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Cardiovascular consequences of obstructive sleep apnea
Clin Chest Med 24 (2003) 195 – 205
Cardiovascular consequences of obstructive sleep apnea Robert Wolk, MD, PhD, Virend K. Somers, MD, PhD* Mayo Clinic, Department of Medicine, Division of Cardiovascular Diseases and Division of Hypertension, 200 First Street Southwest, Rochester, MN 55905, USA
Sleep disorders are common, with an estimated prevalence of approximately 40 million cases in the United States alone. Fifteen million persons in the United States are believed to have sleep apnea, which is defined as recurrent episodes of cessation of respiratory airflow during sleep, with a consequent decrease in oxygen saturation. Sleep apnea can be considered as central or obstructive. Central sleep apnea (CSA) is characterized by periodic apneas and hypopneas secondary to diminution or cessation of respiratory efforts. In contrast, obstructive sleep apnea (OSA) is secondary to upper airway collapse during inspiration and is accompanied by strenuous breathing efforts. CSA and OSA often may coexist. There is an increasing recognition of the widespread prevalence of OSA and its potential cardiovascular consequences. CSA also has been implicated in cardiovascular disease, primarily in patients with heart failure. This article addresses the association between OSA and specific cardiovascular disease conditions and examines the evidence that implicates OSA in the pathophysiology and progression of these disorders.
Hypertension Much work has focused on the link between sleep apnea and hypertension, and the evidence that sugWork for this article was funded by the Mayo Foundation, HL-61560, HL-65176, HL-70302, MO1-RR00585. * Corresponding author. Mayo Foundation, St. Mary’s Hospital, DO-4-350, 1216 Second Street SW, Rochester, MN 55902. E-mail address: [email protected] (V.K. Somers).
gests a causal association between these two conditions is compelling. The prevalence of hypertension is greater in patients with OSA, and hypertensive patients (especially the nondippers) have a higher incidence of OSA [1,2], which suggests that OSA may be etiologically linked to chronic daytime hypertension. The evidence for a causal relationship between OSA and daytime hypertension has been strengthened by recent epidemiologic studies. The Wisconsin Sleep Cohort Study demonstrated a dose-response association between sleep-disordered breathing at baseline (diagnosed by in-hospital polysomnography) and the development of new hypertension 4 years later, independent of other known risk factors [3]. Specifically, the odds ratios for the presence of hypertension at follow-up were 1.42, 2.03, and 2.89 with an apnea-hypopnea index of less than 5, 5 to 15, and more than 15 events/hour at baseline, respectively (Fig. 1). A similar relationship between OSA and the risk of hypertension was seen in other studies [4,5]. Further support for some causal interaction between OSA and hypertension is provided by evidence that successful treatment of OSA with continuous positive airway pressure (CPAP) reduces blood pressure, especially in patients with hypertension [6 – 11]. Taken together, these data suggest that OSA is likely to contribute to hypertension in some patients and that the management of hypertension in these patients may be augmented by treating the underlying sleep apnea. Neurogenic mechanisms may contribute importantly to the acute and chronic hypertensive effects of OSA. Acute nocturnal surges in blood pressure occur in response to chemoreflex-mediated hypoxic stimulation of sympathetic activity [12 – 14]. These responses are potentiated in hypertensive subjects [15]. Activation of the chemoreflex leads to an
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Fig. 1. Odds ratios for the presence of incident hypertension at 4-year follow-up according to the apnea-hypopnea index (AHI) at baseline. The odds ratios are adjusted for baseline hypertension status, age, gender, body habitus (body mass index, waist and neck circumference), alcohol consumption, and cigarette use. Data are shown as odds ratio (lower and upper 95% confidence interval). P for trend = 0.002. (Data from Peppard PE, Young T, Palta M, Skatrud J. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 2000;342:1378 – 84.)
increase in vascular sympathetic nerve activity and circulating catecholamines, which increase peripheral vascular resistance. Upon termination of apnea, cardiac output increases (caused by changes in intrathoracic pressures) in the presence of a constricted peripheral vascular bed, which leads to dramatic surges in blood pressure (sometimes to levels as high as 240/120 mm Hg) [14]. There seems to be a ‘‘carry-over’’ effect, such that sympathetic activity remains elevated even in normoxic conditions, serving as one of several possible mechanisms that maintain elevated blood pressure even during daytime wakefulness. Daytime hypertension in OSA may be mediated by enhanced sympathetic activity, as evidenced by elevated circulating catecholamine levels, increased sympathetic nerve activity [14,16 – 21], and other mechanisms. Normotensive OSA patients, who are free of any overt cardiovascular disease, have decreased heart rate variability and increased blood pressure variability [22]—characteristics that may predispose to the development of hypertension [23] and end-organ damage [24]. These abnormalities in daytime neural circulatory control may be related to chemoreceptor resetting and tonic chemoreceptor activation (even in normoxia) [21,25]. By attenuating apneas, acute CPAP therapy prevents blood pressure surges and nocturnal sympathetic activation. Long-
term CPAP therapy results in lower daytime sympathetic traffic in OSA patients [26]. Other mechanisms are also important in contributing to hypertension in OSA. One such potential mechanism is endothelial dysfunction, with a decrease in endothelium-dependent vasodilatation [27 – 29] (Fig. 2). OSA also may enhance production of vasoconstrictor and trophic agents, such as endothelin [30,31], and attenuate production of nitric oxide [32,33], further favoring vasoconstriction. Metabolic factors, such as those related to obesity, insulin resistance, or hyperleptinemia [34 – 41], are also likely to play a role. Finally, an intriguing but unproven possibility is that OSA-induced neuroendocrine activation, together with the mechanical effects of blood pressure surges, may lead to vascular remodeling, increased wall-to-lumen ratio, and sustained hypertension. From the clinical standpoint, OSA always should be considered in the differential diagnosis of causes of refractory hypertension, particularly in obese hypertensive patients and in patients in whom there is a blunted nocturnal blood pressure decline (nondippers). Appropriate therapy is effective in decreasing blood pressure acutely at night [14] and even during the daytime [11].
