On Keeping an Eye on the Right Ventricle in Sleep Apnea

Alfred P. Fishman, M.D.

University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

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Cyclic swings in the composition of alveolar air and systemic arterial blood, ranging between normoxia and hypoxia occasionally accompanied by hypercapnia, are a regular feature of the sleep apnea syndrome (1). The systemic consequences of the abnormal blood gases, for example, hypertension and heightened sympathetic and increased mortality from cardiovascular disease, have been extensively documented. Much less is known about the effects of sleep-disordered breathing on the pulmonary circulation.

The effects on the pulmonary circulation of the abnormal blood gases are of clinical interest because they can elicit pulmonary hypertension, which, in turn, can overload the right ventricle causing it to hypertrophy and even to fail. The effects are also of physiological interest because they can be related to the large number of studies during the past 50 yr of the effects of hypoxia and hypercapnia on the pulmonary circulation (1).

Unfortunately, study of the pulmonary circulation in patients with sleep apnea is no simple matter. Direct measurements by cardiac catheterization are invasive and are apt to be prolonged; noninvasive technologies, such as echocardiography, are still being upgraded. Moreover, the hypoxia-normoxia cycles under scrutiny can vary considerably from patient to patient with respect to depth, frequency, and duration. Finally, there are few relevant animal models for reference.

Guidry and coworkers (pp. 933-938) resorted to two- dimensional (2D) and M-mode transthoracic echocardiography to examine right ventricular structure and function in patients with disordered breathing during sleep (2). In principle, right ventricular hypertrophy would reflect overload on the right ventricle imposed by pulmonary hypertension. At issue was whether the intermittent hypoxia that accompanied sleep apnea would cause right ventricular hypertrophy, a surrogate marker of persistent pulmonary hypertension. Unfortunately, the use of transthoracic echocardiography to estimate ventricular wall thickness coupled with measures of time spent at low oxygen saturation as a gauge of hypoxia did not address this question directly. However, the study did disclose that the patients with more severely disordered breathing had slightly but significantly greater thickness (0.1 m difference) of the right ventricular wall.

This finding of only a minimal increase in thickness automatically raises two questions: What was the accuracy, sensitivity, and reproducibility of the measurements of cardiac wall thickness by 2D and M-mode echocardiography? And to what extent did obesitya common occurrence in patients with sleep apneahandicap the transthoracic echocardiographic evaluation of right ventricular wall thickness?

Current understanding indicates that hypoxia rather than hypercapnia is the predominant driving force for pulmonary hypertension even though hypercapnia, presumably by way of the acidosis that it evokes, may play a supporting role (1). Thus, it has long been known that acute hypoxia, as occurs cyclically in sleep apnea, increases pulmonary arterial pressure, and that return to normoxia reverses this increase.

Chronic hypoxia is a different matter. In native residents at high altitude who spend their lives at levels of oxygenation similar to those reached during sleep apnea, pulmonary hypertension is unremitting and exaggerated by the activities of daily life. The peripheral muscular pulmonary arteries and arterioles undergo remodeling. Right ventricular hypertrophy is the rule but remains asymptomatic unless hypoxia reaches intolerable levels due to either chronic lung disease or sustained alveolar hypoventilation; for example, Monge's disease. Only then is the right ventricular hypertrophy succeeded by right ventricular failure (3).

The observations on high-altitude dwellers underscore the importance of persistent hypoxia and pulmonary hypertension in causing right ventricular hypertrophy. They also relate to patients with sleep apnea. In 220 patients with sleep apnea subjected to right heart catheterization, daytime pulmonary hypertension (>20 mm Hg) was found in only 17% in association with an average arterial saturation of 88%. Higher pulmonary arterial pressures (>35 mm Hg) were found in only 2 of 37 patients (4). Moreover, the abnormally higher pulmonary arterial pressures occurred in patients in whom hypoxia and pulmonary hypertension were increased by chronic lung disease, possibly abetted by chronic obesity.

The finding by Guidry and coworkers (2) of minimal right ventricular hypertrophy in patients with sleep-disordered breathing drawn from the general population raises the possibility that more severely affected patients, such as those referred to sleep study clinics, may experience more severe hypoxia, higher pulmonary arterial pressures, and greater thickness of right ventricular walls. In such patients more traditional methods, such as electrocardiography, may suffice to detect right ventricular hypertrophy (5). Moreover, recent advances in echocardiography and more direct approaches to recording hold promise not only of increasing the accuracy of measurements of right ventricular wall thickness but also of affording less indirect estimates of pulmonary arterial pressures.

Studies of intermittent hypoxia and hypercapnia in sleep apnea afford the tantalizing prospect of filling gaps in the understanding of how abnormal respiratory gases influence the pulmonary circulation. Remodeling of the small pulmonary arteries in response to chronic hypoxia is one likely target for study. Another is identification of the mediators of the proliferative response in the small pulmonary vessels in chronic hypoxia. A third is the intensity and duration of the hypoxic stimulus required for remodeling. There are others. Studies on animal models of sleep-disordered breathing have already begun to clarify the effects of intermittently abnormal respiratory gases on the control of the pulmonary circulation and the pathogenesis of pulmonary hypertension (6).

	References

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1. Fishman AP. Hypoxia on the pulmonary circulation: how and where it acts. Circ Res 1976; 38: 221-231 [Free Full Text].

2. Guidry UC, Mendes LA, Evans JC, Levy D, O'Connor GT, Larson MG, Gottlieb DJ, Benjamin EJ. Echocardiographic features of the right heart in sleep-disordered breathing: The Framingham Heart Study. Am J Respir Crit Care Med 2001; 164: 933-938 [Abstract/Free Full Text].

3. Penaloza D, Sime F, Banchero N, Gambo R, Cruz J, Marticorena E. Pulmonary hypertension in healthy men born and living at high altitude. J Appl Physiol 1963; 11: 150-157 .

4. Chaouat A, Weitzenblum E, Krieger J, Oswald M, Kessler R. Pulmonary hemodynamics in the obstructive sleep apnea syndrome: Results in 220 consecutive patients. Chest 1966; 109: 380-386 [Abstract/Free Full Text].

5. Incalzi RA, Fuso L, DeRosa M, Di Napoli A, Basso S, Pagliari G, Pistelli R. Electrocardiographic signs of chronic cor pulmonale: a negative prognostic finding in chronic obstructive pulmonary disease. Circulation 1999;1600-1605.

6. Fagan KA. Pulmonary hypertension in mice following intermittent hypoxia. J Appl Physiol 2001; 90: 2502-2507 [Abstract/Free Full Text].