Introduction

Obstructive sleep apnea (OSA) is a common disorder that traditionally has been predominantly recognized by specialists in pulmonary disease, neurology and psychiatry. However, recent data clearly linking OSA with cardiovascular disease (CVD), and evidence of a very high prevalence of OSA within cardiology practices, supports the need for the cardiology community to understand OSA’s key presenting features, its role as a risk factor for the development and progression of CVD, and potential of improving CVD through better efforts to screen and manage OSA. The following reviews the incidence, prevalence and associations of OSA with CVD, relative to cardiology practice.

The prevalence of OSA varies according to the threshold applied for defining abnormality (e.g., AHI > 5, >10, >15). Using minimal thresholds for diagnosis, numerous epidemiological studies have identified OSA as a very common disorder, affecting between 2-15% of middle-aged adults and more than 20% of the elderly.^1,2 Prevalence may be particularly high among certain groups of the population, including men, obese individuals, diabetics, the elderly, and minority groups. Considering recent data on obesity, a major risk factor for OSA, Young and associates estimated that one out of five adults suffer from mild OSA, and one out of 15 have moderate OSA.² Furthermore it appears that a majority of adults with OSA are undiagnosed. Given that excess weight is the strongest known contributing factor to OSA³ and given the burgeoning obesity epidemic, it is very likely that these numbers underestimate current values and that the incidence of OSA will continue to rise, especially in patients with multiple OSA risk factors, which overlap with risk factors for CVD.

The physiological derangements caused by recurrent periods of airway obstruction adversely impact the cardiovascular system. With recurrent episodes of pharyngeal obstruction, there may be marked swings in intra-thoracic pressure and changes in cardiac pre- and afterload, potentially contributing to cardiac remodeling and reduced cardiac function. Sleep fragmentation, cortical arousal and intermittent hypoxemia stimulate sympathetic over-activity, leading to acute blood pressure surges during sleep, endothelial damage, and nocturnal as well as daytime hypertension. Further, OSA can result in increases in mean arterial pressure (MAP) of up to 30 mm Hg.^16,17 OSA-related hypoxemia also enhances release of acute phase proteins and reactive oxygen species, causing secondary release of mediators that exacerbate insulin resistance, stimulates lipolysis, and causes an augmented pro-thrombotic and pro-inflammatory state, creating a potent milieu for atherogenesis.

OSA has been established to contribute to a variety of cardiovascular diseases, including but not limited to systemic and pulmonary arterial hypertension (HTN), heart failure with and without reduced ejection fraction (EF), atherosclerosis and coronary artery disease (CAD), and arrhythmias.^4-11 Treatment of OSA has been shown to reduce several markers of cardiovascular risk and to improve various outcomes in patients with active cardiovascular disease.^12,13 However, definitive large scale trials evaluating the role of OSA treatment in cardiovascular events and mortality are lacking, and currently OSA is widely under-recognized disease in both primary care and cardiovascular clinics.

OSA and Hypertension

A number of epidemiological studies and several modest sized clinical trials have provided data indicating that OSA is an independent risk factor for the development of HTN.^5,14,15 The Wisconsin Sleep Cohort, a prospective population-based analysis, has shown a dose-response relationship between severity of OSA and risk of developing HTN. Even small elevations in AHI (< 5) are associated with a 42% increased odds of HTN over four years. Further, mild (AHI of 5-14.9) and moderate OSA (AHI>15) are associated with two and three times the odds of developing HTN, respectively.⁴ A non-dipping blood pressure profile is particularly common with OSA. JNCV7 now recognizes OSA as a leading cause of resistant HTN. Both short and long term studies have shown that treatment of OSA lowers blood pressure, with results appearing largest in patients with more severe OSA and accompanying symptoms of sleepiness.^18,37 In a prospective analysis of Spanish patients without HTN referred to a sleep center, Marin et al. demonstrated that OSA, independent of obesity and other known OSA risk factors, increased the risk of HTN development. They also demonstrated that treatment of OSA with continuous positive airway pressure (CPAP) resulted in a long term reduction in this risk.¹² Given the high prevalence of OSA and evidence that even mild OSA increases risk of HTN independently of excess body weight and other known risk factors, it is important to screen hypertensive patients for OSA, especially those at risk for OSA due to obesity and symptoms.

OSA and Coronary Artery Disease

OSA and CAD commonly co-aggregate.19 CAD is estimated to be present in 20-25% of OSA patients from clinical studies of sleep clinic cohorts.^20,21 OSA is estimated to have a prevalence of approximately 30% in patients with CAD in multiple case control studies.^22,23 There is growing evidence that OSA is independently associated with CAD, though direct causality remains controversial, and associations may vary across population subsets, with associations appearing strongest in middle-aged men.³⁵ Patients with OSA and CAD have an increased incidence of major acute cardiac events, and effective treatment of OSA with CPAP may significantly reduce such events.¹³ Peker et al. studied a sleep clinic cohort of 182 men free of any CVD including HTN, diabetes mellitus (DM), and other significant co-morbidities and found that 36.7% of subjects with OSA developed CAD compared to 6.6% of subjects without OSA (p<0.001) independent of obesity and other known risk factors. Furthermore, of the patients with OSA, 56% of those inadequately treated for OSA developed CAD compared to only 6.7% of those treated appropriately (p<0.001).¹³ The same study demonstrated that the frequency of apneas and hypopneas is an independent predictor of mortality in patients with CAD.^24,25 Given the high prevalence and increased incidence of CAD in patients with OSA, as well as potential for improved outcomes with adequate treatment, it is important to screen for both disorders in patients at risk for one, and consider co-management strategies. Further research is needed, however, to define the impact of OSA treatment on primary and secondary disease prevention.

