ORIGINAL ARTICLE. Heart Failure

Transcription

1 Circulation Journal Official Journal of the Japanese Circulation Society ORIGINAL ARTICLE Heart Failure A Single Night Beneficial Effects of Adaptive Servo-Ventilation on Cardiac Overload, Sympathetic Nervous Activity, and Myocardial Damage in Patients With Chronic Heart Failure and Sleep-Disordered Breathing Akiomi Yoshihisa, MD, PhD; Satoshi Suzuki, MD, PhD; Makiko Miyata, MD; Takayoshi Yamaki, MD, PhD; Koichi Sugimoto, MD, PhD; Hiroyuki Kunii, MD, PhD; Kazuhiko Nakazato, MD, PhD; Hitoshi Suzuki, MD, PhD; Shu-ichi Saitoh, MD, PhD; Yasuchika Takeishi, MD, PhD Background: Sleep-disordered breathing (SDB), including Cheyne-Stokes respiration with central sleep apnea (CSR-CSA), causes a deterioration in the prognosis of patients with chronic heart failure (CHF). Adaptive servoventilation (ASV) and oxygen therapy (O2) are useful for improving the CSR-CSA of CHF. The purpose of the present study was to examine the short-term effects of ASV and O2 on suppressing SDB (CSR-CSA dominant) in CHF, and the accompanying neurohumoral abnormalities (cardiac overload, sympathetic nervous activation, and myocardial damage). Methods and Results: Forty-two patients with CHF and SDB (mean LVEF 34.6%, apnea hypopnea index (AHI) 39.0/h, central apnea index (CAI) 17.6/h, obstructive apnea index (OAI) 2.6/h) were enrolled. We performed polysomnography (baseline, O2, and ASV) for 3 consecutive days, and we measured levels of atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), noradrenalin, urinary catecholamines, and high-sensitivity troponin T. Both O2 and ASV reduced the AHI, CAI, arousal index, mean heart rate during sleep, and the levels of noradrenalin, urinary catecholamines, and high-sensitivity troponin T. However, only ASV, not O2, decreased the levels of ANP and BNP. Conclusions: ASV reduces cardiac overload, attenuates sympathetic nervous activity and ongoing myocardial damage effectively in CHF patients with SDB, and for patients who cannot use ASV, O2 is an alternative therapy. (Circ J 2012; 76: ) Key Words: Adaptive servo-ventilation; B-type natriuretic peptide; High-sensitivity troponin T; Oxygen therapy; Sympathetic nervous activity Sleep-disordered breathing (SDB), including Cheyne-Stokes respiration with central sleep apnea (CSR-CSA), is associated with adverse outcomes in patients with chronic heart failure (CHF). 1 3 Approximately half of CHF patients reportedly have SDB, which consists of obstructive sleep apnea (OSA) and CSR-CSA. OSA is thought to be caused by upper airway obstruction during sleep, whereas instability of respiratory control is the major cause of CSR-CSA. SDB, either OSA or CSR-CSA, results in multiple pathological consequences such as an imbalance in myocardial oxygen delivery/consumption, activation of sympathetic nervous system and other neurohumoral factors, and increased right and left ventricular afterload. 4,5 Oxygen therapy (O2) improves exercise capacity and attenuates cardiac sympathetic nervous activity in patients with CHF and CSR-CSA. 6,7 Adaptive servo-ventilation (ASV) is a ventilator support system specifically designed to normalize ventilation in patients with CSR-CSA. 8 Moreover, ASV has an automatic airway tracing feedback function, and several advantages of ASV have been reported over continuous positive airway pressure (CPAP), bi-level PAP, and O2. 9,10 ASV Received April 5, 2012; revised manuscript received May 8, 2012; accepted May 15, 2012; released online June 13, 2012 Time for primary review: 20 days Department of Advanced Cardiac Therapeutics (A.Y., S. Suzuki, Y.T.), Department of Cardiology and Hematology (A.Y., S. Suzuki, M.M., T.Y., K.S., H.K., K.N., H.S., S. Saitoh, Y.T.), Fukushima Medical University, Fukushima, Japan Mailing address: Akiomi Yoshihisa, MD, PhD, Department of Cardiology and Hematology, Fukushima Medical University, 1 Hikarigaoka, Fukushima , Japan. yoshihis@fmu.ac.jp ISSN doi: /circj.CJ All rights are reserved to the Japanese Circulation Society. For permissions, please cj@j-circ.or.jp

