Chapter 10

Sleep apnoea and systemic hypertension

M.R. Bonsignore*,#, S. Battaglia*,#, A. Zito*,#, C. Lombardi",+ and G. Parati",+

Summary
Obstructive sleep apnoea (OSA) causes nocturnal hypertensive peaks at the end of apnoeas and is often associated with daytime systemic hypertension. A causal relationship between OSA and increased blood pressure (BP) during wakefulness has been shown in humans and experimental models, and recent guidelines on hypertension recognised OSA as a frequent cause of secondary hypertension. The pathogenesis of hypertension in OSA patients involves sympathetic hyperactivity secondary to intermittent hypoxia, decreased baroreflex sensitivity, endothelial dysfunction, neurohumoral mechanisms involving the hypothalamic-pituitaryadrenal axis, and increased platelet activation. Associated conditions such as obesity significantly contribute to the pathogenesis of both OSA and hypertension. Hypertension in OSA patients can affect target organs (heart, blood vessels and kidney), and may play a role in the increased cardiovascular risk found in untreated OSA. OSA is a frequent cause of masked hypertension, i.e. hypertension undetected by office BP measurements. Patients with resistant hypertension should be investigated for the presence of OSA. Treatment of OSA with continuous positive airway pressure (CPAP) decreases BP especially in severe OSA and hypertensive patients. Hypertensive OSA patients treated with CPAP usually also need anti-hypertensive treatment, as prevention of respiratory events during sleep may be insufficient to normalise BP. Keywords: Anti-hypertensive treatment, cardiovascular risk, continuous positive airway pressure treatment, pathophysiology
*Biomedical Dept of Internal and Specialistic Medicine, Section of Pneumology, University of Palermo, # Institute of Biomedicine and Molecular Immunology, National Research Council, Palermo, " Dept of Clinical Medicine and Prevention, University of MilanoBicocca, and + Dept of Cardiology, S. Luca Hospital, IRCCS Istituto Auxologico Italiano, Milan, Italy. Correspondence: M.R. Bonsignore, Dip. Biomedico Medicina Interna e Specialistica (DIBIMIS), University of Palermo, V Cervello Hospital, Via Trabucco 180, 90146 Palermo, Italy, Email marisa@ibim.cnr.it

HYPERTENSION IN OSA

Eur Respir Mon 2010. 50, 150173. Printed in UK all rights reserved. Copyright ERS 2010. European Respiratory Monograph; ISSN: 1025-448x. DOI: 10.1183/1025448x.00024609

he pathophysiology of blood pressure (BP) regulation in patients with obstructive sleep apnoea (OSA) is very complex. Nocturnal respiratory events affect BP during sleep by several mechanisms including the mechanical effects of apnoeas, hypoxaemia and hypercapnia, and sleep

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fragmentation. Increased BP in untreated OSA patients may be limited to nocturnal hours, but also occurs during wakefulness possibly as a consequence of changes in autonomic cardiovascular control involving the activity of arterial baroreflexes and peripheral chemoreceptors. The current knowledge about BP in OSA patients has been extensively summarised in recent review papers [15]. This chapter will try to answer some practical questions that carry diagnostic and prognostic implications and could help the clinician in the choice of the most effective approach to treatment. The literature on the topic is extensive (almost 2,500 papers retrieved in March 2010 by searching sleep apnoea and systemic hypertension in PubMed), and due to space limitations only selected references could be included in this review.

What are the features of nocturnal hypertension in OSA patients?

An increase in systemic arterial BP occurs at the end of each apnoea [6, 7]. Early studies found that BP peaks associated with OSA were completely abolished by tracheostomy [8]. In beat-by-beat recordings of BP, OSA patients show continuous oscillations associated with apnoeas (fig. 1). A positive evening-to-morning change in BP [912] and increased mean BP during sleep [13, 14] have been reported in patients with OSA. In addition, the nocturnal BP pattern observed in OSA is profoundly different from the physiological fall in BP during sleep [1517] and contributes to increased mean 24-h BP values in OSA patients. Several studies reported a positive correlation between mean BP over 24 h and OSA severity [1823]. Among the different mechanisms involved in the pathogenesis of nocturnal hypertensive peaks [24], OSA-associated intermittent hypoxia probably plays a major role. Recordings of sympathetic nervous activity during sleep have shown increased burst frequency and duration during OSA, abruptly abolished at resumption of ventilation [25]. Hypertensive peaks coincide with the lowest values of oxygen saturation and are associated with peripheral vasoconstriction [26]. In patients with moderate-to-severe OSA, post-apnoeic BP values correlated with the severity of nocturnal hypoxemia [2729]. Although mean BP values in OSA patients may be similar to those recorded in controls, OSA patients show a much higher BP variability than controls [30]. Increased BP variability has been found to independently predict cardiovascular events [31]. This issue has been recently supported by re-analysis of clinical trials [32], although the relative importance of increased mean BP levels and increased BP variability is still under debate [33]. Respiratory efforts during upper airway obstruction are associated with increased BP during sleep in clinical and experimental studies [3438]. Breathing efforts exert complex effects on haemodynamics by causing large changes in transmural pressure of intrathoracic vessels and the heart. Transmural pressure is the difference between the pressure inside and outside the vessels. If external pressure becomes very negative, such as during upper airway obstruction, transmural pressure will increase even if intravascular pressure does not change. Negative intrathoracic pressure increases venous return to the right heart and decreases left ventricular output. A leftward shift of the interventricular septum was shown to occur during OSA in humans, often associated with pulsus paradoxus (i.e. a o10 mmHg decrease in systemic BP coincident with maximal inspiration compared to expiratory BP values) [39], similar to what occurs in acute severe asthma [40]. During obstructive apnoeas in humans, left ventricular stroke volume correlates inversely with intrathoracic pressure [41]. In experimental animals, changes in intrathoracic pressure were shown to affect arterial baroreflex output, suggesting that changes in autonomic modulation of cardiovascular variables occur during obstructive apnoeas [35, 42]. Decreased baroreflex function has been shown in OSA patients during both sleep and wakefulness, and may contribute to nocturnal hypertension [43]. Sleep disruption is another potential pathogenetic factor in OSA-associated nocturnal and daytime hypertension. Arousals during sleep acutely increase BP in normal subjects [44], nonapnoeic snorers [45, 46], patients with upper airway resistance syndrome [36] and patients with OSA [47]. In the Wisconsin population cohort, sleep fragmentation without hypoxaemia was found to