OSA and Heart Failure

There is a high prevalence of sleep apnea in patients with heart failure (HF) both with reduced and with preserved ejection fraction (EF). Earlier studies estimated the prevalence of OSA in heart failure with reduced EF to be 12-15%, while the prevalence of central sleep apnea (CSA) was between 37-38%.^26,27 More recent studies have found an even higher prevalence of both CSA and OSA in heart failure patients. Out of 126 patients with NYHA classes II-IV HF, 71% were diagnosed with sleep apnea of which 65% had CSA and 35% OSA.²⁸ One of the largest studies to date prospectively evaluated 700 patients with NYHA class II or higher HF or EF≤40% and determined that 76% of patients had sleep disordered breathing, of which 40% had CSA and 36% OSA.29 Only one study found the prevalence of OSA to be higher than CSA in HF with reduced EF. Prospective evaluation of 103 patients reported that 73% had sleep apnea, 60% of which had OSA.³⁰ This is the first study that found a predominance of OSA as opposed to CSA in heart failure patients with reduced EF.

Less data are available on the prevalence of OSA in heart failure patients with preserved EF. A recent study evaluating 115 patients with heart failure, 38% of whom had preserved EF, found that those with preserved EF also had a high prevalence of sleep disordered breathing (SDB). Of the 44 patients with HF with preserved EF, 80% had sleep apnea and the majority of those cases (62%) had OSA.³¹ The largest study evaluating SDB in heart failure patients with preserved and reduced EF assessed 244 patients with HF with preserved EF using polygraphy. They found that 48% of these patients had an AHI≥15, 25% of whom had OSA.³² Many of the patients in the above studies did not have typical symptoms of sleep apnea, and body habitus ranged from thin to obese (with obese patients more likely to have OSA than CSA).

Although there are likely bi-directional associations between sleep apnea and HF, it is also likely that the presence of sleep apnea amplifiers the morbidity of HF via negative effects on cardiac function associated with sympathetic activity, cardiac afterload, and cardiac oxygen delivery. The high prevalence of sleep apnea in patients both with preserved and reduced EF warrant efforts by the cardiologist to recognize patients appropriate for further screening and treatment.

OSA and Atrial Fibrillation

OSA has been associated with a number of arrhythmias, but perhaps the strongest association is with atrial fibrillation (AF). Etiologically, OSA may trigger arrhythmias through effects on electrical remodeling of the heart and effects on sympathetic-parasympathetic balance (leading to shortening of the effective refractory period), ischemia-based myoctye injury, and possibly through effect on left atrial size. Several studies have now established a link between OSA and AF, particularly in cases of refractory or resistant AF.^7,32,33 One study has estimated the prevalence of SDB to be 74% in adults with persistent AF and normal left ventricular function. Of these patients, 43% had OSA,³² similar to an older study that found a 49% prevalence of OSA in patients with AF prior to cardioversion.⁷ The one year recurrence of AF after cardioversion has been estimated to be approximately two-fold higher in untreated than treated OSA patients.⁸ A recent study has reported the prevalence was documented to be much higher at 84% in patients with chronic AF.³³ Incident AF has been associated in a dose-dependent manner with level of overnight hypoxemia.⁷ A recent study in Germany compared adults with refractory (recurrence after ≥2 PV-isolation procedures), symptomatic paroxysmal AF to a cohort successfully treated after one PV isolation. All patients underwent overnight polygraphy and the prevalence of OSA was 48% in the control group and 87% in the therapy refractory group. AHI was also significantly higher in the therapy resistant group.³⁴ A careful analysis of the occurrence of paroxysms of AF or ventricular ectopy in association with the occurrence of apnea and hypopnea events on the sleep study further provided evidence that individual apneas/hypopneas serve as stimuli that trigger the occurrence of AF.³⁶

Conclusion

OSA is a strong risk factor for hypertension (including resistant hypertension), coronary artery disease, heart failure and arrhythmias. OSA occurs commonly in these disorders and effective treatment of OSA may improve blood pressure control, reduce the risk of major adverse cardiac events, reduce the incidence and recurrence of atrial fibrillation, and improve ejection fraction. Efforts to integrate OSA screening in cardiology practice, integrating with efforts to reduce the other and related CVD risk factors, may help reduce both CVD morbidity as well as improve quality of life associated with improved sleep.

Keywords: Acute-Phase Proteins, Airway Obstruction, Apnea, Arousal, Atherosclerosis, Atrial Fibrillation, Atrial Remodeling, Blood Pressure, Cardiovascular Diseases, Cardiovascular System, Case-Control Studies, Continuous Positive Airway Pressure, Control Groups, Coronary Artery Disease, Diabetes Mellitus, Electric Countershock, Heart Failure, Hypertension, Incidence, Insulin Resistance, Lipolysis, Lung Diseases, Middle Aged, Minority Groups, Neurology, Obesity, Oxygen, Polysomnography, Prevalence, Primary Health Care, Prospective Studies, Psychiatry, Quality of Life, Reactive Oxygen Species, Risk Factors, Sleep Apnea Syndromes, Sleep Apnea, Obstructive, Sleep Apnea, Central, Sleep Deprivation, Specialization, Ventricular Function, Left, Wisconsin

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