Version October 2024
INTRODUCTION — Obstructive sleep apnea (OSA) is a common sleep-related breathing disorder characterized by repetitive episodes of apnea or reduced inspiratory airflow due to upper airway obstruction during sleep. Patients with OSA are often obese and have an increased prevalence of numerous other cardiovascular risk factors, including hypertension and type 2 diabetes mellitus. Although OSA is two to four times more common in men, relationships of biomarkers of myocardial injury and incident heart failure in relation to OSA appear to be stronger in women than in men [1].
Observational studies have demonstrated a consistent association between OSA and hypertension, coronary heart disease, cardiac arrhythmia, and heart failure. Although most studies have demonstrated these associations independent of the confounding influence of obesity, whether OSA lies directly along the causal pathway or is linked through common comorbidities such as obesity is not always clear in any given patient, and all of these diseases carry multifactorial etiologic risk. However, accumulating evidence also suggests that successful treatment of OSA with continuous positive airway pressure (CPAP) can improve cardiovascular outcomes.
The association between OSA and cardiovascular disease and the potential impact of OSA-specific therapy on cardiovascular outcomes are discussed here. The evaluation and management of sleep-related breathing disorders in patients with heart failure and stroke are discussed separately. (See "Sleep-disordered breathing in heart failure" and "Sleep-related breathing disorders and stroke".)
PATHOPHYSIOLOGY — Patients with OSA experience repetitive episodes of apnea or reduced inspiratory airflow due to upper airway obstruction during sleep. These events are associated with intermittent hypoxemia and possibly hypercapnia and usually provoke an arousal from sleep. The arousal is associated with restoration of upper airway patency and ventilation.
The resulting hemodynamic, autonomic, inflammatory, and metabolic effects of this abnormal breathing and arousal pattern may contribute to the pathogenesis of a range of cardiovascular diseases (figure 1) [2].
OSA is associated with a significant increase in sympathetic activity during sleep, which in turn influences heart rate and blood pressure [3]. Increased sympathetic activity appears to be induced through a variety of different mechanisms, including chemoreflex stimulation by hypoxia and hypercapnia, baroreflexes, pulmonary afferents, impairment in venous return to the heart, alterations in cardiac output, and possibly the arousal response. Endothelial dysfunction may also play a role [4].
CARDIOVASCULAR EVENTS
Clinical evidence — Experimental and population-based data identify OSA as a significant risk factor for cardiovascular disease and support its association with increased cardiovascular morbidity and mortality [5-9]. Observational data in men with severe OSA support the benefit of continuous positive airway pressure (CPAP) treatment on reduction of fatal and non-fatal cardiovascular events [10]. Sex-specific differences have been observed such that with extended cohort follow-up, women had higher Troponin-T levels, greater left ventricular mass index and higher risk of heart failure and death compared with men [1]. Therefore, several clinical trials have been designed to examine the effect of CPAP therapy on cardiovascular events [11-15].
Impact of treatment — While most studies report improvement in sleep-related respiratory events, daytime sleepiness, blood pressure control, and intermediate cardiovascular endpoints, none has unequivocally shown benefits in the reduction of cardiovascular events (eg, cardiovascular mortality, acute myocardial infarction, stroke) as a whole. As examples:
●The Sleep Apnea Cardiovascular Endpoints (SAVE) study is one of the largest multicenter randomized clinical trials to examine the impact of CPAP on cardiovascular outcomes. In SAVE, 2717 patients with moderate to severe OSA and established cardiovascular disease were randomized to CPAP therapy plus usual care or usual care alone (eg, education, risk factor modification) and followed for 3.7 years (ie, secondary prevention) [14]. Despite a reduction in the apnea-hypopnea index from 29 to 3.7 events per hour per night (ie, indicating overall adequate control of OSA), CPAP was not associated with a significant reduction in cardiovascular events (cardiovascular deaths, myocardial infarction, stroke or hospitalizations for heart failure, unstable angina or transient ischemic attack; 17 percent [CPAP] versus 15.4 percent [usual care]). Although the rate of cardiovascular events was slightly improved in those adherent to CPAP (ie, ≥4 hours per night), the benefit was not statistically significant. However, several aspects limited interpretability and generalizability including the exclusion of patients with "sleepy" OSA, patients at high risk of an accident and patients with severe hypoxemia, as well as use of automated oximetry data rather than polysomnography for diagnosis and an overall low adherence rate to CPAP (mean was 3.3 hours per night), which may have lessened the impact of the therapy on the outcome.
●In a similar population of non-sleepy OSA patients, smaller randomized trials reported a similar lack of benefit from CPAP during several years of follow-up in 725 patients with OSA who did not have established cardiovascular disease (ie, primary prevention), 224 patients who had just undergone coronary revascularization, and 140 patients with recent stroke [11-13].