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a) 200 Blood pressure mmHg 150 100 50 0 b) Insp

independently contribute to daytime hypertension in subjects without respiratory events during sleep [48]. However, this may be of lesser importance in elderly people since aging may blunt the BP response to arousal [49]. In summary, arterial BP is affected by respiratory events during sleep. OSA prevents the physiological decrease in sympathetic activity and BP during sleep. In subjects with OSA, BP increases at the end of each apnoea due to hypoxiainduced sympathetic activation and arousal. Decreased baroreflex function has been observed during sleep in OSA patients, and may contribute to sympathetic hyperactivity and increased BP during sleep.

Airflow Exp

c) 100
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Does OSA cause daytime hypertension?

Prevalence of hypertension in OSAS patients ranges from 35% to .80%, and appears to be 90 influenced by OSA severity. Over 60% of subjects with a respiratory disturbance index .30 were found 85 to be hypertensive [5056]. Lower prevalence figures were reported in 80 Asian population samples [5760] 0 50 100 150 200 and in elderly subjects [61]. Time s Although elderly patients may be less responsive to arousals comFigure 1. Beat-by-beat noninvasive blood pressure recording pared to young subjects [49], during sleep in a patient with obstructive sleep apnoea (obtained by recent studies in elderly subjects Finapres1; Finapres Medical Systems BV, Amsterdam, the with OSA showed that nocturnal Netherlands). a) Blood pressure increases coincident with resumpBP increases compared to control tion of b) ventilation (airflow) and c) lowest arterial oxygen saturation (Sa,O2). Insp: inspiration; Exp: expiration. subjects, while daytime BP does not appear to be affected by OSA [62].
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As for the type of daytime hypertension associated with OSA, the majority of patients showed systolic and diastolic hypertension or isolated diastolic hypertension [61, 63]. Diastolic hypertension may be the earliest effect of OSA on BP [64, 65]. Conversely, systolic hypertension was rarely found in OSA patients both in clinical [63] and population samples [61], with the only exception of patients with chronic heart failure [66]. Some features of OSA differ between sexes [67], including systemic hypertension. OSA-associated hypertension was reported to occur predominantly in males in some studies [68, 69], while other studies found a similar prevalence of hypertension in male and female patients [53, 54, 56, 58, 70]. Hormonal factors could play a role in the lower prevalence of OSA among females in population

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studies [71], as well as in the increased prevalence of OSA in post-menopausal females [67]. However, these were not found to affect the prevalence of hypertension in the general population [53]. Snoring and obstructive sleep-disordered breathing (SDB) during pregnancy were found to be associated with hypertension or fetal growth retardation by some [7276], but not all studies [77, 78]. A role of upper airway obstruction during sleep in hypertension during pregnancy [79] is supported by the positive effects of continuous positive airway pressure (CPAP) on BP levels in pregnant hypertensive females [80, 81]. Both SDB and BP were found to improve after delivery [82]. Excessive daytime sleepiness (EDS), a major symptom of OSA, is increasingly considered as an important clinical marker of OSA severity. Patients with OSA and no EDS may represent a specific subgroup with lower cardiovascular risk compared to sleepy OSA patients [83]. Occurrence of EDS increased the risk of hypertension in epidemiological studies [84, 85]. Daytime sleepiness in OSA patients was also found to be associated with altered autonomic modulation [86] and signs of cardiac dysfunction [87]. OSA syndrome (OSAS) is a recognised cause of resistant (or refractory) hypertension, which is defined as the absence of normalisation of BP despite anti-hypertensive treatment with three or more drugs [88]. OSA patients with resistant hypertension show increased BP fluctuations during sleep compared to normotensive patients [89]. In patients with resistant hypertension, a high prevalence of OSA has been found [9093]. In these patients, OSA treatment improved BP control [93, 94], suggesting a major causal role of OSA in the pathogenesis of resistant hypertension. In summary, daytime hypertension is common in patients with OSA. It shows some differences according to age and sex, as it is more common in young subjects and among males. Sleepiness may be a marker of increased BP in OSA patients. Finally, OSA may contribute to the pathogenesis of hypertension during pregnancy and of resistant hypertension.

What are the mechanisms of increased BP during wakefulness in OSA patients?

