Chapter 11

Early atherosclerosis and cardiovascular events

L. Grote*,# and D. Sommermeyer#

Summary
There is a substantial body of evidence that obstructive sleep apnoea (OSA) causes vascular dysfunction, promotes early atherosclerosis and increases the incidence of cardiovascular (CV) events. However, this does not seem to be applicable for the population in general. Therefore, OSA may not be classified as a traditional risk factor for the development of CV disease but it can definitely be classified as an important comorbid condition. In studies performed in clinical populations with elevated CV risk profiles, the occurrence of moderate-to-severe OSA was very often accompanied by a worsened vascular function and increased prevalence of structural abnormalities. The use of continuous positive airway pressure treatment could provide significant improvements in vascular functionality and structure. In fact, the majority of data on incidences of CV disease and mortality suggest a disadvantage in patients with untreated OSA or ineffectively treated OSA. Furthermore, the consequences of OSA are more pronounced in patients who are male, young and obese, with some studies suggesting that consequences may be more pronounced in subjects with daytime hypersomnolence. Diagnosis and treatment of these subgroups appear to be very important. It is obvious that obesity, in this context, is a key comorbid condition and that future research may focus on areas where data currently are more sparse, i.e. in subjects without apparent comorbidities, pre- and post-menopausal females, children and adults. Finally, the age paradox claiming that OSA has a protective mechanism against CV mortality or CV dysfunctions, needs to be addressed with prospective, mechanistic, and epidemiological research.
*Sleep Disorders Center, Sahlgrenska University Hospital, and # Center for Sleep and Wakefulness Disorders, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden. Correspondence: L. Grote, Sleep Disorders Center, Pulmonary Medicine, Sahlgrenska University Hospital, 413 45 Gothenburg, Sweden, Email ludger.grote@lungall.gu.se

ATHEROSCLEROSIS AND CARDIOVASCULAR EVENTS

Eur Respir Mon 2010. 50, 174188. Printed in UK all rights reserved. Copyright ERS 2010. European Respiratory Monograph; ISSN: 1025-448x. DOI: 10.1183/1025448x.00024709

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umerous clinical cohorts and population based samples have demonstrated that obstructive sleep apnoea (OSA) is frequently associated with increased cardiovascular (CV) morbidity and mortality [16]. The proposed mechanisms behind this association included increased sympathetic activity [7], pro-inflammatory activity [8, 9], elevated CV variability [10], diurnal hypertension [11] and a decrease in vascular dilatory capacity [12]. Comorbidities like obesity or other metabolic diseases are frequently observed in patients with OSA, and CV dysfunction is often found to be aggravated [13, 14]. In addition, exposure to OSA, over a longer period of time, is associated with cardiac and vascular dysfunction in some patients. Specific predispositions, e.g. age and sex, established CV risk factors such as hyperlipidemia or smoking, and/or the degree of expression in defense mechanisms; proposedly anti-inflammatory pathways or genetic variances may determine the individuals susceptibility to develop cardiovascular disease (CVD) under the condition of frequent and repetitive exposition to a nocturnal breathing disorder (fig. 1). Research during the past 15 yrs has identified evidence, but not final proof, that OSA may promote and cause endothelial and vascular dysfunction, which leads to an early onset of atherosclerosis and an increased risk for premature occurrence of CV events. There are data to suggest that the effect of OSA on atherosclerosis may be age and sex dependent, and has its highest impact in males aged below 70 yrs [3, 15, 16]. Ischaemic preconditionPro-atherosclerotic factors ing has been proposed as one potential mechanism behind these Functional/structural observations, that OSA in the elderly Functional aspect Additional comorbidity vascular changes of OSA provides a survival advantage when compared with mortality data from Endothelial dysfunction Hyperlipidemia Hypoxia the general population [17]. This exciting and rapidly developing area of research focuses on vascular beds and uses various methodological approaches for the assessment of vascular functionality and structure. Most of these recent studies included mutiple phenotypes of OSA patients and this heterogeneity may at least in part explain the differences in research findings. Tables 14 summarise the main findings and methodology of available studies, which are further discussed in the following sections.
L. GROTE AND D. SOMMERMEYER

Free oxygen radicals Increased sympathetic activity Pro-inflammatory activity

Insuline resistance Vascular dysfunction Intima media thickness Other metabolic Vascular stiffness, disease Smoking plaques

Functional aspect of OSA

Protective mechanisms

Functional/structural vascular changes Collaterals Ischaemic preconditioning

Vascular and endothelial dysfunction

One important task of the endothelium is to maintain the balance between locally produced vasodilating and vasoconstricting substances. The term endothelial dysfunction is defined as a pathological condition where this balance is altered. Endothelial dysfunction is thought to be an important intermediate step in the development of atherosclerosis

Physical activity Vascular receptor down Antioxidants regulation Increased anti-inflammatory Medication activity Protecting factors

Figure 1. Obstructive sleep apnoea (OSA) plays a role in the

interaction of pro- and anti-atherosclerotic factors leading to the development of 1) endothelial dysfunction, and 2) atherosclerosis and cardiovascular (CV) events over time. It is important to note that other comorbidities, e.g. existing cardiovascular disease (CVD), life style factors and actual medication as well as genetic predispositions, are all involved in the long-term process of CVD development.

