Sleep-disordered breathing and cardiovascular disease

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1 Prine Phillip Hospital, Llanelli, Wales, UK Correspondene to: Dr J Amit Benjamin, Prine Phillip Hospital, Bryngwnmawr Dafen, Llanelli SA14 8QF, Wales, UK;amitbenjal@hotmail.om Reeived 4 July 2007 Aepted 20 November 2007 Sleep-disordered breathing and ardiovasular disease J Amit Benjamin, K E Lewis ABSTRACT Sleep-disordered breathing (SDB) desribes a group of disorders haraterised by abnormalities in the frequeny and/or depth of breathing while asleep. The most ommon type is the obstrutive sleep apnoea/hypopnoea syndrome (OSAHS); it affets 2 4% of the adult population and is an independent risk fator for hypertension. Another type is entral sleep apnoea (CSA), whih inludes Cheyne Stokes respiration; it is most ommonly seen in patients with ongestive heart failure and other ritial illnesses inluding erebrovasular aidents. There is aumulating evidene that both these types of SDB are assoiated with ardia failure, arrhythmias and oronary artery disease. Treatment of OSAHS with ontinuous positive airway pressure (CPAP) has lowered blood pressure, redued the frequeny and severity of some arrhythmias, and improved markers of endovasular inflammation. CPAP has had a mild positive effet on left ventriular funtion in hroni heart failure by treating o-existent SDB, but it has not improved mortality, possibly beause it does not fully treat assoiated CSA. Cliniians need to be aware of the inreasing assoiations of SDB, espeially OSAHS, with ardiovasular dysfuntion, as treatment of o-existent SDB will not only improve sleepiness, quality of life, and driving risk, but there is growing evidene that it may also improve ardiovasular risk itself, even in non-sleepy subjets. Sleep-disordered breathing (SDB) was first desribed in the medial literature in 1936, 1 but has been desribed as far bak as the 4th entury BC, when Dionysius, tyrant of Heralea, lived in fear of suffoation from fat. 2 Obstrutive sleep apnoea/hypopnoea syndrome (OSAHS) is the most ommon type of SDB, affeting,4% of men and 2% of women aged years with a total population prevalene of 1 2%, making it as least as ommon as type I diabetes. 3 There are several different types of SDB, inluding: OSAHS Obesity hypoventilation syndrome Central sleep apnoea (CSA) Upper airway resistane syndrome Cheyne Stokes respiration (CSR) In this review, we onentrate on the assoiation between the most prevalent type of SDB, namely OSAHS, and ardia dysfuntion, but, unlike in other reviews, we also desribe some assoiations between CSA and CSR and ardiovasular disease. OSAHS is defined as the oexistene of exessive daytime sleepiness with irregular breathing at night due to omplete or partial losure of the upper airways. 4 An apnoea is the absene of airflow Review at the nose and mouth for at least 10 s (due to omplete airway olusion), and a hypopnoea is a major redution (.50%) in airflow also for at least 10 s (partial airway narrowing). 5 These are diagnosed during limited-hannel sleep studies or polysomnography. The Apnoea/Hypopnoea Index (AHI) is the total number of apnoeas and/or hypopnoea events per hour of sleep. The 4% dip rate is the number of oxygen desaturations (from baseline) of at least 4% assoiated with the apnoeas/hypopnoeas. CSA has two distint types. Hyperapni CSA results from a hronially depressed respiratory drive assoiated with hyperapnia in wakefulness and sleep. 6 The more ommon hypoapni CSA is aused by a noturnal pattern of breathing typified by regular resendo deresendo osillation of tidal volume, thought to be aused by dysfuntion of entral respiratory ontrol. As the entral drive to breathe fades, ventilation temporarily eases before resuming again. Apnoeas and/or hypopnoeas an our in CSA also. 7 CSR refers to a type of normoapni CSA followed by periodi hyperventilation, with both hypopnoeas and apnoeas. The presene of this respiratory pattern appears to be a partiularly poor prognosti indiator of the presene of heart failure. CSA ours when there is essation of inspiratory effort, but, in ontrast with upper airway ollapse, ours sporadially and repetitively during sleep. Inspiratory efforts ontinue in obstrutive sleep apnoea (OSA) but are ineffetive beause of upper airway obstrution. In OSAHS, apnoeas are terminated by reurrent arousals from sleep, whih are needed to inrease the tone of dilator musles and open the upper airway; these reurrent miroarousals ause sleep fragmentation, whih often (but not always) auses the hallmark symptom of daytime tiredness and therefore the OSAHS. Treatment of OSAHS with ontinuous positive airway pressure (CPAP) dereases the exess healthare osts inurred by patients 8 9 and redues the risk of ar aidents from an exess risk of 2 7 times greater than to equal to the bakground population. 10 In the UK, CPAP is urrently only reommended for treatment in symptomati patients (ie, exessive daytime somnolene) and with an AHI.15/h or a 4% oxygen dip rate of.10/h Why would CPAP redue the medial osts inurred by patients with OSAHS independently of reduing driving/oupational aidents? There is inreasing evidene of an assoiation between OSAHS and ardiovasular disease, and numerous reviews reflet this OSAHS is ertainly an independent risk fator for hypertension, but, not only is there growing evidene Postgrad Med J 2008;84: doi: /pgmj