Atherosclerosis In patients with established coronary artery disease, severe OSA may trigger acute nocturnal cardiac ischemia with ST-segment depression (predominantly
Fig. 2. Percent change in forearm blood flow (FBF) during infusion of acetylcholine (ACh) and verapamil (VER) in patients with OSA (circles) and matched normal control subjects (squares). Data are mean F SEM. (Modified from Kato M, Roberts-Thomson P, Phillips BG, Haynes WG, Winnicki M, Accurso V, et al. Impairment of endothelium-dependent vasodilation of resistance vessels in patients with obstructive sleep apnea. Circulation 2000;102: 2607 – 10; with permission.)
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in rapid eye movement sleep) that is often resistant to traditional therapy [42 – 44]. ST-segment depression in association with OSA was also noted in patients without clinically significant coronary artery disease and was reduced by CPAP treatment [45]. Nocturnal ischemia in these patients is probably a result of simultaneous oxygen desaturation, increased sympathetic activity, tachycardia and increased systemic vascular resistance (all increasing cardiac oxygen demand), a prothrombotic state (see later discussion), and any underlying subclinical coronary artery disease and impaired coronary reserve. Cardiac ischemia may be exacerbated further by left ventricular hypertrophy, especially in patients with OSA who have long-standing hypertension. Conceivably, the hemodynamic stress induced by apneas and arousals may increase the risk of coronary plaque rupture. Whether nocturnal ischemia is directly related to cardiovascular endpoints or mortality in patients with OSA has not been established. The observation that untreated OSA may be associated with an increased risk of cardiovascular mortality in patients with coronary artery disease [46,47] argues for the recognition and treatment of any sleep apnea in these patients, however. Clinical and epidemiologic evidence suggests a possible direct role for OSA in the pathophysiology of atherosclerosis and ischemic heart disease. First, several studies have reported a high prevalence of OSA in patients with coronary artery disease [48 – 51]. Second, several case-control studies of patients with myocardial infarction or angina pectoris suggested that the presence of sleep apnea is an independent predictor of coronary artery disease [50 – 54]. Third, patients with OSA have a greater prevalence of increased carotid wall thickness (a marker of generalized atherosclerosis) and calcified carotid artery atheromas [55,56]. Finally, in a large cross-sectional study of 6424 free-living individuals, sleep apnea (diagnosed by unattended polysomnography at home) was associated with increased multivariable-adjusted relative odds of self-reported coronary heart disease [57]. This observation has been supported by another prospective study [5]. These findings suggest that sleep apnea perhaps may be associated with, or even predispose to, coronary artery disease. Any such predisposition may be indirect (eg, through hypertension, dyslipidemia) or may be directly related to promoting the process of atherogenesis independent of other comorbidities. Experimental studies lend further support to the notion that there might be a cause-and-effect relationship between OSA and atherosclerosis. In OSA, repetitive surges in blood pressure, sympathetic activity,
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and increased oxidative stress [58,59] may lead to vascular injury. Increased plasma endothelin levels [30,31], decreased nitric oxide production [32,33], and endothelial dysfunction [27 – 29] also may contribute to the initiation and progression of atherogenic lesions and vascular damage. Atherogenic processes can be initiated and potentiated by endothelial damage and the ensuing and coexisting inflammatory response [60]. Specifically, leukocyte accumulation and adhesion to the endothelium (with consequent leukocyte-endothelial cell interactions) may impair endothelial function and promote atherogenic processes. It is possible that OSA may influence atherogenesis by inducing such inflammatory reactions. C-reactive protein level (an index of the presence of systemic inflammation and probably a direct mediator of vascular dysfunction, damage, and atherogenesis) is elevated in persons with OSA (Fig. 3) [61]. Elevated plasma levels of various adhesion molecules, increased expression of adhesion molecules on leukocytes, and their enhanced adherence to endothelial cells also have been reported in patients with OSA [59,62 – 64]. The correlation between these changes and OSA severity [63] and their reversal after CPAP therapy [59,63] point to a possible causal relationship between OSA and the systemic activation of inflammatory processes.
Stroke Several studies have investigated the association between sleep-related breathing disorders and the incidence of stroke. A history of snoring seems to increase the risk of stroke, independent of other cardiovascular risk factors. A recent large prospective study in women also supported this conclusion [65]. Similarly, many studies that used polysomnography noted that the prevalence of OSA is greatly elevated in patients with stroke [66 – 71]. A high incidence of OSA in patients with stroke raises the possibility that perhaps stroke may cause OSA (rather than being a result of it), especially when the evidence is based on case-control studies of patients with and without a history of stroke. This possibility cannot be excluded. However, it seems that breathing disorders consequent on a cerebrovascular accident are more likely to cause changes in respiratory pattern leading to primarily central sleep apnea [70,72]. These breathing disorders are most likely to manifest in the first hours after stroke, but may aggravate preexisting OSA or even cause ob-
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Fig. 3. Plasma CRP levels in OSA patients and controls. Middle horizontal line inside box indicates median. Bottom and top of the box are 25th and 75th percentiles, respectively. (From Shamsuzzaman AS, Winnicki M, Lanfranchi P, Wolk R, Kara T, Accurso V, et al. Elevated C-reactive protein in patients with obstructive sleep apnea. Circulation 2002;105:2462 – 4; with permission.)
