more than 6,500 patients with HFrEF re-
ported a strong association between SDB (either OSA
or CSA) and obesity, male sex, AF, age, and poorer left
ventricular (LV) systolic function (116).
The prevalence of CSA increases as the symptom-
atic severity of the HF syndrome increases (110,112),
and the severity mirrors underlying cardiac dysfunc-
tion (117). SDB is independently associated with
increased mortality (118,119).
PULMONARY ARTERIAL HYPERTENSION. Acute hypox-
ia during episodes of OSA may increase pulmonary
artery pressures transiently due to hypoxic vasocon-
striction (120). To what extent these transient in-
creases in pulmonary vascular resistance carry over
into sustained vasoconstriction remains unclear.
Although OSA may often coexist with pulmonary (or
systemic) hypertension, it is unclear the extent to
which the OSA drives this association. Nevertheless,
it is important to identify pulmonary hypertension in
patients with OSA, because such patients are at risk
for increased mortality (121,122). The prevalence of
pulmonary hypertension (pulmonary artery
pressures $20 mm Hg) in patients with OSA has been
reported to be around 20% in those regardless of
coexisting lung disease (123). In 169 patients with
pulmonary hypertension, the prevalence of OSA was
estimated to be 16%, with an additional 10% having
CSA (124).
Whether treatment of comorbid OSA lowers pul-
monary artery pressures in patients with pulmonary
hypertension has not been examined in a large, long-
term RCT. In a meta-analysis of 6 small studies, a
Cowie et al. 617
Sleep Disordered Breathing and CV Disease
median reduction of only 1.3 mm Hg was reported
(125).
MANAGEMENT
LIFESTYLE. Individuals with OSA are advised to lose
weight if they are overweight or obese, to exercise
moderately, stop smoking, avoid alcohol and sedative
medication intake before sleep, and to improve sleep
habits. A recent cross-sectional observational study
reported that increased total physical activity,
vigorous-intensity activity, and walking were inde-
pendently associated with a decreased prevalence of
OSA, irrespective of body mass index (126). The
mechanism of benefit is unclear but may be related to
less nocturnal rostral fluid shift due to increased ac-
tivity of the musculovenous pump (127).
W e i g h t l o s s . Obesity is a major risk factor for OSA.
Weight loss has a variable effect on the severity of
OSA. Obesity may be worsened by OSA due to limi-
tation of physical activity, reduced energy expendi-
ture, and sleep deprivation leading to increased
appetite. In the Wisconsin Sleep cohort, a 10% weight
gain was associated with a 32% increase in AHI, but a
10% weight loss resulted in a 26% decrease in AHI
(128).
In a systematic review, interventions combining
weight loss and exercise training were most effective
in men with moderate or severe OSA: although AHI,
oxygen desaturation index, and sleepiness were
reduced, full remission of OSA was not achieved in
moderate or severely affected patients. Pooled mean
reduction in AHI was around 9/h, from a baseline AHI
of 30/h. Weight loss can be more successful in less
severe OSA—in almost 60% of patients with mild OSA,
the SDB resolved 2 years after weight loss interven-
tion (129).
B a r i a t r i c s u r g e r y . Substantial bariatric weight loss
(c. 50 kg) was associated with a fall in AHI from 54 to
19/h, but in those who attained weight loss from
surgery or diet, residual OSA remained in 70%-90%
(130).
In current practice, a strategy of weight loss and
exercise combined with CPAP therapy is therefore
recommended in patients with moderate or severe
OSA, and can be used in symptomatic patients with
mild OSA. Their relative contributions have been
investigated in a 3-armed RCT (comparing intensive
weight loss alone with CPAP combined with an
intensive weight loss program, and with CPAP
alone) in obese patients with AHI >15/h (131).