2 that OSAHS is linked to other ardiovasular illnesses suh as stroke, arrhythmias, oronary artery disease (CAD) and heart failure, but treating OSAHS may also improve these onditions Given the widespread prevalene of heart disease and potential of undiagnosed sleep pathology, any assoiations would have impliations for the urrent provision of sleep servies. There is still muh debate about whether SDB, in partiular OSAHS, is an independent risk fator for ardiovasular dysfuntion or a marker of another disease state. This review summarises the present evidene on ardiovasular risk and SDB, with partiular emphasis on OSAHS and CSA. We suggest situations where it may be useful to sreen for SDB and when treatment of o-existent SDB would be of benefit in patients with ardiovasular disease. OSAHS AND CARDIOVASCULAR DISEASE Many studies have alluded to a link between SDB and ardiovasular disease, but both (partiularly OSAHS) may purely o-exist with type 2 diabetes, for example, 25 therefore proving that SDB as an independent risk fator for ardiovasular disease is not straightforward. Previous ross-setional and longitudinal population-based studies (Wisonsin Sleep Cohort, 3 Pennsylvania Sleep Cohort and the Cleveland Family Study ) onfirmed only an assoiation with OSAHS and multiple ardiovasular risk fators suh as hypertension and diabetes. However, a large, prospetive (11-year follow-up), multientre, ohort study alled the Sleep Heart Health Study 30 showed exess ardiovasular mortality and morbidity in those with OSAHS after orretion of results for known onfounders. The Swedish 7-year ohort study of Peker et al 31 showed a higher inidene of adverse ardiovasular events in untreated patients with OSAHS (who refused/or had poor CPAP ompliane) than in both subjets without OSAHS and OSAHS patients with good CPAP ompliane. 31 Two more-reent studies onfirmed exess ardia events over a 10-year period in patients with untreated severe OSAHS. Reent data from more than Table 1 Referene subjets suggest that ardiovasular events are partiularly prevalent in younger patients with OSAHS. 34 However, these studies were not randomised ontrolled trials, as suh long-term studies (needed to measure mortality) annot be justified on ethial grounds beause of the proven benefit of CPAP for hypertension, quality of life, and driving risk. Table 1 summarises the results of the main trials. OSAHS AND HYPERTENSION There is stronger evidene that OSAHS is an independent risk fator for hypertension than any other ardiovasular disease state and, moreover, that treatment with CPAP an redue blood pressure. 18 Previous work estimated that,40% of patients with OSAHS are hypertensive while awake 35 and 40% of patients with refratory hypertension have OSAHS. 36 More-reent ohort studies have suggested that OSAHS is present in up to 83% of patients with unontrolled hypertension, despite taking three or more antihypertensive agents at optimum doses. 37 Four large population-based studies have shown that OSAHS is an independent risk fator for hypertension All four studies were able to adjust for age, body mass index (BMI) and sex. The Sleep Heart Health Study reported that the adjusted odds ratio for hypertension was 1.37 (95% CI 1.03 to 1.83; p for trend = 0.005), omparing subjets with an AHI.30 events per hour with those with an AHI,1.5 events per hour. 39 The Wisonsin prospetive sleep ohort of 709 subjets onfirmed that those with minimal, mild-moderate and moderate-severe SDB had adjusted odds ratios of developing hypertension of 1.42, 2.03 and 2.89, respetively, over the next 4 years, ompared with subjets without SDB. This was after adjustment for baseline hypertension status, age, sex, BMI, waist and nek irumferene, and weekly alohol and igarette use. 41 Table 2 summarises some of these studies. Two interventional (randomised ontrolled) studies showed a signifiant fall in blood pressure (BP) in patients reeiving therapeuti CPAP (set at a pressure that abolished OSAHS) but no hange in BP with plaebo CPAP, set at sub-therapeuti Prevalene studies on ardiovasular disease and obstrutive sleep apnoea/hypopnoea syndrome (OSAHS) Study type Type of SDB Sample size Outome Comments Sahar et al CS OSAHS 1023 Relative odds (95% CI) for: OSAHS and heart failure 2.38 (1.22 to 4.62) OSAHS and stroke 1.58 (1.02 to 2.46) OSAHS and oronary heart disease 1.27 (0.99 to 1.62)(where no OSAHS ( = AHI of 0 1.3) to definite OSAHS (AHI.11)) Peker et al C OSAHS 182 The inidene of at least one ardiovasular disease was observed in 36.7% of ases with OSA (4% dip rate.30/h) vs 6.6% subjets without OSA (p,0.001) Marin et al C OSAHS 1044 Multivariate analysis. Odds ratios (95% CI) for ardiovasular events in untreated severe OSAHS vs healthy partiipants: fatal events 2.87 (1.17 to 7.51) non-fatal events 3.17 (1.12 to 7.51) Doherty et al C OSAHS 168 Total ardiovasular events (ie, death and new ardiovasular disease ombined). More ommon in the untreated group (31%) than in the CPAP-treated group (18%) (p,0.05) Representative population seletion. Multivariate analysis (as opposed to true mathing) All subjets (ontrols and OSAHS) free from ardiovasular disease/hypertension at baseline. 