Sleep — A New Cardiovascular Frontier
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《新英格兰医药杂志》
Sleep occupies a third of our lives. The cardiovascular implications of normal and disturbed sleep, and of sleep apnea1 in particular, have only recently gained prominence. Central sleep apnea is characterized by intermittent loss of respiratory drive, resulting in apnea followed by compensatory periods of hyperventilation. Obstructive sleep apnea occurs when mechanisms that maintain upper-airway tone during sleep are dysfunctional, resulting in a narrowing or collapse of the airway. Obstructive sleep apnea is often treatable by some combination of postural change, weight loss, and therapy with continuous positive airway pressure (CPAP); treatment paradigms for central sleep apnea are less clear. Although obstructive sleep apnea and central sleep apnea differ in many respects, they are both linked to the modern-day epidemics of obesity, cardiovascular disease, and heart failure. In this regard, they present opportunities for an improved understanding of cardiovascular pathophysiology and for the development of new strategies to prevent and treat cardiac and vascular disease. Two provocative studies in this issue of the Journal2,3 speak directly to this promise.
In the much anticipated Canadian Positive Airway Pressure (CANPAP) trial, Bradley and colleagues randomly assigned patients with both heart failure and central sleep apnea to receive either CPAP or no treatment in order to test whether intervention improved transplant-free survival.2 This hypothesis was predicated on previous data indicating that central sleep apnea was frequently observed in patients with heart failure4,5 and that central sleep apnea was associated with a striking increase in mortality6; furthermore, pilot studies showed that treatment with CPAP reduced catecholamines and improved exercise tolerance, ejection fraction, and survival in patients with heart failure.7 Although treatment of central sleep apnea in the CANPAP trial resulted in lower norepinephrine levels, a slightly increased ejection fraction, and an early but transient improvement in exercise tolerance, no mortality benefit was found. In fact, early divergence of survival curves favoring the control group contributed to premature termination of the study, which was already underpowered, in part because of the lower-than-expected recruitment rate of subjects and greatly improved survival regardless of randomization. At the end of the study, total mortality was similar in both groups, although sudden death, death from heart failure, and cardiac transplantation occurred in 19 control patients (15 percent) and in 24 patients treated with CPAP (19 percent). Although the results of the trial are disappointing, they give cause to revisit the implications of central sleep apnea in patients with heart failure and to question whether central sleep apnea contributes directly to the progression of heart failure or is merely an epiphenomenon.
In order to better appreciate the insights offered by the CANPAP trial, it is important first to recognize the limitations of the study. Despite a careful titration protocol in treatment with CPAP, the apnea–hypopnea index was reduced by only 50 percent, with a substantial residual apnea–hypopnea index of about 20 events per hour. At one year, CPAP was being used for only 3.6 hours per night. Assuming seven hours of sleep time, only 25 percent of the total apnea "burden" was being relieved. Perhaps as a consequence, neither sleep quality nor arousals from sleep (each with its own implications for cardiovascular health and disease8) showed any improvement with the treatment. Another limitation is the omission of baseline levels or changes in heart rate or blood pressure, which are key measures that are characteristic of contemporary heart-failure trials. This deficiency constrains a definitive interpretation of the data, since there is precedent for supposing that CPAP would have significant hemodynamic effects, perhaps affecting outcomes.
These caveats notwithstanding, the CANPAP trial raises interesting questions, some of which challenge conventional wisdom. First, given the lower-than-expected recruitment rate of subjects over the course of the study, we need to consider whether the prevalence of central sleep apnea in heart failure is truly as high as has been projected on the basis of selected patients with heart failure who were referred to the sleep laboratory. Has the advent of widespread use of beta-blockers in heart failure — with the consequent effects on cardiac remodeling, neurohumoral mechanisms, and ventilatory control9 — been accompanied by an attenuation of the prevalence of central sleep apnea? Second, there was a striking time-dependent decline in mortality in all patients with central sleep apnea and congestive heart failure. Are previous studies showing high mortality among patients with both congestive heart failure and central sleep apnea still relevant, or have advances in heart-failure therapy blunted those mechanisms by which central sleep apnea may have accelerated the death rate among patients with heart failure? Third, and most important, is what to conclude from the surprising absence of survival benefit of CPAP. Among patients with heart failure and central sleep apnea, is there a threshold for adverse cardiovascular consequences that lies below the apnea–hypopnea index achieved in the CANPAP trial? Perhaps CPAP is simply not a viable therapeutic option for death-rate reduction in patients with heart failure. On the other hand, alternative approaches such as newer, more effective positive airway pressure devices, cardiac resynchronization therapy, and pharmacologic interventions may enable a more complete resolution of central sleep apnea and improved sleep quality and may conceivably translate into good outcomes. The CANPAP trial is better interpreted as providing an impetus for the development of superior treatment strategies, rather than as a reason to discard central sleep apnea as a worthy therapeutic target in heart failure.
