Journal of Cardiology

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1 Journal of Cardiology 60 (2012) Contents lists available at SciVerse ScienceDirect Journal of Cardiology jo u rn al hom epa ge: te/jjcc Review Sleep apnea and heart failure Takatoshi Kasai (MD, PhD) a,b, a Cardio-Respiratory Sleep Medicine, Department of Cardiology, Juntendo University, School of Medicine, Tokyo, Japan b Sleep Center, Toranomon Hospital, Tokyo, Japan a r t i c l e i n f o Article history: Received 17 May 2012 Accepted 28 May 2012 Available online 21 July 2012 Keywords: Cardiovascular disease Prevention Heart failure Non-pharmacological treatment Sympathetic nerve Ventilation a b s t r a c t Sleep apnea is frequently observed in patients with heart failure (HF). In general, sleep apnea consists of two types: obstructive and central sleep apnea (OSA and CSA, respectively). OSA results from upper airway collapse, whereas CSA arises from reductions in central respiratory drive. In patients with OSA, blood pressure is frequently elevated as a result of sympathetic nervous system overactivation. The generation of exaggerated negative intrathoracic pressure during obstructive apneas further increases left ventricular (LV) afterload, reduces cardiac output, and may promote the progression of HF. Intermittent hypoxia and post-apneic reoxygenation cause vascular endothelial damage and possibly atherosclerosis and consequently coronary artery disease and ischemic cardiomyopathy. CSA is also characterized by apnea, hypoxia, and increased sympathetic nervous activity and, when present in HF, is associated with increased risk of death. In patients with HF, abolition of coexisting OSA by continuous positive airway pressure (CPAP) improves LV function and may contribute to the improvement of long-term outcomes. Although treatment options of CSA vary compared with OSA treatment, CPAP and other types of positive airway ventilation improve LV function and may be a promising adjunctive therapy for HF patients with CSA. Since HF remains one of the major causes of mortality in the industrialized countries, the significance of identifying and managing sleep apnea should be more emphasized to prevent the development or progression of HF Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved. Contents 1. Introduction Risk factors and pathogenesis of sleep apnea Adverse effect of sleep apnea on cardiac function Effect of disrupted sleep Effects of obstructive sleep apnea Direct effects on cardiac function Indirect effect predisposing to heart failure Effects of central sleep apnea on cardiac function Sleep apnea in heart failure Clinical features Epidemiology Treatment for patients with heart failure and sleep apnea Effect of heart failure treatment on sleep apnea Effect of sleep apnea treatment on heart failure Treatment for obstructive sleep apnea Treatment for central sleep apnea Correspondence address: Cardio-Respiratory Sleep Medicine, Department of Cardiology, Juntendo University, School of Medicine, Hongo, Bunkyoku, Tokyo , Japan. Tel.: ; fax: address: kasai-t@mx6.nisiq.net /$ see front matter 2012 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

2 T. Kasai / Journal of Cardiology 60 (2012) Conclusions Source of funding References Introduction In patients with heart failure (HF), two types of sleep apnea can be seen: obstructive and central sleep apnea (OSA and CSA, respectively). OSA results from upper airway collapse, whereas CSA arises from reductions in central respiratory drive. During OSA, the respiratory effort generated against the narrowed upper airway causes the rib cage and abdomen to distort and move out of phase. In contrast, in CSA, respiratory movements are absent or attenuated, but in phase. In HF patients, CSA usually occurs as Cheyne Stokes respiration (CSR) which is a form of periodic breathing characterized by a crescendo decrescendo pattern of breathing followed by central apnea or hypopnea. Since this review aims to highlight the pathophysiology and therapies of sleep apnea in HF due to left ventricular (LV) systolic dysfunction, the terms CSA and HF are used as synonymous with CSR and HF due to LV systolic dysfunction, respectively, unless indicated otherwise. 