Canadian Journal of Cardiology 31 (2015) 889e897

Review

Hypertension and Sleep Apnea John S. Floras, MD, DPhil, FRCPC University Health Network and Mount Sinai Hospital Division of Cardiology, University of Toronto, Toronto, Ontario, Canada

ABSTRACT

  RESUM E

Obstructive sleep apnea is more prevalent in patients with hypertension than in the general population and many with obstructive sleep apnea also have hypertension. Obstructive sleep apnea increases the risk of hypertension-related morbidities such as stroke, heart failure, and premature death. Are such associations coincidental or causal and if the latter, what are their implications for clinical practice? Despite compelling epidemiological and mechanistic links between obstructive sleep apnea and hypertension, the effect in clinical trials of the treatment of obstructive sleep apnea on blood pressure has been modest and variable. The purpose of this review is to summarize our present understanding of: (1) the relevant epidemiology and mechanisms that might be responsible for the bidirectional relationship between obstructive sleep apnea and hypertension; and (2) available evidence regarding the effect of treating obstructive sleep apnea on blood pressure.

e obstructive du sommeil est plus re pandue chez les patients L’apne ne rale. De plus, souffrant d’hypertension que dans la population ge e obstructive du sommeil beaucoup de patients souffrant d’apne galement d’hypertension. L’apne e obstructive du sommeil souffrent e es à l’hypertension telles que augmente le risque de maladies lie re bral, l’insuffisance cardiaque et la mort l’accident vasculaire ce mature e. Ces associations sont-elles fortuites ou causales? Et si pre taient causales, quelles sont ses conse quences sur la pratique elles e pit des liens e pide miologiques et me canistiques clinique? En de futables entre l’apne e obstructive du sommeil et l’hypertension, les irre montre  que l’effet du traitement de l’apne e essais cliniques ont de rielle e tait modeste et obstructive du sommeil sur la pression arte sumer notre compre hension variable. Le but de cette revue est de re pide miologie et des me canismes pertinents qui actuelle de : 1) l’e e seraient responsables de la relation bidirectionnelle entre l’apne es probantes obstructive du sommeil et l’hypertension; 2) des donne e obstructive du disponibles concernant l’effet du traitement de l’apne rielle. sommeil sur la pression arte

Moderate or severe obstructive sleep apnea (OSA) can be detected in a third or more of patients with primary hypertension and in up to 80% of individuals with drug-resistant hypertension. Is this a coincidence or a manifestation of causal mechanisms? The intent of this brief review is to summarize: the epidemiology of OSA and its relation to blood pressure and cardiovascular risk; mechanisms by which OSA could promote the development or progression of hypertension; and the effect of treating OSA on blood pressure.

waking values and increase by a corresponding amount upon awakening.4,5 In most patients with hypertension but without sleep-related breathing disorders, blood pressure decreases to normotensive levels during sleep.5 This circadian hemodynamic rhythm, with corresponding reductions in myocardial load and oxygen demand, is critical for cardiovascular health, because cardiac metabolic gene expression exhibits a similar rhythm. Diurnal variations in myocardial workload are anticipated and substrate availability is synchronized accordingly. Temporal misalignment of gene expression and myocardial demand promotes left ventricular hypertrophy and insulin resistance and exacerbates a number of pathological processes, such as ischemia-reperfusion injury and adverse remodelling after experimental infarction.6-10 In humans, nighttime systolic and diastolic blood pressures are more potent predictors of subsequent cardiovascular morbidity and mortality than corresponding office, average 24-hour, or average daytime ambulatory blood pressure readings,11,12 particularly in women13 and in patients with diabetes.14

Sleep and Circadian Hemodynamic Rhythms Blood pressure and heart rate exhibit circadian rhythms of principally neurogenic origin. During nonrapid eye movement sleep, central sympathetic outflow diminishes and cardiac vagal tone is augmented.1-3 As a result, blood pressure and heart rate decrease by approximately 25% from average Received for publication May 4, 2015. Accepted May 7, 2015. Corresponding author: Dr John S. Floras, Suite 1614, 600 University Ave, Toronto, Ontario M5G 1X5, Canada. Tel.: þ1-416-586-8704; fax: þ1416-586-8702. E-mail: john.fl[email protected] See page 894 for disclosure information.

OSA OSA, resulting from complete or partial collapse of the pharynx during sleep, is the most potent expression in human

http://dx.doi.org/10.1016/j.cjca.2015.05.003 0828-282X/Ó 2015 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

890

biology of a chronic circadian misalignment between hemodynamic and metabolic demands and these rhythms of myocardial and vascular gene expression. Obstructive apneas or hypopneas (Table 1) will occur if muscle dilator nerves fail to maintain normal upper airway patency and airflow throughout sleep. Some are genetically at risk for OSA. Some are predisposed to develop OSA because of altered craniofacial structure, a small upper airway lumen or low lung volume, poor upper airway muscle function, respiratory instability, visceral or neck obesity, advancing age, a low arousal threshold, nasal congestion, or peripheral edema.16-18 Each episode of airway occlusion initiates a train of adverse hemodynamic, chemical, and autonomic events (Fig. 1).19 First is the abrupt generation of negative intrathoracic pressure, to as low as 60 mm Hg. This cardiac afterload, which is undetected by any conventional blood pressure measurement device, acutely increases ventricular and atrial wall tension and myocardial oxygen demand. Over time this can stimulate ventricular hypertrophy and atrial remodelling. Apnea disengages pulmonary stretch receptors, and releases their inhibitory reflex constraint on sympathetic outflow. The partial pressure of oxygen decreases, disturbing the myocardial oxygen supply/demand ratio. The partial pressure of carbon dioxide increases. Hypoxia and hypercapnia are potent, chemoreceptor reflex-mediated stimuli to efferent sympathetic discharge and neuronal norepinephrine release. The sleeper is spared asphyxia by a brief arousal, but the adverse consequences of this event include sleep fragmentation, further adrenergic activation coupled with vagal inhibition, surges in blood pressure and heart rate, and a burst of oxidative stress. Breathing instability recurs with the resumption of sleep. The cycle of apnea and hyperpnea repeats itself, minute after minute, over the course of the night (Fig. 2). The apnea-hypopnea index (AHI), quantified by polysomnography, is a measure of the frequency of apneas and hypopneas detected during each hour of sleep (Table 1). There is a dose-response relationship between the AHI and the risk of premature death,21-23 cardiovascular death, and events such as stroke.23-27 Men with an OSA > 30% are 58% more likely to develop heart failure.28 Other indices of OSA severity, such as the frequency and depth of oxygen desaturation,27 or the frequency of arousal from sleep, or of accompanying periodic leg movement also have prognostic implications.15,16,29 In the first systematic study of the prevalence of sleepdisordered breathing in a general sample of the American population aged between 30 and 60 years, 24% of Wisconsin men and 9% of its women were identified as having an AHI  5 events per hour and 9% of men and 4% of women with an AHI  15 events per hour.30 Two decades later, present estimates of the prevalence of moderate or severe OSA in adult Americans of all ages are much higher.31 Only a minority of individuals with cardiovascular disease and OSA will complain of excessive daytime sleepiness.17,32 Its absence might be a consequence of chronic activation, by OSA, of central adrenergic alerting mechanisms: in heart failure patients with OSA subjective daytime sleepiness relates inversely and significantly with efferent sympathetic discharge to skeletal muscle.33 Daytime sleepiness commonly draws patients to medical attention; its absence has important implications. Patients with untreated OSA remain at greater risk

