Virend K. Somers Sleep, which usually comprises up to a third of our lifetime, is a complex and dynamic physiologic process.1 Rapid eye movement (REM) sleep accounts for approximately 25% of a night of sleep. It is a tonic state punctuated by periods of phasic activity during which autonomic and cardiac functions are erratic.2 Thermoregulation is reduced, and sympathetic neural drive, heart rate, and blood pressure increase. Non–rapid eye movement (NREM) sleep accounts for approximately 75% of sleep. During NREM sleep, in contrast to REM sleep, autonomic and cardiac regulation is stable. Sympathetic neural activity decreases and parasympathetic tone predominates, which decreases the arterial baroreceptor set point, heart rate, blood pressure, cardiac output, and systemic vascular resistance. Because of the predominance of parasympathetic neural tone, it is not unusual for healthy individuals to have sinus bradycardia, marked sinus arrhythmia, sinus pauses, or first-degree and type I second-degree atrioventricular block during sleep. Thus most sleep is quiescent with respect to cardiac function, with the exception being the dynamic changes of phasic REM sleep. The two principal sleep disorders with a recognized impact on cardiovascular function and disease are obstructive sleep apnea (OSA) and central sleep apnea (CSA). OSA is a sleep-related breathing disorder. Its principal feature is upper airway occlusion, which causes partial or complete cessation of air flow. This causes hypoxia and strenuous ventilatory efforts, followed by transient arousal and restoration of airway patency and air flow. This sequence of events can recur hundreds of times nightly. In symptomatic individuals, the condition is called obstructive sleep apnea syndrome. Obstructive apnea is defined as the absence of air flow for at least 10 seconds in the presence of active ventilatory efforts, as reflected by thoracoabdominal movements. Obstructive hypopnea is defined as a decrease of more than 50% in thoracoabdominal movements for at least 10 seconds associated with a decrease of greater than 4% in oxygen saturation. The apnea-hypopnea index (AHI) is the average number of apneic and hypopneic events per hour of sleep, and it is the most common metric used to describe the severity of OSA. OSA is present when the AHI is 5 or higher and is considered severe when the AHI is 30 or higher; however, these figures are essentially arbitrary thresholds created by expert consensus. In the context of cardiovascular disease and risk assessment,3,4 low AHI thresholds are reasonable because clinically important cardiovascular outcomes are associated with an AHI as low as 5 events per hour.2 Individuals with OSA demonstrate increased sensitivity of peripheral chemoreceptors, which results in an increased ventilatory response to hypoxemia during sleep and wakefulness.3 Activation of chemoreceptors also stimulates sympathetic traffic to the skeletal muscle vasculature, which results in peripheral vasoconstriction. During apnea, as hypoxemia worsens, peripheral sympathetic activity increases markedly and blood pressure rises acutely.2 Severe oxygen desaturation may be associated with ventricular ectopy. In some individuals, peripheral sympathetic overactivity may be accompanied by cardiac parasympathetic activation, which results in peripheral vasoconstriction and bradycardia (i.e., the homeostatic “diving reflex” that simultaneously decreases myocardial oxygen demand and increases cerebral and cardiac perfusion).2,3 Even during daytime wakefulness, individuals with OSA have persistently heightened sympathetic activity, partly because of tonic chemoreflex activation. These mechanisms may be manifested clinically by lack of the usual dip in nocturnal blood pressure, drug-resistant hypertension (see Chapters 43 and 44), automatic tachycardias driven by sympathetic activity, and profound nocturnal bradycardias caused by cardiac vagal activity. Common nocturnal arrhythmias, such as marked sinus arrhythmia and second-degree atrioventricular block (Mobitz type I), are exacerbated, and higher-degree conduction abnormalities, such as long sinus pauses and advanced atrioventricular block, may occur transiently (see Chapters 34 and 37).2–4 The chronically elevated sympathetic activity results in increased resting heart rates, decreased heart rate variability, and increased blood pressure variability. In conjunction with structural heart disease or heart failure, this may have prognostic implications. The true prevalence of OSA in the population is unknown because most people with OSA have not undergone polysomnography and the condition remains undiagnosed. Population-based studies estimate that one in five middle-aged Western adults with a body mass index (BMI) of 25 to 28 kg/m2 have OSA and that 1 in 20 have symptoms of OSA syndrome. OSA is strongly associated with obesity, and there is a direct relationship between BMI and AHI.3 OSA is present in more than 40% of those with a BMI of 30 and is especially common in individuals with a BMI of 40. OSA is also associated with multiple metabolic abnormalities, including abdominal obesity, diabetes, and dyslipidemia, and it is highly prevalent in patients with metabolic syndrome.10 Given its putative roles in predisposing to and exacerbating insulin resistance,10,11 OSA may conceivably contribute to the underlying pathophysiologic process of metabolic syndrome. Indeed, a recent double-blind, placebo-controlled, randomized crossover trial compared 3 months of