structive apnea secondary to changes in tone of the upper airway muscles and upper airway resistance. The concept that OSA actually precedes and predisposes to stroke is based on several lines of evidence. First, in some studies the prevalence of OSA has been shown to be equally high in patients with transient ischemic attacks, which suggests the possibility that OSA precedes stroke events [69,70]. Second, patients with stroke and OSA demonstrate persistence of OSA when repeated polysomnographic studies are performed several months after the acute event (although the incidence of central apnea may actually decrease) [67,70]. Third, the obstructive events are independent of the type of stroke and its location [70]. Finally, a possible causal relationship between OSA and stroke is supported by several pathophysiologic studies that investigated the actual mechanisms whereby OSA may predispose to stroke. For example, Doppler measurements of cerebral blood flow suggest that obstructive apneas are associated with blood flow reduction in association with individual apneic episodes [73 – 75] and, probably, impairment of cerebrovascular autoregulation and diminished cerebral vasodilator reserve. The decreases in cerebral blood flow are most likely related to the presence of negative intrathoracic pressures and increased intracranial pressure. Ischemic effects of decreased cerebral blood flow would be further potentiated by hypoxemia secondary to apnea. Indeed, cerebral tissue hypoxia has been recorded during episodes of OSA [76]. OSA also is a prothrombotic state that is characterized by higher levels of platelet
aggregation and activation [77 – 80], elevated fibrinogen levels (correlating with the severity of OSA) [81], decreased fibrinolytic activity [82], and increased whole blood viscosity—all of which may contribute to thrombosis and ischemic stroke. It is relevant that the cerebral hemodynamic changes may be reversed [83], platelet aggregability can be decreased [79,80], and the increase in morning fibrinogen levels can be blunted [84] by CPAP treatment. Atherosclerosis also may be an important factor predisposing to stroke. Increased carotid wall thickness (a marker of generalized atherosclerosis and a risk factor for stroke) and calcified carotid artery atheromas are significantly more prevalent in individuals with OSA [55,56]. Finally, hypertension, the prevalence of which is high in OSA, is a known risk factor for stroke and may contribute substantially to any association between OSA and stroke. Although OSA is an attractive potential contributor to stroke, the evidence that links OSA to stroke is primarily observational, and any causality is inferred from these data and the experimental data that suggest that OSA contributes to abnormalities in cerebral blood flow and a prothrombotic state. There is a clear need for more definitive longitudinal studies of stroke risk in patients with OSA, independent of other risk factors, particularly hypertension and hyperlipidemia. Importantly, there is some indication that OSA in stroke survivors may be associated with increased mortality and a worse long-term functional outcome [67,68,85]. Hence, it may be prudent to use CPAP therapy in compliant
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patients after stroke with documented evidence of sleep-disordered breathing.
Heart failure Patients with systolic heart failure have a significant prevalence of sleep apnea (primarily CSA) [86 – 90]. OSA may be especially common in patients with left ventricular diastolic dysfunction [91,92], although not all studies are consistent [93]. The relative contribution of CSA and OSA to sleep-disordered breathing varies in different congestive heart failure (CHF) populations studied, with a general predominance of CSA. Recent observations suggest that there may be an important pathophysiologic link between OSA and CSA. Namely, it has been observed that in heart failure patients the proportion of OSA decreases and the proportion of CSA increases from the first to the last quarter of the night, with an accompanying decrease in transcutaneous carbon dioxide levels and a significant lengthening of circulation time [94]. This overnight shift from OSA to CSA may be related to a deterioration of cardiac function (caused by the assumption of a recumbent position and by the detrimental hemodynamic effects of OSA), with a subsequent increase in left ventricular filling pressures. The significance of OSA in CHF is twofold. First, OSA might predispose a person to CHF. Some preliminary epidemiologic data suggest that the presence of OSA is associated with a relative odds for self-reported CHF of 2.38 (independent of other risk factors) [57]. Such a causal relationship between OSA and CHF may be explained by the association of OSA with other direct or indirect risk factors for CHF (eg, hypertension, ischemic heart disease, ventricular hypertrophy, oxidative tissue damage, systemic inflammation, neuroendocrine activation, or autonomic dysfunction). Second, CHF might contribute to new-onset OSA, especially in susceptible individuals. In this case, OSA may be caused by the collapse of the upper airway because of soft tissue edema and changes in upper airway muscle tone. OSA superimposed on CHF may lead to further deterioration of cardiac function (caused by hypoxemia, sympathetic activation, vasoconstriction, endothelial dysfunction) and set up a vicious cycle of progressing, refractory CHF. An independent association between the severity of sleep apnea and depression of left ventricular ejection fraction has been reported [95]. In small study samples, treatment of OSA with CPAP has been shown to substantially improve left ventricular ejection frac-
Fig. 4. Effects of nasal continuous positive airway pressure (nCPAP) therapy on improving left ventricular ejection fraction (LVEF) and functional class (NYHA) in patients with congestive heart failure. (Modified from Malone S, Liu PP, Holloway R, Rutherford R, Xie A, Bradley TD. Obstructive sleep apnea in patients with idiopathic dilated cardiomyopathy: effects of continuous positive airway pressure. Lancet 1991;338:1480 – 4; with permission.)
tion and functional class in patients with CHF [96] (Fig. 4).
