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Obstructive sleep apnea - an important cardiovascular risk factor


Obstructive sleep apnea - an important cardiovascular risk factor

Obstructive sleep apnea (OSA) is associated with an increased cardiovascular risk regardless of other influencing factors such as age, body weight and metabolic diseases. This applies above all to system arterial hypertension, but also to myocardial infarction and stroke. Nocturnal arrhythmias can also be induced by OSA, including AV blocks, sinus arrest, and atrial fibrillation. Finally, OSA can also contribute to the development of heart failure. Pathophysiologically, the development of OSA-associated cardiovascular diseases is explained by a complex interaction of neural, mechanical, hemodynamic and humoral factors. The focus here is on a specific disruption of the vascular microenvironment in the context of nocturnal hypoxemia. The vascular microenvironment in OSA is characterized by sympathetic activation, increased oxidative stress and proinflammatory changes. The common end route is endothelial dysfunction, an established precursor to arterial hypertension and atherosclerosis. The treatment of OSA by means of "continuous positive airway pressure" (CPAP) therapy has a cardioprotective effect. Favorable effects on cardiovascular biomarkers, vasoreactivity, 24-hour blood pressure, nocturnal cardiac arrhythmias and left ventricular function have been described. Cardiovascular endpoints such as the rate of myocardial infarction and stroke are also positively influenced.

Keywords: sleep apnea, cardiovascular disease, arterial hypertension, atherosclerosis, CPAP therapy

Obstructive sleep apnea - an important cardiovascular risk factor
Obstructive sleep apnea (OSA) is independently associated with an increased risk of cardiovascular disease. OSA predisposes to arterial hypertension in particular, but also atherosclerosis, myocardial infarction, stroke, and nocturnal heart rhythm disorders, such as atrioventricular block, sinus arrest and atrial fibrillation. It can also contribute to the development of heart failure. Its etiology relates to a complex interaction of neural, mechanical, hemodynamic and humoral factors, with a specific disturbance of the vascular microenvironment in response to nocturnal hypoxia playing a key role. The vascular microenvironment in OSA is characterized by sympathetic activation, increased oxidative stress and pro-inflammatory changes. This leads via endothelial dysfunction to arterial hypertension and atherosclerosis. Treatment with continuous positive airway pressure (CPAP) ventilation is cardioprotective, by restoring the vascular microenvironment and endothelial-dependent vasodilation, lowering 24 hour blood pressure, eliminating nocturnal heart rhythm disorders and improving left ventricular function. Furthermore, long-term CPAP treatment reduces the rate of important adverse clinical outcomes such as myocardial infarction and stroke.

Key words: sleep apnea, cardiovascular disease, arterial hypertension, atherosclerosis, CPAP therapy