●Several meta-analyses of randomized trials of patients with OSA, have reported that compared with no treatment or sham, CPAP did not result in a reduction in the risk of major cardiovascular events (acute coronary events, stroke, or vascular death) or all-cause death [15,16]. The lack of benefit was reported despite OSA severity as well as duration of therapy.
Further randomized trials are required to fully elucidate whether or not clinically meaningful cardiovascular benefit can be derived from CPAP in patients with OSA. It also remains unclear whether the "sleepy" OSA patient may derive cardiovascular benefit from OSA treatment and whether considering larger sample sizes with longer duration follow-up may enhance the ability to detect significant cardiovascular benefit.
HYPERTENSION — Hypertension and OSA frequently coexist. OSA-related autonomic dysfunction is evidenced by elevated levels of plasma and urinary catecholamines and also peroneal microneurography [17,18]. It has been well established that OSA is associated with lack of the normal pattern of reduction of blood pressure during sleep (ie, a nondipping blood pressure) [18], even in those with established cardiovascular disease or risk on antihypertensive therapy [19].
Clinical evidence — Approximately 50 percent of patients with OSA have coexisting hypertension, which is often most elevated in the morning. Similarly, patients with resistant hypertension have a very high prevalence of OSA (see "Definition, risk factors, and evaluation of resistant hypertension", section on 'Obstructive sleep apnea'). Cross-sectional population-based studies consistently find an increased prevalence of hypertension in patients with OSA, compared with controls, which remains significant after controlling for potential confounding factors such as age and obesity [5,20-24]. The association between hypertension and OSA has been noted across a variety of patient groups, including the general adult population, older adult patients [25], those with spinal cord injury [26], and stroke survivors [27].
Prospective longitudinal studies have also demonstrated an increased risk of incident hypertension in patients with OSA who are normotensive at baseline [5,28], although this finding has not been entirely consistent [29,30]. Most studies support a monotonic, dose-response effect between the severity of OSA and the likelihood of hypertension [5,20-25]. As an example, a prospective epidemiologic cohort study of 709 subjects estimated that patients with mild OSA (apnea hypopnea index [AHI] of 5 to 15 events per hour of sleep) had twice the risk of newly identified incident systemic hypertension, compared with those with an AHI of 0 (adjusted odds ratio 2.03, 95% CI 1.29-3.17), while subjects with an AHI of ≥15 events per hour of sleep had nearly three times the risk (adjusted odds ratio 2.89, 95% CI 1.46-5.64) (figure 2) [5]. Another large study found that OSA was only modestly associated with incident systolic hypertension after adjusting for relevant confounders [30]. However, those with a body mass index of <27 kg/m2 and a severe burden of apnea had an almost threefold higher odds of incident hypertension.
Some studies have also found that OSA is not as strongly related to isolated systolic hypertension as it is to isolated diastolic or combined systolic/diastolic hypertension [31]. Others have found that the severity of OSA during rapid eye movement (REM) sleep is more strongly associated with both prevalent and incident hypertension than OSA severity during non-REM sleep [32].
Observational data examining the natural history of the effect of continuous positive airway pressure therapy (CPAP) on incident hypertension suggest a benefit of OSA treatment. As an example, a prospective epidemiologic cohort study that followed 1889 individuals for a median of 12 years identified an increased risk of incident hypertension among those with OSA untreated with CPAP due to refusal (adjusted hazard ratio [HR] 2.0), nonadherence (HR 1.8), or ineligibility (HR 1.3), compared with controls; patients with OSA treated with CPAP had a lower risk of incident hypertension, compared with controls (HR 0.7) [28].
The association between OSA and hypertension appears to be particularly prominent in patients with resistant hypertension. In one study, OSA was found in 71 percent of patients with resistant hypertension, compared with 38 percent of patients with controlled systemic hypertension [33]. In another study, severe compared with moderate OSA in those with increased cardiovascular risk was associated with increased blood pressure despite use of an intensive antihypertensive regimen [34]. (See "Definition, risk factors, and evaluation of resistant hypertension", section on 'Obstructive sleep apnea'.)
Impact of treatment — Randomized trials and meta-analyses have found that effective treatment of OSA using positive airway pressure reduces systemic blood pressure, regardless of whether the patients are hypertensive at baseline [35-46].
Four key observations can be made on the basis of these trials:
●First, the reduction in systemic blood pressure due to positive airway pressure therapy is usually small, albeit clinically relevant. In a 2014 meta-analysis that included 30 randomized trials and over 1900 patients, CPAP therapy was associated with a mean net lowering in systolic blood pressure of 2.6 mmHg [47]. The clinical relevance of this level of reduction is highlighted by data demonstrating that a 1 to 2 mmHg reduction in blood pressure is associated with a reduction in major cardiovascular events, stroke, and heart failure [48].