Plasma CRP concentration decreased (as did BP,
insulin sensitivity, and lipid concentrations) more
in the weight loss group (and weight loss combined
618 Cowie et al.
Sleep Disordered Breathing and CV Disease
T A B L E 2 Randomized Trials of OSA Treatment With CPAP Therapy in Patients With CVD
Patient OSA Follow-Up,
Trial (Ref. #) Group Diagnosis Intervention (n) Mean
SAVE (135) Prevalent CVD ODI >12/h CPAP vs control 43 months
(1,346/1,341)
RICCADSA (136) Revascularized CVD AHI >15/h CPAP vs control 57 months
(122/122)
ISAAC (137) Acute coronary AHI >15/h CPAP vs control 40 months
syndrome (631/631)
AHI ¼ apnea-hypopnea index; CPAP ¼ continuous positive airway pressure; CVD ¼ cardiovascular disease; ESS ¼ Epworth Sleepiness Scale; ISAAC ¼ Continuous Positive Airway Pressure (CPAP) in Patients
With Acute Coronary Syndrome and Obstructive Sleep Apnea (OSA) trial; MACE ¼ major adverse cardiovascular events; ODI ¼ oxygen desaturation index; OSA ¼ obstructive sleep apnea;
RICCADSA ¼ Continuous Positive Airway Pressure [CPAP] Treatment in Coronary Artery Disease and Sleep Apnea trial; SAVE ¼ Continuous Positive Airway Pressure Treatment of Obstructive Sleep Apnea to
Prevent Cardiovascular Disease trial.
with CPAP group) compared with the CPAP alone
group.
C P A P . CPAP is established as first-line therapy in OSA
patients with moderate or severe OSA due to its
impact on both symptoms and quality of life. It has
also been shown to improve vitality and quality of life
in mild OSA.
A limitation in carrying out RCTs with cardiac
endpoints in OSA is that ethical considerations have
often resulted in excluding patients with severe
sleepiness or hypoxemia—the groups who might
benefit the most from treatment. Improvements in
design of masks and devices (plus telemonitoring)
with more consistent feedback and patient support
have helped adherence to therapy (132), but CPAP
tolerance remains a key issue in interpreting results.
Adherence of more than 4 h per night is judged as
sufficient, but this is based largely on the grounds
that this “dose” reduces sleepiness, but it may still
mean that for one-half the night, OSA is not
controlled (133).
P r i m a r y p r e v e n t i o n o f C V e v e n t s w i t h C P A P . The
CERCAS (Effect of Continuous Positive Airway Pres-
sure [CPAP] on Hypertension and Cardiovascular
Morbidity-Mortality in Patients With Sleep Apnea and
no Daytime Sleepiness) trial (62) randomized 725
nonsleepy patients with moderate or severe OSA to
CPAP or no active intervention, after excluding those
with previous CVD events. CPAP did not result in a
reduction in the incidence of hypertension or CVD
events during 3 years’ follow-up, although a post
hoc secondary analysis showed that adherence to
CPAP for more than 4 h per night did reduce both
endpoints.
The effect of CPAP on uncontrolled BP was
explored in an RCT of patients with poorly controlled
BP and ischemic heart disease (134). The CPAP group
showed improved hypertension control (CPAP 69.4%
vs 43.2% control; P ¼ 0.02), and sleepiness was
reduced, but cerebrovascular and CVD events were
unchanged.
JACC VOL. 78, NO. 6, 2021
AUGUST 10, 2021:608–624
Primary Higher Adherence Daytime Sleepiness
Outcome: MACE Subgroup, >4 h per Night at Baseline
HR: 1.10 HR: 0.52 ESS <15
(95% CI: 0.91-1.32) (95% CI: 0.30-0.90) for stroke Severe sleepiness excluded
HR: 0.80 HR: 0.29 ESS <10
(95% CI: 0.46-1.41) (95% CI: 0.10-0.86) MACE Nonsleepy
HR: 0.89 HR: 0.08 ESS <10
(95% CI: 0.68-1.17) (95% CI: 0.52-1.23) MACE Nonsleepy
Secondary prevention of CV events with
C P A P . The 3 major RCTs designed to assess the ef-
fects of CPAP on secondary prevention of CVD events
are summarized in Table 2. The SAVE (Continuous
Positive Airway Pressure Treatment of Obstructive
Sleep Apnea to Prevent Cardiovascular Disease) trial
(135) randomized over 2,000 patients with estab-
lished CV or cerebrovascular disease to CPAP plus
usual care, or usual care alone. An effort was made to
familiarize patients with CPAP using a run-in period.
