Hypertension (HTN) affects two-thirds of Americans over the age of 60 and over 1 billion people worldwide. For hypertensive adults, obstructive sleep apnea (OSA) and short and fragmented sleep may be important underrecognized factors influencing their response to blood pressure (BP) medications and may in part explain these patients’ high rates of morbidity and mortality. OSA and short and fragmented sleep are associated with daytime HTN, resistant HTN [1–5], absence of nocturnal BP fall (nondipping) , left ventricular hypertrophy , cardiovascular disease [8,9], mortality [10,11], and diminished quality of life [12,13]. Although most of the literature examines the effect of sleep apnea on BP, the relationship between OSA and HTN may be bidirectional. The treatment of HTN to a lower BP target may improve sleep apnea by improving upper airway tone , by targeting hormone pathways that may exacerbate OSA , and by reducing the nocturnal rostral fluid shifts through the use of a low-sodium diet, diuretics, and dialysis [16,17▪▪,18,19].
The aim of this review is to summarize the current literature supporting a bidirectional relationship of sleep apnea and HTN. We review the emerging evidence and discuss the potential clinical implications of intensive BP control on sleep apnea.
HYPERTENSION AND OBSTRUCTIVE SLEEP APNEA ARE HIGHLY PREVALENT AND COEXISTENT
HTN and OSA are coexistent in millions of people and both have been associated with heart disease, stroke, and premature death . HTN has been increasing in prevalence in the United States  and has a major impact on public health. The prevalence of HTN is particularly high in older adults with up to 60% of those over the age of 60 years and 90% of those in the eighth and ninth decades having elevated BP. The relationship of HTN to heart disease and stroke appears consistent across age groups, with those in every decade with higher SBP at increased risk in both community-based studies  and a meta-analysis of nearly one-million patients . OSA is present in up to one of five adults in the USA and is particularly common among adults with HTN [4,24,25]. Moreover, those with resistant HTN have a 2.5 times higher risk of OSA compared with those with more responsive HTN .
OBSTRUCTIVE SLEEP APNEA AS A RISK FACTOR FOR HYPERTENSION
OSA leads to repetitive episodes of hypoxemia, hypercapnia, sleep disruption, and activation of the sympathetic nervous system, all of which are thought to contribute to HTN in humans [27,28]. Recurrent intermittent hypoxia in OSA is also known to cause oxidative stress, endothelial dysfunction, metabolic dysregulation, sympathetic activation, and systemic inflammation [29▪▪]; all or some of these factors could lead to vascular remodeling, atherosclerosis, and HTN in this already at-risk, frequently obese population. In addition to being an independent risk factor for HTN , OSA has been associated with cardiovascular disease including stroke, myocardial infarction, and congestive heart failure after adjustment for obesity and other potential confounders [20,30–32]. Additionally, OSA has been shown to be independently associated with resistant HTN . In a study from a HTN clinic, moderate OSA was demonstrated in 83% of patients with resistant HTN . We have also previously reported that OSA is significantly associated with resistant HTN, especially in patients with end-stage renal disease (ESRD)  (Fig. 1). This growing literature has led the national committees to consider OSA as a cause of HTN and resistant HTN. However, despite the strong observational data relating OSA to HTN, treatment of OSA with CPAP has demonstrated only modest improvement in daytime BP in randomized controlled trials [35–37,38▪▪,39]. These findings call into question whether the observed association between HTN and OSA may in fact be bidirectional.