Pulmonary hypertension Apnea and hypoxemia also may elicit acute elevations of pulmonary artery pressure during sleep. Conceivably, these nocturnal events of hypoxia and pulmonary hypertension might contribute to endothelial damage and vascular remodeling, which may further lead to sustained pulmonary hypertension. Several studies have reported the presence of daytime pulmonary hypertension in patients with OSA. In many studies, however, other comorbidities were also present (most notably lung disease, heart failure, or systemic hypertension), so that any independent contribution of OSA to chronic pulmonary hypertension remains unclear. Several studies have investigated the occurrence of daytime pulmonary hypertension in patients with OSA in the absence of lung and heart disease. These
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studies generally support the concept that OSA is associated with daytime pulmonary hypertension [97 – 100]. The frequency of pulmonary hypertension varies among various populations studied. It should be noted that in several studies there was no difference between pulmonary hypertensive and normotensive OSA subjects with respect to nocturnal oxygenation and OSA severity [97,98,100], which suggests that individual variation in pulmonary vascular sensitivity to hypoxic stimuli may be important or, alternatively, that factors other than OSA per se may be responsible for the apparent increased pulmonary artery pressures in patients with OSA. Patients with OSA with daytime pulmonary hypertension have been reported to have greater elevations of pulmonary artery vascular tone during rapid eye movement sleep, independent of the degree of hypoxia [101]. In some [100,102,103], although not all [97,104] studies, patients with OSA and pulmonary hypertension have been suggested to differ from their nonhypertensive counterparts in that they tend to have a greater body mass index and lower daytime arterial oxygen saturation. It is possible, at least in some patients with OSA, that mild daytime hypoxemia caused by the obesity-hypoventilation syndrome might play a role in increasing daytime pulmonary artery pressures. Interestingly, CPAP therapy seems to reduce pulmonary pressures in OSA patients with either pulmonary hypertension or with normal pulmonary pressures [100,105], which suggests the possibility that in many cases even ‘‘normal’’ pulmonary pressures may be elevated compared with individual baseline values. A recent report on subjects drawn from the general population suggested that sleep-disordered breathing is associated with increased right ventricular wall thickness [106]. Right ventricular hypertrophy has been found in selected subjects with OSA [107,108]. Depressed right ventricular ejection fraction and clinical evidence of right ventricular failure also have been reported in patients with OSA [109 – 111]. Echocardiographic studies of right ventricular morphology and function and Doppler estimates of right ventricular systolic pressure (and hence pulmonary artery systolic pressure) in OSA patients are limited by several factors, however, including (1) the difficulty in obtaining high-quality images in a population that is often obese, (2) the potential influence of comorbidities and medication on these measurements, (3) the difficulties in selecting appropriate control subjects for comparison, and (4) the natural scatter of measurements within a population, together with margins of error inherent in these measurements. As with other cardiovascular conditions, there is a clear need for more
stringent longitudinal studies before any definitive assessment of the risk of chronic pulmonary hypertension in patients with OSA can be made. Further studies also are needed to investigate the relationship between OSA, pulmonary hypertension, right ventricular hypertrophy, and right ventricular failure and to establish whether these pathologic changes have any impact on prognosis and require specific treatment.
Cardiac arrhythmias Most studies that investigate the association between OSA and cardiac arrhythmias have methodologic limitations related to small sample sizes and lack of control groups. The exact prevalence of arrhythmias in patients with sleep apnea is also difficult to assess because of comorbidities, medication, and differences among the populations studied. There is nevertheless a general perception that sleep apnea is associated with an increased incidence of bradyarrhythmias and tachyarrhythmias (both supraventricular and ventricular). The most frequent arrhythmias described in association with sleep apnea are severe sinus bradycardia and atrioventricular block (including sinus arrest and complete heart block). These arrhythmias are purely functional because they have been reported in the absence of any primary disease of the cardiac conduction system and they readily respond to atropine. The most important pathophysiologic mechanism of bradyarrhythmias in OSA is a reflex (chemoreceptor mediated) increase in vagal tone, which is elicited by a combination of apnea and hypoxemia [112 – 115] that activates the diving reflex (increased sympathetic traffic to peripheral blood vessels and increased vagal drive to the heart). The occurrence of OSA-related bradycardia seems to be linked to apnea severity [116 – 118]. Bradyarrhythmias also may be more likely to occur in patients with impaired baroreflex function (eg, persons with hypertension or heart failure) [115]. The number of bradyarrhythmias seems to be greater in rapid eye movement sleep [118], which may be related in part to greater OSA severity in this sleep stage. The causal relationship between these bradyarrhythmias and OSA is supported by the observation that bradycardia occurs only during the night (in association with nocturnal apnea episodes) in otherwise asymptomatic subjects [119,120] and is readily prevented by tracheostomy or CPAP therapy [116, 117,119 – 122]. CPAP therapy has been shown to be curative in a sample of patients primarily referred for pacemaker therapy with asymptomatic brady-
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arrhythmias during sleep, most of whom were subsequently diagnosed with OSA [123]. Although the prognostic significance of severe nocturnal bradyarrhythmias in OSA is not known, it is prudent to evaluate all patients with asymptomatic bradyarrhythmias for the presence of sleep apnea, which should be treated appropriately. Cardiac tachyarrhythmias also have been reported in OSA, including ventricular tachycardia [116,120, 124] and supraventricular tachycardias. The prevalence and severity of these rhythm disturbances are low in otherwise healthy patients with OSA, however, and the clinical significance of these arrhythmias is unclear. In contrast, sleep apnea may be an important trigger for clinically significant arrhythmias in the presence of serious comorbidities, such as ischemic heart disease or heart failure. For example, sleep apnea (central and obstructive) has been associated with a greater prevalence of atrial fibrillation in patients with heart failure [125,126] or after coronary artery bypass surgery [127]. Similarly, CSA and OSA are related to the occurrence of ventricular arrhythmias in the heart failure population [126,128], with a decrease in arrhythmias after CPAP therapy [129].
Summary Sleep apnea is associated with several cardiovascular disease conditions. A causal relationship between sleep apnea and each of these diseases is likely, but remains to be proven. The clearest evidence implicating OSA in the development of new cardiovascular disease involves data that show an increased prevalence of new hypertension in patients with OSA followed over 4 years [3]. Circumstantial evidence and data from small study samples suggest that OSA, in the setting of existing cardiovascular disease, may exacerbate symptoms and accelerate disease progression. The diagnosis of OSA always should be considered in patients with refractory heart failure, resistant hypertension, nocturnal cardiac ischemia, and nocturnal arrhythmias, especially in individuals with risk factors for sleep apnea (eg, central obesity, age, and male gender). Treating sleep apnea may help to achieve better clinical control in these diseases and may improve long-term cardiovascular prognosis.