2. Risk factors and pathogenesis of sleep apnea OSA is 2 3 times more common in men than in women, and in elderly than in young both in the general population and in patients with HF [1]. Obesity is regarded as one of the major risk factors for OSA. Nevertheless, OSA can occur in individuals of normal weight in whom other factors can contribute to pharyngeal collapsibility, such as macroglossia, and adenotonsillar hypertrophy. Anomalies of craniofacial structure, such as retrognathia, which can displace the tongue backward and narrow the pharynx, can be important in non-obese Asians. Nasal obstruction can also increase the risk for developing OSA, possibly by causing increased collapsibility or airway narrowing in the pharynx as a result of increased airway resistance upstream from the collapsible portion on inspiration. Hereditary factors and respiratory control system instability may also contribute to the pathogenesis of OSA, but these remain controversial. Previous studies showed that topical (to the pharyngeal mucosa) administration of vasomotor agents can alter the pharyngeal resistance [2]. These observations suggest that fluid accumulation in nuchal and peripharyngeal soft tissues may cause pharyngeal narrowing and increase the likelihood of pharyngeal occlusion in patients predisposed to OSA. In addition, Shepard et al. [3] proposed that fluid displacement from the lower extremities to the upper body might play a role in narrowing the pharynx in patients with OSA. Dependent fluid accumulation in the legs while upright during the day could shift rostrally into the neck when recumbent during sleep. Such fluid displacement might cause distension of the neck veins and/or edema of the peripharyngeal soft tissue that increases tissue pressure, predisposing to pharyngeal obstruction. Yumino et al. [4] demonstrated that the greater the amount of fluid displaced spontaneously from the legs overnight, the greater the overnight increase in neck circumference and the severity of OSA as assessed by frequency of apnea and hypopnea per hour of sleep (i.e. apnea hypopnea index, AHI) in HF patients with OSA. Fluid volume displaced from the legs was directly proportional to the time spent sitting during the day. CSA is also 2 3 times more common in men than in women [1]. Being elderly, male, with low PaCO 2, coexistence of atrial fibrillation, and use of diuretics were reported as independent predictors of CSA in HF patients [1]. CSA appears to arise secondary to HF and occurs when PaCO 2 falls below apnea threshold. In general, HF patients tend to hyperventilate chronically owing to stimulation of pulmonary vagal irritant receptors by pulmonary congestion and to increased central and peripheral chemosensitivity (Fig. 1) [5]. When PaCO 2 falls below apnea threshold because of increase in the apnea threshold during transition from wakefulness to sleep or acute increase in ventilation which is triggered by a spontaneous arousal, the CSA ensues [5]. Apnea persists until PaCO 2 raises above apnea threshold then ventilation will resume and ventilatory overshoot occurs and PaCO 2 will go down below the apnea threshold in association with arousal during ventilatory phase and increased chemosensitivity which is characteristic of HF patients with CSA. The length of the ventilatory phase following CSA is directly proportional to the lung to peripheral chemoreceptor circulation time and inversely proportional to cardiac output, reflecting delayed transmission of change in arterial blood gas tensions from the lungs to the chemoreceptor in association with impaired cardiac output in HF patients. This could also contribute to the pathogenesis of CSA with CSR pattern by facilitating ventilatory overshoot and undershoot. Thus, once triggered, the pattern of CSR will be sustained by the combination of increased respiratory chemoreceptor drive, pulmonary congestion, arousals, and apnea-induced hypoxia, which cause oscillations in PaCO 2 above and below the apnea threshold [5]. As well as OSA, the degree of rostral fluid displacement from the legs overnight is directly related to the severity of CSA, but is inversely proportional to PaCO 2 during sleep and in men with HF [4]. It is therefore likely that a portion of this fluid was redistributed into the lungs and caused pulmonary congestion that stimulates pulmonary vagal irritant receptors to elicit reflex hyperventilation. In both OSA and CSA patients, the concept of nocturnal rostral fluid shift which is suggested as contributing to the pathogenesis of both OSA and CSA was also supported by a recent report which showed that in patients with HF, there was a significant positive correlation between the AHI and amount of dietary sodium intake [6]. 3. Adverse effect of sleep apnea on cardiac function 3.1. Effect of disrupted sleep In healthy subjects, metabolic rate, sympathetic nervous activity (SNA), blood pressure (BP), and heart rate (HR) fall and cardiac vagal activity increases during non-rapid eye movement (non- REM) sleep, which constitutes approximately 85% of total sleep time. Thus, in general, sleep is a state of cardiovascular relaxation. On the other hand, intermittent surges in SNA, BP, and HR occur in REM sleep, but in general, REM comprises only 15% of total sleep time, and average BP and HR remain below waking levels. Thus, sleep is generally a state of cardiovascular quiescence. Sleep apnea interrupts such cardiovascular quiescence with potential adverse consequences, such that the sufferer may not enjoy the restorative effect of sleep Effects of obstructive sleep apnea Direct effects on cardiac function A unique feature of OSA is the generation of exaggerated negative intrathoracic pressure. During obstructive apneas, negative inspiratory intrathoracic pressure generated against the occluded pharynx increases LV transmural pressure (i.e. intra-cardiac minus intra-thoracic pressure), and hence LV afterload. It also increases