2 2154 YOSHIHISA A et al. can regulate airway ventilation volume according to demand, based on the variable tidal volume throughout the period of CSR-CSA. In addition, ASV automatically provides positive pressure ventilation during apnea when necessary. Editorial p 2088 Treating SDB may improve cardiac function in patients with CHF. CPAP reportedly suppresses the abnormal breathing pattern, attenuates sympathetic nervous activity, 11 and improves the left ventricular ejection fraction (LVEF) in CHF patients with either OSA or CSR-CSA. 12 Furthermore, there are several reports about mid-term (several months) effects of ASV on cardiac function, 8,13 16 and we have reported that ASV improves the long-term prognosis in patients with CHF and CSR- CSA. 17 However, the short-term (a single night) effects, and the mechanisms of O2 and ASV on cardiac function in patients with CHF and CSR-CSA, are not fully understood. Sympathetic nervous activation, ongoing myocardial damage, and inflammation play critical roles in the progression of CHF and are associated with adverse prognosis. Levels of plasma noradrenalin, 18 serum troponin T, 19,20 and C-reactive protein (CRP) 21,22 are useful prognostic markers in patients with CHF. However, the acute effects of O2 and ASV on atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), plasma noradrenalin, serum troponin T, and CRP levels have not been rigorously examined. ASV is more useful for improving CSR-CSA than O2, as previously reported, 9 but compliance with long-term use of ASV is not enough. On the other hand, O2 therapy has better compliance than ASV. Therefore, the primary purpose of the present study was to review the short-term (a single night) multiple effects in suppressing SDB (CSR-CSA dominant) and neurohumoral abnormalities of ASV compared with O2. The secondary purpose was to determine which of ASV or O2 was more effective for CHF with SDB in a single night. We compared the short-term (a single night) multiple effects of ASV and O2 on cardiac function, sympathetic nervous activity, ongoing myocardial damage, and inflammation in CHF patients with SDB (CSR-CSA dominant). Methods Study Subjects and Study Protocol This study enrolled 42 consecutive patients with CHF and SDB (CSR-CSA dominant) who were referred for overnight polysomnography (PSG) at Fukushima Medical University. The inclusion criteria were (1) the presence of symptomatic CHF, which was defined as the New York Heart Association (NYHA) class II, (2) LVEF <50%, (3) enforcement of standard pharmacotherapy (including angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, β-blockers and diuretics), (4) stable clinical status, which was defined as receiving optimal medical therapy and without worsening of CHF at least 3 months prior to study enrollment, and (5) diagnosed as having moderate-severe SDB, and CSR-CSA dominant, which was defined as an apnea hypopnea index (AHI) 15/h with a majority of central sleep apnea events. The exclusion criteria were (1) age <20 or >80 years, (2) resynchronization therapy within 6 months prior to study enrollment, (3) the presence of severe chronic pulmonary disease, (4) on dialysis, (5) a history of stroke with neurological deficit, (6) psychotic disorders, (7) pharyngeal disease, and (8) acute coronary syndrome and acute decompensated heart failure. This study used an acute prospective random crossover design. We examined 3 consecutive days because of the exclusion of a change in HF condition and treatment. We performed polysomnography for 3 sequential night (baseline, O2, and ASV): baseline PSG done on the first night, and then subjects were tested on 2 treatment nights in random order: O2 and ASV. The 42 patients were divided into 2 groups and randomly assigned to either baseline, O2, and ASV (n=21) or baseline, ASV, and O2 (n=21). In addition, we measured levels of ANP, BNP, plasma noradrenalin, high-sensitivity troponin T, highsensitivity C-reactive protein (hscrp) each morning, and 24- h accumulated urinary catecholamines. Written informed consent was given by all study subjects. The study protocol was approved by the Ethical Committee of Fukushima Medical University. Polysomnography All subjects underwent overnight complete polysomnography with the use of standard techniques and scoring criteria for sleep stages and arousals from sleep as previously reported. 