Neurogenic, hormonal, and local regulatory systems play significant roles in hypertension and cardiovascular diseases
Sleep-disordered breathing (SDB) plays a causal or contributing role in the development of comorbidities such as hypertension and cardiovascular events. Snoring, SDB, and obstructive sleep apnea (OSA) have been reported to be associated with hypertension since the early 1980s.1 There is substantial epidemiological and pathophysiological evidence to suggest that SDB causes hypertension. Moreover, an association between sleep apnea and hypertension that is independent of age, sex, and body weight has been reported.
Systemic hypertension is seen in up to 70% to 90% of cases of OSA.2 On the other hand, OSA is detected in about 30% to 35% of individuals with a primary diagnosis of essential hypertension.1,3-5 There is epidemiological and pathophysiological evidence that OSA is an independent risk factor for essential hypertension.6 Patients with OSA are also at increased risk of developing pulmonary hypertension, coronary heart disease, and cerebrovascular accident.7 Inadequate nocturnal and diurnal blood-pressure control, structural vascular changes, altered homeostatic mechanisms such as thrombogenic factors (increased platelet aggregability), and adverse metabolic effects all contribute to increased risk of latent cardiovascular complications.7
In their large cross-sectional study, Nieto et al8 studied healthy middle-aged and older adults who demonstrated that SDB is associated with prevalent hypertension. After controlling for age, sex, body-mass index (BMI), adiposity, alcohol intake, and smoking, they found that high apnea-hypopnea indices and oxygen saturations of less than 90% were associated with greater odds of hypertension in a dose-response fashion.8,9 In contrast, self-reported snoring had little or no association with hypertension.8 Association between SDB and hypertension was seen in both sexes and in all ethnic groups and was slightly stronger among obese individuals.8
The hypothesis that there is a causal association between sleep apnea and hypertension is further supported by evidence from intervention trials. Successful treatment of sleep apnea using continuous positive airway pressure (CPAP) is accompanied by significant decreases in both daytime and nighttime blood pressures.10
In a case-controlled study, Davies et al11 reported 24 hours of ambulatory blood-pressure measurements in 45 OSA patients and came to the conclusion that, when compared with a closely matched control population, OSA patients have significant elevation of systemic blood pressure, and that this contributes to an increased risk of cardiovascular morbidity and mortality. This study supports an independent association between OSA and systemic hypertension.11
The mechanisms underlying the association between SDB and hypertension are not entirely clear. Several pathophysiological mechanisms have been proposed.6,11-13 These include hemodynamic disturbances resulting from intermittent negative intrathoracic pressure during apneic episodes, recurrent episodes of hypoxemia and hypercapnia resulting in abnormal activation of arterial chemoreceptors and increased sympathetic activity, and an increase in sympathetic activity associated with repeated arousals during sleep.6
Excess sympathetic activity is a consistent finding in patients with sleep apnea syndrome and is presumed to contribute to the high incidence of hypertension.14 Prior studies have shown relationships between the severity of sleep apnea and sympathetic activity or blood pressure.6,14 A linear relationship has been found between compliance with CPAP and sympathetic activity.13 Urinary catecholamine excretion has been shown to decrease after long-term use of CPAP and following tracheostomy for severe sleep apnea.15
Acute apnea is associated with many autonomic responses, including a significant elevation of blood pressure at apnea termination, bradytachyarrhythmias, high sympathetic output, and increased intracranial pressure. Repetitive apneas contribute to a crescendo rise in mean arterial pressure. Sympathetic activity during acute apnea may extend beyond apnea termination.6,12,14
Chronic treatment of OSA with nasal CPAP or tracheostomy ameliorates or eliminates essential hypertension.2,13 The acute blood-pressure response to apnea is probably initiated by arousal (which can evoke an acute pressor response, even in the absence of apnea)11,16; episodic hypoxemia; excessive muscular effort; and intrathoracic blood-volume shifts. Recurrent arousal at the termination of apneas provokes a chronic sympathetic response, leading to sustained hypertension.6 Acute hypoxia may stimulate peripheral chemoreceptors, leading to increased sympathetic output to the heart and peripheral vasculature. Excessive muscular effort to overcome upper-airway obstruction may induce acute hemodynamic changes. Intrathoracic blood volume shifts associated with negative inspiratory pressure may contribute to elevated blood pressure during apnea.6 Airway obstruction during sleep can increase blood pressure without arousal.17
Episodic Hypoxia and Sympathetic Output
Acute hypoxia contributes to an acute rise in blood pressure during and following apnea. In fact, the level of oxygen-hemoglobin desaturation during acute apnea is directly related to the magnitude of blood pressure change associated with apnea.18,19 Supplemental oxygen provided to subjects with simulated recurrent apneas ameliorates the blood-pressure increase in response to apnea.19
Human and experimental studies6,7,17 have shown that hypoxia and arousals are major stimulants of acute sympathetic output, which increases vascular resistance via a-adrenergic receptors in peripheral vasculature, as well as cardiac receptors (increased heart rate and cardiac output). These events cause acute blood-pressure elevation associated with apnea. At apnea termination, the sudden release of intrathoracic pressure allows right ventricular filling and increase in cardiac output, accounting for the sharp rise in blood pressure at apnea termination.17
Hypoxia also stimulates epinephrine secretion from the adrenal medulla, which can further magnify the peripheral sympathetic response.6 Hedner et al14 showed increased motor nerve sympathetic activity during apnea using perineal nerve electrodes in patients with sleep apnea. Respiratory effort against obstruction produced increased sympathetic nerve activity, which was progressive throughout the apnea and peaked at apnea termination. Apnea is a more potent stimulus toward increased sympathetic activity than hypoxia alone. Furthermore, at the same level of hypoxia and hypercarbia, apnea leads to a much stronger acute sympathetic response than hypoxia or hypercarbia alone.20,21
Patients with OSA have been shown to have increased vascular reactivity to a hypoxic challenge (compared with subjects without apnea) whether they have elevated diurnal blood pressure or not.22 Resting sympathetic activity (measured as muscle nerve activity) is higher in apnea patients than in matched controls.23 Increased sympathetic activity, vasoconstriction, and alterations in cardiac output are likely mechanisms for elevated blood pressure sustained beyond the apnea period.6
Urinary catecholamine levels are elevated in patients with sleep apnea.15 Urinary norepinephrine and normetanephrine levels are elevated in patients with severe OSA.15 This implies that peripheral sympathetic neurotransmission is increased not only during sleep (apnea), but throughout the day. Following tracheostomy, catecholamine levels returned to control levels. A significant correlation between urinary norepinephrine and the respiratory disturbance index (apneas per hour) has been demonstrated.24 Plasma norepinephrine was shown to be higher in patients than in controls and correlated with the level of muscle nerve sympathetic activity.6 It may take several years for heightened sympathetic activity in sleep apnea patients to result in a sustained, diurnal blood-pressure increase.6
Overactivity of the Sympathetic Nervous System
Overactivity of the sympathetic nervous system may be a fundamental mechanism in hypertension. Plasma norepinephrine in the heart and kidneys is elevated in young individuals with hypertension.25,26 Heightened activity of the renal sympathetic nerves contributes to increased renal vascular resistance in essential hypertension.6 Increased muscle nerve sympathetic overactivity is seen in mildly hypertensive patients.27 Sympathetic overactivity in the early stages of hypertension is followed by renal vascular disease or vascular remodeling.6 Hypoxia-driven arterial chemoreceptors are potent stimulators of sympathetic activity.6 Recurrent episodic hypoxia stimulates carotid chemoreceptors and, thus, sympathetic activity.6 Subsequently, adrenal and renal sympathetic nerves maintain this heightened sympathetic activity.6 Local endothelial factors may play a role in blood pressure.
