Heart failure (HF) is a public health problem associated

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1 Circ J doi: /circj.CJ Advance Publication by-j-stage ORIGINAL ARTICLE Cardiovascular Surgery Impact of Recurrent Ventricular Tachyarrhythmia on Outcome in Japanese Heart Transplant Candidates With a Left Ventricular Assist Device Hidetoshi Hattori, MD; Atsushi Suzuki, MD; Tsuyoshi Shiga, MD; Tomohiro Nishinaka, MD; Satoshi Saito, MD; Kenji Yamazaki, MD; Shinichi Nunoda, MD; Nobuhisa Hagiwara, MD Background: Recurrent ventricular tachyarrhythmias (VTA) are A factor modifiers in the Interagency Registry for Mechanically Assisted Circulatory Support profile. The effect of recurrent VTA on clinical outcome, however, is controversial. We evaluated the impact of recurrent VTA on outcome in Japanese heart transplant candidates with a left ventricular assist device (LVAD). Methods and Results: Sixty-six adult patients with advanced heart failure who were listed for heart transplantation between January 2005 and October 2017 were enrolled in the study. Recurrent VTA (modifier A status) was defined as a sustained ventricular tachycardia or fibrillation that required implantable cardioverter defibrillator shocks or an external defibrillator more than twice weekly. The primary outcome was death from any cause. The secondary outcomes were the first occurrence of VTA and recurrent VTA after LVAD implantation. Sixteen patients (24%) met the criteria for modifier A status, and 15 patients had an LVAD implanted. During a median follow-up of 1,124 days, 21 of 60 patients with an LVAD died. There was a significantly higher mortality rate in LVAD patients with modifier A status than in those who did not meet the modifier A criteria. On multivariate analysis, patients with modifier A status had an increased risk of mortality (HR, 3.43; 95% CI: , P=0.001). Conclusions: Recurrent VTA might be a marker for worse outcome in Japanese heart transplant candidates with an LVAD. Key Words: Implantable cardioverter defibrillator; Left ventricular assist device; Mortality; Transplantation; Ventricular arrhythmia Heart failure (HF) is a public health problem associated with morbidity and mortality that affects more than 23 million patients worldwide. 1 Despite the advances and improvements in the medical treatment of HF, the prognosis for HF patients remains poor and many patients progress to advanced HF. 1,2 There is no effective treatment other than heart transplantation for severe HF despite improvements in optimal medical therapy and mechanical and surgical management. The number of organ donors, however, is extremely limited in Japan, and there is a very long waiting period (>1,000 days) for transplants. Additionally, ventricular assist devices (VAD) are required as a bridge to transplantation in approximately 90% of recipients. 3 In Japan, clinical trials for continuous flow-type left VAD (LVAD) have been carried out for the EVAHEART (Sun Medical Technology Research Corporation, Suwa, Nagano, Japan, 2005), DuraHeart (Terumo Heart, Ann Arbor, MI, USA, 2008), Jarvik 2000 (Jarvik Heart, New York, NY, USA, 2008), and HeartMate II (Thoratec, Pleasanton, CA, USA, 2010). The EVAHEART and DuraHeart were approved in 2011, HeartMate II in 2013, and Jarvik 2000 in Currently, the continuous flow-type LVAD is permitted for use as a bridge to transplantation for heart transplant candidates who are listed with the Japan Organ Transplant Network (JOT), who have received approval from the Heart Transplant Candidate Registry Committee of the Japanese Circulation Society or from 1 of 3 institutions with experience of >50 heart transplant procedures. Japanese patients with advanced HF associated with other comorbidities are treated with an extracorporeal pulsatile VAD. The Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile has been designed to stratify the need for mechanical circulatory support (MCS) by defining subsets within the New York Heart Association III and IV categories. 4 Recent guidelines recommend that all patients assessed for MCS should have their INTERMACS profile determined. 5,6 Complicated recurrent ventricular tachyarrhythmias (VTA) may lead to hemodynamic deterioration and worse outcome in patients with advanced HF. Therefore, recur- Received March 7, 2018; revised manuscript received May 12, 2018; accepted May 29, 2018; released online July 13, 2018 Time for primary review: 23 days Department of Cardiology (H.H., A.S., T.S., N.H.), Department of Cardiovascular Surgery (T.N., S.S., K.Y.), Tokyo Women s Medical University, Tokyo; Department of Therapeutic Strategy for Severe Heart Failure, Tokyo Women s Medical University Graduate School of Medical Science, Tokyo (S.N.), Japan Mailing address: Tsuyoshi Shiga, MD, Department of Cardiology, Tokyo Women s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo , Japan. shiga.tsuyoshi@twmu.ac.jp ISSN All rights are reserved to the Japanese Circulation Society. For permissions, please cj@j-circ.or.jp