3 80 T. Kasai / Journal of Cardiology 60 (2012) Heart Failure Cardiac Output LVEDP Pulmonary Conges on Vagal S mula on Circula on Time Hyperven la on Chemosensi vity Delayed Transmission in ABG Altera ons Acute in Ven la on PCO 2 Tii Triggering CSA Ven latory Overshoot/Undershoot Arousal Apneic CO 2 Threshold Sleep Cheyne-Stokes respira on CSA Fig. 1. Pathogenesis of CSA in HF. ABG, arterial blood gas; CSA, central sleep apnea; LVEDP, left ventricular end diastolic pressure. venous return, augmenting right ventricular (RV) preload, while OSA-induced hypoxic pulmonary vasoconstriction increases RV afterload. Consequent RV distension and leftward septal displacement during diastole impair LV filling. The combination of increased LV afterload and diminished LV preload during obstructive apneas causes a progressive reduction in stroke volume and cardiac output [7]. OSA-induced hypoxia might also directly impair cardiac function [7]. Autonomic cardiovascular dysregulation, characterized by elevated SNA and parasympathetic withdrawal, is another hallmark of OSA. All of apnea-induced intermittent hypoxia and CO 2 retention, the absence of breathing during apnea, baroreceptor reflex stimulated by reductions in stroke volume and cardiac output, and arousal from sleep at apnea termination also augment SNA [7]. Importantly, the adverse effects of OSA on the autonomic nervous system are not confined to sleep but may persist into wakefulness [7]. The mechanism of such daytime carry over effects remains unclear. Repetitive apneas expose the cardiovascular system to exaggerated negative intrathoracic pressure, intermittent hypoxia, surges in SNA and frequent awakenings. Over time, such stresses may directly contribute to development or progression of HF Indirect effect predisposing to heart failure Several experimental studies suggested that OSA can raise BP. Indeed, it was shown that there is an association between OSA and incidence of hypertension [8]. Although two other recent studies [9,10] failed to show significant independent association between OSA and risk of hypertension, in patients with OSA, physiological dipping in nighttime BP is often lacking [11] in association with nocturnal sympathetic activation and consequent increase in BP. Moreover, there is evidence that indicates the association between drug-resistant hypertension and OSA. Thus, hypertension which is an important factor for LV hypertrophy and dysfunction, is likely an intermediate step between OSA and HF. Intermittent apnea-related hypoxia and post-apneic reoxygenation can induce oxidative stress with production of reactive oxygen species which diminishes bioavailability of nitric oxide, and activation of inflammatory mediators possibly through the activation of nuclear transcriptional factors [12], that are capable of impairing vascular endothelial function (Fig. 2). Indeed, patients with OSA have low plasma nitrite concentrations and high levels of oxidative stress markers [12]. In addition, patients with OSA have greater blood levels of several inflammatory mediators [12]. However, although it remains under debate, most of them are reversible by continuous positive airway pressure (CPAP) therapy for OSA [12]. More recently, it was reported that blood level of pentraxin-3 which is regarded as a more specific marker of vascular inflammation than C-reactive protein was greater in patients with moderate to severe OSA compared with subjects without OSA and 1 month of CPAP therapy significantly decreased pentraxin-3 level in association with usage of CPAP [13]. Combined with increased sympathetic vasoconstrictor activity, all these could predispose to advanced endothelial dysfunction, and moreover have the potential to accelerate atherogenesis. Randomized trials demonstrated that CPAP therapy for OSA resulted in a significant improvement in endothelial function [14], indicating a cause and effect relationship between OSA and endothelial dysfunction. It was also reported that patients with OSA had impaired myocardial perfusion but that was significantly improved by alleviation of OSA with CPAP [15]. Furthermore, patients with OSA display greater signs of early atherosclerosis, including increased carotid intima-media thickness and increased arterial stiffness [13,16]. A randomized trial demonstrated that 4 months of CPAP therapy to OSA reduced carotid intima-media thickness and arterial stiffness [17]. Recent observational studies showed that short-term CPAP therapy can reduce arterial stiffness parameters in association with reduction of SNA and that long-term (>1 year) CPAP therapy can retard progression of arterial stiffness [18]. As a consequence of such OSA-related atherogenesis, patients with OSA are likely to have coronary artery disease (CAD) and ischemic cardiomyopathy, although a recent longitudinal analysis of the Sleep Heart Health Study including 1927 men and 2495 women without any cardiovascular diseases at the baseline (mean follow-up duration, 8.7 years) showed that after adjustment for

