Valve Repair Improves Central Sleep Apnea in Heart Failure Patients With Valvular Heart Diseases

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1 ORIGINAL ARTICLE Valvular Heart Disease Circ J 2009; 73: Valve Repair Improves Central Sleep Apnea in Heart Failure Patients With Valvular Heart Diseases Hidetoshi Abe, MD*, **, ; Masafumi Takahashi, MD*, ; Hironobu Yaegashi, MD**; Seiichiro Eda, MD**; Hiroto Kitahara, MD ; Hideo Tsunemoto, MD ; Mamoru Kamikozawa, MD ; Jun Koyama, MD*; Kyohei Yamazaki, MD ; Uichi Ikeda, MD* Background: Recent studies suggest that treatment of heart failure (HF) could improve cardiac function and sleep apnea syndrome (SAS), but it is unknown how cardiac surgery may affect SAS in HF patients. Relationships between HF with valvular heart diseases and 2 types of SAS (obstructive sleep apnea (OSA) and central sleep apnea (CSA)) were examined. The effects of valve repair surgery on OSA and CSA was also investigated. Methods and Results: Polysomnography, echocardiography and right cardiac catheterization were used to study 0 severe HF patients with mitral valvular and/or aortic valvular diseases. Significant associations between SAS and age, gender, body mass index, or hypertension were observed. The value of the CSA-apnea index (AI) was significantly correlated with pulmonary capillary wedge pressure (PCWP) and mean pulmonary artery pressure (PAP). These associations were not identified for. Valve repair surgery was used to treat 74 patients with severe SAS. The treatment led to a significant improvement in PCWP and mean PAP, and, but not in. Conclusions: These findings suggest close associations between CSA and cardiac function in HF patients with valvular heart diseases. Furthermore, improvement of cardiac function with valvular surgery reduces the severity of CSA in HF patients with valvular heart diseases. (Circ J 2009; 73: ) Key Words: Cardiac function; Heart failure; Sleep apnea; Valvular diseases Sleep apnea syndrome (SAS) is characterized by repetitive episodes of decreased or total cessation of respiratory airflow during sleep and occurs in approximately % of the population. 1,2 SAS can be categorized as obstructive sleep apnea (OSA) or central sleep apnea (CSA). 3 OSA is characterized by episodes of upper airway obstruction during sleep. In contrast, CSA is characterized by recurrent episodes of apnea in the absence of upper airway obstructions during sleep. OSA is widely acknowledged to correlate with high rates of morbidity and mortality, predominantly as a result of cardiovascular disorders and traffic accidents. However, the role of CSA in patients with cardiovascular disease is not fully understood. Editorial p 2019 Recent epidemiologic studies have demonstrated that CSA with Cheyne-Stokes respiration affects approximately 2 40% of patients with chronic heart failure (HF). 4, CSA may expose the failing heart to hypoxia, and causes arousal from sleep, sympathetic nervous system activation and ventricular arrhythmias. 4 Some evidence indicates that sleep apnea can contribute to the development of HF, 4,6 and that treatments for HF (eg, cardiac resynchronization therapy (CRT)) could improve both cardiac function and SAS in HF However, there is currently no information available on the effects of cardiac surgery on SAS in HF patients. In this study, we examined the relationships between HF with valvular heart diseases and OSA and CSA. We further investigated the effects of valve repair surgery on OSA and CSA in patients with severe valvular diseases and HF. Methods Study Design and Patient Selection A schematic representation of the study is provided in Figure 1. Data were collected from 0 patients with HF (New York Heart Association (NYHA) class II or III) and with severe mitral valvular (MV) and/or aortic valvular (AV) heart diseases. Patients were recruited on the basis of diagnoses by echocardiography and cardiac catheterization between July 200 and March 2008 at Matsumoto Kyoritsu Hospital. Each patient was diagnosed and underwent optimal therapy prior to the study, and was on at least 