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Table 1. Vascular and endothelial dysfunction in patients with obstructive sleep apnoea (OSA) Experimental method Main finding

Study population

Casecontrol studies C ARLSSON [12]

K ATO [18]

Normotensive and hypertensive patients with Arterial infusion of ACH, OSA and matched controls n58/8 and 8/8 nitroprussid, venous occlusion plethysmography Severely obese, otherwise healthy OSA Flow-mediated vasodilation, patients and obese controls, n59/9 intra-arterial infusion, ultrasound

G ROTE [19]

K RAICZI [20]

B OREL [21]

Normotensive OSA patients and matched Arterial infusion of norepinephrine controls without any CV disease or and isoprotenerol, venous medication, n510/10 plethysmography Normotensive OSA patients and matched Arterial infusion of angiotensin II controls without any CV disease or and ACH, venous medication, n510/10 plethysmography 14 patients with OHS and 39 eucapnic Reactive hyperaemia by means OSA patients of peripheral arterial tonometry#

Endothelium dependent vasodilation impaired in normo- and hypertensive OSA patients compared with controls Attenuated vasodilation of resistance vessels in OSA, no change in conduct vessels when compared with controls Reduced vasoconstriction (possible vascular alpha receptor downregulation), impaired vascular dilation in OSA patients Increased vasoconstriction after angiotension II infusion, unchanged vascular dilation after ACH in OSA Impaired vasodilation in OHS when compared with severe OSA, in part explained by cofounders

Cross-sectional studies K RAICZI [22]

N IETO [23]

C HAMI [24]

20 OSA patients without CV medication/ FMD and nitrate-induced dilation, Nocturnal hypoxaemia but no AHI correlation previous CVD sonography of brachial artery with attenuated dilation of the conduit artery Population based cohort of 1037 elderly Brachial artery diameter and Brachial artery diameter is increased and FMD is subjects, mean age 77 yrs, 44.2% males, 61% FMD assed by ultrasound reduced by OSA in a dose-response fashion hypertensive Population based cohort of 682 subjects, Brachial artery diameter and Brachial artery diameter associated with age 59 yrs, AHI o15 in 100 subjects FMD AHI, FMD not related to OSA severity

Interventional studies; treatment of OSA with CPAP: peripheral resistance vessels I MADOJEMu [25]

OSA patients n59, BMI 40, AHI 47 Matched controls n59, BMI 35

FMD, MSNA, plethysmography

Resting and post-ischaemic blood flow is attenuated in OSA, reversal after CPAP No association between MSNA and blood flow

Table 1. Continued Experimental method FMD ultrasound, RCT with CPAP n514 versus observation n513 Main finding Post-ischaemic blood flow is attenuated in OSA, reversal after CPAP

Study population

Ip [26]

L ATTIMORE [27]

OSA patients n528, AHI 47, BMI 29, no CVD Matched controls n512 10 OSA patients aged 49 yrs, AHI 39, BMI 31, free of CVD and CV medication

C ROSS [28]

29 desaturators with ODI 20 versus controls

B AYRAM [29]

29 OSA patients, AHI 60, BMI 30, aged 44 yrs 17 snorers, BMI 28, aged 43 yrs

Intra-arterial infusion, occlusion ACH induced vasodilation is improved by plethysmography, uncontrolled CPAP, increased NO production after CPAP CPAP treatment Venous occlusion plethysmography Baseline vasodilation was attenuated in the during infusion of ACH and OSA group, CPAP significantly improved nitroprussid, RCT CPAP versus vasodilatory responses to all stimuli placebo in OSA patients FMD, brachial artery ultrasound Baseline: attenuated FMD response in OSA, reassessment in 20 OSA patients after reversed after CPAP treatment in CPAP 6 months with CPAP therapy users, unchanged in CPAP nonusers

Interventional studies; treatment of OSA with CPAP: intracerebral vessels 8 male OSA patients at baseline and after F OSTER [30] 46 weeks CPAP, matched controls n510 20 severely obese patients with severe OSA R EICHMUTH [31] aged 36 yrs and 20 obese controls aged 34 yrs, CPAP treatment in OSA population Interventional study with antioxidants 16 OSA patients and 16 controls G REBE [32] Intravenous infusion of high dosage vitamin C or placebo

Transcranial Doppler, stimulus via isocapnic hypoxia Exposure to isocapnic hypoxia and hyperoxic hypercapnia; transcranial Doppler

Reduced cerebral blood flow sensitivity to hypoxia in OSA patients, reversed by CPAP Attenuated cerebrovascular dilation to hypoxic and hypercapnic stimuli in OSA, improved hypoxic response by CPAP therapy

Attenuated flow mediated dilation in OSA, reversal after vitamin C infusion

CPAP: continuous positive airway pressure; ACH: acetylcholine; CV: cardiovascular; CVD: cardiovascular disease; OHS: obesity hypoventilation syndrome; FMD: flowmediated dilation; AHI: apnoea/hypoapneoa index; BMI: body mass index; MSNA: muscle sympathetic nerve activity; RCT: randomised control clinical trial; NO: nitric oxide; ODI: oxygen desaturation index. #: the peripheral arterial tonometry was measured using an EndoPAT (Itamar Medical, Caesarea, Israel).