4 T. Kasai / Journal of Cardiology 60 (2012) OSA Intermi ent Hypoxia Post-Apneic Reoxygena on ROS Produc on Oxida ve Stress Ac va on of Transcrip onal Factor (NFκB, HIF-1α, etc.) Bioavailability of NO Inflammatory Mediators Adhesion Molecules Vascular Endothelial Dysfunc on Atherosclerosis Fig. 2. Schema of intermittent hypoxia-induced vascular damage in OSA. HIF-1, hypoxia induced factor-1 ; NF B, nuclear factor B; NO, nitric oxide; OSA, obstructive sleep apnea; ROS, reactive oxygen species. other risk factors, presence of OSA at baseline was a significant predictor of incident CAD only in men <70 years of age (adjusted hazard ratio [HR], 1.10; 95%CI, in each 10-unit AHI increase, and adjusted HR, 1.68; 95%CI, for those with AHI 30 compared with those with AHI < 5) but not in older men or in women at any age [19]. Nevertheless, once severe CAD such as myocardial infarction occurred, OSA-related intermittent hypoxia, negative intrathoracic pressure, and hypertension can provoke myocardial oxygen demand-supply mismatch and may cause LV dysfunction and HF by impairing recovery of LV systolic function following myocardial infarction [20]. A longitudinal analysis of the Sleep Heart Health Study [19] showed that after adjustment for other risk factors, presence of OSA at baseline was a significant predictor of incident HF in men (adjusted HR, 1.13; 95%CI, in each 10-unit AHI increase). Since this relationship was not observed in women, we still need further studies including not only population-based study but also randomized study investigating effect of OSA treatment on preventing incident HF Effects of central sleep apnea on cardiac function Although CSA appears to arise secondary to HF, once initiated it may participate in a pathophysiologic vicious cycle that contributes to deterioration in cardiac function. However, it is still under debate whether CSA is simply a marker of severely impaired cardiac function with pulmonary congestion, or whether CSA exerts independent pathologic effects on the impairment of cardiac function. Nevertheless, there is evidence that CSA may have detrimental physiologic effects on cardiac function. As well as OSA, during central apnea, the absence of breathing eliminates reflex inhibition of central sympathetic nerve traffic arising from pulmonary stretch receptors, that are activated during normal breathing and as a result, SNA is enhanced. This effect summates with apnea-related intermittent hypoxia and CO 2 retention and with arousals to cause cyclical surges in SNA and cause a generalized increase in overnight SNA [21]. In addition, the adverse effects of CSA on SNA are not confined to sleep but may persist into wakefulness [22]. Indeed, ventricular arrhythmias are more common in HF patients with CSA than those without it in association with increased SNA [23]. On the other hand, the role of intermittent hypoxia and its related mechanisms such as oxidative stress and inflammation in CSA remains unclear in contrast to OSA. 4. Sleep apnea in heart failure 4.1. Clinical features Key clinical features of OSA include coexisting obesity and excessive daytime sleepiness (EDS). However, some OSA patients do not have any such symptoms and signs despite quite severe disorder. Although clinical features of OSA in patients with HF share several features with OSA in the general population, they differ in some important aspects. Although obesity is also associated with OSA in patients with HF [1], a larger population are non-obese than in the general population [24]. Therefore, in the HF population, the presence of obesity is an insensitive factor for predicting the presence of OSA. Hence, in the HF population, factors other than obesity must play a more important role in the pathogenesis of OSA than in the general population. One such factor may be fluid retention in the legs and rostral fluid shift from the legs to the upper body as mentioned earlier. In contrast to the general population, most patients with HF who have OSA do not complain of EDS and have an Epworth Sleepiness Scale (ESS) score within normal limits (generally <11) [24], indicating that a complaint or symptoms of EDS are insensitive indices of the presence of OSA in the HF population. A recent study suggests that such lack of subjective sleepiness in HF patients with OSA is associated with HF-related increase in the SNA [25]. It was also reported that obesity is not a good indicator of CSA [1]. Similar to OSA patients with HF, most CSA patients do not complain of EDS [26].