Canadian Journal of Cardiology Volume 31 2015 Table 1. Definitions Term Polysomnography

Apnea Hypopnea

AHI Obstructive sleep apnea and hypopnea Mild OSA Moderate OSA Severe OSA Central sleep apnea and hypopnea Oxygen desaturation Sleep apnea syndrome

Arousal

Definition Multi-channel recording during sleep of electroencephalographic, electro-oculographic, electromyographic, electrocardiographic, and respiratory activity Cessation of airflow for more than 10 seconds Reduction in, but not complete cessation of, airflow to < 50% of normal, usually in association with a reduction in oxyhemoglobin saturation The frequency of apneas and hypopneas per hour of sleep Apnea or hypopnea due to complete or partial collapse, respectively, of the pharynx during sleep OSA with an AHI of 5-15 events per hour OSA with an AHI of 15-30 events per hour OSA with an AHI > 30 events per hour Apnea or hypopnea due to complete or partial withdrawal or central respiratory drive, respectively, to the muscles of respiration during sleep Reduction in oxyhemoglobin saturation, usually as a result of an apnea or hypopnea At least 10 to 15 apneas and hypopneas per hour of sleep associated with symptoms of sleep apnea including loud snoring, restless sleep, nocturnal dyspnea, morning headaches, and excessive daytime sleepiness Transient awakening from sleep lasting less than 10 seconds

AHI, apnea-hypopnea index; CSA, central sleep apnea; OSA, obstructive sleep apnea. Adapted from Bradley and Floras15 with permission of the American Heart Association.

of developing a range of cardiovascular morbidities. Reliance on symptoms as an entry criterion for clinical research is an important cause of selection bias in the present literature; many age-matched ‘control’ subjects might in fact have significant but unrecognized OSA. Mechanisms That Link OSA and Blood Pressure OSA is characterized by oscillations, entrained to the apnea cycle, in vasoconstrictor muscle sympathetic nerve activity (MSNA), blood pressure, and heart rate (Fig. 2). Blood pressure by the end of each apnea might exceed that recorded during wakefulness.20 OSA often evokes a ‘nondipping’ ambulatory blood pressure phenotype and nocturnal hypertension.20,34-36 Is this sufficient to cause chronic daytime hypertension? A sustained aftereffect of OSA on MSNA has been documented during wakefulness in subjects with normal and impaired left ventricular systolic function. In the latter, MSNA is increased on average by 11 bursts per 100 cardiac cycles and decreases equally if OSA is abolished with the use of continuous positive airway pressure (CPAP) therapy,37-39 a finding consistent with the concept that OSA and heart failure interact through a process of additive summation to increase central sympathetic outflow.40 Summation of the independent excitatory effects of OSA and heart failure might occur via sensitization of chemoreceptor reflexes, which elicits increased sympathetic nerve discharge,40 or by sleep apnea, which engages a cortical autonomic network.41

John S. Floras Hypertension and Sleep Apnea

891

Figure 1. Acute and chronic adverse consequences of obstructive sleep apnea. BP, blood pressure; HR, heart rate; LA, left atrial; LV, left ventricular; O2, oxygen; PCO2, partial pressure of carbon dioxide; PNA, parasympathetic nerve activity; PO2, partial pressure of oxygen; SNA, sympathetic nerve activity. Adapted from Bradley and Floras19 from The Lancet with permission from Elsevier.

Grassi et al.42 recorded daytime MSNA in 4 otherwise similar lean and obese cohorts with and without severe OSA (AHI averaging 40 events per hour). MSNA burst incidence was significantly greater in lean and in obese subjects with OSA vs their respective control subjects, indicating that these neural disturbances are not due to confounding effects of obesity. This group also have documented significantly greater daytime MSNA in individuals characterized as having ‘nondipping’ or ‘reverse dipping’ nocturnal ambulatory blood pressure, a clue to the presence of OSA, compared with individuals who are normotensive during day and night.43 Is this adrenergic aftereffect of OSA important for blood pressure regulation and the development of hypertension (Fig. 3)? In heart failure patients with OSA, Sin et al.44 identified a significant positive relationship between AHI and systolic blood pressure after adjustment for body mass

index (BMI), age, sex, oxygen saturation, and left ventricular ejection fraction. CPAP, applied for 1 month, increased daytime left ventricular ejection fraction and caused concurrent reductions in heart rate, MSNA, and blood pressure.38,45 Efferent renal sympathetic nerve stimulation elicits increases in renin release from juxtaglomerular cells, renal sodium and water reabsorption, and renal vascular resistance.46 Thus, if OSA activates efferent renal sympathetic nerve discharge in parallel with MSNA (Fig. 2), this could increase blood pressure acutely via sympathetically-mediated vasoconstriction and sustain hypertension chronically by engaging sodium and water retention in addition to entraining and resetting the sympathetic nervous system. Aldosterone has emerged as a key factor linking OSA, dietary sodium intake, renal sympathetic activation, fluid retention, and hypertension.47 Any fluid retention resulting

Figure 2. Recordings of efferent muscle sympathetic nerve activity (SNA), respiration (RESP), and blood pressure (BP) during 3 minutes of stage II sleep, demonstrating entrainment of sympathetic outflow and blood pressure by the recurring cycles of apnea and hyperpnea characteristic of obstructive sleep apnea (OSA). Republished by permission of The American Society for Clinical Investigation, Inc from Somers et al.20 Permission conveyed through Copyright Clearance Center, Inc.