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Cardiovascular consequences of obstructive sleep apnea Robert Wolk, MD, PhD, Virend K. Somers, MD, PhD* Mayo Clinic, Department of Medicine, Division of Cardiovascular Diseases and Division of Hypertension, 200 First Street Southwest, Rochester, MN 55905, USA
Sleep disorders are common, with an estimated prevalence of approximately 40 million cases in the United States alone. Fifteen million persons in the United States are believed to have sleep apnea, which is defined as recurrent episodes of cessation of respiratory airflow during sleep, with a consequent decrease in oxygen saturation. Sleep apnea can be considered as central or obstructive. Central sleep apnea (CSA) is characterized by periodic apneas and hypopneas secondary to diminution or cessation of respiratory efforts. In contrast, obstructive sleep apnea (OSA) is secondary to upper airway collapse during inspiration and is accompanied by strenuous breathing efforts. CSA and OSA often may coexist. There is an increasing recognition of the widespread prevalence of OSA and its potential cardiovascular consequences. CSA also has been implicated in cardiovascular disease, primarily in patients with heart failure. This article addresses the association between OSA and specific cardiovascular disease conditions and examines the evidence that implicates OSA in the pathophysiology and progression of these disorders.
Hypertension Much work has focused on the link between sleep apnea and hypertension, and the evidence that sugWork for this article was funded by the Mayo Foundation, HL-61560, HL-65176, HL-70302, MO1-RR00585. * Corresponding author. Mayo Foundation, St. Mary’s Hospital, DO-4-350, 1216 Second Street SW, Rochester, MN 55902. E-mail address: [email protected] (V.K. Somers).
gests a causal association between these two conditions is compelling. The prevalence of hypertension is greater in patients with OSA, and hypertensive patients (especially the nondippers) have a higher incidence of OSA [1,2], which suggests that OSA may be etiologically linked to chronic daytime hypertension. The evidence for a causal relationship between OSA and daytime hypertension has been strengthened by recent epidemiologic studies. The Wisconsin Sleep Cohort Study demonstrated a dose-response association between sleep-disordered breathing at baseline (diagnosed by in-hospital polysomnography) and the development of new hypertension 4 years later, independent of other known risk factors [3]. Specifically, the odds ratios for the presence of hypertension at follow-up were 1.42, 2.03, and 2.89 with an apnea-hypopnea index of less than 5, 5 to 15, and more than 15 events/hour at baseline, respectively (Fig. 1). A similar relationship between OSA and the risk of hypertension was seen in other studies [4,5]. Further support for some causal interaction between OSA and hypertension is provided by evidence that successful treatment of OSA with continuous positive airway pressure (CPAP) reduces blood pressure, especially in patients with hypertension [6 – 11]. Taken together, these data suggest that OSA is likely to contribute to hypertension in some patients and that the management of hypertension in these patients may be augmented by treating the underlying sleep apnea. Neurogenic mechanisms may contribute importantly to the acute and chronic hypertensive effects of OSA. Acute nocturnal surges in blood pressure occur in response to chemoreflex-mediated hypoxic stimulation of sympathetic activity [12 – 14]. These responses are potentiated in hypertensive subjects [15]. Activation of the chemoreflex leads to an
0272-5231/03/$ – see front matter D 2003, Elsevier Inc. All rights reserved. doi:10.1016/S0272-5231(03)00020-0
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Fig. 1. Odds ratios for the presence of incident hypertension at 4-year follow-up according to the apnea-hypopnea index (AHI) at baseline. The odds ratios are adjusted for baseline hypertension status, age, gender, body habitus (body mass index, waist and neck circumference), alcohol consumption, and cigarette use. Data are shown as odds ratio (lower and upper 95% confidence interval). P for trend = 0.002. (Data from Peppard PE, Young T, Palta M, Skatrud J. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 2000;342:1378 – 84.)
increase in vascular sympathetic nerve activity and circulating catecholamines, which increase peripheral vascular resistance. Upon termination of apnea, cardiac output increases (caused by changes in intrathoracic pressures) in the presence of a constricted peripheral vascular bed, which leads to dramatic surges in blood pressure (sometimes to levels as high as 240/120 mm Hg) [14]. There seems to be a ‘‘carry-over’’ effect, such that sympathetic activity remains elevated even in normoxic conditions, serving as one of several possible mechanisms that maintain elevated blood pressure even during daytime wakefulness. Daytime hypertension in OSA may be mediated by enhanced sympathetic activity, as evidenced by elevated circulating catecholamine levels, increased sympathetic nerve activity [14,16 – 21], and other mechanisms. Normotensive OSA patients, who are free of any overt cardiovascular disease, have decreased heart rate variability and increased blood pressure variability [22]—characteristics that may predispose to the development of hypertension [23] and end-organ damage [24]. These abnormalities in daytime neural circulatory control may be related to chemoreceptor resetting and tonic chemoreceptor activation (even in normoxia) [21,25]. By attenuating apneas, acute CPAP therapy prevents blood pressure surges and nocturnal sympathetic activation. Long-
term CPAP therapy results in lower daytime sympathetic traffic in OSA patients [26]. Other mechanisms are also important in contributing to hypertension in OSA. One such potential mechanism is endothelial dysfunction, with a decrease in endothelium-dependent vasodilatation [27 – 29] (Fig. 2). OSA also may enhance production of vasoconstrictor and trophic agents, such as endothelin [30,31], and attenuate production of nitric oxide [32,33], further favoring vasoconstriction. Metabolic factors, such as those related to obesity, insulin resistance, or hyperleptinemia [34 – 41], are also likely to play a role. Finally, an intriguing but unproven possibility is that OSA-induced neuroendocrine activation, together with the mechanical effects of blood pressure surges, may lead to vascular remodeling, increased wall-to-lumen ratio, and sustained hypertension. From the clinical standpoint, OSA always should be considered in the differential diagnosis of causes of refractory hypertension, particularly in obese hypertensive patients and in patients in whom there is a blunted nocturnal blood pressure decline (nondippers). Appropriate therapy is effective in decreasing blood pressure acutely at night [14] and even during the daytime [11].