17,23,24 Briefly, the polysomnography was performed using a computerized system (Alice 5, Philips Respironics, Murrysville, PA, USA) that consisted of monitoring of the electro-encephalogram, electro-oculogram, submental electromyogram, electrocardiogram, thoracoabdominal motion, oronasal airflow by an airflow pressure transducer, and arterial oxyhemoglobin saturation (SPO2) by pulse oximetry. 8,23 25 Apnea was defined as an absence of airflow for >10 s. Hypopnea was defined as a >30% reduction in monitored airflow accompanied by a decrease in SPO2 >4%. 23 An AHI 15/h was defined as moderate severe SDB. A diagnosis of moderate severe CSR-CSA was assigned at an AHI 15/h with a majority of CSA events. The major polysomnographic parameters investigated were AHI, central apnea index (CAI), obstructive apnea index (OAI), hypopnea index (HI), arousal index, 3% oxidative desaturation index (3%ODI), lowest pulse oxyhemoglobin saturation (lowest SPO2), mean pulse oxyhemoglobin saturation (mean SPO2), %time <SPO2 90%/total sleep time (CT90), %time <SPO2 95%/total sleep time (CT95), slow wave sleep (SWS) (stage III+IV/total sleep time (%)), REM sleep (rapid eye movement (REM) sleep/total sleep time (%)), and sleep efficacy (total sleep time/time in bed (%)), as previously reported. 8,17,23 25 Echocardiography Echocardiography was performed blindly only at baseline daytime using the standard techniques by an experienced echocardiographer. Two-dimensional echocardiographic images were acquired from the parasternal long and short axes, apical long axis, and apical 4-chamber views. Echocardiographic parameters investigated were left ventricular end-diastolic volume index (LVEDVI), left ventricular end-systolic volume index (LVESVI), LVEF, left atrial volume index (LAVI), estimated right ventricular systolic pressure (RVPS), and the ratio of early transmitral flow velocity to mitral annular velocity (E/E ). The LVEDVI, LVESVI, LVEF and LAVI were calculated using a modification of Simpson s method. E/E was calculated by transmitral Doppler flow and tissue Doppler imaging. All recordings were performed on the ultrasound system (ACUSON Sequoia, Siemens Medical Solutions USA, Inc, Mountain View, CA, USA). Measurement of ANP, BNP, Plasma Noradrenalin, High-Sensitivity Troponin T, hscrp, and Urinary Catecholamines The patients underwent polysomnography for 3 consecutive

3 Overnight Effects of ASV for CHF With SDB 2155 days. After waking up each morning, we asked the patients to rest for at least 30 min before we took blood samples to measure levels of plasma ANP, plasma BNP, plasma noradrenalin, serum high-sensitive troponin T, and serum hscrp. The 24-h urinary catecholamines, such as metanephrine and normetanephrine, were measured. Oxygen Therapy Patients were administered oxygen at a rate of 3 L/min through a nasal cannula during sleep as previously described. 6,7 Adaptive Servo-Ventilation (ASV) We used ASV (VPAP Adapt SV/Auto Set CS, ResMed, Sydney, NSW, Australia). Patients underwent a titration of the device overnight while attended by the polysomnographer. The aim was to reduce the AHI to <10/h using a minimum of positive airway pressure. In summary, we set expiratory positive airway pressure (EEP) to cause the disappearance of OSA, and next set minimum and maximum pressure support (PS) to cause the disappearance CSR-CSA. All patients were able to tolerate ASV until the next morning. Statistical Analysis Data are presented as mean ± SD. ANP and BNP are