There is increased release of arterial natriuretic peptide (ANP) during apneas due to increased right atrial filling and hypoxia, facilitating new synthesis and release of ANP.28-30 It has a modest vasodilatory action, besides its main effect on blood volume.7 Episodic hypoxia causes a progressive increase in blood pressure mediated, in part, through renal sympathetic nerves acting to increase renin-angiotensin activity through angiotensin-I receptors.31
The activity of the renin-angiotensin-aldosterone system may be suppressed in patients with OSA.32 Angiotensin-II activity may contribute to vascular hypertrophy and remodeling.7 Hence, reduced angiotensin II in OSA may be a beneficial effect.7 Angiotensin-
convertingenzyme inhibitors may be helpful in individuals with hypertension and sleep apnea, but b-adrenergic antagonists have been shown to be more beneficial by some investigators.33
Endothelium Derived Factors
The vascular endothelium secretes vasodilators and vasoconstrictors, thus modulating vascular tone.7 Increased endothelin activity is seen in OSA.34 With nasal CPAP therapy, there is reduced renal excretion of endothelin.34 Hypoxemia increases endothelin gene expression and endothelin release.35,36
Altered eicosanoid activity has the potential to increase vasoconstrictor tone in OSA.7 Endothelin-derived nitric oxide is a potent mediator of vasodilation; thus, it regulates blood pressure.37 Nitric oxide is generated from the amino acid L-arginine by nitric oxide-synthase.7 Impaired nitric-oxidedependent vasodilation in OSA patients has been reported in experimental studies.7 It is also speculated that reduced vasodilation in hypertensive OSA patients suggests an attenuated effect of nitric oxide.7
The features of syndrome Z include hypertension, central obesity, insulin resistance, hyperlipidemia, and OSA.38 The factors influencing the relationship between blood pressure and cardiovascular risk include systolic blood pressure, diastolic blood pressure, circadian blood pressure patterns (dippers vs nondippers), blood pressure variability, and cardiac and vascular hypertrophy.38 Abnormal vascular endothelial function has been reported in hypertension, diabetes mellitus, and hyperlipidemia. This may precede the onset of cardiovascular disease symptoms by many years. As discussed above, abnormal endothelial function may be present in patients with sleep apnea and hypertension.39 Whether sleep apnea affects endothelial function independently of hypertension and insulin resistance requires further research.
OSA is closely linked to the cluster of cardiovascular risk factors known as syndrome X (a cluster of risk factors including systemic hypertension, insulin resistance, hyperlipidemia, and central obesity) and the converse is also likely but has not yet been proven (syndrome Z). These relationships should help physicians consider that patients with sleep apnea may have coexistent modifiable cardiovascular risk factors and, conversely, that sleep apnea should be suspected in patients with hypertension, central obesity, insulin resistant diabetes, or dyslipidemia.38 There are specific effects of untreated sleep apnea that increase the cardiovascular consequences as discussed above. Hence, syndrome X may include sleep apnea and could better be defined as syndrome Z.38
The effective treatment of sleep apnea eliminates recurrent episodes of hypoxemia, reduces blood pressure and variability, and may reduce insulin resistance and, thus, triglycerides. Brooks et al40 demonstrated an improvement in insulin sensitivity in most patients with type II diabetes mellitus and sleep apnea treated with nasal CPAP.
The obstructive SDB syndrome causes an increased risk of mortality and hypertension and is associated with an increased frequency of cerebrovascular accidents and heart attacks. Effective and consistent treatment of obstructive SDB syndrome using CPAP, dental devices, surgery, and weight loss results in little or no risk of excess mortality from cardiovascular events.41
OSA is associated with an increased prevalence of cardiovascular disease. A number of factors may play a role: common genetic traits in both disease populations, OSA-induced increased thrombogenicity, vascular remodeling, a change in functional cardiovascular regulation, sympathetic excitation, hormonal factors, and impaired endothelium-dependent nitric-oxidemediated vasodilation.7
In summary, neurogenic, hormonal, and local regulatory systems play significant roles in hypertension and cardiovascular diseases.7 Further scientific research is needed to study the hemodynamic effects of OSA and counteract the abnormal homeostasis seen in sleep apnea.
Taj M. Jiva, MD, is clinical assistant professor of medicine, State University of New York at Buffalo, and a pulmonologist, intensivist, and sleep specialist at Buffalo Medical Group PC, NY.
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