In a large, randomized trial of 194 patients with resistant hypertension, those randomized to CPAP had a greater reduction in 24-hour mean blood pressure (3.1 mmHg) and 24-hour diastolic blood pressure (3.2 mmHg), but not 24-hour systolic blood pressure (3.1 mmHg, 95% CI -0.6-6.7), compared with those who did not receive CPAP [49]. A meta-analysis using patient-level data from eight randomized trials also found that the presence of uncontrolled hypertension at baseline was an important predictor of reduction in blood pressure with CPAP therapy, independent of OSA severity [50].
●Second, the reduction in systemic blood pressure due to positive airway pressure therapy appears to be less than that due to antihypertensive medication. In a randomized crossover trial of 23 patients with both untreated hypertension and untreated OSA, antihypertensive medication (valsartan 160 mg per day) lowered mean 24-hour blood pressure significantly more than CPAP therapy (-9 versus -2.1 mmHg) [51]. Moreover, for patients whose blood pressure was not controlled with CPAP or valsartan, an extended trial of treatment that combined the two therapies showed further significant reduction in blood pressure.
●Third, although the finding that positive airway pressure therapy reduces systemic blood pressure has been fairly consistent, findings have not been universal [52-56]. The conflicting results may be related to methodological differences among the trials, including different study populations, co-interventions, CPAP adherence rates, sample sizes, outcome measures (single time point or 24-hour blood pressure), and durations of follow-up. Some of the more common or important methodological differences include the following:
•Use of antihypertensive medications – Studies have differed in terms of whether antihypertensive medications were allowed during the study and, if so, how they were initiated, maintained, or discontinued [57]. Studies have also differed in terms of how antihypertensive therapy was accounted for in the analysis, which may contribute to the conflicting results.
•Excessive daytime sleepiness – Most studies are comprised primarily of OSA patients with excessive daytime sleepiness. In those that have evaluated patients without excessive daytime sleepiness, most have found no reduction in the blood pressure or incidence of hypertension following the initiation of CPAP [11,53,55,58]. One trial found only a small reduction in the diastolic blood pressure and may have been confounded by the inclusion of patients with OSA-related sleepiness that was not severe enough to be defined as excessive daytime sleepiness [59]. Taken together, these trials suggest that blood pressure reduction achieved by CPAP therapy is less in non-sleepy patients than in sleepy patients [57].
•OSA severity – The decrease in blood pressure in response to treatment with CPAP has been shown to be related to the severity of sleep apnea (as measured by the degree of nocturnal hypoxemia), with a greater decrease in blood pressure among those with more severe OSA [35]. The severity of hypoxemia varies among studies and may influence the results.
•Follow-up duration – Most trials have performed follow-up assessments at two to three months. However, a randomized trial of 83 males with moderate to severe OSA, coronary heart disease, and verified hypertension showed a reduction in systolic blood pressure, but not diastolic blood pressure, compared with controls over a median follow-up period of 36 months [60]. These results support a long-lasting benefit of systolic blood pressure reduction in patients with moderate to severe OSA treated with CPAP therapy. However, CPAP withdrawal may be associated with a rebound increase in blood pressure [61].
●Fourth, alternative or CPAP-adjunctive approaches to improve blood pressure have also been studied. A multicenter randomized trial in 318 patients with moderate to severe OSA and increased cardiovascular risk demonstrated that CPAP was more effective than supplemental oxygen in reducing 24-hour mean arterial blood pressure (-2.8 mmHg, 95% CI -5.1 to -0.5) [44]. These results suggest that pathways independent of hypoxia play a role in augmentation of blood pressure in OSA. In a per protocol analysis that included those with a prespecified CPAP adherence threshold, another randomized trial demonstrated a more pronounced reduction of mean arterial and systolic pressures with CPAP plus a weight loss intervention, compared with either approach alone [62].
Among the therapies, the impact of positive airway pressure, the most common therapy used for sleep apnea, is the most widely studied [35-40,42,46].
In contrast, the effects of alternative therapies (eg, oral appliances or upper airway surgery) on blood pressure are less well studied but suggest similar benefit [46,63,64]. One meta-analysis of 51 studies of patients with hypertension and obstructive sleep apnea reported that compared with patients on placebo or not receiving therapy, mandibular advancement devices were associated with a significant reduction in systolic blood pressure (SBP; -2.1 mmHg, 95% CI -0.8 to -3.4) and diastolic blood pressure (DBP; -1.9 mmHg; 95% CI -0.5 to -3.2) [46]. In addition, the level SBP and DBP reduction was similar to that reported in patients treated with CPAP.
Taken together, the evidence indicates that treatment of OSA with positive airway pressure reduces systemic blood pressure in many patients. However, the reduction is usually modest and may not occur in patients with longstanding systemic hypertension or without excessive sleepiness. Despite this small reduction, it should be noted that a decrease of only 2 mmHg in blood pressure is enough to significantly reduce cardiovascular risk. Such modest reductions may be attributable to limited ability to reverse vascular pathology in those with chronic exposure to OSA and underscore the notion that early and prolonged OSA treatment may be required as a more effective therapeutic preventative approach.
