Recipient Outcomes With Extended Criteria Donors Using Advanced Heart Preservation: An Analysis of the GUARDIAN-Heart Registry.

BACKGROUND: The prevalence of end-stage heart failure and patients who could benefit from heart transplantation requires an expansion of the donor pool, relying on the transplant community to continually re-evaluate and expand the use of extended criteria donor organs. Introduction of new technologies such as the Paragonix SherpaPak Cardiac Transport System aids in this shift. We seek to analyze the impact of the SherpaPak system on recipient outcomes who receive extended criteria organs in the GUARDIAN-Heart Registry. METHODS: Between October 2015 and December 2022, 1,113 adults from 15 US centers receiving donor hearts utilizing either SherpaPak (n = 560) or conventional ice storage (ice, n = 453) were analyzed from the GUARDIAN-Heart Registry using summary statistics. A previously published set of criteria was used to identify extended criteria donors, which included 193 SherpaPak and 137 ice. RESULTS: There were a few baseline differences among recipients in the 2 cohorts; most notably, IMPACT scores, distance traveled, and total ischemic time were significantly greater in SherpaPak, and significantly more donor hearts in the SherpaPak cohort had >4 hours total ischemia time. Posttransplant mechanical circulatory support utilization (SherpaPak 22.3% vs ice 35.0%, p = 0.012) and new extracorporeal membrane oxygenation/ventricular assist device (SherpaPak 7.8% vs ice 15.3%, p = 0.033) was significantly reduced, and the rate of severe primary graft dysfunction (SherpaPak 6.2% vs ice 13.9%, p = 0.022) was significantly reduced by over 50% in hearts preserved using SherpaPak. One-year survival between cohorts was similar (SherpaPak 92.9% vs ice 89.6%, p = 0.27). CONCLUSIONS: This subgroup analysis demonstrates that SherpaPak can be safely used to utilize extended criteria donors with low severe PGD rates.

Prioritizing direct heart procurement in organ donors after circulatory death does not jeopardize lung transplant outcomes.

Background: Controlled donation after circulatory death (cDCD) has become a standard in liver, kidney, and lung transplantation (LTx). Based on recent innovations in ex vivo heart preservation, heart transplant centers have started to accept cDCD heart allografts. Because the heart has very limited tolerance to warm ischemia, changes to the cDCD organ procurement procedures are needed. These changes entail delayed ventilation and prolonged warm ischemia for the lungs. Whether this negatively impacts lung allograft function is unclear. Methods: A retrospective analysis of cDCD lungs transplanted between 2012 and February 2022 at the Medical University of Vienna was performed. The heart + lung group consisted of cases in which the heart was procured by a cardiac team for subsequent normothermic ex vivo perfusion. A control group (lung group) was formed by cases where only the lungs were explanted. In heart + lung group cases, the heart procurement team placed cannulas after circulatory death and a hands-off time, collected donor blood for ex vivo perfusion, and performed rapid organ perfusion with Custodiol solution, after which the heart was explanted. Up to this point, the lung procurement team did not interfere. No concurrent lung ventilation or pulmonary artery perfusion was performed. After the cardiac procurement team left the table, ventilation was initiated, and lung perfusion was performed directly through both stumps of the pulmonary arteries using 2 large-bore Foley catheters. This study analyzed procedural explant times, postoperative outcomes, primary graft dysfunction (PGD), duration of mechanical ventilation, length of intensive care unit (ICU) stay, and early survival after LTx. Results: A total of 56 cDCD lungs were transplanted during the study period. In 7 cases (12.5%), the heart was also procured (heart + lung group); in 49 cases (87.5%), only the lungs were explanted (lung group). Basic donor parameters were comparable in the 2 groups. The median times from circulatory arrest to lung perfusion (24 minutes vs 13.5 minutes; P = .002) and from skin incision to lung perfusion (14 minutes vs 5 minutes; P = .005) were significantly longer for the heart + lung procedures. However, this did not affect post-transplantation PGD grade at 0 hours (P = .851), 24 hours (P = .856), 48 hours (P = .929), and 72 hours (P = .874). At 72 hours after transplantation, none of the lungs in the heart + lung group but 1 lung (2.2%) in lung group was in PGD 3. The median duration of mechanical ventilation (50 hours vs 41 hours; P = .801), length of ICU stay (8 days vs 6 days; P = .951), and total length of hospital stay (27 days vs 25 days; P = .814) were also comparable in the 2 groups. In-hospital mortality occurred in only 1 patient of the lung group (2.2%). Conclusions: Although prioritized cDCD heart explantation is associated with delayed ventilation and significantly longer warm ischemic time to the lungs, post-LTx outcomes within the first year are unchanged. Prioritizing heart perfusion and explantation in the setting of cDCD procurement can be considered acceptable.