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Table 2. Early markers of atherosclerosis Study protocol Main finding

Vascular stiffness 44 normotensive and hypertensive OSA patients, both sexes, J ELIC [33] applanation tonometry 57 suspected OSA patients free of CVD, pulse wave analysis P HILIPPS [34] 46 hypertensive subjects with OSA and 53 hypertensive T SIOUFIS [35] subjects without OSA, carotid-femoral, PWV

P HILLIPS [36]

20 OSA patients pre- and post-CPAP and 20 OSA patients before and after CPAP withdrawal, pulse wave analysis

K OHLER [37]

60 OSA patients (ODI 23), 41% hypertension, minimal daytime symptoms, 15 controls, PWA by radial artery tonometry

K ELES [38]

24 obese OSA patients and 17 controls, echocardiography

P HILIPPS [39]

93 obese male OSA patients, weight reduction with sibutramine

K UMAGAI [40]

543 patients with mild-to-severe OSA, CAVI

S HIINA [41]

50 OSA patients pre post CPAP, 50% smokers, in part known CVD, pulse wave form and PWV

Increase in arterial stiffness during the course of an apnoea in both NREM/REM sleep independent of changes in blood pressure AIX increased overnight, AIX correlated positively with RDI PWV was increased in patients with hypertension plus OSA after adjustment for confounders, PWV correlated with AHI and nocturnal minimum Sa,O2 Reduction of large-conduit arterial stiffness after 2 months of CPAP therapy No change after 7 nights of CPAP withdrawal Baseline AIX was decreased by OSA and correlated negatively to ODI, AIX after forearm ischaemia was reduced in OSA patients, no blood pressure difference Aortic strain and and distensibility reduced in OSA, reversed by 6 months CPAP therapy 7.9 kg weight loss, 30% AHI reduction, unchanged arterial stiffness and blood pressure Arterial stiffness is increased by age and OSA severity independent from blood pressure level Reduced stiffness in the large to middle sized arteries by CPAP therapy independent from maintained peripheral blood pressure level

Structural cerebrovascular alterations S ILVESTRINI [42]

Carotid IMT was increased in OSA patients (1.4 versus 1.0 mm)

S UZUKI [43]

S CHULZ [44]

23 subjects with severe OSA aged 62 yrs, BMI 31, ODI 62, and 23 controls 167 patients referred to a sleep centre without pulmonary/CV disease 35 OSA patients aged 56 yrs, BMI 32, AHI 57 and matched controls, high degree of CV comorbidity

AHI and measure of nocturnal hypoxia were associated with carotid IMT independent of confounders Increased carotid IMT, (1.04 versus 0.79), plaque score (1.43 versus 0.96) and stenosis (14 versus 0%) in OSA patients

Table 2. Continued Study protocol Main finding

M INOGUCHI [45]

36 OSA patients and 16 obese controls aged 47/48 yrs, BMI 28

S ALETU [46]

103 OSA patients of varying severity and 44 controls, carotid ultrasound, biomarkers of atherosclerosis

D RAGER [47]

W ATTANAKIT [48]

B AGUET [49]

D RAGER [14]

24 patients with severe OSA, randomised CPAP trial over 4 months, ultrasound and PWV, 24-h blood pressure Population based sample of 985 subjects aged 62 yrs with RDI 9 and without known coronary heart disease/stroke, carotid ultrasound 65 patients with mild-to-moderate (RDI ,37) versus severe OSA (RDI .37), no CVD at baseline, echocardiography, ultrasound 81 patients with metabolic syndrome, 51 with concomitant OSA 30 without OSA (aged 47/45 yrs, BMI 32/32, AHI 51/4)

D UBERN [50]

51 obese children (age 12 yrs), 24 with OSA (defined ODI .10), 27 controls, carotid and brachial artery ultrasound

Carotid IMT elevated in mild/moderate-severe OSA (1.17/0.92 versus 0.71), correlated with CRP, IL-6, IL-18, AHI and markers of nocturnal hypoxia Carotid IMT at different sites and plaques are associated with OSA severity, the degree of daytime sleepiness and inflammatory serum markers 4 months of CPAP reduced carotid IMT, PWV, CRP and catecholamines (latter three inter-correlated) Linear relationship between RDI and carotid IMT/occurrence of plaques, association disappeared after control for known CV risk factors No group difference in carotid IMT and PWV, however increased prevalence of carotid plaques and carotid hypertrophy in both groups, ,20% Patients with MS+OSA had increased IMT (767 versus 661 mm), carotid diameter (7811 versus 6705 mm) and prevalence of plaques (20 versus 10%) unrelated to symptoms of increased daytime sleepiness Vasular response to glyceryltrinitrate (but not FMD) is enhanced in OSA children reflecting increased basal vasoconstriction Elastic vascular properties, not IMT, is altered