892

Canadian Journal of Cardiology Volume 31 2015

Nocturnal and Daytime Hypertension

Sympathetic excitation

Sleep apnea

Figure 3. Induction by obstructive sleep apnea of acute nocturnal and chronic daytime blood pressure increase via sympathetic nervous system activation and nonadrenergic (including humoural, inflammatory, and vascular) mechanisms.

from increased renal- and aldosterone-mediated sodium retention will shift at night from the legs to the neck. The resultant peripharygeal edema and increase in neck circumference will increase upper airway resistance and the severity of OSA.17,48 This positive feedback loop might be exacerbated by antihypertensive therapies associated with peripheral edema. Conversely, combining the mineralocorticoid receptor antagonist spironolactone with conventional antihypertensive therapy significantly reduces the AHI, nocturnal desaturation, and ambulatory blood pressure.49 OSA reduces endothelial nitric oxide synthase, blunts brachial artery flow-mediated dilation (a reflection of the bioavailability of shear stress-stimulated endothelial nitric oxide synthase), and increases nitrotyrosine and nuclear factor-kB.50 Thus, over months or years the inflammation and retrograde arterial flow induced acutely by obstructive-apnea elicited sympathetic activation and arteriolar constriction can impair endothelial health.50,51 In normotensive male patients with OSA, pulse wave velocity is increased (and conduit artery compliance decreased) proportionate to nocturnal oxygen desaturation.52 Wellmatched subjects with OSA (but normotensive) and with hypertension (but without apnea) have similar increases in carotid intima-media thickness and diameter, pulse wave velocity, and left ventricular mass relative to healthy control subjects. When both morbidities are present the changes are additive.53,54 Carotid baroreceptor afferents reflexively modulate blood pressure, heart rate, and their variability.55,56 Thus, remodelling of the external carotid artery and increased conduit artery stiffness are an additional potential prohypertensive consequence of OSA.

Evidence for a Causal Role of OSA in Hypertension An AHI  15 events per hour is present in  30% of patients with hypertension and up to 80% of drug-resistant hypertensive individuals.17,19,29,52,57,58 This prevalence supports the concept that the neural, humoural, and vascular consequences of recurring airway obstruction during sleep are sufficient to establish sustained daytime hypertension. Indeed, in one clinic series, OSA was identified as the condition most often associated with resistant hypertension and the one most amenable to treatment.59,60

Experiments in beagles subjected to computer-controlled airway occlusion during sleep provided the first experimental demonstration of a causal relationship between OSA and hypertension. Mean daytime blood pressure increased as early as 2 weeks and at 5 weeks peaked at approximately 16% above baseline values. Blood pressure normalized a few weeks after undisturbed sleep was restored.61 In a series of normotensive and primarily male Spanish patients referred to a sleep centre and followed for a median of 12.2 years, Marin et al. found a crude incidence of hypertension per 100 person-years of 2.19 in participants without OSA. In comparison, in those with OSA who declined CPAP therapy the hazard ratio for incident hypertension was 1.96 (95% confidence interval, 1.44-2.66).62 Prospective community-based cohort studies have not replicated this finding consistently. There was a 2.89 (95% confidence interval, 1.46-5.64) adjusted odds ratio for developing hypertension after 4 years in the Wisconsin Sleep Cohort if the initial AHI was  15 events per hour,63 but in the larger American Sleep Heart Health Study, there was no significant BMI-adjusted dose-response relationship between the baseline AHI and incident hypertension.64 The Vitoria Sleep Cohort study investigators reported a similarly neutral result after adjustment for age and confounding variables.65 OSA and Drug-Resistant Hypertension Moderate to severe OSA can be detected in  2/3 of patients with drug-resistant hypertension.57,59,66,67 In a Spanish report, 70% of ambulatory monitoring-confirmed drugresistant hypertensive individuals had an AHI  30 events per hour and a diastolic ‘nondipping’ blood pressure pattern if daytime somnolence was present.66 Drug-resistant hypertension in patients with OSA is likely multifactorial, with contributions from increased sympathetic tone and intravascular volume. Pratt-Ubunama et al. identified a significant correlation between plasma aldosterone and the AHI in drugresistant hypertension but not in normotensive or controlled hypertensive individuals, consistent with a pathogenic role for volume excess.47 Compared with patients with drugcontrolled hypertension, drug-resistant hypertensive patients shift a greater volume of fluid rostrally from the legs overnight, and have a correspondingly higher AHI.68 OSA Treatment and Blood Pressure Control Abolishing OSA apnea with CPAP immediately relieves the hemodynamic, chemical, and autonomic consequences. In a pre-post CPAP study in which 20 subjects newly diagnosed with OSA acted as their own controls, 4 weeks of CPAP therapy downregulated the intrarenal renin-angiotensin system and reduced supine blood pressure (by 6/5 mm Hg), renal vascular resistance, filtration fraction, and plasma aldosterone concentrations, but had no effect on plasma renin activity or angiotensin II concentrations.69 In the 21,003 person-year Spanish study by Marin and his colleagues,62 incident hypertension was detected in 37.3% of subjects. After adjustment for AHI, age, sex, baseline blood pressure, and BMI, if OSA was treated the risk of developing new-onset hypertension was similar to that of individuals without OSA. In contrast, in an observational study that