Obstructive sleep apnea (OSA) is a common condition. This affects around four percent of men and two percent of women in middle adulthood. In women, the incidence of OSA increases significantly after menopause, and there is still evidence of a familial disposition. The disease is based on repeated states of collapse of the pharynx during sleep. The main risk factors are obesity, old age and regular alcohol consumption. The cardinal symptoms of OSA are snoring, observed nocturnal pauses in breathing as well as sequelae of the fragmented sleep architecture such as excessive daytime sleepiness, neurocognitive dysfunction and an increased risk of accidents.
If OSA is clinically suspected, according to the guidelines of the German Society for Pneumology (DGP; and the German Society for Sleep Research and Sleep Medicine (DGSM;, an outpatient procedure is initially carried out to confirm the diagnosis.
re night polygraphy. Mainly respiratory parameters are derived, including respiratory flow, thoracoabdominal respiratory excursions and oxygen saturation. The next step is an additional recording of sleep parameters using electroencephalography (EEG), electrooculography (EOG) and electromyography (EMG) under stationary, monitored conditions - that is, a so-called polysomnography.
By definition, there is a nocturnal breathing disorder if more than ten apneas / hypopneas per hour of sleep are found (apnea-hypopnea index [AHI]> 10 / h) and there are corresponding clinical symptoms.
The standard therapy of OSA is the non-invasive continuous positive pressure ventilation, the so-called "continuous positive airway pressure" (CPAP) therapy by means of a nose or
Nose and mouth mask. This achieves pneumatic splinting of the pharynx. With regular use, CPAP therapy eliminates snoring and apneas and improves daytime sleepiness in the affected patients.
Cardiovascular and cerebrovascular diseases
Patients with OSA often suffer from cardiovascular and cerebrovascular diseases. A distinction can be made between acute and chronic effects of OSA on the cardiovascular system (table). The acute effects primarily include cardiac arrhythmias that occur during sleep and are directly associated with OSA. In contrast, the chronic effects, which can also be felt during the day, include systemic and pulmonary arterial hypertension as well as atherosclerosis and its secondary diseases. The prevalence of the latter diseases in OSA is increased by a factor of two to three compared to patients without sleep-related breathing disorders (SBAS).
Several large epidemiological studies carried out in recent years, such as the Wisconsin Sleep Cohort Study and the Sleep Heart Health Study, suggest a causal relationship between OSA and cardiovascular / cerebrovascular diseases (1, 2). It was found that the odds ratios for these diseases are increased in OSA patients, regardless of established influencing factors such as body weight, age and metabolic diseases such as diabetes mellitus or hyperlipidemia.
Pathophysiology of
OSA-associated cardiovascular disease
The pathophysiology of OSA-associated cardiovascular diseases is characterized by a complex interaction of neural, mechanical, hemodynamic and humoral factors (Figure 1). The neural component involves activation of the sympathetic nervous system. This could be shown by measurements of plasma and urine catecholamines as well as sympathetic nerve activity - microneurography of the peroneal nerve (e1, e2). Mechanical influences are mainly exerted by the intrathoracic pressure fluctuations in the context of apneas. During apneas, negative intrapleural pressure occurs, as measurements with esophageal pressure probes have shown. Hemodynamic factors are, for example, the apnoesynchronous, repetitive increases in blood pressure in the large and small circulation, which can mean considerable shear stress for the vascular wall. However, the focus is on a specific disruption of the vascular microenvironment, which can be read from various humoral parameters or biomarkers (Figure 2) (3). The decisive stimulus for the changes mentioned here is OSA-associated chronic intermittent hypoxia. This specific hypoxia pattern is characterized by cyclical fluctuations in oxygen saturation during the night: The apneas / hypopneas cause desaturations again and again. The subsequent hyperventilation phases cause the oxygen saturation to rise again - a so-called reoxygenation. In contrast to these nocturnal desaturations, OSA patients usually have normal saturation values ​​during the day.
The aforementioned activation of the sympathetic nervous system is very important for the disruption of the vascular microenvironment in OSA. This probably also leads to increased insulin resistance in the affected patients via a counter-insulin effect (e3). In addition, there is clear evidence of increased intravascular oxidative stress. Direct evidence of this is the observation that isolated leukocytes from OSA patients release more free oxygen radicals in vitro (4). The free O2 radicals then cause a reduction in nitrogen monoxide (NO) bioavailability and increased lipid peroxidation. In untreated OSA patients, for example, the plasma levels of the NO metabolites nitrite and nitrate and markers of lipid peroxidation are increased (5, 6). There are also indications of procoagulatory changes, such as increased platelet activation and aggregation and increased fibrinogen levels (e4, e5).
Chronic intermittent hypoxia also activates the transcription factors HIF-1a and NF-kB, as in vitro experiments on cell cultures have shown (e6, e7). This promotes the expression of hypoxia-dependent gene products, for example endothelin, adrenomedullin or "vascular endothelial growth factor" (VEGF) (7, 8, e8), as well as numerous proinflammatory mediators, for example soluble adhesion molecules and cytokines such as TNF-a and interleukin-6 ( 9, 10). The cytokines finally induce the synthesis of acute phase proteins in the liver. In addition to fibrinogen, these primarily include highly sensitive C-reactive protein (hsCRP) and serum amyloid A (SAA) (11, 12).