HYPERTENSION AS A RISK FACTOR FOR OBSTRUCTIVE SLEEP APNEA
HTN by itself may be a risk factor and cause OSA through the following potential mechanisms:
Upper airway tone and hypertension
Intensive BP control may influence OSA by stabilizing the upper airway as genioglossus activity is influenced by increases in BP . Acute increases in SBP cause an inhibitory effect on the EMG of upper airway muscles in sleeping intact cats , decerebrate cats [41,42], and anesthetized dogs , which thereby facilitates sleep apnea. Garpestad et al. demonstrated in five awake young men without sleep disorders that mean genioglossal EMG decreased with higher mean arterial pressure. The results of acute BP increases in a sample of nine sleeping young adults without sleep apnea performed by Wilson et al. were mixed, with the average airway resistance largely unchanged during elevations of BP. However, there were important exceptions as those with higher airway resistance at baseline were more likely to demonstrate increases in airway resistance with increased BP, suggesting that this may be an important mechanism for those at risk of sleep apnea. In summary, animal and human data demonstrate that acute increases in BP lead to decrements in upper airway tone and these findings support the position that more intensive treatment of HTN may attenuate sleep apnea severity.
Role of volume overload in hypertension and obstructive sleep apnea
Volume overload or fluid redistribution may also help explain the bidirectional relationship between OSA and HTN as volume excess is thought to contribute to HTN and it may also exacerbate sleep apnea. The hypothesis that volume overload exacerbates OSA is supported by small studies of patients with ESRD and by emerging studies of healthy individuals and OSA patients. Upper airway edema and reduced lung volume because of pulmonary edema caused by fluid overload in ESRD appear to contribute to reduced airway size [45,46]. We view the mounting evidence relating volume overload in ESRD [47,48] to sleep apnea as a model for this novel mechanism in the larger population of those with HTN and sleep apnea. Also, fluid displacement from the legs by application of lower body positive pressure via antishock trousers in healthy individuals has been shown to increase neck circumference and airflow resistance of the pharynx , suggesting that fluid displacement to the upper body during recumbency may predispose to pharyngeal obstruction during sleep. In a study of 12 patients with sleep apnea and chronic venous insufficiency, compression stockings reduced the severity of sleep apnea by 36%, which supports the position that the displacement of fluid from the legs to neck exacerbates OSA . In a study of 25 patients with resistant HTN, increased rostral fluid redistribution was significantly associated with more severe sleep apnea . Similar findings were reported by Elias et al. in 26 ESRD patients on hemodialysis. However, Jafari and Mohsenin  demonstrated a significant rostral fluid shift that was not related to sleep apnea severity.
Hypertensive patients usually have a reduction in the plasma and extracellular fluid volume by 10–12% in the initial few weeks of treatment with diuretics , which may potentially improve OSA in these patients. In a recent study among 16 patients with uncontrolled HTN, intensified diuretic therapy with metolazone and spironolactone resulted in significant improvement in OSA severity and overnight change in leg fluid volume, thus supporting the hypothesis that leg fluid redistribution plays an important role in the pathogenesis of OSA [17▪▪]. This study complements the growing evidence from ESRD patients, in whom improvement in sleep apnea has been shown following nocturnal hemodialysis , change from continuous ambulatory peritoneal dialysis to nocturnal peritoneal dialysis (NPD) [19,54], and kidney transplantation , presumably by more effective fluid removal. Although the findings from these studies are limited by the lack of an adequate control group, small sample size, and selected patient population, the results support the need to examine the impact of intensive BP and volume control on sleep apnea in hypertensive patients in a larger randomized controlled trial.
Hyperaldosteronism and obstructive sleep apnea
There is increasing evidence on the role of aldosterone in resistant HTN and OSA. Among patients with resistant HTN, hyperaldosteronism is significantly associated with prevalence and severity of OSA , and blockade of aldosterone reduces the severity of OSA by almost 50% . One potential mechanism by which hyperaldosteronism contributes to OSA may be intravascular fluid retention and resultant pharyngeal edema . On the other hand, OSA may also cause hyperaldosteronism by stimulation of the renin–angiotensin system, which mediates HTN. This is suggested by a previous study that demonstrated that BP reduction following continuous positive airway pressure treatment correlated with reductions in plasma renin and angiotensin II levels . Recently, improvement in OSA severity was demonstrated after renal denervation , further suggesting the role of sympathetic nerve stimulation in fluid retention and OSA.
