OSA & Cardiovascular Diseases
OSA has been shown to increase the risk for systemic hypertension, pulmonary vascular disease, ischemic heart disease, cerebral vascular disease, congestive heart failure and arrhythmias.[60] Increased sympathetic activity, oxidative stress, systemic inflammation, endothelial dysfunction, metabolic dysregulation and intrathoracic pressure changes during OSA are contributory factors for cardiovascular consequences in OSA.[61] Although there are evidences that show a causal relationship between OSA and cardiovascular disorders, more data from randomized controlled intervention trials are required to establish a causal relationship. Many risk factors of OSA (age, male gender and obesity) are also risk factors for cardiovascular disease. OSA is also associated with conditions (diabetes mellitus and hypertension) that are known to increase the risk for cardiovascular disease. Therefore, it is difficult to prove whether OSA can independently cause cardiovascular disease.
Systemic Hypertension
In normal individuals, sleep is associated with a reduced BP compared with wakefulness and this is known as 'dipping' phenomenon. In normal individuals, systolic and diastolic BPs may decline as much as 10–15%. Sleep apnea has been found to blunt the dipping of BP during sleep. Disordered breathing during sleep has also been found to be associated with acute peripheral vasoconstriction and rise in BP during sleep.[8] Several studies have shown that OSA increases the relative risk of hypertension, independent of other confounding factors. The Sleep Heart Health Study (SHHS), in a cross-sectional analysis of >6000 patients, has shown a linear relationship between systolic and diastolic BP and OSA severity.[62] A Canadian population-based study involving 2677 adults between 20 and 85 years of age has shown that each apneic event per hour increased the odds of hypertension by 1%, and each 10% reduction in nocturnal O2 saturation increased the likelihood of developing hypertension by 13%.[63] As the above studies were cross-sectional in nature, linking sleep-disordered breathing to chronically elevated BP, a prospective population-based study was conducted to discover the association between objectively measured sleep-disordered breathing and hypertension.[64] This Wisconsin sleep cohort study in 709 participants has demonstrated a dose–response association between sleep-disordered breathing at baseline and the presence of hypertension 4 years later, and this was independent of known confounding factors. Relative to the reference category of an AHI of zero events per hour at baseline, the odds ratios (ORs) for the presence of hypertension at follow-up were 1.42 with an AHI of 0.1–4.9 events per hour at baseline as compared with none, 2.03 with an AHI of 5.0–14.9 events per hour and 2.89 with an AHI of 15.0 or more events per hour.[64] This study suggested that sleep-disordered breathing is probably a risk factor for hypertension and consequent cardiovascular morbidity in the general population.[64] In another prospective study of 2470 participants of SHHS over 40 years of age without baseline hypertension and not on antihypertensive medication, it has been shown that there is a significant relationship between the risk of developing hypertension and OSA. However, this association was lost after adjustment for BMI. A moderate influence of an AHI >30 on hypertension could not be excluded in this study.[65] In a longitudinal study in the general population (Victoria sleep cohort) involving 2148 subjects and with a 7.5-year follow-up, there is no suggestion of an association between OSA and incident systemic hypertension in the middle-aged general population.[66] CPAP has been shown to acutely attenuate sympathetic drive and nocturnal BP in OSA.[67] Observational studies from uncontrolled and highly selected populations have suggested improvement in BP control with CPAP.[68] A meta-analysis of 12 placebo-controlled randomized trials (n = 572) found a statistically pooled reduction in mean BP of 1.69 mmHg with CPAP treatment.[69] Most of these trials were limited to normotensive individuals. Although there is no conclusive proof that OSA is associated with incident systemic hypertension, the seventh report of the Joint Committee on Prevention, Detection, Evaluation and Treatment of High BP has listed sleep apnea as a significant cause of secondary hypertension.[70]
Pulmonary Hypertension
Pulmonary hypertension is defined as a mean pulmonary arterial pressure >25 mmHg at rest or >30 mmHg with exercise as measured by right heart catheterization. It has been demonstrated that hypoxic vasoconstriction over time may result in pulmonary vascular remodeling, contributing to the development of pulmonary hypertension, as seen in patients with chronic lung diseases. It may, therefore, be possible that repetitive upper airway collapse and oxyhemoglobin desaturation characteristic of OSA could also provide a pathophysiologic basis for elevations in pulmonary arterial pressure.[71] Data from case series mainly in male patients have suggested that the prevalence of pulmonary hypertension in OSA varies between 17 and 53%. However, there are no population-based data to show the prevalence of pulmonary hypertension in OSA. In a study of patients with OSA with no clinically significant cardiac and pulmonary disease, 41% had pulmonary hypertension. There was no difference in AHI, BMI, smoking history and lung function between patients with pulmonary hypertension and those without pulmonary hypertension.[72] Pulmonary hypertension in these patients is only mild and does not lead to right heart failure. A placebo-controlled, randomized-crossover trial of CPAP and sham CPAP over 12 weeks has been conducted in 23 patients with OSA, and CPAP therapy was found to reduce pulmonary arterial systemic pressure in all patients with pulmonary hypertension at baseline.[73] The revised 'Clinical Classification of Pulmonary Hypertension' has identified sleep-disordered breathing as part of the category of respiratory disorders associated with pulmonary hypertension.[74]
Cardiac Arrhythmias & Cardiovascular Mortality
The prevalence of cardiac arrhythmias in two samples of participants from the SHSS showed that compared with subjects with respiratory disturbance index <5, those with severe OSA (respiratory disturbance index >30) had higher rates of atrial fibrillation, nonsustained ventricular tachycardia, complex ventricular ectopy (bigeminy, trigeminy and quandrigeminy). In comparison to with those without sleep-disordered breathing and adjusting for age, sex, BMI and prevalent coronary heart disease (CHD), individuals with sleep-disordered breathing had four-times the odds of atrial fibrillation (OR: 4.02), three-times the odds of nonsustained ventricular tachycardia (OR: 3.40), and almost twice the odds of complex ventricular ectopy (OR: 1.74).[75] Bradyarrhythmias are also reported in OSA and can occur with a structurally normal heart. Effective CPAP therapy has been shown to attenuate bradyarrhythmias.[76] The relative risk of sudden death from cardiac causes from midnight to 6 a.m. was 2.57 for people with OSA. By contrast, the risk of sudden death from cardiac causes in the general population peaks from 6 a.m. to noon and has a nadir from midnight to 6 a.m..[77] However, a causative role for sleep apnea in serious arrhythmias or sudden death has not been proven.[75,78] In an observational study, it has been observed that severe obstructive sleep apnea-hypopnea significantly increased the risk of fatal and nonfatal cardiovascular events in men and CPAP treatment reduced this risk.[79] In another observational study of 1116 women with a median follow-up of 72 months, it has been shown that untreated severe OSA was associated with increased cardiovascular mortality in women and that adequate CPAP treatment was associated with a decrease in mortality risk.[80] As both these studies that have demonstrated increased mortality in untreated OSA in men and women are observational, randomized longitudinal studies are required to prove the risk of OSA on cardiovascular mortality and also to establish the effect of CPAP treatment in patients with OSA.
