Curr Cardiol Rep (2014) 16:535 DOI 10.1007/s11886-014-0535-y
MANAGEMENT OF ACUTE CORONARY SYNDROMES (R GULATI, SECTION EDITOR)
Obstructive Sleep Apnea and Acute Coronary Syndromes: Etiology, Risk, and Management B. Cepeda-Valery & S. Acharjee & A. Romero-Corral & G. S. Pressman & A. S. Gami
Published online: 19 August 2014 # Springer Science+Business Media New York 2014
Abstract Obstructive sleep apnea (OSA) is characterized by upper airway collapse and airflow reduction despite respiratory effort, resulting in intermittent hypoxia and arousals, leading to a cascade of hemodynamic, autonomic, inflammatory, and metabolic effects, responsible for its adverse cardiovascular effect. OSA is an independent risk factor for cardiovascular disease, and its prevalence in patients presenting with acute coronary syndromes is up to 69 %. Furthermore, OSA has been associated with increased risk of adverse events after an acute coronary syndrome. Continuous positive airway pressure is considered the mainstay of treatment of OSA and has been shown to reduce the risk of cardiovascular events. However, the proper time to start treatment in the acute setting is unknown. A prospective randomized clinical trial is currently underway to answer this question. This article is part of the Topical Collection on Management of Acute Coronary Syndromes B. Cepeda-Valery : S. Acharjee : A. Romero-Corral : G. S. Pressman The Institute for Heart and Vascular Health and Cardiovascular Diseases, Einstein Medical Center, 5501 Old York Road, Philadelphia, PA 19144, USA B. Cepeda-Valery e-mail: [email protected] S. Acharjee e-mail: [email protected] A. Romero-Corral e-mail: [email protected] G. S. Pressman e-mail: [email protected] A. S. Gami (*) Cardiac Electrophysiology, Midwest Heart Specialists-Advocate Medical Group, Elmhurst, IL, USA e-mail: [email protected]
Keywords Obstructive sleep apnea (OSA) . Acute coronary syndrome (ACS) . Coronary artery disease (CAD) . Risk factor
Introduction Obstructive sleep apnea (OSA) is characterized by upper airway collapse that results in repetitive airflow reduction despite respiratory effort. OSA creates high negative intrathoracic pressure and leads to intermittent hypoxia and central nervous system arousals. These, in turn, are associated with a cascade of hemodynamic, autonomic, inflammatory, and metabolic effects [1, 2]. An apnea is a >10-s pause in respiration associated with ongoing ventilatory effort, while hypopneas are decreases in ventilation associated with a fall in oxygen saturation or arousal. OSA is diagnosed when the apnea-hypopnea index (AHI) is >5 events/h. The term OSA syndrome is applied when a patient has OSA and symptoms, which can include loud snoring, restless and unrefreshing sleep, morning headaches, cognitive changes, and excessive daytime sleepiness. The severity of OSA is graded according to the AHI: an AHI of 5–15 defines mild OSA, 15–30 moderate OSA, and >30 severe OSA [1]. OSA affects male individuals more commonly. The risk of OSA rises with increasing body weight; active smoking; diabetes; age; and influence of alcohol, sedatives, and muscle relaxants [1]. Screening of patients for sleep breathing disorders can be done by several different methods, including several validated questionnaires or overnight oximetry. The gold standard for diagnosis is polysomnography, which requires spending a night in a sleep laboratory during
535, Page 2 of 7
which multiple physiological variables are continuously recorded [1].