Extracorporeal Photopheresis With Low-Dose Immunosuppression in High-Risk Heart Transplant Patients-A Pilot Study.

In severely ill patients undergoing urgent heart transplant (HTX), immunosuppression carries high risks of infection, malignancy, and death. Low-dose immunosuppressive protocols have higher rejection rates. We combined extracorporeal photopheresis (ECP), an established therapy for acute rejection, with reduced-intensity immunosuppression. Twenty-eight high-risk patients (13 with high risk of infection due to infection at the time of transplant, 7 bridging to transplant via extracorporeal membrane oxygenation, 8 with high risk of malignancy) were treated, without induction therapy. Prophylactic ECP for 6 months (24 procedures) was initiated immediately postoperatively. Immunosuppression consisted of low-dose tacrolimus (8-10 ng/ml, months 1-6; 5-8 ng/ml, >6 months) with delayed start; mycophenolate mofetil (MMF); and low maintenance steroid with delayed start (POD 7) and tapering in the first year. One-year survival was 88.5%. Three patients died from infection (POD 12, 51, 351), and one from recurrence of cancer (POD 400). Incidence of severe infection was 17.9% (n = 5, respiratory tract). Within the first year, antibody-mediated rejection was detected in one patient (3.6%) and acute cellular rejection in four (14.3%). ECP with reduced-intensity immunosuppression is safe and effective in avoiding allograft rejection in HTX recipients with risk of severe infection or cancer recurrence.

A Novel Endothelial Damage Inhibitor Reduces Oxidative Stress and Improves Cellular Integrity in Radial Artery Grafts for Coronary Artery Bypass.

The radial artery (RA) is a frequently used conduit in coronary artery bypass grafting (CABG). Endothelial injury incurred during graft harvesting promotes oxidative damage, which leads to graft disease and graft failure. We evaluated the protective effect of DuraGraft®, an endothelial damage inhibitor (EDI), on RA grafts. We further compared the protective effect of the EDI between RA grafts and saphenous vein grafts (SVG). Samples of RA (n = 10) and SVG (n = 13) from 23 patients undergoing CABG were flushed and preserved with either EDI or heparinized Ringer's lactate solution (RL). The effect of EDI vs. RL on endothelial damage was evaluated ex vivo and in vitro using histological analysis, immunofluorescence staining, Western blot, and scanning electron microscopy. EDI-treated RA grafts showed a significant reduction of endothelial and sub-endothelial damage. Lower level of reactive oxygen species (ROS) after EDI treatment was correlated with a reduction of hypoxic damage (eNOS and Caveolin-1) and significant increase of oxidation-reduction potential. Additionally, an increased expression of TGFß, PDGFα/ß, and HO-1 which are indicative for vascular protective function were observed after EDI exposure. EDI treatment preserves functionality and integrity of endothelial and intimal cells. Therefore, EDI may have the potential to reduce the occurrence of graft disease and failure in RA grafts in patients undergoing CABG.