2 Advance Publication by-j-stage HATTORI H et al. Table 1. Heart Transplantation Candidate Characteristics n=66 Age (years) 39±12 Female 18 Underlying heart disease Ischemic cardiomyopathy 2 Idiopathic dilated cardiomyopathy 50 End-stage hypertrophic cardiomyopathy 6 Restrictive cardiomyopathy 1 Arrhythmogenic RV cardiomyopathy 1 Secondary cardiomyopathy 4 Congenital heart disease 1 Others 1 LVEF (%) 21±10 History of atrial fibrillation 19 History of sustained VT/VF 23 Bilirubin (mg/dl) 1.4±1.1 Creatinine (mg/dl) 1.2±0.4 Sodium (meq/l) 137±4 ICD/CRT-D implantation 7/37 CRT-pacemaker implantation 1 Inotropes 57 IABP 20 Data given as mean ± SD or n. CRT, cardiac resynchronization therapy; CRT-D, CRT with a defibrillator; IABP, intra-aortic balloon pumping; ICD, implantable cardioverter defibrillator; LVEF, left ventricular ejection fraction; RV, right ventricular; VF, ventricular fibrillation; VT, ventricular tachycardia. rent VTA (more than twice weekly) are considered to be A factor modifiers of the INTERMACS profile. 4 The effect of pre-lvad recurrent VTA on clinical outcome, including mortality, however, is controversial. Modifier A status has been shown to be not predictive of mortality after VAD implantation, 7 whereas pre-lvad VTA have been shown to predict VTA after LVAD implantation, and VTA are associated with an increased risk of mortality in patients with an LVAD. 8 In Japanese patients with a long waiting period before transplantation, it is not clear whether pre-lvad recurrent VTA (modifier A status) increase the mortality risk in patients with VAD implanted as a bridge to transplantation. The aim of this study was therefore to evaluate the incidence of modifier A status and resultant outcome in Japanese heart transplant candidates, most of whom have an implanted LVAD. Methods Patients All patients aged 18 years with advanced HF who were listed for heart transplantation between January 2005 and October 2017 at Tokyo Women s Medical University Hospital were retrospectively included in this analysis. All patients were approved as transplant candidates after being assessed by both Tokyo Women s Medical University Hospital and the Heart Transplant Candidate Registry Committee of the Japanese Circulation Society. Patients were registered for heart transplant with the JOT and were eligible for receipt of an appropriate donor heart. 9 This study was approved by the Institutional Review Board of Tokyo Women s Medical University. VTA VTA were defined as sustained ventricular tachycardia (VT), ventricular fibrillation (VF), or VT/VF requiring appropriate implantable cardioverter defibrillator (ICD) shock. Modifier A status was defined as VT/VF requiring frequent ICD shocks or the use of an external defibrillator more than twice weekly. 4 Outcome and Follow-up The primary outcome was death from any cause. The secondary outcomes were the occurrence of sustained VTA, including VT/VF that required appropriate ICD shock from the time of VAD implantation to the first recurrence of a VTA; and recurrent VTA that occurred more than twice weekly after LVAD implantation. Patients were followed until death from any cause or until 31 October Information regarding deceased patients was obtained from medical records, family members, and the hospitals to which the patients had been admitted. No patients were lost to follow-up. ICD Programming and Data The occurrence of VTA requiring ICD shock was obtained by reviewing event details and electrocardiograms (ECG) stored on the ICD disks. Only episodes of VT/VF requiring ICD shock for termination were included in the analysis. ICD detection was programmed for 2 zones: the VF zone ( ms; number of intervals to detect, 18/24) and the VT zone ( ms; number of intervals to detect, 16). In 5 patients, the fast VT zone (via VF, 360 ms) was also programmed. VT therapy was set with anti-tachycardia pacing, burst and/or autodecremental ramp pacing. Therapy involved a first coupling interval of 75 86% of the tachycardia cycle length and up to 6 sequences with 8 stimuli, with cardioversion if pacing failed to terminate VT. At Tokyo Women s Medical University Hospital we continue to set ICD therapy after implantation of an LVAD. When a patient receives frequent shocks, we turn off the ICD shock option. If the ICD shock option is turned off, however, intracardiac ECG monitoring is continued with the VT/VF zone setting intact. Follow-up was performed every 3 6 months at the ICD clinic at Tokyo Women s Medical University Hospital, and additional checks were performed when patients were admitted to hospital or had any episodes of suspected arrhythmia. More recently, we have been able to continuously monitor ICD therapy using a home monitoring system. Statistical Analysis The data are presented as mean ± SD, median (range) or frequency. Subgroup analyses of LVAD patients according to recurrent VTA status were performed using Student s t-test and Mann-Whitney U-test. Categorical variables were analyzed using chi-squared test. The cumulative proportions of the event-free rates were calculated using the Kaplan-Meier method. Differences in the event-free rates were compared using the log-rank test. Univariate and multivariate analyses using the Cox proportional hazards model were performed to assess the relationships of clinical variables with mortality. The forward stepwise method was used for multivariate analysis with entry or removal based on P=0.05. Statistical analysis was performed with SPSS (version 11.01, SPSS, Chicago, IL, USA).