Prevalence of Sleep Apnea in Coronary Artery Disease and Acute Coronary Syndromes OSA has been recognized as an independent risk factor for cardiovascular disease. Hypertension, coronary artery disease (CAD), diabetes, cardiovascular (CV) rhythm and conduction abnormalities (including atrial fibrillation), cerebrovascular disease, and heart failure have all been linked to this disorder (Fig. 1). OSA is a common chronic condition that affects an estimated 9 and 24 % of middle-aged women and men, respectively [1]. However, its prevalence in subjects with CAD is up to twofold greater than in those without CAD [1, 3], and it is estimated that in patients presenting with acute coronary syndromes (ACSs), prevalence ranges from 54 to 69 % [2–5]. OSA has also been shown to be an independent risk factor for CV events, including myocardial infarction (MI) [6•, 7]. Data from the Sleep Heart Health Study, a large populationbased study of patients free of CAD, showed an increased risk of incident CAD among OSA patients with an odds ratio (OR) of 1.2 (0.99–1.6) [8], suggesting OSA is a risk factor for CAD. Furthermore, at 8-year follow-up, OSA was a significant predictor of incident CAD (MI, revascularization procedure, or CV death) in men ≤70 years (adjusted hazard ratio (HR) 1.1, 95 % confidence interval 1 to 1.20 per 10-unit increase in apnea—AHI) though not in older men or women [9••]. In other long-term studies, the presence of OSA in patients with CAD was an independent predictor of CV mortality and was
Fig. 1 Reported prevalence of OSA in associated cardiovascular conditions. HTN, hypertension; CAD, coronary artery disease; ESRD, endstage renal disease; CVA/TIA, cerebrovascular accident/transient ischemic attack; CHF, congestive heart failure
Curr Cardiol Rep (2014) 16:535
associated with a significant increase in major adverse CV events (MACE; death, MI, and cerebrovascular events) at a 5year median follow-up interval [6•, 10]. Patients with suspected OSA presenting with ACS are more likely to be men and have conventional risk factors, such as hypertension, diabetes mellitus, and obesity. On admission, these patients have significantly higher systolic and diastolic blood pressure, higher plasma C-reactive protein (a marker of inflammation and CV risk), and higher brain natriuretic peptide (BNP) levels (a long-term predictor of CV morbidity and mortality), despite the fact that obese patients generally tend to have lower BNP levels [11]. OSA has also been associated with increased risk of adverse events after percutaneous coronary intervention (PCI) in ACS. One study followed 89 consecutive patients post-PCI for ACS for a mean of 227 days. The incidence of MACE (cardiac death, reinfarction, and target vessel revascularization) was significantly higher in patients with OSA (23.5 vs. 5.3 %, p=0.02). By multivariate analysis, the presence of OSA was an independent predictor of MACE (HR 11.6, 95 % confidence interval 2.1 to 62.2, p=0.004) [4]. In spite of its high prevalence and impact on CVoutcomes, OSA is under-recognized and under-diagnosed. In patients presenting with ACS, there is a low rate of documentation of diagnosed or suspected OSA, ranging from 12 to 14 %, suggesting a lack of awareness and detection of this condition during treatment of acute MI [11, 12].