Less Invasive Left Ventricular Assist Device Implantation Is Safe and Reduces Intraoperative Blood Product Use: A Propensity Score Analysis VAD Implantation Techniques and Blood Product Use.

Despite increasing popularity and multiple postulated benefits, less invasive (LIS) left ventricular assist device (LVAD) implantation has not been sufficiently compared with standard full sternotomy (FS). We report the outcomes of a propensity score analysis designed to compare LIS and FS LVAD implantation, with perioperative blood product use, adverse event rates, and mortality as primary objective. From September 2010 to August 2016, 159 consecutive patients received a Medtronic HVAD or Abbott HeartMate 3 LVAD via a FS or LIS approach. Outcomes were analyzed using proportional hazard Cox regression, with risk adjustment based on a LIS approach propensity score model computed from demographics, risk factors, and operative covariates. Seventy-five patients were matched and compared (HVAD 83% [n = 62]; LIS approach 43% [n = 32]; mean age 60 ± 12 years; 89% [n = 67] male; 48% [n = 36] ischemic cardiomyopathy [ICMP]; 37% [n = 28]). Patient groups were comparable with regard to preoperative patient characteristics. Less invasive LVAD implantation was successful in all patients with no intraoperative conversions. In-hospital mortality was 16% in both groups, despite 37% Interagency Registry for Mechanically Assisted Circulatory Support Level I patients. Overall, 28% of the LIS patients did not receive any blood products intraoperatively, whereas, in the FS group, only two patients (5%) did not require the administration of blood products (p = 0.000). This was also a significant finding in the overall perioperative phase in which seven LIS patients (22%) who not receive any blood products versus two FS patients (5%; p = 0.033). Otherwise, outcomes were comparable. Less invasive LVAD implantation is a feasible, safe, and reduces blood product use.

Thrombolysis as first-line therapy for Medtronic/HeartWare HVAD left ventricular assist device thrombosis.

OBJECTIVES: We reviewed our institutional experience with intravenous thrombolysis (TL) as first-line therapy in patients with Medtronic/HeartWare HVAD left ventricular assist device pump thrombosis (PT). METHODS: From March 2006 to November 2018, 30 Medtronic/HeartWare HVAD left ventricular assist device patients had 48 PT events. We analysed outcomes with intravenous Alteplase as a first-line therapy for PT. Pump exchange or urgent heart transplantation was only considered after the failure of TL or existing contraindications to TL. RESULTS: TL was used as the first-line therapy in 44 PT events in 28 patients without a contraindication to TL. TL was successful in 61.4% of PT events. More than 1 cycle of TL was necessary in 55.6% of events. The combined success of TL and heart transplantation or device exchange was 81.8%. In 15.9% of events, PT was fatal. Causes of death were severe complications (9.1%) related to TL or discontinuation of therapy for multi-organ failure (6.8%). Intracranial bleeding and arterial thromboembolism were observed in 4.5% and 11.5% of the PT events after TL. CONCLUSIONS: Intravenous TL as a first-line therapy for PT in Medtronic/HeartWare HVAD patients can be a reasonable treatment option and does not preclude subsequent heart transplantation or device exchange. However, thromboembolic and bleeding complications are common. The decision to perform TL or device exchange should, therefore, be made on an individual basis after balancing the risks and benefits of different treatment approaches.

Molecular-level HLA mismatch is associated with rejection and worsened graft survival in heart transplant recipients - a retrospective study.