The pathophysiology of hypertension in OSA patients probably includes the activation of multiple mechanisms which may exert synergistic detrimental effects on BP regulation [95]. BROOKS et al. [96] elegantly showed in a chronic dog model that OSA increased BP during wakefulness, whereas sleep fragmentation did not. Increased sympathetic activity in OSA patients is not limited to the sleep state but extends to wakefulness [97], possibly as a result of the disrupting effects of chronic intermittent hypoxia on the function of the carotid body [98]. Increased pressor responsiveness to peripheral chemoreceptor stimulation has been found in awake OSA patients [99, 100], together with increased cardiovascular variability [101] and decreased baroreflex function [102]. In rare instances, OSA can present with a clinical presentation that is hardly distinguishable from pheochromocytoma, which resolves after CPAP treatment [103, 104]. Endothelial dysfunction could play a major role in the pathogenesis of daytime hypertension in OSA. Several recent reviews have summarised the extensive literature on this topic in adults [105 107] and children [108]. The endothelium normally contributes to vascular homeostasis, but the hypoxiaoxygenation cycles occurring in OSA disrupt endothelial cell function [109111]. Oxidative stress occurs in OSA and could participate in several pro-inflammatory pathways in circulating inflammatory and endothelial cells [107]. Clinically, endothelial function was found to be impaired in untreated OSA and associated with decreased bioavailability of nitric oxide, a potent vasodilator [106, 112114]. Interestingly, endothelial dysfunction was associated with increased apoptosis of endothelial cells and low release of bone marrow-derived angiogenetic

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progenitors in adults [109, 110] and children with OSA [111], suggesting not only endothelial cell damage, but also decreased endothelial cell repair capability associated with OSA. Controversial data have been published about increased endothelin-1 or vascular endothelial growth factor (VEGF) release in OSA patients [106]. The differences among studies can partly be secondary to the heterogeneity of the samples of patients, as coexistence of cardiovascular disease can affect the results. Alternatively, since VEGF and endothelin-1 could exert their effects locally rather than at the systemic level, their blood concentration may not increase despite their increased release in target tissues. Some studies assessed whether OSA may induce a pro-coagulant state [115]. Increased platelet aggregability was found in patients with severe OSA during sleep [116, 117] and wakefulness [118 126], returning towards normal values after prolonged CPAP treatment [118121, 123125]. Two studies highlighted the importance of the association of OSA with known cardiovascular disease and/or risk factors in increasing platelet aggregability [120, 124]. Severe intermittent hypoxia during sleep [124, 126] and apnoea index [121] predicted platelet activation in OSA. Hormonal dysregulation could affect BP in OSA patients. Increased angiotensin-II and aldosterone were found in untreated OSA, together with a positive correlation between angiotensin-II concentration and daytime BP [22]. While a significant association of OSA and increased aldosterone has been shown in patients with resistant hypertension [127, 128], a normal aldosterone concentration has been found in moderate-to-severe OSA patients without cardiovascular comorbidities compared to controls [129]. The early study by FOLLENIUS et al. [130] found that plasma renin activity (PRA) and aldosterone were in the normal range in untreated OSA patients, but CPAP treatment re-established normal PRA and aldosterone oscillations during sleep. Other hormones are affected by OSA and may contribute to the pathogenesis of hypertension, including the hypothalamicpituitaryadrenal axis (HPA) and cortisol. The results are somewhat controversial as decreased [131, 132] or increased [133135] cortisol levels and altered cortisol circadian rhythm [133, 136] have been reported in untreated OSA. Altogether, most studies agree on disturbed function of the HPA which is corrected after CPAP treatment. Neuroendocrine alterations in obese OSA patients have been recently reviewed [137]. Obesity is the most important comorbidity in OSA. Obesity has a pathophysiological role in promoting upper airway collapse during sleep via several mechanisms [138], carries an increased risk for hypertension, and represents the major confounder in the analysis of pathogenetic factors for hypertension in OSA [139]. In several clinical and epidemiological studies, BP increased with increasing apnoea/hypopnoea index (AHI) and body mass index (BMI) [5056]. Metabolic disturbances associated with obesity (i.e. dyslipidaemia and impaired glucose tolerance) and hypertension are under intense investigation, and OSA has been proposed as an additional component of the Metabolic Syndrome (MetS) [140]. Indeed, a high prevalence of the MetS has been found in OSA patients [140143]. There is also increasing evidence that weight loss has multiple positive effects on BP, metabolic alterations of obesity and OSA severity [144146].

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What is the best method to measure BP in OSA patients?

Different methods have been used to study BP in OSA patients, each of them showing advantages and disadvantages (table 1). Clearly, the simple measurement of office BP, performed according current guidelines [147], is useful to identify patients with stable hypertension but is insufficient to provide information about the complex alterations in the 24-h BP profile found in OSA patients. The evening-to-morning change in BP has been used as a marker of nocturnal hypertension in OSA patients [912], but results varied according to BMI [9], systolic or diastolic BP [10], or sex [11]. A recent study used this method, together with catecholamine, cortisol and cholesterol levels and obesity assessment, to study the pathogenetic role of these factors in OSA-associated hypertension [148].