Pathophysiology: Obstructive Sleep Apnea, Atherosclerosis, and Acute Coronary Syndrome The mechanisms by which OSA may lead to atherosclerosis are multiple and complex. However, it is thought that both direct mechanisms (e.g., intermittent hypoxia) and indirect mechanisms (e.g., OSA-related hypertension) are responsible (Fig. 2). With each apneic episode and post-apneic reoxygenation, there is increased sympathetic activation, vasoconstriction, induction of oxidative stress, generation of reactive oxygen species, and provocation of inflammation leading to endothelial dysfunction and early atherosclerosis [1, 13]. Over the long term, this pathophysiology is believed to promote coronary artery damage. In addition to the neurohormonal effects of OSA, there are mechanical effects. Apneas generate high negative intrathoracic pressure that causes increase in LV transmural pressure and increased myocardial oxygen demand. At the same time, reduced coronary blood flow and apnea-related hypoxia lead to reduced oxygen delivery to the myocardium; these effects can precipitate myocardial ischemia and impair cardiac contractility as well as diastolic relaxation [14]. Another important mechanical effect resulting from high negative
Curr Cardiol Rep (2014) 16:535
Fig. 2 Potential mechanisms of cardiovascular risk in obstructive sleep apnea. Adapted with permission from Somers et al. [1]
intrathoracic pressure is increased venous return to the right side of the heart. This can produce ventricular interdependence with decreases in left ventricular compliance and filling [14]. OSA is associated with acute increases in heart rate and blood pressure (and hence increased myocardial work) and decreases in arterial oxygen saturation. These changes are maximal during the period of hyperpnea that follows apnea resolution. Hamilton et al. reported transient uncoupling of coronary blood flow and myocardial oxygen demand following an obstructive apnea. This disturbed flow-metabolic coupling led to nocturnal myocardial ischemia and injury in stable CAD patients with OSA [15]. Platelet aggregability increases significantly overnight in association with elevated nocturnal catecholamine levels. Furthermore, there is evidence of predisposition to clot formation, owing to the increase in hematocrit, fibrinogen levels, and blood viscosity in OSA [16]. In patients with CAD, it is thought that the acute nocturnal pathophysiological responses to OSA, including hypoxemia, sympathetic activation, inflammation, and surges in blood pressure, may lead to plaque rupture, coronary thrombosis, and ACS.
Further Links Between OSA and Coronary Ischemia Early atherosclerosis could be one of the intermediary mechanisms linking OSA with CAD and CV mortality. Atherosclerosis is an inflammatory disease of the arterial wall and involves a dynamic interaction between the endothelium and pro-inflammatory molecules in the general circulation. OSA has been implicated in the secretion of these pro-
Page 3 of 7, 535
inflammatory molecules, progression of atherosclerotic lesions, and also plaque rupture, which can precipitate acute MI [17]. Patients with OSA and no significant comorbidities have higher carotid intimal media thickness, a marker of early atherosclerosis [18–20]. Furthermore, the severity of oxygen desaturation during the apneic episode is a predictor of carotid wall thickness. In a study of 83 patients, mean nocturnal SaO2
MANAGEMENT OF ACUTE CORONARY SYNDROMES (R GULATI, SECTION EDITOR)
Obstructive Sleep Apnea and Acute Coronary Syndromes: Etiology, Risk, and Management B. Cepeda-Valery & S. Acharjee & A. Romero-Corral & G. S. Pressman & A. S. Gami
Published online: 19 August 2014 # Springer Science+Business Media New York 2014
Abstract Obstructive sleep apnea (OSA) is characterized by upper airway collapse and airflow reduction despite respiratory effort, resulting in intermittent hypoxia and arousals, leading to a cascade of hemodynamic, autonomic, inflammatory, and metabolic effects, responsible for its adverse cardiovascular effect. OSA is an independent risk factor for cardiovascular disease, and its prevalence in patients presenting with acute coronary syndromes is up to 69 %. Furthermore, OSA has been associated with increased risk of adverse events after an acute coronary syndrome. Continuous positive airway pressure is considered the mainstay of treatment of OSA and has been shown to reduce the risk of cardiovascular events. However, the proper time to start treatment in the acute setting is unknown. A prospective randomized clinical trial is currently underway to answer this question. This article is part of the Topical Collection on Management of Acute Coronary Syndromes B. Cepeda-Valery : S. Acharjee : A. Romero-Corral : G. S. Pressman The Institute for Heart and Vascular Health and Cardiovascular Diseases, Einstein Medical Center, 5501 Old York Road, Philadelphia, PA 19144, USA B. Cepeda-Valery e-mail: [email protected] S. Acharjee e-mail: [email protected] A. Romero-Corral e-mail: [email protected] G. S. Pressman e-mail: [email protected] A. S. Gami (*) Cardiac Electrophysiology, Midwest Heart Specialists-Advocate Medical Group, Elmhurst, IL, USA e-mail: [email protected]