The CANPAP trial cannot be readily extrapolated to the treatment of obstructive sleep apnea, which is decidedly more prevalent and more amenable to treatment. Hypoxemia and sleep disturbances are more severe, and there is clear evidence that the nighttime obstructive apneas activate a breadth of cardiovascular disease mechanisms.10 The most recent Joint National Committee guidelines recognized the likely etiologic role of obstructive sleep apnea in new-onset hypertension.11 However, because obstructive sleep apnea is often accompanied by coexisting illnesses (including hypertension, obesity, and insulin resistance), evidence implicating it as a causal factor in other forms of cardiovascular disease is limited and largely circumstantial.10 The data have been especially inconsistent regarding stroke, in which any relationship has been obscured by the effects of stroke itself on upper-airway control so that it remains unclear whether sleep apnea is a cause or a consequence of stroke.
Yaggi and colleagues,3 also in this issue of the Journal, shed important new light on this question. In an observational cohort study, they examine the role of obstructive sleep apnea as a contributor to the risk of stroke or death from any cause. Even after adjusting for traditional risk factors, sleep apnea retained an independent association with the composite end point of stroke or death. For patients with the most severe sleep apnea, which was defined as an apnea–hypopnea index greater than 36, the hazard ratio for the composite outcome was 3.3. Although an important strength of the study was that sleep apnea was confirmed by overnight polysomnography, the study sample consisted of patients who were referred to the sleep laboratory. This selection bias may be unavoidable, given the prohibitive costs of polysomnography in large numbers of patients, but it needs to be considered when applying these findings to the population at large.
Nevertheless, Yaggi and colleagues confirm a likely role for obstructive sleep apnea in the risk of new stroke, transient ischemic attack, or sudden death. They appropriately note that several factors, including decreased cerebral blood flow and hypercoagulability, may provide the mechanistic links between obstructive sleep apnea and stroke. Sleep apnea and atrial fibrillation are frequently coexisting conditions,12 and obstructive sleep apnea has been implicated in the recurrence of atrial fibrillation after cardioversion.13 Occult paroxysmal atrial fibrillation, not evident by history or during polysomnography, may thus have been another mechanism linking sleep apnea to stroke. What also comes across in the study by Yaggi et al. is that the high risk of stroke was present even in a population that was being treated for sleep apnea. It is possible that the risk of stroke would have been even greater in the absence of treatment. A less appealing alternative, but one that needs consideration, particularly in light of the surprising findings of the CANPAP trial, is that perhaps the treatment of obstructive sleep apnea may have conferred only limited, if any, beneficial effects in stroke prevention.
A clear majority of studies are supportive of the notion that obstructive sleep apnea is a causal mechanism in cardiac and vascular disease. Inherent in this observation is the expectation that effective treatment, which is best achieved by CPAP, would reasonably be anticipated to improve cardiovascular outcomes. It has been the experience of many physicians that treatment of obstructive sleep apnea often provides substantial symptomatic benefit and even tangible improvements in disease state. Certainly, successful treatment of obstructive sleep apnea in the overweight, somnolent, hypertensive truck driver is gratifying and of likely benefit not only to the patient but also to the spouse, the physician, and perhaps even society at large. However, although the use of CPAP in obstructive sleep apnea may lower blood pressure,14 sympathetic activity,15 and other surrogates of cardiovascular risk, there are no large-scale, randomized trials of cardiovascular events or survival with the treatment. Although therapy should always be tailored to the individual patient, the intriguing data from Bradley, Yaggi, and their colleagues provide a timely reminder of the importance of evidence-based recommendations in any widespread therapeutic strategy, particularly when treatment options carry a substantial economic burden.
Supported by grants (HL 73211, HL 65176, HL 70302, and MO1-RR-00585) from the National Institutes of Health.
Source Information
From the Department of Medicine, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minn.
References
Malhotra A, White DP. Obstructive sleep apnoea. Lancet 2002;360:237-245.