5 82 T. Kasai / Journal of Cardiology 60 (2012) Epidemiology As compared with the general population, the prevalence of OSA is generally higher in HF populations. For instance, prevalence of OSA in HF is 12 26% at an AHI cut-off of 15 [1,26]. A high frequency of CSA in patients with HF has been widely noted [1,26]. CSA defined by an AHI 15 with >50% central events was observed in 21 37% of HF patients [1,26]. In patients with HF, adverse effects of sleep apnea described earlier may promote further progression of cardiac dysfunction and worsen prognosis. Indeed, a recent observational study suggest that the presence of untreated OSA (defined as AHI 15) among HF patients is associated with increased mortality compared to those with an AHI < 15 even after adjustment for other confounding factors [27]. A number of studies reported that CSA is a significant independent predictor of mortality in HF patients with HF [5]. However, it remains unclear whether there is a direct cause and effect relationship between sleep apnea and risk for morbidity and mortality of HF. 5. Treatment for patients with heart failure and sleep apnea 5.1. Effect of heart failure treatment on sleep apnea There are several interventions for HF whose effects on sleep apnea have been tested. Considering the issue of fluid retention and rostral fluid shift in patients with HF [4], decreased intravascular volume and attenuated venous congestion caused by treatment of HF may potentiate the reduction of both OSA and CSA severities. In particular, first-line therapy for CSA patients should be optimization of HF treatment which can cause a reduction of systemic and pulmonary congestion since CSA is largely a consequence of HF and pulmonary congestion. Bucca et al. reported that administration of furosemide and spironolactone for 3 days induced significant increase in the upper airway caliber and reduction in AHI (from 75 to 57, p < 0.001) in patients with severe OSA and diastolic HF [28]. Ueno and colleagues demonstrated that after 4 months of exercise training, as a specific treatment for HF, AHI significantly decreased in HF patients with OSA but not in those patients with HF and CSA [29]. In another study, 6 months of exercise training caused 64% reduction in AHI in HF patients with CSA [30]. It was reported that cardiac resynchronization therapy (CRT) induced reduction in the AHI in HF patients with OSA although a recent meta-analysis suggested a negative effect of CRT on OSA [31]. Similarly, CRT was accompanied by alleviation of CSA in association with an improvement in cardiac function [31]. Heart transplantation can also alleviate CSA in patients with HF [32]. Thus, optimizing HF therapy can stabilize ventilatory control and attenuate both OSA and CSA severities. However, none of them was a randomized controlled study Effect of sleep apnea treatment on heart failure Treatment for obstructive sleep apnea The standard treatment for OSA in patients with HF is CPAP. CPAP splints the pharynx and maintains its patency, thereby preventing apneas and hypopneas and may have beneficial positive airway pressure effects on HF independent from treating OSA. In general population, oral appliances or surgery are less effective than CPAP. It remains unclear whether treating OSA using these options is beneficial or not in patients with HF. Weight loss has been shown to decrease the AHI in general OSA population. However, as mentioned earlier, in the HF population, obesity must play a less important role in the pathogenesis of OSA than in the general population. In addition, it takes a long time to lose clinically significant weight and it is quite difficult to sustain achieved weight loss especially in patients with HF. As an OSA treatment, in addition to the alleviation of OSA, one night application of CPAP caused abolition of negative intrathoracic pressure swings and reductions in nocturnal BP, that caused a dramatic reduction in LV afterload that was accompanied by a decrease in HR [33]. Randomized trials of fixed-pressure CPAP involving HF patients with OSA demonstrated an improvement in LV systolic function in association with reductions in BP, HR, and SNA [34,35]. In terms of long-term clinical outcome, there are two observational studies. In a study involving 218 HF patients among 51 patients with OSA and an AHI 15, there was a trend to a lower mortality rate in the 14 who accepted CPAP therapy than in the 37 who did not (mortality rate of 0 versus 7.2 per 100 person-years, p = 0.07) over mean and maximum follow up periods of 2.9 and 7.3 years, respectively [27]. In another study among 88 HF patients with moderate to severe OSA, 65 CPAP-treated patients had significantly greater hospitalization-free survival than 23 untreated patients over mean and maximum follow up periods of 2.1 and 4.8 years, respectively [36]. Furthermore, among the 65 CPAP-treated patients, the