CORONARY HEART DISEASE — There is increasing evidence that severe (but probably not mild) OSA is associated with an increased risk for cardiovascular events related to coronary heart disease, independent of obesity and other shared risk factors, and that comorbid OSA is a risk factor for worse outcomes in patients with established coronary heart disease. This effect may be mediated by the association between OSA and multiple vascular risk factors, including hypertension, decreased high density lipoproteins [65], increased C-reactive protein [66,67], increased homocysteine [66], elevated blood glucose [68,69], and insulin resistance/diabetes mellitus [68].
Concentrations of high-sensitivity troponin-I have been associated with increasing severity of OSA (defined by the apnea hypopnea index [AHI]) as well as nocturnal hypoxia (percentage sleep time <90 percent oxygen saturation), suggesting that increasing OSA burden may result in low-grade myocardial injury [70]. Subclinical markers of atherosclerosis such as coronary artery calcification, a predictor of major adverse cardiovascular events, have also been associated with increasing OSA severity.
Clinical evidence — The range of cardiovascular morbidity associated with OSA was demonstrated by a large, prospective, cohort study that followed 1651 men for a mean of 10 years following polysomnography [10]. Patients with untreated, severe OSA (mean AHI of 43 events per hour of sleep) had a higher incidence of fatal and nonfatal cardiovascular events than untreated patients with mild-moderate OSA, simple snorers, and healthy participants, even after adjustment for confounding variables. Cardiovascular events included myocardial infarction, acute coronary syndrome, and stroke.
These findings have been supported by numerous subsequent studies that also found an increased risk of cardiovascular events (including mortality) among patients with untreated, severe OSA, compared with patients without OSA [6,7,71-73].It is important to keep in mind that such an association suggests but does not necessarily indicate a causal relationship.
OSA may also exacerbate pre-existing coronary artery disease [74]. In a prospective cohort study, polysomnography was performed on 89 consecutive patients who had undergone a percutaneous coronary intervention for acute coronary syndrome (53 with acute myocardial infarction and 36 with unstable angina) . OSA (defined as AHI ≥10 events per hour of sleep) was detected in 51 patients (57 percent). During a mean follow up of 227 days, the incidence of major adverse cardiac events (cardiac death, reinfarction, target vessel revascularization) was higher among patients with OSA than those without OSA (adjusted hazard ratio [HR] 11.6, 95% CI 2.2-62.2).
While the evidence above supports the association between untreated, severe OSA and the development of adverse cardiovascular events (eg, myocardial infarction, acute coronary syndrome), the reverse may also be true; that is, myocardial infarction may be associated with worsening of sleep-disordered breathing. This was demonstrated by a prospective cohort study of 2721 individuals (mean age 62 years) without known cardiovascular disease who were followed for a mean of five years, which included polysomnography performed at baseline and at five years [75]. Fifty-seven subjects (2 percent) had a myocardial infarction during the study. The adjusted AHI increased a mean of 6.37 respiratory events per hour of sleep among those who had a myocardial infarction, compared with only 2.71 respiratory events per hour of sleep among those who had not had a myocardial infarction. It was not determined whether the increased respiratory event rate among individuals who had a myocardial infarction only was due to an increase in obstructive events, central events, or both, although, among patients who developed either a myocardial infarction or heart failure, the rates of both obstructive and central respiratory events increased.
Impact of treatment — Observational data suggest that treatment of OSA with positive airway pressure may reduce the incidence of cardiovascular events, including events related to coronary artery disease [10,74,76,77]. Some of the larger studies supporting this effect include the following:
●A prospective cohort study followed 1651 men for a mean of 10 years following polysomnography [10]. Patients with OSA who were treated with CPAP (mean AHI of 42 events per hour of sleep prior to therapy) had a lower incidence of fatal and nonfatal cardiovascular events than patients with untreated, severe OSA (mean AHI of 43 events per hour of sleep). In fact, the incidence of fatal and nonfatal cardiovascular events among patients treated with CPAP did not differ significantly from that in individuals without OSA. Cardiovascular events included myocardial infarction, acute coronary syndrome, and stroke.
●A prospective cohort study followed 449 patients with mild or moderate OSA for a median of six years [76]. Treatment of OSA (primarily CPAP) was associated with a reduction of the likelihood of a cardiovascular event (adjusted HR 0.36, 95% CI 0.21-0.62), compared with no treatment. Cardiovascular events were defined as myocardial infarction, stroke, or acute coronary syndrome requiring a revascularization procedure. An important limitation of this study was that combining patients with mild and moderate OSA made it impossible to determine whether treatment benefited only patients with moderate OSA, mild OSA, or both.
A limitation of these studies is the nonrandomized design and the possibility that those who were not adherent with CPAP represent a group at increased cardiovascular risk due to engaging in unhealthy lifestyle behaviors or nonadherence with other aspects of their medical care.
The potential benefit of OSA therapy on reducing cardiovascular events has not yet been confirmed in randomized trials. For the most part, randomized trials of positive airway pressure therapy in patients with OSA have been short-term studies that have not measured endpoints related to coronary heart disease. One exception was a multicenter randomized trial in which 725 patients without a history of cardiovascular events who had moderate to severe OSA (AHI ≥20 events per hour) and no daytime sleepiness (Epworth sleepiness scale [ESS] score ≤10) were randomly assigned to receive CPAP therapy or no active intervention [11]. After a median follow-up of four years, there was no significant difference in the rate of systemic hypertension or cardiovascular events (including nonfatal myocardial infarction, nonfatal stroke, transient ischemic attack, hospitalization for unstable angina or arrhythmia, or cardiovascular death) in patients treated with CPAP, compared with controls (incidence density ratio 0.83, 95% CI 0.63-1.1). A post-hoc analysis suggested that CPAP therapy did reduce hypertension and cardiovascular events in those patients who adhered to CPAP for at least four hours per night.
ATRIAL FIBRILLATION — A strong association (up to fourfold higher odds) between OSA and atrial fibrillation (AF), independent of obesity and other confounding influences, has been described in multiple studies, and limited observational data suggest that OSA may be a modifiable risk factor for recurrent AF after cardioversion or ablation.
Several pathophysiologic features of OSA provide a basis of biologic plausibility for atrial arrhythmogenesis, including: autonomic dysfunction and hypoxia [78], hypercapnia (particularly the recovery phase), and exaggerated negative intrathoracic pressures leading to increased juxtacardiac and transmural pressures affecting the thin-walled atria.
Clinical evidence — Cross-sectional and case-control studies have found an increased prevalence of AF in patients with OSA, compared with controls or the general population [79-81], although this finding has not been universal [82]. In a study that included 400 patients with moderate to severe OSA, the prevalence of AF on 24-hour Holter monitoring was 3 percent, which was approximately threefold higher than the expected prevalence in the general population. In another large, cross-sectional study, there was an increased prevalence of AF in patients with and without sleep-disordered breathing by polysomnogram (5 versus 1 percent), which was independent of age, sex, body mass index, and prevalent cardiovascular disease including heart failure (odds ratio 4.0, 95% CI 1.0-15.7) [79].
Dose-response relationships have been observed in a cohort of nearly 3000 older men, with increasing severity of sleep-disordered breathing associated with increasing prevalence of AF [83]. Such findings were more pronounced with central versus obstructive sleep apnea. Although not definitive, support for an immediate causal temporal relationship of respiratory events (mainly hypopneas) preceding paroxysms of AF has been demonstrated using a case crossover design [84]. These findings suggest that discrete episodes of upper airway compromise may lead to proximate arrhythmia generation.
Conversely, the prevalence of OSA in patients with AF is much higher, with estimates ranging from 30 to 80 percent [80,85]. Most, but not all, studies have found that the association is independent of shared risks factors such as increased age, obesity, hypertension, and heart failure. (See "Epidemiology, risk factors, and prevention of atrial fibrillation", section on 'Obstructive sleep apnea'.)
Several studies have examined the relationship between OSA and the risk of incident AF. In a large clinic-based cohort, nocturnal hypoxia predicted a threefold increased risk of incident AF in those less than 65 years of age, even after adjustment for confounding by obesity [86]. Another retrospective cohort study of nearly 7000 middle-aged adults demonstrated that those with an AHI >5 had a 55 percent increased risk of incident AF over a median follow-up period of 12 years [8]. Prospective data involving older men support an approximate twofold increase in odds of AF associated with baseline central sleep apnea or Cheyne-Stokes respirations over a 6.5-year mean follow-up period [79].
Accumulating data implicate OSA as a risk factor for recurrent AF after cardioversion or ablation. In a meta-analysis of six observational studies, a diagnosis of OSA increased the risk of recurrent AF after radiofrequency catheter ablation by 25 percent [87].
Impact of treatment — Whether treatment of OSA improves AF burden and outcomes is unclear. Three meta-analyses have been conducted which identify that OSA is associated with greater risk of AF recurrence after catheter ablation, that CPAP confers a 42 percent reduction in AF recurrence, and that untreated OSA is associated with a 57 percent increased risk of AF recurrence [88-91]. However, a small, randomized trial of non-sleepy patients with mild OSA (apnea hypopnea index [AHI] >5) and AF following cardioversion identified no reduction in AF recurrence with CPAP [92]. Another trial of minimally symptomatic patients with moderate to severe OSA (AHI >15), also identified no difference in three-month AF burden with CPAP compared with supportive care [93]. (See "Atrial fibrillation: Catheter ablation", section on 'Prevention of recurrence'.)
OTHER ARRHYTHMIAS
Clinical evidence — OSA is associated with nocturnal cardiac arrhythmias. The bradycardia-tachycardia phenomenon may be observed with respiratory events (apneas and hypopneas). During the apnea, there is absence of ventilation and hypoxic stimulation of the carotid body is vagotonic, resulting in bradycardia. Subsequent to the respiratory event, sympathetic activation occurs due to synergistic influences of hypoxia, hypercapnia, and increasing thoracoabdominal efforts resulting in tachycardia. Although it is unknown whether or not the relationship is causal, there may be a temporal relationship, with arrhythmias occurring more frequently after a respiratory event [84]. Arrhythmogenesis is also enhanced in OSA due to intermittent hypoxia, which may result in delayed depolarization, respiratory acidosis resulting in triggered automaticity, and re-entrant mechanisms likely due to autonomic nervous system fluctuations.
Although conduction delay arrhythmias including atrioventricular block and sinus pauses have been highlighted in older reports and anecdotally observed in OSA, multicenter epidemiologic data do not demonstrate a significant association of OSA and these arrhythmias compared with those with lesser degree or without OSA [94]. As these bradyarrhythmias are likely more pronounced in severe OSA, older reports may reflect historical case finding selection bias during a time when primarily severe cases of OSA were detected and diagnosed. For example, bradyarrhythmias, including atrioventricular (AV) block, sinus pause, and asystole, occur in up to 18 percent of patients with severe OSA (ie, apnea hypopnea index [AHI] >30 events per hour) and lower oxygen saturation nadirs during sleep [95]. Bradyarrhythmias anecdotally appear to be more common during rapid eye movement (REM) sleep due to enhanced parasympathetic tone. In extreme cases, asystole can last longer than 10 seconds. The contribution of asystole to the increase in mortality associated with OSA is unclear. (See "Permanent cardiac pacing: Overview of devices and indications".)
Bradycardia and asystole in patients with OSA may result from enhanced vagal tone, structural disease of the conduction system, or both [96]. In one study, 15 patients with OSA and asystole who underwent electrophysiology exams all had normal (or only slightly abnormal) sinus and AV node function [97]. Activation of the parasympathetic nervous system may result from hypoventilation, hypoxemia, respiratory acidosis, or repeated intrathoracic pressure changes due to airway obstruction during sleep.
Ventricular ectopy and tachyarrhythmias have also been associated with OSA [98]. In an observational study, 228 patients with a sleep-related breathing disorder (respiratory disturbance index [RDI] ≥30 events per hour of sleep) were compared with 338 control subjects (RDI <5 events per hour of sleep) [79]. The sleep-related breathing disorder group had a higher prevalence of nocturnal atrial fibrillation (AF; 4.8 versus 0.9 percent), nonsustained ventricular tachycardia (5.3 versus 1.2 percent), and complex ventricular ectopy (25 versus 14.5 percent). These relationships persisted after adjustment for confounding variables. Examples of complex ventricular ectopy include nonsustained ventricular tachycardia, bigeminy, trigeminy, and quadrigeminy. In a large cohort of older men, severity of obstructive versus central sleep apnea appeared to be more closely related to ventricular arrhythmias than atrial fibrillation, as did the extent of hypoxia [83].
In a cohort study of more than 10,000 patients that identified nadir oxygen saturation as a predictor of sudden cardiac death (SCD), it is noteworthy that 31 percent of those with SCD had definite ventricular arrhythmia as a verified cause, and ventricular ectopy or nonsustained ventricular tachycardia was an independent risk factor for SCD among those with OSA (hazard ratio [HR] 4.1, 95% CI 1.6-10.1) [99].
The biologic plausibility of the relationship of OSA with clinically significant cardiac arrhythmias is supported by data demonstrating that OSA is associated with QT prolongation corrected for heart rate in patients with congenital long QT syndrome (LQTS), a familial arrhythmogenic cardiac channelopathy associated with prolonged ventricular repolarization [100].
Impact of treatment — Preliminary data support a role for positive airway pressure therapy in abolishing nocturnal ventricular asystole and improving other arrhythmias in patients with OSA [97,101,102].
In a prospective cohort study, a loop recorder capable of monitoring the heart rhythm for 16 months was implanted in 23 patients with moderate or severe OSA [101]. Recording was performed for two months prior to the initiation of continuous positive airway pressure (CPAP) and then for 14 months after initiation of CPAP. Nocturnal ventricular bradycardia or asystole were noted in 47 percent of patients prior to the initiation of CPAP. This decreased by eight weeks. No nocturnal arrhythmias were detected during the final six months. A randomized trial in patients with heart failure and OSA demonstrated a 58 percent reduction in the frequency of ventricular premature beats in patients treated with CPAP, while there was no significant reduction in the control arm [103].
There are several important gaps in our knowledge about the impact of OSA therapy on nocturnal arrhythmias:
●It is unknown whether nocturnal arrhythmia suppression improves mortality.
●Diurnal patterns of arrhythmia burden in relation to OSA require further study.