presented as median and interquartile range. The data measured repeatedly at baseline, on O2, and on ASV, such as the polysomnographic data and blood examinations, were analyzed by 1-way repeated-measures analysis of variance (ANOVA) followed by Bonferroni post-hoc test. ANP and BNP were analyzed by Kruskal-Wallis test. P<0.05 was considered significant for all comparisons. All analyses were performed using a statistical software package (StatView version 5.0, SAS Institute, Abacus Concepts, Berkeley, CA, USA). Results Clinical Characteristics of Study Subjects Clinical characteristics are shown in Table 1. Males accounted for 88%, and the major etiology of CHF was cardiomyopathy (69%); 7 patients underwent cardiac resynchronization therapy. Median BNP was pg/ml, and mean LVEF was 34.6%. The results of the polysomnographic recordings (baseline) are shown in Table 2. Mean AHI was 39.0/h, mean CAI was 17.6/h, OAI was 2.6/h and mean lowest SPO2 was 79.1%. These data suggest that these patients had severe SDB (CSR-CSA dominant). Effects of O2 and ASV on Polysomnographic Data and Vital Signs We set the EEP to eliminate OSA, and then set the minimum and maximum PS to eliminate CSR-CSA by attended manual titration. Consequently, mean EEP was 6.0±2.0 cmh2o (range 4 10), mean minimum PS was 3.6±2.4 cmh2o (range 3 6), mean maximum PS was 8.5±4.1 cmh2o (range 6 12) and the respiratory rate was set to automatic in the present study. All patients were successfully titrated on ASV. Table 2 shows the polysomnographic data of the patients at baseline, on O2, and on ASV. Both O2 and ASV significantly improved the polysomnographic data in terms of AHI, CAI, HI, arousal index, 3%ODI, lowest SPO2, mean SPO2, CT90, and CT95 (P<0.01 for each) compared to baseline. However, only ASV increased the SWS (P<0.05). In addition, AHI and OAI were significantly lower with ASV than with O2 (P<0.05). The mean SPO2 was significantly higher with O2 than with Table 1. Clinical Characteristics of the CHF Patients Physical Age (years) 62.0±11.8 Male (n, %) 37 (88.0) BMI 25.4±4.6 NYHA (I/IIs/IIm/III/IV) 0/4/20/16/2 Etiology Cardiomyopathy (n, %) 29 (69.0) Ischemic (n, %) 8 (19.0) Valvular (n, %) 4 (10.3) Others (n, %) 1 (2.6) Rhythm Sinus rhythm (n, %) 19 (45.2) Atrial fibrillation (n, %) 21 (50.0) Pacemaker (n, %) 2 (4.8) ICD (n, %) 2 (5.1) CRT (n, %) 7 (16.7) Medication ACEI (n, %) 22 (56.4) ARBs (n, %) 14 (35.9) β-blockers (n, %) 36 (92.3) Diuretics (n, %) 28 (71.8) Aldosterone antagonists (n, %) 25 (64.1) Digitalis (n, %) 7 (17.9) Amiodarone (n, %) 8 (20.5) Pimobendan (n, %) 9 (23.1) Laboratory data BNP (pg/ml) (517.5) PaO2 (mmhg) 95.3±19.5 PaCO2 (mmhg) 35.9±4.8 Hb (g/dl) 15.1±1.7 BUN (mg/dl) 21.8±10.4 Creatinine (mg/dl) 1.1±0.3 Echocardiography LVEDVI (ml/m 2 ) 93.2±41.6 LVESVI (ml/m 2 ) 64.6±36.2 LVEF (%) 34.6±12.6 LAVI (ml/m 2 ) 55.4±25.9 RVPS (mmhg) 38.6±13.9 E/E 13.4±6.1 Data are presented as median (inter quartile range). CHF, chronic heart failure; BMI, body mass index; NYHA, New York Heart Association; ICD, implantable cardioverter defibrillator; CRT, cardiac resynchronization therapy; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; BNP, B-type natriuretic peptide; BUN, blood urea nitrogen; LVEDVI, left ventricular end-diastolic volume index; LVESVI, left ventricular end-systolic volume index; LVEF, left ventricular ejection fraction; LAVI, left atrial volume index; RVPS, right ventricular systolic pressure; E/E, ratio of early transmitral flow velocity to mitral annular velocity. ASV (P<0.05). By the next morning, both O2 and ASV had reduced the mean heart rate during sleep (P<0.01), the heart rate during REM (P<0.01) and NREM sleep (P<0.01), and systolic and diastolic blood pressures (Table 2). Effects of O2 and ASV on Neuropeptides, Plasma Noradrenalin, High-Sensitivity Troponin T, hscrp, and Urinary Catecholamines ASV reduced the levels of ANP (P<0.01), BNP (P<0.01), plas-