7-year follow-up Control group mathed for age and BMI. Not mathed for hypertension or diabetes. Untreated CPAP group may be poor ompliers with other treatments, also 10-year follow-up Average follow-up period of 7.5 years. Mathed for BMI. Follow-up of OSAHS patients only. No healthy ontrols. Untreated CPAP group may be poor ompliers with other treatments AHI, Apnoea/Hypopnoea Index; BMI, body mass index; C, ohort; CPAP, ontinuous positive airway pressure; CS, ross-setional; OSA, obstrutive sleep apnoea; SDB, sleepdisordered breathing. 16 Postgrad Med J 2008;84: doi: /pgmj

3 Table 2 Prevalene studies on hypertension and obstrutive sleep apnoea/hypopnoea syndrome (OSAHS) Study Type Subjets Outome Comments Hla et al (Wisonsin) CS 147 OR for hypertension above bakground population: mild OSAHS, 2.0 moderate/severe OSAHS, 5.0 Grote et al PC 1190 RR for hypertension inreased with SDB severity. OR for hypertension in severe OSAHS vs no OSAHS = 4.15 (95% CI 2.7 to 6.5) Lavie et al CS 2677 Multiple logisti regressions showed that eah additional apnoei event per hour of sleep inreased the odds of hypertension by about 1%, and eah 10% derease in noturnal oxygen saturation inreased the odds by 13% Nieto et al CS 6132 OR (95% CI) for hypertension in severe OSAHS vs no OSAHS: 1.37 (1.03 to 1.83), p = Peppard et al (Wisonsin ohort) Bixler et al (Pennsylvania) CS and C 709 (4-year follow-up) and 184 (8-year follow-up) pressure settings (table 3) In one study, the improvement in BP orrelated as strongly with improvement in sleepiness as with OSA severity. 35 The study of Kaneko et al 44 ompared CPAP and optimal medial therapy with optimal therapy alone in OSA patients with heart failure. The fall in daytime systoli BP was,10 mm Hg after 4 weeks of treatment in the CPAP group. All three studies not only suggest that OSAHS ontributes to hypertension but that a fall of this magnitude in BP ould potentially redue the risk of a oronary heart disease event by 37% and the risk of a stroke event by 56%. 45 The pathogeni mehanism(s) linking SDB to hypertension are still not lear. Chroni hypoxia has been impliated, but a study omparing CPAP, sham CPAP and noturnal oxygen showed no improvement in BP in the oxygen group, despite a signifiant improvement in mean saturations, a mean AHI (61 to 44) and redution in time spent with saturations,90% in the oxygen group. The group reeiving therapeuti CPAP spent a similar amount of time with saturations,90% to the oxygen group, but showed muh greater improvements in mean AHI (66.1 to 3.4) and BP. This suggests that it is atual reurrent hanges in saturation (or some other marker suh as sleepiness) rather than mean saturations that are important in determining BP. 46 An alternative theory whereby OSAHS may ause hypertension is overativity of the sympatheti nervous system. Repetitive episodes of upper airways obstrution in OSA, resulting in intermittent hypoxia, and large swings in intrathorai pressure Relative to AHI of 0 at baseline, OR (95% CI) for the presene of hypertension at follow-up: 1.42 (1.13 to 1.78) for no OSAHS 2.03 (1.29 to 3.17) for mild OSAHS 2.89 (1.46 to 5.64) for moderate OSAHS CS 1741 OR for OSAHS and hypertension: 6.8 for moderate to severe SDB 2.3 for mild SDB Workplae population seletion Large numbers, onfounders ontrolled for. Statistis based on logisti regression, groups differed in BMI/age Subgroup analysis. OSAHS patients and ontrols mathed for age and BMI, but had higher BP. No mention of sleepiness symptoms. Multiple logisti regression Large numbers, onfounders ontrolled for. Stats based on logisti regression, groups differed in BMI/age Large numbers, onfounders ontrolled for. Logisti regression, but groups differed in BMI/Age Representative population seletion. Not mathed for BMI, diabetes, smoking, gender AHI, Apnoea/Hypopnoea Index; BMI, body mass index; BP, blood pressure; C, ohort; CS, ross-setional; PC, prospetive ohort; SDB, sleep-disordered breathing. Table 3 Intervention studies on hypertension and obstrutive sleep apnoea/hypopnoea syndrome Study Type Subjets Outome Comments (needed to overome upper airways obstrution) have both been shown to trigger autonomi responses rather than hypoxia per se. 47 Markers of this sympatheti overativity (eg, urinary norepinephrine onentrations) are raised in untreated OSAHS and an be reversed by CPAP therapy. 48 Even if the mehanisms are still being debated, the assoiation between OSAHS and BP is now so lear that the US Joint National Committee on Hypertension puts OSAHS first on the list of the auses of seondary hypertension. 