Atherosclerosis In patients with established coronary artery disease, severe OSA may trigger acute nocturnal cardiac ischemia with ST-segment depression (predominantly
Fig. 2. Percent change in forearm blood flow (FBF) during infusion of acetylcholine (ACh) and verapamil (VER) in patients with OSA (circles) and matched normal control subjects (squares). Data are mean F SEM. (Modified from Kato M, Roberts-Thomson P, Phillips BG, Haynes WG, Winnicki M, Accurso V, et al. Impairment of endothelium-dependent vasodilation of resistance vessels in patients with obstructive sleep apnea. Circulation 2000;102: 2607 – 10; with permission.)
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in rapid eye movement sleep) that is often resistant to traditional therapy [42 – 44]. ST-segment depression in association with OSA was also noted in patients without clinically significant coronary artery disease and was reduced by CPAP treatment [45]. Nocturnal ischemia in these patients is probably a result of simultaneous oxygen desaturation, increased sympathetic activity, tachycardia and increased systemic vascular resistance (all increasing cardiac oxygen demand), a prothrombotic state (see later discussion), and any underlying subclinical coronary artery disease and impaired coronary reserve. Cardiac ischemia may be exacerbated further by left ventricular hypertrophy, especially in patients with OSA who have long-standing hypertension. Conceivably, the hemodynamic stress induced by apneas and arousals may increase the risk of coronary plaque rupture. Whether nocturnal ischemia is directly related to cardiovascular endpoints or mortality in patients with OSA has not been established. The observation that untreated OSA may be associated with an increased risk of cardiovascular mortality in patients with coronary artery disease [46,47] argues for the recognition and treatment of any sleep apnea in these patients, however. Clinical and epidemiologic evidence suggests a possible direct role for OSA in the pathophysiology of atherosclerosis and ischemic heart disease. First, several studies have reported a high prevalence of OSA in patients with coronary artery disease [48 – 51]. Second, several case-control studies of patients with myocardial infarction or angina pectoris suggested that the presence of sleep apnea is an independent predictor of coronary artery disease [50 – 54]. Third, patients with OSA have a greater prevalence of increased carotid wall thickness (a marker of generalized atherosclerosis) and calcified carotid artery atheromas [55,56]. Finally, in a large cross-sectional study of 6424 free-living individuals, sleep apnea (diagnosed by unattended polysomnography at home) was associated with increased multivariable-adjusted relative odds of self-reported coronary heart disease [57]. This observation has been supported by another prospective study [5]. These findings suggest that sleep apnea perhaps may be associated with, or even predispose to, coronary artery disease. Any such predisposition may be indirect (eg, through hypertension, dyslipidemia) or may be directly related to promoting the process of atherogenesis independent of other comorbidities. Experimental studies lend further support to the notion that there might be a cause-and-effect relationship between OSA and atherosclerosis. In OSA, repetitive surges in blood pressure, sympathetic activity,
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and increased oxidative stress [58,59] may lead to vascular injury. Increased plasma endothelin levels [30,31], decreased nitric oxide production [32,33], and endothelial dysfunction [27 – 29] also may contribute to the initiation and progression of atherogenic lesions and vascular damage. Atherogenic processes can be initiated and potentiated by endothelial damage and the ensuing and coexisting inflammatory response [60]. Specifically, leukocyte accumulation and adhesion to the endothelium (with consequent leukocyte-endothelial cell interactions) may impair endothelial function and promote atherogenic processes. It is possible that OSA may influence atherogenesis by inducing such inflammatory reactions. C-reactive protein level (an index of the presence of systemic inflammation and probably a direct mediator of vascular dysfunction, damage, and atherogenesis) is elevated in persons with OSA (Fig. 3) [61]. Elevated plasma levels of various adhesion molecules, increased expression of adhesion molecules on leukocytes, and their enhanced adherence to endothelial cells also have been reported in patients with OSA [59,62 – 64]. The correlation between these changes and OSA severity [63] and their reversal after CPAP therapy [59,63] point to a possible causal relationship between OSA and the systemic activation of inflammatory processes.
Stroke Several studies have investigated the association between sleep-related breathing disorders and the incidence of stroke. A history of snoring seems to increase the risk of stroke, independent of other cardiovascular risk factors. A recent large prospective study in women also supported this conclusion [65]. Similarly, many studies that used polysomnography noted that the prevalence of OSA is greatly elevated in patients with stroke [66 – 71]. A high incidence of OSA in patients with stroke raises the possibility that perhaps stroke may cause OSA (rather than being a result of it), especially when the evidence is based on case-control studies of patients with and without a history of stroke. This possibility cannot be excluded. However, it seems that breathing disorders consequent on a cerebrovascular accident are more likely to cause changes in respiratory pattern leading to primarily central sleep apnea [70,72]. These breathing disorders are most likely to manifest in the first hours after stroke, but may aggravate preexisting OSA or even cause ob-
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Fig. 3. Plasma CRP levels in OSA patients and controls. Middle horizontal line inside box indicates median. Bottom and top of the box are 25th and 75th percentiles, respectively. (From Shamsuzzaman AS, Winnicki M, Lanfranchi P, Wolk R, Kara T, Accurso V, et al. Elevated C-reactive protein in patients with obstructive sleep apnea. Circulation 2002;105:2462 – 4; with permission.)