4 2156 YOSHIHISA A et al. Table 2. Comparisons of Data for Polysomnography and Blood and Urinary Examinations Baseline O2 ASV ANOVA P value AHI (times/h) 39.0± ±13.4** 9.9±7.9**,# <0.01 CAI (times/h) 17.6± ±5.2** 1.1±1.6** <0.01 OAI (times/h) 2.6± ±8.8* 1.0±2.1 # <0.01 HI (times/h) 18.0± ±4.4** 6.3±4.8** <0.01 Arousal index 25.9± ±7.5** 16.7±7.5** <0.01 3% ODI (times/h) 27.5± ±15.6** 6.5±15.2** <0.01 Lowest SPO2 (%) 79.1± ±7.5** 89.2±5.8** <0.01 Mean SPO2 (%) 94.7± ±1.6** 96.7±1.6**,# <0.01 CT90 (%) 9.7± ±4.0** 0.8±2.8** <0.01 CT95 (%) 33.1± ±15.8** 9.5±21.8** <0.01 SWS (%) 2.1± ± ±8.1* 0.04 REM sleep (%) 18.3± ± ± Sleep efficacy (%) 67.2± ± ± Mean HR during sleep (beats/min) 72.1± ±11.0** 67.4±9.8** <0.01 Mean HR during REM (beats/min) 68.8± ±9.8** 64.4±8.9** <0.01 Mean HR during NREM (beats/min) 68.0± ±10.4** 63.9±9.1** <0.01 SBP (mmhg) 113.3± ±15.6* 103.6±13.9** 0.02 DBP (mmhg) 66.5± ±9.7* 61.8±9.1* 0.04 ANP (pg/ml) (205.7) (233.1) (229.8)** <0.01 BNP (pg/ml) (517.5) (477.8) (491.1)** <0.01 Plasma noradrenalin (pg/ml) 848.8± ±401.8* 705.1±402.9** 0.02 Urinary catecholamines (mg/day) 0.450± ±0.131** 0.358±0.093** <0.01 High-sensitivity troponin T (ng/ml) 0.042± ±0.018* 0.026±0.017* 0.04 High-sensitivity CRP (mg/dl) 0.263± ± ± Data are presented as median (inter quartile range). *P<0.05, **P<0.01 vs. baseline, # P<0.05 vs. O2. AHI, apnea hypopnea index; CAI, central apnea index; OAI, obstructive apnea index; HI, hypopnea index; ODI, oxidative desaturation index; Lowest SPO2, lowest oxyhemoglobin saturation; Mean SPO2, mean oxyhemoglobin saturation; CT90, %time <SPO2 90%/total sleep time; CT95, %time <SPO2 95%/total sleep time; SWS, slow wave sleep; REM, rapid eye movement; SBP, systolic blood pressure; DBP, diastolic blood pressure; ANP, atrial natriuretic peptide; BNP, B-type natriuretic peptide; CRP, C-reactive protein. ma noradrenalin (P<0.01), urinary catecholamine excretion (P<0.01), and high-sensitive troponin T (P<0.05) compared to baseline (Table 2). O2 reduced plasma noradrenalin (P<0.05), urinary catecholamines (P<0.01), and high-sensitivity troponin T (P<0.05), but not ANP and BNP. However, the hscrp level did not change with either O2 or ASV. Discussion Effects of O2 and ASV on Cardiac Overload in HF Noninvasive ventilation increases cardiac output in HF patients whose pulmonary arterial wedge pressure is high. 26,27 Intrathoracic positive pressure by noninvasive ventilation is thought to reduce cardiac preload and afterload, 28 and decrease left ventricular volume, leading to an improvement in mitral regurgitation, 16,27 but it is still uncertain whether short-term use of ASV is beneficial for cardiac overload in CHF patients with SDB. There are several reports about a reduction in the BNP level after several months of using ASV. 17,25,29,30 In the present study, only single night use of ASV directly decreased cardiac overload as demonstrated by significant decreases in the ANP and BNP levels in CHF patients with SDB. This effect by ASV seems to be driven by intrathoracic positive pressure. O2 does not have a direct effect of decreasing cardiac end-diastolic wall stress. To the best of our knowledge, this is the first reporting of acute reduction of cardiac overload in patients with CHF and SDB (CSR-CSA dominant) by the use of ASV in a single night. Effects of O2 and ASV on Sympathetic Nervous Activity in HF Sympathetic nervous activation plays a critical role in the progression of CHF and is associated with adverse clinical outcomes. 18 Sympathetic nervous activity affects the mean heart rate during sleep, arousal index, plasma noradrenalin level, and daily urinary catecholamine excretion, which were reduced by O2 and ASV in the present study. The magnitude of the heart rate reduction and sympathetic nervous activity are associated with a survival benefit in HF patients under β-blocker therapy. 