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Table 1. Methods used to measure blood pressure (BP) in patients with obstructive sleep apnoea Methods to measure BP Office BP (auscultatory or oscillometric methods) Advantages Low cost, equipment largely available in health facilities Disadvantages Limited information, results may be falsely positive (white coat effect) or falsely negative (nocturnal hypertension only) Possible inaccuracies of auscultatory method for diastolic BP Affected by observers bias and digit preference No information on time course of BP during sleep Possible inaccuracies of auscultatory method for diastolic BP, which is also affected by observers bias and digit preference Cuff inflation can disturb sleep, causing an artefactual increase in nocturnal BP Does not provide information about BP behaviour during apnoeas due to discontinuous automated measurements Free from white coat effect, observers bias and digit preference High cost of equipment, large amount of data for each subject may restrict its use to research environment Finger BP levels may be different form brachial BP readings Possible pulse wave distortion in peripheral arteries Need for arterial cannulation, restricted to selected research laboratories Ethical issues

BP measurements before and after the sleep study (auscultatory or oscillometric methods)

Low cost, equipment also largely available for home monitoring, does not disturb sleep, allows detection of BP increase directly after sleep

Ambulatory BP monitoring over 24 h (usually oscillometric, rarely microphonic)

Standardised technique, provides circadian BP profile, allows detection of nocturnal nondipping or increased BP during sleep

Nocturnal or 24-h noninvasive beat-by-beat BP recording (Finapres1, Portapres1)

Allows detailed analysis of BP during sleep and wakefulness, and assessment of BP changes during apnoeas Useful to detect and analyse BP variability better than BP mean levels Same as noninvasive technique

Invasive beat-by-beat BP recording during sleep

Finapres1 and Portapres1 are manufactured by Finapres Medical Systems BV (Amsterdam, the Netherlands).

BP monitoring over 24 h (ambulatory BP monitoring; ABPM) or during the night has allowed the study of positive correlation between mean BP over 24 h, in particular during night-time sleep, and OSA severity [1823]. However, ABPM-related sleep disturbance may affect the nocturnal BP profile [149151], although in most patients these disturbances do not appear able to disrupt the physiological night-time BP reduction [152]. OSA can be associated with nocturnal nondipping of BP. Nondipping is common in OSA and could contribute to the increased cardiovascular risk in OSA patients [153]. A nondipping pattern was found in 4884% of patients with OSA, and its frequency increased with OSA severity [18, 20, 154, 155]; only one study reported a normal daytime/night-time pattern of BP in OSA [156]. The nondipping pattern was not consistently associated with daytime hypertension, as it occurred in

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50% of normotensive and 43% of hypertensive OSAS patients [155]. Other studies found that OSA-associated nondipping correlated to obesity [157] or to sleep-related variables, such as percentage of slow wave sleep or arousals [153]. High BP values recorded by ABPM during sleep should raise the suspicion of OSA in hypertensive patients. A study on hypertensive subjects selected on the basis of a nondipping pattern at ABPM reported that 10 out of 11 patients had an AHI .10 [158], in agreement with data indicating a high prevalence of nocturnal hypertension in subjects with suspected OSAS [64]. OSA is a known cause of masked hypertension, defined as high BP values recorded by ABPM in subjects with normal office BP [159, 160]. Masked hypertension is associated with a higher risk of cardiovascular events and with target organ damage, which may progress if patients are left untreated. To overcome the technical disadvanges of programming a lower number of measurements during sleep in order to limit the sleep disturbance induced by ABPM, a device has been recently developed in which an increased frequency of measurements is triggered by periods of decreased arterial oxygen saturation [161]. The device has been tested in OSA patients both in the untreated condition and during CPAP application, with promising results [162]. Important information on the BP changes occurring in OSA patients can also be obtained by using home BP monitoring techniques which, although unable to quantify nocturnal BP levels, are more easily available at a lower cost than ABPM [163]. BP is rarely measured by invasive means nowadays, given the availability of noninvasive techniques. Beat-by-beat noninvasive BP monitoring during sleep or 24 h by sophisticated devices equipped with finger BP cuffs coupled with a photopletysmograph allows a more accurate analysis of BP variability during daytime and night-time compared to ABPM [164]. Mean BP during sleep was found to be increased in OSA patients [13], and post-apnoeic hypertensive peaks correlated with the severity of nocturnal hypoxaemia in patients with moderate-to-severe OSA [27, 29]. In summary, some of the variability in results reported in the literature on BP in OSA can be attributed to the measurement technique used to assess hypertension. In OSA patients, repeated measurements during 24 h, either by ABPM or noninvasive beat-by-beat monitoring, allow the BP profile to be defined during both wakefulness and sleep.

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Does increased BP in OSA affect target organs?

Heart
Several studies have assessed systolic and diastolic left ventricular (LV) function in OSA patients. A decreased LV systolic function compared to controls has been reported by some studies in the general population [165] and patients with uncomplicated OSA [166168], but the vast majority of studies have examined LV hypertrophy and diastolic function. Increased BP during sleep and wakefulness in OSA patients may be one mechanism contributing to LV hypertrophy and other echocardiographic abnormalities [169]. However, the pathogenesis of cardiac abnormalities can be very hard to assess when several different comorbities such as OSA, obesity and hypertension are commonly found in the same patients. For example, LV hypertrophy was found in 78% of obese patients [170], and loss of weight after bariatric surgery was associated with regression of cardiac structural abnormalities, even after adjustment for hypertension or OSA [171]. Conversely, prevalence of increased interventricular septum thickness was shown to be much higher in obese patients with OSA (50%) compared to obese patients without OSA (15%) [172]. Most studies agree that OSA patients show LV diastolic dysfunction, directly correlated with markers of OSA severity such as AHI or oxygen desaturation during sleep [165, 167, 173179]. BAGUET et al. [179] studied OSA patients without any known cardiovascular morbidity and