3 VTA and Japanese LVAD Patients Advance Publication by-j-stage Table 2. HT Candidate Characteristics vs. Modifier A Status at LVAD Implantation Modifier A ( ) (n=45) Modifier A (+) (n=15) P-value Age 39±12 42± Female gender INTERMACS profile LVAD type 0.68 Continuous flow Pulsatile 6 3 LVEF (%) 21±7 22± Prior atrial fibrillation Prior sustained VT/VF 7 15 <0.01 SBP (mmhg) 88±11 88± Heart rate (beats/min) 83±16 77± Bilirubin (mg/dl) 1.1± ± Creatinine (mg/dl) 1.3± ± Sodium (meq/l) 136±4 135± ICD/CRT-D implantation ACEI/ARB β-blockers Amiodarone Inotropes use IABP use Data given as mean ± SD or n. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; BMI, body mass index; HT, heart transplant; INTERMACS, Interagency Registry for Mechanically Assisted Circulatory Support; LVAD, left ventricular assist device; SBP, systolic blood pressure. Other abbreviations as in Table 1. Results Patients This study involved a total of 66 consecutive patients listed for heart transplantation between 2005 and The subject baseline clinical characteristics are listed in Table 1. Of these, 60 patients had implanted LVAD: 51 patients were implanted with the continuous flow-type LVAD as follows: EVAHEART, n=42; DuraHeart, n=1; Jarvik 2000, n=3; and HeartMate II, n=5; and the remaining 9 patients had the extracorporeal pulsatile Nipro-LVAD (Nipro, Osaka, Japan). Incidence and Risk of Modifier A Status Of the present heart transplant candidates, 16 patients (24%) met the criteria for modifier A status. Of these, 15 patients had an LVAD. Of the 50 patients who did not meet the criteria for modifier A status, 45 patients had an LVAD. The prevalence of history of VT/VF, and presence of ICD implantation was higher in patients with modifier A status than in those who did not meet the criteria for modifier A status. There were no significant differences, however, in other parameters related to clinical background (Table 2). VTA and Prognosis in Patients With LVAD Of the 60 patients with an LVAD, 15 patients with an implanted LVAD had modifier A status. During a median follow-up of 1,124 days (range, 14 4,499 days), 26 patients had VTA, including appropriate ICD shock, and 21 patients Figure 1. Cumulative event-free rate of death from any cause after left ventricular assist device (LVAD) implantation vs. modifier A status.