The use of CPAP (over a mean follow-up of 43 months)
did not significantly reduce the primary composite
endpoint of MACE, although sleepiness did improve.
In a prespecified subgroup analysis, those with CPAP
adherence >4 h per night had a lower risk of stroke
(HR: 0.56; 95% CI: 0.32-1.00) and total cerebrovascu-
lar events (HR: 0.52; 95% CI: 0.30-0.90).
In the RICCADSA (Continuous Positive Airway
Pressure [CPAP] Treatment in Coronary Artery Dis-
ease and Sleep Apnea) trial (136), patients with
moderate or severe OSA (but with no daytime sleep-
iness) were randomized to CPAP or control after cor-
onary revascularization, and followed up for a mean
of 57 months. The CPAP group showed no change in
CVD endpoints including repeat revascularization,
although the subgroup using CPAP >4 h per night had
a lower CV risk (HR: 0.29; 95% CI: 0.10-0.86).
A further study (ISAACC [Continuous Positive
Airway Pressure (CPAP) in Patients With Acute Coro-
nary Syndrome and Obstructive Sleep Apnea (OSA)]
trial) (137) examined patients with acute coronary
syndrome and moderate or severe OSA. CPAP had no
significant effect on the primary composite end point
of CVD events or death. In this trial, there was no
relationship between hours of CPAP use and out-
comes, although median adherence to CPAP was low
at 2.78 h per night. CPAP users did have an
improvement in hypertension control and daytime
sleepiness, but not in quality of life.
A meta-analysis of 9 trials involving 3,314 patients
with CVD who were randomized to CPAP or usual care
JACC VOL. 78, NO. 6, 2021
AUGUST 10, 2021:608–624
reported no improvement in survival or CVD events
with median treatment duration ranging
1 month to 57 months (138).
The reasons for these randomized trials failing to
demonstrate CV benefit has been debated (6,139),
with consensus that there needs to be a better phe-
notyping of SDB—patients with similar AHI have
widely different combinations of abnormalities in
airways anatomy, neuromuscular responsiveness,
respiratory chemosensitivity, and loop gain (3)—
closer collaboration between respiratory and CV
physicians and trialists, adequately powered studies,
and a broader range of therapies are required. Poor
adherence with airway pressure support in patients
with no EDS (and thereby lower CV risk) may also bias
randomized trials to find no effect of intervention.
ORAL APPLIANCES. Mandibular advancements splints
(MAS) can be used in patients with mild or moderate
OSA, and work by lifting the mandible forward and
stabilizing the upper airway. A meta-analysis (140) of
trials comparing effects of CPAP and MAS on BP
confirmed that compared with control patients, sys-
tolic and diastolic BP were reduced by a similar de-
gree by both therapies.
UPPER AIRWAY SURGERY. The evidence for surgical
solutions to OSA is mixed: multiple interventions are
performed, cardiovascular endpoints are
measured, and follow-up is rarely long term (141).
Sleepiness may improve and AHI reduce, but not to
within the normal range. Recently, in patients with
moderate or severe OSA who refused (or could not
tolerate) CPAP or MAS, a randomized trial of stan-
dardized multilevel oropharyngeal and tongue sur-
gery produced an improvement (although
normalization) of AHI, and reduction in sleepiness,
compared with control patients (142). Mean BP did
not change, and the only serious adverse events
(including a cardiac event) were reported in the
operative group.
MANAGEMENT OF HF. Optimal medical management
of HF is likely to improve SDB (23). This should
include the appropriate use of diuretic agents, which
also may reduce the nocturnal rostral fluid shift that
can exacerbate both OSA and CSA, and disease-
modifying drug therapy for HFrEF. Cardiac resynch-
ronization therapy for patients with reduced ejection
fraction and a broad QRS complex significantly re-
duces CSA (but not OSA) (143).