John S. Floras Hypertension and Sleep Apnea

recruited nonsleepy conventionally treated hypertensive patients with an AHI  15 events per hour who were offered CPAP and followed for 3 years, clinic and 24-hour ambulatory blood pressures and antihypertensive medication use were similar in those that refused and those that adhered to CPAP therapy.70 In a likely underpowered randomized prevention trial involving 725 subjects, the Spanish sleep apnea consortium tested the hypothesis that treating nonsleepy patients (Epworth Sleepiness Scale score  10) with an AHI  20 events per hour with CPAP would reduce the incidence of hypertension or cardiovascular events.71 Patients were followed for a median of 4 years. There was no significant reduction in hypertension or cardiovascular events with treatment but post hoc analyses generated the hypothesis that these end points might be attenuated if CPAP was used > 4 hours nightly. Several randomized trials have evaluated the effects of CPAP on blood pressure. Not all recruited OSA patients with hypertension. In one study of 24 middle-aged normotensive overweight men, there were significant 4 mm Hg reductions in daytime and nighttime ambulatory diastolic blood pressure after 4 months of treatment with CPAP, but this change did not differ significantly from control subjects.72 In a randomized study that allocated subjects with prehypertension or masked hypertension to therapeutic CPAP or no treatment over a 3-month period, those allocated to CPAP had a significant reduction in office systolic pressure (5 mm Hg) and in daytime and nighttime ambulatory systolic and diastolic blood pressures. The prevalence of masked hypertension (normal office blood pressure but increased ambulatory blood pressure), decreased from 39% to 5%.73 The most rigourous trial methodologically measured blood pressure continuously over approximately 19 hours using digital photoplethysmography in 60 patients with an AHI  5 events per hour and daytime sleepiness randomized to either therapeutic or subtherapeutic CPAP. Those who continued in the trial (16 per group) were restudied after a mean of 65 days. Most had hypertension. Compared with patients who received subtherapeutic CPAP, blood pressure decreased significantly with full therapeutic CPAP by 10.3/11.2 mm Hg and by 12.6/11.4 mm Hg for mean daytime and nighttime blood pressures, respectively.74 In 318 patients (88% hypertensive) with cardiovascular disease or multiple risk factors allocated randomly to 12 weeks of CPAP, nocturnal supplementary oxygen, or no therapy, daytime and nighttime blood pressures were respectively 2.9/ 2.6 mm Hg (P ¼ 0.10/P ¼ 0.02) and 4.2/3.2 mm Hg lower (P ¼ 0.02/P ¼ 0.003) in CPAP-treated vs oxygen-treated subjects.75 It has been difficult to replicate consistently the findings of Becker et al74 in studies that used discontinuous ambulatory recording.76-78 Several meta-analyses of trials involving CPAP reported modest reductions in ambulatory blood pressure, in the range of 2-3 mm Hg.79-83 However, caution should be exercised when interpreting these findings.84 These metaanalyses incorporated trials involving individuals with normal blood pressure and treated and untreated hypertension. Most examined only a few weeks of treatment. Some meta-analyses conflated data from patients with heart failure and without heart failure.80,83 Most investigators used

893

intermittent noninvasive ambulatory recording methods, which are incapable of detecting OSA-induced cyclical surges in blood pressure and the effect of treatment on their peaks. Finally, none of the meta-analyses considered the far greater hemodynamic benefit of abolishing cyclical oscillations in left ventricular and left atrial transmural pressures with CPAP.79,82-86 Considering the adverse autonomic, humoural, and cardiovascular effects of OSA, it is curious that the effect of CPAP on the blood pressure of hypertensive patients is so modest or in some studies nonexistent. A recent meta-analysis argued against the proposition that the response to therapy is a function of pretreatment somnolence85 whereas the hypothesis that a minimum threshold of adherence is required to detect benefit is biologically plausible.77 The severity of daytime somnolence before treatment81 and the time of day that blood pressure is measured might be critical: one of the largest decreases in average blood pressure reported, albeit in a heart failure cohort, was detected when patients were evaluated shortly after waking.45 A concurrent 0.2 kg/m2 increase in BMI, as has been noted in a recent meta-analysis of 3181 patients from 25 randomized treatment trials lasting more than 4 weeks,87 could blunt any potential hypotensive effect of abolishing OSA. However, the most plausible explanations for the seemingly modest effect are the level of blood pressure documented before treatment and the limitations of conventional intermittent blood pressure measurements. The greatest and most clinically relevant reductions are detected if blood pressure readings are acquired continuously at night and during the day.74 A patient-level meta-analysis of 968 adults with OSA but without major comorbidities identified uncontrolled hypertension at baseline and treatment duration as the only significant predictors of antihypertensive effects of CPAP treatment.85 These findings suggest that the greatest opportunity to decrease blood pressure resides with patients who exhibit true drug-resistant hypertension. Logan et al.88 studied 11 patients with refractory hypertension before CPAP, during the night on which it was first applied, and again after 2 months of treatment. On the first night, peak sleep blood pressure, measured using continuous monitoring with digital photoplethysmography decreased by 15/16 mm Hg. Average sleep blood pressure decreased from 138/78 to 126/73 mm Hg, heart rate from 67 to 64 beats per minute and baroreflex modulation of heart rate, an index of cardiac vagal tone, increased. Using 24-hour monitoring before and after 2 months of nightly therapy, these authors identified significant (11/6 mm Hg) reductions in 24-hour and nighttime (9/8 mm Hg) blood pressure and a significant 14 mm Hg reduction in daytime systolic blood pressure.88 Subsequently, several randomized trials evaluated the effects of therapeutic CPAP for up to 6 months on blood pressure in cohorts with OSA and drug-resistant hypertension.60,89-91 In meta-analyses,92,93 reductions in 24hour systolic/diastolic blood pressures ranged between 3.9/ 3.5 mm Hg93 and 6.7/5.9 mm Hg,92 greater than reductions observed in patients with OSA and either untreated or drugcontrolled hypertension. There was no evident difference in the blood pressure response between those with and without excess daytime sleepiness.92 Whereas the calculated mean change in average daytime blood pressure was significant