31,32 In addition, only ASV increased SWS in the present study. High-quality sleep decreases sympathetic nervous activity. ASV and O2 decreased both the plasma noradrenalin level the next morning and daily urinary catecholamine excretion. It has been reported that mid-term (several months) use of O2 and CPAP attenuates cardiac sympathetic nervous activity in patients with CHF and CSR-CSA. 7,33 Short-term use of ASV improves periodic breathing and attenuates sympathetic overactivation, such as muscle sympathetic nerve activity. 34 Effects of O2 and ASV on Myocardial Damage and Inflammation in HF High-sensitivity troponin T as a marker of ongoing myocardial damage 19,20 and hscrp as a marker of inflammation 21,22 are useful in understanding the clinical condition of CHF pa-

5 Overnight Effects of ASV for CHF With SDB 2157 tients. In the present study, O2 and ASV reduced high-sensitive troponin T levels, but this effect may depend on an improvement in oxygenation, and a decrease in sympathetic activity and cardiac overload. Although, mid-term (4 weeks) use of ASV has an anti-inflammatory effect, 25 we did not observe such an effect with single-night use of O2 and ASV. Further examination may be required to confirm the anti-inflammatory effect of O2 and/or ASV. O2 and ASV for HF With CSR-CSA O2 improves exercise capacity and attenuates cardiac sympathetic nervous activity in patients with CHF and CSR-CSA. 6,7 A large-scale randomized clinical trial, the Canadian Continuous Positive Airway Pressure for Patients with Central Sleep Apnea and Heart Failure (CANPAP), has shown that CPAP does not improve long-term transplant-free survival in CHF patients with CSR-CSA. 35 However, in a CANPAP subanalysis, improvement of CSR-CSA (especially AHI <15) was important for cardiac function and prognosis in CHF patients. 36 ASV has an automatic airway tracing feedback function and several advantages (eg, suppressing AHI in CSR-CSA) over CPAP, bi-level PAP, and O2 have been reported. 9,10,13 ASV has better compliance 13 and improvement effect on CSR-CSA than CPAP, so the use of ASV may have resulted in good consequences for cardiac function and prognosis. 8,10,17,25,37 In the present study, the indices of improved SDB (eg, AHI, OAI, SWS) by O2 were inferior to those for ASV, but O2 has good compliance, and we can expect long-term use of O2. Both ASV and O2 are important non-pharmacotherapies for HF patients with CSR-CSA. Study Limitations Firstly, a crossover design with 2 active treatment arms does not allow for comparison with true placebo and therefore does not account for time-dependent effects. The subjects did not have washout periods before undergoing ASV or O2. The crossover design has limitations compared to an independent parallel group design. Secondly, polysomnography was done on consecutive days. We are unclear whether the interval between the tests was sufficient for the patient to return to the baseline condition. Thirdly, we used only a fixed O2 flow of 3 L/min, as previously described, 7,8 and we did not examine the effects of another dose of O2. Finally, acute effects do not necessarily predict long-term effects. However, an acute study has the merit of excluding effects in the long term by a change in the HF condition and treatment. Further, long-term studies are necessary to establish ASV as a promising therapy for CHF patients with SDB. Conclusions In this study, use of ASV led to more improvement in SDB (CSR-CSA dominant) than did O2 therapy. To the best of our knowledge, the present study is the first to show an acute shortterm (a single night) beneficial effect of ASV on multiple parameters such as ANP, BNP, noradrenalin, high-sensitive troponin T, and urinary catecholamine levels. These data suggest that short-term use of ASV has the multiple effect of not only improving SDB (CSR-CSA dominant) but also attenuating sympathetic nervous activity, reducing cardiac overload and myocardial damage. ASV might be a promising non-pharmacotherapy for CHF. On the other hand, although O2 was inferior to ASV in terms of improving SDB, it has good compliance. For patients who cannot use