POSITIVE AIRWAY PRESSURE IN HF. In a RCT of 55
patients with HF and OSA, nocturnal CPAP for
3 months improved LV ejection fraction and reduced
urinary norepinephrine excretion (144).
improved right ventricular function, LV mass, and
Cowie et al. 619
Sleep Disordered Breathing and CV Disease
pulmonary hypertension after 3 months of treatment,
from and these improvements persisted at 1 year (145). A
small observational study of CPAP versus medical
therapy for those with HF and moderate or severe
OSA demonstrated a significantly higher rate of hos-
pitalization or death in the non-CPAP group
compared with those treated with CPAP (146). Pa-
tients who were not compliant with CPAP also had a
higher risk of the composite endpoint. Two other
large registry studies found similar results (147,148).
More robust data will emerge from a randomized
trial of an adaptive servoventilation (ASV) device in
patients with HFrEF and SDB (149). ASV increases
inspiratory support during hypopnea, withdraws
support during hyperventilation, provides mandatory
breaths during apnea, and generates background
positive airway pressure. It is therefore effective in
both CSA and OSA (150).
Early trials of CPAP in CSA with HF reported an
improvement in AHI, reduced daytime plasma natri-
uretic peptide and catecholamine concentrations, and
improved LV ejection fraction. A larger RCT was
designed to evaluate the effect of CPAP on transplant-
free survival in patients with CSA and HF (151).
Although CPAP improved the AHI, LV ejection frac-
tion, 6-min walk test distance, and reduced plasma
norepinephrine concentrations, there was no differ-
not
ence in transplant-free survival over 2 years’ follow-up
in 258 patients. Post hoc subgroup analysis suggested
that there was a survival advantage in those in whom
the AHI was suppressed to <15/h by the CPAP (152).
In small RCTs, beneficial effects of ASV treatment
of CSA-CSB in HF patients include significant re-
ductions in AHI, plasma NT-proBNP, and urinary
not
catecholamine concentrations, and LV end-systolic
diameter, increases in 6-min walk distance and LV
ejection fraction, and improved New York Heart As-
sociation (NYHA) functional class (151,152). However,
the SERVE-HF (Treatment of Predominant Central
Sleep Apnoea by Adaptive Servo Ventilation in Pa-
tients With Heart Failure) trial, a large RCT to assess
the impact of ASV on hospitalization, life-saving
cardiovascular intervention, or death in those with
HF and CSA in patients with a LV ejection
fraction #45% and moderate-to-severe CSA reported
no difference between the 2 groups, despite a
powerful effect on AHI (95). Surprisingly, there was a
higher all-cause (and CV) mortality in those treated
with ASV, largely driven by an increase in sudden
death (153). Various explanations have been proposed
including a direct toxic effect of ASV on patients with
poor LV function and a low pulmonary capillary
CPAP wedge pressure; or that CSB may be at least partially
adaptive for patients with severe HF (154). Further
620 Cowie et al.
Sleep Disordered Breathing and CV Disease
data will emerge from the subgroup of patients with
CSA in the ADVENT-HF (Effect of Adaptive Servo
Ventilation [ASV] on Survival and Hospital Admis-
sions in Heart Failure) study (149). In the meantime,
the use of ASV (or perhaps other airway pressure
therapies) for the treatment of predominantly CSA in
HFrEF cannot be recommended. It is important to
note that different ASV algorithms may have different
effects on minute ventilation and sleep architecture
(155).
CSA is found in the majority of patients with acute
decompensated HF, is usually severe, and is associ-
ated with an increased risk of readmission and mor-
tality (156). A randomized trial of ASV in this patient
group was initiated, but was terminated after the re-
sults of the SERVE-HF trial became available (157).
Early results suggest that ASV can improve cardiac
diastolic function, improve symptoms, and decrease
plasma BNP concentrations in patients with HF with
preserved ejection fraction and CSA-CSB (158,159). No
adequately powered randomized CV outcome trial
has been undertaken.
OXYGEN THERAPY FOR CSA-CSB. The CHF-HOT
(Chronic Heart Failure–Home Oxygen Therapy) trials
demonstrated a decrease in AHI and an improvement
in LV ejection fraction in those with severe CSA treated
with home oxygen at 3 L/min via an oxygen concen-
trator, at least out to 12 weeks (160). There was also an
improvement in mean NYHA functional class, but no
overall improvement in ventricular ectopy or plasma
catecholamine concentrations. A meta-analysis of 14
studies concluded that oxygen therapy does reduce
overnight desaturations, but prolongs apneas and
hypopneas, at least in OSA (161). A larger randomized
trial, with cardiovascular endpoints, is currently un-
derway (The Impact of Low Flow Nocturnal Oxygen
Therapy on Hospital Admissions and Mortality in Pa-
tients With Heart Failure and Central Sleep Apnea
[LOFT-HF]; NCT03745898).
PHRENIC NERVE STIMULATION FOR CSA. Trans-
venous unilateral phrenic nerve stimulation has been
studied in a trial of 151 patients with predominantly
severe CSA of different etiologies (162). Central apnea
events were nearly eliminated, with residual events
being largely obstructive. Oxygen desaturation
improved, as did daytime sleepiness and quality of
life. Most patients were male, and the randomized
controlled period of follow-up was only 6 months.
The trial was not powered for CV events. Further
JACC VOL. 78, NO. 6, 2021
AUGUST 10, 2021:608–624
studies are ongoing, including a post-marketing reg-
istry (163).
ACETAZOLAMIDE. Two small trials of acetazolamide
have been reported to reduce AHI and improve oxy-
gen saturation in HF and CSA, perhaps due to its
respiratory stimulating properties or its diuretic ac-
tion (164,165). A slightly larger (N ¼ 85) randomized
study addressing the effect of acetazolamide on the
severity of SDB in HF is currently being conducted
(Predicting Successful Sleep Apnea Treatment With
Acetazolamide in Heart Failure Patients [HF-
ACZ]; NCT01377987).
CONCLUSIONS
The diagnosis of SDB should be considered in anyone
with symptoms of daytime sleepiness, fatigue, or
snoring—particularly if they are obese or have a his-
tory of CVD. Weight loss and CPAP therapy are likely
to improve daytime sleepiness and quality of life in
patients with at least moderate OSA, and may help
improve hypertension control and paroxysmal AF.
Randomized trials in patients without sleepiness or
marked nocturnal hypoxemia have not demonstrated
an impact on CV endpoints. CSA is typically found in
patients with HF and/or AF, and although mask-based
therapy can ameliorate the breathing disorder, it has
not been shown to improve CV outcome, and may be
harmful in HFrEF. Better phenotyping and quantifi-
cation of SDB, targeting those at highest CV risk, and
with a broader range of more personalized therapies
show promise in unlocking benefit from diagnosing
and treating the pathophysiological abnormalities
associated with SDB.
FUNDING SUPPORT AND AUTHOR DISCLOSURES
Dr Somers is supported by the National Institutes of Health (NIH)
grants HL65176 and HL134885. Prof. Cowie has had research funding
from and provided consultancy advice to ResMed. Dr Linz’s institu-
tion has received on his behalf lecture fees and/or consulting fees
and/or research grants from Bayer, LivaNova, and Respicardia. Dr
Redline has received grant funding from the NIH and Jazz Pharma;
and has received consulting fees from Jazz Pharma, Eisai Inc, Respi-
cardia Inc, and Apnimed Inc. Dr Somers has served as a consultant for
Jazz Pharmaceuticals, Respicardia, Sleep Number, and Baker Tilly. Dr
Simonds has received research funding from ResMed.
ADDRESS FOR CORRESPONDENCE: Prof. Martin R
Cowie, Cardiology, Royal Brompton Hospital, Sydney
Street, London SW3 6NP, United Kingdom. E-mail:
martin.cowie@kcl.ac.uk. Twitter: @ProfMartinCowie,
@Dominik_Linz, @SusanRedline, @anitaKS1.
JACC VOL. 78, NO. 6, 2021
AUGUST 10, 2021:608–624
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KEY WORDS cardiovascular disease,
diagnosis, prognosis, sleep apnea, treatment