There is increasing evidence that untreated severe obstructive sleep apnea can lead to serious or fatal complications. Only limited data exist regarding the natural progression of this disorder in untreated individuals. A study concluded that respiratory disturbance index score does not necessarily increase over time, but associated hypertension or ischemic heart disease often develops. In addition, the patients who developed cardiovascular disease had significantly higher respiratory disturbance index than the patients who did not (Fisher et al 2002; McNicholas and Bonsignore 2007; Levy et al 2008; Young et al 2008).
In a prospective study, respiratory disturbance index score proved an independent predictor of cardiovascular mortality in coronary artery disease patients during a follow-up period of 5 years (Peker et al 2000).
Compared to normal controls, patients with myocardial infarction or stroke have an increased incidence of obstructive sleep apnea (Ali and Avidan 2008). Intracranial pressure may rise as much as 50 mm Hg during obstructive apneas, with a resulting fall in cerebral perfusion pressure, and there may be marked changes in cerebral blood flow velocity (Siebler et al 1990). A higher percentage of silent ischemic brain lesions has been described in patients with moderate to severe obstructive sleep apnea (25.0%) compared to obese control subjects (6.7%) or patients with mild obstructive sleep apnea (7.7%) (Minoguchi et al 2007). Yaggi and colleagues conducted an observational cohort study of 1022 patients and showed that, after adjustment for other risk factors (age, sex, race, smoking status, alcohol-consumption status, body mass index, diabetes, hyperlipidemia, atrial fibrillation, and hypertension), obstructive sleep apnea syndrome is significantly correlated to stroke and death from any cause (Yaggi et al 2005).
The risk for ischemic heart disease is almost twice as high for habitual snorers as it is for non-snorers and remains elevated after controlling for the effects of age, hypertension, smoking, obesity, and alcohol use (Koskenvuo et al 1987). Interestingly, one study showed that people with nocturnal sudden death from cardiac causes had a significantly higher apnea-hypopnea index than those with cardiac sudden death during daytime (Gami et al 2005).
Cardiac arrhythmias are serious complications of obstructive sleep apnea. A pattern of repeated cycles of bradycardia during the apnea and followed by tachycardia with arousal that terminates the apnea is the most common. Other arrhythmias include sinus arrest lasting up to 10 seconds, second- or third-degree heart block, premature ventricular contractions, and potentially lethal tachyarrhythmias. The mechanism for bradycardia appears to be a reflex increase in vagal tone caused by stimulation of carotid body receptors by hypoxemia. Hypoxemia that occurs in the absence of apnea induces an increase in respiration that causes lung distention. Lung distention inhibits vagal activity (the Hering-Breuer reflex) and permits cardiac acceleration to occur. During apnea the increased vagal tone induced by hypoxia and by mechanical effects of obstructive sleep apnea associated with intrathoracic pressure swings leads to bradycardia. Increased vagal tone also contributes to periods of asystole and arteriovenous block. The increased sympathetic tone that accompanies the arousals at the end of apneas appears to contribute to premature ventricular contractions, sinus tachycardia, and ventricular tachyarrhythmias. Hypoxemia also increases ventricular irritability. Arrhythmias are more common during REM sleep, probably because of more severe hypoxemia and because of autonomic discharge related to phasic events of REM sleep. It is also suggested that obstructive sleep apnea represents an important independent risk factor for the appearance of atrial fibrillation in patients with hypertrophic cardiomyopathy (Pedrosa et al 2010).
Habitual snoring also appears to be an independent risk factor for the development of hypertension, and even low levels of sleep-disordered breathing appear to increase the risk for hypertension (Young et al 1997b; Nieto et al 2000). In an animal model, sustained daytime hypertension developed in dogs after a 1 to 3 month period of experimentally induced obstructive sleep apnea (Brooks et al 1997). Moreover, the nondipper condition is associated with apneic snoring (Portaluppi et al 1997; Wolf et al 2010). Drug-resistant hypertension should prompt the clinician to consider a diagnosis of obstructive sleep apnea (Wolk et al 2003; Mancia et al 2007; Ahmed et al 2009; Pisoni et al 2009).
