sleep apnoea and systemic hypertension

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Chapter 10

Sleep apnoea and

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

Summary

Obstructive sleep apnoea (OSA) causes nocturnal hypertensivepeaks at the end of apnoeas and is often associated with daytime

systemic hypertension. A causal relationship between OSA andincreased blood pressure (BP) during wakefulness has beenshown in humans and experimental models, and recentguidelines on hypertension recognised OSA as a frequent causeof secondary hypertension.

The pathogenesis of hypertension in OSA patients involvessympathetic hyperactivity secondary to intermittent hypoxia,decreased baroreflex sensitivity, endothelial dysfunction, neuro-humoral mechanisms involving the hypothalamic-pituitary-adrenal axis, and increased platelet activation. Associatedconditions such as obesity significantly contribute to thepathogenesis of both OSA and hypertension. Hypertension inOSA patients can affect target organs (heart, blood vessels andkidney), and may play a role in the increased cardiovascular riskfound 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 thepresence of OSA.

Treatment of OSA with continuous positive airway pressure(CPAP) decreases BP especially in severe OSA and hypertensivepatients. Hypertensive OSA patients treated with CPAP usuallyalso need anti-hypertensive treatment, as prevention ofrespiratory events during sleep may be insufficient to normaliseBP.

Keywords: Anti-hypertensive treatment, cardiovascularrisk, continuous positive airway pressure treatment,pathophysiology

*Biomedical Dept of Internal andSpecialistic Medicine, Section ofPneumology, University of Palermo,#Institute of Biomedicine and

Molecular Immunology, NationalResearch Council, Palermo,"Dept of Clinical Medicine andPrevention, University of Milano-Bicocca, and+Dept of Cardiology, S. LucaHospital, IRCCS Istituto AuxologicoItaliano, Milan, Italy.

Correspondence: M.R. Bonsignore,Dip. Biomedico Medicina Interna eSpecialistica (DIBIMIS), University ofPalermo, V Cervello Hospital, ViaTrabucco 180, 90146 Palermo, Italy,Email [email protected]

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

The pathophysiology of blood pressure (BP) regulation in patients with obstructive sleepapnoea (OSA) is very complex. Nocturnal respiratory events affect BP during sleep by severalmechanisms 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, butalso occurs during wakefulness possibly as a consequence of changes in autonomic cardiovascularcontrol involving the activity of arterial baroreflexes and peripheral chemoreceptors.

The current knowledge about BP in OSA patients has been extensively summarised in recentreview papers [15]. This chapter will try to answer some practical questions that carry diagnosticand prognostic implications and could help the clinician in the choice of the most effectiveapproach 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 tospace 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 thatBP peaks associated with OSA were completely abolished by tracheostomy [8]. In beat-by-beatrecordings of BP, OSA patients show continuous oscillations associated with apnoeas (fig. 1). Apositive 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 isprofoundly different from the physiological fall in BP during sleep [1517] and contributes toincreased mean 24-h BP values in OSA patients. Several studies reported a positive correlationbetween 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 sympatheticnervous activity during sleep have shown increased burst frequency and duration during OSA,abruptly abolished at resumption of ventilation [25]. Hypertensive peaks coincide with the lowestvalues of oxygen saturation and are associated with peripheral vasoconstriction [26]. In patientswith 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 recordedin controls, OSA patients show a much higher BP variability than controls [30]. Increased BPvariability has been found to independently predict cardiovascular events [31]. This issue has beenrecently supported by re-analysis of clinical trials [32], although the relative importance ofincreased mean BP levels and increased BP variability is still under debate [33].