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showed that severe OSA was associated with a high prevalence of nondipping of BP during the night and high LV mass. Studies using tissue Doppler imaging reported similar results in adults [180184] and children [185]. Echocardiographic abnormalities significantly improved after CPAP treatment for 6 months [167, 168, 175, 176, 186] or after adenotonsillectomy in children [185]. Some studies found no independent role of OSA in the pathogenesis of LV hypertrophy or diastolic dysfunction, since LV abnormalities were explained by obesity, hypertension and age [187]. One study reported similar echocardiographic abnormalities in apnoeic and non-apnoeic snorers [188]. Conversely, the study by GAO et al. [189] found a detrimental effect of OSA on cardiac function, evaluated as myocardial performance index, independent of hypertension in a casecontrol study examining newly diagnosed essential hypertensive subjects. An earlier study by HEDNER et al. [190] had also shown LV hypertrophy in OSA independent of hypertension. DRAGER et al. [191] recently assessed the independent effect of OSA and hypertension on LV hypertrophy [191]. They examined patients with hypertension, OSA or both, and found that the thickness of interventricular septum or LV posterior wall increased with each condition, but much larger changes occurred when both conditions were associated [191]. MORO et al. [192] documented greater septal thickness and worse diastolic function in hypertensive compared to normotensive OSA patients, with significant improvement after CPAP for 6 months occurring only in the normotensive group [192]. Therefore, it is possible to speculate that at least part of the cardiac dysfunction of OSA could be attributed to the associated hypertension, or that hypertension amplifies the detrimental effects of OSA on cardiac function. Importantly, these changes appear to be reversed after effective treatment of OSA. There is need for further studies addressing the question of cardiac structural and functional changes in female OSA patients, as most studies have been conducted in males.

Blood vessels
Hypertension could contribute to the progression of atherosclerotic lesions associated with OSA. Arterial stiffness [166, 168, 191, 193203], aortic strain and distensibility [204], and pulse wave amplitude attenuation [205] have all been shown to be abnormal in OSA patients, especially in severe disease, and improved after CPAP treatment [198, 200, 203, 204, 206]. The effects of hypertension and OSA on arterial stiffness were additive [191, 197], and a similar picture emerged when patients with MetS with or without OSA were studied [207]. For further information on early OSA-induced cardiovascular changes refer to the chapter by GROTE and SOMMERMEYER [208] in this issue of the monograph. Our understanding of vascular abnormalities in OSA is still far from being complete, since most data have been obtained in middle-aged, male patients. More data are needed, especially in females and elderly patients, on the changes in vascular function associated with OSA.
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Kidney
Some studies have examined whether OSA and the associated hypertension may cause kidney damage. Patients with end-stage renal disease often present with sleep disorders including OSA [209], suggesting the possibility that OSA may worsen prognosis. However, the prognostic impact of OSA in patients with renal failure is still unknown. Patients with untreated OSA showed pressure natriuresis during the night [210, 211], which normalised during CPAP treatment [210]. One study reported that increased nocturnal sodium excretion correlated with changes in nocturnal diastolic BP in hypertensive patients only [211]. The albumin-to-creatinine ratio (ACR) was found to increase with OSA severity in a general population sample, and a significant relationship between ACR and OSA persisted after adjustment for hypertension, glomerular filtration rate and diabetes [212]. However, albuminuria was very modest, i.e. below the commonly used definiton of microalbuminuria [212]. These results are

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in line with the slightly increased albumin excretion reported in nondiabetic, normotensive OSA patients by URSAVAS et al. [213]. In morbidly obese patients undergoing bariatric surgery, ACR did not differ between patients with and without OSA, while serum creatinine was higher in OSA patients [214]. Diastolic BP was the only variable found to correlate with urine albumin excretion, but most patients were on anti-hypertensive treatment, limiting the clinical significance of this result [214]. Two studies assessed renal function in hypertensive OSA patients. One study reported increased serum creatinine in OSA patients compared to non-OSA patients, with similar microalbuminuria in the two groups [215]. The other study in untreated essential hypertensive patients found a greater degree of microalbuminuria in patients who also had OSA compared to those without OSA, and AHI and 24-h pulse pressure independently predicted ACR [216]. Clearly, more data are needed to further assess whether a detrimental interaction of hypertension and OSA affects renal function. Some early reports suggested that proteinuria might be increased in OSA patients [217, 218], but later studies did not confirm this finding as clinically significant [219]. In overweight and obese adolescents with OSA, microalbuminuria and proteinuria correlated to insulin resistance rather than to SDB [220].

Does treatment of OSA decrease BP?