49 SDB AND HEART FAILURE SDB (in partiular CSA) is ommon in heart failure, and these patients seem to have a worse prognosis than those without SDB. Heart failure is beoming more ommon, affeting 1 3% of the UK population (rising to 10% in the elderly). 50 In 2006, Javaheri 51 found that 49% of patients with a left ventriular (LV) ejetion fration of,45% had severe SDB (defined as an AHI.44/h) with 37% having CSA and 12% OSA, with or without daytime tiredness (OSAHS) (table 4). The Sleep Heart Health Study found that heart failure was 2.38 times more prevalent in mild moderate OSA than in mild no OSAH. 30 Two previous studies suggested that SDB was present in 68% 52 and 72% 53 of patients with heart failure, but many of these patients were not optimally treated, in partiular, b bloker use only in the range 0 33%. Wang and olleagues 54 followed 164 Pepperall et al RCT 95 Mean BP fall 3.3 mm Hg Sham CPAP. 4/52 of Treatment. Some subjets on antihypertensive drugs Beker et a 45 l 2003 RCT 32 Mean BP fall 9.9 mm Hg Partially therapeuti sham CPAP in plaebo group. 9/52 of Treatment. All subjets had more severe disease. Two-thirds on antihypertensive drugs Kaneko et al RCT 24 Redution in daytime systoli BP from a mean (SE) of 126 (6) mm Hg to 116 (5) mm Hg (p = 0.02) Both groups mathed for BMI/AHI/sleepiness sores/ ejetion fration at baseline. Small numbers. All had poor LV funtion. No sham CPAP AHI, Apnoea/Hypopnoea Index; BMI, body mass index; BP, blood pressure; CPAP, ontinuous positive airway pressure; LV, left ventriular; RCT, randomised ontrolled trial. Postgrad Med J 2008;84: doi: /pgmj

4 Table 4 (CSA)) Referene Prevalene studies of heart failure and sleep-disordered breathing (SDB) (both obstrutive sleep apnoea (OSA) and entral sleep apnoea Study type Subjets Outome Comments Sinn et al RCA 450 In a ohort of patients with heart failure, 70% of subjets had SDB: 32% had predominantly CSA 38% had predominantly OSAHS Sahar et al CS 1023 Relative odds (95% CI) for OSAHS vs no OSAHS in heart failure patients, 2.38 (1.22 to 4.62) Ferrier et al PC 53 SDB (AHI.10) demonstrated in 36 of 53 patients with heart failure (68%). OSA (53%) and CSA (15%) Javaheri PC 100 Severe SDB seen in 49% of patients who had a LVEF of,45%. 37% had CSA and 12% had OSA. Most were not sleepy Wang et al PLC 218 In a ohort of patients with heart failure, 46% had definite SDB (45 subjets with CSA and 56 with OSA): 21% had predominantly CSA 25% had predominantly OSA patients with heart failure over a mean of 3 years and found the death rate was signifiantly higher in the 37 untreated patients (AHI.15) than in the 113 patients with mild or no SDB (AHI,25/h), even after ontrolling for onfounding fators (age, LV ejetion fration and New York Heart Assoiation funtional lass), with 8.7 vs 4.2 deaths per 100 patient-years (p = 0.029). One important aspet of SDB in heart failure is the ourrene of CSA (inluding CSR), whih is estimated to our in 40 63% of patients and, when present, is assoiated with a partiularly poor prognosis. 55 The pathophysiology (inluding effet on LV volume and the sympatheti nervous system) of CSA is important but beyond the remit of this paper; it has been desribed elsewhere OSAs an adversely affet ardia funtion through large intrathorai pressure swings ourring during respiratory efforts, inreasing venous return and therefore ventriular afterload. Sympatheti ativation, seondary to hypoxia and arousal, further inreases BP and therefore myoardial oxygen onsumption at the end of apnoeas. These adverse effets on LV funtion an be at least partially reversed by CPAP CPAP is now reommended in the aute treatment of ardiogeni pulmonary oedema irrespetive of the presene of SDB; it works by improving intrathorai fluid dynamis. 61 Standard treatments for symptomati SDB assoiated with hroni heart failure are oxygen (for CSA) and CPAP (for OSA) in their own right, but evidene for their use in improving longer-term ardiovasular outomes in non-sleepy patients is still equivoal. Noturnal oxygen has been found to improve the AHI and some sympatheti parameters of patients with OSAHS, but it has had no effet on quality of life 64 or LV ejetion fration. 65 (Both studies were short term and so ould not look at mortality.) The results from trials with CPAP in hroni heart failure have been only slightly more promising, but by no means onlusive (table 5). Early studies showed an improvement in LV ejetion fration of up to 7%, but they all had small numbers in both the CPAP and onventional treatment arms, and many patients were not presribed drugs (espeially b blokers) aording to urrent heart failure guidelines The largest trial so far to address sample size, adequate duration and maximising medial treatment is the multientre CANPAP trial. Here, over 400 patients with ongestive ardia failure and SDB were randomised to best medial are or CPAP Patients reruited from referrals to sleep lini, ie, seleted for sleepiness. Not all patients had an ejetion fration,45%; initial diagnosis made linially Sreening of over 6000 subjets from general population Unseleted