Central Sleep Apnea in Congestive Heart Failure: Prevalence, Mechanisms, Impact, and Therapeutic Options

Shahrokh Javaheri, M.D.


Semin Respir Crit Care Med. 2005;26(1):44-55. 

In This Article

Pathophysiological Consequences of Central Sleep Apnea

Periodic breathing is characterized by intermittent decreases and increases in ventilation. Therefore, there are three major adverse consequences of sleep apnea and hypopnea (Fig. 3): (1) intermittent arterial blood gas abnormalities characterized by hypoxemia-reoxygenation and hypercapnia-hypocapnia, (2) arousals and shift to light sleep stages, and (3) large negative swings in intrathoracic pressure occurring in the hypercapnic phase of periodic breathing.[1] These adversely affect various cardiovascular functions and are potentially most detrimental in the presence of established left ventricular systolic and diastolic dysfunction and coronary artery disease.

Pathophysiological consequences of sleep apnea and hypopnea. Pleural pressure (Pp1) is a surrogate of the pressure surrounding the heart and other vascular structures. ↑, increased; ↓, decreased; RV, right ventricle; SVR, systemic vascular resistance; R, right; L, left; vent, ventricle; Pulm, pulmonary. With permission from Javaheri.[1]

The adverse cardiovascular effects of hypoxemia are multiple and include decreased myocardial O2 delivery, activation of the sympathetic nervous system, endothelial cell dysfunction, and pulmonary arteriolar vasoconstriction[1] (Fig. 3).

The pathophysiological importance of hypoxemia-reoxygenation, analogous to ischemia-reperfusion, has recently been recognized. This process, which occurs repetitively in patients with sleep apnea, could promote endothelial cell dysfunction. Coronary endothelial cells play a central role in vasoregulation, coagulation, and inflammation.[43,44] State of blood flow and coagulation is regulated by production and release of vasoactive substances, which include vasodilators and platelet deaggregators (e.g., NO, prostacyclin), and vasoconstrictors and platelet aggregators (e.g., endothelin and thromboxane). The balance between vasoregulatory agents is important in coronary blood flow and state of coagulation under normal and disease states.

Through activation of certain transcription factors such as hypoxia-inducible factor-1 (HIF-1) and nuclear factor (NF) kB,[45,46] hypoxia increases the expression of the number of genes such as those encoding endothelin-1, the most potent vasoconstrictor with proinflammatory properties, vascular endothelial growth factor, and platelet-derived growth factor. Hypoxia also enhances expression of adhesion molecules and promotes leukocyte rolling and endotholial adherence. Importantly, recent studies show that intermittent hypoxia (i.e., hypoxia-reoxygenation)[47,48,49,50,51,52,53,54,55] results in the same effects of sustained hypoxia.

Another important pathological consequence of sleep apnea is increased sympathetic activity during sleep, which has important implications because increased sympathetic activity predicts poor survival in heart failure. Studies have reported that central apnea increases sympathetic activity as measured by microneurography,[56,57] overnight urinary excretion of norepinephrine,[58] and early morning plasma concentration of norepinephrine.[58] One study,[59] which measured sympathetic activity during daytime, also reported a higher activity in patients with central sleep apnea than those without. However, in multiple regression analysis, the main independent variable for increased sympathetic activity was the severity of heart failure, not central apnea. The results of this study do not mean that central sleep apnea is not a cause of increased sympathetic activity in heart failure. First of all, presence of central apnea could have indirectly contributed to the worsening of heart failure, increasing sympathetic activity;[58] but, more importantly, the increased sympathetic activity due to periodic breathing should be most profound during sleep as observed in increased overnight urinary or early morning plasma norepinephrine.[58] Finally, treatment of central sleep apnea with either oxygen or continuous positive airway pressure (CPAP) decreases sympathetic activity (see later), strongly suggesting that central apnea is a cause of sympathetic overactivity in heart failure.

Sleep-related breathing disorders increase sympathetic activity via several mechanisms, but particularly by hypoxic stimulation of the chemosensitive carotid bodies. Central sleep apnea could also contribute to increased sympathetic activity via an increased number of arousals and a lack of thoracoabdominal excursions.

Finally, another pathophysiological consequence of central apnea that adversely affects cardiac function is development of negative intrathoracic pressure, which occurs during hyperpnea following a central apnea. Particularly in the face of stiff lungs and chest wall due to heart failure, negative intrathoracic pressure becomes pronounced during the the hyperpnea phase of periodic breathing. The increased negative intrathoracic pressure increases the transmural pressure (pressure inside minus pressure outside) of the intrathoracic vascular structures, including the left ventricle, aorta, and pulmonary vascular bed (Fig. 3). According to Laplace's law, left ventricular wall tension is directly proportional to transmural pressure. Therefore, the increased negative pressure increases the wall tension (afterload) and oxygen consumption of the left ventricle. In regard to pulmonary vascular bed, negative pulmonary interstitial pressure should promote pulmonary edema, which is also a common occurrence in heart failure. I must emphasize that negative defections in intrathoracic pressure are generally more pronounced in obstructive than in central sleep apnea. However, even changes in intrathoracic pressure could be pathologically important to the failing heart, which is so sensitive to small increases in afterload.


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