Michael A. Lucia, M.D.
University of Nevada School of Medicine
April 2001
Introduction:
Other than obesity, hypertension remains the single most common chronic medical condition among adults in the U.S. The morbidity and costs associated with this condition are profound. Many causes and exacerbating factors have been associated with essential hypertension, most recently including sleep apnea and other forms of sleep-disordered breathing (SDB). While this association is common, the multiple common co-existent variables such as obesity have made the link difficult to establish. As a result, this topic remains highly controversial among professionals in both the fields of hypertension and sleep medicine. Recent studies have added greatly to our understanding of the apparent link between these two disease states and have even suggested the specific mechanisms of hypertension in apneic patients. SDB is measured as the Apnea-Hypopnea Index (AHI), the number of episodes of interrupted breathing that occur during sleep.
Hypertension Among Patients With Sleep-Disordered Breathing (SDB): Is there an independent link?
Large population studies performed both in the US and Europe have confirmed the presence of symptomatic sleep-disordered breathing (SDB) in at least 2-4% of the general adult population depending on sex and age. If asymptomatic individuals are included in these surveys, the prevalence of SDB increases to between 9 and 24% of all adults. If the population in question is further narrowed to those patients with hypertension, the incidence of SDB is even higher, with estimates ranging from 12 to 83%. For example, in a recent analysis of a small group of both normotensive and hypertensive patients in Australia, 38% of both treated and untreated hypertensive patients had SDB, compared with 4% of the normotensive patients. This was independent of sex, age, obesity or alcohol use. Conversely, surveys of SDB patients have found a high prevalence of hypertension (40-60%), usually with poor control associated with more severe apnea.
This large range of findings reflects the variable populations studied as well as the criteria used to define SDB and hypertension. Also, the impact of prior antihypertensive medication has not been well examined in these studies. Such results and criticisms of prior survey methodology have been the impetus for large, prospective population studies such as the Sleep Heart Health Study and the Wisconsin Sleep Cohort Study. Findings from both of these groups of investigators published in the last two years have greatly strengthened the link between SDB and hypertension, even when accounting for all the likely confounding variables. With hypertension affecting nearly one third of the US population, the overlap between these two chronic illnesses is likely to be substantial, especially given the risk factors that predispose to both (see Table 1 below).
Risks of HTN in SDB Patients:
Several of the recent large prospective studies have assessed risks of hypertension in the SDB population. Most have grouped patients according to degrees of apnea and adjusted for confounding variables including weight, sex, alcohol and tobacco use. The independent association of SDB with hypertension persists despite these variables in all of these studies, with odds ratios for hypertension between 1.4 and greater than 4, depending mostly on severity of apnea (see table 2 below). This represents a 42% increase in risk for HTN even amongst the mildest SDB patients (AHI<5), and a risk 2-3 greater than controls for patients with more severe apnea. Similar studies have determined that quantitative risk of hypertension increases approximately 1-2% for every additional apneic event per hour.
Mechanisms of Hypertension Following Apnea Episodes:
With every obstructive event during sleep, a series of well-described physiological changes occurs. After the initial diving reflex during the apnea, associated with bradycardia and hypotension, there is a compensatory sympathetic discharge following the apnea, mediated primarily by CNS arousal. This manifests as tachycardia, tachypnea, and elevated blood pressure. Also important to the hypertensive response is the increased venous return that results from more negative intrathoracic pressures generated during the apnea.
Measured catecholamine levels during these episodes are increased transiently, and often remain elevated even during wakefulness compared to non-apneic controls (see Figure 1 below). Furthermore, serum epinephrine levels have been correlated with both daytime and nocturnal hypertension. Recent data also indicate that the CNS arousal occurring with each apnea is the main factor in the initiation of this response, independent of oxygen desaturation or other measurable variables. Thus, the degree of sleep fragmentation and number of arousals is most predictive of sympathetic activation and resultant hypertension. This has implications for SDB therapy, giving credence to using normalization of sleep as the treatment endpoint, not just elimination of hypoxia or apnea.
Development of sustained HTN from the Apnea Response: accumulating evidence
These cyclical increases in blood pressure throughout the night are thought to alter the normal circadian rhythm of BP. Normal patients and even hypertensives typically have a nocturnal dip in BP with sleep, which is most significant during stage 3 & 4 sleep. Several reports have noted a lack of nocturnal dipping of BP in SDB patients. The mechanism for daytime hypertension to develop from this lack of nocturnal BP dipping is the main area of research at present. Additionally, investigators have demonstrated an altered vascular reactivity to endogenous vasodilators such as nitric oxide in SDB patients (see Figure 2 below), as well as an exaggerated BP response to hypoxia while awake. This autonomic over activity suggest a resetting of peripheral chemoreceptor sensitivity as one possible mechanism for the development of sustained hypertension, especially when superimposed on a less compliant vasculature. More importantly, treatment of SDB with CPAP reverses this exaggerated autonomic response, and is one proposed mechanism for the BP reduction seen with CPAP treatment.
Normotensive patients with SDB often have normal catecholamine levels, and normal or even reduced levels of response to hypoxia. It is theorized that this represents an adjustment for the chronic episodes of hypoxia that occur at night. Hypertensive SDB patients, on the other hand, demonstrate an increased hypoxia-mediated respiratory drive. In fact, many of these patients will have a resting respiratory alkalosis during wakefulness. Why some SDB patients develop an overly sensitive peripheral chemoreceptor versus an overly damped feedback mechanism is unknown. More importantly, what factors might predict which SDB patients will progress from normotensive to hypertensive is also a mystery. A genetic predisposition to essential hypertension is certainly a possibility. The lack of nocturnal dipping in BP remains the most promising predictor of sustained hypertension elucidated to date.