A direct causal relationship between OSA and hypertension would imply that correction of OSA should cause a fall in BP. This simple statement has been very hard to test. The majority of studies have analysed the effects of CPAP treatment, whereas evidence-based information on the effects of other treatments (oral appliances, surgery) is quite limited [221, 222].
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Oral appliances
Three randomised controlled trials have assessed the effects of oral appliances (OA) on BP in patients with mild-to-moderate OSAS [223225]. They included variable numbers of patients on anti-hypertensive treatment (1039% of the entire sample) and measured daytime [225] or 24-h BP [223, 224]. After 4 weeks to 3 months of OA use, diastolic BP decreased by ,3 mmHg; in one study mostly at night [223] and during daytime in another study [225]. Similar results, with decreased mean BP and decreased systolic, diastolic and mean BP at night, were reported after 28 months of OA treatment [226]. OA appeared more effective than CPAP in restoring the nocturnal dipping pattern in one study [223]. A large observational study in 161 patients (of whom 81 were hypertensive and 51 received hypertension treatment) found decreased systolic, diastolic and mean office BP significantly correlated to the effectiveness of OSA treatment, i.e. to baseline BP level [227]. Finally, a longitudinal observational study reported that the decrease in BP observed after 3 months of OA use was maintained after 3 yrs of treatment [228]. No change in daytime BP was found in two small studies in normotensive patients, which documented a significant improvement in cardiac autonomic modulation [229] or endothelial function and oxidative stress [230] after OA treatment. The effectiveness of OA in decreasing diastolic BP by a figure comparable to the results of CPAP studies (see below) could be explained by a better compliance to OA than to CPAP, especially in mild OSAS [223225]. One randomised study has assessed the effects of OA or CPAP on LV hypertrophy and natriuretic peptides after 23 months of treatment in OSA patients (,50% of hypertensive) [231]. Nterminal pro-brain natriuretic peptide values only decreased in the OA group, while echocardiographic measures of LV hypertrophy were unchanged. However, the results should not be considered to be conclusive, due to the methodological limitations of the study (short follow-up period, hypertensive patients on BP-lowering treatment).

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Surgery
Before introduction of CPAP in clinical practice, tracheostomy was shown to decrease BP in adult [8, 232] and paediatric [233] OSAS patients. These studies were important to demonstrate that upper airway abnormalities were central in the pathogenesis of hypertension. Tracheostomy is no longer used in OSA patients. Few studies have assessed the effects of upper airway surgery on BP. One case report showed major positive effects of uvulopalatopharyngoplasty (UPPP) on daytime and nocturnal hypertension in one young, non-obese patient 6 weeks post-operatively [234]. Other studies found that daytime BP was unchanged 3 months after UPPP in patients with mild-to-moderate OSAS [235237], while only one study reported ABPM data showing decreased systolic and diastolic BP at night and in the morning after revised UPPP [237]. Bariatric surgery is an increasingly common intervention in morbidly obese OSA patients due to the poor results obtained with diet or pharmacological treatments. One meta-analysis reported the results of 131 studies [238], but SDB was assessed before and after weight loss in approximately 10% of the total population (2,000 patients). Effective weight loss resolved or improved hypertension in .75% of the patients, and OSA in .80% of the cases, irrespective of the type of intervention (gastric banding, gastroplasty, biliopancreatic diversion or duodenal switch). Prevalence of SDB before surgery was unexpectedly low (19.6%) in a population at high risk for OSA, possibly because females accounted for 72.6% of total cases. Because of the strong effect of obesity on BP, weight loss was probably the main factor for improving hypertension. Assessing the independent contribution of improved respiration during sleep after weight loss will require large studies specifically addressing this question.
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Nasal CPAP
A meta-analysis conducted in 1997 concluded that the relationship between OSAS and hypertension was uncertain and the effects of CPAP on BP undefined [239]. Following this study, randomised controlled studies have been conducted in several laboratories around the world. Despite the large number of studies, recent meta-analyses have confirmed some of the uncertainties of the past: one showed a modest effect of CPAP on BP in severe OSAS [240], while the other two concluded for a small decrease in BP in CPAP-treated patients at least in short-term studies [241, 242]. The benefits of CPAP treatment may be restricted to as yet undefined subgroups of OSA patients [240], and the effects on BP did not differ according to presence or absence of EDS [242]. A recent systematic review on the overall effects of CPAP in OSA confirmed these results [243]. In summary, there is agreement that CPAP treatment does decrease BP in the medium term (13 months), but the effect is rather small. Please refer to a recent review for a detailed analysis of the available studies [1]. Since a linear correlation exists between BP level and cardiovascular risk [244], even small treatment-induced changes in BP could contribute to the survival benefit experienced by severe OSA patients on CPAP treatment [245, 246]. The problems of studying the effects of CPAP on BP have been effectively summarised by DIMSDALE et al. [247]. Differences in the methodology of BP measurement, small numbers of patients, variable length of CPAP treatment, inclusion of normotensive and hypertensive patients, and lack of control for anti-hypertensive medications are commonly encountered, especially in the early studies and may be responsible for the variability in results. The main effect of acute application (i.e. 1 to 3 consecutive nights) of fixed or auto-adjusting CPAP is a decrease in BP variability during sleep [10, 248251]. Uncertainty remains on absolute BP values during acute CPAP application, since some studies found no change [248, 250, 251] while others reported that CPAP decreased mean [252, 253], systolic [10] or systolic and diastolic BP [254]. In patients with OSAS and refractory hypertension [93] or heart failure [255, 256] acute CPAP decreased systolic BP.