ASV, O2 to some extent is effective for CSR-CSA and suppressing sympathetic nervous activation and myocardial damage. Acknowledgment The authors acknowledge Dr Aya Goto (Department of Public Health, Fukushima Medical University) for advice on medical statistics. Disclosures Akiomi Yoshihisa, Satoshi Suzuki: affiliation with endowed department: Fukuda Denshi Co Ltd. This study was supported in part by grants-in-aid for Scientific Research (Nos and ) from Japan Society for the Promotion of Science. References 1. Sin DD, Fitzgerald F, Parker JD, Newton G, Floras JS, Bradley TD. Risk factors for central and obstructive sleep apnea in 450 men and women with congestive heart failure. Am J Respir Crit Care Med 1999; 160: Wang H, Parker JD, Newton GE, Floras JS, Mak S, Chiu KL, et al. Influence of obstructive sleep apnea on mortality in patients with heart failure. J Am Coll Cardiol 2007; 49: Javaheri S, Shukla R, Zeigler H, Wexler L. Central sleep apnea, right ventricular dysfunction, and low diastolic blood pressure are predictors of mortality in systolic heart failure. J Am Coll Cardiol 2007; 49: Shiomi T, Guilleminault C, Stoohs R, Schnittger I. Leftward shift of the interventricular septum and pulsus paradoxus in obstructive sleep apnea syndrome. Chest 1991; 100: Buda AJ, Pinsky MR, Ingels NB Jr, Daughters GT 2nd, Stinson EB, Alderman EL. Effect of intrathoracic pressure on left ventricular performance. N Engl J Med 1979; 301: Sasayama S, Izumi T, Matsuzaki M, Matsumori A, Asanoi H, Momomura S, et al. Improvement of quality of life with nocturnal oxygen therapy in heart failure patients with central sleep apnea. Circ J 2009; 73: Toyama T, Seki R, Kasama S, Isobe N, Sakurai S, Adachi H, et al. Effectiveness of nocturnal home oxygen therapy to improve exercise capacity, cardiac function and cardiac sympathetic nerve activity in patients with chronic heart failure and central sleep apnea. Circ J 2009; 73: Oldenburg O, Schmidt A, Lamp B, Bitter T, Muntean BG, Langer C, et al. Adaptive servoventilation improves cardiac function in patients with chronic heart failure and Cheyne-Stokes respiration. Eur J Heart Fail 2008; 10: Teschler H, Dohring J, Wang YM, Berthon-Jones M. Adaptive pressure support servo-ventilation: A novel treatment for Cheyne-Stokes respiration in heart failure. Am J Respir Crit Care Med 2001; 164: Philippe C, Stoica-Herman M, Drouot X, Raffestin B, Escourrou P, Hittinger L, et al. Compliance with and effectiveness of adaptive servoventilation versus continuous positive airway pressure in the treatment of Cheyne-Stokes respiration in heart failure over a six month period. Heart 2006; 92: Otsuka N, Ohi M, Chin K, Kita H, Noguchi T, Hata T, et al. Assessment of cardiac sympathetic function with iodine-123-mibg imaging in obstructive sleep apnea syndrome. J Nucl Med 1997; 38: Kaneko Y, Floras JS, Usui K, Plante J, Tkacova R, Kubo T, et al. Cardiovascular effects of continuous positive airway pressure in patients with heart failure and obstructive sleep apnea. N Engl J Med 2003; 348: Kasai T, Usui Y, Yoshioka T, Yanagisawa N, Takata Y, Narui K, et al. Effect of flow-triggered adaptive servo-ventilation compared with continuous positive airway pressure in patients with chronic heart failure with coexisting obstructive sleep apnea and Cheyne-Stokes respiration. Circ Heart Fail 2010; 3: Hastings PC, Vazir A, Meadows GE, Dayer M, Poole-Wilson PA, McIntyre HF, et al. Adaptive servo-ventilation in heart failure patients with sleep apnea: A real world study. Int J Cardiol 2010; 139: Bitter T, Westerheide N, Faber L, Hering D, Prinz C, Langer C, et al. Adaptive servoventilation in diastolic heart failure and Cheyne-Stokes respiration. Eur Respir J 2009; 36: Kasai T, Narui K, Dohi T, Takaya H, Yanagisawa N, Dungan G, et al. First experience of using new adaptive servo-ventilation device for Cheyne-Stokes respiration with central sleep apnea among Japanese patients with congestive heart failure: Report of 4 clinical cases.