Structural alterations in the coronary arteries H AYASHI [51] Y UMINO [52]

43 OSA pts and 16 controls, Gensini score from angiography 51 OSA patients with acute coronary syndrome, 38 controls, treated with a PCI 6 month follow-up angiograph

S ORAJJA [53]

S TEINER [54]

More pronounced CAD in patients with nocturnal hypoxia Major adverse events elevated in OSA (24 versus 5%), late lumen loss (1.3 versus 0.7 mm) and binary restenosis (37 versus 15%) increased in patients with OSA 200 patients with CAD Coronary calcification score was nine in OSA patients and none in controls, independent influence of OSA 78 patients with CAD and percutanuous coronary intervention, 7 month follow up 25 versus 14% restenosis and late lumen loss 0.7 versus 0.4 mm in OSA versus controls reduced late lumen loss in 35 OSA patients CPAP users (AHI 28, BMI 28, aged 67 yrs), 43 controls
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OSA is associated with an attenuated coronary collateral development in chronic occlusion state

OSA: obstructive sleep apnoea; NREM: nonrapid eye movement; REM: rapid eye movement; CVD: cardiovascular disease; AIX: augmentation index; RDI: respiratory disturbance index; PWV: pulse wave velocity; Sa,O2: arterial oxygen saturation; ODI: oxygen desaturation index; CAVI: cardio ankle vascular index: IMT: intima-media thickness; CRP: C-reactive protein; IL: interleukin; MS: metabolic syndrome; FMD: flow mediation dilation; CAD: coronary artery disease; PCI: percutaneous coronary intervention. CV: cardiovascular; CPAP: continuous positive airway pressure; BMI: body mass index.

Main finding

and may occur several years prior to detection of clinically manifest vascular pathology [58]. Traditional risk factors like smoking, old age, sedentary lifestyle and obesity are known to facilitate endothelial dysfunction. The occurrence of free oxygen radicals, the reduction of nitric oxide production and the imbalance between pro- and anticoagulant factors caused by repetitive hypoxia may be key players in the development of endothelial dysfunction in OSA patients [8, 9]. In addition, elimination of nocturnal hypoxia by interventions like nCPAP has been identified to reduce signs of inflammatory activation in most studies. Forearm venous occlusion plethysmography has been used to assess enodothelial and vascular dysfunction in OSA patients [12, 18, 28]. Basal blood flow and the change in blood flow by intervention have been applied as a measure of vascular functionality. Experimental models include intra-arterial infusion of an endothelium-dependent vasodilator like acetylcholine (ACH) or endothelium-independent direct vasodilators like nitroprusside. Similar methods for assessment of blood flow may be used to investigate vasoconstrictory patterns in OSA patients by direct vascular stimulation with norepinephrine or angiotensin II [19, 20]. A number of studies used ultrasound and Doppler techniques to determine flow characteristics before and after a period of 510 min of experimental forearm ischaemia, so called flow-mediated dilation (FMD). The test investigates the maximal capacity of a vascular bed to dilate after profound ischaemia, including both endothelium dependent and endothelium independent mechanisms. It is notable that study designs for the evaluation of vascular function in this area have varied considerably between casecontrol, cross-sectional and interventional studies. A comprehensive listing of studies in this area is provided in table 1. Several casecontrol studies of endothelial and vascular function reported an attenuated response to endothelium dependent dilatory stimuli by ACH in the majority [12, 18, 27, 28], but not in all studies. In addition, FMD assessed by the forearm ischaemia model was attenuated in OSA patients in most [18, 23, 25, 26, 29, 37,], but not all studies [24]. This attenuation of the dilatory response was observed in resistance vessels but may not be automatically transferred to conduit vessels [18]. For the interpretation of results it is important to take potential confounders into account. Therefore, some studies excluded patients with known CV or metabolic disease, smoking history or hyperlipidemia [12, 18, 19, 22, 26], whereas others adjusted the analysis for these factors [23, 24]. Interestingly, the degree of obesity and sex distribution vary considerably between studies and data are mainly derived from male patients with moderate-to-severe obesity. Given the fact that obesity itself is characterised by increased inflammatory activity and vascular abnormalities, data from normal weighted subjects are warranted in the future. Furthermore, a generalisation of the findings from existing studies cannot be made, due to the subjects having represented a narrow age range of between 4060 yrs and only a few of the studies included female patients. Indeed, one large

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Table 2. Continued

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S TEINER [55]