Bradley TD, Logan AG, Kimoff RJ, et al. Continuous positive airway pressure for central sleep apnea and heart failure. N Engl J Med 2005;353:2025-2033.
Yaggi HK, Concato J, Kernan WN, Lichtman JH, Brass LM, Mohsenin V. Obstructive sleep apnea as a risk factor for stroke and death. N Engl J Med 2005;353:2034-2041.
Javaheri S, Parker TJ, Liming JD, et al. Sleep apnea in 81 ambulatory male patients with stable heart failure: types and their prevalences, consequences, and presentations. Circulation 1998;97:2154-2159.
Sin DD, Fitgerald F, Parker JD, Newton G, Floras JS, Bradley TD. Risk factors for central and obstructive sleep apnea in 450 men and women with congestive heart failure. Am J Respir Crit Care Med 1999;160:1101-1106.
Lanfranchi PA, Braghiroli A, Bosimini E, et al. Prognostic value of nocturnal Cheyne-Stokes respiration in chronic heart failure. Circulation 1999;99:1435-1440.
Sin DD, Logan AG, Fitzgerald FS, Liu PP, Bradley TD. Effects of continuous positive airway pressure on cardiovascular outcomes in heart failure patients with and without Cheyne-Stokes respiration. Circulation 2000;102:61-66.
Spiegel K, Leproult R, Van Cauter E. Impact of sleep debt on metabolic and endocrine function. Lancet 1999;354:1435-1439.
Wolk R, Johnson BD, Somers VK, et al. Effects of beta-blocker therapy on ventilatory responses to exercise in patients with heart failure. J Card Fail 2005;11:333-339.
Shamsuzzaman ASM, Gersh BJ, Somers VK. Obstructive sleep apnea: implications for cardiac and vascular disease. JAMA 2003;290:1906-1914.
Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;289:2560-2572.
Gami AS, Pressman G, Caples SM, et al. Association of atrial fibrillation and obstructive sleep apnea. Circulation 2004;110:364-367.
Kanagala R, Murali NS, Friedman PA, et al. Obstructive sleep apnea and the recurrence of atrial fibrillation. Circulation 2003;107:2589-2594.
Pepperell JC, Ramdassingh-Dow S, Crosthwaite N, et al. Ambulatory blood pressure after therapeutic and subtherapeutic nasal continuous positive airway pressure for obstructive sleep apnoea: a randomised parallel trial. Lancet 2002;359:204-210.
Narkiewicz K, Kato M, Phillips BG, Pesek CA, Davison DE, Somers VK. Nocturnal continuous positive airway pressure decreases daytime sympathetic traffic in obstructive sleep apnea. Circulation 1999;100:2332-2335.(Virend K. Somers, M.D., P)
In the much anticipated Canadian Positive Airway Pressure (CANPAP) trial, Bradley and colleagues randomly assigned patients with both heart failure and central sleep apnea to receive either CPAP or no treatment in order to test whether intervention improved transplant-free survival.2 This hypothesis was predicated on previous data indicating that central sleep apnea was frequently observed in patients with heart failure4,5 and that central sleep apnea was associated with a striking increase in mortality6; furthermore, pilot studies showed that treatment with CPAP reduced catecholamines and improved exercise tolerance, ejection fraction, and survival in patients with heart failure.7 Although treatment of central sleep apnea in the CANPAP trial resulted in lower norepinephrine levels, a slightly increased ejection fraction, and an early but transient improvement in exercise tolerance, no mortality benefit was found. In fact, early divergence of survival curves favoring the control group contributed to premature termination of the study, which was already underpowered, in part because of the lower-than-expected recruitment rate of subjects and greatly improved survival regardless of randomization. At the end of the study, total mortality was similar in both groups, although sudden death, death from heart failure, and cardiac transplantation occurred in 19 control patients (15 percent) and in 24 patients treated with CPAP (19 percent). Although the results of the trial are disappointing, they give cause to revisit the implications of central sleep apnea in patients with heart failure and to question whether central sleep apnea contributes directly to the progression of heart failure or is merely an epiphenomenon.