structive apnea secondary to changes in tone of the upper airway muscles and upper airway resistance. The concept that OSA actually precedes and predisposes to stroke is based on several lines of evidence. First, in some studies the prevalence of OSA has been shown to be equally high in patients with transient ischemic attacks, which suggests the possibility that OSA precedes stroke events [69,70]. Second, patients with stroke and OSA demonstrate persistence of OSA when repeated polysomnographic studies are performed several months after the acute event (although the incidence of central apnea may actually decrease) [67,70]. Third, the obstructive events are independent of the type of stroke and its location [70]. Finally, a possible causal relationship between OSA and stroke is supported by several pathophysiologic studies that investigated the actual mechanisms whereby OSA may predispose to stroke. For example, Doppler measurements of cerebral blood flow suggest that obstructive apneas are associated with blood flow reduction in association with individual apneic episodes [73 – 75] and, probably, impairment of cerebrovascular autoregulation and diminished cerebral vasodilator reserve. The decreases in cerebral blood flow are most likely related to the presence of negative intrathoracic pressures and increased intracranial pressure. Ischemic effects of decreased cerebral blood flow would be further potentiated by hypoxemia secondary to apnea. Indeed, cerebral tissue hypoxia has been recorded during episodes of OSA [76]. OSA also is a prothrombotic state that is characterized by higher levels of platelet
aggregation and activation [77 – 80], elevated fibrinogen levels (correlating with the severity of OSA) [81], decreased fibrinolytic activity [82], and increased whole blood viscosity—all of which may contribute to thrombosis and ischemic stroke. It is relevant that the cerebral hemodynamic changes may be reversed [83], platelet aggregability can be decreased [79,80], and the increase in morning fibrinogen levels can be blunted [84] by CPAP treatment. Atherosclerosis also may be an important factor predisposing to stroke. Increased carotid wall thickness (a marker of generalized atherosclerosis and a risk factor for stroke) and calcified carotid artery atheromas are significantly more prevalent in individuals with OSA [55,56]. Finally, hypertension, the prevalence of which is high in OSA, is a known risk factor for stroke and may contribute substantially to any association between OSA and stroke. Although OSA is an attractive potential contributor to stroke, the evidence that links OSA to stroke is primarily observational, and any causality is inferred from these data and the experimental data that suggest that OSA contributes to abnormalities in cerebral blood flow and a prothrombotic state. There is a clear need for more definitive longitudinal studies of stroke risk in patients with OSA, independent of other risk factors, particularly hypertension and hyperlipidemia. Importantly, there is some indication that OSA in stroke survivors may be associated with increased mortality and a worse long-term functional outcome [67,68,85]. Hence, it may be prudent to use CPAP therapy in compliant
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patients after stroke with documented evidence of sleep-disordered breathing.
Heart failure Patients with systolic heart failure have a significant prevalence of sleep apnea (primarily CSA) [86 – 90]. OSA may be especially common in patients with left ventricular diastolic dysfunction [91,92], although not all studies are consistent [93]. The relative contribution of CSA and OSA to sleep-disordered breathing varies in different congestive heart failure (CHF) populations studied, with a general predominance of CSA. Recent observations suggest that there may be an important pathophysiologic link between OSA and CSA. Namely, it has been observed that in heart failure patients the proportion of OSA decreases and the proportion of CSA increases from the first to the last quarter of the night, with an accompanying decrease in transcutaneous carbon dioxide levels and a significant lengthening of circulation time [94]. This overnight shift from OSA to CSA may be related to a deterioration of cardiac function (caused by the assumption of a recumbent position and by the detrimental hemodynamic effects of OSA), with a subsequent increase in left ventricular filling pressures. The significance of OSA in CHF is twofold. First, OSA might predispose a person to CHF. Some preliminary epidemiologic data suggest that the presence of OSA is associated with a relative odds for self-reported CHF of 2.38 (independent of other risk factors) [57]. Such a causal relationship between OSA and CHF may be explained by the association of OSA with other direct or indirect risk factors for CHF (eg, hypertension, ischemic heart disease, ventricular hypertrophy, oxidative tissue damage, systemic inflammation, neuroendocrine activation, or autonomic dysfunction). Second, CHF might contribute to new-onset OSA, especially in susceptible individuals. In this case, OSA may be caused by the collapse of the upper airway because of soft tissue edema and changes in upper airway muscle tone. OSA superimposed on CHF may lead to further deterioration of cardiac function (caused by hypoxemia, sympathetic activation, vasoconstriction, endothelial dysfunction) and set up a vicious cycle of progressing, refractory CHF. An independent association between the severity of sleep apnea and depression of left ventricular ejection fraction has been reported [95]. In small study samples, treatment of OSA with CPAP has been shown to substantially improve left ventricular ejection frac-
Fig. 4. Effects of nasal continuous positive airway pressure (nCPAP) therapy on improving left ventricular ejection fraction (LVEF) and functional class (NYHA) in patients with congestive heart failure. (Modified from Malone S, Liu PP, Holloway R, Rutherford R, Xie A, Bradley TD. Obstructive sleep apnea in patients with idiopathic dilated cardiomyopathy: effects of continuous positive airway pressure. Lancet 1991;338:1480 – 4; with permission.)
tion and functional class in patients with CHF [96] (Fig. 4).