patients with stable heart failure. High proportion of loal ethni subjets (Maori) and only men studied Patients reruited from ardiology linis and primary are Death rate higher in the untreated SDB group, but these onsisted of those who were unable/unwilling to use CPAP whih may be a marker of poor ompliane with other health behaviours. A mean 2.9-year follow-up AHI, Apnoea/Hypopnoea Index; CPAP, ontinuous positive airway pressure; CS, ross-setional; LVEF, left ventriular ejetion fration; OSAHS, obstrutive sleep apnoea/hypopnoea syndrome; PC, prospetive ohort; PLC, prospetive longitudinal ohort; RCA, retrospetive ohort analysis. in addition to best medial are. The improvement in LV ejetion fration in the CPAP arm was only 2.2%, but there was a statistially signifiant improvement in the 6 min walk test by 20 m, ompared with a mean deterioration of 0.8 m in the optimal treatment group, over the same time period. The study was stopped early beause of lower than expeted enrolment rate, a falling primary event rate (beause of advanes in management of ongestive ardia failure), and onerns after inreased mortality in the CPAP arm at 3 months. However, the early divergene in survival urves reversed after 18 months to favour the CPAP group, but the overall mortality was no different after 18 months. When assessing differenes in ejetion fration, it is important to note that 70% of subjets in this trial were presribed b blokers (ompared with 20% or less in previous studies) whih may render some of the benefiial effets of CPAP on sympatheti ativation redundant. 69 Others suggest that, although the prevalene of CSA remains high in patients with LV dysfuntion, there was no differene in prevalene in those presribed b blokers ompared with those not using b blokers, but this was a small study (n = 14). 70 In summary, the urrent data do not support routine use of CPAP in hroni stable ongestive ardia failure unless there is o-existent OSAHS. Bi-level pressure support using newer devies that may more effetively treat both CSA and OSA (whih often o-exist) are being evaluated (K E Lewis and M Arzt, personal ommuniation). OSAHS AND ARRHYTHMIAS Cyli variation in heart rate is typial in SDB. Apnoea and hypoxaemia-indued bradyardia is often followed by tahyardia during the post-apnoei hyperventilation. This setion reviews the urrent evidene for a strong assoiation between arrhythmias and SDB and shows how treatment of the SDB an potentially abolish the arrhythmia. The assoiation between OSAHS and arrhythmias was first doumented over 30 years ago. In the study of Guilleminault et al, 71 of 400 patients with OSAHS, 48% had doumented ardia arrhythmias, inluding sustained ventriular tahyardia in 2%, sinus arrest in 11%, seond-degree atrioventriular blok in 8%, and frequent premature ventriular ontrations in 19%. 18 Postgrad Med J 2008;84: doi: /pgmj

5 Table 5 Referene Naughton et al Summary of the treatment of sleep-disordered breathing (SDB) in subjets with heart failure Study type Subjets Traheostomy in 50 patients ured the OSAHS and abolished these arrhythmias. This study only looked at patients with OSAHS, and 246 patients were already presribed amphetamine for daytime sleepiness, whih is pro-arrhythmogeni. Other weaknesses of this study are that no distintion is made between patients with pre-existing ardia disease. The 1995 study of Bekers et al 72 revealed that 7% of 239 patients with OSAHS had signifiant bradyarrhythmias, and, of these 17 patients, only one ontinued to experiene bradyarrhythmias after CPAP therapy. Most of these patients had established or newly diagnosed ardia abnormalities (hypertension, ongestive ardia failure, pulmonary hypertension), so any independent effet of OSAHS is diffiult to establish. In a muh smaller study, Tilkian et al 73 found bradyarrhythmias in five out of 15 patients with OSAHS. In most of these prevalene studies, arrhythmias were diagnosed in patients with OSAHS using simple h ardia Holter monitoring. However, in an elegant study (albeit again with small numbers), Simantirakis et al 74 inserted loop reording devies in 23 patients with OSAHS in whom other ardia and pulmonary disease was first exluded with exerise tests, invasive eletrophysiologial studies, ehoardiography, and lung funtion tests, and diabetes was also exluded. Over 2 months of ontinuous reording, 48% had signifiant rhythm disturbanes, mostly ourring at night. They also noted a near-total failure of 48 h Holter monitoring to detet events during the same time period. On an intention-totreat basis, there was a signifiant improvement in rhythm disturbanes within 8 weeks, and all rhythm disturbanes were abolished after 6 months of CPAP therapy, although the bakground prevalene of undiagnosed arrhythmias was not reported and there was no ontrol group not reeiving CPAP in the arrhythmia group, nor a desription of CPAP usage. Atrial fibrillation (AF) is another arrhythmia widely reported to be assoiated with OSAHS. A subgroup analysis of the Sleep Heart Health Study revealed a fourfold inrease (odds ratio 