●There are few data about the impact of therapy on arrhythmias other than ventricular bradycardia or asystole.
●The effect of therapies other than positive airway pressure (eg, oral appliances, pharmacotherapy, surgery, tracheostomy) on nocturnal arrhythmias is unknown.
SUDDEN CARDIAC DEATH — Limited data suggest that severe or untreated OSA may increase risk of fatal cardiac arrhythmias [77,99,104].
A longitudinal study of 107 patients with OSA followed for seven years found that the rate of sudden cardiac death (SCD) was increased in patients who had discontinued positive airway pressure therapy, compared with those who were adherent (7 versus 0 percent) [77]. In the absence of OSA or other sleep disorders, sleep is considered to be cardioprotective, typically associated with a nadir of cardiovascular risk. However, those with OSA appear to have a nocturnal (midnight to 6 AM) predilection to SCD, with an approximately threefold increased risk, compared with the general population and those without OSA [104].
In a large, observational study of over 10,000 individuals referred for diagnostic polysomnography, nearly 80 percent of whom met criteria for OSA, several indicators of OSA severity (nadir nocturnal oxygen saturation, apnea hypopnea index [AHI] of 20 or greater) were associated with increased risk of incident SCD (fatal or resuscitated), although at a much lower magnitude of risk than established factors such as coronary heart disease, cardiomyopathy, and heart failure [99]. Nadir SpO2 was the only independent sleep-disordered breathing predictor of SCD in the multivariate model. (See "Overview of sudden cardiac arrest and sudden cardiac death".)
HEART FAILURE — Sleep-disordered breathing, which includes both OSA and central sleep apnea, is commonly observed in patients with heart failure, with a prevalence of 50 to 75 percent in those with reduced ejection fraction. OSA may be underdiagnosed in this population since typical symptoms of heart failure, such as nocturnal dyspnea and nocturia related to diuretics, may be ascribed to heart failure when they actually represent signs and symptoms of OSA. The pathophysiology of sleep-disordered breathing and heart failure involves a variety of mechanisms including obstructive apneas which increase left ventricular transmural pressures in response to increasingly negative intrathoracic pressure. This results in reduction of left ventricular preload and increased afterload [105]. Neurohumoral effects involve pulmonary congestion which stimulates pulmonary vagal irritant receptors resulting in hyperventilation and elicitation of central apnea [105]. Rostral neck edema is an important factor in both obstructive and central apnea generation in heart failure [106]. Sleep-disordered breathing is important to recognize since its presence is a negative prognostic factor, and treatment can improve heart failure-related outcomes such as left ventricular ejection fraction, walk distance, and catecholamine levels [107]. Although treatment with continuous positive airway pressure (CPAP) may be beneficial in those with central sleep apnea (CSA) [108], those with systolic heart failure (ejection fraction ≤45 percent) and OSA treated with adaptive servo-ventilation (ASV) versus standard medical management have increased all-cause and cardiovascular-specific mortality, such that ASV is avoided in this population [109,110]. This is discussed separately. (See "Sleep-disordered breathing in heart failure".)
OSA may itself be a risk factor for incident heart failure and for recurrence of heart failure after an episode of acute cardiogenic pulmonary edema [7,73,111,112]. This was suggested by a prospective cohort study of 1927 men and 2495 women without baseline heart failure who were followed for a median of 8.7 years after baseline polysomnography [7]. Among men, OSA appeared to be associated with an increased risk of developing heart failure, even after adjustment for potential confounders. The increased risk appeared to be highest among men with severe OSA (defined as an apnea hypopnea index [AHI] >30 events per hour of sleep), who were 58 percent more likely to develop heart failure than those with an AHI <5. OSA was not associated with heart failure among women; however, there may have been an insufficient sample size to detect a significant association. Cohort studies performed since then have shown similar results [73]. CSA and Cheyne-Stokes respirations also increase risk of incident heart failure by approximately 80 percent and twofold respectively in a community-based study of older men [113]. One study of a nationwide database suggested that CPAP may lower the risk of heart failure [112].
PULMONARY HYPERTENSION
Clinical evidence — The prevalence of pulmonary hypertension in patients with moderate to severe OSA is approximately 20 percent [114,115]. When present in patients without coexisting lung disease, the degree of pulmonary hypertension is typically mild. Risk factors for pulmonary hypertension identified in one or more studies include comorbid lung disease, daytime hypoxemia, increasing apnea hypopnea index (AHI), and comorbid obesity hypoventilation syndrome. (See "Clinical manifestations and diagnosis of obesity hypoventilation syndrome".)
The presence of pulmonary hypertension may have prognostic importance in patients with OSA. An observational study of 83 patients with OSA (defined as clinical suspicion plus an AHI >5 events/hour) who underwent pulmonary artery catheterization for unspecified reasons found that one-, four-, and eight-year survival rates were lower among patients with pulmonary hypertension (93, 75, and 43 percent, respectively) than among those without pulmonary hypertension (100, 90, and 76 percent, respectively) [116]. The study defined pulmonary hypertension as a mean pulmonary arterial pressure >25 mmHg at rest. OSA-PH has also been associated with decreased functional capacity and quality of life [117,118]. Data support that nocturnal hypoxia, more so than sleep apnea defined by the apnea hypopnea index, is associated with increased mortality in PH [119].
Impact of treatment — Nasal CPAP, in several studies, has been shown to reduce pulmonary arterial systolic pressure (sPAP) and pulmonary vascular resistance (PVR) in patients with obstructive sleep apnea (OSA) over a period of three to four months [120,121]. In one trial, 23 patients with OSA were randomly assigned to receive therapeutic or subtherapeutic continuous positive airway pressure (CPAP) for 12 weeks [121]. Therapeutic CPAP reduced the estimated pulmonary artery systolic pressure from 29 to 24 mmHg. The extent of reduction was greatest among patients who had OSA plus pulmonary hypertension.
Surgical weight loss in OSA may also result in improved pulmonary hemodynamics . The impact of other therapies (eg, oral appliances, pharmacotherapy, surgery, tracheostomy) on pulmonary hypertension is unknown.
While treatment targeting OSA with positive airway pressure reduces pulmonary arterial systolic pressure in many patients, the reduction is modest, and evidence of improved patient-important outcomes (eg, mortality) is lacking. Therapy directed at the pulmonary hypertension is discussed in detail separately. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy".)
VENOUS THROMBOEMBOLISM — OSA may be a risk factor for venous thromboembolism (VTE). One review of 15 studies reported that OSA may be an independent risk factor for VTE and that the risk may be two- to threefold higher than in those without OSA [122]. The impact of treatment with positive airway pressure is unknown. This is consistent with observation of increased hypercoagulable markers including fibrinogen and plasminogen activator inhibitor-1, which appear to demonstrate diurnal patterning with increases in the morning (after OSA-related overnight physiologic stress) relative to the evening even in those with a milder degree of OSA [94].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sleep-related breathing disorders in adults".)
SUMMARY AND RECOMMENDATIONS
●Definition - Obstructive sleep apnea (OSA) is a disorder characterized by repetitive episodes of apnea or reduced inspiratory airflow due to upper airway obstruction during sleep, despite an increase in respiratory effort. The resulting hemodynamic, autonomic, inflammatory, and metabolic effects of this abnormal breathing and arousal pattern may contribute to the pathogenesis of a range of cardiovascular diseases. (See 'Introduction' above.)
●Impact of OSA therapy on cardiovascular events overall - Although OSA is a risk factor for cardiovascular disease, there is no convincing evidence that treatment of OSA with CPAP is associated with a reduction on cardiovascular events as a whole (cardiovascular mortality, myocardial infarction, stroke). (See 'Cardiovascular events' above.)
●Hypertension - Hypertension and OSA frequently coexist. Evidence that OSA may be a cause of hypertension includes the increased prevalence and incidence of hypertension among patients with OSA, an observed dose-response effect between the severity of OSA and the likelihood of hypertension, and the fact that treatment of OSA can lower blood pressure, albeit modestly, but by levels that are clinically significant. (See 'Hypertension' above.)
●Coronary artery disease - There is increasing evidence that severe (but probably not mild) OSA is associated with an increased risk for cardiovascular events related to coronary heart disease, independent of obesity and other shared risk factors, and that comorbid OSA is a risk factor for worse outcomes in patients with established coronary heart disease. It is not yet clear whether treatment of OSA with positive airway pressure therapy or other modalities can improve outcomes related to coronary heart disease. (See 'Coronary heart disease' above.)
●Atrial fibrillation - Patients with OSA have an increased prevalence of atrial fibrillation (AF), compared with the general population and control subjects, and patients with established AF have a high prevalence of comorbid OSA. Limited observational data suggest that OSA may be a modifiable risk factor for recurrent AF after cardioversion or ablation. (See 'Atrial fibrillation' above.)
●Other arrythmias - OSA has been associated with prolongation of the QT interval in those predisposed to prolonged ventricular repolarization, the latter providing a potential mechanism for the observed sudden nocturnal cardiac death observed in OSA. (See 'Other arrhythmias' above.)
●Heart failure - Sleep-disordered breathing is common in patients with heart failure, and OSA and possibly central sleep apnea (CSA) may be risk factors for incident heart failure in men. Bidirectional relationships are likely at play in terms of these sleep-disordered breathing subtypes and heart failure. (See 'Heart failure' above.)
●Pulmonary hypertension - Pulmonary hypertension is present in approximately 20 percent of patients with moderate to severe OSA and may be associated with decreased survival. (See 'Pulmonary hypertension' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Renaud Tamisier, MD, and J Woodrow Weiss, MD, who contributed to an earlier version of this topic review.
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