The Influence of Hypertension & Antihypertensive Medication On SDB:
Hypertension itself is thought to play a role in SDB by affecting peripheral chemoreceptors, possibly explaining why treatment of hypertension may improve SDB in some patients independent of CPAP. Animal studies have demonstrated the de novo development of respiratory events during sleep with artificially induced hypertension. What influence essential hypertension may have on the development of SDB in human subjects remains an unanswered question, and may account for some of the difficulty with establishing SDB as an independent cause of HTN.
The type of medication used for treatment of HTN in SDB patients has also received little study. In general, beta-blockers (and perhaps peripheral alpha-blockers) are assumed to be the agent of choice. Beta-blockers both suppress the arousal associated with apneas, which may reduce sympathetic activation, and are direct antagonist to the catecholamines produced as a result of the arousal. However, some authors have speculated that beta-blockers, might actually worsen SDB by causing CNS sedation. A Finnish group of investigators has shown no difference in the absolute BP reduction in SDB hypertensives with different medications (calcium blockers, ACEI’s, diuretics, & beta-blockers), at least for an 8-week period. There was also no discernible effect of medications on the degree of SDB either. Beta-blockers did, however, normalize autonomic activity as measured by BP and heart rate variability, and it is possible that greater than 8-week follow-up may be necessary to see the full effect of beta-blockade. Similarly, a recent Swedish report noted that only beta-blocker therapy was associated with reductions in nocturnal hypertension. Whether this may result in improved cardiovascular outcomes long-term is unknown.
Effects of SDB Treatment on Hypertension:
CPAP remains the primary modality of treatment for SDB patients, despite issues of compliance. It has been previously shown to reverse all of the attributable cardiovascular morbidity and mortality of SDB, if used consistently. Similar results have been demonstrated with tracheostomy for SDB as well. Recent reports have also documented decreased BP (see Figure 3 below), catecholamine levels and sympathetic activity in SDB patients treated with CPAP. The reduced sympathetic activity likely results in less hypercoagulable state as measured by C-reactive protein or other inflammatory mediators. This may also influence the occurrence of cardiovascular events. One small study has even documented a normalization of endothelial reactivity to vasodilators after 6 months of CPAP therapy. However, there remains a subset of the population whose HTN does not respond to therapy. Purported mechanisms included permanent vascular changes from long-standing SDB, an overlap of essential HTN, and poor CPAP compliance. Long-term influences of CPAP on HTN remain to be established by ongoing investigations.
Summary & Conclusions:
While far from conclusive, the evidence for a causal link between SDB and hypertension continues to mount. The most recent studies performed with large populations adjusted for confounding variables such as obesity have strengthened the link between these two increasingly common diseases. This is especially true among less obese, younger subjects. In addition, there seems to be a dose-dependent relationship between apnea severity and risk of hypertension, with those having the worst apnea at the highest risk. There does not seem to be a lower threshold for this increased risk, as even patients with simple snoring, but no apnea, also represent a higher risk population.
Significant progress has also been made in elucidating the mechanisms of hypertension in SDB patients. The majority of current theory implicates an overactive sympathetic nervous system, as measured by increased catecholamine levels and vascular reactivity. CNS arousal during apneas appears to be the strongest stimulus for the sympathetic response. Chronic sympathetic over activity likely leads to altered vascular physiology, endothelial dysfunction and resetting of peripheral chemoreceptors, all of which are purported mechanisms of essential hypertension. All of these measurable changes are reversible with CPAP therapy. This has led some investigators to no longer consider the hypertension associated with SDB as essential, but rather secondary, similar to that caused by pheochromocytoma or other endocrine abnormalities. Consequently, SDB should be considered as a potential treatable cause of hypertension in all patients. In deciding on treatment for HTN in the SDB patient, beta-blockers (and perhaps peripheral alpha-blockers) appear to have an advantage due to their blockade of sympathetic activity, but this remains to be established in long-term clinical trials.
References:
Bixler EO, Vgontzas AN, Lin HM, et al. Association of hypertension and sleep-disordered breathing. Arch Intern Med 2000;160:2289-2295
Duchna HW, Guilleminault C, Stoohs RA, et al. Vascular reactivity in obstructive sleep apnea syndrome. Am J Resp Crit Care Med 2000;161:187-191
Garcia-Rio F, Racionero MA, Pino JM, et al. Sleep apnea and hypertension: The role of peripheral chemoreceptors and the sympathetic system.
Chest 2000;117:1417-1425
Mayer J, Backer H, Brandenburg U, Penzel T Peter AJH, Wichert PV. Blood pressure and sleep apnea:result of long-term nasal continuous airway pressure therapy. Cardiology 1991;79:84-92
Nieto FJ, Young TB, Lind BK, et al. Association of sleep-disordered breathing, sleep apnea, and hypertension in a large community-based study. JAMA 2000;283:1829-1836
Peppard PE, Young T, Palta M and Skatrud J. Prospective study of the association between sleep-disordered breathing and hypertension. N Eng J Med 2000;342:1378-1384
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