4.02; 95% CI 1.03 to 15.74) in the prevalene of AF in subjets with an AHI.30 ompared with patients with no SDB mathed for age, sex, ethniity and BMI. 75 Gami et al 76 used the Berlin Sleep Questionnaire to estimate the prevalene of OSAHS in 468 ardiology patients. They found that AF ourred in 49% of patients with OSAHS ompared with 32% of general ardiology outpatients deemed at low risk of OSAHS but mathed for age, gender and omorbidity (p = ). Sleep studies were only SDB type Outome Comments RCT 29 CSA Greater improvement in LVEF in the CPAP group (7.7%) than in the ontrol group (22.2%), p = Sinn et al RCT 66 CSA CSA subjets on CPAP had a 7% improvement in LVEF after 3 months and a relative risk redution of 81% (+26% to 95% ) in mortality after 4 years Artz et al PCT 26 CSA CSA subjets on CPAP had improved ventilatory effiieny and greater improvement in LVEF (to mean 35%) after 12 weeks, vs oxygen alone (mean LVEF 32%), p = 0.04 Bradley et al 69 RCT 258 CSA CPAP-treated group had an improvement in LVEF of % vs ontrols 0.4%, p = 0.02, and distane walked in 6 min (20.0 m vs 20.8 m, p = 0.016). No differene in primary endpoint of survival rates/time to transplant Groups similar at baseline. Study performed before widespread introdution of b blokers 2 4 year follow-up. Allowed for CPAP usage in ontrols and subjets with SDB. Small numbers in eah group. Blinding not possible. Only 3-month ehoardiogram hanges Looked at both ventilatory effiieny and ehoardiographi hanges. Comparison of CPAP and oxygen (no ontrols). Assignment to groups not randomised Largest trial to date, powered to look at survival. Stopped early beause of slow reruitment and falling primary event rate CPAP, ontinuous positive airway pressure; CS, ross-setional; CSA, entral sleep apnoea; LVEF, left ventriular ejetion fration; OSAHS, obstrutive sleep apnoea/hypopnoea syndrome; PC, prospetive ohort; PCT, prospetive ontrolled trial; PLC, prospetive longitudinal ohort; RCT, randomised ontrolled trial. performed in 44 patients (to validate the questionnaire, and the AF group had a larger nek size, an independent preditor of OSAHS). A smaller Finnish study from the same year, using objetive sleep studies, disagreed and atually found no differene in the prevalene of OSAHS in 59 patients with lone AF ompared with 56 ontrols mathed for age, gender and ardiovasular morbidity. 77 Inreased rates of reurrene of AF (after ardioversion) have been shown in inadequately treated patients with OSAHS ompared with non-osahs and welltreated OSAHS patients. 78 The bradyarrhythmias in patients with OSAHS possibly reflet the reflex parasympatheti ativity evoked by apnoeas, but AF may be aused by inreased sympatheti ativity after apnoeas or inreased atrial size seen in patients with OSAHS. 47 Even if the ausal mehanisms are not yet lear, the overlap between arrhythmias and OSAHS should at least prompt liniians to ask about OSAHS symptoms in patients with ardia rhythm disturbanes. OSAHS AND CORONARY ARTERY DISEASE Patients with SDB have a high prevalene of CAD, and patients with CAD have a high prevalene of SDB. The ase ontrol study of Peker et al 79 looked at 62 patients with CAD and 62 patients without CAD, mathed for age, sex, BMI, hypertension, hyperholesterolaemia, diabetes mellitus and urrent smoking. In a multiple logisti regression model, the presene of OSAHS remained independently assoiated with CAD (odds ratio 3.1vs 9.8 for urrent smoking and 4.2 for diabetes mellitus). The large Swedish ohort studies of Mooe et al also suggested that OSAHS was muh more prevalent in the 142 patients with established CAD (angiography) than in the 50 ontrols (with normal angiography). This was true for both men 80 and women, 81 even after adjustment for onfounders. Cross-setional results from the population-based Sleep Heart Health Study 30 showed that, in patients with SDB, the multivariable-adjusted relative odds (95% CI) with self-reported oronary heart disease was a more modest 1.27 (0.99 to 1.62) (omparing upper with lower quartiles of severity of SDB). Sudden ardia death is more ommon in patients with OSAHS, after adjustment for onfounders. Gami et al 82 looked at 112 subjets who had undergone polysomnography over a 5- year period; sudden death from ardia auses (between the hours of midnight and 6 am) ourred in 46% of patients with Postgrad Med J 2008;84: doi: /pgmj