894

(5.3/4.8 mm Hg) the mean change in average night time blood pressure (2.1/1.5 mm Hg) was not. There was a significant correlation between hours of CPAP use and the decrease in diastolic blood pressure.92 In contrast, in a subsequent report involving 117 drugresistant hypertensive patients (baseline AHI 41 events per hour but average 24-hour blood pressure at the time of enrollment only 129/75 mm Hg), intention-to-treat analysis revealed no significant effect of CPAP on clinic or ambulatory blood pressure.94 Only in a subgroup with uncontrolled blood pressure was a significant 4.7 mm Hg effect on nighttime systolic blood pressure detected.94 Analysis and Conclusions A third or more of individuals with hypertension also will have OSA. Neurogenic, hormonal, and vascular mechanisms elicited by recurrent obstructive apnea all have the capacity to increase peripheral resistance, heart rate, sodium and water retention, arterial inflammation, and conduit artery stiffness. A rostral shift during recumbent sleep into the neck of fluid retained in the legs over the course of the day can, in turn, exacerbate OSA by decreasing upper airway diameter and increasing upper airway resistance. Despite this coexistence and bidirectional relationship between OSA and hypertension, it has been difficult to demonstrate a consistent, clinically important, and statistically significant blood pressure-decreasing response to CPAP. Thus, many questions remain. Why do so many with moderate or severe OSA not develop hypertension?53,74,95 In most individuals, OSA might increase daytime and nighttime blood pressure by a significant, but limited, amount that is insufficient to establish hypertension unless other prohypertensive factors are present. In the beagle model of OSA-induced hypertension the peak blood pressure achieved was only 16% above baseline.61 In many who develop heart failure as a consequence of OSA28 blood pressure might decrease over time to normotensive values. Why do some individuals with OSA develop left ventricular hypertrophy, some left ventricular dilatation and systolic dysfunction, and others neither condition? Why do hypertension-related complications, such as stroke or heart failure, differ in their event rates between men and women? It has been proposed that this is because women often develop OSA later in life and thus have a shorter duration of exposure at the time of diagnosis.23 Why has it been so difficult to consistently detect a substantive or in some instances any blood pressure response to CPAP treatment? Is this because CPAP fails to address all mechanisms responsible for the development of hypertension, or because some of the vascular adaptations to longstanding OSA are irreversible, or because conventional ambulatory monitoring cannot detect the impact of treatment on the OSA-entrained 30-60 second oscillations in blood pressure and heart rate? Newer methods under development have the potential to address this latter question with greater fidelity.96 If the objective is to reduce the burden of cardiovascular mortality or morbidity in this population, should control of hypertension be our principal therapeutic target? Other features of severe OSA, such as the frequency and depth of

Canadian Journal of Cardiology Volume 31 2015

oxygen desaturation, predict more potently the development of ventricular cardiovascular events such as sudden cardiac death.27 Importantly, with each obstructive apnea the profound acute reductions in intrathoracic pressure (with corresponding increases in atrial and ventricular wall tension) will stimulate atrial dilatation and ventricular hypertrophy,53,97,98 and compromise recovery of left ventricular function after acute myocardial infarction.99 Nonrandomized observational data are consistent with the concept that short-term (3-6 months) treatment of OSA leads to a reversal of concentric left ventricular hypertrophy and a reduction of left ventricular mass index.97,98 In some patients, the convergence of atrial stretch and increased sympathetic and vagal drive will trigger atrial fibrillation that can become persistent and resistant to conventional pulmonary vein isolation and ablative therapy.100-103 The modest blood pressure responses to CPAP reported in current meta-analyses should not dissuade clinicians from considering its prescription for patients with severe OSA and hypertension. A greater and clinically important blood pressure reduction, with a magnitude proportional to pretreatment values, is indeed evident if blood pressure is measured continuously rather than with conventional ambulatory monitoring before and during CPAP use. Importantly, the benefits of treatment of OSA include also abolishing nocturnal hypoxia and reversal of the left ventricular hypertrophy and left atrial enlargement stimulated by negative intrathoracic pressure. However, to establish whether treatment of OSA indeed decreases the risk of cardiovascular events associated with longstanding hypertension will require evidence from adequately powered randomized clinical trials. Funding Sources The author holds the Canada Research Chair in Integrative Cardiovascular Biology. His research on sleep apnea in cardiovascular disease has been supported by Operating Grants from the Canadian Institutes of Health Research and the Heart and Stroke Foundation of Ontario. Disclosures The author has no conflicts of interest to disclose. References 1. Somers VK, Dyken ME, Mark AL, Abboud FM. Sympathetic-nerve activity during sleep in normal subjects. N Engl J Med 1993;328:303-7. 2. Vanoli E, Adamson PB, Ba-Lin, et al. Heart rate variability during specific sleep stages. A comparison of healthy subjects with patients after myocarial infarction. Circulation 1995;91:1918-22. 3. Hossmann V, Fitzgerald GA, Dollery CT. Circadian rhythm of baroreflex reactivity and adrenergic vascular response. Cardiovasc Res 1980;14:125-9. 4. Floras JS, Jones JV, Johnston JA, et al. Arousal and the circadian rhythm of blood pressure. Clin Sci Mol Med Suppl 1978;4:395s-7s. 5. Floras JS, Sleight P. Ambulatory monitoring of blood pressure. In: Sleight P, Jones JV, eds. Scientific Foundations of Cardiology. London: Heineman, 1983:155-64.

John S. Floras Hypertension and Sleep Apnea 6. Young ME. The circadian clock within the heart: potential influence on myocardial gene expression, metabolism, and function. Am J Physiol Heart Circ Physiol 2006;290:H1-16. 7. Young ME, Razeghi P, Taegtmeyer H. Clock genes in the heart: characterization and attenuation with hypertrophy. Circ Res 2001;88: 1142-50. 8. Young ME, Razeghi P, Cedars AM, Guthrie PH, Taegtmeyer H. Intrinsic diurnal variations in cardiac metabolism and contractile function. Circ Res 2001;89:1199-208. 9. Martino TA, Sole MJ. Molecular time: an often overlooked dimension to cardiovascular disease. Circ Res 2009;105:1047-61. 10. Alibhai FJ, Tsimakouridze EV, Chinnappareddy N, et al. Short-term disruption of diurnal rhythms after murine myocardial infarction adversely affects long-term myocardial structure and function. Circ Res 2014;114:1713-22. 11. Fan HQ, Li Y, Thijs L, et al. Prognostic value of isolated nocturnal hypertension on ambulatory measurement in 8711 individuals from 10 populations. J Hypertens 2010;28:2036-45. 12. Dolan E, Stanton A, Thijs L, et al. Superiority of ambulatory over clinic blood pressure in predicting mortality. Hypertension 2005;46:156-61. 13. Boggia J, Thijs L, Hansen TW, et al. Ambulatory blood pressure monitoring in 9357 subjects from 11 populations highlights missed opportunities for cardiovascular prevention in women. Hypertension 2011;57:397-405.

895

without continuous positive airway pressure treatment: a cohort study. Ann Intern Med 2012;156:115-22. 26. Loke YK, Brown JW, Kwok CS, Niruban A, Myint PK. Association of obstructive sleep apnea with risk of serious cardiovascular events: a systematic review and meta-analysis. Circ Cardiovasc Qual Outcomes 2012;5:720-8. 27. Gami AS, Olson EJ, Shen WK, et al. Obstructive sleep apnea and the risk of sudden cardiac death. J Am Coll Cardiol 2013;62:610-6. 28. Gottlieb DJ, Yenokyan G, Newman AB, et al. Prospective study of obstructive sleep apnea and incident coronary heart disease and heart failure: the sleep heart health study. Circulation 2010;122:352-60. 29. Somers VK, White DP, Amin R, et al. Sleep apnea and cardiovascular disease: an American Heart Association/American College of Cardiology Foundation scientific statement from the American Heart Association Council for High Blood Pressure Research Professional Education Committee, Council on Clinical Cardiology, Stroke Council, and Council on Cardiovascular Nursing. Circulation 2008;118:1080-111. 30. Young T, Palta M, Dempsey J, et al. The occurence of sleep-disordered breathing among middle-aged adults. N Engl J Med 1993;328:1230-5. 31. Peppard PE, Young T, Barnet JH, et al. Increased prevalence of sleepdisordered breathing in adults. Am J Epidemiol 2013;177:1006-14. 32. Arzt M, Young T, Finn L, et al. Sleepiness and sleep in patients with both systolic heart failure and obstructive sleep apnea. Arch Intern Med 2006;166:1716-22.

14. Draman MS, Dolan E, van der Poel L, et al. The importance of nighttime systolic blood pressure in diabetic patients: Dublin Outcome Study. J Hypertens 2015;33:1373-7.

33. Taranto Montemurro L, Floras JS, Millar PJ, et al. Inverse relationship of subjective daytime sleepiness to sympathetic activity in patients with heart failure and obstructive sleep apnea. Chest 2012;142:1222-8.

15. Bradley TD, Floras JS. Sleep apnea and heart failure: part I: obstructive sleep apnea. Circulation 2003;107:1671-8.

34. Seif F, Patel SR, Walia HK, et al. Obstructive sleep apnea and diurnal nondipping hemodynamic indices in patients at increased cardiovascular risk. J Hypertens 2014;32:267-75.

16. American Academy of Sleep Medicine Task Force. Classification of OSA according to AHI. Sleep 1999;22:667-89. 17. Kasai T, Floras JS, Bradley TD. Sleep apnea and cardiovascular disease: a bidirectional relationship. Circulation 2012;126:1495-510. 18. Jordan AS, McSharry DG, Malhotra A. Adult obstructive sleep apnoea. Lancet 2014;383:736-47. 19. Bradley TD, Floras JS. Obstructive sleep apnoea and its cardiovascular consequences. Lancet 2009;373:82-93. 20. Somers VK, Dyken ME, Clary MP, Abboud FM. Sympathetic neural mechanisms in obstructive sleep apnea. J Clin Invest 1995;96: 1897-904. 21. Punjabi NM, Caffo BS, Goodwin JL, et al. Sleep-disordered breathing and mortality: a prospective cohort study. PLoS Med 2009;6:e1000132. 22. Young T, Finn L, Peppard PE, et al. Sleep disordered breathing and mortality: eighteen-year follow-up of the Wisconsin sleep cohort. Sleep 2008;31:1071-8. 23. Kendzerska T, Gershon AS, Hawker G, Leung RS, Tomlinson G. Obstructive sleep apnea and risk of cardiovascular events and all-cause mortality: a decade-long historical cohort study. PLoS Med 2014;11: e1001599. 24. Marin JM, Carrizo SJ, Vicente E, Agusti AG. Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observation study. Lancet 2005;365:1046-53. 25. Campos-Rodriguez F, Martinez-Garcia MA, de la Cruz-Moron I, et al. Cardiovascular mortality in women with obstructive sleep apnea with or

35. Kario K. Obstructive sleep apnea syndrome and hypertension: ambulatory blood pressure. Hypertens Res 2009;32:428-32. 36. Suzuki M, Guilleminault C, Otsuka K, Shiomi T. Blood pressure “dipping” and “non-dipping” in obstructive sleep apnea syndrome patients. Sleep 1996;19:382-7. 37. Spaak J, Egri ZJ, Kubo T, et al. Muscle sympathetic nerve activity during wakefulness in heart failure patients with and without sleep apnea. Hypertension 2005;46:1327-32. 38. Usui K, Bradley TD, Spaak J, et al. Inhibition of awake sympathetic nerve activity of heart failure patients with obstructive sleep apnea by nocturnal continuous positive airway pressure. J Am Coll Cardiol 2005;45:2008-11. 39. Floras JS. Should sleep apnoea be a specific target of therapy in chronic heart failure? Heart 2009;95:1041-6. 40. Floras JS. Sympathetic nervous system activation in human heart failure: clinical implications of an updated model. J Am Coll Cardiol 2009;54: 375-85. 41. Kimmerly DS, Morris BL, Floras JS. Apnea-induced cortical BOLDfMRI and peripheral sympathoneural firing response patterns of awake healthy humans. PLoS One 2013;8:e82525. 42. Grassi G, Facchini A, Quarti F, et al. Obstructive sleep apnea dependent and - independent adrenergic activation in obesity. Hypertension 2005;46:321-5. 43. Grassi G, Seravalle G, Quarti-Trevano F, et al. Sympathetic and baroreflex cardiovascular control in hypertension-related left ventricular dysfunction. Hypertension 2009;53:205-9.

896

Canadian Journal of Cardiology Volume 31 2015

44. Sin DD, Fitzgerald F, Parker JD, et al. Relationship of systolic BP to obstructive sleep apnea in patients with heart failure. Chest 2003;123: 1536-43.

62. Marin JM, Agusti A, Villar I, et al. Association between treated and untreated obstructive sleep apnea and risk of hypertension. J Am Med Assoc 2012;307:2169-76.

45. Kaneko Y, Floras JS, Usui K, et al. Cardiovascular effects of continuous positive airway pressure in patients with heart failure and obstructive sleep apnea. N Engl J Med 2003;348:1233-41.

63. Peppard PE, Young T, Palta M, Skatrud J. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 2000;342:1378-84.

46. DiBona GF. Physiology in perspective: the wisdom of the body. Neural control of the kidney. Am J Physiol Regul Integr Comp Physiol 2005;289:R633-41.

64. O’Connor GT, Caffo B, Newman AB, et al. Prospective study of sleepdisordered breathing and hypertension: the Sleep Heart Health Study. Am J Respir Crit Care Med 2009;179:1159-64.

47. Pratt-Ubunama MN, Nishizaka MK, Boedefeld RL, et al. Plasma aldosterone is related to severity of obstructive sleep apnea in subjects with resistant hypertension. Chest 2007;131:453-9.

65. Cano-Pumarega I, Duran-Cantolla J, Aizpuru F, et al. Obstructive sleep apnea and systemic hypertension: longitudinal study in the general population: the Vitoria Sleep Cohort. Am J Respir Crit Care Med 2011;184:1299-304.

48. Redolfi S, Yumino D, Ruttanaumpawan P, et al. Relationship between overnight rostral fluid shift and obstructive sleep apnea in nonobese men. Am J Respir Crit Care Med 2009;179:241-6.

66. Lloberes P, Lozano LS, Romero O, et al. Obstructive sleep apnoea and 24-h blood pressure in patients with resistant hypertension. J Sleep Res 2010;19:597-602.

49. Gaddam K, Pimenta E, Thomas SJ, et al. Spironolactone reduces severity of obstructive sleep apnoea in patients with resistant hypertension: a preliminary report. J Hum Hypertens 2010;24:532-7.

67. Muxfeldt ES, Margallo VS, Guimaraes GM, Salles GF. Prevalence and associated factors of obstructive sleep apnea in patients with resistant hypertension. Am J Hypertens 2014;27:1069-78.

50. Jelic S, Lederer DJ, Adams T, et al. Vascular inflammation in obesity and sleep apnea. Circulation 2010;121:1014-21.

68. Friedman O, Bradley TD, Chan CT, Parkes R, Logan AG. Relationship between overnight rostral fluid shift and obstructive sleep apnea in drugresistant hypertension. Hypertension 2010;56:1077-82.

51. Millar PJ, Murai H, Floras JS. Neurogenic retrograde arterial flow during obstructive sleep apnea: a novel mechanism for endothelial dysfunction? Hypertension 2011;58:e17-8. 52. Drager LF, Lopes HF, Maki-Nunes C, et al. The impact of obstructive sleep apnea on metabolic and inflammatory markers in consecutive patients with metabolic syndrome. PLoS One 2010;5:e12065. 53. Drager LF, Bortolotto LA, Figueiredo AC, et al. Obstructive sleep apnea, hypertension, and their interaction on arterial stiffness and heart remodeling. Chest 2007;131:1379-86.

69. Nicholl DD, Hanly PJ, Poulin MJ, et al. Evaluation of continuous positive airway pressure therapy on renin-angiotensin system activity in obstructive sleep apnea. Am J Respir Crit Care Med 2014;190:572-80. 70. Kasiakogias A, Tsioufis C, Thomopoulos C, et al. Effects of continuous positive airway pressure on blood pressure in hypertensive patients with obstructive sleep apnea: a 3-year follow-up. J Hypertens 2013;31: 352-60.

54. Drager LF, Bortolotto LA, Krieger EM, Lorenzi-Filho G. Additive effects of obstructive sleep apnea and hypertension on early markers of carotid atherosclerosis. Hypertension 2009;53:64-9.

71. Barbe F, Duran-Cantolla J, Sanchez-de-la-Torre M, et al. Effect of continuous positive airway pressure on the incidence of hypertension and cardiovascular events in nonsleepy patients with obstructive sleep apnea: a randomized controlled trial. J Am Med Assoc 2012;307: 2161-8.

55. Floras JS, Hassan MO, Jones JV, et al. Consequences of impaired arterial baroreflexes in essential hypertension: effects on pressor responses, plasma noradrenaline and blood pressure variability. J Hypertens 1988;6:525-35.

72. Drager LF, Bortolotto LA, Figueiredo AC, Krieger EM, LorenziFilho G. Effects of continuous positive airway pressure on early signs of atherosclerosis in obstructive sleep apnea. Am J Respir Crit Care Med 2007;176:706-12.

56. Floras JS, Hassan MO, Jones JV, et al. Factors influencing blood pressure and heart rate variability in hypertensive humans. Hypertension 1988;11:273-81.

73. Drager LF, Pedrosa RP, Diniz PM, et al. The effects of continuous positive airway pressure on prehypertension and masked hypertension in men with severe obstructive sleep apnea. Hypertension 2011;57: 549-55.

57. Logan AG, Perlikowski SM, Mente A, et al. High prevalence of unrecognized sleep apnoea in drug-resistant hypertension. J Hypertens 2001;19:2271-7. 58. Pedrosa RP, Drager LF, Genta PR, et al. Obstructive sleep apnea is common and independently associated with atrial fibrillation in patients with hypertrophic cardiomyopathy. Chest 2010;137:1078-84. 59. Pedrosa RP, Drager LF, Gonzaga CC, et al. Obstructive sleep apnea: the most common secondary cause of hypertension associated with resistant hypertension. Hypertension 2011;58:811-7. 60. Pedrosa RP, Drager LF, de Paula LK, et al. Effects of OSA treatment on BP in patients with resistant hypertension: a randomized trial. Chest 2013;144:1487-94. 61. Brooks D, Horner RL, Kozar LF, Render-Teixeira CL, Phillipson EA. Obstructive sleep apnea as a cause of systemic hypertension: evidence from a canine model. J Clin Invest 1997;99:106-9.

74. Becker HF, Jerrentrup A, Ploch T, et al. Effect of nasal continuous positive airway pressure treatment on blood pressure in patients with obstructive sleep apnea. Circulation 2003;107:68-73. 75. Gottlieb DJ, Punjabi NM, Mehra R, et al. CPAP versus oxygen in obstructive sleep apnea. N Engl J Med 2014;370:2276-85. 76. Robinson GV, Smith DM, Langford BA, Davies RJ, Stradling JR. Continuous positive airway pressure does not reduce blood pressure in nonsleepy hypertensive OSA patients. Eur Respir J 2006;27:1229-35. 77. Barbe F, Duran-Cantolla J, Capote F, et al. Long-term effect of continuous positive airway pressure in hypertensive patients with sleep apnea. Am J Respir Crit Care Med 2010;181:718-26. 78. Duran-Cantolla J, Aizpuru F, Montserrat JM, et al. Continuous positive airway pressure as treatment for systemic hypertension in people with obstructive sleep apnoea: randomized controlled trial. Br Med J 2010;341:c5991.

John S. Floras Hypertension and Sleep Apnea

897

79. Montesi SB, Edwards BA, Malhotra A, Bakker JP. The effect of continuous positive airway pressure treatment on blood pressure: a systemic review and meta-analysis of randomized controlled trials. J Clin Sleep Med 2012;8:587-96.

92. Iftikhar IH, Valentine CW, Bittencourt LR, et al. Effects of continuous positive airway pressure on blood pressure in patients with resistant hypertension and obstructive sleep apnea: a meta-analysis. J Hypertens 2014;32:2341-50.

80. Alajmi M, Mulgrew AT, Fox J, et al. Impact of continuous positive airway pressure therapy on blood pressure in patients with obstructive sleep apnea hypopnea: a meta-analysis of randomized controlled trials. Lung 2007;185:67-72.

93. Varounis C, Katsi V, Kallikazaros IE, et al. Effect of CPAP on blood pressure in patients with obstructive sleep apnea and resistant hypertension: a systematic review and meta-analysis. Int J Cardiol 2014;175: 195-8.

81. Bratton DJ, Stradling JR, Barbe F, Kohler M. Effect of CPAP on blood pressure in patients with minimally symptomatic obstructive sleep apnoea: a meta-analysis using individual patient data from four randomised controlled trials. Thorax 2014;69:1128-35.

94. Muxfeldt ES, Margallo V, Costa LM, et al. Effects of continuous positive airway pressure treatment on clinic and ambulatory blood pressures in patients with obstructive sleep apnea and resistant hypertension: a randomized controlled trial. Hypertension 2015;65:736-42.

82. Haentjens P, Van Meerhaeghe A, Moscariello A, et al. The impact of continuous positive airway pressure on blood pressure in patients with obstructive sleep apnea syndrome: evidence from a meta-analysis of placebo-controlled randomized trials. Arch Intern Med 2007;167: 757-64.

95. Davies RJ, Crosby J, Prothero A, Stradling JR. Ambulatory blood pressure and left ventricular hypertrophy in subjects with untreated obstructive sleep apnoea and snoring, compared with matched control subjects, and their response to treatment. Clin Sci (Lond) 1994;86: 417-24.

83. Bazzano LA, Khan Z, Reynolds K, He J. Effect of nocturnal nasal continuous positive airway pressure on blood pressure in obstructive sleep apnea. Hypertension 2007;50:417-23.

96. Shirasaki O, Kuwabara M, Saito M, et al. Development and clinical application of a new technique for detecting ‘sleep blood pressure surges’ in sleep apnea patients based on a variable desaturation threshold. Hypertens Res 2011;34:922-8.

84. Floras JS, Bradley TD. Treating obstructive sleep apnea: is there more to the story than 2 millimeters of mercury? Hypertension 2007;50:289-91. 85. Bakker JP, Edwards BA, Gautam SP, et al. Blood pressure improvement with continuous positive airway pressure is independent of obstructive sleep apnea severity. J Clin Sleep Med 2014;10:365-9.

97. Cloward TV, Walker JM, Farney RJ, Anderson JL. Left ventricular hypertrophy is a common echocardiographic abnormality in severe obstructive sleep apnea and reverses with nasal continuous positive airway pressure. Chest 2003;124:594-601.

86. Schein AS, Kerkhoff AC, Coronel CC, Plentz RD, Sbruzzi G. Continuous positive airway pressure reduces blood pressure in patients with obstructive sleep apnea; a systematic review and meta-analysis with 1000 patients. J Hypertens 2014;32:1762-73.

98. Koga S, Ikeda S, Nakata T, Yasunaga T, Maemura K. Effects of nasal continuous positive airway pressure on left ventricular concentric hypertrophy in obstructive sleep apnea syndrome. Intern Med 2012;51: 2863-8.

87. Drager LF, Brunoni AR, Jenner R, et al. Effects of CPAP on body weight in patients with obstructive sleep apnoea: a meta-analysis of randomized trials. Thorax 2015;70:258-64.

99. Nakashima H, Katayama T, Takagi C, et al. Obstructive sleep apnoea inhibits the recovery of left ventricular function in patients with acute myocardial infarction. Eur Heart J 2006;27:2317-22.

88. Logan AG, Tkacova R, Perlikowski SM, et al. Refractory hypertension and sleep apnoea: effect of CPAP on blood pressure and baroreflex. Eur Respir J 2003;21:241-7.

100. Kanagala R, Murali NS, Friedman PA, et al. Obstructive sleep apnea and the recurrence of atrial fibrillation. Circulation 2003;107:2589-94.

89. Lloberes P, Sampol G, Espinel E, et al. A randomized controlled study of CPAP effect on plasma aldosterone concentration in patients with resistant hypertension and obstructive sleep apnea. J Hypertens 2014;32:1650-7. 90. Litvin AY, Sukmarova ZN, Elfimova EM, et al. Effects of CPAP on “vascular” risk factors in patients with obstructive sleep apnea and arterial hypertension. Vasc Health Risk Manag 2013;9:229-35. 91. Lozano L, Tovar JL, Sampol G, et al. Continuous positive airway pressure treatment in sleep apnea patients with resistant hypertension: a randomized, controlled trial. J Hypertens 2010;28:2161-8.

101. Mehra R, Benjamin EJ, Shahar E, et al. Association of nocturnal arrhythmias with sleep-disordered breathing: the Sleep Heart Health Study. Am J Respir Crit Care Med 2006;173:910-6. 102. Patel D, Mohanty P, Di Biase L, et al. Safety and efficacy of pulmonary vein antral isolation in patients with obstructive sleep apnea: the impact of continuous positive airway pressure. Circ Arrhythm Electrophysiol 2010;3:445-51. 103. Hoyer FF, Lickfett LM, Mittmann-Braun E, et al. High prevalence of obstructive sleep apnea in patients with resistant paroxysmal atrial fibrillation after pulmonary vein isolation. J Interv Card Electrophysiol 2010;29:37-41.