Keywords Obstructive sleep apnea (OSA) . Acute coronary syndrome (ACS) . Coronary artery disease (CAD) . Risk factor
Introduction Obstructive sleep apnea (OSA) is characterized by upper airway collapse that results in repetitive airflow reduction despite respiratory effort. OSA creates high negative intrathoracic pressure and leads to intermittent hypoxia and central nervous system arousals. These, in turn, are associated with a cascade of hemodynamic, autonomic, inflammatory, and metabolic effects [1, 2]. An apnea is a >10-s pause in respiration associated with ongoing ventilatory effort, while hypopneas are decreases in ventilation associated with a fall in oxygen saturation or arousal. OSA is diagnosed when the apnea-hypopnea index (AHI) is >5 events/h. The term OSA syndrome is applied when a patient has OSA and symptoms, which can include loud snoring, restless and unrefreshing sleep, morning headaches, cognitive changes, and excessive daytime sleepiness. The severity of OSA is graded according to the AHI: an AHI of 5–15 defines mild OSA, 15–30 moderate OSA, and >30 severe OSA [1]. OSA affects male individuals more commonly. The risk of OSA rises with increasing body weight; active smoking; diabetes; age; and influence of alcohol, sedatives, and muscle relaxants [1]. Screening of patients for sleep breathing disorders can be done by several different methods, including several validated questionnaires or overnight oximetry. The gold standard for diagnosis is polysomnography, which requires spending a night in a sleep laboratory during
535, Page 2 of 7
which multiple physiological variables are continuously recorded [1].
Prevalence of Sleep Apnea in Coronary Artery Disease and Acute Coronary Syndromes OSA has been recognized as an independent risk factor for cardiovascular disease. Hypertension, coronary artery disease (CAD), diabetes, cardiovascular (CV) rhythm and conduction abnormalities (including atrial fibrillation), cerebrovascular disease, and heart failure have all been linked to this disorder (Fig. 1). OSA is a common chronic condition that affects an estimated 9 and 24 % of middle-aged women and men, respectively [1]. However, its prevalence in subjects with CAD is up to twofold greater than in those without CAD [1, 3], and it is estimated that in patients presenting with acute coronary syndromes (ACSs), prevalence ranges from 54 to 69 % [2–5]. OSA has also been shown to be an independent risk factor for CV events, including myocardial infarction (MI) [6•, 7]. Data from the Sleep Heart Health Study, a large populationbased study of patients free of CAD, showed an increased risk of incident CAD among OSA patients with an odds ratio (OR) of 1.2 (0.99–1.6) [8], suggesting OSA is a risk factor for CAD. Furthermore, at 8-year follow-up, OSA was a significant predictor of incident CAD (MI, revascularization procedure, or CV death) in men ≤70 years (adjusted hazard ratio (HR) 1.1, 95 % confidence interval 1 to 1.20 per 10-unit increase in apnea—AHI) though not in older men or women [9••]. In other long-term studies, the presence of OSA in patients with CAD was an independent predictor of CV mortality and was
Fig. 1 Reported prevalence of OSA in associated cardiovascular conditions. HTN, hypertension; CAD, coronary artery disease; ESRD, endstage renal disease; CVA/TIA, cerebrovascular accident/transient ischemic attack; CHF, congestive heart failure
Curr Cardiol Rep (2014) 16:535
associated with a significant increase in major adverse CV events (MACE; death, MI, and cerebrovascular events) at a 5year median follow-up interval [6•, 10]. Patients with suspected OSA presenting with ACS are more likely to be men and have conventional risk factors, such as hypertension, diabetes mellitus, and obesity. On admission, these patients have significantly higher systolic and diastolic blood pressure, higher plasma C-reactive protein (a marker of inflammation and CV risk), and higher brain natriuretic peptide (BNP) levels (a long-term predictor of CV morbidity and mortality), despite the fact that obese patients generally tend to have lower BNP levels [11]. OSA has also been associated with increased risk of adverse events after percutaneous coronary intervention (PCI) in ACS. One study followed 89 consecutive patients post-PCI for ACS for a mean of 227 days. The incidence of MACE (cardiac death, reinfarction, and target vessel revascularization) was significantly higher in patients with OSA (23.5 vs. 5.3 %, p=0.02). By multivariate analysis, the presence of OSA was an independent predictor of MACE (HR 11.6, 95 % confidence interval 2.1 to 62.2, p=0.004) [4]. In spite of its high prevalence and impact on CVoutcomes, OSA is under-recognized and under-diagnosed. In patients presenting with ACS, there is a low rate of documentation of diagnosed or suspected OSA, ranging from 12 to 14 %, suggesting a lack of awareness and detection of this condition during treatment of acute MI [11, 12].