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The medium-term studies (i.e. 4 weeks to 3 months) on the effect of CPAP on BP include the majority of the randomised, placebo-controlled trials conducted to date. Most investigators reported positive effects of CPAP treatment on daytime [203, 204, 257259] or daytime and nighttime BP [19, 156, 260265]. In patients with resistant hypertension and OSAS, CPAP treatment decreased BP [94, 263]. Some observational studies were negative [266], found a transient early decrease in BP [267], or reported that daytime BP only decreased in patients showing a shift from a nondipper to a dipper pattern [268]. No significant changes in BP after CPAP were found in randomised controlled trials conducted in patients with mild OSAS [223, 269] or without EDS [270272]. In patients with chronic heart failure, randomised controlled trials showed decreased systolic BP after CPAP treatment for 4 weeks [273] but not after 3 months [274]. Several factors can affect the response to CPAP (summarised in table 2). The effects of CPAP treatment on BP may be expected to be more easily shown in patients with severe OSA than in mild cases, in hypertensive compared to normotensive patients, or in patients showing a good compliance to CPAP treatment. Indeed, two meta-analyses found that the effect of CPAP on BP was largest in patients with severe OSAS and correlated with compliance to treatment [240, 242]. A significant decrease in BP associated with good compliance to CPAP (o4 h?night-1) was recently reported after treatment for 8 weeks [259]. As for the effect of baseline BP levels, a small decrease in BP was found after CPAP in a randomised controlled trial conducted in mostly normotensive patients [260]. Two recent randomised controlled trials in patients with normal ABPM and no evidence of cardiovascular risk factors failed to show any change in BP after 12 weeks of treatment with sham or effective CPAP [276, 277]. A small early study in patients with good compliance to treatment found significant daytime and night-time BP reduction only in hypertensive subjects [278].
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The results of observational studies in hypertensive subjects [93, 94, 263, 267, 269] are complicated by the use of anti-hypertensive medications and their effectiveness in controlling BP. Positive effects of CPAP were found in hypertensive OSA patients receiving no treatment [262] or with resistant hypertension [93, 94], but not in a randomised controlled trial including only optimally treated hypertensive patients [279]. Conversely, a nonrandomised study including a large percentage of hypertensive patients, about half of them being untreated [266], and a small study on hypertensive subjects receiving no treatment [267] reported negative results. Finally, in the rare instance of OSA presenting as a pseudo-pheochromocytoma, CPAP treatment normalised or greatly reduced BP [102, 103]. Few studies have been published on BP after prolonged CPAP treatment (o6 months). These studies show the same limitations of short- and medium-term observations, especially regarding possible changes in anti-hypertensive treatment and compliance to CPAP use. Moreover, randomised controlled trials are restricted by the ethical problem of maintaining severe OSA
Table 2. Factors affecting blood pressure reduction by continuous positive airway pressure (CPAP) treatment
in patients with obstructive sleep apnoea (OSA)

Presence or absence of daytime sleepiness in association with OSA OSA severity Blood pressure levels before treatment Resistant hypertension Patients age and sex Duration of treatment (short versus long follow-up) CPAP proper titration Patients compliance with CPAP treatment Methods of blood pressure measurement (conventional measurements versus home or ambulatory monitoring)
Reproduced from [275] with permission from the publisher.

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Anti-hypertensive medications and compliance to CPAP may modify the long-term effects of CPAP treatment on BP. One study suggested that the response to CPAP or bilevel positive airway pressure could be predicted by absence of anti-hypertensive treatment and severity of hypertension at diagnosis [288]. As compliance to treatment is concerned, persistently decreased diastolic BP was found after 23 yrs of treatment only in hypertensive patients using CPAP for o3 h?day-1 [289]. Two studies tried to identify which factors may be clinically useful to predict the BP response to CPAP treatment. The BP level at diagnosis of OSA [290, 291] and treatment-associated changes in EDS and BMI [291] were reported to predict reduction of BP in the short [290] and long term [291], respectively. The conclusions of the latter study are in line with another study suggesting a major role of sleep disruption in the pathogenesis of hypertension [282]. Finally, to the best of our knowledge, only one study investigated the possible interaction between genetic background and decreased BP after 6 months of CPAP treatment. A b1-adrenoceptor polymorphism was not associated with baseline BP, but diastolic BP decreased after treatment only in Gly389 carriers [292]. Refer to a recent review for extended analysis of the genetic aspects of OSA and hypertension [293]. In summary, some points can be reasonably considered as evidence-based or sufficiently supported by clinical studies. 1) In hypertensive OSA patients effective CPAP treatment causes substantial reduction in 24-h BP [93, 261, 262], although many of these patients still require antihypertensive medication. 2) In patients without hypertension or with well-controlled hypertension, CPAP will lower nocturnal BP, with minimal or no reduction in daytime BP [260, 263, 264]. 3) The effect of CPAP on BP lowering increases with OSA severity [242]. 4) CPAP might not lower BP in nonsleepy OSA patients [270, 271]. The relatively small change in BP reported by studies after CPAP treatment may depend on additional factors known to affect BP values, such as vascular remodeling in long-standing hypertension, genetic predisposition or comorbidities