34 patients with coronary occlusion divided into OSA status

Study protocol

Table 3. Overall mortality in obstructive sleep apnoea (OSA)-population based studies Wisconsin Sleep Cohort Study [1] Recruitment Sample n Age yrs BMI kg?m-2 AHI 15,30% AHI o30% Deaths % CV versus all-cause mortality OR for all-cause mortality in untreated OSA Started 1988 1522 488 28.6 5.4 4.1 5.3 at 18 yrs 25 versus 80 3.8 (1.69.0) in severe OSA, AHI .30 Sleep Heart Health Study [3] 19951998 6294 6311 28.45.3 11.6 5.4 16.6 at 8.2 yrs 220 versus 1047 1.46 (1.141.86); 2.09 (1.313.33) in males aged ,70 yrs, AHI.30 Busselton Health Study [2] 1990 380 53 26.9 20.2 4.7 8.7 at 14 yrs Not stated versus 33 6.2 (2.019.4) in moderate -to-severe OSA (RDI .15)

Data are presented as n, nSD or OR (95% CI) unless otherwise stated. BMI: body mass index; AHI: apnoea/ hypopnoea index; CV: cardiovascular; RDI: respiratory disturbance index.

Evaluation of the effect of nasal CPAP (nCPAP) therapy on vascular reactivity in OSA patients is another way to explore the question whether OSA has a causative role in vascular/endothelial dysfunction. Indeed, a number of short- and long-term studies with CPAP have consistently demonstrated an improvement or even normalisation of vascular/endothelial function [2529] compared with the pre-treatment condition and/or with control subjects. Some trials were controlled by placebo treatment [28] or an observational control group [26]. Again most, but not all patients [28], in these trials were obese and suffered from severe OSA (table 1). Another interventional approach was addressed by the intravenous application of high-dosage vitamin C in 10, otherwise healthy, OSA patients and 10 age- and sex-matched controls [32]. Vitamin C is a free oxygen radical scavenger and the hypothesis was that vascular dysfunction in OSA is mainly facilitated by an increased production of free oxygen radicals [8]. Following vitamin C infusion the attenuated vascular dilatory response to local ischaemia (FMD) at baseline was always normalised in the OSA group, whereas the response remained unchanged in the control group. Vascular reactivity in the cerebrovascular bed has recently been investigated in OSA patients and controls, transcranial Doppler was used during awake-hypoxic and -hypercapnic exposure as the standardised stimuli [30, 31]. The dilatory-response sensitivity to hypoxia was attenuated in OSA patients and could be normalised by nCPAP therapy. Interestingly, one study selected young patients with a mean age of 36 yrs with severe OSA and marked obesity [31], supporting the hypothesis that OSA at a younger age may accelerate the development of vascular dysfunction and atherosclerosis. Milder forms of OSA in later stages of life may have different effects on vascular disease development [59]. In conclusion, functional in vivo investigations suggest that vascular and endothelial dysfunction is not only common in OSA patients but it can be substantially improved by acute, short-term and long-term CPAP therapy. According to these results, it is likely that OSA provides a negative impact on the balance between dilatory and constrictive influences on vascular tone in arterial vessels. It may be speculated that this influence towards increased resistance, in part, maybe responsible for the development of systemic hypertension [11] and for an acceleration of the atherosclerotic process in

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population-based sample was not able to show a blunted dilatory vascular response after control for age, sex and body weight [24]. In contrast, vascular responses have also been investigated in specific subgroups of patients. For example, the dilatory vascular response to reactive hyperaemia (modified FMD using a peripheral arterial tonometry (PAT) technique) was attenuated in patients with the hypercapnic obesity hypoventilation syndrome when compared with eucapnic obese OSA patients [21].

Table 4. Incident cardiovascular (CV) end-points in clinical based obstructive sleep apnoea (OSA) studies P EKER [6] End-points Incidence of CAD events L AVIE [16] All cause mortality M ARIN [4] Buchner [56] Y AGGI [57]

ATHEROSCLEROSIS AND CARDIOVASCULAR EVENTS

Incidence of Fatal and nonfatal Fatal stroke and fatal and CV events all-cause mortality nonfatal CVD Sample 203 snorers, 13853 1387 OSA 449 patients sleep Sleep laboratory 105 OSA patients sleep patients and laboratory cohort patients, 697 with patients laboratory 264 controls OSA, 325 used cohort as controls Age yrs 4910 488 ,50 ,56 61 patients and 59 controls 28.8 28.8 Range 2631 ,30 34 versus 31 BMI kg?m-2 Not stated 48.8% RDI 403/1551 Not stated Not stated AHI 15,30 1130 1530 events?h-1 Not stated, 28% RDI 39% AHI .30 Not stated, AHI AHI o30 Not stated mean mean ODI .30 mean treated events?h-1 AHI 36 in patients 17.8 in OSA patients n531, and and 2 in controls versus 1.6 in untreated patient nonapnoeic n515 snorers Deaths 9 over 372 over 5 yrs 81 over 27 over 6 yrs 50 in OSA group 7 yrs 10.1 yrs and 14 in controls CV mortality 8 in OSA Not stated 76 events, 27 22 strokes in OSA group, 1 in deaths and 11 CV group and 2 in nonapnoeic deaths; analysis control group snorers mainly in mild-tomoderate OSA Mortality rate OR 2.9 for HR (95% CI) 0.36 Adjusted HR for OR for all-cause OR for 0.42 in fatal and 3.2 (0.210.62) for death and stroke mortality in fatal/nonfatal for nonfatal CPAP, absolute was 1.97 in OSA untreated CAD event moderate risk reduction group versus severe OSA 4.6 in OSA OSA (survival CV events in versus advantage) severe OSA, 28%, 3.5 patients non-OSA patients nonapnoeic AHI.30, fully to be treated for snorers at adjusted prevention of one baseline model CV event
Data are presented as n or n SD, unless otherwise stated. OSA: obstructive sleep apnoea; BMI: body mass index; AHI: apnoea/hypoapnoea index; CAD: coronary artery disease; CVD: cardiovascular disease; RDI: respiratory disturbance index; ODI: oxygen desaturation index; CPAP: continuous positive airway pressure.