hospitalization-free survival rate was significantly higher in more compliant group (N = 32), whose average nightly usage was more than the median level (4.9 h), than in the less compliant group (N = 33) whose average nightly usage was 4.9 h or less. In the American Heart Association/American College of Cardiology Foundation scientific statement on sleep apnea and cardiovascular disease [37], treatment of OSA in HF patients is considered as being investigational because the effect of OSA treatment by CPAP in HF patients has not yet been clarified in randomized trials, and because most HF patients with OSA do not complain of EDS and therefore, indications for treating OSA in such patients have not been clearly defined. As mentioned earlier, a recent study showed an inverse relationship between EDS and SNA in HF patients with OSA [25]. This finding suggests, paradoxically, that among HF patients with OSA, those with the less daytime sleepiness may have greater potential for benefit from therapy of OSA than those with more daytime sleepiness. This possibility warrants further investigation Treatment for central sleep apnea There are several options in CSA treatment [38,39]. Theophilline which stimulates central respiratory drive and augments cardiac contractility, and raising PaCO 2 above the apneic threshold either via inhaled CO 2 or addition of dead space were effective to reduce the AHI or abolish CSA instantaneously [38,39]. However, both options are no longer used for this purpose because theophilline may increase the incidence of cardiac arrhythmias and sudden death, and because raising PaCO 2 may cause adverse effects by enhancing SNA [38]. A recent study which reported the effect of real-time dynamic carbon dioxide administration on CSA [40] may be a hint for minimizing such adverse effects. Acetazolamide can reduce the AHI possibly by the stimulation of respiration via causing metabolic acidosis [38,39]. Recently, two groups reported that one night application of transvenous phrenic nerve stimulation significantly reduced AHI [41,42]. However, their long-term safety and effects on cardiovascular outcomes remains unclear. Small short-term randomized trials have demonstrated that nocturnal oxygen causes approximately 50% reductions in the AHI in HF patients with CSA [38,39]. In addition to such AHI reductions, supplemental oxygen reduced overnight urinary norepinephrine excretion, and improved peak oxygen consumption and ventilatory efficiency [38,39]. A Japanese group found improvement in quality-of-life in by 3- and 13-month nocturnal oxygen despite no improvement in cardiac event rate [39]. Therefore, there is no

6 T. Kasai / Journal of Cardiology 60 (2012) Table 1 Randomized controlled trials investigating effect of ASV on LV function. Author, year Study design N Duration (months) Type of SDB Baseline Device usage Changes AHI EF AHI EF Pepperell (2003) Philippe (2006) Fietze (2008) Kasai (2010) Subtherapeutic 15 1 CSA Therapeutic CPAP 13 6 CSA ASV Bi-level PAP CSA * ASV CPAP 15 3 CSA+OSA ASV Randerath (2012) CPAP CSA+OSA ASV AHI, apnea hypopnea index; ASV, adaptive-servo ventilation; bi-level PAP, bi-level positive airway pressure; C, central; CPAP, continuous positive airway pressure; EF, ejection fraction; LV, left ventricular; O, obstructive;, randomized control trial; SA, sleep apnea; SDB, sleep-disordered breathing. consistent evidence that it improves cardiovascular function or clinical outcomes by supplemental oxygen. Since HF patients with CSA are associated with increased LV filling pressures, CPAP has been applied to them to improve hemodynamics. However, the effects of CPAP on CSA have not been consistent. This is probably due to differences in how it is applied. If CPAP was applied acutely and at low pressure (i.e cm H 2 O), CSA was not alleviated [38]. On the other hand, if CPAP were gradually initiated with pressures of cm H 2 O, the AHI reduced by >50% [38]. Furthermore, if CPAP was titrated gradually, CSA was alleviated in association with an increase in PaCO 2, reduction in SNA, and improvements in cardiac functions including increases in LV ejection fraction (LVEF) [38]. In one small-randomized trial in HF patients with and without CSA [43], although CPAP had no effect on either LVEF or the composite of mortality and cardiac transplantation in those without CSA. In those with CSA, CPAP improved LVEF at 3 months and revealed a trend toward a reduced event rate (p = 0.059, the median follow-up period, 2.2 years). In particular, a sub-group of patients who were compliant with CPAP revealed a significant reduction in the event rate (p = 0.017). The Canadian Continuous Positive Airway Pressure for Treatment of Central Sleep Apnea in Heart Failure (CANPAP) trial sought to determine whether CPAP would improve CSA, morbidity, mortality, and cardiovascular function in HF patients with CSA receiving