In order to better appreciate the insights offered by the CANPAP trial, it is important first to recognize the limitations of the study. Despite a careful titration protocol in treatment with CPAP, the apnea–hypopnea index was reduced by only 50 percent, with a substantial residual apnea–hypopnea index of about 20 events per hour. At one year, CPAP was being used for only 3.6 hours per night. Assuming seven hours of sleep time, only 25 percent of the total apnea "burden" was being relieved. Perhaps as a consequence, neither sleep quality nor arousals from sleep (each with its own implications for cardiovascular health and disease8) showed any improvement with the treatment. Another limitation is the omission of baseline levels or changes in heart rate or blood pressure, which are key measures that are characteristic of contemporary heart-failure trials. This deficiency constrains a definitive interpretation of the data, since there is precedent for supposing that CPAP would have significant hemodynamic effects, perhaps affecting outcomes.
These caveats notwithstanding, the CANPAP trial raises interesting questions, some of which challenge conventional wisdom. First, given the lower-than-expected recruitment rate of subjects over the course of the study, we need to consider whether the prevalence of central sleep apnea in heart failure is truly as high as has been projected on the basis of selected patients with heart failure who were referred to the sleep laboratory. Has the advent of widespread use of beta-blockers in heart failure — with the consequent effects on cardiac remodeling, neurohumoral mechanisms, and ventilatory control9 — been accompanied by an attenuation of the prevalence of central sleep apnea? Second, there was a striking time-dependent decline in mortality in all patients with central sleep apnea and congestive heart failure. Are previous studies showing high mortality among patients with both congestive heart failure and central sleep apnea still relevant, or have advances in heart-failure therapy blunted those mechanisms by which central sleep apnea may have accelerated the death rate among patients with heart failure? Third, and most important, is what to conclude from the surprising absence of survival benefit of CPAP. Among patients with heart failure and central sleep apnea, is there a threshold for adverse cardiovascular consequences that lies below the apnea–hypopnea index achieved in the CANPAP trial? Perhaps CPAP is simply not a viable therapeutic option for death-rate reduction in patients with heart failure. On the other hand, alternative approaches such as newer, more effective positive airway pressure devices, cardiac resynchronization therapy, and pharmacologic interventions may enable a more complete resolution of central sleep apnea and improved sleep quality and may conceivably translate into good outcomes. The CANPAP trial is better interpreted as providing an impetus for the development of superior treatment strategies, rather than as a reason to discard central sleep apnea as a worthy therapeutic target in heart failure.
The CANPAP trial cannot be readily extrapolated to the treatment of obstructive sleep apnea, which is decidedly more prevalent and more amenable to treatment. Hypoxemia and sleep disturbances are more severe, and there is clear evidence that the nighttime obstructive apneas activate a breadth of cardiovascular disease mechanisms.10 The most recent Joint National Committee guidelines recognized the likely etiologic role of obstructive sleep apnea in new-onset hypertension.11 However, because obstructive sleep apnea is often accompanied by coexisting illnesses (including hypertension, obesity, and insulin resistance), evidence implicating it as a causal factor in other forms of cardiovascular disease is limited and largely circumstantial.10 The data have been especially inconsistent regarding stroke, in which any relationship has been obscured by the effects of stroke itself on upper-airway control so that it remains unclear whether sleep apnea is a cause or a consequence of stroke.
Yaggi and colleagues,3 also in this issue of the Journal, shed important new light on this question. In an observational cohort study, they examine the role of obstructive sleep apnea as a contributor to the risk of stroke or death from any cause. Even after adjusting for traditional risk factors, sleep apnea retained an independent association with the composite end point of stroke or death. For patients with the most severe sleep apnea, which was defined as an apnea–hypopnea index greater than 36, the hazard ratio for the composite outcome was 3.3. Although an important strength of the study was that sleep apnea was confirmed by overnight polysomnography, the study sample consisted of patients who were referred to the sleep laboratory. This selection bias may be unavoidable, given the prohibitive costs of polysomnography in large numbers of patients, but it needs to be considered when applying these findings to the population at large.
Nevertheless, Yaggi and colleagues confirm a likely role for obstructive sleep apnea in the risk of new stroke, transient ischemic attack, or sudden death. They appropriately note that several factors, including decreased cerebral blood flow and hypercoagulability, may provide the mechanistic links between obstructive sleep apnea and stroke. Sleep apnea and atrial fibrillation are frequently coexisting conditions,12 and obstructive sleep apnea has been implicated in the recurrence of atrial fibrillation after cardioversion.13 Occult paroxysmal atrial fibrillation, not evident by history or during polysomnography, may thus have been another mechanism linking sleep apnea to stroke. What also comes across in the study by Yaggi et al. is that the high risk of stroke was present even in a population that was being treated for sleep apnea. It is possible that the risk of stroke would have been even greater in the absence of treatment. A less appealing alternative, but one that needs consideration, particularly in light of the surprising findings of the CANPAP trial, is that perhaps the treatment of obstructive sleep apnea may have conferred only limited, if any, beneficial effects in stroke prevention.
