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Long-term heart transplant outcomes after lowering fixed pulmonary hypertension using left ventricular assist devices†

Long-term heart transplant outcomes after lowering fixed pulmonary hypertension using left... Abstract OBJECTIVES Fixed pulmonary hypertension (fPH) is a contraindication for heart transplantation (HTX). Left ventricular assist device (LVAD) implantation as a bridge to candidacy can reverse fPH in patients with terminal heart failure by chronic left ventricular unloading. We report our institutional experience with terminal heart failure patients and fPH that were successfully bridged to candidacy and underwent subsequent HTX. METHODS We retrospectively reviewed the data of 79 patients with terminal heart failure and fPH who were successfully bridged to candidacy for HTX with 6 different LVAD devices at our centre from October 1998 to September 2016 (Novacor n = 4, MicroMed DeBakey n = 29, DuraHeart n = 2, HeartMate II n = 14, HVAD n = 29 and MVAD n = 1). Median duration of LVAD support was 288 days (range 45–2279 days). Within the same timeframe, a control group of 48 patients underwent HTX after bridge-to-transplant LVAD therapy for reasons other than PH. Study end points were (i) development of fPH after LVAD implantation, (ii) post-transplant outcomes and (iii) incidence of severe adverse events. RESULTS Pulmonary vascular resistance, assessed by vasodynamic catheterization, was 4.3 ± 1.8 WU before LVAD implantation. After a median support period of 89 days (interquartile range 4–156 days), pulmonary vascular resistance decreased to 2.0 ± 0.9 WU (P ≤ 0.001), and patients were listed for HTX. Median duration of LVAD support in the study group was 288 days (45–2279 days). We observed 2 patients (2.5%) with acute right heart failure who required extracorporeal mechanical support after HTX in the study group. Long-term post-transplant survival between the study group (3 years: 83.5%, 5 years: 81.0%) and the control group (3 years: 87.5%, 5 years: 85.4%) was comparable (log-rank: P = 0.585). CONCLUSIONS LVAD implantation as a bridge to candidacy reverses fPH in patients with terminal heart failure. Post-HTX survival is excellent and comparable to results obtained in patients without fPH at the time of HTX listing. Left ventricular assist device, Heart transplantation, Pulmonary hypertension, Long-term outcome INTRODUCTION Heart transplantation (HTX) is the standard treatment for end-stage heart failure patients. Fixed pulmonary hypertension (fPH) is an established contraindication for HTX [1]. Although cut-off values for HTX in patients with fPH vary throughout the literature, there is a consensus that a systolic pulmonary arterial pressure (PAPsys) ≥50 mmHg, a transpulmonary gradient (TPG) ≥15 mmHg and a pulmonary vascular resistance (PVR) >3.0 WU, when unresponsive to fully exploited vasodilator treatment, are useful threshold values [2–4]. Previous reports demonstrated that HTX recipients with pretransplant fPH are subjected to higher post-transplant mortality due to a higher risk of post-transplant failure of the non-conditioned right ventricle [2, 3, 5–9]. Treatment options in HTX recipients with fPH are limited. Procedures such as heterotopic and right ventricle sparing transplantation techniques have been described in previous studies [10–13]. Recognized complications of these surgical techniques include (i) technical difficulties during heart implantation, as well as (ii) ventricular arrhythmias, (iii) reduced exercise capacity, (iv) persistence of angina and (v) progression of native valvular disease as a result of interactions between the donor and recipient hearts [14]. Due to significantly higher mortality rates compared to orthotopic HTX following left ventricular assist device (LVAD) implantation, the use of heterotopic HTX is only considered under special circumstances [14]. Reversing fPH using LVADs prior to HTX is a potential treatment option for HTX recipients suffering from fPH [4]. This is attributed to the LVAD’s ability to continuously unload the left ventricle and thereby reduce left-sided filling pressures [1]. We report our institutional experience with terminal heart failure patients and fPH that were successfully bridged to candidacy and underwent subsequent HTX. MATERIALS AND METHODS The Ethics Committee of the Medical University Vienna (EC Number: 1733/2017) approved this retrospective single-centre study. Patient population From October 1998 to September 2016, 677 consecutive patients with terminal heart failure, of which 127 received an LVAD prior to transplantation, underwent HTX at our centre. Of these 127 patients, 79 were diagnosed with fPH during right heart catheterization with vasodynamic testing at the time of transplant evaluation and were therefore refused from HTX listing. Following an institutional protocol that has been described previously [5], these patients then underwent LVAD implantation as a bridge to candidacy. After successful LVAD implantation and rehabilitation, these 79 patients underwent re-catheterization and were listed as soon as haemodynamic values had normalized to a PAPsys <50 mmHg, a TPG <15 mmHg and a PVR <3.0 WU. Subsequently, all 79 patients underwent successful HTX. During the study period, fPH could successfully be reversed using the described approach in all patients. No treatment failures were observed. Besides fPH, patients had to have no other HTX contraindication to qualify for this protocol (see also Fig. 1). Figure 1: View largeDownload slide Decision-making tree. HTX: heart transplantation; LVAD: left ventricular assist device; PAPsys: systolic pulmonary artery pressure; PVR: pulmonary vascular resistance; TPG: transpulmonary pressure gradient. Figure 1: View largeDownload slide Decision-making tree. HTX: heart transplantation; LVAD: left ventricular assist device; PAPsys: systolic pulmonary artery pressure; PVR: pulmonary vascular resistance; TPG: transpulmonary pressure gradient. Study end points were defined as (i) development of fPH after LVAD implantation, (ii) post-transplant outcome and long-term survival after HTX and (iii) incidence of severe adverse events. The last follow-up date of the study was 30 May 2017. No patient was lost to follow-up. Within the same timeframe, a total of 48 patients without pulmonary hypertension served as a control group. These patients underwent elective cardiac transplantation after bridge-to-transplant therapy via LVAD for reasons other than fPH. The main reasons for ventricular assist device implantation in the control group were acute cardiogenic shock and end-stage heart failure with reversible contraindications for cardiac transplantation. Right heart catheterization, vasodynamic testing and definition of fixed pulmonary hypertension Cardiac transplant candidates must undergo haemodynamic testing for pulmonary hypertension evaluation. Right heart catheterization was performed according to the guidelines published by the American College of Cardiology Foundation/American Heart Association (ACCF/AHA) using a Swan-Ganz thermodilution catheter [15]. The assessed variables crucial for PH diagnosis included (i) PAPsys (mmHg), (ii) mean pulmonary artery pressure (mmHg), (iii) PVR (WU) and (iv) cardiac output (litres per minute, measured by the Fick method). An elevated central venous pressure as a result of volume overload was measured pretransplant at an average of 13 ± 6 mmHg (n = 56), and thus it was not a contributing factor to pulmonary hypertension. PH was defined as a PAPsys ≥50 mmHg, a TPG ≥15 mmHg and a PVR >3.0 WU. Any potential to pharmacologically influence pulmonary pressures was tested in all patients by nitroglycerine, prostaglandin (PGI2) or levosimendan. Nitroglycerine was administered as an intravenous bolus injection with an initial dosage of 0.5 mg, followed by an additional dosage of 0.5 mg 10 min later. Prostaglandin was administered intravenously in dosages ranging from 0.01 to 0.2 µg/kg/min for a maximum of 24 h. Levosimendan was administered intravenously in dosages ranging from 0.1 to 0.2 µg/kg/min for 24 h. Pulmonary hypertension was considered irreversible if the haemodynamic measurements could not be significantly reduced to a PAPsys <50 mmHg, a TPG <15 mmHg and a PVR <3.0 WU after vasodynamic testing. Per our institutional guidelines, right heart catheterization was performed at an average of 3 months post-LVAD implantation. If pulmonary hypertension could be significantly reduced by LVAD support, patients were considered eligible for cardiac transplantation. However, if pulmonary hypertension was persistent, right heart catheterization had to be repeated every 3 months until a significant reduction of pulmonary hypertension could be achieved. In the presented patient population, haemodynamic measurements were performed during HTX evaluation as well as after a median of 89 days post-LVAD implantation. Twenty-six patients (32.9%) received oral pulmonary vasodilators (sildenafil) after successful LVAD implantation in dosages varying from 20 to 60 mg per day to promote normalization of pulmonary artery pressures. Left ventricular assist devices used Over the course of this study, 6 different LVAD systems were used to reverse fPH in HTX candidates. The technical details and implantation procedures of the MicroMed De Bakey (MicroMed Technology Inc., Houston, TX, USA), DuraHeart (Terumo Heart Inc., MI, USA), Novacor (World Heart Inc., Oakland, CA, USA), HeartMate II (Abbott, North Chicago, IL, USA) and HVAD (Medtronic, MN, USA) have been described previously [16–18]. One patient received the miniaturized ventricular assist device (MVAD, Medtronic) as part of a multicentre, prospective, non-randomized, single-arm trial to investigate the safety and performance of the device. Post-transplant immunosuppression regimen Early postoperative period induction therapy consists of antithymocyte globulin and mycophenolate mofetil. Maintenance immunosuppressive therapy was started 3–7 days post-induction therapy and utilized calcineurin inhibitors, Tacrolimus (Prograf®) or Cyclosporine (Sandimmun Neoral®), as well as tapering doses of glucocorticoids over the first year post-transplant. In high-risk patients prone to opportunistic infections with cytomegalovirus, antiviral therapy (valganciclovir; Valcyte®) was routinely performed in the early postoperative period. Statistical analysis The data are presented as frequency distributions and percentages. Continuous variable values are expressed as mean ± standard deviation or median and ranges. Categorical variables were compared using the χ2 test between the study group and the control group as appropriate. As a result of the sample size, the χ2 test was preferred to the Fisher’s exact test. Testing for normality of distribution was performed by the Kolmogorov–Smirnov test. Continuous data between HTX groups with and without fPH were compared using the 2-sample, unpaired t-test. The paired t-test was used to compare haemodynamic variables such as PAPsys, mean pulmonary artery pressure, cardiac output and PVR, both before and after LVAD implantation. Kaplan–Meier analysis was used to evaluate post-transplant survival, and the log-rank test was used to compare groups with a 2-sided P-value <0.05 being considered significant. All analyses were performed using IBM SPSS 23.0 (IBM Corp., Armonk, NY, USA) and GraphPad Prism Version 7.0a (GraphPad Software Inc., La Jolla, CA, USA). RESULTS Patient demographics Seventy-nine patients suffering from fPH were successfully bridged to candidacy for HTX and subsequently underwent HTX. Mean patient age was 54 ± 10 years (88.6% male). Underlying diseases were dilative (57.0%) and ischaemic cardiomyopathy (43.0%). All patients were in NYHA class IV and received maximum heart failure therapy prior to LVAD implantation. Besides fPH, patients had no other contraindication for HTX. The majority of patients (94.9%) received continuous blood flow LVADs (MicroMed DeBakey n = 29, DuraHeart n = 2, HeartMate II n = 14, HVAD n = 29). The Novacor pulsatile LVAD was implanted in 4 patients (5.1%). Median duration of LVAD support was 288 days (range 45–2279 days). The detailed patient characteristics of cardiac transplant recipients with and without fPH are presented in Table 1. Table 1: Patient demographics Pre-transplant patient demographics LVAD with fPH LVAD without fPH P-value (n = 79) (n = 48) Age at implant (years), mean ± SD 54 ± 10 50 ± 11 0.106 Sex: male, n (%) 70 (88.6) 42 (87.5) 0.851 Weight (kg), mean ± SD 81 ± 13 84 ± 14 0.270 Height (cm), mean ± SD 175 ± 8 177 ± 8 0.251 BMI (kg/m2), mean ± SD 26.5 ± 3.8 26.6 ± 3.3 0.829 Underlying disease, n (%) 0.010  Ischaemic CMP 34 (43.0) 22 (45.8)  Dilatative CMP 45 (57.0) 21 (43.8)  Other 0 (0) 5 (10.4) Device system, n (%) 0.314  Novacor 4 (5.1) 0 (0)  MicroMed DeBakey 29 (36.7) 13 (27.1)  DuraHeart Terumo 2 (2.5) 2 (4.2)  HeartMate II 14 (17.7) 13 (27.1)  HeartWare HVAD 29 (36.7) 19 (39.6)  HeartWare MVAD 1 (1.3) 0 (0)  Berlin Heart Incor 0 (0) 1 (2.1) High urgency, n (%) 17 (21.5) 8 (16.7) 0.505 High urgency reason, n (%) 0.739  Right heart failure 4 (23.5) 3 (37.5)  Pump thrombosis 5 (29.4) 2 (25.0)  Infection 3 (17.6) 2 (25.0)  Neurological event 2 (11.8) 0 (0)  Device malfunction 1 (5.9) 1 (12.5)  Electrical instability 2 (11.8) 0 (0) PRA, n (%)  0–10% 75 (94.9) 47 (97.9)  >10–30% 1 (1.3) 1 (2.1)  >30–90% 2 (2.5) 0 (0)  >90% 1 (1.3) 0 (0) Duration on LVAD, median (min−max) 288 (45–2279) 394 (0–2297) Donor age (years), mean ± SD 37 ± 12 36 ± 14 0.336 Donor sex male, n (%) 63 (79.7) 44 (91.7) 0.074 Sex mismatch, n (%) 13 (16.5) 6 (12.5) 0.545 Pre-transplant patient demographics LVAD with fPH LVAD without fPH P-value (n = 79) (n = 48) Age at implant (years), mean ± SD 54 ± 10 50 ± 11 0.106 Sex: male, n (%) 70 (88.6) 42 (87.5) 0.851 Weight (kg), mean ± SD 81 ± 13 84 ± 14 0.270 Height (cm), mean ± SD 175 ± 8 177 ± 8 0.251 BMI (kg/m2), mean ± SD 26.5 ± 3.8 26.6 ± 3.3 0.829 Underlying disease, n (%) 0.010  Ischaemic CMP 34 (43.0) 22 (45.8)  Dilatative CMP 45 (57.0) 21 (43.8)  Other 0 (0) 5 (10.4) Device system, n (%) 0.314  Novacor 4 (5.1) 0 (0)  MicroMed DeBakey 29 (36.7) 13 (27.1)  DuraHeart Terumo 2 (2.5) 2 (4.2)  HeartMate II 14 (17.7) 13 (27.1)  HeartWare HVAD 29 (36.7) 19 (39.6)  HeartWare MVAD 1 (1.3) 0 (0)  Berlin Heart Incor 0 (0) 1 (2.1) High urgency, n (%) 17 (21.5) 8 (16.7) 0.505 High urgency reason, n (%) 0.739  Right heart failure 4 (23.5) 3 (37.5)  Pump thrombosis 5 (29.4) 2 (25.0)  Infection 3 (17.6) 2 (25.0)  Neurological event 2 (11.8) 0 (0)  Device malfunction 1 (5.9) 1 (12.5)  Electrical instability 2 (11.8) 0 (0) PRA, n (%)  0–10% 75 (94.9) 47 (97.9)  >10–30% 1 (1.3) 1 (2.1)  >30–90% 2 (2.5) 0 (0)  >90% 1 (1.3) 0 (0) Duration on LVAD, median (min−max) 288 (45–2279) 394 (0–2297) Donor age (years), mean ± SD 37 ± 12 36 ± 14 0.336 Donor sex male, n (%) 63 (79.7) 44 (91.7) 0.074 Sex mismatch, n (%) 13 (16.5) 6 (12.5) 0.545 BMI: body mass index; CMP: cardiomyopathy; fPH: fixed pulmonary hypertension; LVAD: left ventricular assist device; PRA: panel reactive antibody; SD: standard deviation. Table 1: Patient demographics Pre-transplant patient demographics LVAD with fPH LVAD without fPH P-value (n = 79) (n = 48) Age at implant (years), mean ± SD 54 ± 10 50 ± 11 0.106 Sex: male, n (%) 70 (88.6) 42 (87.5) 0.851 Weight (kg), mean ± SD 81 ± 13 84 ± 14 0.270 Height (cm), mean ± SD 175 ± 8 177 ± 8 0.251 BMI (kg/m2), mean ± SD 26.5 ± 3.8 26.6 ± 3.3 0.829 Underlying disease, n (%) 0.010  Ischaemic CMP 34 (43.0) 22 (45.8)  Dilatative CMP 45 (57.0) 21 (43.8)  Other 0 (0) 5 (10.4) Device system, n (%) 0.314  Novacor 4 (5.1) 0 (0)  MicroMed DeBakey 29 (36.7) 13 (27.1)  DuraHeart Terumo 2 (2.5) 2 (4.2)  HeartMate II 14 (17.7) 13 (27.1)  HeartWare HVAD 29 (36.7) 19 (39.6)  HeartWare MVAD 1 (1.3) 0 (0)  Berlin Heart Incor 0 (0) 1 (2.1) High urgency, n (%) 17 (21.5) 8 (16.7) 0.505 High urgency reason, n (%) 0.739  Right heart failure 4 (23.5) 3 (37.5)  Pump thrombosis 5 (29.4) 2 (25.0)  Infection 3 (17.6) 2 (25.0)  Neurological event 2 (11.8) 0 (0)  Device malfunction 1 (5.9) 1 (12.5)  Electrical instability 2 (11.8) 0 (0) PRA, n (%)  0–10% 75 (94.9) 47 (97.9)  >10–30% 1 (1.3) 1 (2.1)  >30–90% 2 (2.5) 0 (0)  >90% 1 (1.3) 0 (0) Duration on LVAD, median (min−max) 288 (45–2279) 394 (0–2297) Donor age (years), mean ± SD 37 ± 12 36 ± 14 0.336 Donor sex male, n (%) 63 (79.7) 44 (91.7) 0.074 Sex mismatch, n (%) 13 (16.5) 6 (12.5) 0.545 Pre-transplant patient demographics LVAD with fPH LVAD without fPH P-value (n = 79) (n = 48) Age at implant (years), mean ± SD 54 ± 10 50 ± 11 0.106 Sex: male, n (%) 70 (88.6) 42 (87.5) 0.851 Weight (kg), mean ± SD 81 ± 13 84 ± 14 0.270 Height (cm), mean ± SD 175 ± 8 177 ± 8 0.251 BMI (kg/m2), mean ± SD 26.5 ± 3.8 26.6 ± 3.3 0.829 Underlying disease, n (%) 0.010  Ischaemic CMP 34 (43.0) 22 (45.8)  Dilatative CMP 45 (57.0) 21 (43.8)  Other 0 (0) 5 (10.4) Device system, n (%) 0.314  Novacor 4 (5.1) 0 (0)  MicroMed DeBakey 29 (36.7) 13 (27.1)  DuraHeart Terumo 2 (2.5) 2 (4.2)  HeartMate II 14 (17.7) 13 (27.1)  HeartWare HVAD 29 (36.7) 19 (39.6)  HeartWare MVAD 1 (1.3) 0 (0)  Berlin Heart Incor 0 (0) 1 (2.1) High urgency, n (%) 17 (21.5) 8 (16.7) 0.505 High urgency reason, n (%) 0.739  Right heart failure 4 (23.5) 3 (37.5)  Pump thrombosis 5 (29.4) 2 (25.0)  Infection 3 (17.6) 2 (25.0)  Neurological event 2 (11.8) 0 (0)  Device malfunction 1 (5.9) 1 (12.5)  Electrical instability 2 (11.8) 0 (0) PRA, n (%)  0–10% 75 (94.9) 47 (97.9)  >10–30% 1 (1.3) 1 (2.1)  >30–90% 2 (2.5) 0 (0)  >90% 1 (1.3) 0 (0) Duration on LVAD, median (min−max) 288 (45–2279) 394 (0–2297) Donor age (years), mean ± SD 37 ± 12 36 ± 14 0.336 Donor sex male, n (%) 63 (79.7) 44 (91.7) 0.074 Sex mismatch, n (%) 13 (16.5) 6 (12.5) 0.545 BMI: body mass index; CMP: cardiomyopathy; fPH: fixed pulmonary hypertension; LVAD: left ventricular assist device; PRA: panel reactive antibody; SD: standard deviation. Development of pulmonary artery pressures Baseline vasodynamic right heart catheterization revealed severe fPH in all patients after maximal pharmacological testing (PVR was 4.3 ± 1.8 WU, PAPsys was 59 ± 13 mmHg). After an average period of 104 ± 135 days post-LVAD implantation, patients underwent re-catheterization. Haemodynamic re-evaluation revealed a significantly reduced PVR (2.0 ± 0.9 WU vs 4.3 ± 1.8 WU prior to LVAD implantation, P < 0.001) and PAPsys (38 ± 12 mmHg vs 59 ± 13 mmHg prior to LVAD implantation, P < 0.001). Detailed haemodynamic data are presented in Table 2. Importantly, reversal of PH was successful in all patients with no treatment failures. Table 2: Haemodynamic measurements of the study group Variables Pre-LVAD baseline (n = 38), mean ± SD Pre-LVAD after testing (n = 73), mean ± SD Post-LVAD (n = 75), mean ± SD P-valuea PA systolic (mmHg) 67 ± 13 59 ± 13 38 ± 12 <0.001 PA mean (mmHg) 45 ± 9 40 ± 9 25 ± 8 <0.001 PVR (WU) 5.4 ± 3.0 4.3 ± 1.8 2.0 ± 0.9 <0.001 PCWP (mmHg) 28 ± 6 25 ± 8 14 ± 7 <0.001 CO (l/min) 3.7 ± 1.1 4.0 ± 1.3 5.9 ± 1.6 <0.001 TPG (mmHg) 17 ± 7 15 ± 6 11 ± 5 <0.001 Variables Pre-LVAD baseline (n = 38), mean ± SD Pre-LVAD after testing (n = 73), mean ± SD Post-LVAD (n = 75), mean ± SD P-valuea PA systolic (mmHg) 67 ± 13 59 ± 13 38 ± 12 <0.001 PA mean (mmHg) 45 ± 9 40 ± 9 25 ± 8 <0.001 PVR (WU) 5.4 ± 3.0 4.3 ± 1.8 2.0 ± 0.9 <0.001 PCWP (mmHg) 28 ± 6 25 ± 8 14 ± 7 <0.001 CO (l/min) 3.7 ± 1.1 4.0 ± 1.3 5.9 ± 1.6 <0.001 TPG (mmHg) 17 ± 7 15 ± 6 11 ± 5 <0.001 a P-value: compared haemodynamics after testing before LVAD implantation to haemodynamics post-LVAD implantation. CO: cardiac output; LVAD: left ventricular assist device; PA mean: mean pulmonary artery pressure; PA systolic: systolic pulmonary artery pressure; PCWP: pulmonary capillary wedge pressure; PVR: pulmonary vascular resistance; SD: standard deviation; TPG: transpulmonary pressure gradient. Table 2: Haemodynamic measurements of the study group Variables Pre-LVAD baseline (n = 38), mean ± SD Pre-LVAD after testing (n = 73), mean ± SD Post-LVAD (n = 75), mean ± SD P-valuea PA systolic (mmHg) 67 ± 13 59 ± 13 38 ± 12 <0.001 PA mean (mmHg) 45 ± 9 40 ± 9 25 ± 8 <0.001 PVR (WU) 5.4 ± 3.0 4.3 ± 1.8 2.0 ± 0.9 <0.001 PCWP (mmHg) 28 ± 6 25 ± 8 14 ± 7 <0.001 CO (l/min) 3.7 ± 1.1 4.0 ± 1.3 5.9 ± 1.6 <0.001 TPG (mmHg) 17 ± 7 15 ± 6 11 ± 5 <0.001 Variables Pre-LVAD baseline (n = 38), mean ± SD Pre-LVAD after testing (n = 73), mean ± SD Post-LVAD (n = 75), mean ± SD P-valuea PA systolic (mmHg) 67 ± 13 59 ± 13 38 ± 12 <0.001 PA mean (mmHg) 45 ± 9 40 ± 9 25 ± 8 <0.001 PVR (WU) 5.4 ± 3.0 4.3 ± 1.8 2.0 ± 0.9 <0.001 PCWP (mmHg) 28 ± 6 25 ± 8 14 ± 7 <0.001 CO (l/min) 3.7 ± 1.1 4.0 ± 1.3 5.9 ± 1.6 <0.001 TPG (mmHg) 17 ± 7 15 ± 6 11 ± 5 <0.001 a P-value: compared haemodynamics after testing before LVAD implantation to haemodynamics post-LVAD implantation. CO: cardiac output; LVAD: left ventricular assist device; PA mean: mean pulmonary artery pressure; PA systolic: systolic pulmonary artery pressure; PCWP: pulmonary capillary wedge pressure; PVR: pulmonary vascular resistance; SD: standard deviation; TPG: transpulmonary pressure gradient. Listing status Of the study population, 21.5% (n = 17) were listed as high–urgent (HU) due to adverse events while on LVAD support. The main indications for Eurotransplant HU status listing were right heart failure, infection and pump thrombosis. Four patients (5.1%) were categorized as HU due to right heart decompensation resulting in hospitalization and inotropic support via dobutamine and/or levosimendan. Post-transplant outcome of the study group Thirty-day and in-hospital mortality were 3.8% and 5.1%, respectively (see also Table 3). Two patients (8.7%) experienced acute right heart failure and required extracorporeal membrane oxygenation shortly after transplantation. Both cases resulted in death due to complications likely related to ECMO support, with 1 patient having experienced systemic thromboembolism and the other intracerebral bleeding. Other causes of death in the early postoperative period include infection (50%) and neurological complications (16.7%). Table 3: Thirty-day and in-hospital mortality after cardiac transplantation Post-transplant mortality (%) LVAD with PH (n = 79), n (%) LVAD without PH (n = 48), n (%) 30-Day mortality 3.8 (3) 0 (0) In-hospital mortality 5.1 (4) 4.2 (2) Post-transplant mortality (%) LVAD with PH (n = 79), n (%) LVAD without PH (n = 48), n (%) 30-Day mortality 3.8 (3) 0 (0) In-hospital mortality 5.1 (4) 4.2 (2) LVAD: left ventricular assist device; PH: pulmonary hypertension. Table 3: Thirty-day and in-hospital mortality after cardiac transplantation Post-transplant mortality (%) LVAD with PH (n = 79), n (%) LVAD without PH (n = 48), n (%) 30-Day mortality 3.8 (3) 0 (0) In-hospital mortality 5.1 (4) 4.2 (2) Post-transplant mortality (%) LVAD with PH (n = 79), n (%) LVAD without PH (n = 48), n (%) 30-Day mortality 3.8 (3) 0 (0) In-hospital mortality 5.1 (4) 4.2 (2) LVAD: left ventricular assist device; PH: pulmonary hypertension. One-year survival rate was 89.9% with the main reasons for early post-transplant death being of cerebrovascular origin (n = 4; 50%) and infections (n = 3; 37.5%). The 3- and 5-year survival rates were 83.5% and 81.0%, respectively. Mean follow-up was 5.9 ± 4.6 years. The main causes of long-term post-transplant death were infections (29.2%), neoplasia (12.5%) and neurological complications (12.5%). Post-transplant outcome of the control group Peritransplant mortality, defined as 30-day mortality, was 0% (see also Table 3). We observed zero cases of acute right heart failure in this patient cohort. One-year survival rate was 93.8% with the causes of death including infections (66.7%) and neurological complications (33.3%). Long-term 3- and 5-year survival rates, 87.5% and 85.4% respectively, were comparable to the study group’s 3-year survival rate of 83.5% and 5-year survival rate of 81.0% (log-rank: P = 0.585). Mean follow-up was 4.7 ± 4.2 years. Kaplan–Meier analysis displaying the overall post-transplant survival is presented in Fig. 2. Causes of death are presented in Table 4. Table 4: Reasons for death after cardiac transplantation Post-transplant causes of death (%) LVAD with PH (n = 23) (29.1), n (%) LVAD without PH (n = 10) (20.4), n (%) Sudden cardiac death 2 (8.7) 1 (10.0) Right heart failure 2 (8.7) 0 (0) Cardiac allograft vasculopathy 0 (0) 1 (10.0) Rejection 0 (0) 1 (10.0) Infection 7 (30.4) 3 (30.0) Neurological 3 (13.0) 1 (10.0) Neoplasia 3 (13.0) 2 (20.0) Other 2 (8.7) 0 (0) Unknown 4 (17.4) 1 (10.0) Post-transplant causes of death (%) LVAD with PH (n = 23) (29.1), n (%) LVAD without PH (n = 10) (20.4), n (%) Sudden cardiac death 2 (8.7) 1 (10.0) Right heart failure 2 (8.7) 0 (0) Cardiac allograft vasculopathy 0 (0) 1 (10.0) Rejection 0 (0) 1 (10.0) Infection 7 (30.4) 3 (30.0) Neurological 3 (13.0) 1 (10.0) Neoplasia 3 (13.0) 2 (20.0) Other 2 (8.7) 0 (0) Unknown 4 (17.4) 1 (10.0) LVAD: left ventricular assist device; PH: pulmonary hypertension. Table 4: Reasons for death after cardiac transplantation Post-transplant causes of death (%) LVAD with PH (n = 23) (29.1), n (%) LVAD without PH (n = 10) (20.4), n (%) Sudden cardiac death 2 (8.7) 1 (10.0) Right heart failure 2 (8.7) 0 (0) Cardiac allograft vasculopathy 0 (0) 1 (10.0) Rejection 0 (0) 1 (10.0) Infection 7 (30.4) 3 (30.0) Neurological 3 (13.0) 1 (10.0) Neoplasia 3 (13.0) 2 (20.0) Other 2 (8.7) 0 (0) Unknown 4 (17.4) 1 (10.0) Post-transplant causes of death (%) LVAD with PH (n = 23) (29.1), n (%) LVAD without PH (n = 10) (20.4), n (%) Sudden cardiac death 2 (8.7) 1 (10.0) Right heart failure 2 (8.7) 0 (0) Cardiac allograft vasculopathy 0 (0) 1 (10.0) Rejection 0 (0) 1 (10.0) Infection 7 (30.4) 3 (30.0) Neurological 3 (13.0) 1 (10.0) Neoplasia 3 (13.0) 2 (20.0) Other 2 (8.7) 0 (0) Unknown 4 (17.4) 1 (10.0) LVAD: left ventricular assist device; PH: pulmonary hypertension. Figure 2: View largeDownload slide Kaplan–Meier curve demonstrating long-term post-transplant survival. Blue curve: cardiac transplant patients with pretransplant PH; red curve: cardiac transplant patients without pretransplant PH; vertical axis (survival in %) starts at 60% for easier readability. HTX: heart transplantation; PH: pulmonary hypertension. Figure 2: View largeDownload slide Kaplan–Meier curve demonstrating long-term post-transplant survival. Blue curve: cardiac transplant patients with pretransplant PH; red curve: cardiac transplant patients without pretransplant PH; vertical axis (survival in %) starts at 60% for easier readability. HTX: heart transplantation; PH: pulmonary hypertension. DISCUSSION fPH is an established contraindication for HTX due to an inacceptable risk for post-transplant right heart failure associated with elevated post-transplant mortality rates [1, 3]. LVAD implantation reverses fPH in HTX candidates with fPH as part of a bridge to candidacy strategy and facilitates safe HTX [1, 4, 5, 9]. Secondary PH affects up to 72% of end-stage heart failure patients and is the consequence of elevated left atrial pressure resulting from impaired left ventricular systolic function [11]. Left atrial hypertension increases post-capillary pressures in the pulmonary vascular system, prompting increased pulmonary endothelial dysfunction. In the initial stages of this process, pulmonary vasoconstriction occurs as a result of decreasing nitric oxide, prostacyclin concentrations and increased thromboxane A2 and endothelin-1 production [5, 19]. At a later stage, up-regulated subendothelial serine elastase gives rise to glycoprotein deposition as well as smooth muscle cell hypertrophy and hyperplasia [5, 19]. In combination with the development of platelet fibrin microthrombi as a result of changes in the expression of the von Willebrand factor, this pathophysiological process can lead to the remodelling of the pulmonary vascular tree [5]. Reversible PH differs from fPH in its response to vasodilator treatment [3]. Specifically, fPH is refractory to medical therapy and is the result of prolonged exposure to elevated left atrial pressures [19]. The irreversibility of fPH is a consequence of the pulmonary vascular system’s remodelling process. A higher risk of post-transplant failure in the non-conditioned right ventricle of the donor heart, as well as associated higher post-transplant mortality, makes fPH an established contraindication for HTX [2, 3, 5–9]. Cut-off values for HTX candidacy in patients with fPH vary throughout the literature, but most transplant centres will not accept a PVR >3–4 WU for HTX [5]. Mechanical circulatory support is the standard treatment in HTX recipients suffering from fPH [19]. By continuously unloading the left ventricle, LVADs reduce the left atrial pressure, thus leading to the reduction of pulmonary artery pressures [19]. The excellent long-term post-transplant survival of this study after reversing fPH using LVAD therapy (3 year: 83.5%, 5 year: 81.0%) is comparable to that of patients bridged to transplant via LVAD for reasons other than PH (3 year: 87.5%, 5 year: 85.4%). The 1- and 3-year survival rates, 89.9% and 83.5%, respectively, are comparable to those reported in previous studies [20, 21]. Furthermore, we note that the results of this study are non-inferior when compared with recent international post-transplant 1- and 5-year survival rates (84% and 75% respectively) after orthotopic HTX in recipients without fPH [22]. Previous studies have shown that there is no significant difference with regard to the reduction of fPH by the support of continuous or pulsatile flow devices [1, 9]. In the present study, the majority of patients (93.8%) received continuous-flow LVADs. The increased usage of continuous-flow device systems can be attributed to the improved long-term survival rates and lower adverse event occurrences reported in studies utilizing these devices [23–26]. Despite device updates, morbidity and mortality remain major concerns in LVAD therapy. The 1- and 2-year survival rates of patients while on continuous-flow LVAD support are reported at 80% and 70%, respectively [25]. Typical LVAD complications include pump thrombosis, infections, neurological events and right heart failure [25]. From the present study population, 17 of the patients on LVAD support (21.5%) required Eurotransplant HU registration due to severe adverse events. Pump thrombosis and right heart failure occurred in 5 (6.3%) and 4 (5.0%) of these patients, respectively, with only 1 patient (1.3%) having experienced device malfunction in a MicroMed DeBakey LVAD. Limitations The study is limited by its retrospective design as well as the unadjusted baseline risk in the comparison of the HTX groups with and without fPH. CONCLUSION LVAD implantation as a bridge to candidacy reverses fPH in patients with terminal heart failure. Post-HTX survival is excellent and comparable to the results obtained in patients without fPH at the time of HTX listing. Conflict of interest: none declared. REFERENCES 1 Mikus E , Stepanenko A , Krabatsch T , Loforte A , Dandel M , Lehmkuhl HB et al. . Reversibility of fixed pulmonary hypertension in left ventricular assist device support recipients . Eur J Cardiothorac Surg 2011 ; 40 : 971 – 7 . Google Scholar PubMed 2 Mehra MR , Kobashigawa J , Starling R , Russell S , Uber PA , Parameshwar J et al. . Listing criteria for heart transplantation: International Society for Heart and Lung Transplantation guidelines for the care of cardiac transplant candidates—2006 . J Heart Lung Transplant 2006 ; 25 : 1024 – 42 . Google Scholar CrossRef Search ADS PubMed 3 Butler J , Stankewicz MA , Wu J , Chomsky DB , Howser RL , Khadim G et al. . Pre-transplant reversible pulmonary hypertension predicts higher risk for mortality after cardiac transplantation . J Heart Lung Transplant 2005 ; 24 : 170 – 7 . Google Scholar CrossRef Search ADS PubMed 4 Mehra MR , Canter CE , Hannan MM , Semigran MJ , Uber PA , Baran DA et al. . The 2016 International Society for Heart Lung Transplantation listing criteria for heart transplantation: a 10-year update . J Heart Lung Transplant 2016 ; 35 : 1 – 23 . Google Scholar CrossRef Search ADS PubMed 5 Zimpfer D , Zrunek P , Roethy W , Czerny M , Schima H , Huber L et al. . Left ventricular assist devices decrease fixed pulmonary hypertension in cardiac transplant candidates . J Thorac Cardiovasc Surg 2007 ; 133 : 689 – 95 . Google Scholar CrossRef Search ADS PubMed 6 Tedford RJ , Hemnes AR , Russell SD , Wittstein IS , Mahmud M , Zaiman AL et al. . PDE5A inhibitor treatment of persistent pulmonary hypertension after mechanical circulatory support . Circ Heart Fail 2008 ; 1 : 213 – 19 . Google Scholar CrossRef Search ADS PubMed 7 Delgado JF , Gómez-Sánchez MA , Sáenz de la Calzada C , Sánchez V , Escribano P , Hernández-Afonso J et al. . Impact of mild pulmonary hypertension on mortality and pulmonary artery pressure profile after heart transplantation . J Heart Lung Transplant 2001 ; 20 : 942 – 8 . Google Scholar CrossRef Search ADS PubMed 8 Radovancevic B , Vrtovec B , Thomas CD , Croitoru M , Myers TJ , Radovancevic R et al. . Nitric oxide versus prostaglandin E1 for reduction of pulmonary hypertension in heart transplant candidates . J Heart Lung Transplant 2005 ; 24 : 690 – 5 . Google Scholar CrossRef Search ADS PubMed 9 Salzberg SP , Lachat ML , von Harbou K , Zünd G , Turina MI. Normalization of high pulmonary vascular resistance with LVAD support in heart transplantation candidates . Eur J Cardiothorac Surg 2005 ; 27 : 222 – 5 . Google Scholar CrossRef Search ADS PubMed 10 Bleasdale RA , Banner NR , Anyanwu AC , Mitchell AG , Khaghani A , Yacoub MH. Determinants of outcome after heterotopic heart transplantation . J Heart Lung Transplant 2002 ; 21 : 867 – 73 . Google Scholar CrossRef Search ADS PubMed 11 Elefteriades JA , Lovoulos CJ , Tellides G , Goldstein LJ , Rocco EJ , Condos SG et al. . Right ventricle-sparing heart transplant: promising new technique for recipients with pulmonary hypertension . Ann Thorac Surg 2000 ; 69 : 1858 – 63 . Google Scholar CrossRef Search ADS PubMed 12 Newcomb AE , Esmore DS , Rosenfeldt FL , Richardson M , Marasco SF. Heterotopic heart transplantation: an expanding role in the twenty-first century? Ann Thorac Surg 2004 ; 78 : 1345 – 50 . Google Scholar CrossRef Search ADS PubMed 13 Taegtmeyer AB , Crook AM , Barton PJ , Banner NR. Reduced incidence of hypertension after heterotopic cardiac transplantation compared with orthotopic cardiac transplantation: evidence that excision of the native heart contributes to post-transplant hypertension . J Am Coll Cardiol 2004 ; 44 : 1254 – 60 . Google Scholar PubMed 14 Flécher E , Fouquet O , Ruggieri VG , Chabanne C , Lelong B , Leguerrier A. Heterotopic heart transplantation: where do we stand? Eur J Cardiothorac Surg 2013 ; 44 : 201 – 6 . Google Scholar CrossRef Search ADS PubMed 15 McLaughlin VV , Archer SL , Badesch DB , Barst RJ , Farber HW , Lindner JR et al. . ACCF/AHA 2009 Expert Consensus Document on Pulmonary Hypertension: a Report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association . Circulation 2009 ; 53 : 1573 – 619 . 16 Wieselthaler GM , Schima H , Lassnigg A , Pacher R , Ovsenk T , Laufer G et al. . [The DeBakey VAD axial flow pump: first clinical experience with a new generation of implantable, nonpulsatile blood pumps for long-term support prior to transplantation] . Wien Klin Wochenschr 1999 ; 111 : 629 – 35 . Google Scholar PubMed 17 Stewart GC , Givertz MM. Mechanical circulatory support for advanced heart failure: patients and technology in evolution . Circulation 2012 ; 125 : 1304 – 15 . Google Scholar CrossRef Search ADS PubMed 18 Moazami N , Fukamachi K , Kobayashi M , Smedira NG , Hoercher KJ , Massiello A et al. . Axial and centrifugal continuous-flow rotary pumps: a translation from pump mechanics to clinical practice . J Heart Lung Transplant 2013 ; 32 : 1 – 11 . Google Scholar CrossRef Search ADS PubMed 19 Houston BA , Tedford RJ. Making the Call: Pulmonary Hypertension in Cardiac Transplant Candidates. http://www.ishlt.org/ContentDocuments/2016FebLinks_Houston_Tedford.html (5 June 2018, date last accessed). 20 Zimpfer D , Zrunek P , Sandner S , Schima H , Grimm M , Zuckermann A et al. . Post-transplant survival after lowering fixed pulmonary hypertension using left ventricular assist devices . Eur J Cardiothorac Surg 2007 ; 31 : 698 – 702 . Google Scholar CrossRef Search ADS PubMed 21 Tsukashita M , Takayama H , Takeda K , Han J , Colombo PC , Yuzefpolskaya M et al. . Effect of pulmonary vascular resistance before left ventricular assist device implantation on short- and long-term post-transplant survival . J Thorac Cardiovasc Surg 2015 ; 150 : 1352 – 60, 1361.e1–2. Google Scholar CrossRef Search ADS PubMed 22 Lund LH , Edwards LB , Kucheryavaya AY , Benden C , Christie JD , Dipchand AI et al. . The registry of the International Society for Heart and Lung Transplantation: thirty-first official adult heart transplant report—2014; focus theme: retransplantation . J Heart Lung Transplant 2014 ; 33 : 996 – 1008 . Google Scholar CrossRef Search ADS PubMed 23 Cheng A , Williamitis CA , Slaughter MS. Comparison of continuous-flow and pulsatile-flow left ventricular assist devices: is there an advantage to pulsatility? Ann Cardiothorac Surg 2014 ; 3 : 573 – 81 . Google Scholar PubMed 24 Slaughter MS , Rogers JG , Milano CA , Russell SD , Conte JV , Feldman D et al. . Advanced heart failure treated with continuous-flow left ventricular assist device . N Engl J Med 2009 ; 361 : 2241 – 51 . Google Scholar CrossRef Search ADS PubMed 25 Kirklin JK , Naftel DC , Pagani FD , Kormos RL , Stevenson LW , Blume ED et al. . Seventh INTERMACS annual report: 15,000 patients and counting . J Heart Lung Transplant 2015 ; 34 : 1495 – 504 . Google Scholar CrossRef Search ADS PubMed 26 Slaughter MS , Pagani FD , McGee EC , Birks EJ , Cotts WG , Gregoric I et al. . HeartWare ventricular assist system for bridge to transplant: combined results of the bridge to transplant and continued access protocol trial . J Heart Lung Transplant 2013 ; 32 : 675 – 83 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. 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/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Journal of Cardio-Thoracic Surgery Oxford University Press

Long-term heart transplant outcomes after lowering fixed pulmonary hypertension using left ventricular assist devices†

European Journal of Cardio-Thoracic Surgery , Volume Advance Article – Jun 13, 2018

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Oxford University Press
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© The Author(s) 2018. 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
DOI
10.1093/ejcts/ezy214
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Abstract

Abstract OBJECTIVES Fixed pulmonary hypertension (fPH) is a contraindication for heart transplantation (HTX). Left ventricular assist device (LVAD) implantation as a bridge to candidacy can reverse fPH in patients with terminal heart failure by chronic left ventricular unloading. We report our institutional experience with terminal heart failure patients and fPH that were successfully bridged to candidacy and underwent subsequent HTX. METHODS We retrospectively reviewed the data of 79 patients with terminal heart failure and fPH who were successfully bridged to candidacy for HTX with 6 different LVAD devices at our centre from October 1998 to September 2016 (Novacor n = 4, MicroMed DeBakey n = 29, DuraHeart n = 2, HeartMate II n = 14, HVAD n = 29 and MVAD n = 1). Median duration of LVAD support was 288 days (range 45–2279 days). Within the same timeframe, a control group of 48 patients underwent HTX after bridge-to-transplant LVAD therapy for reasons other than PH. Study end points were (i) development of fPH after LVAD implantation, (ii) post-transplant outcomes and (iii) incidence of severe adverse events. RESULTS Pulmonary vascular resistance, assessed by vasodynamic catheterization, was 4.3 ± 1.8 WU before LVAD implantation. After a median support period of 89 days (interquartile range 4–156 days), pulmonary vascular resistance decreased to 2.0 ± 0.9 WU (P ≤ 0.001), and patients were listed for HTX. Median duration of LVAD support in the study group was 288 days (45–2279 days). We observed 2 patients (2.5%) with acute right heart failure who required extracorporeal mechanical support after HTX in the study group. Long-term post-transplant survival between the study group (3 years: 83.5%, 5 years: 81.0%) and the control group (3 years: 87.5%, 5 years: 85.4%) was comparable (log-rank: P = 0.585). CONCLUSIONS LVAD implantation as a bridge to candidacy reverses fPH in patients with terminal heart failure. Post-HTX survival is excellent and comparable to results obtained in patients without fPH at the time of HTX listing. Left ventricular assist device, Heart transplantation, Pulmonary hypertension, Long-term outcome INTRODUCTION Heart transplantation (HTX) is the standard treatment for end-stage heart failure patients. Fixed pulmonary hypertension (fPH) is an established contraindication for HTX [1]. Although cut-off values for HTX in patients with fPH vary throughout the literature, there is a consensus that a systolic pulmonary arterial pressure (PAPsys) ≥50 mmHg, a transpulmonary gradient (TPG) ≥15 mmHg and a pulmonary vascular resistance (PVR) >3.0 WU, when unresponsive to fully exploited vasodilator treatment, are useful threshold values [2–4]. Previous reports demonstrated that HTX recipients with pretransplant fPH are subjected to higher post-transplant mortality due to a higher risk of post-transplant failure of the non-conditioned right ventricle [2, 3, 5–9]. Treatment options in HTX recipients with fPH are limited. Procedures such as heterotopic and right ventricle sparing transplantation techniques have been described in previous studies [10–13]. Recognized complications of these surgical techniques include (i) technical difficulties during heart implantation, as well as (ii) ventricular arrhythmias, (iii) reduced exercise capacity, (iv) persistence of angina and (v) progression of native valvular disease as a result of interactions between the donor and recipient hearts [14]. Due to significantly higher mortality rates compared to orthotopic HTX following left ventricular assist device (LVAD) implantation, the use of heterotopic HTX is only considered under special circumstances [14]. Reversing fPH using LVADs prior to HTX is a potential treatment option for HTX recipients suffering from fPH [4]. This is attributed to the LVAD’s ability to continuously unload the left ventricle and thereby reduce left-sided filling pressures [1]. We report our institutional experience with terminal heart failure patients and fPH that were successfully bridged to candidacy and underwent subsequent HTX. MATERIALS AND METHODS The Ethics Committee of the Medical University Vienna (EC Number: 1733/2017) approved this retrospective single-centre study. Patient population From October 1998 to September 2016, 677 consecutive patients with terminal heart failure, of which 127 received an LVAD prior to transplantation, underwent HTX at our centre. Of these 127 patients, 79 were diagnosed with fPH during right heart catheterization with vasodynamic testing at the time of transplant evaluation and were therefore refused from HTX listing. Following an institutional protocol that has been described previously [5], these patients then underwent LVAD implantation as a bridge to candidacy. After successful LVAD implantation and rehabilitation, these 79 patients underwent re-catheterization and were listed as soon as haemodynamic values had normalized to a PAPsys <50 mmHg, a TPG <15 mmHg and a PVR <3.0 WU. Subsequently, all 79 patients underwent successful HTX. During the study period, fPH could successfully be reversed using the described approach in all patients. No treatment failures were observed. Besides fPH, patients had to have no other HTX contraindication to qualify for this protocol (see also Fig. 1). Figure 1: View largeDownload slide Decision-making tree. HTX: heart transplantation; LVAD: left ventricular assist device; PAPsys: systolic pulmonary artery pressure; PVR: pulmonary vascular resistance; TPG: transpulmonary pressure gradient. Figure 1: View largeDownload slide Decision-making tree. HTX: heart transplantation; LVAD: left ventricular assist device; PAPsys: systolic pulmonary artery pressure; PVR: pulmonary vascular resistance; TPG: transpulmonary pressure gradient. Study end points were defined as (i) development of fPH after LVAD implantation, (ii) post-transplant outcome and long-term survival after HTX and (iii) incidence of severe adverse events. The last follow-up date of the study was 30 May 2017. No patient was lost to follow-up. Within the same timeframe, a total of 48 patients without pulmonary hypertension served as a control group. These patients underwent elective cardiac transplantation after bridge-to-transplant therapy via LVAD for reasons other than fPH. The main reasons for ventricular assist device implantation in the control group were acute cardiogenic shock and end-stage heart failure with reversible contraindications for cardiac transplantation. Right heart catheterization, vasodynamic testing and definition of fixed pulmonary hypertension Cardiac transplant candidates must undergo haemodynamic testing for pulmonary hypertension evaluation. Right heart catheterization was performed according to the guidelines published by the American College of Cardiology Foundation/American Heart Association (ACCF/AHA) using a Swan-Ganz thermodilution catheter [15]. The assessed variables crucial for PH diagnosis included (i) PAPsys (mmHg), (ii) mean pulmonary artery pressure (mmHg), (iii) PVR (WU) and (iv) cardiac output (litres per minute, measured by the Fick method). An elevated central venous pressure as a result of volume overload was measured pretransplant at an average of 13 ± 6 mmHg (n = 56), and thus it was not a contributing factor to pulmonary hypertension. PH was defined as a PAPsys ≥50 mmHg, a TPG ≥15 mmHg and a PVR >3.0 WU. Any potential to pharmacologically influence pulmonary pressures was tested in all patients by nitroglycerine, prostaglandin (PGI2) or levosimendan. Nitroglycerine was administered as an intravenous bolus injection with an initial dosage of 0.5 mg, followed by an additional dosage of 0.5 mg 10 min later. Prostaglandin was administered intravenously in dosages ranging from 0.01 to 0.2 µg/kg/min for a maximum of 24 h. Levosimendan was administered intravenously in dosages ranging from 0.1 to 0.2 µg/kg/min for 24 h. Pulmonary hypertension was considered irreversible if the haemodynamic measurements could not be significantly reduced to a PAPsys <50 mmHg, a TPG <15 mmHg and a PVR <3.0 WU after vasodynamic testing. Per our institutional guidelines, right heart catheterization was performed at an average of 3 months post-LVAD implantation. If pulmonary hypertension could be significantly reduced by LVAD support, patients were considered eligible for cardiac transplantation. However, if pulmonary hypertension was persistent, right heart catheterization had to be repeated every 3 months until a significant reduction of pulmonary hypertension could be achieved. In the presented patient population, haemodynamic measurements were performed during HTX evaluation as well as after a median of 89 days post-LVAD implantation. Twenty-six patients (32.9%) received oral pulmonary vasodilators (sildenafil) after successful LVAD implantation in dosages varying from 20 to 60 mg per day to promote normalization of pulmonary artery pressures. Left ventricular assist devices used Over the course of this study, 6 different LVAD systems were used to reverse fPH in HTX candidates. The technical details and implantation procedures of the MicroMed De Bakey (MicroMed Technology Inc., Houston, TX, USA), DuraHeart (Terumo Heart Inc., MI, USA), Novacor (World Heart Inc., Oakland, CA, USA), HeartMate II (Abbott, North Chicago, IL, USA) and HVAD (Medtronic, MN, USA) have been described previously [16–18]. One patient received the miniaturized ventricular assist device (MVAD, Medtronic) as part of a multicentre, prospective, non-randomized, single-arm trial to investigate the safety and performance of the device. Post-transplant immunosuppression regimen Early postoperative period induction therapy consists of antithymocyte globulin and mycophenolate mofetil. Maintenance immunosuppressive therapy was started 3–7 days post-induction therapy and utilized calcineurin inhibitors, Tacrolimus (Prograf®) or Cyclosporine (Sandimmun Neoral®), as well as tapering doses of glucocorticoids over the first year post-transplant. In high-risk patients prone to opportunistic infections with cytomegalovirus, antiviral therapy (valganciclovir; Valcyte®) was routinely performed in the early postoperative period. Statistical analysis The data are presented as frequency distributions and percentages. Continuous variable values are expressed as mean ± standard deviation or median and ranges. Categorical variables were compared using the χ2 test between the study group and the control group as appropriate. As a result of the sample size, the χ2 test was preferred to the Fisher’s exact test. Testing for normality of distribution was performed by the Kolmogorov–Smirnov test. Continuous data between HTX groups with and without fPH were compared using the 2-sample, unpaired t-test. The paired t-test was used to compare haemodynamic variables such as PAPsys, mean pulmonary artery pressure, cardiac output and PVR, both before and after LVAD implantation. Kaplan–Meier analysis was used to evaluate post-transplant survival, and the log-rank test was used to compare groups with a 2-sided P-value <0.05 being considered significant. All analyses were performed using IBM SPSS 23.0 (IBM Corp., Armonk, NY, USA) and GraphPad Prism Version 7.0a (GraphPad Software Inc., La Jolla, CA, USA). RESULTS Patient demographics Seventy-nine patients suffering from fPH were successfully bridged to candidacy for HTX and subsequently underwent HTX. Mean patient age was 54 ± 10 years (88.6% male). Underlying diseases were dilative (57.0%) and ischaemic cardiomyopathy (43.0%). All patients were in NYHA class IV and received maximum heart failure therapy prior to LVAD implantation. Besides fPH, patients had no other contraindication for HTX. The majority of patients (94.9%) received continuous blood flow LVADs (MicroMed DeBakey n = 29, DuraHeart n = 2, HeartMate II n = 14, HVAD n = 29). The Novacor pulsatile LVAD was implanted in 4 patients (5.1%). Median duration of LVAD support was 288 days (range 45–2279 days). The detailed patient characteristics of cardiac transplant recipients with and without fPH are presented in Table 1. Table 1: Patient demographics Pre-transplant patient demographics LVAD with fPH LVAD without fPH P-value (n = 79) (n = 48) Age at implant (years), mean ± SD 54 ± 10 50 ± 11 0.106 Sex: male, n (%) 70 (88.6) 42 (87.5) 0.851 Weight (kg), mean ± SD 81 ± 13 84 ± 14 0.270 Height (cm), mean ± SD 175 ± 8 177 ± 8 0.251 BMI (kg/m2), mean ± SD 26.5 ± 3.8 26.6 ± 3.3 0.829 Underlying disease, n (%) 0.010  Ischaemic CMP 34 (43.0) 22 (45.8)  Dilatative CMP 45 (57.0) 21 (43.8)  Other 0 (0) 5 (10.4) Device system, n (%) 0.314  Novacor 4 (5.1) 0 (0)  MicroMed DeBakey 29 (36.7) 13 (27.1)  DuraHeart Terumo 2 (2.5) 2 (4.2)  HeartMate II 14 (17.7) 13 (27.1)  HeartWare HVAD 29 (36.7) 19 (39.6)  HeartWare MVAD 1 (1.3) 0 (0)  Berlin Heart Incor 0 (0) 1 (2.1) High urgency, n (%) 17 (21.5) 8 (16.7) 0.505 High urgency reason, n (%) 0.739  Right heart failure 4 (23.5) 3 (37.5)  Pump thrombosis 5 (29.4) 2 (25.0)  Infection 3 (17.6) 2 (25.0)  Neurological event 2 (11.8) 0 (0)  Device malfunction 1 (5.9) 1 (12.5)  Electrical instability 2 (11.8) 0 (0) PRA, n (%)  0–10% 75 (94.9) 47 (97.9)  >10–30% 1 (1.3) 1 (2.1)  >30–90% 2 (2.5) 0 (0)  >90% 1 (1.3) 0 (0) Duration on LVAD, median (min−max) 288 (45–2279) 394 (0–2297) Donor age (years), mean ± SD 37 ± 12 36 ± 14 0.336 Donor sex male, n (%) 63 (79.7) 44 (91.7) 0.074 Sex mismatch, n (%) 13 (16.5) 6 (12.5) 0.545 Pre-transplant patient demographics LVAD with fPH LVAD without fPH P-value (n = 79) (n = 48) Age at implant (years), mean ± SD 54 ± 10 50 ± 11 0.106 Sex: male, n (%) 70 (88.6) 42 (87.5) 0.851 Weight (kg), mean ± SD 81 ± 13 84 ± 14 0.270 Height (cm), mean ± SD 175 ± 8 177 ± 8 0.251 BMI (kg/m2), mean ± SD 26.5 ± 3.8 26.6 ± 3.3 0.829 Underlying disease, n (%) 0.010  Ischaemic CMP 34 (43.0) 22 (45.8)  Dilatative CMP 45 (57.0) 21 (43.8)  Other 0 (0) 5 (10.4) Device system, n (%) 0.314  Novacor 4 (5.1) 0 (0)  MicroMed DeBakey 29 (36.7) 13 (27.1)  DuraHeart Terumo 2 (2.5) 2 (4.2)  HeartMate II 14 (17.7) 13 (27.1)  HeartWare HVAD 29 (36.7) 19 (39.6)  HeartWare MVAD 1 (1.3) 0 (0)  Berlin Heart Incor 0 (0) 1 (2.1) High urgency, n (%) 17 (21.5) 8 (16.7) 0.505 High urgency reason, n (%) 0.739  Right heart failure 4 (23.5) 3 (37.5)  Pump thrombosis 5 (29.4) 2 (25.0)  Infection 3 (17.6) 2 (25.0)  Neurological event 2 (11.8) 0 (0)  Device malfunction 1 (5.9) 1 (12.5)  Electrical instability 2 (11.8) 0 (0) PRA, n (%)  0–10% 75 (94.9) 47 (97.9)  >10–30% 1 (1.3) 1 (2.1)  >30–90% 2 (2.5) 0 (0)  >90% 1 (1.3) 0 (0) Duration on LVAD, median (min−max) 288 (45–2279) 394 (0–2297) Donor age (years), mean ± SD 37 ± 12 36 ± 14 0.336 Donor sex male, n (%) 63 (79.7) 44 (91.7) 0.074 Sex mismatch, n (%) 13 (16.5) 6 (12.5) 0.545 BMI: body mass index; CMP: cardiomyopathy; fPH: fixed pulmonary hypertension; LVAD: left ventricular assist device; PRA: panel reactive antibody; SD: standard deviation. Table 1: Patient demographics Pre-transplant patient demographics LVAD with fPH LVAD without fPH P-value (n = 79) (n = 48) Age at implant (years), mean ± SD 54 ± 10 50 ± 11 0.106 Sex: male, n (%) 70 (88.6) 42 (87.5) 0.851 Weight (kg), mean ± SD 81 ± 13 84 ± 14 0.270 Height (cm), mean ± SD 175 ± 8 177 ± 8 0.251 BMI (kg/m2), mean ± SD 26.5 ± 3.8 26.6 ± 3.3 0.829 Underlying disease, n (%) 0.010  Ischaemic CMP 34 (43.0) 22 (45.8)  Dilatative CMP 45 (57.0) 21 (43.8)  Other 0 (0) 5 (10.4) Device system, n (%) 0.314  Novacor 4 (5.1) 0 (0)  MicroMed DeBakey 29 (36.7) 13 (27.1)  DuraHeart Terumo 2 (2.5) 2 (4.2)  HeartMate II 14 (17.7) 13 (27.1)  HeartWare HVAD 29 (36.7) 19 (39.6)  HeartWare MVAD 1 (1.3) 0 (0)  Berlin Heart Incor 0 (0) 1 (2.1) High urgency, n (%) 17 (21.5) 8 (16.7) 0.505 High urgency reason, n (%) 0.739  Right heart failure 4 (23.5) 3 (37.5)  Pump thrombosis 5 (29.4) 2 (25.0)  Infection 3 (17.6) 2 (25.0)  Neurological event 2 (11.8) 0 (0)  Device malfunction 1 (5.9) 1 (12.5)  Electrical instability 2 (11.8) 0 (0) PRA, n (%)  0–10% 75 (94.9) 47 (97.9)  >10–30% 1 (1.3) 1 (2.1)  >30–90% 2 (2.5) 0 (0)  >90% 1 (1.3) 0 (0) Duration on LVAD, median (min−max) 288 (45–2279) 394 (0–2297) Donor age (years), mean ± SD 37 ± 12 36 ± 14 0.336 Donor sex male, n (%) 63 (79.7) 44 (91.7) 0.074 Sex mismatch, n (%) 13 (16.5) 6 (12.5) 0.545 Pre-transplant patient demographics LVAD with fPH LVAD without fPH P-value (n = 79) (n = 48) Age at implant (years), mean ± SD 54 ± 10 50 ± 11 0.106 Sex: male, n (%) 70 (88.6) 42 (87.5) 0.851 Weight (kg), mean ± SD 81 ± 13 84 ± 14 0.270 Height (cm), mean ± SD 175 ± 8 177 ± 8 0.251 BMI (kg/m2), mean ± SD 26.5 ± 3.8 26.6 ± 3.3 0.829 Underlying disease, n (%) 0.010  Ischaemic CMP 34 (43.0) 22 (45.8)  Dilatative CMP 45 (57.0) 21 (43.8)  Other 0 (0) 5 (10.4) Device system, n (%) 0.314  Novacor 4 (5.1) 0 (0)  MicroMed DeBakey 29 (36.7) 13 (27.1)  DuraHeart Terumo 2 (2.5) 2 (4.2)  HeartMate II 14 (17.7) 13 (27.1)  HeartWare HVAD 29 (36.7) 19 (39.6)  HeartWare MVAD 1 (1.3) 0 (0)  Berlin Heart Incor 0 (0) 1 (2.1) High urgency, n (%) 17 (21.5) 8 (16.7) 0.505 High urgency reason, n (%) 0.739  Right heart failure 4 (23.5) 3 (37.5)  Pump thrombosis 5 (29.4) 2 (25.0)  Infection 3 (17.6) 2 (25.0)  Neurological event 2 (11.8) 0 (0)  Device malfunction 1 (5.9) 1 (12.5)  Electrical instability 2 (11.8) 0 (0) PRA, n (%)  0–10% 75 (94.9) 47 (97.9)  >10–30% 1 (1.3) 1 (2.1)  >30–90% 2 (2.5) 0 (0)  >90% 1 (1.3) 0 (0) Duration on LVAD, median (min−max) 288 (45–2279) 394 (0–2297) Donor age (years), mean ± SD 37 ± 12 36 ± 14 0.336 Donor sex male, n (%) 63 (79.7) 44 (91.7) 0.074 Sex mismatch, n (%) 13 (16.5) 6 (12.5) 0.545 BMI: body mass index; CMP: cardiomyopathy; fPH: fixed pulmonary hypertension; LVAD: left ventricular assist device; PRA: panel reactive antibody; SD: standard deviation. Development of pulmonary artery pressures Baseline vasodynamic right heart catheterization revealed severe fPH in all patients after maximal pharmacological testing (PVR was 4.3 ± 1.8 WU, PAPsys was 59 ± 13 mmHg). After an average period of 104 ± 135 days post-LVAD implantation, patients underwent re-catheterization. Haemodynamic re-evaluation revealed a significantly reduced PVR (2.0 ± 0.9 WU vs 4.3 ± 1.8 WU prior to LVAD implantation, P < 0.001) and PAPsys (38 ± 12 mmHg vs 59 ± 13 mmHg prior to LVAD implantation, P < 0.001). Detailed haemodynamic data are presented in Table 2. Importantly, reversal of PH was successful in all patients with no treatment failures. Table 2: Haemodynamic measurements of the study group Variables Pre-LVAD baseline (n = 38), mean ± SD Pre-LVAD after testing (n = 73), mean ± SD Post-LVAD (n = 75), mean ± SD P-valuea PA systolic (mmHg) 67 ± 13 59 ± 13 38 ± 12 <0.001 PA mean (mmHg) 45 ± 9 40 ± 9 25 ± 8 <0.001 PVR (WU) 5.4 ± 3.0 4.3 ± 1.8 2.0 ± 0.9 <0.001 PCWP (mmHg) 28 ± 6 25 ± 8 14 ± 7 <0.001 CO (l/min) 3.7 ± 1.1 4.0 ± 1.3 5.9 ± 1.6 <0.001 TPG (mmHg) 17 ± 7 15 ± 6 11 ± 5 <0.001 Variables Pre-LVAD baseline (n = 38), mean ± SD Pre-LVAD after testing (n = 73), mean ± SD Post-LVAD (n = 75), mean ± SD P-valuea PA systolic (mmHg) 67 ± 13 59 ± 13 38 ± 12 <0.001 PA mean (mmHg) 45 ± 9 40 ± 9 25 ± 8 <0.001 PVR (WU) 5.4 ± 3.0 4.3 ± 1.8 2.0 ± 0.9 <0.001 PCWP (mmHg) 28 ± 6 25 ± 8 14 ± 7 <0.001 CO (l/min) 3.7 ± 1.1 4.0 ± 1.3 5.9 ± 1.6 <0.001 TPG (mmHg) 17 ± 7 15 ± 6 11 ± 5 <0.001 a P-value: compared haemodynamics after testing before LVAD implantation to haemodynamics post-LVAD implantation. CO: cardiac output; LVAD: left ventricular assist device; PA mean: mean pulmonary artery pressure; PA systolic: systolic pulmonary artery pressure; PCWP: pulmonary capillary wedge pressure; PVR: pulmonary vascular resistance; SD: standard deviation; TPG: transpulmonary pressure gradient. Table 2: Haemodynamic measurements of the study group Variables Pre-LVAD baseline (n = 38), mean ± SD Pre-LVAD after testing (n = 73), mean ± SD Post-LVAD (n = 75), mean ± SD P-valuea PA systolic (mmHg) 67 ± 13 59 ± 13 38 ± 12 <0.001 PA mean (mmHg) 45 ± 9 40 ± 9 25 ± 8 <0.001 PVR (WU) 5.4 ± 3.0 4.3 ± 1.8 2.0 ± 0.9 <0.001 PCWP (mmHg) 28 ± 6 25 ± 8 14 ± 7 <0.001 CO (l/min) 3.7 ± 1.1 4.0 ± 1.3 5.9 ± 1.6 <0.001 TPG (mmHg) 17 ± 7 15 ± 6 11 ± 5 <0.001 Variables Pre-LVAD baseline (n = 38), mean ± SD Pre-LVAD after testing (n = 73), mean ± SD Post-LVAD (n = 75), mean ± SD P-valuea PA systolic (mmHg) 67 ± 13 59 ± 13 38 ± 12 <0.001 PA mean (mmHg) 45 ± 9 40 ± 9 25 ± 8 <0.001 PVR (WU) 5.4 ± 3.0 4.3 ± 1.8 2.0 ± 0.9 <0.001 PCWP (mmHg) 28 ± 6 25 ± 8 14 ± 7 <0.001 CO (l/min) 3.7 ± 1.1 4.0 ± 1.3 5.9 ± 1.6 <0.001 TPG (mmHg) 17 ± 7 15 ± 6 11 ± 5 <0.001 a P-value: compared haemodynamics after testing before LVAD implantation to haemodynamics post-LVAD implantation. CO: cardiac output; LVAD: left ventricular assist device; PA mean: mean pulmonary artery pressure; PA systolic: systolic pulmonary artery pressure; PCWP: pulmonary capillary wedge pressure; PVR: pulmonary vascular resistance; SD: standard deviation; TPG: transpulmonary pressure gradient. Listing status Of the study population, 21.5% (n = 17) were listed as high–urgent (HU) due to adverse events while on LVAD support. The main indications for Eurotransplant HU status listing were right heart failure, infection and pump thrombosis. Four patients (5.1%) were categorized as HU due to right heart decompensation resulting in hospitalization and inotropic support via dobutamine and/or levosimendan. Post-transplant outcome of the study group Thirty-day and in-hospital mortality were 3.8% and 5.1%, respectively (see also Table 3). Two patients (8.7%) experienced acute right heart failure and required extracorporeal membrane oxygenation shortly after transplantation. Both cases resulted in death due to complications likely related to ECMO support, with 1 patient having experienced systemic thromboembolism and the other intracerebral bleeding. Other causes of death in the early postoperative period include infection (50%) and neurological complications (16.7%). Table 3: Thirty-day and in-hospital mortality after cardiac transplantation Post-transplant mortality (%) LVAD with PH (n = 79), n (%) LVAD without PH (n = 48), n (%) 30-Day mortality 3.8 (3) 0 (0) In-hospital mortality 5.1 (4) 4.2 (2) Post-transplant mortality (%) LVAD with PH (n = 79), n (%) LVAD without PH (n = 48), n (%) 30-Day mortality 3.8 (3) 0 (0) In-hospital mortality 5.1 (4) 4.2 (2) LVAD: left ventricular assist device; PH: pulmonary hypertension. Table 3: Thirty-day and in-hospital mortality after cardiac transplantation Post-transplant mortality (%) LVAD with PH (n = 79), n (%) LVAD without PH (n = 48), n (%) 30-Day mortality 3.8 (3) 0 (0) In-hospital mortality 5.1 (4) 4.2 (2) Post-transplant mortality (%) LVAD with PH (n = 79), n (%) LVAD without PH (n = 48), n (%) 30-Day mortality 3.8 (3) 0 (0) In-hospital mortality 5.1 (4) 4.2 (2) LVAD: left ventricular assist device; PH: pulmonary hypertension. One-year survival rate was 89.9% with the main reasons for early post-transplant death being of cerebrovascular origin (n = 4; 50%) and infections (n = 3; 37.5%). The 3- and 5-year survival rates were 83.5% and 81.0%, respectively. Mean follow-up was 5.9 ± 4.6 years. The main causes of long-term post-transplant death were infections (29.2%), neoplasia (12.5%) and neurological complications (12.5%). Post-transplant outcome of the control group Peritransplant mortality, defined as 30-day mortality, was 0% (see also Table 3). We observed zero cases of acute right heart failure in this patient cohort. One-year survival rate was 93.8% with the causes of death including infections (66.7%) and neurological complications (33.3%). Long-term 3- and 5-year survival rates, 87.5% and 85.4% respectively, were comparable to the study group’s 3-year survival rate of 83.5% and 5-year survival rate of 81.0% (log-rank: P = 0.585). Mean follow-up was 4.7 ± 4.2 years. Kaplan–Meier analysis displaying the overall post-transplant survival is presented in Fig. 2. Causes of death are presented in Table 4. Table 4: Reasons for death after cardiac transplantation Post-transplant causes of death (%) LVAD with PH (n = 23) (29.1), n (%) LVAD without PH (n = 10) (20.4), n (%) Sudden cardiac death 2 (8.7) 1 (10.0) Right heart failure 2 (8.7) 0 (0) Cardiac allograft vasculopathy 0 (0) 1 (10.0) Rejection 0 (0) 1 (10.0) Infection 7 (30.4) 3 (30.0) Neurological 3 (13.0) 1 (10.0) Neoplasia 3 (13.0) 2 (20.0) Other 2 (8.7) 0 (0) Unknown 4 (17.4) 1 (10.0) Post-transplant causes of death (%) LVAD with PH (n = 23) (29.1), n (%) LVAD without PH (n = 10) (20.4), n (%) Sudden cardiac death 2 (8.7) 1 (10.0) Right heart failure 2 (8.7) 0 (0) Cardiac allograft vasculopathy 0 (0) 1 (10.0) Rejection 0 (0) 1 (10.0) Infection 7 (30.4) 3 (30.0) Neurological 3 (13.0) 1 (10.0) Neoplasia 3 (13.0) 2 (20.0) Other 2 (8.7) 0 (0) Unknown 4 (17.4) 1 (10.0) LVAD: left ventricular assist device; PH: pulmonary hypertension. Table 4: Reasons for death after cardiac transplantation Post-transplant causes of death (%) LVAD with PH (n = 23) (29.1), n (%) LVAD without PH (n = 10) (20.4), n (%) Sudden cardiac death 2 (8.7) 1 (10.0) Right heart failure 2 (8.7) 0 (0) Cardiac allograft vasculopathy 0 (0) 1 (10.0) Rejection 0 (0) 1 (10.0) Infection 7 (30.4) 3 (30.0) Neurological 3 (13.0) 1 (10.0) Neoplasia 3 (13.0) 2 (20.0) Other 2 (8.7) 0 (0) Unknown 4 (17.4) 1 (10.0) Post-transplant causes of death (%) LVAD with PH (n = 23) (29.1), n (%) LVAD without PH (n = 10) (20.4), n (%) Sudden cardiac death 2 (8.7) 1 (10.0) Right heart failure 2 (8.7) 0 (0) Cardiac allograft vasculopathy 0 (0) 1 (10.0) Rejection 0 (0) 1 (10.0) Infection 7 (30.4) 3 (30.0) Neurological 3 (13.0) 1 (10.0) Neoplasia 3 (13.0) 2 (20.0) Other 2 (8.7) 0 (0) Unknown 4 (17.4) 1 (10.0) LVAD: left ventricular assist device; PH: pulmonary hypertension. Figure 2: View largeDownload slide Kaplan–Meier curve demonstrating long-term post-transplant survival. Blue curve: cardiac transplant patients with pretransplant PH; red curve: cardiac transplant patients without pretransplant PH; vertical axis (survival in %) starts at 60% for easier readability. HTX: heart transplantation; PH: pulmonary hypertension. Figure 2: View largeDownload slide Kaplan–Meier curve demonstrating long-term post-transplant survival. Blue curve: cardiac transplant patients with pretransplant PH; red curve: cardiac transplant patients without pretransplant PH; vertical axis (survival in %) starts at 60% for easier readability. HTX: heart transplantation; PH: pulmonary hypertension. DISCUSSION fPH is an established contraindication for HTX due to an inacceptable risk for post-transplant right heart failure associated with elevated post-transplant mortality rates [1, 3]. LVAD implantation reverses fPH in HTX candidates with fPH as part of a bridge to candidacy strategy and facilitates safe HTX [1, 4, 5, 9]. Secondary PH affects up to 72% of end-stage heart failure patients and is the consequence of elevated left atrial pressure resulting from impaired left ventricular systolic function [11]. Left atrial hypertension increases post-capillary pressures in the pulmonary vascular system, prompting increased pulmonary endothelial dysfunction. In the initial stages of this process, pulmonary vasoconstriction occurs as a result of decreasing nitric oxide, prostacyclin concentrations and increased thromboxane A2 and endothelin-1 production [5, 19]. At a later stage, up-regulated subendothelial serine elastase gives rise to glycoprotein deposition as well as smooth muscle cell hypertrophy and hyperplasia [5, 19]. In combination with the development of platelet fibrin microthrombi as a result of changes in the expression of the von Willebrand factor, this pathophysiological process can lead to the remodelling of the pulmonary vascular tree [5]. Reversible PH differs from fPH in its response to vasodilator treatment [3]. Specifically, fPH is refractory to medical therapy and is the result of prolonged exposure to elevated left atrial pressures [19]. The irreversibility of fPH is a consequence of the pulmonary vascular system’s remodelling process. A higher risk of post-transplant failure in the non-conditioned right ventricle of the donor heart, as well as associated higher post-transplant mortality, makes fPH an established contraindication for HTX [2, 3, 5–9]. Cut-off values for HTX candidacy in patients with fPH vary throughout the literature, but most transplant centres will not accept a PVR >3–4 WU for HTX [5]. Mechanical circulatory support is the standard treatment in HTX recipients suffering from fPH [19]. By continuously unloading the left ventricle, LVADs reduce the left atrial pressure, thus leading to the reduction of pulmonary artery pressures [19]. The excellent long-term post-transplant survival of this study after reversing fPH using LVAD therapy (3 year: 83.5%, 5 year: 81.0%) is comparable to that of patients bridged to transplant via LVAD for reasons other than PH (3 year: 87.5%, 5 year: 85.4%). The 1- and 3-year survival rates, 89.9% and 83.5%, respectively, are comparable to those reported in previous studies [20, 21]. Furthermore, we note that the results of this study are non-inferior when compared with recent international post-transplant 1- and 5-year survival rates (84% and 75% respectively) after orthotopic HTX in recipients without fPH [22]. Previous studies have shown that there is no significant difference with regard to the reduction of fPH by the support of continuous or pulsatile flow devices [1, 9]. In the present study, the majority of patients (93.8%) received continuous-flow LVADs. The increased usage of continuous-flow device systems can be attributed to the improved long-term survival rates and lower adverse event occurrences reported in studies utilizing these devices [23–26]. Despite device updates, morbidity and mortality remain major concerns in LVAD therapy. The 1- and 2-year survival rates of patients while on continuous-flow LVAD support are reported at 80% and 70%, respectively [25]. Typical LVAD complications include pump thrombosis, infections, neurological events and right heart failure [25]. From the present study population, 17 of the patients on LVAD support (21.5%) required Eurotransplant HU registration due to severe adverse events. Pump thrombosis and right heart failure occurred in 5 (6.3%) and 4 (5.0%) of these patients, respectively, with only 1 patient (1.3%) having experienced device malfunction in a MicroMed DeBakey LVAD. Limitations The study is limited by its retrospective design as well as the unadjusted baseline risk in the comparison of the HTX groups with and without fPH. CONCLUSION LVAD implantation as a bridge to candidacy reverses fPH in patients with terminal heart failure. Post-HTX survival is excellent and comparable to the results obtained in patients without fPH at the time of HTX listing. Conflict of interest: none declared. REFERENCES 1 Mikus E , Stepanenko A , Krabatsch T , Loforte A , Dandel M , Lehmkuhl HB et al. . Reversibility of fixed pulmonary hypertension in left ventricular assist device support recipients . Eur J Cardiothorac Surg 2011 ; 40 : 971 – 7 . Google Scholar PubMed 2 Mehra MR , Kobashigawa J , Starling R , Russell S , Uber PA , Parameshwar J et al. . 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Journal

European Journal of Cardio-Thoracic SurgeryOxford University Press

Published: Jun 13, 2018

References