Over the last few years, there has been increasing interest in the role of extrarenal mineralocorticoid receptors found in heart, brain, vascular smooth muscles, adipocytes, and macrophages. The effect of aldosterone on the mineralocorticoid receptors in vascular smooth muscle cells is being recognized as an important mechanism for BP regulation and vascular remodeling . In animal models, aldosterone has been shown to act on central mineralocorticoid receptors to increase brain renin–angiotensin activity and oxidative stress . Perhaps, this aldosterone-induced activation of central mineralocorticoid receptors leads to dysregulation of normal central breathing mechanisms and thus sleep apnea. Aldosterone has also been demonstrated to alter endothelial integrity and increase paracellular permeability . It is possible that similar receptors exist in upper airway smooth muscles and aldosterone plays a direct role in increasing parapharyngeal edema locally, thus causing OSA. Future studies are needed to determine the mechanisms by which hyperaldosteronism may contribute to increasing the severity of OSA.
Effect of antihypertensive medications on obstructive sleep apnea
Human studies examining the impact of antihypertensive medications on sleep apnea have been limited by small sample sizes, lack of a control group, short-term follow-up, and a paucity of women and minorities. We discuss here the results of eight studies that included 187 participants, of which 6 of 187 (3%) were African-American and 10 of 187 (5%) were women. Briefly, Kraiczi et al. tested the effects of common antihypertensives on OSA among 40 European men with an average age of 57 years over 6 weeks, showing that there was a small effect of antihypertensive use. This study lacked a placebo control and was underpowered to allow a comparison of drugs. Mayer et al. compared the effects of metoprolol and cilazapril on 12 sleep apnea patients. Peter et al. demonstrated a marked improvement in sleep apnea severity with treatment in six men treated with cilazapril. This study had been planned to include up to 24 individuals, but was terminated early. Weichler et al. examined a sample of 24 hypertensive patients with a mean age of 51 years, comparing the effect of metoprolol to cilazapril and demonstrating that both agents reduced apnea–hypopnea index (AHI) from 40 to 26 in 6 days. Heitmann et al. compared the effects of nebivolol and valsartan, showing modest effects of these antihypertensives on OSA after 6 weeks. In an uncontrolled trial performed in 12 patients with resistant HTN, Gaddam et al. demonstrated a significant improvement in both SBP and OSA with the use of spironolactone. Planes et al. assessed the effect of celiprolol in seven patients in a cross-over design, demonstrating that treatment was associated with a nonsignificant reduction in AHI of 5 h over 3 weeks. Grote et al. examined the effects of cilazapril on sleep apnea among 55 hypertensive European men using a randomized controlled trial, and showed no significant effect of cilazapril on AHI after 6 days of therapy. This study was limited by very short follow-up and a difference in average BP of only 5 mmHg during non-rapid eye movement sleep (NREM). Further, the placebo group's baseline SBP was 10 mmHg lower, such that even with treatment, the cilazapril group had a higher SBP and DBP. In order to better understand these findings, secondary analyses of this study demonstrated that the AHI was significantly reduced during NREM with the use of cilazapril (−8.6 ± 3.2; P = 0.01). This study was limited to a small number of men and was unable to discern whether the impact of the cilazapril was because of a class effect or because of improved BP control. Given the emerging evidence of an increased propensity toward OSA among older adults because of the changes in upper airway anatomy [70,71] and among African-Americans because of the observed differences in upper airway diameter , it is important to study the effect of lower BP in a diverse sample of older adults. In sum, the evidence from small, single-center studies with short-term follow-up suggests that the use of antihypertensives may reduce OSA, but high-quality evidence on whether intensive BP control improves OSA in hypertensive patients is lacking.
Recent research recommendations from the American Academy of Sleep Medicine call for more studies in patients with chronic illness as these populations are most at risk for sleep disorders. As HTN has also been recognized as a health priority by the Center for Disease Control's Division for Heart Diseases and Stroke Prevention and the Institute of Medicine , there is a critical need to study the impact of intensive BP control on OSA and sleep quality among hypertensive patients.