Ultimately, the disruption of the vascular microenvironment in OSA leads to endothelial dysfunction. This reduction in endothelial-dependent vasodilation is an established precursor for the development of arterial hypertension and atherosclerosis.
Evidence of endothelial dysfunction was impressively demonstrated in otherwise healthy OSA patients by means of ultrasound measurements on the brachial artery by determining the so-called flow-mediated vasodilation (13). The restriction of vasoreactivity even depends on the severity of the OSA. Correlations with the AHI and the extent of nocturnal hypoxia were found (14). The aforementioned oxidative stress is responsible for the endothelial dysfunction in OSA. Acute improvements in flow-mediated vasodilation after intravenous administration of the antioxidant vitamin C have been demonstrated (15).
Nocturnal arrhythmias
The overall frequency of cardiac arrhythmias during sleep is certainly lower with OSA than was assumed a few years ago. In the majority of patients, cyclical undulations of the heart rate (= sinus bradycardia / tachycardia running parallel to the apneas / hypopneas) can be observed. The cause is imbalances in the autonomic nerve activity with dominance of the parasympathetic nervous system during apnea and the sympathetic nervous system during the hyperventilation phases.
Sinus arrest / AV blockages occur in five to ten percent of cases. Patients with severe OSA in "rapid eye movement" (REM) sleep are preferably affected. The main pathogenetic mechanism is the activation of the parasympathetic nervous system during the nightly pauses in breathing. Structural changes in the cardiac stimulation and conduction system play no role in the development of these arrhythmias, as electrophysiological studies have shown (e9).
Nocturnal hypoxemia is mainly responsible for the genesis of ventricular extrasystoles (VES) in the context of OSA. In doing so, very strong desaturations must probably occur (SaO2 < 60="" prozent)="" (e10).="" ob="" über="" die="" induktion="" von="" ves="" und="" die="" genannten="" bradykarden="" rhythmusstörungen="" auch="" das="" risiko="" für="" den="" plötzlichen="" herztod="" erhöht="" wird,="" ist="" noch="" nicht="" abschließend="" geklärt.="" eine="" kürzlich="" publizierte="" studie="" deutet="" zwar="" in="" diese="" richtung="" –="" es="" wurde="" eine="" häufung="" des="" plötzlichen="" herztodes="" bei="" osa-patienten="" während="" der="" nacht="" verzeichnet="" –="" (16),="" letztendlich="" steht="" ein="" beweis="" hierfür="" aber="" noch="" aus.="">
Recently, OSA has also been associated with the occurrence of atrial fibrillation. It has been shown that atrial fibrillation recurs more frequently after successful electrical cardioversion if there is an OSA (17). Furthermore, unselected patients with atrial fibrillation have a high percentage - up to 50 percent - of SBAS in the sense of OSA (18). Finally, it was possible to document with polysomnography that OSA can trigger episodes of atrial fibrillation (19).
System arterial
During sleep, the OSA develops apnea-synchronous blood pressure peaks, so that in the 24-hour long-term ECG a lack of physiological blood pressure lowering during the night can be observed. During the day, increased RR values ​​persist in 40 to 60 percent of the affected patients. Conversely, 20 to 30 percent of all hypertensive patients suffer from OSA. The prevalence rates are even higher in patient groups with hypertension that is difficult to control or refractory to therapy (e11).
The epidemiological studies mentioned showed that the odds ratios for the development of arterial hypertension increase with increasing AHI (1). Pathogenetically, it is assumed that arterial hypertension in OSA primarily arises from the aforementioned activation of the sympathetic nervous system. Based on the available data, OSA is now recognized as one of the most common causes of secondary arterial hypertension in the US guidelines on hypertension (e12).
Pulmonary arteries
In OSA, too, there are repetitive increases in pressure during sleep in the small circulation. Pulmonary arterial hypertension can also be demonstrated during the day in around a quarter of OSA patients. Initially it was assumed that this complication primarily affects patients with simultaneous ventilation disorders - for example in the context of chronic obstructive airways disease or extreme obesity - but the development of pulmonary hypertension has now also been demonstrated in patients with OSA alone (e13 ).
The pathogenesis of OSA-associated pulmonary hypertension is not fully understood. The increase in pulmonary artery (PA) pressure is probably caused by activation of the von Euler-Liljestrand mechanism, that is, hypoxia-triggered pulmonary vasoconstriction. Mediator activation in the pulmonary vascular bed may also contribute to this. It must be emphasized that pulmonary hypertension in OSA is usually only mild, with average PA pressures < 30="" mm="" hg.="" folglich="" leiden="" auch="" nur="" wenige="" dieser="" patienten="" an="" einem="" klinisch="" manifesten="" cor="" pulmonale.="">
Atherosclerosis, myocardial infarction and stroke
The disruption of the vascular microenvironment in OSA also contributes to accelerated atherosclerosis. In this context, the oxidative stress observed in OSA and the increased proinflammatory activity are presumably of decisive importance. Both phenomena are known to be involved in the development of atherosclerotic vascular lesions. Measurements of the thickness of the intima media in the common carotid artery provided direct indications that the OSA favored atherosclerosis. This sonographically determinable parameter reflects the remodeling processes of the vessel wall in the early stages of atherosclerosis and also correlates with the cardiovascular risk. OSA patients show greater intima media thicknesses than comparable control patients without SBAS. In addition, it was found that the thickness of the intima media in OSA is greater, the more pronounced the nocturnal desaturations are (20).