sleep apnoea [9]. The limited data from population-based cohorts are conflicting and the effect attributable to OSA was reduced or even disappeared after adjustment for other risk factors. As expected, disease severity of OSA is often mild in general population studies but often moderate-tosevere in clinical cohorts. The assessment of vascular function is complex and further scientific efforts are necessary to evaluate whether OSA is a relevant risk factor for the development of endothelial dysfunction and atherosclerosis in the general population.

Early markers of atherosclerosis

Structural and functional indicators of early atherosclerosis have been further addressed in different OSA populations. Vascular dimensions (e.g. brachial artery diameter and intima-media thickness (IMT)) and spontaneous vascular reactivity (e.g. pulsatile elasticity, pulse wave attenuations, pulse

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wave velocity (PWV) and central aortic pressure waves) have been assessed using noninvasive techniques in different vascular beds, i.e. the brachial artery, the carotid artery or the aorta.

Vascular stiffness
Several studies investigated the properties of the large conduit arteries in OSA (table 2). The studies were performed in clinical cohorts of normotensive and hypertensive patients using applanation tonometry, peripheral pulse wave analysis, pulse velocity assessments or echocardiography. Data suggests an almost homogenous picture of increased vascular stiffness as a function of OSA. Stiffness was increased during the course of obstructive apnoeas during both rapid eye movement (REM) and non-REM sleep [33]. Additionally, OSA patients without concomitant CV disease or risk factors were found to have an increased arterial stiffness index across the night. Both the evening and the morning augmentation index (AIX) were associated with the degree of OSA activity [34]. In a subsequent study, the effect of CPAP on vascular stiffness was evaluated in two separate settings: one group with de novo CPAP treatment and one group of highly compliant long-term CPAP users following CPAP withdrawal for 7 nights [36]. Interestingly, 2 months of CPAP treatment induced a significant reduction of arterial stiffness, whereas short-term CPAP withdrawal did not deteriorate vascular stiffness. This finding may indicate that the development of vascular stiffness as a marker of early atherosclerosis may need an intermediate time period of several weeks or months to develop. In addition, CPAP treatment does not only modify circulating inflammatory markers or vascular reactivity during short-term experiments, it also appears to modify structural abnormalities over a longer period of use. Indeed, two more recent CPAP follow-up studies described a partial reduction of vascular stiffness in large and middle sized arteries independent of an unchanged peripheral blood pressure level [38, 41]. Hypertension per se is associated with increased vascular stiffness, so part of the modification in vascular stiffness induced by CPAP is potentially linked to a change in central haemodynamics and blood pressure. Consequently, the potential additive impact of OSA in hypertension on vascular stiffness has been addressed in 46 hypertensive patients with OSA and 53 hypertensive patients without OSA [35]. Carotid-femoral pulse velocity, as a measure of vascular stiffness, was significantly elevated in hypertensive OSA patients and the amount of apnoeas and nocturnal hypoxic events was linearly related to pulse velocity. Interestingly, even mild-to-moderate OSA without excessive daytime sleepiness (mean Epworth Sleepiness Scale eight out of 24) was associated with a reduced AIX reflecting increased vascular stiffness [37]. Finally, the effect of sibutramine-induced weight loss did not affect measures of arterial stiffness, despite the reduction of body weight (males 7.9 kg) and an approximate 30% reduction of the AHI [39]. This unexpected finding may relate to a direct pharmacological effect of the drug on sympathetic nerve activity. In fact, sibutramine has recently been withdrawn in Europe due to a possible increase in CV complications associated with its use.