Respiratory efforts during upper airway obstruction are associated with increased BP during sleepin clinical and experimental studies [3438]. Breathing efforts exert complex effects onhaemodynamics by causing large changes in transmural pressure of intrathoracic vessels andthe heart. Transmural pressure is the difference between the pressure inside and outside thevessels. If external pressure becomes very negative, such as during upper airway obstruction,transmural pressure will increase even if intravascular pressure does not change. Negativeintrathoracic pressure increases venous return to the right heart and decreases left ventricularoutput. A leftward shift of the interventricular septum was shown to occur during OSA inhumans, often associated with pulsus paradoxus (i.e. a o10 mmHg decrease in systemic BPcoincident with maximal inspiration compared to expiratory BP values) [39], similar to whatoccurs in acute severe asthma [40]. During obstructive apnoeas in humans, left ventricular strokevolume correlates inversely with intrathoracic pressure [41]. In experimental animals, changes inintrathoracic pressure were shown to affect arterial baroreflex output, suggesting that changes inautonomic 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 daytimehypertension. Arousals during sleep acutely increase BP in normal subjects [44], nonapnoeicsnorers [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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independently contribute to day-time hypertension in subjects with-out respiratory events during sleep[48]. However, this may be of lesserimportance in elderly people sinceaging may blunt the BP response toarousal [49].

In summary, arterial BP is affectedby respiratory events during sleep.OSA prevents the physiologicaldecrease in sympathetic activityand BP during sleep. In subjectswith OSA, BP increases at the endof each apnoea due to hypoxia-induced sympathetic activation andarousal. Decreased baroreflex func-tion has been observed during sleep

in OSA patients, and may contrib-ute to sympathetic hyperactivityand increased BP during sleep.

Does OSA causedaytime hypertension?

Prevalence of hypertension inOSAS patients ranges from 35%

to .80%, and appears to beinfluenced by OSA severity. Over60% of subjects with a respiratorydisturbance index.30 were foundto be hypertensive [5056]. Lowerprevalence figures were reported inAsian population samples [5760]and in elderly subjects [61].Although elderly patients may beless responsive to arousals com-

pared to young subjects [49],recent studies in elderly subjectswith OSA showed that nocturnalBP increases compared to controlsubjects, while daytime BP does notappear to be affected by OSA [62].

As for the type of daytime hypertension associated with OSA, the majority of patients showedsystolic and diastolic hypertension or isolated diastolic hypertension [61, 63]. Diastolichypertension may be the earliest effect of OSA on BP [64, 65]. Conversely, systolic hypertensionwas rarely found in OSA patients both in clinical [63] and population samples [61], with the onlyexception of patients with chronic heart failure [66].

Some features of OSA differ between sexes [67], including systemic hypertension. OSA-associatedhypertension was reported to occur predominantly in males in some studies [68, 69], while otherstudies 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

Blo

odpressuremmHg

150

100

50

200a)

b)

c)

0

A

irflow

Insp

Exp

0 15010050 200

Time s

Sa,O2

%

100

95

90

85

80

Figure 1. Beat-by-beat noninvasive blood pressure recordingduring sleep in a patient with obstructive sleep apnoea (obtained byFinapres1; Finapres Medical Systems BV, Amsterdam, the

Netherlands). a) Blood pressure increases coincident with resump-

tion of b) ventilation (airflow) and c) lowest arterial oxygen saturation(Sa,O2). Insp: inspiration; Exp: expiration.

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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 generalpopulation [53].

Snoring and obstructive sleep-disordered breathing (SDB) during pregnancy were found to beassociated 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 afterdelivery [82].

Excessive daytime sleepiness (EDS), a major symptom of OSA, is increasingly considered as animportant clinical marker of OSA severity. Patients with OSA and no EDS may represent a specificsubgroup with lower cardiovascular risk compared to sleepy OSA patients [83]. Occurrence ofEDS increased the risk of hypertension in epidemiological studies [84, 85]. Daytime sleepiness inOSA patients was also found to be associated with altered autonomic modulation [86] and signs ofcardiac dysfunction [87].

OSA syndrome (OSAS) is a recognised cause of resistant (or refractory) hypertension, which isdefined as the absence of normalisation of BP despite anti-hypertensive treatment with three ormore drugs [88]. OSA patients with resistant hypertension show increased BP fluctuations duringsleep compared to normotensive patients [89]. In patients with resistant hypertension, a highprevalence 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 differencesaccording to age and sex, as it is more common in young subjects and among males. Sleepinessmay be a marker of increased BP in OSA patients. Finally, OSA may contribute to the pathogenesisof hypertension during pregnancy and of resistant hypertension.