2 weeks of stable medication, as confirmed by a cardiologist. Exclusion criteria included the inability to undergo polysomnography (PSG) as a result of severe HF (NYHA class IV), and a diagnosis of acute coronary syndrome within the prior 2 weeks. Written informed consent was obtained from each patient prior to participation. This study was approved Received May 7, 2009; revised manuscript received June 28, 2009; accepted July 1, 2009; released online August 28, 2009 *Department of Cardiovascular Medicine, Shinshu University Graduate School of Medicine, **Sleep Center and Cardiovascular Center, Matsumoto Kyoritsu Hospital, Matsumoto, Japan Present address: Division of Bioimaging Sciences, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan. Mailing address: Masafumi Takahashi, MD, Department of Cardiovascular Medicine, Shinshu University Graduate School of Medicine, Asahi, Matsumoto , Japan. masafumi2@jichi.ac.jp All rights are reserved to the Japanese Circulation Society. For permissions, please cj@j-circ.or.jp

2 Valve Repair Improves CSA valve disease subjects underwent PSG from December 200 to March SAS ( AHI 20 ) 47 M-NSA ( AHI < 20 ) 11 did not undergo surgery 92 underwent valve surgery 74 underwent final assessment 18 could not undergo final assessment Figure 1. Study profile: 0 patients with heart failure (HF) (New York Heart Association class II and III) and with mitral valvular and/or aortic valvular heart diseases were enrolled. Based on the polysomnography data, the patients were divided into 2 groups: sleep apnea syndrome (SAS) (n= 103, apnea-hypopnea index (AHI) 20) and mildto-no sleep apnea (M-NSA) (n=47, AHI <20). Among 103 HF patients with SAS, 92 patients underwent valve repair surgery and 74 patients were reassessed. Table 1. Heart Valve Disease None AR AS ASR Total None MR MS MSR Total AR, aortic valve regurgitation; AS, aortic valve stenosis; ASR, aortic valve stenosis with regurgitation; MR, mitral valve regurgitation; MS, mitral valve stenosis; MSR, mitral stenosis with regurgitation. by the Institutional Review Board of the Matsumoto Kyoritsu Hospital. PSG analyses were used to divide patients into 2 groups: SAS (n=103, apnea-hypopnea index (AHI) 20 /h of sleep) and mild-to-no sleep apnea (M-NSA) (n=47, AHI <20 /h of sleep). The AHI cutoff of 20 /h was chosen to conform to that used in previous studies in which mortality risk was associated with OSA, 12 and to abide by the guidelines of Japanese Respiratory Society to treat severe OSA patients with CPAP therapy. Among 103 HF patients with SAS, 92 patients received valve repair surgery and 74 patients were reassessed (Figure 1). To select patients receiving surgery, the criteria published by ACC/AHA 13,14 was used. Patient Assessments Body mass index (BMI) was calculated as the weight (kg) divided by the square of the height (m). Hypertension was defined as elevation of blood pressure levels ( 140/ 90 mmhg) or antihypertensive treatment at the time of participation in the study. Diabetes mellitus was defined as elevation in fasting blood glucose levels ( 126 mg/dl) or pharmacological treatments. Hyperlipidemia was defined as elevation in fasting levels of serum cholesterol ( 220 mg/dl) and triglycerides ( 0 mg/dl), and decrease in HDLcholesterol (<40 mg/dl). Echocardiography (ie33, Philips) was performed to assess left ventricular ejection fraction (LVEF), left ventricular diameter in the diastolic phase (LVDd) and tricuspid regurgitation. Right cardiac catheterization (via the transbrachial approach) was carried out Table 2. Patient Characteristics M-NSA group SAS group (AHI <20) (AHI 20) P value n Age (years) 66.0± ± Male 26 (0.9%) 69 (71.1%) 0.0 BMI (kg/m 2 ) 22.0± ± Smoking 8 (17.0%) 19 (18.4%) NS Hypertension (31.9%) 46 (44.7%) Diabetes mellitus (10.6%) 9 (8.7%) NS Hyperlipidemia 6 (12.8%) 14 (13.6%) NS OMI 2 (4.2%) 10 (9.7%) NS Revascularization 4 (8.%) 8 (7.8%) NS AF at hospitalization (10.6%) (14.6%) NS Pacemaker implantation 0 2 (1.9%) NS ICD implantation 0 1 (1.0%) NS CRT 0 1 (1.0%) NS Stroke 1 (2.1%) 1 (1.0%) NS COPD 2 (4.2%) 4 (3.9%) NS TR (>2nd degree) 11 (23.4%) 29 (28.2%) NS NYHA Class II 33 (70.2%) 69 (67.0%) NS Class III 14 (29.8%) 34 (33.0%) NS AHI 11.2± ±.1 <0.001 Apnea 2.1± ±17.6 < ±0. 