Structural alterations in the cerebral vasculature

Carotid IMT is an early sign of atherosclerosis and an established risk marker for the development of a cerebrovascular event and stroke. Linear associations have frequently been described between carotid IMT and the severity of OSA, expressed as the amount of nocturnal hypoxia episodes or the AHI, in clinical OSA cohorts (table 2) [4246]. One recent study failed to demonstrate a clear dose-response relationship between OSA severity and carotid IMT, which appeared to be comparable in mild-to-moderate (respiratory disturbance index, RDI ,37) versus severe OSA (RDI .37). However, an elevated prevalence of approximately 20% carotid plaques was observed in this patient cohort, indicating a more advanced stage of atherosclerosis [49]. Vascular status has also been assessed in specific subpopulations, e.g. children and patients with a metabolic syndrome, to address additive effects of concomitant OSA. Indeed, the vascular response to glyceryl trinitrate was enhanced in OSA children, whereas structural properties of the carotid IMT were still unchanged [50]. The additional effect of OSA on structural vascular properties was pronounced in patients with the metabolic syndrome [14]. Both IMT and the frequency of plaques were significantly elevated in the OSA group and treatment with nCPAP, over a period of 4 months, resulted in a marked reduction of carotid IMT, a slowing of PWV and a concomitant decrease in

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both sympathetic outflow and C-reactive protein [47]. In contrast to these findings in clinical cohorts, vascular assessments in 985 participants of the population based Sleep Heart Health Study demonstrated a linear relationship between the amount of sleep apnoea and carotid IMT/ occurrence of plaques, but the association disappeared after statistical control for anthropometric, as well as other CV risk variables [48]. This study re-emphasises that the association between OSA and early atherosclerotic markers can be demonstrated in pre-selected patient cohorts with elevated CV risk profile, whereas the association may not apply in the general population.

Structural alteration in the coronary arteries

The influence of OSA on coronary artery status is less well documented and this may have a methodological explanation. The Gensini score has been used to quantify the amount of coronary artery stenosis in symptomatic patients with coronary artery disease (CAD). In one study patients with mild OSA (defined as oxygen desaturation index (ODI) 515, n527) and moderate-to-severe OSA (ODI .15, n516), had higher Gensini scores compared with the controls (ODI ,5, n516), the Gensini scores were 31.7, 37.2 and 21.3, respectively. Multivariate analysis demonstrated that ODI was a strong and independent predictor for the Gensini score [51]. This finding has been confirmed by a subsequent study of 202 consecutive patients who were investigated with electron beam computer tomography. Patients were asymptomatic with regard to CAD and were investigated with an overnight sleep study (OSA prevalence 76%). Coronay artery calcification (CAC) was present in 67% of those with OSA and in 31% of those without OSA (p,0.001). Median CAC score was nine in OSA patients and zero in non-OSA patients (p,0.001), and OSA was an independent risk factor for CAC [53]. There is additional evidence suggesting that OSA may potentially be harmful to the CV outcome in patients with established CAD. Two studies performed 67 month control angiography after successful percutaneous coronary intervention (PCI) procedures were undertaken in patients with acute coronary syndrome [52] or stable CAD [54]. Both studies demonstrated that late lumen loss of coronary artery diameter, a quantitative marker of re-stenosis, was significantly elevated in OSA patients when compared with CAD patients without OSA (1.3 versus 0.7 mm and 0.7 versus 0.4 mm, respectively). In the group of patients with stable CAD, late lumen loss was marginally lower in CPAP users when compared with patients who did not accept CPAP treatment (nonrandomised treatment allocation) [54]. In contrast, a recent study demonstrated that the capability for coronary artery collateral development in the situation of chronic coronary artery occlusion may be increased in patients with OSA when compared with a non-OSA group [55]. This interesting finding, obtained in a limited number of subjects (n534), needs further investigations. In conclusion, a number of clinical cohort studies demonstrated that OSA is independently associated with an increased prevalence of vascular dysfunction, vascular stiffness, IMT and plaques. Even coronary artery stenosis and restenosis after PCI appear to be negatively influenced by untreated OSA. It has been speculated that a stiffening of the vasculature in OSA patients may contribute to increased left ventricular (LV) load and in a later stage to LV remodelling. However, recent data also indicate that OSA may have beneficial effects for the development of collaterals in patients with chronic coronary artery occlusion.

ATHEROSCLEROSIS AND CARDIOVASCULAR EVENTS

Cardiovascular events
Population-based studies addressing composite mortality
Three major population based studies have been published that analysed overall mortality after an observational period of between 8.218 yrs (table 3) [13]. Two of these studies reported CV versus all-cause mortality. Interestingly, all studies reported an independent influence of OSA on overall mortality, but the relative impact varied substantially between OR 1.46 in the largest study [3] up to 6.2 in the smallest study [2]. The effect sizes are comparable in the two cohorts where mean age at baseline was approximately 50 yrs [1, 2]. The impact of OSA is less pronounced in the elderly population [3] as strongly suggested by the mortality studies in the clinical patient cohorts [16, 59]

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and in one population based study that used the combination of snoring and excessive daytime sleepiness as surrogate markers for the OSA syndrome [15]. In addition, the severity of OSA is also strongly associated with mortality. A cut-off level of AHI 30 events?h-1 was identified for excessive mortality in two of these four studies. Notably, CV events were less common as the cause of death when compared with previous reports from clinical cohorts; 31.3% in the Wisconsin Sleep Cohort [1] and 21.0% in the Sleep Heart Health Study [3]. Part of this discrepancy may be explained by the difference in age and the presence of comorbid disease between these studies. Moreover, sex specific differences on the influence of OSA on mortality are only reported in the Sleep Heart Health Study [2]. The significant impact of OSA on mortality was only documented in males and not in females. This finding may be related to fact that only this study had sufficient statistical power to allow an analysis in subpopulations stratified for sex and age. Finally, a specific analysis on incidence of CV events, e.g. stroke, myocardial infarction or cardiac intervention like PCI procedures, has not yet been provided.