The sequelae of atherosclerosis - coronary heart disease (CHD) including myocardial infarction and cerebrovascular diseases including cerebral infarction - are consequently often encountered in OSA. The prevalence rate of CHD in OSA is 20 to 30 percent, a previous stroke is found in five to 10 percent of OSA patients. Conversely, in patient collectives with angiographically confirmed CHD, OSA occurs in up to 50 percent of cases. Polysomnographic examinations of patients in the acute stroke phase even show relevant SBAS in up to two thirds of the cases. Here, however, a distinction must be made between central apneas that occurred as a result of the stroke and obstructive apneas that existed before the stroke (e14).
As with arterial hypertension, epidemiological studies suggest a causal relationship between OSA and CHD or stroke. Even comparable odds ratios have recently been found for cerebrovascular diseases (21). A recently published study carried out prospectively over ten years could also demonstrate that untreated patients with higher-grade OSA (AHI> 30 / h) developed myocardial infarction and strokes more frequently than control persons without SBAS during this observation period (22).
In OSA, myocardial ischemia can result not only from promoting atherosclerotic vascular changes, but also from nocturnal desaturations resulting from a reduction in the myocardial oxygen supply. This is supported by ST segment analyzes of the nocturnal ECG of patients with OSA (e15). The development of strokes in the context of OSA must also be understood as multifactorial. Strokes can also be triggered by OSA-associated arterial hypertension or cardiac arrhythmias.
Left heart failure
OSA patients have left heart failure in five to ten percent of cases.Possible links between OSA and left heart failure are arterial hypertension and CAD. In this context, the negative inotropic effects of the sometimes considerable intrathoracic pressure fluctuations in the context of nocturnal apneas must also be taken into account.
Patients with severe left heart failure, that is, a left ventricular ejection fraction (EF) < 40="" prozent,="" zeigen="" häufig="" sbas.="" so="" wurde="" in="" einer="" aktuellen="" deutschen="" multicenterstudie="" zur="" prävalenz="" von="" sbas="" bei="" diesen="" patienten="" in="" 40="" prozent="" der="" fälle="" eine="" osa="" nachgewiesen="" (e16).="">
Cheyne-Stokes respiration must be distinguished from the differential diagnosis. This is a special form of central sleep apnea with characteristic spindle-shaped hyperventilation phases, which is primarily seen as a consequence of heart failure (e17).
Cardioprotective effects
of CPAP therapy
The treatment of OSA by means of CPAP ventilation can interrupt the pathophysiological chain mentioned and thereby develop cardioprotective effects (box). CPAP therapy not only improves sleep architecture and daytime sleepiness, but also leads to a "restoration" of the vascular microenvironment and endothelial reactivity by largely normalizing nocturnal oxygenation (13).
Placebo-controlled studies - placebo means ventilation with sub-therapeutic CPAP pressures - has also shown that CPAP therapy can lower blood pressure values ​​in OSA patients (23). After initiating CPAP therapy, it is then entirely possible that the antihypertensive medication can be reduced or, in individual cases, even completely discontinued. In pulmonary arterial hypertension, effective CPAP therapy also reduces PA pressures (e18).
Nocturnal myocardial ischemia or angina pectoris attacks can be reduced or even eliminated with CPAP therapy (e19). It has recently been shown that CPAP therapy can also reduce the rate of cardiovascular endpoints, such as the number of myocardial infarctions or strokes (22). Finally, a study of stroke patients with OSA shows that cerebrovascular events occur less frequently after initiation of CPAP therapy than in patients who remain untreated (24). In OSA patients with concomitant heart failure, CPAP therapy improves the EF (25). A positive effect of CPAP therapy has also been proven for nightly cardiac arrhythmias. With OSA-associated AV blocks / sinus arrest, in most cases a regression is achieved with adequate CPAP therapy. Only a few patients need a pacemaker (e20).
Untreated OSA is an important cardiovascular risk factor. In particular, the risk of developing system arterial hypertension is increased. In addition, there is increasing evidence that OSA accelerates the process of atherosclerosis and thus contributes to the development of the sequelae myocardial infarction and stroke. Left heart failure in OSA can result from arterial hypertension and CAD. The arrhythmogenic potential of OSA is overall lower than initially assumed, but there is a clinically significant connection with atrial fibrillation. Relevant pulmonary artery hypertension is only rarely a consequence of OSA.
By interrupting the pathophysiological chain, CPAP therapy has a cardioprotective effect: the nocturnal oxygenation, the vascular microenvironment and the endothelium-dependent vasodilation are normalized.
Manuscript submitted: June 15, 2005, revised version accepted on November 4, 2005
The authors declare that there is no conflict of interest within the meaning of the guidelines of the International Committee of Medical Journal Editors.
How this article is cited:
Dtsch Arztebl 2006; 103 (12): A 775-81.

Address for the authors:
Priv. Doz. med. Richard Schulz
Medical clinic II / sleep laboratory
University Hospital Giessen and Marburg
Giessen location
Paul-Meimberg-Strasse 5, 35392 Giessen
Email: [email protected]
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