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Background: Donor‐derived cell‐free DNA (dd‐cfDNA) has emerged as a reliable, noninvasive method for the surveillance of allograft rejection in heart transplantation (HT) patients, but its utility in multi‐organ transplants (MOT) is unknown. We describe our experience using dd‐cfDNA in simultaneous MOT recipients. Methods: A single‐center retrospective review of all HT recipients between 2018 and 2022 that had at least one measurement of dd‐cfDNA collected. Patients who had simultaneous MOT were identified and included in this study. Levels of dd‐cfDNA were paired with endomyocardial biopsies (EMB) performed within 1 month of blood testing if available. Acute cellular rejection (ACR) was defined as ISHLT (International Society for Heart and Lung Transplantation) grade ≥ 2R. and antibody‐mediated rejection (AMR) was defined as pAMR grade > 0. The within‐patient variability score of the dd‐cfDNA was calculated by the variance/average. Results: The study included 25 multiorgan transplant recipients: 13 heart–kidney (H‐K), 8 heart–liver (H‐Li), and 4 heart–lung (H‐Lu). The median age was 55 years, 44% were female; the median time from HT until the first dd‐cfDNA measurement was 4.5 months (IQR 2, 10.5). The median dd‐cfDNA level was 0.18% (IQR 0.15%, 0.27%) for H‐K, 1.15% (IQR 0.77%, 2.33%) for H‐Li, and 0.69% (IQR 0.62%, 1.07%) for H‐Lu patients (p < 0.001). Prevalence of positive dd‐cfDNA tests (threshold of 0.20%) were 42.2%, 97.3%, and 92.3% in the H‐K, H‐Li, and H‐Lu groups, respectively. The within‐patient variability score was highest in the H‐Li group (median of 0.45 [IQR 0.29, 0.94]) and lowest in the H‐K group (median of 0.09 [IQR 0.06, 0.12]); p = 0.002. No evidence of cardiac ACR or AMR was found. Three patients experienced renal allograft ACR and/or AMR, two patients experienced rejection of the liver allograft, and one patient experienced an episode of AMR‐mediated lung rejection. One person in the H‐K group experienced an episode of cardiac allograft dysfunction that was not associated with biopsy‐confirmed rejection. Conclusion: Dd‐cfDNA is chronically elevated in most MOT recipients. There is a high degree of within‐patient variability in levels (particularly for H‐Li and H‐Lu recipients), which may limit the utility of this assay in monitoring MOT recipients. [ABSTRACT FROM AUTHOR]

Introduction: The scarcity of donors coupled with the improvements in left ventricular assist devices (LVAD) technology has led to the use of LVAD as a bridge to transplantation (BTT). Areas covered: The authors provide an overview of the current status of LVAD BTT implantation with special focus ranging from patient selection and pre-implantation optimization to post-transplant outcomes. Expert Opinion: The United Network for Organ Sharing 2018 policy amendment resulted in a significant reduction in the number of LVADs used for BTT in the US. To overcome this issue, modifications in the US allocation policy to consider factors such as days on device support, age, and type of complications may be necessary to potentially increase implantation rates. [ABSTRACT FROM AUTHOR]

Background: Since the 2018 allocation system change in heart transplantation (HT), ischemic times have increased, which may be associated with peri‐operative and post‐operative complications. This study aimed to compare ischemia reperfusion injury (IRI) in hearts preserved using ice‐cold storage (ICS) and the Paragonix SherpaPak TM Cardiac Transport System (CTS). Methods: From January 2021 to June 2022, consecutive endomyocardial biopsies from 90 HT recipients were analyzed by a cardiac pathologist in a single‐blinded manner: 33 ICS and 57 CTS. Endomyocardial biopsies were performed at three‐time intervals post‐HT, and the severity of IRI manifesting histologically as coagulative myocyte necrosis (CMN) was evaluated, along with graft rejection and graft function. Results: The incidence of IRI at weeks 1, 4, and 8 post‐HT were similar between the ICS and CTS groups. There was a 59.3% statistically significant reduction in CMN from week 1 to 4 with CTS, but not with ICS. By week 8, there were significant reductions in CMN in both groups. Only 1 out of 33 (3%) patients in the ICS group had an ischemic time >240 mins, compared to 10 out of 52 (19%) patients in the CTS group. During the follow‐up period of 8 weeks to 12 months, there were no significant differences in rejection rates, formation of de novo donor‐specific antibodies and overall survival between the groups. Conclusion: The CTS preservation system had similar rates of IRI and clinical outcomes compared to ICS despite longer overall ischemic times. There is significantly more recovery of IRI in the early post operative period with CTS. This study supports CTS as a viable option for preservation from remote locations, expanding the donor pool. [ABSTRACT FROM AUTHOR]