therapeutic continuous positive airway pressure (CPAP) with 3 months of sham CPAP. CPAP reduced blood pressure, triglycerides, glycated hemoglobin, and total and low-density lipoprotein cholesterol and reduced the frequency of metabolic syndrome.10 OSA is highly prevalent in patients with cardiovascular disease (Table 75-1). Estimates of prevalence may differ geographically according to the BMI of patient populations. Many of these cardiovascular disease associations may be due to the comorbid conditions associated with OSA, namely, obesity and its metabolic consequences, which together increase the risk for organic heart disease. However, observational studies have suggested that OSA itself may lead to incident cardiovascular disease. In a large population sample, the AHI correlated independently and directly with the development of hypertension during a period of 4 years.3 Recent observational data from Spain confirmed that the presence of increasing severity of OSA is accompanied by an increase in incident hypertension and suggested that CPAP therapy lowers the risk for hypertension.12 However, a Spanish multicenter randomized trial of CPAP in nonsleepy patients showed only a trend toward a reduction in incident hypertension or cardiovascular events in the CPAP-treated group.13 Importantly, post hoc analysis of these data suggested that CPAP may reduce incident hypertension or cardiovascular events in those who use it for 4 hours per night or longer. OSA may also be a risk factor for new-onset atrial fibrillation. In 3542 people observed for an average of approximately 5 years after diagnostic polysomnography, nonelderly adults (younger than 65 years) with OSA (AHI = 5) were more likely than those without OSA to have incident atrial fibrillation (Fig. 75-1). The severity of the nocturnal oxygen desaturation was associated with the magnitude of this risk independently of other risk factors for atrial fibrillation, including obesity, hypertension, and heart failure.14 OSA may be present in up to 50% of patients requiring cardioversion for atrial fibrillation, and untreated OSA may increase the likelihood of recurrence of atrial fibrillation after cardioversion3 and even after catheter ablation.15 Emerging evidence has implicated obstructive apnea in the pathophysiologic process and complications of hypertrophic cardiomyopathy.16 Patients with hypertrophic cardiomyopathy and comorbid sleep apnea may be at greater risk for atrial fibrillation.17 Reliable evidence also exists for direct effects of OSA on heart failure.18,19 Interventional studies of CPAP, which can effectively abolish obstructive apnea and hypopnea (see later), have shown increases in the left ventricular ejection fraction.4 OSA may also increase the risk for stroke, myocardial infarction, and death (Fig. 75-2). Data from the Sleep Heart Health Study of more than 6000 subjects suggest that nocturnal desaturation of 4% or greater is independently associated with cardiovascular disease.20 A prospective cohort of 6441 men and women from the same study demonstrated that sleep-related disordered breathing was accompanied by an increase in all-cause mortality and coronary artery disease–related mortality in men aged 40 to 70 years (Fig. 75-3).21 Finally, the unique nocturnal pathophysiology of OSA may be associated with increased risk for nocturnal cardiac events. A retrospective study of 112 individuals who had undergone polysomnography and then experienced sudden cardiac death found that those with OSA had a peak in sudden cardiac death during the sleeping hours, which contrasted with the nadir of sudden cardiac death during this period in those without OSA and in the general population (Fig. 75-4).22 Subsequent studies in patients with implanted cardioverter-defibrillators confirmed the nocturnal propensity for arrhythmic events in patients with sleep apnea23 and further suggested that both OSA and CSA increase the overall risk for appropriate device discharge.24 In a prospective study of patients admitted to the hospital for myocardial infarction, those with a nocturnal onset of symptoms had a much greater likelihood of having OSA, thus suggesting that OSA may have triggered the nocturnal myocardial infarction. Overall, patients with myocardial infarction had a high prevalence of OSA, which is frequently underdiagnosed (Fig. 75-5).25 Currently, however, the evidence available does not definitively implicate OSA as an independent cause of cardiovascular events. Interestingly, recent data suggest that incident cardiovascular disease may itself contribute to worsening of sleep-related disordered breathing.26 Figure 75-6 summarizes the pathophysiology of OSA, its possible intermediate cardiovascular disease mechanisms, and its cardiovascular disease associations and risks. TABLE 75-1 Estimated Prevalence of Obstructive Sleep Apnea in Patients with Cardiovascular Diseases
Sleep Apnea and Cardiovascular Disease
Normal Sleep Physiology
Sleep Disorders
Obstructive Sleep Apnea
Definition and Physiology
Pathophysiologic Mechanisms Linking Obstructive Sleep Apnea to Cardiovascular Disease
Obstructive Sleep Apnea and Cardiovascular Disease Associations and Outcomes
CARDIOVASCULAR DISEASE
PREVALENCE (%)
Hypertension
50
Coronary artery disease
33
Acute coronary syndrome
50
Myocardial infarction
60
Heart failure with systolic dysfunction
30-40
Acute stroke
50 
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Sleep Apnea and Cardiovascular Disease
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