Pathophysiology: Obstructive Sleep Apnea, Atherosclerosis, and Acute Coronary Syndrome The mechanisms by which OSA may lead to atherosclerosis are multiple and complex. However, it is thought that both direct mechanisms (e.g., intermittent hypoxia) and indirect mechanisms (e.g., OSA-related hypertension) are responsible (Fig. 2). With each apneic episode and post-apneic reoxygenation, there is increased sympathetic activation, vasoconstriction, induction of oxidative stress, generation of reactive oxygen species, and provocation of inflammation leading to endothelial dysfunction and early atherosclerosis [1, 13]. Over the long term, this pathophysiology is believed to promote coronary artery damage. In addition to the neurohormonal effects of OSA, there are mechanical effects. Apneas generate high negative intrathoracic pressure that causes increase in LV transmural pressure and increased myocardial oxygen demand. At the same time, reduced coronary blood flow and apnea-related hypoxia lead to reduced oxygen delivery to the myocardium; these effects can precipitate myocardial ischemia and impair cardiac contractility as well as diastolic relaxation [14]. Another important mechanical effect resulting from high negative
Curr Cardiol Rep (2014) 16:535
Fig. 2 Potential mechanisms of cardiovascular risk in obstructive sleep apnea. Adapted with permission from Somers et al. [1]
intrathoracic pressure is increased venous return to the right side of the heart. This can produce ventricular interdependence with decreases in left ventricular compliance and filling [14]. OSA is associated with acute increases in heart rate and blood pressure (and hence increased myocardial work) and decreases in arterial oxygen saturation. These changes are maximal during the period of hyperpnea that follows apnea resolution. Hamilton et al. reported transient uncoupling of coronary blood flow and myocardial oxygen demand following an obstructive apnea. This disturbed flow-metabolic coupling led to nocturnal myocardial ischemia and injury in stable CAD patients with OSA [15]. Platelet aggregability increases significantly overnight in association with elevated nocturnal catecholamine levels. Furthermore, there is evidence of predisposition to clot formation, owing to the increase in hematocrit, fibrinogen levels, and blood viscosity in OSA [16]. In patients with CAD, it is thought that the acute nocturnal pathophysiological responses to OSA, including hypoxemia, sympathetic activation, inflammation, and surges in blood pressure, may lead to plaque rupture, coronary thrombosis, and ACS.
Further Links Between OSA and Coronary Ischemia Early atherosclerosis could be one of the intermediary mechanisms linking OSA with CAD and CV mortality. Atherosclerosis is an inflammatory disease of the arterial wall and involves a dynamic interaction between the endothelium and pro-inflammatory molecules in the general circulation. OSA has been implicated in the secretion of these pro-
Page 3 of 7, 535
inflammatory molecules, progression of atherosclerotic lesions, and also plaque rupture, which can precipitate acute MI [17]. Patients with OSA and no significant comorbidities have higher carotid intimal media thickness, a marker of early atherosclerosis [18–20]. Furthermore, the severity of oxygen desaturation during the apneic episode is a predictor of carotid wall thickness. In a study of 83 patients, mean nocturnal SaO2