4 Advance Publication by-j-stage HATTORI H et al. Table 3. Cause of Death in Japanese HT Candidates With LVAD Modifier A ( ) Modifier A (+) (n=45) (n=15) P-value Infection Neurologic event Multiorgan failure Other 2 0 NA Data given as n. NA, not available. Other abbreviations as in Table 2. Figure 2. Cumulative event-free rate for (A) first recurrence of ventricular tachyarrhythmia (VTA) and (B) recurrent VTA after left ventricular assist device (LVAD) implantation vs. modifier A status. died after LVAD implantation. Kaplan-Meier curves for death from any cause are given in Figure 1. There was a significantly higher mortality rate in LVAD patients with modifier A status after implantation compared with those patients without this status. Causes of death are listed in Table 3. The incidence rates of sepsis, stroke and multisystem organ failure were high regardless of modifier A status. On Kaplan-Meier curves for death from any cause after LVAD implantation, patients with a continuous flow-type LVAD and modifier A status had a tendency toward a higher mortality rate than those without this status (Figure S1). On Kaplan-Meier curve analysis for first occurrence of VTA or recurrent VTA after LVAD implantation, There was a significantly higher rate of subsequent VTA in LVAD patients with modifier A status than in those patients without this status (Figure 2A), and there was also a significantly higher rate of recurrent VTA in LVAD patients with modifier A status compared with those without this status (Figure 2B). On multivariate analysis, modifier A status was associated with an increased risk of mortality (HR, 3.43; 95% CI: , P=0.001) independent of pulsatile LVAD (Table 4). Discussion In the present study the rate of modifier A status was 24% in Japanese heart transplant candidates, most of whom had an implanted LVAD. Although modifier A status is an indication for VAD implantation, there was a significantly higher incidence of death from any cause in the present LVAD patients with modifier A status than in those who did not meet the criteria for this status. Modifier A status was an independent factor for worse clinical outcome in LVAD patients. Modifier A Status and LVAD Implantation There have been few reports on the prevalence of the development of recurrent VTA (modifier A status) in heart transplant candidates. In a recent US report, 2,963 (27%) of 10,802 patients who were entered in the INTERMACS registry and underwent implantation of continuous flowtype LVAD between 2009 and 2014, had a modifier A status. 7 In the present study, 15 (25%) of 60 LVAD patients met the criteria for modifier A status. The prevalence of modifier A status immediately before LVAD implantation was similar to the US data. VTA After LVAD Implantation VTA are reported to occur in 22 59% of patients with an

5 VTA and Japanese LVAD Patients Advance Publication by-j-stage Table 4. Indicators of the Primary Outcome in HT Candidates With LVAD Univariate analysis Multivariate analysis HR (95% CI) P-value HR (95% CI) P-value Age (per year) 1.01 ( ) 0.54 Female 2.51 ( ) 0.06 Modifier A status 2.95 ( ) ( ) 0.01 Prior sustained VT/VF 1.92 ( ) 0.14 Prior atrial fibrillation 1.64 ( ) 0.31 INTERMACS I/II 1.99 ( ) 0.12 Pulsatile LVAD 4.29 ( ) < ( ) <0.01 LVEF (1% decrease) 1.03 ( ) 0.41 SBP (1-mmHg decrease) 1.01 ( ) 0.54 Heart rate (1-beat/min increase) 1.00 ( ) 0.58 Bilirubin (0.1-mg/dL increase) 1.03 ( ) 0.24 Creatinine (0.1-mg/dL increase) 1.04 ( ) 0.45 Sodium (1-mg/dL decrease) 0.98 ( ) 0.70 ACEI/ARB 0.91 ( ) 0.85 β-blockers 0.91 ( ) 0.85 Amiodarone 0.95 ( ) 0.93 Inotropes 1.12 ( ) 0.88 IABP 1.88 ( ) 0.15 Death from any cause. Abbreviations as in Tables 1,2. implanted continuous flow-type LVAD. 10 In a previous study, 28% of patients were asymptomatic, but the other patients had signs and symptoms such as palpitation, dyspnea syncope, hypotension or decreased LVAD flow. 11 In the present LVAD patients without ICD, VTA were indicated by complicated symptoms such as palpitation and pre-syncope, and were also detected on ECG during hospitalization. In the present study, the incidence of VTA after LVAD implantation, including appropriate ICD shock, was higher in LVAD patients with preoperative modifier A status than in those patients without this status. Moreover, LVAD patients with modifier A status had more frequent recurrent VTA than those without this status. LVAD patients with recurrent VTA might have an arrhythmogenic substrate, automaticity and triggered activity caused by a repolarization abnormality, leading to the development of VTA even after LVAD implantation. 10 Pre-LVAD VTA is a predictor of VTA after implantation of LVAD. 8,12 14 VTA and Prognosis in LVAD Patients It is unclear whether VTA contribute to poor prognosis in LVAD patients. Bedi et al reported a significantly higher mortality rate in patients with VTA compared with those without such arrhythmias. Furthermore, patients who had VTA in the first week after LVAD placement had a 5-fold higher mortality rate compared with patients with late presentation of VTA. 14 In a meta-analysis, ICD use was associated with a significant reduction in mortality in LVAD patients, but this effect was not significant in patients with continuous flow-type LVAD. 15 On United Network for Organ Sharing data, there was no difference in survival during device support according to ICD status in patients with an implanted LVAD serving as a bridge to transplantation. 