Sleep-Disordered Breathing and Arrhythmias

Pathophysiology

OSA is characterized by the failure of neuromuscular mechanisms governing upper airway patency during sleep, resulting in airway narrowing or collapse. Although apnea can occur in any position, the upper airway is more vulnerable to obstruction in the supine position because of dorsal displacement of the tongue and soft tissues. Upper airway collapse can occur during any stage of sleep, but susceptibility is greatest during rapid eye movement (REM). Heralded by atonia of skeletal muscles, including that of the pharynx and upper airway but excluding the respiratory diaphragm and extraocular muscles, REM occurs cyclically (four to six times) throughout sleep and accounts for about 25% of total sleep time. Of potential pathophysiologic importance in arrhythmogenesis, REM is a state of autonomic instability marked by surges in both sympathetic and vagal activity, with attendant variations in heart rate, blood pressure, and peripheral vascular resistance.

Obstructive disordered breathing events are repetitive, numbering in the hundreds per night in extreme cases. Each is associated with oxyhemoglobin desaturation followed by a central nervous system (CNS) arousal, thereby reestablishing upper airway patency with resumption of ventilation and subsequent reoxygenation. Associated with each repetitive cycle is a cascade of acute stressors, including, among others, hypoxemia, surges in sympathetic neural output, production of reactive oxygen species, and fluctuations of intrathoracic and cardiac pressures. The relevance of these acute pathophysiologic changes to specific arrhythmia syndromes is discussed later.

Diagnosis of OSA is made using attended in-lab multichannel polysomnography. These data generate the apnea-hypopnea index (AHI), which is the average number of apneas and hypopneas per hour of sleep. The AHI is the traditional composite measurement of OSA severity, but it does not directly quantify other processes that are operative in the pathophysiology of cardiovascular disease, which correlate better with the burden of oxygen desaturation. Standard polysomnography does not assess sleep-related blood pressure changes, and evaluation of electrocardiographic (ECG) changes are limited and usually based on a single-lead tracing. Ongoing investigations explore the use of technological advances to achieve a more comprehensive assessment of sleep apnea, which would allow for the development of a sleep apnea severity index that better reflects the pathophysiologic links between sleep apnea and arrhythmias. Such investigations are particularly important in the context of the suboptimal results of recent large randomized trials, which primarily relied on the traditional diagnostic and treatment algorithms based on the AHI.

The diagnosis of OSA is increasingly made using home sleep testing, which is appropriate for patients with a high pretest probability of the disorder but without underlying cardiopulmonary disease. In those with heart failure, chronic obstructive pulmonary disease (COPD), or suspicion for an underlying hypoventilation syndrome (such as neuromuscular disease), in-lab polysomnography remains the standard test.

Epidemiology and Clinical Features

The best available data from population-based studies that used polysomnographic monitoring in adults provide estimates of the prevalence of OSA to be between 3% and 28%. Men, in part because of truncal distribution of adipose tissue and muscle, have a higher risk for OSA than women, but the sex prevalence gap narrows after menopause. Age, obesity, and increased neck circumference are additional strong risk factors for OSA. Updated data from the Wisconsin Sleep Cohort show that rates of moderate to severe OSA have increased by as much as 50% over the past two decades. There has been increased recognition of the importance of screening for OSA in patients with arrhythmias: The documented prevalence of OSA in patients with AF rose from 1% in 2005% to 16% in 2015, but the actual prevalence of OSA in AF patients may still be markedly greater, likely nearing 50%, especially in regions with a high prevalence of obesity.

Excessive daytime sleepiness, a result of frequent nocturnal central nervous system arousals, is the most important symptom of OSA and a potential contributor to motor vehicle accidents. Nevertheless, fewer than 25% of individuals with OSA actually report excessive sleepiness; and it is likely that subjective reporting underrepresents the true symptomatic burden of OSA. AF patients, in particular, manifest a poor correlation between daytime sleepiness and sleep apnea presence and severity. Other typical signs and symptoms of OSA include loud snoring, interrupted and unrefreshing sleep, and headache and dry mouth upon awakening. A most helpful and specific sign is provided by a bed partner who witnesses pauses in breathing.

Pathophysiology

CSA is characterized by the loss of ventilatory output from the central respiratory generator in the brainstem, resulting in interruptions of respiratory muscle output that lead to apneas and hypopneas. Generally, the maintenance of upper airway patency distinguishes CSA from OSA; however, the conditions may coexist. CSA is broadly composed of a few heterogeneous disorders, such as high-altitude periodic breathing, idiopathic CSA, and some hypoventilation syndromes. The most common and studied form of CSA is Cheyne-Stokes respiration (CSA-CSR), which is most often encountered in the setting of heart failure and manifests as a characteristic waxing and waning periodicity of ventilation.

CSA-CSR reflects derangements in ventilatory control mechanisms caused by the hemodynamic consequences of left atrial hypertension and decreased cardiac output (usually because of left ventricular [LV] dysfunction). Partly because of irritant receptor stimulation by pulmonary microvascular congestion, heart failure patients chronically hyperventilate, resulting in low blood carbon dioxide tensions during wakefulness. The relative hypocapnia, together with a heightened chemoreflex response to carbon dioxide and prolonged circulation time, destabilize the ventilatory control system during sleep and result in CSA-CSR. As would be expected by these mechanisms, inhalation of a carbon dioxide–enriched gas abolishes CSA.

CSA-CSR, like OSA, is diagnosed by multichannel polysomnography and is quantified by the central AHI. The characteristic waxing and waning pattern of ventilation, which may also be seen during wakefulness, is most prominent during non-REM sleep and is characteristically absent during REM sleep, where cortical influences on ventilation often override the chemoreflex. Similar to OSA, CSA-CSR is associated with repetitive cycles of acute stressors, including hypoxemia, sympathetic activation, and fluctuations in heart rate and blood pressure. In contrast to OSA, the influence of these processes on cardiovascular outcomes, including arrhythmias, has been relatively unexplored. Some data suggest that CSA-CSR contributes to worse cardiovascular outcomes beyond what is attributable to the accompanying heart failure. Nevertheless, recent data showing increased mortality in heart failure patients who received state-of-the-art CSA-CSR therapy lend pause to any certainty regarding these complex relationships. What is known regarding the effect of CSA-CSR on specific arrhythmia syndromes is described in subsequent sections.

Epidemiology and Clinical Features

The prevalence of CSA-CSR in the general population or in unselected individuals with LV dysfunction is unknown. In two studies of more than 500 patients with predominantly New York Heart Association (NYHA) class II heart failure and an average LV ejection fraction (EF) of about 25%, the prevalence of sleep apnea identified using polysomnography was between 33% and 40%. ^, The prevalence of CSA-CSR increases directly with the severity of heart failure. Like OSA, age and male sex increase the risk for CSA-CSR, with narrowing of the gender gap after menopause.

It is unclear if CSA-CSR results in symptoms independent of those related to the underlying cardiac condition. Nocturnal dyspnea attributable to cardiac dysfunction may also be explained by the hyperpneas of CSA-CSR. Despite the fact that CSA may coexist with OSA, symptoms of sleepiness referable to OSA are notably absent in individuals with heart failure.