The aim was to evaluate the association of molecular-level human leukocyte antigen (HLA) mismatching with post-transplant graft survival, rejection, and cardiac allograft vasculopathy (CAV). We retrospectively analyzed all primary cardiac transplant recipients between 01/1984-06/2016. 1167 patients fulfilled inclusion criteria and had HLA typing information available. In 312 donor-recipient pairs, typing at serological split antigen level was available. We used the Epitope MisMatch Algorithm to calculate the number of amino acid differences in antibody-verified HLA eplets (amino acid mismatch load (AAMM)) between donor and recipient. Patients with a higher HLA-DR AAMM load had inferior 1-year graft survival (hazard ratio [HR], 1.14; 95% confidence interval [CI], 1.01-1.28). The HLA-AB AAMM load showed no impact on graft survival. In the subgroup with available split-level information, we observed an inferior graft survival for a higher HLA-DR AAMM load 3 months after transplantation (HR, 1.22; 95% CI, 1.04-1.44) and a higher risk for rejection for an increasing HLA-AB (HR, 1.70; 95% CI, 1.29-2.24) and HLA-DR (HR, 1.32; 95% CI, 1.09-1.61) AAMM load. No impact on the development of CAV was found. Molecular-level HLA mismatch analysis could serve as a tool for risk stratification after heart transplantation and might take us one step further into precision medicine.

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

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.

Donor heart selection and outcomes: An analysis of over 2,000 cases.

BACKGROUND: Decision-making when offered a donor heart for transplantation is complex, and supportive data describing outcomes according to acceptance or non-acceptance choices are sparse. Our aim was to analyze donor heart acceptance decisions and associated outcomes at a single center, and after subsequent acceptance elsewhere. METHODS: This investigation was a retrospective analysis of data obtained from the University of Vienna Medical Center and Eurotransplant centers for the period 2001 to 2015. RESULTS: Our center accepted 31.8% (699 of 2,199) of donor hearts offered. Unlike other centers, the acceptance rate, with or without transplantation, did not increase over time. Of the donor hearts rejected by our center, 38.1% (572 of 1,500) were later accepted elsewhere. Acceptance rates were twice as high for donor hearts initially rejected for non-quality reasons (339 of 601, 56.4%) compared with initial rejection for quality reasons (233 of 899, 25.9%). Three-year patient survival rate was 79% at Vienna; for donor hearts initially rejected by Vienna for non-quality reasons or quality reasons, it was 73% and 63%, respectively (p < 0.001). Outcomes at other centers after transplantation of grafts rejected by Vienna varied according to the reason for rejection, with good 3-year survival rates for rejection due to positive virology (77%), high catecholamines (68%), long ischemic time (71%), or low ejection fraction (68%), but poor survival was observed for hearts rejected for hypernatremia (46%), cardiac arrest (21%), or valve pathology (50%). CONCLUSIONS: A less restrictive policy for accepting donor hearts at our center, particularly regarding rejection for non-quality reasons or for positive virology, high catecholamine levels, longer ischemic time, or low ejection fraction, could expand our donor pool while maintaining good outcomes.

Diminished impact of cytomegalovirus infection on graft vasculopathy development in the antiviral prophylaxis era - a retrospective study.

Evidence concerning an association between cytomegalovirus (CMV) infection and accelerated cardiac allograft vasculopathy (CAV) is inconclusive. Data were analyzed retrospectively from 297 consecutive heart transplants between 1.1.2002 and 31.12.2012. Patients ≤18 years of age, survival, and follow-up ≤1-year post-transplant and patients with early CAV were excluded. CMV-infection was diagnosed and monitored closely in the first year. CAV was diagnosed by coronary angiography via left heart catheterization, and results were categorized according to the International Society of Heart and Lung Transplantation (ISHLT) scoring system. Risk factors for CAV were tested in a multivariable model. Median follow-up was 7.5 years (IQR: 5.6-10.3). CMV infection in the first year after transplantation occurred in 26% of patients (n = 78), CMV disease in 5% (n = 15). CAV ≥1 ISHLT was detected in 36% (n = 108). Incidence of CAV >1 ISHLT and severity of CAV increased over time. No statistically significant association between CMV infection and disease within the first year and risk of CAV after 1-year post-HTx was detected in the univariate (P = 0.16) and multivariable [hazard ratio (HR), 1.36; confidence interval (CI), 0.89-2.07; P = 0.16] Cox regression. In the multivariable Cox regression, donor age (HR, 1.04; 95% CI, 1.02-1.06; P < 0.01) and acute cellular rejection (ACR) ≥2R in the first year after HTx (HR, 1.77; 95% CI, 1.06-2.95; P = 0.03) were independent risk factors for CAV development. In our cohort, CMV infection and disease in the first year after transplantation did not significantly influence the risk of CAV in the long-term follow-up.