To this end, we are conducting two randomized controlled trials comparing the effect of intensive versus standard BP control on sleep apnea and sleep quality. The overarching hypothesis in both these trials is that there is a bidirectional relationship between sleep apnea, sleep quality and HTN. The Impact of Blood Pressure Control on Sleep Apnea and Sleep Quality in SPRINT (SPRINT-SLEEP) study is ancillary to the Systolic Blood Pressure Intervention Trial (SPRINT). SPRINT is a two-arm, multicenter, randomized controlled trial designed to test whether treatment to reduce SBP to a goal of 120 mmHg compared to a SBP goal of 140 reduces the risk of cardiovascular events over at least 6 years of follow-up among hypertensive older adults. We are using state-of-the-art home apnea monitors, actigraphy to assess sleep–wake behavior, and computer-assisted telephone interviews to measure self-reported sleep quality at baseline and 1 year. This study offers the unique opportunity to use a diverse sample of adults with HTN and validated measures of apnea and sleep quality to assess whether more intensive BP control impacts OSA and sleep quality, and whether OSA and short and fragmented sleep are associated with achievement of BP targets. The SPRINT Study protocolizes diet and medication use so that patients will be advised to follow low Na diets, and diuretics are among the first-line agents. In the ACCORD Study, which used a similar approach to BP control, there were significant differences in the use of diuretics by study arm (83% of intensive versus 52% of standard at month 12) . Therefore, by incorporating diuretic use and weight as surrogates for better volume control, the SPRINT Study will provide some estimation of volume status. We are aware of only one other ongoing RCT comparing the effect of chlorthalidone versus amlodipine on sleep apnea among hypertensive patients with moderate OSA .
As ESRD patients provide an excellent model for understanding the role of volume overload in exacerbating sleep apnea and HTN, we are also conducting a similar multicenter study to examine the impact of intensive BP control on sleep apnea and sleep quality among patients on conventional hemodialysis. The Impact of Blood Pressure Control on Sleep Apnea and Sleep Quality in BID (BID-SLEEP) is an ancillary to the NIH-sponsored Blood Pressure in Dialysis (BID) trial , a multicenter randomized pilot study to determine the feasibility and safety of treating hemodialysis patients to two predialysis standardized SBP goals (110–140 versus 155–165 mmHg) and to evaluate the effect on cardiovascular function and health-related quality of life over a 12-month period. Achievement of the BP goal will be accomplished by a stepped care algorithm consisting of reduction in dry weight and uptitration of antihypertensive agents.
If intensive BP control improves sleep apnea and sleep quality in hypertensive patients, then the treatment of sleep apnea among those with HTN could be targeted to improving the treatment of BP. This may serve as a foundation for the development of a clinical practice protocol for volume removal and intensive BP control to improve sleep quality in hemodialysis patients; this work could dramatically impact public health. Such an approach could also be extended to other settings in which patients suffer from extracellular volume overload such as congestive heart failure and nephrotic syndrome. Thus, the findings from SPRINT-SLEEP and BID-SLEEP will impact the care of patients with HTN and ESRD, and the future directions of research in sleep apnea.
Sleep apnea is widely prevalent among hypertensive adults. There may be a bidirectional relationship between sleep apnea and HTN. Intensive BP and volume overload control may have a favorable effect on sleep apnea. Future studies exploring the potential mediators including the sympathetic nervous system and volume status, and comparing the effects of different classes of antihypertensive drugs on sleep apnea and sleep quality could lead to effective and personalized treatments for these two frequently co-existent disorders.
This work was supported by the National Institutes of Health grant R01DK077785 (to M.U.) and American Heart Association grant 11FTF7520014 (to M.J.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or American Heart Association.
Conflicts of interest
No conflicts of interest were declared.
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