OSA, Coronary Artery Disease & Heart Failure
There is a close link between OSA and heart failure by their close association with aging and obesity. The Framingham study has shown that increasing BMI is directly correlated with incident heart failure and may be mediated in part by OSA.[81] Incident atrial fibrillation, an important risk factor for heart failure, is also associated with the degree of oxyhemoglobin desaturation in OSA.[81–83] Repetitive upper airway closure in OSA can have deleterious effects on cardiac function. In total, 4422 subjects (1927 men and 2495 women) from the SHSS cohort who were at least 40 years of age and free of CHD and heart failure at the time of baseline polysomnography were monitored for a median of 8.7 years. Multivariable regression analysis after adjusting for age, race, BMI and smoking has shown a significant association between AHI and CHD in men, but not in women, and this relationship was no longer significant after further adjustment for diabetes, hypertension and lipids. Men younger than 70 years had a significant association between AHI and CHD once fully adjusted (hazard ratio: 1.68; AHI >30 vs AHI <5) and had a strong association between AHI and incident heart failure (hazard ratio: 1.58; AHI >30 vs AHI <5).[84,85] In a study of subjects randomly assigned to receive medical therapy either alone or with the addition of CPAP for 1 month, it has been shown that treatment of coexisting OSA by CPAP reduces systolic BP and improves left ventricular systolic function in medically treated patients with heart failure.[86] In another randomized study of patients with congestive heart failure and OSA receiving 3 months of CPAP, it has been shown that there is significant improvements in left ventricular ejection fraction and reductions in urinary catecholamines, but no changes in BP.[87] However, in another rigorous, placebo-controlled crossover study using autotitrating CPAP, the authors found no improvement in any parameter of cardiovascular function, including left ventricular ejection fraction, BP and exercise tolerance.[88] Further trials are required to know the exact role of CPAP in patients with heart failure and OSA.
OSA & Incident Stroke
The incidence of stroke was studied in a geographically diverse, community-based sample of male and female participants in SHHS. Based on 8 years of prospective data from the study, it has been observed that modest-to-severe levels of sleep apnea are associated with an approximately threefold increased risk of ischemic stroke in men.[89] A prospective study has shown that self-reported snoring was an independent risk factor for stroke in women.[90] Data from the Wisconsin sleep cohort have demonstrated that moderate-to-severe sleep-disordered breathing is a risk factor for prevalent stroke and that the pre-existing sleep disorder may be a risk factor for incident stroke.[91] Longitudinal data with a mean follow-up of 3.4 years on mortality from stroke and other causes in patients with pre-existing OSA, it has been demonstrated that there is an increasing risk of events with OSA severity.[92] It is feasible that stroke may itself predispose to sleep-disordered breathing. Apneic events have been found to be associated with reduced cerebral blood flow and this may promote thrombosis.[93] The higher rates of atrial fibrillation observed in OSA may increase the risk of embolic events in OSA. It has been observed that sleep capnea occurs frequently after stroke and CPAP treatment has been found to improve neurological recovery after stroke.[94,95] It was also observed in a prospective observational study of patients admitted for stroke and followed up for 7 years that there was an increased incidence of nonfatal cardiovascular events in stroke patients with moderate-to-severe OSA and treatment with CPAP reduced the incidence observed in these patients.[96] It was further reported that CPAP treatment reduced excess risk of mortality in patients with moderate-to-severe OSA and acute ischemic stroke.[97]
Other Cardiovascular Complications
It has been reported that there is a high prevalence of erectile dysfunction in OSA patients. The mean nocturnal oxygen saturation was independently associated with erectile dysfunction suggesting that intermittent nocturnal hypoxia observed in OSA may contribute to the development of erectile dysfunction.[98] Treatment with nasal CPAP has been found to resolve erectile dysfunction resulting in improvement in quality of life.[99] It was observed that abdominal aortic aneurysm is highly prevalent in OSA and there was further expansion of abdominal aortic aneurysm in patients with severe OSA.[100] In a nested case-control study, it has been shown that sleep-disordered breathing was associated with deep vein thrombosis and pulmonary embolism in female patients with OSA, and this association was independent of established risk factors for thrombosis.[101]
Expert Rev Resp Med. 2012;6(5):557-566. © 2012 Expert Reviews Ltd.