6 2158 YOSHIHISA A et al. Circ J 2006; 70: Yoshihisa A, Shimizu T, Owada T, Nakamura Y, Iwaya S, Yamauchi H, et al. Adaptive servo ventilation improves cardiac dysfunction and prognosis in chronic heart failure patients with Cheyne-Stokes respiration. Int Heart J 2011; 52: Cohn JN, Levine TB, Olivari MT, Garberg V, Lura D, Francis GS, et al. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med 1984; 311: Latini R, Masson S, Anand IS, Missov E, Carlson M, Vago T, et al. Prognostic value of very low plasma concentrations of troponin T in patients with stable chronic heart failure. Circulation 2007; 116: Tsutamoto T, Kawahara C, Nishiyama K, Yamaji M, Fujii M, Yamamoto T, et al. Prognostic role of highly sensitive cardiac troponin I in patients with systolic heart failure. Am Heart J 2010; 159: Anand IS, Latini R, Florea VG, Kuskowski MA, Rector T, Masson S, et al. C-reactive protein in heart failure: Prognostic value and the effect of valsartan. Circulation 2005; 112: Ishikawa C, Tsutamoto T, Fujii M, Sakai H, Tanaka T, Horie M. Prediction of mortality by high-sensitivity C-reactive protein and brain natriuretic peptide in patients with dilated cardiomyopathy. Circ J 2006; 70: Iber C, Ancoli-Israel S, Chesson A, Quan SF; for the American Academy of Sleep Medicine. The AASM manual for the scoring of sleep and associated events: Rules, terminology and technical specifications. 1st edn. Westchester, Illinois: American Academy of Sleep Medicine, American Sleep Disorders Association. EEG arousals: Scoring rules and examples: A preliminary report from the Sleep Disorders Atlas Task Force of the American Sleep Disorders Association. Sleep 1992; 15: Koyama T, Watanabe H, Kobukai Y, Makabe S, Munehisa Y, Iino K, et al. Beneficial effects of adaptive servo ventilation in patients with chronic heart failure. Circ J 2010; 74: Bradley TD, Holloway RM, McLaughlin PR, Ross BL, Walters J, Liu PP. Cardiac output response to continuous positive airway pressure in congestive heart failure. Am Rev Respir Dis 1992; 145: Haruki N, Takeuchi M, Kaku K, Yoshitani H, Kuwaki H, Tamura M, et al. Comparison of acute and chronic impact of adaptive servoventilation on left chamber geometry and function in patients with chronic heart failure. Eur J Heart Fail 2011; 13: Masip J, Roque M, Sanchez B, Fernandez R, Subirana M, Exposito JA. Noninvasive ventilation in acute cardiogenic pulmonary edema: Systematic review and meta-analysis. JAMA 2005; 294: Pepperell JC, Maskell NA, Jones DR, Langford-Wiley BA, Crosthwaite N, Stradling JR, et al. A randomized controlled trial of adaptive ventilation for Cheyne-Stokes breathing in heart failure. Am J Respir Crit Care Med 2003; 168: Takama N, Kurabayashi M. Effectiveness of adaptive servo-ventilation for treating heart failure regardless of the severity of sleep-disordered breathing. Circ J 2011; 75: Flannery G, Gehrig-Mills R, Billah B, Krum H. Analysis of randomized controlled trials on the effect of magnitude of heart rate reduction on clinical outcomes in patients with systolic chronic heart failure receiving beta-blockers. Am J Cardiol 2008; 101: McAlister FA, Wiebe N, Ezekowitz JA, Leung AA, Armstrong PW. Meta-analysis: Beta-blocker dose, heart rate reduction, and death in patients with heart failure. Ann Intern Med 2009; 150: Naughton MT, Benard DC, Liu PP, Rutherford R, Rankin F, Bradley TD. Effects of nasal CPAP on sympathetic activity in patients with heart failure and central sleep apnea. Am J Respir Crit Care Med 1995; 152: Harada D, Joho S, Oda Y, Hirai T, Asanoi H, Inoue H. Short term effect of adaptive servo-ventilation on muscle sympathetic nerve activity in patients with heart failure. Auton Neurosci 2011; 161: Bradley TD, Logan AG, Kimoff RJ, Series F, Morrison D, Ferguson K, et al. Continuous positive airway pressure for central sleep apnea and heart failure. N Engl J Med 2005; 353: Arzt M, Floras JS, Logan AG, Kimoff RJ, Series F, Morrison D, et al. Suppression of central sleep apnea by continuous positive airway pressure and transplant-free survival in heart failure: A post hoc analysis of the Canadian Continuous Positive Airway Pressure for Patients with Central Sleep Apnea and Heart Failure Trial (CANPAP). Circulation 2007; 115: Koyama T, Watanabe H, Igarashi G, Terada S, Makabe S, Ito H. Short-term prognosis of adaptive servo-ventilation therapy in patients with heart failure. Circ J 2011; 75: