Bridge to recovery with Berlin Heart EXCOR in children <10 kg with dilated cardiomyopathy: a histological analysis

Bridge to recovery with Berlin Heart EXCOR in children <10 kg with dilated cardiomyopathy: a... Abstract Open in new tabDownload slide Open in new tabDownload slide OBJECTIVES This study aimed to identify the histological characteristics associated with bridge to recovery using Berlin Heart EXCOR® (BHE) in paediatric patients <10 kg with dilated cardiomyopathy. METHODS Of the 10 consecutive patients <10 kg with dilated cardiomyopathy who underwent BHE implantation between 2013 and 2018, 4 patients showed improvement in left ventricular (LV) function, resulting in successful BHE explantation (recovery group). The remaining 6 patients showed persistent LV dysfunction and underwent heart transplantation (non-recovery group). The following variables were compared between the 2 groups: (i) histological findings in LV myocardium obtained at BHE implantation and (ii) LV function after BHE implantation assessed with echocardiography and cardiac catheterization. RESULTS The degree of myocardial fibrosis was significantly lower, and the capillary vascular density was significantly higher in the recovery group than in the non-recovery group [16% (standard deviation 5.9%) vs 28% (5.9%), P = 0.021, and 65 (11) vs 43 (18) units/high-power field, P = 0.037, respectively]. The changes during 3 months after BHE implantation in LV diastolic dimension (z-score) and ejection fraction were significantly greater in the recovery group than in the non-recovery group [−9.6 (3.5) vs −3.6 (4.5), P = 0.045, and 36% (13%) vs 13% (13%), P = 0.032, respectively]. CONCLUSIONS In paediatric patients <10 kg with dilated cardiomyopathy, bridge to recovery with BHE implantation was achieved in patients with less injured LV myocardial histology at BHE implantation. Berlin Heart EXCOR, Bridge to recovery, Explantation, Myocardial fibrosis, Capillary vascular density, Dilated cardiomyopathy INTRODUCTION Dilated cardiomyopathy (DCM) is the most common cause of heart failure (HF) in paediatric patients [1]. Paediatric DCM often leads to an aggressive clinical course with 1-year mortality or heart transplantation rate of 18–26% [2–4]. Berlin Heart EXCOR® (BHE; Berlin Heart, Berlin, Germany) is the only paediatric-specific ventricular assist device (VAD) currently available and has become an established treatment for bridge to transplantation in paediatric DCM [5, 6]. Whereas BHE achieves significantly improved survival, the management of paediatric patients <10 kg with DCM remains challenging because of the high incidence of morbidity including stroke, bleeding and infection [6–10]. The current mean waiting period for paediatric heart transplantation exceeds 670 days in Japan because of the severe shortage of organ donors for paediatric patients [11]. Therefore, minimizing morbidities associated with BHE support is becoming increasingly important. Considering these circumstances, we have routinely assessed the possible myocardial recovery at 3 months after BHE implantation in paediatric patients with DCM. Accumulating evidence suggests that mechanical unloading with VAD facilitates the recovery of myocardial function of the failing ventricle, which allows the VAD explantation in selected patients [5–8]. In adult patients with DCM, the left ventricular (LV) myocardial histology is reported to predict the recovery of myocardial function after mechanical unloading with VAD support [12, 13]. However, the predictive factors for myocardial recovery with BHE in paediatric patients with DCM are unclear since only limited data are available [5–8, 14]. Herein, the aim of the present study was to review our initial experience of bridge to recovery using BHE in paediatric patients <10 kg with DCM and identify the histological characteristics associated with this phenomenon. MATERIALS AND METHODS Patients This study was approved by the Institutional Review Board of Osaka University Hospital (approval number 16105), and written informed consent for the use of patient records was obtained from the legal guardian of each patient. Between January 2013 and December 2018, BHE was implanted in 12 paediatric patients <10 kg with DCM in our institution. Two patients were excluded because of associated mitochondrial disease (n = 1) and insufficient follow-up examination (n = 1). Finally, 10 consecutive patients were included in this retrospective study (2 males; median age at BHE implantation, 0.6 years). All patients were diagnosed with DCM based on the clinical and histological findings. The histological diagnosis was made by the Department of Pathology in our institution and examined by Heart Transplant Candidate Registry Committee of the Japanese Circulation Society. The myocardial histology showed no evidence of preceding myocarditis in all patients. The cohort was divided into 2 groups according to the clinical course. Four patients showed cardiac recovery after BHE implantation and underwent BHE explantation (recovery group). The remaining 6 patients showed persistent LV dysfunction after BHE implantation and underwent heart transplantation (non-recovery group). The LV function and histological findings of the LV myocardium obtained at BHE implantation were compared between the 2 groups. Cardiac catheterization and concomitant echocardiography were performed at pre-BHE implantation and 3 months after implantation in all patients. In the recovery group, echocardiography was performed within 1 week before BHE explantation [8.0 (standard deviation, SD 4.1) months after BHE implantation]. In the non-recovery group, echocardiography was performed within 1 week before heart transplantation [8.3 (2.3) months after BHE implantation]. Berlin Heart EXCOR implantation and postoperative management The BHE implantation was performed through standard median sternotomy, using mild hypothermic cardiopulmonary bypass. The heart was kept beating throughout the process. Inflow cannulation was achieved through the LV apex, and LV myocardial biopsy was obtained. The pump size was 10 ml, and the pump flow was adjusted in 2.5–3.0 l/min/m2 in all patients. No patients required implantation of VAD for the right ventricle. After BHE implantation, the circulatory conditions were carefully examined with echocardiography to maintain the optimal balance of left and right ventricular volume. Pump operation and transillumination were checked daily. In the event of a large thrombus presenting, we exchanged the pump in the operation room. Anticoagulation Postoperative anticoagulation was started with intravenous heparin 24 h after admission to the intensive care unit. Heparin infusion was titrated to adjust the partial thromboplastin time between 60 and 70 s. When oral feeding commenced, treatment was started with acetylsalicylic acid combined with 5 mg/kg/day of dipyridamole. The chronic anticoagulation regimen was initiated on postoperative day 5 with oral warfarin to keep the international normalized ratio between 2.7 and 3.5. Heart failure treatment As soon as the patient’s general condition was stabilized, medical treatments for HF were initiated. Carvedilol and angiotensin converting enzyme-inhibitor was gradually increased by 0.4 mg/kg/day. Pacemaker implantation was required for complete atrioventricular block in 1 patient after BHE implantation. Off test protocol After a minimum of 3 months of entire unloading by BHE and medical treatment, a BHE-off test was performed in selected patients. The protocol of the BHE-off test and the criteria for BHE explantation were based on previous reports [5, 6]. During systemic heparinization, the BHE rate was gradually decreased and then stopped completely with careful real-time echocardiography. After 10 min of the heart beating without mechanical support, cardiac function was assessed by cardiac catheterization and echocardiography. BHE explantation criteria were the following: (i) left ventricular end-diastolic diameter (LVDd) <98th percentile (z-score < +2); (ii) left ventricular ejection fraction (LVEF) ≥45%; (iii) no inotropic support; (iv) lactate <3 mmol/l; (v) pulmonary capillary wedge pressure <3 mmHg; and (vi) resting cardiac index >2.8 l/min/m2. Berlin Heart EXCOR explantation and follow-up The BHE explantation was performed through median sternotomy with mild hypothermic cardiopulmonary bypass. The heart was kept beating. The inflow apical cannula was completely removed, and the full layer of the cannulation site was closed with mattress running suture and over-and-over suture using 5-mm width strip of expanded polytetrafluoroethylene. After BHE explantation, dobutamine and milrinone were routinely administered. HF medication was restarted as soon as oral feeding recommenced. After the discontinuation of catecholamine, cardiac catheterization was performed to examine the possibility of discharge. Cardiac catheterization was routinely performed to assess cardiac function at 3 months, 6 months and each year after BHE explantation. Histological analysis and correlation study between histological data and clinical data The LV myocardial biopsy was obtained from the LV apex at BHE implantation. Samples were embedded in paraffin, cut into 5-μm-thick sections and stained with haematoxylin–eosin, Masson’s trichrome stain or specific antibody. The percentage of myocardial fibrosis was assessed with MetaMorph 6.2 imaging software (Universal Imaging Corp, Downingtown, PA, USA). Five fields of the mid-layers of the LV wall per slide were analysed, and the average of these fibrotic areas was calculated. The density of CD31+ vessels was assessed by counting the absolute number of CD31 antibody (ab28364; Abcam, Cambridge, UK)-positive microcapillaries out of 5 high-power fields using the BZ-analysis software application (Keyence, Tokyo, Japan). Correlation studies were performed between histological data (the percentage of myocardial fibrosis and capillary vascular density) and clinical data (LVEF and LVDd). Statistical analysis Statistical analysis was performed using JMP Pro, version 14 (SAS Institute Inc., Cary, NC, USA). Data were described as the mean (SD) or median (25th to 75th percentile interquartile range). Categorical variables were analysed using the Pearson’s χ2 test or Fisher’s exact test, as appropriate. Continuous variables with a normal distribution and continuous variables with non-normal distributions were analysed using the Student’s t-test and Man–Whitney U-test, respectively. The z-score of LVDd was calculated according to the report from Lopez et al. [15]. No correction for multiple testing was performed. All the statistical tests were 2-sided, and the P-values of 0.05 or less were considered statistically significant. RESULTS Follow-up was completed in all patients with the median follow-up period of 3.6 years (interquartile range 2.4–4.2) after BHE implantation with no case of mortality. The patient baseline characteristics are shown in Tables 1 and 2. The recovery group (n = 4) showed significant recovery of cardiac function and underwent successful BHE explantation after support periods of 3.7–14 months. All patients were discharged to home 5.6–8.2 months after BHE explantation. During follow-up, all patients were doing well with no re-hospitalization for HF. While the HF symptoms were clinically resolved, the patients in the recovery group still have a risk of future exacerbations. In Japan, the previous waiting period for heart transplantation would not be considered if the patients were removed from the list. For these reasons, patients after explantation are still on the waiting list under status 2. The non-recovery group (n = 6) showed persistent LV dysfunction and underwent heart transplantation after support periods of 9.1–22 months. Table 1: Pre-implant characteristics for each patient . Age at BHE implantation (years) . BW at BHE implantation (kg) . Preoperative MV/MCS . LVDd (mm/z-score) . LVEF (%) . PCWP (mmHg) . BNP (pg/ml) . Recovery group 1 2.1 8.4 +/+ 59/15.0 10 20 969 Recovery group 2 1.3 7.7 −/− 58/15.1 3.9 14 2197 Recovery group 3 0.58 6.8 +/+ 35/6.92 15 11 452 Recovery group 4 0.36 6.1 +/+ 43/12.5 18 8 2763 Non-recovery group 1 0.93 5.8 +/+ 46/13.3 13 21 2307 Non-recovery group 2 0.68 4.4 +/− 40/10.8 8 20 347 Non-recovery group 3 0.46 4.4 +/+ 51/17.6 8 23 2868 Non-recovery group 4 1.9 6.9 −/− 30/4.9 33 16 732 Non-recovery group 5 0.34 5 +/+ 30/5.7 18 15 6352 Non-recovery group 6 0.56 5.9 +/− 29/5.4 32 21 396 . Age at BHE implantation (years) . BW at BHE implantation (kg) . Preoperative MV/MCS . LVDd (mm/z-score) . LVEF (%) . PCWP (mmHg) . BNP (pg/ml) . Recovery group 1 2.1 8.4 +/+ 59/15.0 10 20 969 Recovery group 2 1.3 7.7 −/− 58/15.1 3.9 14 2197 Recovery group 3 0.58 6.8 +/+ 35/6.92 15 11 452 Recovery group 4 0.36 6.1 +/+ 43/12.5 18 8 2763 Non-recovery group 1 0.93 5.8 +/+ 46/13.3 13 21 2307 Non-recovery group 2 0.68 4.4 +/− 40/10.8 8 20 347 Non-recovery group 3 0.46 4.4 +/+ 51/17.6 8 23 2868 Non-recovery group 4 1.9 6.9 −/− 30/4.9 33 16 732 Non-recovery group 5 0.34 5 +/+ 30/5.7 18 15 6352 Non-recovery group 6 0.56 5.9 +/− 29/5.4 32 21 396 BHE: Berlin Heart EXCOR®; BNP: brain natriuretic peptide; BW: body weight; LVDd: left ventricular end-diastolic diameter; LVEF: left ventricular ejection fraction; MCS: mechanical circulatory support; MV: mechanical ventilation; PCWP: pulmonary capillary wedge pressure. Open in new tab Table 1: Pre-implant characteristics for each patient . Age at BHE implantation (years) . BW at BHE implantation (kg) . Preoperative MV/MCS . LVDd (mm/z-score) . LVEF (%) . PCWP (mmHg) . BNP (pg/ml) . Recovery group 1 2.1 8.4 +/+ 59/15.0 10 20 969 Recovery group 2 1.3 7.7 −/− 58/15.1 3.9 14 2197 Recovery group 3 0.58 6.8 +/+ 35/6.92 15 11 452 Recovery group 4 0.36 6.1 +/+ 43/12.5 18 8 2763 Non-recovery group 1 0.93 5.8 +/+ 46/13.3 13 21 2307 Non-recovery group 2 0.68 4.4 +/− 40/10.8 8 20 347 Non-recovery group 3 0.46 4.4 +/+ 51/17.6 8 23 2868 Non-recovery group 4 1.9 6.9 −/− 30/4.9 33 16 732 Non-recovery group 5 0.34 5 +/+ 30/5.7 18 15 6352 Non-recovery group 6 0.56 5.9 +/− 29/5.4 32 21 396 . Age at BHE implantation (years) . BW at BHE implantation (kg) . Preoperative MV/MCS . LVDd (mm/z-score) . LVEF (%) . PCWP (mmHg) . BNP (pg/ml) . Recovery group 1 2.1 8.4 +/+ 59/15.0 10 20 969 Recovery group 2 1.3 7.7 −/− 58/15.1 3.9 14 2197 Recovery group 3 0.58 6.8 +/+ 35/6.92 15 11 452 Recovery group 4 0.36 6.1 +/+ 43/12.5 18 8 2763 Non-recovery group 1 0.93 5.8 +/+ 46/13.3 13 21 2307 Non-recovery group 2 0.68 4.4 +/− 40/10.8 8 20 347 Non-recovery group 3 0.46 4.4 +/+ 51/17.6 8 23 2868 Non-recovery group 4 1.9 6.9 −/− 30/4.9 33 16 732 Non-recovery group 5 0.34 5 +/+ 30/5.7 18 15 6352 Non-recovery group 6 0.56 5.9 +/− 29/5.4 32 21 396 BHE: Berlin Heart EXCOR®; BNP: brain natriuretic peptide; BW: body weight; LVDd: left ventricular end-diastolic diameter; LVEF: left ventricular ejection fraction; MCS: mechanical circulatory support; MV: mechanical ventilation; PCWP: pulmonary capillary wedge pressure. Open in new tab Table 2: Pre-implantation characteristics . Recovery group . Non-recovery group . P-value . Number of patients 4 (m:0, f:4) 6 (m:2, f:4) Age at HF exacerbation (months) 7.1 (3.2) 3.2 (2.6) 0.09 Age at BHE implantation (months) 13 (9.6) 9.6 (7.2) 0.57 BW at BHE implantation (kg) 7.3 (1.0) 5.4 (1.0) 0.026* Pre-implant mechanical ventilation 3 5 1.0 Pre-implant MCS 3 3 0.57 INTERMACS profile 1 3 3 0.57 INTERMACS profile 2 1 3 LVDd (z-score) 12 (3.8) 9.6 (5.2) 0.36 LVEF (%) 12 (6) 19 (11) 0.25 MR > moderate (n) 3 4 0.78 CVP (mmHg) 7.8 (2.4) 5.2 (1.9) 0.12 Mean PAP (mmHg) 21 (6.0) 26 (2.7) 0.15 PCWP (mmHg) 13 (5) 19 (3) 0.093 BNP (pg/ml) 1583 (840–2339) 1519 (480–2728) 0.61 . Recovery group . Non-recovery group . P-value . Number of patients 4 (m:0, f:4) 6 (m:2, f:4) Age at HF exacerbation (months) 7.1 (3.2) 3.2 (2.6) 0.09 Age at BHE implantation (months) 13 (9.6) 9.6 (7.2) 0.57 BW at BHE implantation (kg) 7.3 (1.0) 5.4 (1.0) 0.026* Pre-implant mechanical ventilation 3 5 1.0 Pre-implant MCS 3 3 0.57 INTERMACS profile 1 3 3 0.57 INTERMACS profile 2 1 3 LVDd (z-score) 12 (3.8) 9.6 (5.2) 0.36 LVEF (%) 12 (6) 19 (11) 0.25 MR > moderate (n) 3 4 0.78 CVP (mmHg) 7.8 (2.4) 5.2 (1.9) 0.12 Mean PAP (mmHg) 21 (6.0) 26 (2.7) 0.15 PCWP (mmHg) 13 (5) 19 (3) 0.093 BNP (pg/ml) 1583 (840–2339) 1519 (480–2728) 0.61 Continuous data are presented as mean (standard deviation) or median (interquartile range), while categorical data are shown as the number of observations. * P < 0.05. BHE: Berlin Heart EXCOR®; BNP: brain natriuretic peptide; BW: body weight; CVP: central venous pressure; f: female; HF: heart failure; LVDd: left ventricular end-diastolic diameter; LVEF: left ventricular ejection fraction; m: male; MCS: mechanical circulatory support; MR: mitral regurgitation; n: number; PAP: •••; PCWP: pulmonary capillary wedge pressure. Open in new tab Table 2: Pre-implantation characteristics . Recovery group . Non-recovery group . P-value . Number of patients 4 (m:0, f:4) 6 (m:2, f:4) Age at HF exacerbation (months) 7.1 (3.2) 3.2 (2.6) 0.09 Age at BHE implantation (months) 13 (9.6) 9.6 (7.2) 0.57 BW at BHE implantation (kg) 7.3 (1.0) 5.4 (1.0) 0.026* Pre-implant mechanical ventilation 3 5 1.0 Pre-implant MCS 3 3 0.57 INTERMACS profile 1 3 3 0.57 INTERMACS profile 2 1 3 LVDd (z-score) 12 (3.8) 9.6 (5.2) 0.36 LVEF (%) 12 (6) 19 (11) 0.25 MR > moderate (n) 3 4 0.78 CVP (mmHg) 7.8 (2.4) 5.2 (1.9) 0.12 Mean PAP (mmHg) 21 (6.0) 26 (2.7) 0.15 PCWP (mmHg) 13 (5) 19 (3) 0.093 BNP (pg/ml) 1583 (840–2339) 1519 (480–2728) 0.61 . Recovery group . Non-recovery group . P-value . Number of patients 4 (m:0, f:4) 6 (m:2, f:4) Age at HF exacerbation (months) 7.1 (3.2) 3.2 (2.6) 0.09 Age at BHE implantation (months) 13 (9.6) 9.6 (7.2) 0.57 BW at BHE implantation (kg) 7.3 (1.0) 5.4 (1.0) 0.026* Pre-implant mechanical ventilation 3 5 1.0 Pre-implant MCS 3 3 0.57 INTERMACS profile 1 3 3 0.57 INTERMACS profile 2 1 3 LVDd (z-score) 12 (3.8) 9.6 (5.2) 0.36 LVEF (%) 12 (6) 19 (11) 0.25 MR > moderate (n) 3 4 0.78 CVP (mmHg) 7.8 (2.4) 5.2 (1.9) 0.12 Mean PAP (mmHg) 21 (6.0) 26 (2.7) 0.15 PCWP (mmHg) 13 (5) 19 (3) 0.093 BNP (pg/ml) 1583 (840–2339) 1519 (480–2728) 0.61 Continuous data are presented as mean (standard deviation) or median (interquartile range), while categorical data are shown as the number of observations. * P < 0.05. BHE: Berlin Heart EXCOR®; BNP: brain natriuretic peptide; BW: body weight; CVP: central venous pressure; f: female; HF: heart failure; LVDd: left ventricular end-diastolic diameter; LVEF: left ventricular ejection fraction; m: male; MCS: mechanical circulatory support; MR: mitral regurgitation; n: number; PAP: •••; PCWP: pulmonary capillary wedge pressure. Open in new tab Left ventricular function after Berlin Heart EXCOR implantation No significant differences were shown in the z-score of LVDd and LVEF between the 2 groups at 3 months after BHE implantation. However, the changes in LVDd (ΔLVDd) and LVEF (ΔLVEF) during the 3 months after BHE implantation were significantly greater in the recovery group than in the non-recovery group. The echocardiography within 1 week before BHE explantation or heart transplantation in each group showed significantly lower z-score of LVDd and higher LVEF in the recovery group than in the non-recovery group [1.1 (SD 1.3) vs 6.2 (3.6), P = 0.017, and 58 (9) vs 25 (13), P = 0.002, respectively; Fig. 1 and Table 3]. Figure 1: Open in new tabDownload slide ΔLVDd and ΔLVEF over time after Berlin Heart EXCOR® (BHE) implantation. LVDd and LVEF were measured before BHE implantation, 3 months after BHE and at the final follow-up before BHE explantation or heart transplantation in both groups, including after BHE explantation in the recovery group. ΔLVDd and ΔLVEF during 3 months after BHE implantation were significantly greater in the recovery group. The final echocardiography before BHE explantation or heart transplantation showed a significantly lower z-score of LVDd and higher LVEF in the recovery group. *P < 0.05, †P < 0.01. f/u: follow-up; LVDd: left ventricular end-diastolic diameter; LVEF: left ventricular ejection fraction; post-explant.: post-BHE explantation; ΔLVDd: the change in LVDd; ΔLVEF: the change in LVEF. Figure 1: Open in new tabDownload slide ΔLVDd and ΔLVEF over time after Berlin Heart EXCOR® (BHE) implantation. LVDd and LVEF were measured before BHE implantation, 3 months after BHE and at the final follow-up before BHE explantation or heart transplantation in both groups, including after BHE explantation in the recovery group. ΔLVDd and ΔLVEF during 3 months after BHE implantation were significantly greater in the recovery group. The final echocardiography before BHE explantation or heart transplantation showed a significantly lower z-score of LVDd and higher LVEF in the recovery group. *P < 0.05, †P < 0.01. f/u: follow-up; LVDd: left ventricular end-diastolic diameter; LVEF: left ventricular ejection fraction; post-explant.: post-BHE explantation; ΔLVDd: the change in LVDd; ΔLVEF: the change in LVEF. Table 3: Post-implantation course . Recovery group . Non-recovery group . P-value . 3 months after BHE implantation  LVDd z-score 2.8 (2.0) 6.0 (4.3) 0.15  ΔLVDd z-score (3m-pre) −9.6 (3.5) −3.6 (4.5) 0.045*  LVEF (%) 48 (8) 32 (16) 0.074  ΔLVEF (3m-pre) (%) 36 (13) 13 (13) 0.032*  BNP (pg/ml) 37 (11) 216 (180) 0.059  Aortic valve opening Every beat: 4 Every beat: 3 Intermittent: 3 Last follow-up with BHE  LVDd z-score 1.1 (1.3) 6.0 (4.3) 0.017*  LVEF (%) 58 (9) 25 (13) 0.002†  BNP (pg/ml) 34 (30–39) 275 (138–362) 0.12  Aortic valve opening Every beat: 4 Every beat: 3 Intermittent: 1 Close: 2 BHE support duration (month) 9.1 (3.7–14.2) 12 (9.1–22) 0.23 . Recovery group . Non-recovery group . P-value . 3 months after BHE implantation  LVDd z-score 2.8 (2.0) 6.0 (4.3) 0.15  ΔLVDd z-score (3m-pre) −9.6 (3.5) −3.6 (4.5) 0.045*  LVEF (%) 48 (8) 32 (16) 0.074  ΔLVEF (3m-pre) (%) 36 (13) 13 (13) 0.032*  BNP (pg/ml) 37 (11) 216 (180) 0.059  Aortic valve opening Every beat: 4 Every beat: 3 Intermittent: 3 Last follow-up with BHE  LVDd z-score 1.1 (1.3) 6.0 (4.3) 0.017*  LVEF (%) 58 (9) 25 (13) 0.002†  BNP (pg/ml) 34 (30–39) 275 (138–362) 0.12  Aortic valve opening Every beat: 4 Every beat: 3 Intermittent: 1 Close: 2 BHE support duration (month) 9.1 (3.7–14.2) 12 (9.1–22) 0.23 Continuous data are presented as mean (standard deviation) or median (interquartile range), while categorical data are presented as the number of observations. The final follow-up study was conducted before BHE explantation or heart transplantation. * P < 0.05. † P < 0.01. BHE: Berlin Heart EXCOR®; BNP: brain natriuretic peptide; LVDd: left ventricular end-diastolic diameter; LVEF: left ventricular ejection fraction; ΔLVDd: the change in LVDd; ΔLVEF: the change in LVEF; 3m-pre: difference between 3 months after implantation and pre-implantation. Open in new tab Table 3: Post-implantation course . Recovery group . Non-recovery group . P-value . 3 months after BHE implantation  LVDd z-score 2.8 (2.0) 6.0 (4.3) 0.15  ΔLVDd z-score (3m-pre) −9.6 (3.5) −3.6 (4.5) 0.045*  LVEF (%) 48 (8) 32 (16) 0.074  ΔLVEF (3m-pre) (%) 36 (13) 13 (13) 0.032*  BNP (pg/ml) 37 (11) 216 (180) 0.059  Aortic valve opening Every beat: 4 Every beat: 3 Intermittent: 3 Last follow-up with BHE  LVDd z-score 1.1 (1.3) 6.0 (4.3) 0.017*  LVEF (%) 58 (9) 25 (13) 0.002†  BNP (pg/ml) 34 (30–39) 275 (138–362) 0.12  Aortic valve opening Every beat: 4 Every beat: 3 Intermittent: 1 Close: 2 BHE support duration (month) 9.1 (3.7–14.2) 12 (9.1–22) 0.23 . Recovery group . Non-recovery group . P-value . 3 months after BHE implantation  LVDd z-score 2.8 (2.0) 6.0 (4.3) 0.15  ΔLVDd z-score (3m-pre) −9.6 (3.5) −3.6 (4.5) 0.045*  LVEF (%) 48 (8) 32 (16) 0.074  ΔLVEF (3m-pre) (%) 36 (13) 13 (13) 0.032*  BNP (pg/ml) 37 (11) 216 (180) 0.059  Aortic valve opening Every beat: 4 Every beat: 3 Intermittent: 3 Last follow-up with BHE  LVDd z-score 1.1 (1.3) 6.0 (4.3) 0.017*  LVEF (%) 58 (9) 25 (13) 0.002†  BNP (pg/ml) 34 (30–39) 275 (138–362) 0.12  Aortic valve opening Every beat: 4 Every beat: 3 Intermittent: 1 Close: 2 BHE support duration (month) 9.1 (3.7–14.2) 12 (9.1–22) 0.23 Continuous data are presented as mean (standard deviation) or median (interquartile range), while categorical data are presented as the number of observations. The final follow-up study was conducted before BHE explantation or heart transplantation. * P < 0.05. † P < 0.01. BHE: Berlin Heart EXCOR®; BNP: brain natriuretic peptide; LVDd: left ventricular end-diastolic diameter; LVEF: left ventricular ejection fraction; ΔLVDd: the change in LVDd; ΔLVEF: the change in LVEF; 3m-pre: difference between 3 months after implantation and pre-implantation. Open in new tab Left ventricular function after Berlin Heart EXCOR explantation in the recovery group During the median follow-up period of 24 months (interquartile range 17–27) after BHE explantation, cardiac function and brain natriuretic peptide levels remained almost normal in all patients in the recovery group (Table 4). Table 4: Post-explantation course in recovery group . Pre-explantation . ≤6 months . 1 year . 2 years . Case 1  LVDd (z-score) 0.13 2.13 0.31 −0.46  LVEF (%) 65 52 60 60  PCWP (mmHg) 5 7 5  BNP (pg/ml) 34.9 29 39.6 21.2 Case 2  LVDd (z-score) 0.17 6.26 −0.47 −0.2  LVEF (%) 64 61 59 48  PCWP (mmHg) 10 6 4  BNP (pg/ml) 43.7 36.3 21 16.6 Case 3  LVDd (z-score) 1.19 −0.93 −0.40  LVEF (%) 58 50 68  PCWP (mmHg) 3 6 5  BNP (pg/ml) 29.7 11.9 19.8 Case 4  LVDd (z-score) 2.82 −1.15  LVEF (%) 45 60  PCWP (mmHg) 3 5  BNP (pg/ml) 37 25.8 . Pre-explantation . ≤6 months . 1 year . 2 years . Case 1  LVDd (z-score) 0.13 2.13 0.31 −0.46  LVEF (%) 65 52 60 60  PCWP (mmHg) 5 7 5  BNP (pg/ml) 34.9 29 39.6 21.2 Case 2  LVDd (z-score) 0.17 6.26 −0.47 −0.2  LVEF (%) 64 61 59 48  PCWP (mmHg) 10 6 4  BNP (pg/ml) 43.7 36.3 21 16.6 Case 3  LVDd (z-score) 1.19 −0.93 −0.40  LVEF (%) 58 50 68  PCWP (mmHg) 3 6 5  BNP (pg/ml) 29.7 11.9 19.8 Case 4  LVDd (z-score) 2.82 −1.15  LVEF (%) 45 60  PCWP (mmHg) 3 5  BNP (pg/ml) 37 25.8 BNP: brain natriuretic peptide; LVDd: left ventricular end-diastolic diameter; LVEF: left ventricular ejection fraction; PCWP: pulmonary capillary wedge pressure. Open in new tab Table 4: Post-explantation course in recovery group . Pre-explantation . ≤6 months . 1 year . 2 years . Case 1  LVDd (z-score) 0.13 2.13 0.31 −0.46  LVEF (%) 65 52 60 60  PCWP (mmHg) 5 7 5  BNP (pg/ml) 34.9 29 39.6 21.2 Case 2  LVDd (z-score) 0.17 6.26 −0.47 −0.2  LVEF (%) 64 61 59 48  PCWP (mmHg) 10 6 4  BNP (pg/ml) 43.7 36.3 21 16.6 Case 3  LVDd (z-score) 1.19 −0.93 −0.40  LVEF (%) 58 50 68  PCWP (mmHg) 3 6 5  BNP (pg/ml) 29.7 11.9 19.8 Case 4  LVDd (z-score) 2.82 −1.15  LVEF (%) 45 60  PCWP (mmHg) 3 5  BNP (pg/ml) 37 25.8 . Pre-explantation . ≤6 months . 1 year . 2 years . Case 1  LVDd (z-score) 0.13 2.13 0.31 −0.46  LVEF (%) 65 52 60 60  PCWP (mmHg) 5 7 5  BNP (pg/ml) 34.9 29 39.6 21.2 Case 2  LVDd (z-score) 0.17 6.26 −0.47 −0.2  LVEF (%) 64 61 59 48  PCWP (mmHg) 10 6 4  BNP (pg/ml) 43.7 36.3 21 16.6 Case 3  LVDd (z-score) 1.19 −0.93 −0.40  LVEF (%) 58 50 68  PCWP (mmHg) 3 6 5  BNP (pg/ml) 29.7 11.9 19.8 Case 4  LVDd (z-score) 2.82 −1.15  LVEF (%) 45 60  PCWP (mmHg) 3 5  BNP (pg/ml) 37 25.8 BNP: brain natriuretic peptide; LVDd: left ventricular end-diastolic diameter; LVEF: left ventricular ejection fraction; PCWP: pulmonary capillary wedge pressure. Open in new tab Myocardial fibrosis and capillary vascular density The percentages of myocardial fibrosis assessed by Masson’s trichrome staining were 16 (SD 6) in the recovery group and 28 (6) in the non-recovery group (Fig. 2). The recovery group showed a significantly lower degree of myocardial fibrosis at the mid-mural layer (P = 0.021). Capillary vascular densities assessed by CD31 immunostaining were 65 (11) units/high-power field in the recovery group and 43 (18) units/high-power field in the non-recovery group at the mid-mural layer (Fig. 2). The capillary vascular density was significantly higher in the recovery group (P = 0.037). The degree of myocardial fibrosis and capillary vascular density were correlated with the preoperative pulmonary capillary wedge pressure, respectively (%fibrosis: r2 = 0.41, P = 0.045, and capillary vascular density: r2 = 0.63, P = 0.006; Fig. 2). Figure 2: Open in new tabDownload slide Histological findings. (A) Representative photomicrographs (×200, scale bar = 100 μm) of Masson’s trichrome staining at mid-mural layer. Percentage of myocardial fibrosis was significantly lower in the recovery group. (B) Representative photomicrographs (×400, scale bar = 100 μm) of anti-CD31 staining at the mid-mural layer. The capillary vascular density was significantly lower in the non-recovery group. The degree of myocardial fibrosis and capillary vascular density were correlated with the preoperative PCWP. *P < 0.05, †P < 0.01. HPF: high-power field; PCWP: pulmonary capillary wedge pressure. Figure 2: Open in new tabDownload slide Histological findings. (A) Representative photomicrographs (×200, scale bar = 100 μm) of Masson’s trichrome staining at mid-mural layer. Percentage of myocardial fibrosis was significantly lower in the recovery group. (B) Representative photomicrographs (×400, scale bar = 100 μm) of anti-CD31 staining at the mid-mural layer. The capillary vascular density was significantly lower in the non-recovery group. The degree of myocardial fibrosis and capillary vascular density were correlated with the preoperative PCWP. *P < 0.05, †P < 0.01. HPF: high-power field; PCWP: pulmonary capillary wedge pressure. The degree of pre-BHE myocardial fibrosis was correlated with LVEF, and the capillary vascular density was correlated with the z-score of LVDd and LVEF at a mean of 8 months after BHE implantation (r2 = 0.6, P = 0.009; r2 = 0.65, P = 0.005; and r2 = 0.52, P = 0.019, respectively; Fig. 3). Figure 3: Open in new tabDownload slide The correlation of %fibrosis and capillary vascular density with LVDd and LVEF. The %fibrosis at pre-BHE implantation was correlated with LVEF at the last follow-up, and the capillary vascular density at pre-BHE implantation was correlated with the z-score of LVDd and LVEF at the final follow-up. *P < 0.05, †P < 0.01. BHE: Berlin Heart EXCOR®; f/u: follow-up; LVDd: left ventricular end-diastolic diameter; LVEF: left ventricular ejection fraction; pre-BHE: pre-BHE implantation. Figure 3: Open in new tabDownload slide The correlation of %fibrosis and capillary vascular density with LVDd and LVEF. The %fibrosis at pre-BHE implantation was correlated with LVEF at the last follow-up, and the capillary vascular density at pre-BHE implantation was correlated with the z-score of LVDd and LVEF at the final follow-up. *P < 0.05, †P < 0.01. BHE: Berlin Heart EXCOR®; f/u: follow-up; LVDd: left ventricular end-diastolic diameter; LVEF: left ventricular ejection fraction; pre-BHE: pre-BHE implantation. DISCUSSION The main findings of this study were as the following. First, bridge to recovery with BHE was demonstrated in patients who had significantly less LV myocardial fibrosis and high capillary vascular density at BHE implantation. In these patients, LV function was significantly improved at 3 months after BHE implantation and BHE was successfully explanted. Second, the degree of LV myocardial fibrosis and capillary vascular density at BHE implantation were significantly correlated with haemodynamic parameters before BHE implantation and improvement of LV function during BHE support. Considering severe donor shortage and high incidence of morbidity related to VAD implantation, the bridge to recovery and possibility of VAD explantation could be a useful alternative strategy in patients with end-stage HF. Our group previously reported that a lower degree of fibrosis in the LV was predictive of successful bridge to recovery during VAD support in adult patients with DCM [12, 13]. In paediatric patients, Ihnat et al. [16] initially reported 8 young patients who underwent successful weaning from VAD. Recently, Hetzer et al. and Miera et al. reported almost 20-year experience of bridge to recovery in paediatric patients on VAD [5, 9]. These reports include heterogeneous aetiology of HF supported with inconsistent types of VAD. In the present study, 10 paediatric patients <10 kg with DCM were treated with BHE, 4 of whom showed improvement in LV function, which was sustained for at least 8 months after BHE explantation. Similar to adult patients, the less injured myocardial histology at VAD implantation may predict better outcomes in bridge to recovery in paediatric patients with DCM. The impact of mechanical unloading of the LV with a VAD on the structural reverse remodelling and the improvement of cardiac function have been widely investigated in adult DCM patients [12, 13, 17, 18]. In paediatric patients, Mohapatra et al. [19] demonstrated that short-term left ventricular assist device therapy (8–16 days) in paediatric DCM patients was associated with molecular reverse remodelling of the failing heart. Kasten et al. [20] reported the histological reverse remodelling after mechanical unloading of the LV in paediatric patients with DCM after a support period of median 17.5 (8–223) days. In the present study, less injured myocardial histology at VAD implantation was shown to be associated with a high probability of cardiac recovery with mechanical unloading. According to these results, the less injured myocardial histology would likely be reverse remodelled with mechanical unloading, which may lead to improvement in cardiac function in paediatric patients with DCM. However, it should be noted that whether the histological and functional improvements in LV were sustained after BHE explantation is unclear. While the present study showed the initial experience of BHE explantation with sustained LV function during follow-up, the long-term outcomes after BHE explantation should be examined in further studies. The present study showed a higher recovery rate (40%) in young DCM patients with long-term BHE support than the previous studies [5, 7, 8, 21]. The young age at VAD implantation was reported to be a positive predictor for cardiac recovery in paediatric patients [21, 22]. This is partly explained by the age-dependent reverse remodelling on VAD at the histological level with a higher reduction in interstitial fibrosis in young patients [20]. In most of the previous studies, children weaned from VAD are characterized by short-term support with acute onset of HF typically seen in myocarditis [5, 6, 8, 16]. In the present study, all patients were diagnosed with idiopathic DCM without preceding myocarditis. Considering the chronic myocardial condition in idiopathic DCM, long-term support with VAD might be required to obtain cardiac recovery; however, the long-term support would lead to increased VAD-associated complications. Therefore, the optimal duration for BHE support to obtain successful BHE explantation should be examined in a further study. Limitations First, significant limitations of this study include its small sample size and its retrospective, single-centre design, so any statistical analysis may not have sufficient power to draw firm conclusions. Second, the histological findings from the LV apex do not always represent those of the whole heart. CONCLUSION In paediatric patients <10 kg with DCM, bridge to recovery with BHE implantation was achieved in patients with less injured LV myocardial histology at BHE implantation. The results of the present study contribute to the insights into the factors associated with functional improvement of the LV with BHE implantation. Presented at the 33rd Annual Meeting of the European Association for Cardio-Thoracic Surgery, Lisbon, Portugal, 3–5 October 2019. Acknowledgments The authors are grateful to Shigetoyo Kogaki, Masaki Taira, Sanae Yamauchi, Ryo Ishii, Akima Harada, Naoki Okuda, Kanta Araki and Takuji Watanabe for helpful discussions and comments on the manuscript. The authors would like to thank Editage (http://www.editage.jp) for English language editing. Conflict of interest: none declared. Author contributions Yuji Tominaga: Conceptualization; Data curation; Formal analysis; Investigation; Methodology; Project administration; Writing—original draft; Writing—review & editing. Takayoshi Ueno: Conceptualization; Supervision; Validation; Writing—review & editing. Takashi Kido: Conceptualization; Data curation; Project administration; Supervision; Writing—review & editing. Tomomitsu Kanaya: Data curation; Methodology; Writing—review & editing. Jun Narita: Conceptualization; Methodology; Writing—review & editing. Hidekazu Ishida: Conceptualization; Data curation; Methodology; Supervision; Writing—review & editing. Koichi Toda: Conceptualization; Supervision. Toru Kuratani: Conceptualization; Supervision. Yoshiki Sawa: Conceptualization; Supervision; Writing—review & editing. REFERENCES 1 Morgan CT , Manlhiot C , McCrindle BW , Dipchand AI. Outcome, incidence and risk factors for stroke after pediatric heart transplantation: an analysis of the International Society for Heart and Lung Transplantation Registry . J Heart Lung Transplant 2016 ; 35 : 597 – 602 . Google Scholar Crossref Search ADS PubMed WorldCat 2 Lee TM , Hsu DT , Kantor P , Towbin JA , Ware SM , Colan SD et al. Pediatric cardiomyopathies . Circ Res 2017 ; 121 : 855 – 73 . Google Scholar Crossref Search ADS PubMed WorldCat 3 Puggia I , Merlo M , Barbati G , Rowland TJ , Stolfo D , Gigli M et al. Natural history of dilated cardiomyopathy in children . J Am Heart Assoc 2016 ; 5 : e003450 . Google Scholar Crossref Search ADS PubMed WorldCat 4 Alexander PM , Daubeney PE , Nugent AW , Lee KJ , Turner C , Colan SD et al. Long-term outcomes of dilated cardiomyopathy diagnosed during childhood: results from a national population-based study of childhood cardiomyopathy . Circulation 2013 ; 128 : 2039 – 46 . 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Bridging children of all sizes to cardiac transplantation: the initial multicenter North American experience with the Berlin Heart EXCOR ventricular assist device . J Heart Lung Transplant 2011 ; 30 : 1 – 8 . Google Scholar Crossref Search ADS PubMed WorldCat 9 Miera O , Morales DLS , Thul J , Amodeo A , Menon AK , Humpl T. Improvement of survival in low-weight children on the Berlin Heart EXCOR ventricular assist device support . Eur J Cardiothorac Surg 2019 ; 55 : 913 – 19 . Google Scholar Crossref Search ADS PubMed WorldCat 10 Brancaccio G , Amodeo A , Ricci Z , Morelli S , Gagliardi MG , Iacobelli R et al. Mechanical assist device as a bridge to heart transplantation in children less than 10 kilograms . Ann Thorac Surg 2010 ; 90 : 58 – 62 . Google Scholar Crossref Search ADS PubMed WorldCat 11 Fukushima N , Ono M , Saiki Y , Sawa Y , Nunoda S , Isobe M. Registry report on heart transplantation in Japan (June 2016) . Circ J 2017 ; 81 : 298 – 303 . Google Scholar Crossref Search ADS PubMed WorldCat 12 Matsumiya G , Monta O , Fukushima N , Sawa Y , Funatsu T , Toda K et al. Who would be a candidate for bridge to recovery during prolonged mechanical left ventricular support in idiopathic dilated cardiomyopathy? J Thorac Cardiovasc Surg 2005 ; 130 : 699 – 704 . Google Scholar Crossref Search ADS PubMed WorldCat 13 Saito S , Matsumiya G , Sakaguchi T , Miyagawa S , Yamauchi T , Kuratani T et al. Cardiac fibrosis and cellular hypertrophy decrease the degree of reverse remodeling and improvement in cardiac function during left ventricular assist . J Heart Lung Transplant 2010 ; 29 : 672 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat 14 Rohde S , Antonides CFJ , Dalinghaus M , Muslem R , Bogers A. Clinical outcomes of paediatric patients supported by the Berlin Heart EXCOR: a systematic review . Eur J Cardiothorac Surg 2019 ; 56 : 830 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat 15 Lopez L , Colan S , Stylianou M , Granger S , Trachtenberg F , Frommelt P et al. Relationship of echocardiographic Z scores adjusted for body surface area to age, sex, race, and ethnicity . Circ Cardiovasc Imaging 2017 ; 10 : e006979 . Google Scholar Crossref Search ADS PubMed WorldCat 16 Ihnat CL , Zimmerman H , Copeland JG , Meaney FJ , Sobonya RE , Larsen BT et al. Left ventricular assist device support as a bridge to recovery in young children . Congenit Heart Dis 2011 ; 6 : 234 – 40 . Google Scholar Crossref Search ADS PubMed WorldCat 17 Ambardekar AV , Buttrick PM. Reverse remodeling with left ventricular assist devices: a review of clinical, cellular, and molecular effects . Circ Heart Fail 2011 ; 4 : 224 – 33 . Google Scholar Crossref Search ADS PubMed WorldCat 18 Miyagawa S , Toda K , Nakamura T , Yoshikawa Y , Fukushima S , Saito S et al. Building a bridge to recovery: the pathophysiology of LVAD-induced reverse modeling in heart failure . Surg Today 2016 ; 46 : 149 – 54 . Google Scholar Crossref Search ADS PubMed WorldCat 19 Mohapatra B , Vick GW 3rd , Fraser CD Jr , Clunie SK , Towbin JA , Sinagra G et al. Short-term mechanical unloading and reverse remodeling of failing hearts in children . J Heart Lung Transplant 2010 ; 29 : 98 – 104 . Google Scholar Crossref Search ADS PubMed WorldCat 20 Kasten J , Rakheja D , Zhang S , Thankavel P , Das BB. Reverse histologic remodeling after mechanical unloading of failing hearts in children with dilated cardiomyopathy . J Heart Lung Transplant 2017 ; 36 : 1268 – 71 . Google Scholar Crossref Search ADS PubMed WorldCat 21 Miera O , Germann M , Cho MY , Photiadis J , Delmo Walter EM , Hetzer R et al. Bridge to recovery in children on ventricular assist devices-protocol, predictors of recovery, and long-term follow-up . J Heart Lung Transplant 2018 ; 37 : 1459 – 66 . Google Scholar Crossref Search ADS PubMed WorldCat 22 Weia BC , Adachi I , Jacot JG. Clinical and molecular comparison of pediatric and adult reverse remodeling with ventricular assist devices . Artif Organs 2015 ; 39 : 691 – 700 . Google Scholar Crossref Search ADS PubMed WorldCat ABBREVIATIONS ABBREVIATIONS BHE Berlin Heart EXCOR® DCM Dilated cardiomyopathy HF Heart failure LV Left ventricular LVDd Left ventricular end-diastolic diameter LVEF Left ventricular ejection fraction SD Standard deviation VAD Ventricular assist device © The Author(s) 2020. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Journal of Cardio-Thoracic Surgery Oxford University Press

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Oxford University Press
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© The Author(s) 2020. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.
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1010-7940
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1873-734X
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Abstract

Abstract Open in new tabDownload slide Open in new tabDownload slide OBJECTIVES This study aimed to identify the histological characteristics associated with bridge to recovery using Berlin Heart EXCOR® (BHE) in paediatric patients <10 kg with dilated cardiomyopathy. METHODS Of the 10 consecutive patients <10 kg with dilated cardiomyopathy who underwent BHE implantation between 2013 and 2018, 4 patients showed improvement in left ventricular (LV) function, resulting in successful BHE explantation (recovery group). The remaining 6 patients showed persistent LV dysfunction and underwent heart transplantation (non-recovery group). The following variables were compared between the 2 groups: (i) histological findings in LV myocardium obtained at BHE implantation and (ii) LV function after BHE implantation assessed with echocardiography and cardiac catheterization. RESULTS The degree of myocardial fibrosis was significantly lower, and the capillary vascular density was significantly higher in the recovery group than in the non-recovery group [16% (standard deviation 5.9%) vs 28% (5.9%), P = 0.021, and 65 (11) vs 43 (18) units/high-power field, P = 0.037, respectively]. The changes during 3 months after BHE implantation in LV diastolic dimension (z-score) and ejection fraction were significantly greater in the recovery group than in the non-recovery group [−9.6 (3.5) vs −3.6 (4.5), P = 0.045, and 36% (13%) vs 13% (13%), P = 0.032, respectively]. CONCLUSIONS In paediatric patients <10 kg with dilated cardiomyopathy, bridge to recovery with BHE implantation was achieved in patients with less injured LV myocardial histology at BHE implantation. Berlin Heart EXCOR, Bridge to recovery, Explantation, Myocardial fibrosis, Capillary vascular density, Dilated cardiomyopathy INTRODUCTION Dilated cardiomyopathy (DCM) is the most common cause of heart failure (HF) in paediatric patients [1]. Paediatric DCM often leads to an aggressive clinical course with 1-year mortality or heart transplantation rate of 18–26% [2–4]. Berlin Heart EXCOR® (BHE; Berlin Heart, Berlin, Germany) is the only paediatric-specific ventricular assist device (VAD) currently available and has become an established treatment for bridge to transplantation in paediatric DCM [5, 6]. Whereas BHE achieves significantly improved survival, the management of paediatric patients <10 kg with DCM remains challenging because of the high incidence of morbidity including stroke, bleeding and infection [6–10]. The current mean waiting period for paediatric heart transplantation exceeds 670 days in Japan because of the severe shortage of organ donors for paediatric patients [11]. Therefore, minimizing morbidities associated with BHE support is becoming increasingly important. Considering these circumstances, we have routinely assessed the possible myocardial recovery at 3 months after BHE implantation in paediatric patients with DCM. Accumulating evidence suggests that mechanical unloading with VAD facilitates the recovery of myocardial function of the failing ventricle, which allows the VAD explantation in selected patients [5–8]. In adult patients with DCM, the left ventricular (LV) myocardial histology is reported to predict the recovery of myocardial function after mechanical unloading with VAD support [12, 13]. However, the predictive factors for myocardial recovery with BHE in paediatric patients with DCM are unclear since only limited data are available [5–8, 14]. Herein, the aim of the present study was to review our initial experience of bridge to recovery using BHE in paediatric patients <10 kg with DCM and identify the histological characteristics associated with this phenomenon. MATERIALS AND METHODS Patients This study was approved by the Institutional Review Board of Osaka University Hospital (approval number 16105), and written informed consent for the use of patient records was obtained from the legal guardian of each patient. Between January 2013 and December 2018, BHE was implanted in 12 paediatric patients <10 kg with DCM in our institution. Two patients were excluded because of associated mitochondrial disease (n = 1) and insufficient follow-up examination (n = 1). Finally, 10 consecutive patients were included in this retrospective study (2 males; median age at BHE implantation, 0.6 years). All patients were diagnosed with DCM based on the clinical and histological findings. The histological diagnosis was made by the Department of Pathology in our institution and examined by Heart Transplant Candidate Registry Committee of the Japanese Circulation Society. The myocardial histology showed no evidence of preceding myocarditis in all patients. The cohort was divided into 2 groups according to the clinical course. Four patients showed cardiac recovery after BHE implantation and underwent BHE explantation (recovery group). The remaining 6 patients showed persistent LV dysfunction after BHE implantation and underwent heart transplantation (non-recovery group). The LV function and histological findings of the LV myocardium obtained at BHE implantation were compared between the 2 groups. Cardiac catheterization and concomitant echocardiography were performed at pre-BHE implantation and 3 months after implantation in all patients. In the recovery group, echocardiography was performed within 1 week before BHE explantation [8.0 (standard deviation, SD 4.1) months after BHE implantation]. In the non-recovery group, echocardiography was performed within 1 week before heart transplantation [8.3 (2.3) months after BHE implantation]. Berlin Heart EXCOR implantation and postoperative management The BHE implantation was performed through standard median sternotomy, using mild hypothermic cardiopulmonary bypass. The heart was kept beating throughout the process. Inflow cannulation was achieved through the LV apex, and LV myocardial biopsy was obtained. The pump size was 10 ml, and the pump flow was adjusted in 2.5–3.0 l/min/m2 in all patients. No patients required implantation of VAD for the right ventricle. After BHE implantation, the circulatory conditions were carefully examined with echocardiography to maintain the optimal balance of left and right ventricular volume. Pump operation and transillumination were checked daily. In the event of a large thrombus presenting, we exchanged the pump in the operation room. Anticoagulation Postoperative anticoagulation was started with intravenous heparin 24 h after admission to the intensive care unit. Heparin infusion was titrated to adjust the partial thromboplastin time between 60 and 70 s. When oral feeding commenced, treatment was started with acetylsalicylic acid combined with 5 mg/kg/day of dipyridamole. The chronic anticoagulation regimen was initiated on postoperative day 5 with oral warfarin to keep the international normalized ratio between 2.7 and 3.5. Heart failure treatment As soon as the patient’s general condition was stabilized, medical treatments for HF were initiated. Carvedilol and angiotensin converting enzyme-inhibitor was gradually increased by 0.4 mg/kg/day. Pacemaker implantation was required for complete atrioventricular block in 1 patient after BHE implantation. Off test protocol After a minimum of 3 months of entire unloading by BHE and medical treatment, a BHE-off test was performed in selected patients. The protocol of the BHE-off test and the criteria for BHE explantation were based on previous reports [5, 6]. During systemic heparinization, the BHE rate was gradually decreased and then stopped completely with careful real-time echocardiography. After 10 min of the heart beating without mechanical support, cardiac function was assessed by cardiac catheterization and echocardiography. BHE explantation criteria were the following: (i) left ventricular end-diastolic diameter (LVDd) <98th percentile (z-score < +2); (ii) left ventricular ejection fraction (LVEF) ≥45%; (iii) no inotropic support; (iv) lactate <3 mmol/l; (v) pulmonary capillary wedge pressure <3 mmHg; and (vi) resting cardiac index >2.8 l/min/m2. Berlin Heart EXCOR explantation and follow-up The BHE explantation was performed through median sternotomy with mild hypothermic cardiopulmonary bypass. The heart was kept beating. The inflow apical cannula was completely removed, and the full layer of the cannulation site was closed with mattress running suture and over-and-over suture using 5-mm width strip of expanded polytetrafluoroethylene. After BHE explantation, dobutamine and milrinone were routinely administered. HF medication was restarted as soon as oral feeding recommenced. After the discontinuation of catecholamine, cardiac catheterization was performed to examine the possibility of discharge. Cardiac catheterization was routinely performed to assess cardiac function at 3 months, 6 months and each year after BHE explantation. Histological analysis and correlation study between histological data and clinical data The LV myocardial biopsy was obtained from the LV apex at BHE implantation. Samples were embedded in paraffin, cut into 5-μm-thick sections and stained with haematoxylin–eosin, Masson’s trichrome stain or specific antibody. The percentage of myocardial fibrosis was assessed with MetaMorph 6.2 imaging software (Universal Imaging Corp, Downingtown, PA, USA). Five fields of the mid-layers of the LV wall per slide were analysed, and the average of these fibrotic areas was calculated. The density of CD31+ vessels was assessed by counting the absolute number of CD31 antibody (ab28364; Abcam, Cambridge, UK)-positive microcapillaries out of 5 high-power fields using the BZ-analysis software application (Keyence, Tokyo, Japan). Correlation studies were performed between histological data (the percentage of myocardial fibrosis and capillary vascular density) and clinical data (LVEF and LVDd). Statistical analysis Statistical analysis was performed using JMP Pro, version 14 (SAS Institute Inc., Cary, NC, USA). Data were described as the mean (SD) or median (25th to 75th percentile interquartile range). Categorical variables were analysed using the Pearson’s χ2 test or Fisher’s exact test, as appropriate. Continuous variables with a normal distribution and continuous variables with non-normal distributions were analysed using the Student’s t-test and Man–Whitney U-test, respectively. The z-score of LVDd was calculated according to the report from Lopez et al. [15]. No correction for multiple testing was performed. All the statistical tests were 2-sided, and the P-values of 0.05 or less were considered statistically significant. RESULTS Follow-up was completed in all patients with the median follow-up period of 3.6 years (interquartile range 2.4–4.2) after BHE implantation with no case of mortality. The patient baseline characteristics are shown in Tables 1 and 2. The recovery group (n = 4) showed significant recovery of cardiac function and underwent successful BHE explantation after support periods of 3.7–14 months. All patients were discharged to home 5.6–8.2 months after BHE explantation. During follow-up, all patients were doing well with no re-hospitalization for HF. While the HF symptoms were clinically resolved, the patients in the recovery group still have a risk of future exacerbations. In Japan, the previous waiting period for heart transplantation would not be considered if the patients were removed from the list. For these reasons, patients after explantation are still on the waiting list under status 2. The non-recovery group (n = 6) showed persistent LV dysfunction and underwent heart transplantation after support periods of 9.1–22 months. Table 1: Pre-implant characteristics for each patient . Age at BHE implantation (years) . BW at BHE implantation (kg) . Preoperative MV/MCS . LVDd (mm/z-score) . LVEF (%) . PCWP (mmHg) . BNP (pg/ml) . Recovery group 1 2.1 8.4 +/+ 59/15.0 10 20 969 Recovery group 2 1.3 7.7 −/− 58/15.1 3.9 14 2197 Recovery group 3 0.58 6.8 +/+ 35/6.92 15 11 452 Recovery group 4 0.36 6.1 +/+ 43/12.5 18 8 2763 Non-recovery group 1 0.93 5.8 +/+ 46/13.3 13 21 2307 Non-recovery group 2 0.68 4.4 +/− 40/10.8 8 20 347 Non-recovery group 3 0.46 4.4 +/+ 51/17.6 8 23 2868 Non-recovery group 4 1.9 6.9 −/− 30/4.9 33 16 732 Non-recovery group 5 0.34 5 +/+ 30/5.7 18 15 6352 Non-recovery group 6 0.56 5.9 +/− 29/5.4 32 21 396 . Age at BHE implantation (years) . BW at BHE implantation (kg) . Preoperative MV/MCS . LVDd (mm/z-score) . LVEF (%) . PCWP (mmHg) . BNP (pg/ml) . Recovery group 1 2.1 8.4 +/+ 59/15.0 10 20 969 Recovery group 2 1.3 7.7 −/− 58/15.1 3.9 14 2197 Recovery group 3 0.58 6.8 +/+ 35/6.92 15 11 452 Recovery group 4 0.36 6.1 +/+ 43/12.5 18 8 2763 Non-recovery group 1 0.93 5.8 +/+ 46/13.3 13 21 2307 Non-recovery group 2 0.68 4.4 +/− 40/10.8 8 20 347 Non-recovery group 3 0.46 4.4 +/+ 51/17.6 8 23 2868 Non-recovery group 4 1.9 6.9 −/− 30/4.9 33 16 732 Non-recovery group 5 0.34 5 +/+ 30/5.7 18 15 6352 Non-recovery group 6 0.56 5.9 +/− 29/5.4 32 21 396 BHE: Berlin Heart EXCOR®; BNP: brain natriuretic peptide; BW: body weight; LVDd: left ventricular end-diastolic diameter; LVEF: left ventricular ejection fraction; MCS: mechanical circulatory support; MV: mechanical ventilation; PCWP: pulmonary capillary wedge pressure. Open in new tab Table 1: Pre-implant characteristics for each patient . Age at BHE implantation (years) . BW at BHE implantation (kg) . Preoperative MV/MCS . LVDd (mm/z-score) . LVEF (%) . PCWP (mmHg) . BNP (pg/ml) . Recovery group 1 2.1 8.4 +/+ 59/15.0 10 20 969 Recovery group 2 1.3 7.7 −/− 58/15.1 3.9 14 2197 Recovery group 3 0.58 6.8 +/+ 35/6.92 15 11 452 Recovery group 4 0.36 6.1 +/+ 43/12.5 18 8 2763 Non-recovery group 1 0.93 5.8 +/+ 46/13.3 13 21 2307 Non-recovery group 2 0.68 4.4 +/− 40/10.8 8 20 347 Non-recovery group 3 0.46 4.4 +/+ 51/17.6 8 23 2868 Non-recovery group 4 1.9 6.9 −/− 30/4.9 33 16 732 Non-recovery group 5 0.34 5 +/+ 30/5.7 18 15 6352 Non-recovery group 6 0.56 5.9 +/− 29/5.4 32 21 396 . Age at BHE implantation (years) . BW at BHE implantation (kg) . Preoperative MV/MCS . LVDd (mm/z-score) . LVEF (%) . PCWP (mmHg) . BNP (pg/ml) . Recovery group 1 2.1 8.4 +/+ 59/15.0 10 20 969 Recovery group 2 1.3 7.7 −/− 58/15.1 3.9 14 2197 Recovery group 3 0.58 6.8 +/+ 35/6.92 15 11 452 Recovery group 4 0.36 6.1 +/+ 43/12.5 18 8 2763 Non-recovery group 1 0.93 5.8 +/+ 46/13.3 13 21 2307 Non-recovery group 2 0.68 4.4 +/− 40/10.8 8 20 347 Non-recovery group 3 0.46 4.4 +/+ 51/17.6 8 23 2868 Non-recovery group 4 1.9 6.9 −/− 30/4.9 33 16 732 Non-recovery group 5 0.34 5 +/+ 30/5.7 18 15 6352 Non-recovery group 6 0.56 5.9 +/− 29/5.4 32 21 396 BHE: Berlin Heart EXCOR®; BNP: brain natriuretic peptide; BW: body weight; LVDd: left ventricular end-diastolic diameter; LVEF: left ventricular ejection fraction; MCS: mechanical circulatory support; MV: mechanical ventilation; PCWP: pulmonary capillary wedge pressure. Open in new tab Table 2: Pre-implantation characteristics . Recovery group . Non-recovery group . P-value . Number of patients 4 (m:0, f:4) 6 (m:2, f:4) Age at HF exacerbation (months) 7.1 (3.2) 3.2 (2.6) 0.09 Age at BHE implantation (months) 13 (9.6) 9.6 (7.2) 0.57 BW at BHE implantation (kg) 7.3 (1.0) 5.4 (1.0) 0.026* Pre-implant mechanical ventilation 3 5 1.0 Pre-implant MCS 3 3 0.57 INTERMACS profile 1 3 3 0.57 INTERMACS profile 2 1 3 LVDd (z-score) 12 (3.8) 9.6 (5.2) 0.36 LVEF (%) 12 (6) 19 (11) 0.25 MR > moderate (n) 3 4 0.78 CVP (mmHg) 7.8 (2.4) 5.2 (1.9) 0.12 Mean PAP (mmHg) 21 (6.0) 26 (2.7) 0.15 PCWP (mmHg) 13 (5) 19 (3) 0.093 BNP (pg/ml) 1583 (840–2339) 1519 (480–2728) 0.61 . Recovery group . Non-recovery group . P-value . Number of patients 4 (m:0, f:4) 6 (m:2, f:4) Age at HF exacerbation (months) 7.1 (3.2) 3.2 (2.6) 0.09 Age at BHE implantation (months) 13 (9.6) 9.6 (7.2) 0.57 BW at BHE implantation (kg) 7.3 (1.0) 5.4 (1.0) 0.026* Pre-implant mechanical ventilation 3 5 1.0 Pre-implant MCS 3 3 0.57 INTERMACS profile 1 3 3 0.57 INTERMACS profile 2 1 3 LVDd (z-score) 12 (3.8) 9.6 (5.2) 0.36 LVEF (%) 12 (6) 19 (11) 0.25 MR > moderate (n) 3 4 0.78 CVP (mmHg) 7.8 (2.4) 5.2 (1.9) 0.12 Mean PAP (mmHg) 21 (6.0) 26 (2.7) 0.15 PCWP (mmHg) 13 (5) 19 (3) 0.093 BNP (pg/ml) 1583 (840–2339) 1519 (480–2728) 0.61 Continuous data are presented as mean (standard deviation) or median (interquartile range), while categorical data are shown as the number of observations. * P < 0.05. BHE: Berlin Heart EXCOR®; BNP: brain natriuretic peptide; BW: body weight; CVP: central venous pressure; f: female; HF: heart failure; LVDd: left ventricular end-diastolic diameter; LVEF: left ventricular ejection fraction; m: male; MCS: mechanical circulatory support; MR: mitral regurgitation; n: number; PAP: •••; PCWP: pulmonary capillary wedge pressure. Open in new tab Table 2: Pre-implantation characteristics . Recovery group . Non-recovery group . P-value . Number of patients 4 (m:0, f:4) 6 (m:2, f:4) Age at HF exacerbation (months) 7.1 (3.2) 3.2 (2.6) 0.09 Age at BHE implantation (months) 13 (9.6) 9.6 (7.2) 0.57 BW at BHE implantation (kg) 7.3 (1.0) 5.4 (1.0) 0.026* Pre-implant mechanical ventilation 3 5 1.0 Pre-implant MCS 3 3 0.57 INTERMACS profile 1 3 3 0.57 INTERMACS profile 2 1 3 LVDd (z-score) 12 (3.8) 9.6 (5.2) 0.36 LVEF (%) 12 (6) 19 (11) 0.25 MR > moderate (n) 3 4 0.78 CVP (mmHg) 7.8 (2.4) 5.2 (1.9) 0.12 Mean PAP (mmHg) 21 (6.0) 26 (2.7) 0.15 PCWP (mmHg) 13 (5) 19 (3) 0.093 BNP (pg/ml) 1583 (840–2339) 1519 (480–2728) 0.61 . Recovery group . Non-recovery group . P-value . Number of patients 4 (m:0, f:4) 6 (m:2, f:4) Age at HF exacerbation (months) 7.1 (3.2) 3.2 (2.6) 0.09 Age at BHE implantation (months) 13 (9.6) 9.6 (7.2) 0.57 BW at BHE implantation (kg) 7.3 (1.0) 5.4 (1.0) 0.026* Pre-implant mechanical ventilation 3 5 1.0 Pre-implant MCS 3 3 0.57 INTERMACS profile 1 3 3 0.57 INTERMACS profile 2 1 3 LVDd (z-score) 12 (3.8) 9.6 (5.2) 0.36 LVEF (%) 12 (6) 19 (11) 0.25 MR > moderate (n) 3 4 0.78 CVP (mmHg) 7.8 (2.4) 5.2 (1.9) 0.12 Mean PAP (mmHg) 21 (6.0) 26 (2.7) 0.15 PCWP (mmHg) 13 (5) 19 (3) 0.093 BNP (pg/ml) 1583 (840–2339) 1519 (480–2728) 0.61 Continuous data are presented as mean (standard deviation) or median (interquartile range), while categorical data are shown as the number of observations. * P < 0.05. BHE: Berlin Heart EXCOR®; BNP: brain natriuretic peptide; BW: body weight; CVP: central venous pressure; f: female; HF: heart failure; LVDd: left ventricular end-diastolic diameter; LVEF: left ventricular ejection fraction; m: male; MCS: mechanical circulatory support; MR: mitral regurgitation; n: number; PAP: •••; PCWP: pulmonary capillary wedge pressure. Open in new tab Left ventricular function after Berlin Heart EXCOR implantation No significant differences were shown in the z-score of LVDd and LVEF between the 2 groups at 3 months after BHE implantation. However, the changes in LVDd (ΔLVDd) and LVEF (ΔLVEF) during the 3 months after BHE implantation were significantly greater in the recovery group than in the non-recovery group. The echocardiography within 1 week before BHE explantation or heart transplantation in each group showed significantly lower z-score of LVDd and higher LVEF in the recovery group than in the non-recovery group [1.1 (SD 1.3) vs 6.2 (3.6), P = 0.017, and 58 (9) vs 25 (13), P = 0.002, respectively; Fig. 1 and Table 3]. Figure 1: Open in new tabDownload slide ΔLVDd and ΔLVEF over time after Berlin Heart EXCOR® (BHE) implantation. LVDd and LVEF were measured before BHE implantation, 3 months after BHE and at the final follow-up before BHE explantation or heart transplantation in both groups, including after BHE explantation in the recovery group. ΔLVDd and ΔLVEF during 3 months after BHE implantation were significantly greater in the recovery group. The final echocardiography before BHE explantation or heart transplantation showed a significantly lower z-score of LVDd and higher LVEF in the recovery group. *P < 0.05, †P < 0.01. f/u: follow-up; LVDd: left ventricular end-diastolic diameter; LVEF: left ventricular ejection fraction; post-explant.: post-BHE explantation; ΔLVDd: the change in LVDd; ΔLVEF: the change in LVEF. Figure 1: Open in new tabDownload slide ΔLVDd and ΔLVEF over time after Berlin Heart EXCOR® (BHE) implantation. LVDd and LVEF were measured before BHE implantation, 3 months after BHE and at the final follow-up before BHE explantation or heart transplantation in both groups, including after BHE explantation in the recovery group. ΔLVDd and ΔLVEF during 3 months after BHE implantation were significantly greater in the recovery group. The final echocardiography before BHE explantation or heart transplantation showed a significantly lower z-score of LVDd and higher LVEF in the recovery group. *P < 0.05, †P < 0.01. f/u: follow-up; LVDd: left ventricular end-diastolic diameter; LVEF: left ventricular ejection fraction; post-explant.: post-BHE explantation; ΔLVDd: the change in LVDd; ΔLVEF: the change in LVEF. Table 3: Post-implantation course . Recovery group . Non-recovery group . P-value . 3 months after BHE implantation  LVDd z-score 2.8 (2.0) 6.0 (4.3) 0.15  ΔLVDd z-score (3m-pre) −9.6 (3.5) −3.6 (4.5) 0.045*  LVEF (%) 48 (8) 32 (16) 0.074  ΔLVEF (3m-pre) (%) 36 (13) 13 (13) 0.032*  BNP (pg/ml) 37 (11) 216 (180) 0.059  Aortic valve opening Every beat: 4 Every beat: 3 Intermittent: 3 Last follow-up with BHE  LVDd z-score 1.1 (1.3) 6.0 (4.3) 0.017*  LVEF (%) 58 (9) 25 (13) 0.002†  BNP (pg/ml) 34 (30–39) 275 (138–362) 0.12  Aortic valve opening Every beat: 4 Every beat: 3 Intermittent: 1 Close: 2 BHE support duration (month) 9.1 (3.7–14.2) 12 (9.1–22) 0.23 . Recovery group . Non-recovery group . P-value . 3 months after BHE implantation  LVDd z-score 2.8 (2.0) 6.0 (4.3) 0.15  ΔLVDd z-score (3m-pre) −9.6 (3.5) −3.6 (4.5) 0.045*  LVEF (%) 48 (8) 32 (16) 0.074  ΔLVEF (3m-pre) (%) 36 (13) 13 (13) 0.032*  BNP (pg/ml) 37 (11) 216 (180) 0.059  Aortic valve opening Every beat: 4 Every beat: 3 Intermittent: 3 Last follow-up with BHE  LVDd z-score 1.1 (1.3) 6.0 (4.3) 0.017*  LVEF (%) 58 (9) 25 (13) 0.002†  BNP (pg/ml) 34 (30–39) 275 (138–362) 0.12  Aortic valve opening Every beat: 4 Every beat: 3 Intermittent: 1 Close: 2 BHE support duration (month) 9.1 (3.7–14.2) 12 (9.1–22) 0.23 Continuous data are presented as mean (standard deviation) or median (interquartile range), while categorical data are presented as the number of observations. The final follow-up study was conducted before BHE explantation or heart transplantation. * P < 0.05. † P < 0.01. BHE: Berlin Heart EXCOR®; BNP: brain natriuretic peptide; LVDd: left ventricular end-diastolic diameter; LVEF: left ventricular ejection fraction; ΔLVDd: the change in LVDd; ΔLVEF: the change in LVEF; 3m-pre: difference between 3 months after implantation and pre-implantation. Open in new tab Table 3: Post-implantation course . Recovery group . Non-recovery group . P-value . 3 months after BHE implantation  LVDd z-score 2.8 (2.0) 6.0 (4.3) 0.15  ΔLVDd z-score (3m-pre) −9.6 (3.5) −3.6 (4.5) 0.045*  LVEF (%) 48 (8) 32 (16) 0.074  ΔLVEF (3m-pre) (%) 36 (13) 13 (13) 0.032*  BNP (pg/ml) 37 (11) 216 (180) 0.059  Aortic valve opening Every beat: 4 Every beat: 3 Intermittent: 3 Last follow-up with BHE  LVDd z-score 1.1 (1.3) 6.0 (4.3) 0.017*  LVEF (%) 58 (9) 25 (13) 0.002†  BNP (pg/ml) 34 (30–39) 275 (138–362) 0.12  Aortic valve opening Every beat: 4 Every beat: 3 Intermittent: 1 Close: 2 BHE support duration (month) 9.1 (3.7–14.2) 12 (9.1–22) 0.23 . Recovery group . Non-recovery group . P-value . 3 months after BHE implantation  LVDd z-score 2.8 (2.0) 6.0 (4.3) 0.15  ΔLVDd z-score (3m-pre) −9.6 (3.5) −3.6 (4.5) 0.045*  LVEF (%) 48 (8) 32 (16) 0.074  ΔLVEF (3m-pre) (%) 36 (13) 13 (13) 0.032*  BNP (pg/ml) 37 (11) 216 (180) 0.059  Aortic valve opening Every beat: 4 Every beat: 3 Intermittent: 3 Last follow-up with BHE  LVDd z-score 1.1 (1.3) 6.0 (4.3) 0.017*  LVEF (%) 58 (9) 25 (13) 0.002†  BNP (pg/ml) 34 (30–39) 275 (138–362) 0.12  Aortic valve opening Every beat: 4 Every beat: 3 Intermittent: 1 Close: 2 BHE support duration (month) 9.1 (3.7–14.2) 12 (9.1–22) 0.23 Continuous data are presented as mean (standard deviation) or median (interquartile range), while categorical data are presented as the number of observations. The final follow-up study was conducted before BHE explantation or heart transplantation. * P < 0.05. † P < 0.01. BHE: Berlin Heart EXCOR®; BNP: brain natriuretic peptide; LVDd: left ventricular end-diastolic diameter; LVEF: left ventricular ejection fraction; ΔLVDd: the change in LVDd; ΔLVEF: the change in LVEF; 3m-pre: difference between 3 months after implantation and pre-implantation. Open in new tab Left ventricular function after Berlin Heart EXCOR explantation in the recovery group During the median follow-up period of 24 months (interquartile range 17–27) after BHE explantation, cardiac function and brain natriuretic peptide levels remained almost normal in all patients in the recovery group (Table 4). Table 4: Post-explantation course in recovery group . Pre-explantation . ≤6 months . 1 year . 2 years . Case 1  LVDd (z-score) 0.13 2.13 0.31 −0.46  LVEF (%) 65 52 60 60  PCWP (mmHg) 5 7 5  BNP (pg/ml) 34.9 29 39.6 21.2 Case 2  LVDd (z-score) 0.17 6.26 −0.47 −0.2  LVEF (%) 64 61 59 48  PCWP (mmHg) 10 6 4  BNP (pg/ml) 43.7 36.3 21 16.6 Case 3  LVDd (z-score) 1.19 −0.93 −0.40  LVEF (%) 58 50 68  PCWP (mmHg) 3 6 5  BNP (pg/ml) 29.7 11.9 19.8 Case 4  LVDd (z-score) 2.82 −1.15  LVEF (%) 45 60  PCWP (mmHg) 3 5  BNP (pg/ml) 37 25.8 . Pre-explantation . ≤6 months . 1 year . 2 years . Case 1  LVDd (z-score) 0.13 2.13 0.31 −0.46  LVEF (%) 65 52 60 60  PCWP (mmHg) 5 7 5  BNP (pg/ml) 34.9 29 39.6 21.2 Case 2  LVDd (z-score) 0.17 6.26 −0.47 −0.2  LVEF (%) 64 61 59 48  PCWP (mmHg) 10 6 4  BNP (pg/ml) 43.7 36.3 21 16.6 Case 3  LVDd (z-score) 1.19 −0.93 −0.40  LVEF (%) 58 50 68  PCWP (mmHg) 3 6 5  BNP (pg/ml) 29.7 11.9 19.8 Case 4  LVDd (z-score) 2.82 −1.15  LVEF (%) 45 60  PCWP (mmHg) 3 5  BNP (pg/ml) 37 25.8 BNP: brain natriuretic peptide; LVDd: left ventricular end-diastolic diameter; LVEF: left ventricular ejection fraction; PCWP: pulmonary capillary wedge pressure. Open in new tab Table 4: Post-explantation course in recovery group . Pre-explantation . ≤6 months . 1 year . 2 years . Case 1  LVDd (z-score) 0.13 2.13 0.31 −0.46  LVEF (%) 65 52 60 60  PCWP (mmHg) 5 7 5  BNP (pg/ml) 34.9 29 39.6 21.2 Case 2  LVDd (z-score) 0.17 6.26 −0.47 −0.2  LVEF (%) 64 61 59 48  PCWP (mmHg) 10 6 4  BNP (pg/ml) 43.7 36.3 21 16.6 Case 3  LVDd (z-score) 1.19 −0.93 −0.40  LVEF (%) 58 50 68  PCWP (mmHg) 3 6 5  BNP (pg/ml) 29.7 11.9 19.8 Case 4  LVDd (z-score) 2.82 −1.15  LVEF (%) 45 60  PCWP (mmHg) 3 5  BNP (pg/ml) 37 25.8 . Pre-explantation . ≤6 months . 1 year . 2 years . Case 1  LVDd (z-score) 0.13 2.13 0.31 −0.46  LVEF (%) 65 52 60 60  PCWP (mmHg) 5 7 5  BNP (pg/ml) 34.9 29 39.6 21.2 Case 2  LVDd (z-score) 0.17 6.26 −0.47 −0.2  LVEF (%) 64 61 59 48  PCWP (mmHg) 10 6 4  BNP (pg/ml) 43.7 36.3 21 16.6 Case 3  LVDd (z-score) 1.19 −0.93 −0.40  LVEF (%) 58 50 68  PCWP (mmHg) 3 6 5  BNP (pg/ml) 29.7 11.9 19.8 Case 4  LVDd (z-score) 2.82 −1.15  LVEF (%) 45 60  PCWP (mmHg) 3 5  BNP (pg/ml) 37 25.8 BNP: brain natriuretic peptide; LVDd: left ventricular end-diastolic diameter; LVEF: left ventricular ejection fraction; PCWP: pulmonary capillary wedge pressure. Open in new tab Myocardial fibrosis and capillary vascular density The percentages of myocardial fibrosis assessed by Masson’s trichrome staining were 16 (SD 6) in the recovery group and 28 (6) in the non-recovery group (Fig. 2). The recovery group showed a significantly lower degree of myocardial fibrosis at the mid-mural layer (P = 0.021). Capillary vascular densities assessed by CD31 immunostaining were 65 (11) units/high-power field in the recovery group and 43 (18) units/high-power field in the non-recovery group at the mid-mural layer (Fig. 2). The capillary vascular density was significantly higher in the recovery group (P = 0.037). The degree of myocardial fibrosis and capillary vascular density were correlated with the preoperative pulmonary capillary wedge pressure, respectively (%fibrosis: r2 = 0.41, P = 0.045, and capillary vascular density: r2 = 0.63, P = 0.006; Fig. 2). Figure 2: Open in new tabDownload slide Histological findings. (A) Representative photomicrographs (×200, scale bar = 100 μm) of Masson’s trichrome staining at mid-mural layer. Percentage of myocardial fibrosis was significantly lower in the recovery group. (B) Representative photomicrographs (×400, scale bar = 100 μm) of anti-CD31 staining at the mid-mural layer. The capillary vascular density was significantly lower in the non-recovery group. The degree of myocardial fibrosis and capillary vascular density were correlated with the preoperative PCWP. *P < 0.05, †P < 0.01. HPF: high-power field; PCWP: pulmonary capillary wedge pressure. Figure 2: Open in new tabDownload slide Histological findings. (A) Representative photomicrographs (×200, scale bar = 100 μm) of Masson’s trichrome staining at mid-mural layer. Percentage of myocardial fibrosis was significantly lower in the recovery group. (B) Representative photomicrographs (×400, scale bar = 100 μm) of anti-CD31 staining at the mid-mural layer. The capillary vascular density was significantly lower in the non-recovery group. The degree of myocardial fibrosis and capillary vascular density were correlated with the preoperative PCWP. *P < 0.05, †P < 0.01. HPF: high-power field; PCWP: pulmonary capillary wedge pressure. The degree of pre-BHE myocardial fibrosis was correlated with LVEF, and the capillary vascular density was correlated with the z-score of LVDd and LVEF at a mean of 8 months after BHE implantation (r2 = 0.6, P = 0.009; r2 = 0.65, P = 0.005; and r2 = 0.52, P = 0.019, respectively; Fig. 3). Figure 3: Open in new tabDownload slide The correlation of %fibrosis and capillary vascular density with LVDd and LVEF. The %fibrosis at pre-BHE implantation was correlated with LVEF at the last follow-up, and the capillary vascular density at pre-BHE implantation was correlated with the z-score of LVDd and LVEF at the final follow-up. *P < 0.05, †P < 0.01. BHE: Berlin Heart EXCOR®; f/u: follow-up; LVDd: left ventricular end-diastolic diameter; LVEF: left ventricular ejection fraction; pre-BHE: pre-BHE implantation. Figure 3: Open in new tabDownload slide The correlation of %fibrosis and capillary vascular density with LVDd and LVEF. The %fibrosis at pre-BHE implantation was correlated with LVEF at the last follow-up, and the capillary vascular density at pre-BHE implantation was correlated with the z-score of LVDd and LVEF at the final follow-up. *P < 0.05, †P < 0.01. BHE: Berlin Heart EXCOR®; f/u: follow-up; LVDd: left ventricular end-diastolic diameter; LVEF: left ventricular ejection fraction; pre-BHE: pre-BHE implantation. DISCUSSION The main findings of this study were as the following. First, bridge to recovery with BHE was demonstrated in patients who had significantly less LV myocardial fibrosis and high capillary vascular density at BHE implantation. In these patients, LV function was significantly improved at 3 months after BHE implantation and BHE was successfully explanted. Second, the degree of LV myocardial fibrosis and capillary vascular density at BHE implantation were significantly correlated with haemodynamic parameters before BHE implantation and improvement of LV function during BHE support. Considering severe donor shortage and high incidence of morbidity related to VAD implantation, the bridge to recovery and possibility of VAD explantation could be a useful alternative strategy in patients with end-stage HF. Our group previously reported that a lower degree of fibrosis in the LV was predictive of successful bridge to recovery during VAD support in adult patients with DCM [12, 13]. In paediatric patients, Ihnat et al. [16] initially reported 8 young patients who underwent successful weaning from VAD. Recently, Hetzer et al. and Miera et al. reported almost 20-year experience of bridge to recovery in paediatric patients on VAD [5, 9]. These reports include heterogeneous aetiology of HF supported with inconsistent types of VAD. In the present study, 10 paediatric patients <10 kg with DCM were treated with BHE, 4 of whom showed improvement in LV function, which was sustained for at least 8 months after BHE explantation. Similar to adult patients, the less injured myocardial histology at VAD implantation may predict better outcomes in bridge to recovery in paediatric patients with DCM. The impact of mechanical unloading of the LV with a VAD on the structural reverse remodelling and the improvement of cardiac function have been widely investigated in adult DCM patients [12, 13, 17, 18]. In paediatric patients, Mohapatra et al. [19] demonstrated that short-term left ventricular assist device therapy (8–16 days) in paediatric DCM patients was associated with molecular reverse remodelling of the failing heart. Kasten et al. [20] reported the histological reverse remodelling after mechanical unloading of the LV in paediatric patients with DCM after a support period of median 17.5 (8–223) days. In the present study, less injured myocardial histology at VAD implantation was shown to be associated with a high probability of cardiac recovery with mechanical unloading. According to these results, the less injured myocardial histology would likely be reverse remodelled with mechanical unloading, which may lead to improvement in cardiac function in paediatric patients with DCM. However, it should be noted that whether the histological and functional improvements in LV were sustained after BHE explantation is unclear. While the present study showed the initial experience of BHE explantation with sustained LV function during follow-up, the long-term outcomes after BHE explantation should be examined in further studies. The present study showed a higher recovery rate (40%) in young DCM patients with long-term BHE support than the previous studies [5, 7, 8, 21]. The young age at VAD implantation was reported to be a positive predictor for cardiac recovery in paediatric patients [21, 22]. This is partly explained by the age-dependent reverse remodelling on VAD at the histological level with a higher reduction in interstitial fibrosis in young patients [20]. In most of the previous studies, children weaned from VAD are characterized by short-term support with acute onset of HF typically seen in myocarditis [5, 6, 8, 16]. In the present study, all patients were diagnosed with idiopathic DCM without preceding myocarditis. Considering the chronic myocardial condition in idiopathic DCM, long-term support with VAD might be required to obtain cardiac recovery; however, the long-term support would lead to increased VAD-associated complications. Therefore, the optimal duration for BHE support to obtain successful BHE explantation should be examined in a further study. Limitations First, significant limitations of this study include its small sample size and its retrospective, single-centre design, so any statistical analysis may not have sufficient power to draw firm conclusions. Second, the histological findings from the LV apex do not always represent those of the whole heart. CONCLUSION In paediatric patients <10 kg with DCM, bridge to recovery with BHE implantation was achieved in patients with less injured LV myocardial histology at BHE implantation. The results of the present study contribute to the insights into the factors associated with functional improvement of the LV with BHE implantation. Presented at the 33rd Annual Meeting of the European Association for Cardio-Thoracic Surgery, Lisbon, Portugal, 3–5 October 2019. Acknowledgments The authors are grateful to Shigetoyo Kogaki, Masaki Taira, Sanae Yamauchi, Ryo Ishii, Akima Harada, Naoki Okuda, Kanta Araki and Takuji Watanabe for helpful discussions and comments on the manuscript. The authors would like to thank Editage (http://www.editage.jp) for English language editing. Conflict of interest: none declared. Author contributions Yuji Tominaga: Conceptualization; Data curation; Formal analysis; Investigation; Methodology; Project administration; Writing—original draft; Writing—review & editing. Takayoshi Ueno: Conceptualization; Supervision; Validation; Writing—review & editing. Takashi Kido: Conceptualization; Data curation; Project administration; Supervision; Writing—review & editing. Tomomitsu Kanaya: Data curation; Methodology; Writing—review & editing. Jun Narita: Conceptualization; Methodology; Writing—review & editing. Hidekazu Ishida: Conceptualization; Data curation; Methodology; Supervision; Writing—review & editing. Koichi Toda: Conceptualization; Supervision. Toru Kuratani: Conceptualization; Supervision. Yoshiki Sawa: Conceptualization; Supervision; Writing—review & editing. REFERENCES 1 Morgan CT , Manlhiot C , McCrindle BW , Dipchand AI. 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Journal

European Journal of Cardio-Thoracic SurgeryOxford University Press

Published: Aug 13, 18

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