What are the mechanisms of increased BP during wakefulness inOSA patients?

The pathophysiology of hypertension in OSA patients probably includes the activation of multiplemechanisms which may exert synergistic detrimental effects on BP regulation [95]. BROOKSet al.[96] elegantly showed in a chronic dog model that OSA increased BP during wakefulness, whereassleep fragmentation did not.

Increased sympathetic activity in OSA patients is not limited to the sleep state but extends towakefulness [97], possibly as a result of the disrupting effects of chronic intermittent hypoxia onthe function of the carotid body [98]. Increased pressor responsiveness to peripheralchemoreceptor stimulation has been found in awake OSA patients [99, 100], together withincreased cardiovascular variability [101] and decreased baroreflex function [102]. In rareinstances, OSA can present with a clinical presentation that is hardly distinguishable frompheochromocytoma, which resolves after CPAP treatment [103, 104].

Endothelial dysfunction could play a major role in the pathogenesis of daytime hypertension inOSA. Several recent reviews have summarised the extensive literature on this topic in adults [105107] 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 incirculating inflammatory and endothelial cells [107]. Clinically, endothelial function was found tobe impaired in untreated OSA and associated with decreased bioavailability of nitric oxide, apotent vasodilator [106, 112114]. Interestingly, endothelial dysfunction was associated withincreased 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 celldamage, but also decreased endothelial cell repair capability associated with OSA.

Controversial data have been published about increased endothelin-1 or vascular endothelialgrowth factor (VEGF) release in OSA patients [106]. The differences among studies can partly besecondary to the heterogeneity of the samples of patients, as coexistence of cardiovascular diseasecan affect the results. Alternatively, since VEGF and endothelin-1 could exert their effects locallyrather 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 plateletaggregability was found in patients with severe OSA during sleep [116, 117] and wakefulness [118126], returning towards normal values after prolonged CPAP treatment [118121, 123125]. Twostudies highlighted the importance of the association of OSA with known cardiovascular diseaseand/or risk factors in increasing platelet aggregability [120, 124]. Severe intermittent hypoxiaduring sleep [124, 126] and apnoea index [121] predicted platelet activation in OSA.

Hormonal dysregulation could affect BP in OSA patients. Increased angiotensin-II andaldosterone were found in untreated OSA, together with a positive correlation between

angiotensin-II concentration and daytime BP [22]. While a significant association of OSA andincreased aldosterone has been shown in patients with resistant hypertension [127, 128], anormal aldosterone concentration has been found in moderate-to-severe OSA patients withoutcardiovascular 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 inuntreated OSA patients, but CPAP treatment re-established normal PRA and aldosteroneoscillations during sleep. Other hormones are affected by OSA and may contribute to thepathogenesis of hypertension, including the hypothalamicpituitaryadrenal axis (HPA) andcortisol. 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 correctedafter CPAP treatment. Neuroendocrine alterations in obese OSA patients have been recentlyreviewed [137].

Obesity is the most important comorbidity in OSA. Obesity has a pathophysiological role inpromoting upper airway collapse during sleepviaseveral mechanisms [138], carries an increasedrisk for hypertension, and represents the major confounder in the analysis of pathogenetic factorsfor hypertension in OSA [139]. In several clinical and epidemiological studies, BP increased withincreasing apnoea/hypopnoea index (AHI) and body mass index (BMI) [5056]. Metabolicdisturbances associated with obesity (i.e. dyslipidaemia and impaired glucose tolerance) andhypertension 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 hasbeen found in OSA patients [140143]. There is also increasing evidence that weight loss hasmultiple positive effects on BP, metabolic alterations of obesity and OSA severity [144146].

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 advantagesand disadvantages (table 1). Clearly, the simple measurement of office BP, performed accordingcurrent guidelines [147], is useful to identify patients with stable hypertension but is insufficient toprovide 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 inOSA 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 levelsand obesity assessment, to study the pathogenetic role of these factors in OSA-associatedhypertension [148].

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BP monitoring over 24 h (ambulatory BP monitoring; ABPM) or during the night has allowed thestudy 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 BPprofile [149151], although in most patients these disturbances do not appear able to disrupt thephysiological night-time BP reduction [152].

OSA can be associated with nocturnal nondipping of BP. Nondipping is common in OSA andcould contribute to the increased cardiovascular risk in OSA patients [153]. A nondipping patternwas 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]. Thenondipping pattern was not consistently associated with daytime hypertension, as it occurred in

Table 1. Methods used to measure blood pressure (BP) in patients with obstructive sleep apnoea

Methods to measure BP Advantages Disadvantages

Office BP (auscultatory or

oscillometric methods)

Low cost, equipment largely

available in health facilities

Limited information, results may

be falsely positive (white coat

effect) or falsely negative

(nocturnal hypertension only)

Possible inaccuracies ofauscultatory method for

diastolic BP

Affected by observers bias and

digit preference

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

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

Ambulatory BP monitoring

over 24 h (usually

oscillometric, rarely

microphonic)

Standardised technique, provides

circadian BP profile, allows

detection of nocturnal non-

dipping or increased BP

during sleep

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

preferenceNocturnal 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

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

Invasive beat-by-beat BP

recording during sleep

Same as noninvasive technique Need for arterial cannulation,

restricted to selected

research laboratoriesEthical issues

Finapres1and Portapres1 are manufactured by Finapres Medical Systems BV (Amsterdam, the Netherlands).

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50% of normotensive and 43% of hypertensive OSAS patients [155]. Other studies found thatOSA-associated nondipping correlated to obesity [157] or to sleep-related variables, such aspercentage of slow wave sleep or arousals [153].

High BP values recorded by ABPM during sleep should raise the suspicion of OSA in hypertensivepatients. A study on hypertensive subjects selected on the basis of a nondipping pattern at ABPMreported that 10 out of 11 patients had an AHI .10 [158], in agreement with data indicating ahigh 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 withnormal office BP [159, 160]. Masked hypertension is associated with a higher risk ofcardiovascular events and with target organ damage, which may progress if patients are leftuntreated.

To overcome the technical disadvanges of programming a lower number of measurements duringsleep in order to limit the sleep disturbance induced by ABPM, a device has been recentlydeveloped in which an increased frequency of measurements is triggered by periods of decreasedarterial oxygen saturation [161]. The device has been tested in OSA patients both in the untreatedcondition 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 monitoringtechniques which, although unable to quantify nocturnal BP levels, are more easily available at alower cost than ABPM [163].

BP is rarely measured by invasive means nowadays, given the availability of noninvasivetechniques. Beat-by-beat noninvasive BP monitoring during sleep or 24 h by sophisticated devicesequipped with finger BP cuffs coupled with a photopletysmograph allows a more accurate analysisof BP variability during daytime and night-time compared to ABPM [164]. Mean BP during sleepwas found to be increased in OSA patients [13], and post-apnoeic hypertensive peaks correlatedwith 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 beattributed to the measurement technique used to assess hypertension. In OSA patients, repeatedmeasurements during 24 h, either by ABPM or noninvasive beat-by-beat monitoring, allow the BPprofile to be defined during both wakefulness and sleep.

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 thegeneral population [165] and patients with uncomplicated OSA [166168], but the vast majorityof studies have examined LV hypertrophy and diastolic function.

Increased BP during sleep and wakefulness in OSA patients may be one mechanism contributingto LV hypertrophy and other echocardiographic abnormalities [169]. However, the pathogenesisof cardiac abnormalities can be very hard to assess when several different comorbities such asOSA, obesity and hypertension are commonly found in the same patients. For example, LVhypertrophy was found in 78% of obese patients [170], and loss of weight after bariatric surgerywas associated with regression of cardiac structural abnormalities, even after adjustment forhypertension or OSA [171]. Conversely, prevalence of increased interventricular septum thicknesswas shown to be much higher in obese patients with OSA (50%) compared to obese patientswithout OSA (15%) [172].

Most studies agree that OSA patients show LV diastolic dysfunction, directly correlated withmarkers 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 thenight and high LV mass. Studies using tissue Doppler imaging reported similar results in adults[180184] and children [185]. Echocardiographic abnormalities significantly improved afterCPAP 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 ordiastolic 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 oncardiac function, evaluated as myocardial performance index, independent of hypertension in acasecontrol study examining newly diagnosed essential hypertensive subjects. An earlier study byHEDNERet al.[190] had also shown LV hypertrophy in OSA independent of hypertension. D RAGERet 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 ofinterventricular septum or LV posterior wall increased with each condition, but much largerchanges occurred when both conditions were associated [191]. MORO et al. [192] documentedgreater septal thickness and worse diastolic function in hypertensive compared to normotensiveOSA 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 cardiacdysfunction of OSA could be attributed to the associated hypertension, or that hypertensionamplifies the detrimental effects of OSA on cardiac function. Importantly, these changes appear tobe reversed after effective treatment of OSA. There is need for further studies addressing thequestion of cardiac structural and functional changes in female OSA patients, as most studies havebeen 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 waveamplitude attenuation [205] have all been shown to be abnormal in OSA patients, especially insevere disease, and improved after CPAP treatment [198, 200, 203, 204, 206]. The effects ofhypertension and OSA on arterial stiffness were additive [191, 197], and a similar picture emergedwhen patients with MetS with or without OSA were studied [207].

For further information on early OSA-induced cardiovascular changes refer to the chapter byGROTE and SOMMERMEYER [208] in this issue of the monograph. Our understanding of vascularabnormalities in OSA is still far from being complete, since most data have been obtained inmiddle-aged, male patients. More data are needed, especially in females and elderly patients, onthe changes in vascular function associated with OSA.

Kidney

Some studies have examined whether OSA and the associated hypertension may cause kidneydamage. 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 impactof OSA in patients with renal failure is still unknown.

Patients with untreated OSA showed pressure natriuresis during the night [210, 211], whichnormalised during CPAP treatment [210]. One study reported that increased nocturnalsodium excretion correlated with changes in nocturnal diastolic BP in hypertensive patientsonly [211].

The albumin-to-creatinine ratio (ACR) was found to increase with OSA severity in a generalpopulation sample, and a significant relationship between ACR and OSA persisted after adjust-ment for hypertension, glomerular filtration rate and diabetes [212]. However, albuminuria wasvery 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 OSApatients by URSAVAS et al. [213]. In morbidly obese patients undergoing bariatric surgery, ACRdid not differ between patients with and without OSA, while serum creatinine was higher inOSA patients [214]. Diastolic BP was the only variable found to correlate with urine albuminexcretion, but most patients were on anti-hypertensive treatment, limiting the clinical significance ofthis 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 microalbuminuriain the two groups [215]. The other study in untreated essential hypertensive patients found agreater degree of microalbuminuria in patients who also had OSA compared to those withoutOSA, and AHI and 24-h pulse pressure independently predicted ACR [216]. Clearly, more data areneeded to further assess whether a detrimental interaction of hypertension and OSA affects renalfunction.

Some early reports suggested that proteinuria might be increased in OSA patients [217, 218], butlater studies did not confirm this finding as clinically significant [219]. In overweight and obeseadolescents 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 OSAshould cause a fall in BP. This simple statement has been very hard to test. The majority of studieshave analysed the effects of CPAP treatment, whereas evidence-based information on the effects ofother treatments (oral appliances, surgery) is quite limited [221, 222].

Oral appliances

Three randomised controlled trials have assessed the effects of oral appliances (OA) on BP inpatients with mild-to-moderate OSAS [223225]. They included variable numbers of patientson anti-hypertensive treatment (1039% of the entire sample) and measured daytime [225] or24-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 reportedafter 28 months of OA treatment [226]. OA appeared more effective than CPAP in restoringthe 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 OSAtreatment, i.e. to baseline BP level [227]. Finally, a longitudinal observational study reportedthat the decrease in BP observed after 3 months of OA use was maintained after 3 yrs oftreatment [228].

No change in daytime BP was found in two small studies in normotensive patients, whichdocumented a significant improvement in cardiac autonomic modulation [229] or endothelialfunction and oxidative stress [230] after OA treatment. The effectiveness of OA in decreasingdiastolic BP by a figure comparable to the results of CPAP studies (see below) could be explainedby 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 natriureticpeptides after 23 months of treatment in OSA patients (,50% of hypertensive) [231]. N-terminal pro-brain natriuretic peptide values only decreased in the OA group, whileechocardiographic measures of LV hypertrophy were unchanged. However, the results shouldnot be considered to be conclusive, due to the methodological limitations of the study (shortfollow-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 thatupper airway abnormalities were central in the pathogenesis of hypertension. Tracheostomy is nolonger 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 inone young, non-obese patient 6 weeks post-operatively [234]. Other studies found that daytimeBP 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 andin the morning after revised UPPP [237].

Bariatric surgery is an increasingly common intervention in morbidly obese OSA patients due tothe poor results obtained with diet or pharmacological treatments. One meta-analysis reported theresults of 131 studies [238], but SDB was assessed before and after weight loss in approximately10% of the total population (2,000 patients). Effective weight loss resolved or improvedhypertension in .75% of the patients, and OSA in .80% of the cases, irrespective of the type ofintervention (gastric banding, gastroplasty, biliopancreatic diversion or duodenal switch).Prevalence of SDB before surgery was unexpectedly low (19.6%) in a population at high riskfor OSA, possibly because females accounted for 72.6% of total cases. Because of the strong effectof obesity on BP, weight loss was probably the main factor for improving hypertension. Assessingthe independent contribution of improved respiration during sleep after weight loss will requirelarge studies specifically addressing this question.

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 thisstudy, randomised controlled studies have been conducted in several laboratories around theworld. Despite the large number of studies, recent meta-analyses have confirmed some of theuncertainties of the past: one showed a modest effect of CPAP on BP in severe OSAS [240], whilethe other two concluded for a small decrease in BP in CPAP-treated patients at least in short-termstudies [241, 242]. The benefits of CPAP treatment may be restricted to as yet undefinedsubgroups of OSA patients [240], and the effects on BP did not differ according to presence orabsence of EDS [242]. A recent systematic review on the overall effects of CPAP in OSA confirmedthese results [243]. In summary, there is agreement that CPAP treatment does decrease BP in themedium 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 smalltreatment-induced changes in BP could contribute to the survival benefit experienced by severeOSA patients on CPAP treatment [245, 246]. The problems of studying the effects of CPAP on BPhave been effectively summarised by DIMSDALEet al. [247]. Differences in the methodology of BPmeasurement, small numbers of patients, variable length of CPAP treatment, inclusion ofnormotensive and hypertensive patients, and lack of control for anti-hypertensive medications arecommonly encountered, especially in the early studies and may be responsible for the variability inresults.

The main effect of acute application (i.e. 1 to 3 consecutive nights) of fixed or auto-adjustingCPAP is a decrease in BP variability during sleep [10, 248251]. Uncertainty remains on absoluteBP 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 diastolicBP [254]. In patients with OSAS and refractory hypertension [93] or heart failure [255, 256] acuteCPAP 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 themajority of the randomised, placebo-controlled trials conducted to date. Most investigatorsreported positive effects of CPAP treatment on daytime [203, 204, 257259] or daytime and night-time BP [19, 156, 260265]. In patients with resistant hypertension and OSAS, CPAP treatmentdecreased BP [94, 263]. Some observational studies were negative [266], found a transient earlydecrease in BP [267], or reported that daytime BP only decreased in patients showing a shift froma 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 decreasedsystolic 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 CPAPtreatment on BP may be expected to be more easily shown in patients with severe OSA than inmild cases, in hypertensive compared to normotensive patients, or in patients showing a goodcompliance to CPAP treatment. Indeed, two meta-analyses found that the effect of CPAP on BPwas 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) wasrecently 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 arandomised controlled trial conducted in mostly normotensive patients [260]. Two recentrandomised controlled trials in patients with normal ABPM and no evidence of cardiovascular riskfactors 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 significantdaytime and night-time BP reduction only in hypertensive subjects [278].

The results of observational studies in hypertensive subjects [93, 94, 263, 267, 269] are complicatedby the use of anti-hypertensive medications and their effectiveness in controlling BP. Positiveeffects 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 optimallytreated hypertensive patients [279]. Conversely, a nonrandomised study including a largepercentage of hypertensive patients, about half of them being untreated [266], and a small studyon hypertensive subjects receiving no treatment [267] reported negative results. Finally, in the rareinstance of OSA presenting as a pseudo-pheochromocytoma, CPAP treatment normalised orgreatly reduced BP [102, 103].

Few studies have been published on BP after prolonged CPAP treatment (o6 months). Thesestudies show the same limitations of short- and medium-term observations, especially regardingpossible 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) treatmentin 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 titrationPatients compliance with CPAP treatment

Methods of blood pressure measurement (conventional measurements versushome or ambulatory

monitoring)

Reproduced from [275] with permission from the publisher.

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patients without effective treatment for a prolonged time. Decreased sympathetic markers andunchanged 24-h BP were reported in an early study in 12 patients (hypertensive: n54) after 1426 months of CPAP [280]. Other studies found decreased BP after CPAP treatment. A veryaccurate observational study using invasive methodology documented a decreased mean BP andcardiovascular variability during daytime and sleep in 12 hypertensive patients with severe OSASstudied 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 OSApatients with good compliance to CPAP treatment, daytime systolic and diastolic BP decreasedover 6 months, but no relationship was found between changes in BP and decrease in sympatheticnervous activity [282]. After CPAP treatment for 9 months, the decrease in mean BP was found tocorrelate with high pulse pressure at baseline [21], while another study reported a correlation of24-h BP with renin and angiotensin II after CPAP for 14 months [22]. BP was found to decreaseafter 1 yr of treatment only in hypertensive patients [283, 284], but significant weight loss [283] ordifferences in BMI between hypertensive responders and nonresponders to CPAP [284] may haveinfluenced 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 withoptimally controlled BP [285]. In a series of severely obese OSA patients, office BP decreasedduring the first 6 months of CPAP treatment in both normotensive and hypertensive patients, butthe effect of CPAP was larger in the latter group [286]. In nonsleepy hypertensive OSA patients, arecent multicenter study found that office systolic and diastolic BP decreased by,2 mmHg at 1 yronly in patients with very high compliance to treatment (.5.6 h?night-1) [287]. This response wassmaller than the reported effect of CPAP on BP in sleepy patients, and became significant after6 months of treatment, confirming the previous negative results observed after CPAP treatmentfor 3 months in nonsleepy patients [270].

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 positiveairway pressure could be predicted by absence of anti-hypertensive treatment and severity ofhypertension at diagnosis [288]. As compliance to treatment is concerned, persistently decreaseddiastolic BP was found after 23 yrs of treatment only in hypertensive patients using CPAP foro3 h?day-1 [289].

Two studies tried to identify which factors may be clinically useful to predict the BP response toCPAP treatment. The BP level at diagnosis of OSA [290, 291] and treatment-associated changes inEDS 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 betweengenetic background and decreased BP after 6 months of CPAP treatment. A b1-adrenoceptorpolymorphism was not associated with baseline BP, but diastolic BP decreased after treatment onlyin Gly389 carriers [292]. Refer to a recent review for extended analysis of the genetic aspects ofOSA and hypertension [293].

In summary, some points can be reasonably considered as evidence-based or sufficientlysupported by clinical studies. 1) In hypertensive OSA patients effective CPAP treatment causessubstantial reduction in 24-h BP [93, 261, 262], although many of these patients still require anti-

hypertensive medication. 2) In patients without hypertension or with well-controlled hyperten-sion, 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 lowerBP in nonsleepy OSA patients [270, 271]. The relatively small change in BP reported by studiesafter CPAP treatment may depend on additional factors known to affect BP values, such asvascular remodeling in long-standing hypertension, genetic predisposition or comorbidities

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(diabetes and obesity). Data have been collected mostly in middle-aged males, and little is knownabout effectiveness of OSA treatment in hypertensive females and elderly patients. There is stillneed of long-term data in well characterised and large patient samples, in order to estimate thebenefit 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 normalisesBP, it would be important to know which anti-hypertensive drug(s) are the most effective in OSApatients. Unfortunately, few studies have addressed this important question. The drugs testedinclude 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 loweringdrugs effectively reduced day-time BP, without clear differencesbetween different classes of medi-cations [294297]. Although thereis a general agreement that anti-hypertensive treatment exerts nomajor effect on sleep structure, theeffects of anti-hypertensive drugson nocturnal BP are still contro-

versial. Some studies found noeffect of anti-hypertensive treat-ment on OSA-associated rise inBP or BP variability (celiprolol[294], amlodipine, enalapril andlosartan [296]; several drugs aloneor in combination [298]). Onestudy reported unchanged noctur-nal BP but improvement in arterialstiffness in treated compared

to untreated hypertensive OSApatients, especially those takingcalcium channel blockers [297].Other studies documented a sig-nificant decrease in nocturnal BPwith cilazapril [299], mibefradil[295], atenolol and hydrochlor-othiazide [296]. A study compar-ing enalapril and doxazosin foundthat the former was more effective

than the latter in decreasing noc-turnal BP [297]. Diuretics (furose-mide and spironolactone) were theonly class of drugs shown todecrease in the short term bothOSA severity and BP in OSA

100

90

80

70

110

60

07:00

05:00

03:00

01:00

23:00

21:00

19:00

17:00

Time h

24-h

D

BPmmHg

15:00

13:00

11:00

09:00

09:00

11:00

140

130

120

110

160a)

b)

150

100

24-h

SBPmmHg

Figure 2. The combination of the anti-hypertensive drug valsartanand continuous positive airway pressure (CPAP) treatment effect-

ively decreased both diurnal and nocturnal blood pressure inhypertensive obstructive sleep apnoea patients. a) 24-h systolic

blood pressure (SBP) and b) 24-h diastolic blood pressure (DBP).

???????: CPA P: - - - - - : valsartan; : valsartan+CPAP.Reproduced from [301] with permission from the publisher.

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patients with hypertension and diastolic LV dysfunction [300]. A very recent randomisedcontrolled 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 wasseen when both treatments were combined (fig. 2) [301].

In summary, although the majority of the studies were randomised controlled trials using goodtechniques for BP monitoring (ABPM, beat-by-beat invasive or noninvasive BP recording or pulsewave 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 beeasily 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 complexpathogenesis during sleep and wakefulness and may contribute to the high cardiovascular riskcharacteristic of the disease. In addition, target organ damage may be negatively influenced bycoexistence 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 isstill undefined. There is evidence that treatment of OSA with CPAP decreases BP, but the effect issmall in the majority of patients, possibly in relation to many modifying factors, including thebaseline BP value, compliance to treatment and OSA severity. The major clinical consequence ofthe small BP change usually seen in OSA patients treated with CPAP is that hypertensive patientsdo need anti-hypertensive treatment besides CPAP. The vast majority of the studies haveexamined middle-aged male patients, and additional studies in females and elderly OSA patientsare warranted.

Statement of Interest

None declared.

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