Aortic regurgitation (AR) is a common complication following left ventricular assist device (LVAD) implantation. We evaluated the hemodynamic implications of AR in patients with HeartMate 3 (HM3) LVAD at baseline and in response to speed changes. Clinically stable outpatients supported by HM3 who underwent a routine hemodynamic ramp test were retrospectively enrolled in this analysis. Patients were stratified based on the presence of at least mild AR at baseline speed. Hemodynamic and echocardiographic parameters were compared between the AR and non-AR groups. Sixty-two patients were identified. At the baseline LVAD speed, 29 patients (47%) had AR, while 33 patients (53%) did not. Patients with AR were older and supported on HM3 for a longer duration. At baseline speed, all hemodynamic parameters were similar between the groups including central venous pressure, pulmonary capillary wedge pressure, pulmonary arterial pressures, cardiac output and index, and pulmonary artery pulsatility index (p > 0.05 for all). During the subacute assessment, AR worsened in some, but not all, patients, with increases in LVAD speed. There were no significant differences in 1-year mortality or hospitalization rates between the groups, however, at 1-year, ≥ moderate AR and right ventricular failure (RVF) were detected in higher rates among the AR group compared to the non-AR group (45% vs. 0%; p < 0.01, and 75% vs. 36.8%; p = 0.02, respectively). In a cohort of stable outpatients supported with HM3 who underwent a routine hemodynamic ramp test, the presence of mild or greater AR did not impact the ability of HM3 LVADs to effectively unload the left ventricle during early subacute assessment. Although the presence of AR did not affect mortality and hospitalization rates, it resulted in higher rates of late hemodynamic-related events in the form of progressive AR and RVF. The Hemodynamic Effects of Aortic Regurgitation in Patients Supported with HM3. [Display omitted] [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the clinical implications of adjunctive molecular gene expression analysis (MMDx ) of biopsy specimens in heart transplant (HT ) recipients with suspected rejection., Introduction: Histopathological evaluation remains the standard method for rejection diagnosis in HT. However, the wide interobserver variability combined with a relatively common incidence of "biopsy-negative" rejection has raised concerns about the likelihood of false-negative results. MMDx, which uses gene expression to detect early signs of rejection, is a promising test to further refine the assessment of HT rejection., Methods: Single-center prospective study of 418 consecutive for-cause endomyocardial biopsies performed between November 2022 and May 2024. Each biopsy was graded based on histology and assessed for rejection patterns using MMDx. MMDx results were deemed positive if borderline or definitive rejection was present. The impact of MMDx results on clinical management was evaluated. Primary outcomes were 1-year survival and graft dysfunction following MMDx-guided clinical management. Secondary outcomes included changes in donor-specific antibodies, MMDx gene transcripts, and donor-derived cell-free DNA (dd-cfDNA) levels., Results: We analyzed 418 molecular samples from 237 unique patients. Histology identified rejection in 32 cases (7.7%), while MMDx identified rejection in 95 cases (22.7%). Notably, in 79 of the 95 cases where MMDx identified rejection, histology results were negative, with the majority of these cases being antibody-mediated rejection (62.1%). Samples with rejection on MMDx were more likely to show a combined elevation of dd-cfDNA and peripheral blood gene expression profiling than those with borderline or negative MMDx results (36.7% vs 28.0% vs 10.3%; p<0.001). MMDx results led to the implementation of specific antirejection protocols or changes in immunosuppression in 20.4% of cases, and in 73.4% of cases where histology was negative and MMDx showed rejection. 1-year survival was better in the positive MMDx group where clinical management was guided by MMDx results (87.0% vs 78.6%; log rank p=0.0017)., Conclusions: In our cohort, MMDx results more frequently indicated rejection than histology, often leading to the initiation of antirejection treatment. Intervention guided by positive MMDx results was associated with improved outcomes.

Objective: The HeartMate 3 survival risk score was recently validated in the Multicenter study Of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy with HeartMate 3 to predict patient-specific survival in HeartMate 3 left ventricular assist device candidates. The HeartMate 3 survival risk score stratifies individuals into tertiles according to survival probability., Methods: We performed a single-center retrospective review of all HeartMate 3 left ventricular assist device recipients between September 2017 and August 2022. Baseline characteristics were collected from the electronic medical records. HeartMate 3 survival risk scores were calculated for all eligible patients. One- and 2-year Kaplan-Meier survival analyses were conducted. A univariate and multivariable Cox regression model was used to identify predictors., Results: A total of 181 patients were included in this final analysis. The median age was 62 years, 83% were male, and 26% were Interagency Registry for Mechanically Assisted Circulatory Support Profile 1. The mean HeartMate 3 survival risk score for the entire cohort was 2.66 ± 0.66. Two-year survivals in the high, average, and low survival groups were 93.5% ± 3.2%, 81.6% ± 7.4%, and 82.0% ± 6.6%, respectively. As a continuous variable, the unadjusted HeartMate 3 survival risk score was a significant predictor of mortality (hazard ratio, 2.20; 95% CI, 1.08-4.45; P = .029). The areas under the curve were 0.70 and 0.66 at 1 and 2 years, respectively. We were unable to demonstrate the discriminatory ability of the HeartMate 3 survival risk score using the original stratification, but we found significantly increased survival in the high survival group using a binary cutoff (hazard ratio, 4.8; 95% CI, 1.01-20.9; P = .038)., Conclusions: The unadjusted HeartMate 3 survival risk score was associated with postimplant survival in patients outside of the Multicenter study Of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy with HeartMate 3 but did not remain an independent predictor after adjusting for ischemic etiology and severe diabetes. The HeartMate 3 survival risk score was able to identify patients at high survival using a binary cutoff, but we were unable to demonstrate its discriminatory ability among the previously published risk tertiles., Competing Interests: Conflict of Interest Statement Dr Uriel is on the medical advisory board for Livemetric, Revamp, and Leviticus. Center for Advanced Cardiac Care at Columbia University Irving Medical Center receives grant support from CareDx and Abbott. Dr Sayer has been a consultant for Abbott and is on the medical advisory board for CareDx. Dr Clerkin receives National Institutes of Health grant support K23 HL148528 and the Nelson Family Grant. Dr Topkara receives National Institutes of Health grant support (HL146964). Dr Moeller receives a grant from ISHLT and CareDx. All other authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (Published by Elsevier Inc.)