To Sleep, Perchance to Breathe
Implications for the Failing Heart

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An aging population, enhanced longevity, and cardiovascular therapies that mitigate against mortality, have all contributed to an increasing number of patients with congestive heart failure (CHF). Pharmacologic and lifestyle interventions have been moderately successful in improving outcome and quality of life. Nevertheless, the overall morbidity and mortality of CHF remains high. Innovative mechanistic approachesthe use of beta blockade for exampleare welcomed as complementary therapy, particularly in those patients in whom heart failure is refractory to standard medical therapy. One such novel approach to the management of CHF may be the detection and treatment of sleep-related breathing disorders (SBD) (1).

It has long been recognized that patients with heart failure have a high prevalence of abnormalities in breathing during sleepthe classic CHF symptoms of orthopnea and paroxysmal nocturnal dyspnea relate directly to recumbency and sleep state. More recently, evidence has emerged suggesting that the pathophysiology of CHF and sleep-related breathing disorders may be intimately linked, and indeed may conceivably potentiate each other. Exploration of this concept could have important implications. First, etiologic factors that link heart failure to SBD may provide mechanistic information regarding both disease states. Furthermore, effective treatment of one disorder may impact significantly on the natural history and symptoms of the other.

There is a strong rationale for supposing that CHF and sleep may interact pathologically. First, studies demonstrating positive correlations between cardiac and pulmonary artery pressures with both peripheral (2) and cardiac (3) sympathetic activation in CHF, speak to a theoretical pathophysiologic interplay between recumbency and heightened sympathetic drive in patients with CHF, even in the absence of any abnormalities in breathing during sleep. Second, neurohumoral consequences of obstructive sleep apnea such as sympathetic activation (4) and endothelin release (5) would be deleterious in the setting of preexisting myocardial dysfunction. This is particularly true for heart failure when sympathetic drive is high, and excessive neurohumoral activation likely contributes to poor outcome (6). Third, central apneas, common in patients with heart failure during sleep, provoke further increases in the already heightened sympathetic drive in patients with CHF (7).

Repetitive apneas, both obstructive and central, may therefore potentiate vasoconstriction, raise blood pressure, and impair oxygenation, thus contributing to heart failure progression. The corollary to this, namely that heart failure may predispose to SBD, is less well understood, but equally intriguing. Increased cardiac filling pressures may conceivably induce venous congestion of the upper airway, reducing airway lumen diameter (8) and potentiating obstructive apneas. This effect would be enhanced during sleep. It may also be that the heart failure disease milieu (decreased cardiac output, cardiac distension, derangement in neurohumoral and metabolic homeostasis, etc.) influences central cardiorespiratory control mechanisms, predisposing to central sleep apnea.

Experimental studies have certainly provided precedent for the hypothesis that heart failure and sleep-related breathing disorders may be linked. In the clinical setting, however, any systematic evaluation of the nature of the CHF-SBD interaction is compromised by several factors. First, the different SBDs are not mutually exclusive and often coexist (9). Treatment of one breathing disorder may not necessarily attenuate, and may sometimes enhance, manifestion of another. Second, polysomnographic monitoring is costly and often limited to those patients with CHF in whom a clear indication for sleep studies is present. Third, more severe heart failure is not always symptomatically stable, and often requires close monitoring and frequent titration of medications. The hemodynamic, symptomatic, and therapeutic profile of heart failure is consequently often in flux, and interpretation of a single night's sleep study in the context of a labile disease state has obvious limitations. This necessitates that studies relating heart failure to sleep disorders be carefully scrutinized from the perspective of timely and well-documented objective and subjective indices of heart failure severity.