Clinical cohort-based studies addressing cardiovascular events and mortality

The clinical outcome in patient cohorts with different degrees of OSA has been investigated in clinical cohorts over several decades. It is obvious that the majority of studies have demonstrated an excess of mortality in OSA, which is associated with the severity of the disease. The incidence of CV events, e.g. stroke, myocardial infarction or CV death, is elevated (table 4) [46, 56, 60, 61]. The odds ratio (OR) of CV events or mortality varies in the order of magnitude from two to seven for moderate to severe OSA. A common methodological problem is to find an adequate control group for this type of analysis. In detail, one study described an increased risk for stroke in patients with OSA compared with non-OSA subjects based on a cross-sectional analysis [62]. However, the subsequent prospective part of the study failed to demonstrate an independent influence of OSA on the incidence of stroke. Another study reported on 392 male patients with CAD and concomitant mild-to-severe OSA (AHI o5, observed in 54% of subjects) [63]. During a 10-yr observational period 12% of the patients suffered from a stroke. Mild and moderate/severe OSA was associated with an OR 2.44 (95% CI 1.085.52) and 3.56 (1.568.16) times higher risk of stroke. An additional study recruited patients from a stroke rehabilitation unit [64]. Patients suffering from concomitant OSA had a higher risk of death during a 10-yr observational period (OR 1.76, 95% CI 1.052.95). Central sleep apnoea at baseline was not a predictor for mortality. Overall, in this cohort of elderly patients (age at baseline varied between 7581 yrs in certain subpopulations) CV mortality was as high as 74%. Finally, a large scale observational study in 1,022 stroke patients found an independent risk impact of OSA for stroke or death of all other cause with a hazards ratio (HR) of 2.24 (95% CI 1.303.86) for the unadjusted model and 1.97 (1.123.48) for the fully adjusted analysis [57]. The risk associated with OSA appeared to be dose dependent. The potential role of OSA for incident CAD has been evaluated in the clinical patient cohorts including 308, 1551 and 1436 subjects, respectively [4, 6, 65]. Defined end-points varied between CV mortality [4, 6] or the composite endpoint of myocardial infarction, coronary intervention, or death [65]. In the Spanish study [4], 1387 patients with OSA and 264 controls were followed up over a mean of 10.1 yrs. The multivariate analysis, adjusted for potential confounders, showed that untreated severe OSA (AHI o30) significantly increased the risk of fatal (OR 2.87, 95% CI 1.17 7.51) and nonfatal (3.17, 1.127.51) CV events. CPAP treated patients with severe OSA had no excess CV morbidity or mortality. In a Swedish study, 203 snorers without OSA and 105 OSA patients with absence of CAD at baseline were followed up during a 7-yr period [6]. Incident CAD occurred in 16.2 and 5.4% of OSA patients and controls, respectively, and OSA at baseline came out as independent predictor for incident CAD. Patients successfully treated for OSA (n528) had a reduced incidence of CAD. Data from a recent USA study comprising of 1,024 OSA patients and 412 controls showed a HR (95% CI) of 2.06 (1.103.86) for occurrence of the composite end-point mentioned above. Subgroup analysis demonstrated increasing hazard ratios across the OSA diseaseseverity spectrum. Unfortunately, data were not controlled for type and degree of OSA treatment during the observational period, which may have underestimated the true risk in the untreated patients. Importantly, none of these studies applied a randomised allocation to OSA treatment,

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which reduces the evidence that OSA causes the increased incidence of CV events. Finally, the influence of OSA status on the time of sudden cardiac death has been evaluated in 121 patients who have been investigated by polysomnography prior to the cardiac event [66]. In patients with concomitant OSA 46% died during the time from midnight to 06:00 h compared with 21% in the non-OSA group, 16% in the general population and 25% to be expected by chance. Patients with sudden cardiac death during the night had an elevated AHI. The study points out that OSA may create specific cardiac instability leading to an increased risk for sudden cardiac death.

Statement of Interest
hringer L. Grote has participated in clinical trials sponsored by Organon, GlaxoSmithKline, Bo Ingelheim, Schering Plough, Merck Sharp and Dome, Lundbeck, Actelion, Respironics, and Volvo PV. L. Grote has participated in paid educational activities and lectures for Respironics, Resmed, Nycomed, Weinmann and Organon. L. Grote has served as a medical advisor for Respironics, Weinmann, Breas and Nycomed. The position of D. Sommermeyer is partially funded by MCC GmbH & Co. KG.

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