A position paper was published on the management of patients with obstructive sleep apnea and hypertension (Parati et al 2012; 2013). This paper is aimed at addressing the current state of the art in epidemiology, pathophysiology, diagnostic procedures and treatment options for the appropriate management of obstructive sleep apnea in hypertensive patients, as well as for the management of arterial hypertension in obstructive sleep apnea patients. This document is the result of work done by a panel of experts from different European countries participating in the European Union COST (Cooperation in Scientific and Technological research) ACTION B26 on OSA, with the endorsement of the European Respiratory Society (ERS) and the European Society of Hypertension (ESH).
Epidemiologic studies show that approximately 40% to 50% of congestive heart failure patients suffer from sleep-disordered breathing. Much attention has focused on the effects of sleep-disordered breathing (central and obstructive sleep apnea syndrome) in determining cardiac failure, and vice versa; the role of cardiac dysfunctions can also be used as a possible determinant of sleep-disordered breathing (Caples et al 2005; Kasai and Bradley 2011).
There are studies suggesting a role of sleep-related breathing disorders, in particular of changes in intrathoracic pressure associated with hypoxia, in determining alterations in left and right ventricular mechanics (Koshino et al 2010). A new interesting point is also the observation that the predominant type of sleep apnea in patients with heart failure can change over time in association with alterations in circulation time. It is suggested that spontaneous conversion from predominantly central events to obstructive ones is associated with an improvement in left ventricular systolic function (Ryan et al 2010).
Left ventricular systolic and diastolic dysfunction observed in patients with obstructive sleep apnea syndrome improved with 6-month CPAP or adaptive servo-ventilation therapy (Akar Bayram et al 2009; Hastings et al 2010).
However, further study is still required to monitor and clarify the potential effects of obstructive sleep apnea syndrome treatment (particularly CPAP) on cardiac performance and improvement of long-term outcomes (Somers 2005; Alonso-Fernandez et al 2006; Johnson et al 2008).
A recent meta-analysis suggests that obstructive sleep apnea is an independent predictor of subclinical cardiovascular disease as cardiovascular diseases are more likely to occur in patients with long-standing and severe obstructive sleep apnea (Ali et al 2014).
Pulmonary artery pressure is increased during apneas, most likely due to pulmonary artery constriction induced by hypoxemia. The greatest increase occurs during REM sleep, when hypoxemia is usually greatest. Cardiac output may fall in some patients due to right-to-left shifts of the cardiac interventricular septum, caused by increased negative intrathoracic pressure associated with attempts to breathe against a closed airway. Systemic blood pressure increases during repetitive apneas, with a peak in blood pressure occurring with resumption of ventilation. In patients with moderate to severe obstructive sleep apnea, blood pressure may rise by 25%, and in severe cases, pressure may reach 200 mm Hg systolic and 120 mm Hg diastolic at the end of each apnea. There appear to be several causes of the increase in blood pressure. Arteriolar constriction may occur as a result of hypoxemia and acidosis, leading to an increase in systemic vascular resistance. Arousals that terminate apnea are associated with increased sympathetic tone that may contribute to elevated blood pressure. Obstructive sleep apnea is also associated with increased release of atrial natriuretic peptide during sleep, with increased urine output, increased urine sodium, and decreased renin activity (Krieger et al 1989; Baruzzi et al 1991; Follenius et al 1991). Patients with coronary artery disease may develop myocardial ischemia during apneas.
The hemodynamic changes associated with changes in oxygen arterial saturation are linked to the intracellular ox-redox state (McGown et al 2003). Systemic and local oxidative stress increase is documented by elevation of 8-Isoprostanes in the morning and decreased after onset of CPAP therapy (Carpagnano et al 2003). Antioxidant capacity in serum, an index of excessive oxidative stress, was reduced in obstructive sleep apnea patients (Christou et al 2003).
Observations have led to a hypothesis that obstructive sleep apnea may trigger an inflammatory metabolic syndrome. In fact, various endocrine and cytokine alterations are observed in sleep-disordered breathing patients, such as an increase in IL6, tumor necrosis factor, C-reactive protein, adhesion molecules, leptin, insulin, nuclear factor-kappaB, and nitrotyrosine independently of obesity or age (Vgontzas et al 2000; Hatipoglu and Rubinstein 2003; Arter et al 2004; Jelic et al 2010; Quercioli et al 2010; Maeder et al 2014). These conditions are ameliorated by CPAP therapy (Cuhadaroglu et al 2009).
It is known that obstructive sleep apnea syndrome patients present a nocturnal increase in leptin level associated with sympathetic function increase; these findings, reversed after treatment with nasal CPAP, may have significant effects on cardiovascular mortality (Shimizu et al 2002) and respiratory control (Malli et al 2010. Another study demonstrated elevated homocysteine levels in obstructive sleep apnea syndrome patients with ischemic heart disease in comparison with normal control subjects and ischemic heart disease patients without obstructive sleep apnea syndrome (Lavie et al 2001). Lavie and coworkers demonstrated that CD8+ T-lymphocytes in obstructive sleep apnea patients undergo phenotypic and functional changes. T-lymphocytes are implicated in the development of atherosclerosis, so that these results are compatible with the atherogenic sequelae of obstructive sleep apnea (Dyugovskaya et al 2005).
The Swedish Obese Subjects study is a long-term (2-year follow-up), prospective investigation in obese patients of the effects of surgical weight loss. This study has demonstrated that symptoms of sleep apnea (collected by questionnaire) are improved following surgical weight loss in a dose-dependent fashion and are similar in both men and women. Moreover, obesity-related comorbidities (such as diabetes, hypertension, and hyperlipidemia) are dramatically reduced (Grunstein et al 2007). However, there is evidence that obstructive sleep apnea is independently associated with alterations in glucose metabolism (Pamidi et al 2010; Rasche et al 2010). There is clinical research evidence indicating that obstructive sleep apnea, through the effects of intermittent hypoxemia and sleep fragmentation, could contribute independently to the development of insulin resistance, glucose intolerance, and type 2 diabetes. Early identification of obstructive sleep apnea in patients with metabolic dysfunction, including type 2 diabetes, could reduce cardiovascular disease risk and improve the quality of life of patients with these chronic diseases (Aurora and Punjabi 2013).
Automobile accidents due to sleepiness are an additional cause of morbidity and mortality in obstructive sleep apnea patients (Teran-Santos et al 1999), and a meta-analysis showed a significant risk reduction following CPAP treatment (Tregear et al 2010). Excessive daytime sleepiness is a frequent complication of sleep apnea. The mechanisms determining excessive daytime sleepiness in sleep apnea patients are still not completely clarified. Studies demonstrate an association between impairment of wakefulness and long-term cardiovascular mortality in obstructive sleep apnea syndrome patients (Newman et al 2000; Shamsuzzaman et al 2003; Kapur et al 2008). These data are supported by a study in which the authors showed that excessive daytime sleepiness in obstructive sleep apnea patients is related to impairment of baroreflex sensitivity and of specific indexes of heart rate variability (Lombardi et al 2008).
Cognitive deficit was observed in obstructive sleep apnea syndrome patients. One study showed that obstructive sleep apnea syndrome patients did not present a procedural skill learning deficit, but a subgroup showed deficits in initial skill adaptation and other neuropsychological difficulties mainly correlated with frontal dysfunction (Rouleau et al 2002).
From case-control studies of cognitive performances in obstructive sleep apnea syndrome, it emerged that deficits worsen with disease severity; both apnea-hypopnea index and minimum oxygen saturation link increase disease severity with poorer performance. Sleepiness and hypoxemia constitute major determinants of diurnal cognitive impairments. An association between obstructive sleep apnea and attention deficit hyperactivity disorder in adulthood has been reported (Naseem et al 2001). The reversibility of cognitive function deficits after obstructive sleep apnea treatment has been investigated, but the data are still controversial (Engleman et al 2000; Ancoli-Israel et al 2008; Gabelle and Dauvilliers 2010).
Some studies have shown gray matter deficits in many important brain regions (frontal region, insular gyrus, bilateral caudate nuclei, thalami, amygdalo-hippocampi, temporal region, and cerebellum) in patients with obstructive sleep apnea as compared with healthy volunteers (Morrell et al 2003; Joo et al 2010). Moreover, a magnetic resonance spectroscopy study showed changes in creatine levels in the hippocampal area in obstructive sleep apnea syndrome patients. These data may represent adjustments to brain bioenergetics, similar to those seen in ischemic preconditioning, and may reflect a different susceptibility of these tissues to hypoxic damage in sleep-disordered breathing (Bartlett et al 2004).
A study on nocturnal cerebral hemodynamics in patients with snoring or obstructive sleep apnea of variable severity using near-infrared spectroscopy suggested that a significant impairment of autoregulatory mechanisms related to hypoxia is observed only in the presence of frequent obstructive apneas (AHI > 30) (Pizza et al 2010).