6 Main messages Sleep-disordered breathing (SDB) onsists of obstrutive sleep apnoea/hypopnoea syndrome (OSAHS) and entral sleep apnoea (CSA). OSAHS in partiular appears to be an independent risk fator for ardiovasular disease and should be onsidered in patients with ardiovasular dysfuntion, espeially hypertension, as treatment with ontinuous positive airway pressure (CPAP) an lower blood pressure by as muh as 10 mm Hg in symptomati patients. A sleep history and referral would be useful in the workup of hypertensive patients, espeially those with refratory hypertension. SDB (espeially CSA) is ommon in patients with heart failure. These patients tend not to have the typial exessive daytime sleepiness of OSAHS. At present, only patients with OSAHS who have heart failure are reommended for CPAP therapy. The presene of OSAHS should be onsidered in patients with arrhythmias (espeially atrial fibrillation or bradyarrhythmias), partiularly those who are obese or hypertensive. Future researh will be direted to improving ardiovasular outomes by treating SDB (inluding CSA) more effetively in non-sleepy patients. Larger studies will be performed to see if improvements in blood pressure and endovasular outome translate to mortality benefits in all forms of SDB. OSAHS ompared with 21% of tired people with negative sleep studies (p = 0.01) and 16% of the general population (p,0.001). There was no exess of sudden ardia death in the patients with OSAHS during waking hours. Mooe et al 83 followed 408 patients with verified CAD (on angiogram) for 5 years after they all had sleep studies. Subjets with SDB had an adjusted risk ratio of 1.70 (95% CI 1.2 to 2.5, p = 0.008) for the omposite endpoint of death, erebrovasular events and myoardial infartion. The authors onluded that SDB in subjets with known CAD is assoiated with a worse long-term prognosis. Peker et al 84 followed 105 patients with OSAHS who were free from CAD at baseline for 7 years. CAD ourred in 16% ompared with only 5% of 203 snorers without OSAHS free from CAD at baseline. This study also suggested a protetive effet of CPAP within the OSAHS group: CAD developed in 25% of the 65 inompletely treated patients, but in only one (4%) of the 26 well-treated patients. 84 Suh studies are not prospetive randomised trials and are weakened by the possibility that poor aeptane/ompliane with CPAP may be a marker for poor ompliane with lifestyle modifiations and other treatments shown to redue ardiovasular risk. A smaller but muh longer (10 year) prospetive study showed equal ardia death rates (four of 25) in people with established CAD whether they had OSAHS or not, but groups were not mathed for age, BMI, hypertension, et. 85 OSAHS an ause CAD indiretly via hypertension or diretly by generation of free radials, ativating endovasular inflammation during the reurrent episodes of deoxygenation oxygenation. 12 To summarise, there is an assoiation between OSAHS and anatomial CAD, but the linial signifiane and effet of CPAP treatment remain unlear. CONCLUSIONS Many ardiovasular diseases are independently assoiated with SDB. Early ross- setional and observational studies suggested links, but were open to seletion and reporting bias and may not Key referenes for further reading 1. MNiholas WT, Bonsigore MR. Sleep apnoea as an independent risk fator for ardiovasular disease: urrent evidene, basi mehanisms and researh priorities. Eur Respir J 2007;29: Phillips B. Sleep-disordered breathing and ardiovasular disease. Sleep Med Rev 2005;9: Parish JM, Somers VK. Obstrutive sleep apnea and ardiovasular disease. Mayo Clin Pro 2004;79: Quan SF, Gersh BJ. Cardiovasular onsequenes of sleepdisordered breathing: past, present and future: report of a workshop from the National Center on Sleep Disorders Researh and the National Heart, Lung, and Blood Institute. Cirulation 2004;109: Arzt M, Bradley TD. Treatment of sleep apnea in heart failure. Am J Respir Crit Care Med 2006;173: have adequately ontrolled for important onfounders suh as obesity and hypertension. However, well-designed randomised ontrolled (intervention) trials have now established that OSAHS is an independent and treatable risk fator at least for hypertension. Further prevalene studies and now interventional trials suggest that SDB, and OSAHS in partiular, may ause and exaerbate other ardiovasular dysfuntion, partiularly ardia failure, arrhythmias and possibly CAD. The mehanism(s) behind these assoiations are biologially plausible and, together with the diretion of ause-and-effet, are still being eluidated. Awareness of the assoiation of ardiovasular disease and SDB will prompt the general pratitioner to look for both illnesses when presented with one of them. There is no doubt that CPAP and other treatments for SDB will make symptomati patients who happen to have a ardia disease feel better. It may be that CPAP will be used to improve ardia outomes in their own right, and randomised ontrolled trials of CPAP in patients with ardiovasular risk and OSAHS but who are not sleepy are being designed. TRUE (T)/FALSE (F) QUESTIONS (ANSWERS AFTER THE REFERENCES) (A) OSAHS an be diagnosed from a history of irregular breathing at night. (B) OSAHS is an established independent risk fator for hypertension as well as heart failure, stroke, arrythmias and oronary artery disease. (C) Treatment of OSAHS with CPAP an ause a drop in blood pressure. (D) All patients with heart failure and sleep disordered breathing should be treated with CPAP. (E) There is growing evidene linking OSAHS and arrythmias. Competing interests: None. REFERENCES 1. Spitz A. Das klinishe syndrome: Narolepsy mit Fettsuht und Polyglobulien seinem Beziehungen zum morbus Cushing. Deutsh Arh Klin Med 1937;181: Kryger MH. Sleep apnea. From the needles of Dionysius to ontinuous positive airway pressure. Arh Intern Med 1983;143: Young T, Palta M, Dempsey J, et al. The ourrene of sleep-disordered breathing among middle-aged adults. N Engl J Med 1993;328: Sottish Interollegiate Guidelines Network. Guideline number 73. June (aessed 6 De 2007). 20 Postgrad Med J 2008;84: doi: /pgmj