16 VTA were terminated in a short time by ICD shock in LVAD patients with ICD. Although in some cases the VTA were not terminated, hemodynamic status did not immediately deteriorate because an LVAD can maintain hemodynamic support, even without native LV contractility. Prolonged sustained VTA, however, can cause right ventricular (RV) failure leading to inadequate LVAD flow and worse clinical outcome. Furthermore, appropriate ICD shock occurring 30 days after LVAD implantation was associated with increased RV failure. 17 RV failure in LVAD patients was generally defined as unplanned insertion of a right VAD or the use of i.v. inotrope for >14 days postoperatively In the present study, there was no difference in the rate of patients who met the RV failure criteria between LVAD patients with or without modifier A status (6/15 vs. 16/45, P=0.76). We therefore could not determine that the presence of residual right HF after LVAD implantation significantly contributed to a higher frequency of VTA and subsequent poor prognosis in patients with modifier A status. For VAD patients, the most frequent causes of death are generally infection and neurological complications from the LVAD. Development of VTA may directly or indirectly negatively affect their quality of life, physical activity and adherence, leading to worsening of their physical and psychological conditions and increase the likelihood of rehospitalization. In a substudy of the Sudden Cardiac Death in Heart Failure Trial, in HF patients who received an ICD for primary prevention, the occurrence of an appropriate ICD shock was associated with a markedly increased risk of death. 21 Although the cause of this association was uncertain, patients who received ICD shocks had a substantially higher risk of death. In the present study, 13 of 26 patients with VTA after LVAD implantation died, but the median time from the initial VTA event to death was 376 days. Therefore, VTA may be markers of clinical deterioration or of risk for all-cause mortality rather than the cause of death in patients with an implanted LVAD. A reassessment of the therapeutic options that

6 Advance Publication by-j-stage HATTORI H et al. might modify the prognosis is necessary. In the Japanese population, the duration of use of an LVAD as a bridge to transplantation is similar to that in other countries for LVAD as destination therapy. 22 Although the background of Japanese LVAD patients is different to that of patients who receive an LVAD as destination therapy, pre-lvad recurrent VTA may affect prognosis. To confirm this issue, further investigation is required. Study Limitations There were some limitations in this study. First, this was a retrospective observational study in a single center, and there was a treatment bias. Second, this was a retrospective study, and we obtained information about ventricular arrhythmias only from medical charts. As a result, the true incidence of post-lvad VTA was likely underestimated, and the clinical presentation of VTA episodes is incomplete. Third, ICD detection programmed for the VF zone and VT zone and ICD therapy settings were not identical in all patients. VTA with a rate below the programmed VF/VT zones might have gone unrecognized. Fourth, the number of subjects was small, as was the number of outcomes. Therefore, this study had limited power to detect small differences, and subgroup analysis was not feasible. Additionally, we could not exclude the possibility that the difference in LVAD caused differences in the development of arrhythmias. Conclusions The prevalence of recurrent VTA (modifier A status) was 24% in Japanese heart transplant candidates. Modifier A status was associated with an increased risk of VTA and mortality after LVAD implantation. Pre-LVAD recurrent VTA might be a marker of worse outcome in Japanese heart transplant candidates with an implanted LVAD. Disclosures This study was not funded. K.Y. is a consultant of the Sun Medical Technology Research Corporation. 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The right ventricular failure risk score a pre-operative tool for assessing the risk of right ventricular failure in left ventricular assist device candidates. J Am Coll Cardiol 2008; 51: Kormos RL, Teuteberg JJ, Pagani FD, Russell SD, John R, Miller LW, et al; HeartMate II Clinical Investigators. Right ventricular failure in patients with the HeartMate II continuous-flow left ventricular assist device: Incidence, risk factors, and effect on outcomes. J Thorac Cardiovasc Surg 2010; 139: Poole JE, Johnson GW, Hellkamp AS, Anderson J, Callans DJ, Raitt MH, et al. Prognostic importance of defibrillator shocks in patients with heart failure. N Engl J Med 2008; 359: Nakatani T, Sase K, Oshiyama H, Akiyama M, Horie M, Nawata K, et al; J-MACS investigators. Japanese registry for Mechanically Assisted Circulatory Support: First report. J Heart Lung Transplant 2017; 36: Supplementary Files Supplementary File 1 Figure S1. Cumulative event-free rate of death from any cause after continuous flow-type left ventricular assist device (LVAD) implantation vs. modifier A status. Please find supplementary file(s);