High-dose catecholamine donor support and outcomes after heart transplantation.

BACKGROUND: Higher dose norepinephrine donor support is a frequent reason for donor heart decline, but its associations with outcomes after heart transplantation are unclear. METHODS: We retrospectively analyzed 965 patients transplanted between 1992 and 2015 in the Heart Transplant Program Vienna. Stratification was performed according to donor norepinephrine dose administered before organ procurement (Group 0: 0 µg/kg/min; Group 1: 0.01 to 0.1 µg/kg/min; Group 2: >0.1 µg/kg/min). Sub-stratification of Group 2 was performed for comparison of high-dose subgroups (Group HD 1: 0.11 to 0.4 µg/kg/min; Group HD 2: >0.4 µg/kg/min). Associations between groups and outcome variables were investigated using a multivariable Cox proportional hazards model and logistic regression analyses. RESULTS: Donor norepinephrine dose groups were not associated with overall mortality (Group 1 vs 0: hazard ratio [HR] 1.12, 95% confidence interval [CI] 0.87 to 1.43; Group 2 vs 0: HR 1.07, 95% CI 0.82 to 1.39; p = 0.669). No significant group differences were found for rates of 30-day mortality (p = 0.35), 1-year mortality (p = 0.897), primary graft dysfunction (p = 0.898), prolonged ventilation (p = 0.133) and renal replacement therapy (p = 0.324). Groups 1 and 2 showed higher rates of prolonged intensive care unit stay (18.9% vs 28.5% vs 27.5%, p = 0.005). High-dose subgroups did not differ significantly in 1-year mortality (Group HD 1: 14.3%; Group HD 2: 17.8%; p = 0.549). CONCLUSIONS: Acceptance of selected donor hearts supported by higher doses of norepinephrine may be a safe option to increase the donor organ pool.

Increased Thromboembolic Events With Dabigatran Compared With Vitamin K Antagonism in Left Ventricular Assist Device Patients: A Randomized Controlled Pilot Trial.

BACKGROUND: Left ventricular assist device-supported patients are usually anticoagulated with a combination of aspirin and vitamin K antagonists. Long-term vitamin K antagonist therapy can be complicated by unstable international normalized ratio values and patient-related compliance problems. Therefore, direct thrombin inhibitors may represent an alternative to vitamin K antagonists. METHODS AND RESULTS: Thirty HeartWare ventricular assist device patients with stable renal function were planned for this prospective, randomized, open-label, single-center study. Patients were randomized to receive either phenprocoumon or dabigatran in addition to aspirin for long-term anticoagulation. Treatment duration was scheduled for 1 year and stopped after observation of a primary end point. Dabigatran dose was 110 and 75 mg BID in patients with normal or impaired renal function (glomerular filtration rate >80 mL/min or between 80 and 30 mL/min, respectively). The study was stopped prematurely for safety reasons after 16 patients (61±8 years, 1 female) were randomized. Thromboembolic events occurred in 4 subjects receiving dabigatran (50%) and in 1 receiving phenprocoumon (13%; P=0.28). No major bleeding was recorded, and no patient died during the study. Median time to treatment termination was significantly shorter in dabigatran patients (8.5 versus 12.0 months; P=0.015). CONCLUSIONS: Thromboembolic events on dabigatran led to early termination of a randomized controlled trial of dabigatran versus phenprocoumon in left ventricular assist device patients. CLINICAL TRIAL REGISTRATION: https://www.clinicaltrials.gov. Unique identifier: NCT02872649.