A clear majority of studies are supportive of the notion that obstructive sleep apnea is a causal mechanism in cardiac and vascular disease. Inherent in this observation is the expectation that effective treatment, which is best achieved by CPAP, would reasonably be anticipated to improve cardiovascular outcomes. It has been the experience of many physicians that treatment of obstructive sleep apnea often provides substantial symptomatic benefit and even tangible improvements in disease state. Certainly, successful treatment of obstructive sleep apnea in the overweight, somnolent, hypertensive truck driver is gratifying and of likely benefit not only to the patient but also to the spouse, the physician, and perhaps even society at large. However, although the use of CPAP in obstructive sleep apnea may lower blood pressure,14 sympathetic activity,15 and other surrogates of cardiovascular risk, there are no large-scale, randomized trials of cardiovascular events or survival with the treatment. Although therapy should always be tailored to the individual patient, the intriguing data from Bradley, Yaggi, and their colleagues provide a timely reminder of the importance of evidence-based recommendations in any widespread therapeutic strategy, particularly when treatment options carry a substantial economic burden.
Supported by grants (HL 73211, HL 65176, HL 70302, and MO1-RR-00585) from the National Institutes of Health.
Source Information
From the Department of Medicine, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minn.
References
Malhotra A, White DP. Obstructive sleep apnoea. Lancet 2002;360:237-245.
Bradley TD, Logan AG, Kimoff RJ, et al. Continuous positive airway pressure for central sleep apnea and heart failure. N Engl J Med 2005;353:2025-2033.
Yaggi HK, Concato J, Kernan WN, Lichtman JH, Brass LM, Mohsenin V. Obstructive sleep apnea as a risk factor for stroke and death. N Engl J Med 2005;353:2034-2041.
Javaheri S, Parker TJ, Liming JD, et al. Sleep apnea in 81 ambulatory male patients with stable heart failure: types and their prevalences, consequences, and presentations. Circulation 1998;97:2154-2159.
Sin DD, Fitgerald F, Parker JD, Newton G, Floras JS, Bradley TD. Risk factors for central and obstructive sleep apnea in 450 men and women with congestive heart failure. Am J Respir Crit Care Med 1999;160:1101-1106.
Lanfranchi PA, Braghiroli A, Bosimini E, et al. Prognostic value of nocturnal Cheyne-Stokes respiration in chronic heart failure. Circulation 1999;99:1435-1440.
Sin DD, Logan AG, Fitzgerald FS, Liu PP, Bradley TD. Effects of continuous positive airway pressure on cardiovascular outcomes in heart failure patients with and without Cheyne-Stokes respiration. Circulation 2000;102:61-66.
Spiegel K, Leproult R, Van Cauter E. Impact of sleep debt on metabolic and endocrine function. Lancet 1999;354:1435-1439.
Wolk R, Johnson BD, Somers VK, et al. Effects of beta-blocker therapy on ventilatory responses to exercise in patients with heart failure. J Card Fail 2005;11:333-339.
Shamsuzzaman ASM, Gersh BJ, Somers VK. Obstructive sleep apnea: implications for cardiac and vascular disease. JAMA 2003;290:1906-1914.
Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;289:2560-2572.
Gami AS, Pressman G, Caples SM, et al. Association of atrial fibrillation and obstructive sleep apnea. Circulation 2004;110:364-367.
Kanagala R, Murali NS, Friedman PA, et al. Obstructive sleep apnea and the recurrence of atrial fibrillation. Circulation 2003;107:2589-2594.
Pepperell JC, Ramdassingh-Dow S, Crosthwaite N, et al. Ambulatory blood pressure after therapeutic and subtherapeutic nasal continuous positive airway pressure for obstructive sleep apnoea: a randomised parallel trial. Lancet 2002;359:204-210.
Narkiewicz K, Kato M, Phillips BG, Pesek CA, Davison DE, Somers VK. Nocturnal continuous positive airway pressure decreases daytime sympathetic traffic in obstructive sleep apnea. Circulation 1999;100:2332-2335.(Virend K. Somers, M.D., P)