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8 68. Naughton MT, Liu PP, Bernard DC, et al. Treatment of ongestive heart failure and Cheyne-Stokes respiration during sleep by ontinuous positive airway pressure. Am J Respir Crit Care Med 1995;151: Bradley TD, Logan AG, Kimoff RJ, et al. Continuous positive airway pressure for entral sleep apnea and heart failure. N Engl J Med 2005;353: Bayle JY, Grouet A, Gueyffier F, et al. The entral sleep apnoea syndrome is frequent in the left ventrle systoli dysfuntion treated with betablokers. Am J Respir Crit Care Med 2007;175:A Guilleminault C, Connolly SJ, Winkle RA. Cardia arrhythmias and ondution disturbanes during sleep in 400 patients with sleep apnea syndrome. Am J Cardiol 1983;22: Beker H, Brandenburg U, Peter JH, et al. Reversal of sinus arrest and atrioventriular ondution blok in patients with sleep apnea during nasal ontinuous positive airway pressure. Am J Respir Crit Care Med 1995;151: Tilkian AG, Guilleminault C, Shroeder JS, et al. 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An independent assoiation between obstrutive sleep apnoea and oronary artery disease. Eur Respir J 1999;14: Mooe T, Rabben T, Wiklund U, et al. Sleep-disordered breathing in men with oronary artery disease. Chest 1996;109: Mooe T, Rabben T, Wiklund U, et al. Sleep-disordered breathing in women: ourrene and assoiation with oronary artery disease. Am J Med 1996;101: Gami AS, Howard DE, Olson EJ, et al. Day-night pattern of sudden death in obstrutive sleep apnea. N Engl J Med 2005;352: Mooe T, Franklin KA, Holmstrom K, et al. Sleep disordered breathing and oronary artery disease: long-term prognosis. Am J Respir Crit Care Med 2001;164: Peker Y, Carlson J, Hedner J. Inreased inidene of oronary artery disease in sleep apnoea: a long-term follow-up. Eur Respir J 2006;28: Hagenah GC, Gueven E, Andreas S. Influene of obstrutive sleep apnoea in oronary artery disease: a 10-year follow-up. Respir Med 2006;100: Answers (A) FALSE (OSAHS requires a positive sleep study and daytime sleepiness to make a diagnosis). (B) FALSE (At present OSAHS is only an independent risk fator for hypertension). (C) TRUE (Potentially up to 8 10 mm Hg in some hypertensive patients). (D) FALSE (Treatment is only reommended in those who have oinidental OSAHS). (E) TRUE (Important, as treatment of underlying sleep disorders an abolish the arrhythmia). The Committee on Publiation Ethis (COPE) has established a Grant Sheme to fund researh in the field of publiation ethis. The Sheme is designed to provide finanial support to any member of COPE for a defined researh projet that is in the broad area of the organisation s interests, and speifially in the area of ethial standards and pratie in biomedial publishing. The projet should have a speifi goal and be intended to form the kernel of a future publiation. A maximum sum of 5000 will be alloated to any one projet, but appliations for smaller sums are welomed. The terms and onditions of the Grant are as follows: At least one of the appliants must be a member of COPE. Calls for appliations will be made twie a year with losing dates of 1 Deember and 1 June. An eletroni version of the appliation form must be sent to the Administrator no later than 12 pm (noon GMT) on the losing date for onsideration by COPE Counil. The appliation must ontain a lay summary of the projet, a definition of the question to be posed, suffiient methodologial detail to allow assessment of the viability of the projet, a lear timeline and a definition of the likely deliverables. A full justifiation for the sum requested must aompany the appliation. A report on the progress of the researh should be presented within one year of the award and at the end of the projet. The grant must be used within two years from the date of award, and balane sheets must be forwarded annually. These should be sent to the Administrator. Any remaining funds after two years must be returned. It is antiipated that the work stemming from the projet will be presented at one of COPE s annual seminar meetings within 2 3 years of the award. Suh data may also be published in peer-reviewed journals. Any publiations or related presentations at meetings by the reipient emanating in part or whole from COPE s support should be duly aknowledged and opies sent to the Administrator. Appliations are reviewed by a COPE sub-ommittee. Appliants will be advised of a deision as soon as pratiable after the deadline date. An appliation form an be obtained by ontating Linda Gough, COPE administrator, at LGough@ bmj.om or For more information on COPE, see The losing date for reeipt of appliations is 1 Deember 2007 or 1 June Postgrad Med J 2008;84: doi: /pgmj