7.3±11.2 < ± ±10.9 <0.001 Hypopnea 9.1± ±13.0 <0.001 Lowest SaPO2 88.1± ±.4 <0.001 Ratio of >SaPO2 0.89± ±29. <0.001 Arousal index 2.± ±17.3 < % ODI 14.8± ±14.8 <0.001 Total sleep time (min) 329.0± ±82.2 NS Ratio of sleep stage 3&4 10.9±9. 10.±8. NS Ratio of REM sleep 17.0±7..0±6.7 NS Values are n or mean ± SD. Patients with NYHA I and IV were excluded. M-NSA, mild-to-no sleep apnea; AHI, apnea hypopnea index; SAS, sleep apnea syndrome; BMI, body mass index; OMI, old myocardial infarction; AF, atrial fibrillation; ICD, implantable cardioverter defibrillator; CRT, cardiac resynchronization therapy; COPD, chronic obstructive pulmonary disease; TR, tricuspid regurgitation; NYHA, New York Heart Association;, apnea index of central sleep apnea;, apnea index of obstructive sleep apnea; SaPO2, oxygen saturation of pulse oximeter; ODI, oxygen desaturation index; REM, rapid eye movement.

3 20 ABE H et al. A 4 2 r = p = r = p = LVDd (mm) LVEF (%) 4 r = p < r = p = PCWP (mmhg) mean PAP (mmhg) B LVDd (mm) LVEF (%) PCWP (mmhg) mean PAP (mmhg) Figure 2. Relationships between cardiac parameters and sleep apnea syndrome (SAS), central sleep apnea-apnea index () and obstructive sleep apnea-apnea index (). (A,B) Relationships between left ventricular diameter in the diastolic phase (LVDd), left ventricular ejection fraction (LVEF), pulmonary capillary wedge pressure (PCWP) or mean pulmonary artery pressure (PAP) and (A) or (B) were analyzed. Significant relationships between the and PCWP or mean PAP was observed. Similar relationships were not identified for the. to assess pulmonary capillary wedge pressure (PCWP) and mean pulmonary artery pressure (PAP). For reassessment, PSG, echocardiography and right cardiac catheterization were carried out at 14.6±6. days, 11.0±6.6 days and.8± 4.2 days, respectively, after the surgery. Sleep Study and PSG Scoring PSG recordings were obtained from each participant between h and h, and were scored by PSG technologists at our sleep center laboratory. A SleepWatcher polysomnograph (Compmedics Ltd, Australia) including electroencephalogram was used for all recordings. Apnea was defined as the absence of airflow >10 s, and hypopnea was defined as a discernible, 0% decrease in the amplitude of a valid measure of breathing 10 s. AHI was calculated as the number of episodes of apnea and hypopnea per hour during

4 Valve Repair Improves CSA Table 3. Characteristics of SAS Group Patients With Heart Valve Surgery N 74 Mean age (years) 69.2±8.3 Male (%) (74.3%) Bodyweight (kg) (pre-surgery) 61.8±12.0 BMI (kg/m 2 ) (pre-surgery) 24.2±3.7 Mitral valve only 20 Valvuloplasty Replacement With coronary artery bypass grafting Aortic valve only 41 Replacement 41 With coronary artery bypass grafting Mitral and aortic valve 13 Double valve replacement 9 Aortic valve replacement and mitral valvuloplasty 4 With coronary artery bypass grafting 2 Medications Digitalis 13 Diuretic drugs 38 Statin 8 ACE-inhibitor 21 ARB β-blocker 19 Calcium antagonists 23 Amiodarone 4 Values are n or mean ± SD. ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blocker. Other abbreviations see in Table 2. Table 4. Effects of Valve Surgery on Polysomnography Parameters Before surgery After surgery P value AHI 40.3± ± Apnea 2.9± ±19.8 < ± ±2.9 < ± ±12.1 NS Hypopnea 14.3±9.2.0±8.7 NS Lowest SaPO2 (%) 84.3± ±6.9 NS Ratio of >SaPO2 90%.7± ±7.1 NS Arousal index 39.2± ± % ODI 32.7± ±63.4 NS Total sleep time (min) 349.2± ± Ratio of sleep stage 3&4 10.8± ±9.9 NS Ratio of REM sleep.0± ±8.1 NS PCWP (mmhg) 14.8± ±.3 <0.001 Mean PAP (mmhg) 21.4±8.4.8±.2 <0.001 NYHA class I 23 II 4 41 III IV 0 Values are n (%) or mean ± SD. PCWP, pulmonary capillary wedge pressure; PAP, pulmonary artery pressure. Other abbreviations see in Table 2. sleep. The absence of airflow in the upper airway with and without ribcage and/or abdominal movement was defined as obstructive and central apnea, respectively. CSA-apnea index (AI) and were computed as the number of central and obstructive apnea events, respectively, per hour of sleep. A B before surgery before surgery after surgery after surgery 21 p < Figure 3. Effects of valve repair surgery on the central sleep apneaapnea index () and obstructive sleep apnea-apnea index (). (A) and (B) before and after valve repair surgery was shown. Valve repair surgery significantly reduced CSA- AI, but not. Statistical Analysis Data are presented as the mean ± SD. Pre- and post-surgery measurements were compared via paired t-tests. Unpaired t-tests and Mann-Whitney tests were used to evaluate differences for independent groups on continuous variables. Categorical variables were assessed using chi-squared tests. All analyses were performed using StatView software (Abacus Concepts, Inc, Berkley, CA, USA). P<0.0 was considered to be statistically significant. Results Patient Characteristics We enrolled 0 patients (68.7±9.7 years, 92 men) with HF (NYHA class II and III), including MV and/or AV heart diseases (6 MV, 78 AV, 16 MV+AV, Table 1). Table 2 summarizes the patient characteristics and PSG parameters. There were statistically significant associations between SAS and age (69.±8.8 years vs 66.0±11.4 years, P=0.024), gender (male, 71.1% vs 0.9%, P=0.0) and BMI (23.7± 3.9 vs 22.0±3.0, P=0.017). The number of patients with hypertension was significantly greater in the SAS group than in the M-NSA group (44.7% vs 31.9%, respectively, P=0.042). The number of CSA and OSA patients was 32 and, respectively. In addition, the numbers of both CSA- AI and were significantly higher in the SAS group compared with that in the M-NSA group (, 7.3 vs 0., P<0.001;, 11.1 vs 1.7, P<0.001). SAS and Cardiac Function Figure 2 displays the relationships between SAS and cardiac function as determined by echocardiography and right cardiac catheterization. The SAS group was significantly associated with the LVDd (0.6±9.4 vs 47.6±8.4, P=0.048) (Figure 2). However, there was no significant

5 22 ABE H et al. association with LVEF (P=0.191), PCWP (P=0.146) and mean PAP (P=0.081) between the SAS and M-NSA groups (Figures 2C,D). Because the SAS group contained both CSA and OSA patients, we next evaluated the correlations amongn LVDd, LVEF, PCWP or mean PAP and or. We found that there were significant relationships between and PCWP (r=0.632, P<0.001) or mean PAP (r=0.423, P=0.006). Similar relationships were not identified for. Effects of Valve Repair Surgery Valve repair surgery was performed in 74 patients with HF whose characteristics are described in Table 3. Mitral valve, aortic, and both mitral and aortic surgery was performed in 20, 41 and 13 patients, respectively. Table 4 displays the effects of valve repair surgery on right cardiac pressure and PSG parameters. As hypothesized, the surgery significantly improved PCWP (14.8±7.9 vs 9.7±.3 mmhg, P<0.001) and PAP (21.4±8.4 vs.8±.2 mmhg, P<0.001). Interestingly, it also significantly reduced the AHI (40.3±14.4 vs 31.9±21.1, P=0.002) and (9.0±12.0 vs 1.0±2.9, P<0.001), but not the (11.0±9.2 vs 11.9±12.1, P=0.712) (Figure 3). Discussion We report significant associations between SAS and age, gender, BMI and hypertension in HF patients with valvular disease. The, but not the, significantly correlated in these patients with the parameters of cardiac function, such as LVDd, EF, PCWP and mean PAP. Moreover, valve repair surgery considerably improved not only the parameters of cardiac function, but also the. These results suggest that improvement of cardiac function with surgery may reduce the severity of CSA in HF patients with severe MV and/or AV diseases. Central apnea is characterized by apneic events during sleep with no associated ventilatory effort. 4, Periodic breathing, or nonhypercapnic CSA, is triggered by oscillations in respiratory drive induced by hyperventilation during nonrapid eye movement sleep when respiratory control is under a chemically controlled, negative-feedback loop. The most common form of CSA is manifest in patients with congestive CHF, and is termed Cheyne-Stokes respiration. Several reports have described the correlation between HF and CSA, and have suggested that CSA exacerbates HF and predicts mortality in systolic HF. 16 However, it has not been determined whether CSA is epiphenomenal in the context of HF or whether it directly increases HF risk. 4,17,18 In the present study, we found that CSA correlated with parameters of cardiac function in HF patients with valvular diseases. In addition, multivariate analysis showed that was associated with LVEF (P<0.0001) and PCWP (P=0.001). Consistent with our findings, Solin et al 19 reported that PCWP and PAP were elevated in HF patients with CSA compared to those with OSA or without apnea, and that a significant correlation exists between PCWP and central apnea frequency and severity in HF patients with CSA. Therefore, we hypothesized that improvements in cardiac function would lead to improvements in CSA and this was confirmed by the present study. The standard treatment for CSA includes nocturnal oxygen therapy, 20,21 yet several investigations have indicated that CSA can be alleviated via treatment of the underlying disease. In particular, recent studies have shown that treatment of HF could specifically improve CSA. For instance, Sinha et al 8 reported that CRT leads to a reduction of CSA and to increased sleep quality in patients with HF and SAS. Kara et al 11 also reported that CRT reduced the severity of CSA in the short term, and that this reduction correlated significantly with the CRT-mediated reduction of mitral regurgitation. Furthermore, Tamura et al 22,23 demonstrated that treatment with β-blocker reduced the severity of CSA in patients with chronic HF. Although there are no reports describing a relationship between CSA and valvular heart diseases, 2 case reports suggest that CSA is improved by mitral valve replacement or valvuloplasty. 24,2 In the present study, we found that surgical correction in a subset of patients with valvular diseases resulted in a remarkable reduction in CSA, but not OSA. Differences between stenosis and regurgitation do not pose difficulties for the present findings. There were no differences related to valvular disease for the severity of SAS, right cardiac pressure or the level of improvement of CSA during the investigation period. Therefore, it is reasonable to assume that the improvements in CSA as a result of CHF treatment can occur regardless of the surgical method used. Study Limitations First, although PSG is regarded as the gold standard in diagnosing SAS, we performed a single-night PSG. Second, long-term outcomes (eg, quality of life, mortality) for our surgical patients could not be determined because of the relatively brief follow-up period. Third, because this study included all types of MV and AV diseases and some types of surgical procedures, we should be cautious about the interpretation of this study. Finally, HF and valvular disease are not the sole causes of CSA, but the exact mechanisms responsible are not clearly defined by the present study. In conclusion, our findings suggest close associations between CSA, but not OSA, and cardiac function in HF patients with MV and/or AV diseases. Furthermore, improvement of cardiac function with valve repair surgery reduces the severity of CSA in HF patients with MV and/or AV diseases. Acknowledgments We thank Junko Nakayama, Yuka Ichihara and Kazuko Misawa for their excellent technical assistance. This study was supported by research grants from the Ministry of Health, Labor and Welfare in Japan (to U. I.). Disclosures Conflict of interest: None declared. Funding: Research grants from the Ministry of Health, Labor and Welfare in Japan. References 1. Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med 1993; 328: Parish JM, Somers VK. Obstructive sleep apnea and cardiovascular disease. Mayo Clin Proc 2004; 79: White DP. Pathogenesis of obstructive and central sleep apnea. Am J Respir Crit Care Med 200; 172: Bradley TD, Floras JS. Sleep apnea and heart failure: Part II: Central sleep apnea. 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