contemporary medical therapy for HF [44]. The CANPAP trial which included 258 patients with HF and CSA (130 in a control group and 128 in a CPAP-treated group) reproduced previous findings that CPAP attenuates CSA, improves LVEF, and lowers SNA. However, there were no significant differences in transplant-free survival between the two groups (mean follow-up duration, 2-years). However, since reversal of CSA itself appears to be one means by which CPAP could improve cardiovascular outcome [43], and since it was suggested that there are some HF patients whose CSA cannot be attenuated by CPAP [39], post hoc analysis of the CANPAP trial was carried out [45]. Post hoc analysis of the CANPAP trial suggests that patients whose AHI reduced below 15 by CPAP at 3 months have a significantly better transplant-free survival as compared with control groups. Results of the CANPAP trial do not support routine use of CPAP for HF, post hoc analysis implies potentials of the effective suppression of CSA (i.e. AHI < 15). In this perspective, two newer types of noninvasive positive airway pressure (PAP) which can more effectively suppress CSA than CPAP have been in focus. Bi-level PAP provided two different levels on PAP in inspiratory and expiratory phases with a back-up ventilation. Several studies including ours suggested beneficial effects of bi-level PAP on CSA and cardiac function [38,39]. However, compared with bi-level PAP, the effects of CSA suppression are greater in a newer PAP device, adaptive or auto-servo ventilation (ASV). Thus, ASV is now more focused rather than bi-level PAP. Randomized studies in which effects of ASV on cardiac function were investigated are summarized in Table 1. Pepperell et al. [46] showed that nocturnal urinary metadrenaline and daytime B-type natriuretic peptide concentrations were reduced significantly more by therapeutic than sub-therapeutic ASV. Two studies showed that as compared with CPAP, ASV had greater effects on improvement in cardiac functions in HF patients with predominant CSA [47] and those with coexisting OSA and CSA [48]. On the other hand, Fietze et al. [49] showed that treatment of CSA with bi-level PAP improved LVEF more than that with ASV although the difference in the degree of improvement between two PAPs was not significant. More recently, Randerath et al. reported the longterm effect of ASV on cardiac function in patients with HF and CSA [50]. They found significantly better improvement in B-type natriuretic peptide level but no differences in LV function and exercise performance. However, this study included HF patients with preserved LV systolic function in addition to those with impaired LV systolic function. Thus, results of this study should be interpreted with caution. It is premature to recommend ASV as a routine use for CSA in HF patients because large-scale, long-term randomized trials which investigate effects of ASV on cardiovascular morbidity and mortality are lacking. Among patients with HF and CSA, only CPAP has been shown to have a potential to improve long-term cardiovascular outcomes as long as CSA has been effectively suppressed [45]. Therefore, in HF patients with CSA, CPAP should be tried first and then, if the AHI 15 even on CPAP, ASV should be considered. Two ongoing large-scale randomized trials investigating the effect of ASV in HF patients with CSA on long-term cardiovascular morbidity and mortality will provide further information for CSA treatment strategy. 6. Conclusions OSA has adverse effects on cardiac function and could be associated with incidence and progression of HF. CSA may worsen cardiac function in patients with HF. Data from observational studies strongly suggest relationships between sleep apnea including both OSA and CSA, and cardiovascular morbidity and mortality. Although most of the data are not supported by randomized or

7 84 T. Kasai / Journal of Cardiology 60 (2012) long-term trials, treatment of sleep apnea may have beneficial effects on long-term cardiovascular outcomes in patients with HF. Since HF remains a major life-threatening disease in industrialized countries, the significance of identifying and managing sleep apnea should be more emphasized to prevent the development or progression of HF. Source of funding TK was supported by an unrestricted research fellowship from Fuji-Respironics Inc. References [1] Yumino D, Wang H, Floras JS, Newton GE, Mak S, Ruttanaumpawan P, Parker JD, Bradley TD. Prevalence and physiological predictors of sleep apnea in patients with heart failure and systolic dysfunction. J Card Fail 2009;15: [2] Wasicko MJ, Leiter JC, Erlichman JS, Strobel RJ, Bartlett Jr D. Nasal and pharyngeal resistance after topical mucosal vasoconstriction in normal humans. Am Rev Respir Dis 1991;144: [3] Shepard Jr JW, Pevernagie DA, Stanson AW, Daniels BK, Sheedy PF. 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