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patients without effective treatment for a prolonged time. Decreased sympathetic markers and unchanged 24-h BP were reported in an early study in 12 patients (hypertensive: n54) after 14 26 months of CPAP [280]. Other studies found decreased BP after CPAP treatment. A very accurate observational study using invasive methodology documented a decreased mean BP and cardiovascular variability during daytime and sleep in 12 hypertensive patients with severe OSAS studied after temporary discontinuation of anti-hypertensive medication after 6 months of CPAP [281]. Decreased BP and improved echocardiographic variables were reported after CPAP for 6 months by SHIVALKAR et al. [167], but no data were provided on compliance to treatment, presence of hypertension at diagnosis or anti-hypertensive treatment. In hypertensive OSA patients with good compliance to CPAP treatment, daytime systolic and diastolic BP decreased over 6 months, but no relationship was found between changes in BP and decrease in sympathetic nervous activity [282]. After CPAP treatment for 9 months, the decrease in mean BP was found to correlate with high pulse pressure at baseline [21], while another study reported a correlation of 24-h BP with renin and angiotensin II after CPAP for 14 months [22]. BP was found to decrease after 1 yr of treatment only in hypertensive patients [283, 284], but significant weight loss [283] or differences in BMI between hypertensive responders and nonresponders to CPAP [284] may have influenced these results. More recently, a retrospective study found a significant decrease in BP after CPAP for 1 yr in patients with resistant hypertension, but not in hypertensive patients with optimally controlled BP [285]. In a series of severely obese OSA patients, office BP decreased during the first 6 months of CPAP treatment in both normotensive and hypertensive patients, but the effect of CPAP was larger in the latter group [286]. In nonsleepy hypertensive OSA patients, a recent multicenter study found that office systolic and diastolic BP decreased by ,2 mmHg at 1 yr only in patients with very high compliance to treatment (.5.6 h?night-1) [287]. This response was smaller than the reported effect of CPAP on BP in sleepy patients, and became significant after 6 months of treatment, confirming the previous negative results observed after CPAP treatment for 3 months in nonsleepy patients [270].

(diabetes and obesity). Data have been collected mostly in middle-aged males, and little is known about effectiveness of OSA treatment in hypertensive females and elderly patients. There is still need of long-term data in well characterised and large patient samples, in order to estimate the benefit of even small, CPAP-associated BP reduction on cardiovascular risk.

Which drugs should be used to treat hypertension in OSA patients?

Since hypertension in OSA is very common, and CPAP treatment reduces but rarely normalises BP, it would be important to know which anti-hypertensive drug(s) are the most effective in OSA patients. Unfortunately, few studies have addressed this important question. The drugs tested include several classes of anti-hypertensive medications, i.e. b-blockers (atenolol and celiprolol), a-blockers (doxazosin) calcium channel blockers (amlodipine and mibefradil), diuretics (hydrochlorothiazide, furosemide and spironolactone), angiotensin-converting enzyme inhibitors (cilazapril and enalapril) and angiotensin receptor antagonists (losartan). In patients with untreated OSA and hypertension, BP lowering drugs effectively reduced daytime BP, without clear differences between different classes of medications [294297]. Although there is a general agreement that antihypertensive treatment exerts no major effect on sleep structure, the effects of anti-hypertensive drugs on nocturnal BP are still controversial. Some studies found no effect of anti-hypertensive treatment on OSA-associated rise in BP or BP variability (celiprolol [294], amlodipine, enalapril and losartan [296]; several drugs alone or in combination [298]). One study reported unchanged nocturnal BP but improvement in arterial stiffness in treated compared to untreated hypertensive OSA patients, especially those taking calcium channel blockers [297]. Other studies documented a significant decrease in nocturnal BP with cilazapril [299], mibefradil [295], atenolol and hydrochlorothiazide [296]. A study comparing enalapril and doxazosin found that the former was more effective than the latter in decreasing nocturnal BP [297]. Diuretics (furosemide and spironolactone) were the only class of drugs shown to decrease in the short term both OSA severity and BP in OSA

a) 160 150 24-h SBP mmHg b) 24-h DBP mmHg 140 130 120 110 100 110 100 90 80 70 60 17:00 19:00 21:00 23:00 01:00 03:00 05:00 09:00 13:00 15:00 07:00 09:00 11:00 11:00

HYPERTENSION IN OSA

Time h

Figure 2. The combination of the anti-hypertensive drug valsartan

and continuous positive airway pressure (CPAP) treatment effectively decreased both diurnal and nocturnal blood pressure in hypertensive obstructive sleep apnoea patients. a) 24-h systolic blood pressure (SBP) and b) 24-h diastolic blood pressure (DBP). ???????: CPAP: - - - - -: valsartan; : valsartan +CPAP. Reproduced from [301] with permission from the publisher.

162

patients with hypertension and diastolic LV dysfunction [300]. A very recent randomised controlled trial compared the effects of valsartan and CPAP on BP in hypertensive OSA patients [301]. Valsartan was superior to CPAP in reducing BP, but the largest anti-hypertensive effect was seen when both treatments were combined (fig. 2) [301]. In summary, although the majority of the studies were randomised controlled trials using good techniques for BP monitoring (ABPM, beat-by-beat invasive or noninvasive BP recording or pulse wave amplitude), there is no consistent message regarding the optimal treatment of hypertension in OSA. The most relevant clinical information is that normalisation of BP during daytime can be easily achieved, but CPAP treatment is necessary to eliminate BP fluctuations at night.

Conclusions
Systemic hypertension is a major cardiovascular disorder in OSA patients, which has a complex pathogenesis during sleep and wakefulness and may contribute to the high cardiovascular risk characteristic of the disease. In addition, target organ damage may be negatively influenced by coexistence of OSA and hypertension, but too few studies are available to draw any conclusion on this point. Similarly, the optimal pharmacological treatment for hypertension in OSA patients is still undefined. There is evidence that treatment of OSA with CPAP decreases BP, but the effect is small in the majority of patients, possibly in relation to many modifying factors, including the baseline BP value, compliance to treatment and OSA severity. The major clinical consequence of the small BP change usually seen in OSA patients treated with CPAP is that hypertensive patients do need anti-hypertensive treatment besides CPAP. The vast majority of the studies have examined middle-aged male patients, and additional studies in females and elderly OSA patients are warranted.

Statement of Interest
None declared.

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