Pulmonary hypertension Apnea and hypoxemia also may elicit acute elevations of pulmonary artery pressure during sleep. Conceivably, these nocturnal events of hypoxia and pulmonary hypertension might contribute to endothelial damage and vascular remodeling, which may further lead to sustained pulmonary hypertension. Several studies have reported the presence of daytime pulmonary hypertension in patients with OSA. In many studies, however, other comorbidities were also present (most notably lung disease, heart failure, or systemic hypertension), so that any independent contribution of OSA to chronic pulmonary hypertension remains unclear. Several studies have investigated the occurrence of daytime pulmonary hypertension in patients with OSA in the absence of lung and heart disease. These
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studies generally support the concept that OSA is associated with daytime pulmonary hypertension [97 – 100]. The frequency of pulmonary hypertension varies among various populations studied. It should be noted that in several studies there was no difference between pulmonary hypertensive and normotensive OSA subjects with respect to nocturnal oxygenation and OSA severity [97,98,100], which suggests that individual variation in pulmonary vascular sensitivity to hypoxic stimuli may be important or, alternatively, that factors other than OSA per se may be responsible for the apparent increased pulmonary artery pressures in patients with OSA. Patients with OSA with daytime pulmonary hypertension have been reported to have greater elevations of pulmonary artery vascular tone during rapid eye movement sleep, independent of the degree of hypoxia [101]. In some [100,102,103], although not all [97,104] studies, patients with OSA and pulmonary hypertension have been suggested to differ from their nonhypertensive counterparts in that they tend to have a greater body mass index and lower daytime arterial oxygen saturation. It is possible, at least in some patients with OSA, that mild daytime hypoxemia caused by the obesity-hypoventilation syndrome might play a role in increasing daytime pulmonary artery pressures. Interestingly, CPAP therapy seems to reduce pulmonary pressures in OSA patients with either pulmonary hypertension or with normal pulmonary pressures [100,105], which suggests the possibility that in many cases even ‘‘normal’’ pulmonary pressures may be elevated compared with individual baseline values. A recent report on subjects drawn from the general population suggested that sleep-disordered breathing is associated with increased right ventricular wall thickness [106]. Right ventricular hypertrophy has been found in selected subjects with OSA [107,108]. Depressed right ventricular ejection fraction and clinical evidence of right ventricular failure also have been reported in patients with OSA [109 – 111]. Echocardiographic studies of right ventricular morphology and function and Doppler estimates of right ventricular systolic pressure (and hence pulmonary artery systolic pressure) in OSA patients are limited by several factors, however, including (1) the difficulty in obtaining high-quality images in a population that is often obese, (2) the potential influence of comorbidities and medication on these measurements, (3) the difficulties in selecting appropriate control subjects for comparison, and (4) the natural scatter of measurements within a population, together with margins of error inherent in these measurements. As with other cardiovascular conditions, there is a clear need for more
stringent longitudinal studies before any definitive assessment of the risk of chronic pulmonary hypertension in patients with OSA can be made. Further studies also are needed to investigate the relationship between OSA, pulmonary hypertension, right ventricular hypertrophy, and right ventricular failure and to establish whether these pathologic changes have any impact on prognosis and require specific treatment.
Cardiac arrhythmias Most studies that investigate the association between OSA and cardiac arrhythmias have methodologic limitations related to small sample sizes and lack of control groups. The exact prevalence of arrhythmias in patients with sleep apnea is also difficult to assess because of comorbidities, medication, and differences among the populations studied. There is nevertheless a general perception that sleep apnea is associated with an increased incidence of bradyarrhythmias and tachyarrhythmias (both supraventricular and ventricular). The most frequent arrhythmias described in association with sleep apnea are severe sinus bradycardia and atrioventricular block (including sinus arrest and complete heart block). These arrhythmias are purely functional because they have been reported in the absence of any primary disease of the cardiac conduction system and they readily respond to atropine. The most important pathophysiologic mechanism of bradyarrhythmias in OSA is a reflex (chemoreceptor mediated) increase in vagal tone, which is elicited by a combination of apnea and hypoxemia [112 – 115] that activates the diving reflex (increased sympathetic traffic to peripheral blood vessels and increased vagal drive to the heart). The occurrence of OSA-related bradycardia seems to be linked to apnea severity [116 – 118]. Bradyarrhythmias also may be more likely to occur in patients with impaired baroreflex function (eg, persons with hypertension or heart failure) [115]. The number of bradyarrhythmias seems to be greater in rapid eye movement sleep [118], which may be related in part to greater OSA severity in this sleep stage. The causal relationship between these bradyarrhythmias and OSA is supported by the observation that bradycardia occurs only during the night (in association with nocturnal apnea episodes) in otherwise asymptomatic subjects [119,120] and is readily prevented by tracheostomy or CPAP therapy [116, 117,119 – 122]. CPAP therapy has been shown to be curative in a sample of patients primarily referred for pacemaker therapy with asymptomatic brady-
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arrhythmias during sleep, most of whom were subsequently diagnosed with OSA [123]. Although the prognostic significance of severe nocturnal bradyarrhythmias in OSA is not known, it is prudent to evaluate all patients with asymptomatic bradyarrhythmias for the presence of sleep apnea, which should be treated appropriately. Cardiac tachyarrhythmias also have been reported in OSA, including ventricular tachycardia [116,120, 124] and supraventricular tachycardias. The prevalence and severity of these rhythm disturbances are low in otherwise healthy patients with OSA, however, and the clinical significance of these arrhythmias is unclear. In contrast, sleep apnea may be an important trigger for clinically significant arrhythmias in the presence of serious comorbidities, such as ischemic heart disease or heart failure. For example, sleep apnea (central and obstructive) has been associated with a greater prevalence of atrial fibrillation in patients with heart failure [125,126] or after coronary artery bypass surgery [127]. Similarly, CSA and OSA are related to the occurrence of ventricular arrhythmias in the heart failure population [126,128], with a decrease in arrhythmias after CPAP therapy [129].
Summary Sleep apnea is associated with several cardiovascular disease conditions. A causal relationship between sleep apnea and each of these diseases is likely, but remains to be proven. The clearest evidence implicating OSA in the development of new cardiovascular disease involves data that show an increased prevalence of new hypertension in patients with OSA followed over 4 years [3]. Circumstantial evidence and data from small study samples suggest that OSA, in the setting of existing cardiovascular disease, may exacerbate symptoms and accelerate disease progression. The diagnosis of OSA always should be considered in patients with refractory heart failure, resistant hypertension, nocturnal cardiac ischemia, and nocturnal arrhythmias, especially in individuals with risk factors for sleep apnea (eg, central obesity, age, and male gender). Treating sleep apnea may help to achieve better clinical control in these diseases and may improve long-term cardiovascular prognosis.
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