Nevertheless, several recent studies have provided important information on the prevalence of SBD in patients with CHF. In a study of 20 (17 male, three female) outpatients with systolic dysfunction (LVEF < 25%) and stable severe CHF on the cardiac transplant waiting list, Lofaso and colleagues (10) noted that 45% of the patient group had SBD, predominantly central apneas. They also noted several patients with obstructive apneas. Chan and colleagues (11) evaluated 20 (seven male, 13 female) patients with CHF secondary to diastolic dysfunction, and noted that 55% of their patients had significant SBD, mainly obstructive apneas (11). In two related studies, Javaheri and colleagues (12, 13) studied initially 42 male patients (12), and subsequently an enhanced sample size of 81 male patients (13), all with systolic dysfunction (LVEF < 45%). In their prospective study of unselected patients with CHF, they noted that SBD was evident in 51% of patients with CHF, 40% with predominantly central sleep apnea and 11% with obstructive apnea (13). They further noted a high prevalence of atrial fibrillation and nocturnal ventricular arrhythmias within the sleep apneic patient group.

Sin and colleagues (1) contribute further new information with their retrospective study of a very large group of systolic dysfunction CHF patients, including a substantial number of female patients. In their study, they help address the important question of the characteristics that help identify those patients with heart failure who have central or obstructive sleep apnea. Given the widespread prevalence of SBD and the expense of polysomnographic evaluation, a strategy of weighting the patient history, examination and simple laboratory tests to determine the likelihood of the presence and type of SBD in CHF would be an important contribution to patient management algorithms.

In assimilating and integrating their findings into everyday practice, it is important at the outset to recognize that their data represent retrospective findings in a selected CHF patient group referred for suspected SBD or intractable CHF, and may not apply directly to the CHF population at large. In addition, given the absence of any clear data implicating atrial fibrillation, for example, as a causal mechanism for sleep apnea, the variables they describe are, for now, probably better understood as detection factors for SBD in CHF since risk factors generally "indicate a variable that is believed to be related to the possibility of an individual developing the disease" (14). These limitations do not detract from the important objectives of their study, and their emphasis on the need for incorporating a suspicion for SBD in any evaluation of the patient with CHF. This approach is highlighted by the high prevalence of SBD in CHF and, most importantly, by the probability that treatment of the SBD may improve outcome in CHF.

The contribution of SBD to the pathophysiology of CHF may be linked etiologically to the metabolic, humoral, and hemodynamic stresses induced by repetitive nocturnal apneas. These include, but are not limited to, hypoxemia, hypercapnia, peripheral sympathetic activation, cardiac vagal activation with bradyarrhythmias, acute pressor responses to apnea in both systemic and pulmonary circulations, distortions in myocardial configuration, endothelin release, and decreased sleep quality (4, 5, 7, 15, 16). There are clear consequences of these responses for the hemodynamic and symptom profiles associated with a failing heart.

That appropriate therapy may attenuate these responses, and perhaps even affect substantially the outcomes of CHF, adds a particular urgency to the need for identification of those patients with CHF and coexisting SBD. Treatment of obstructive apnea with continuous positive airway pressure (CPAP) lowers nocturnal blood pressure and sympathetic drive (4) and may result in improvements in ejection fraction (17). Treatment of central sleep apnea with CPAP or oxygen may attenuate sympathetic activation (18, 19). Not all studies describe benefit from treating SBD in CHF (20, 21), in part because of patient intolerance of CPAP during sleep. Nevertheless, it is likely that improved compliance and hence outcomes may be evident with the development of less intrusive and more user-friendly therapeutic options for SBD.

In summary, the high prevalence of sleep breathing disorders in CHF, their potential pathophysiologic interactions, and the likelihood of improvements in CHF outcome with treatment of SBD, together provide compelling grounds for incorporating an evaluation for sleep disorders in patients with CHF, particularly in those with intractable and perhaps even unstable CHF. It is unfortunate therefore that the mainstream of population studies of heart failure generally neglect the potential etiologic and pathophysiologic contributions of sleep disorders to the heart failure risk profile. Building on earlier studies from other investigators, Sin and colleagues (1) provide further convincing arguments for large scale prospective studies, first of the prevalence of sleep-related breathing disorders in heart failure, and second, of effective SBD therapy on objective measures of CHF outcome.

VIREND K. SOMERS, M.D., PH.D.

Divisions of Hypertension and Cardiology

Department of Internal Medicine

Mayo Clinic

Rochester, Minnesota

	References

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