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Nearly half of heart transplant recipients will be diagnosed with cardiac allograft vasculopathy (CAV) within five years after transplantation. Advanced CAV can lead to worsening heart failure as well as arrhythmias and sudden cardiac death. The only curative therapy for end-stage CAV is re-transplantation. Current diagnostic methods are invasive and limited by poor sensitivity in early disease. Despite its high prevalence in the post-transplantpopulation, the underlying pathophysiology of this condition has yet to be fully described. It is thought to be primarily related to endothelial dysfunction, immune activation, and cardiometabolic disease. Biomarkers reflecting these underlying processes, particularly endothelial injury and immune activation, have shown early promise in discriminating prevalent CAV. Next-generation sequencing technologies such as proteomic and transcriptomic profiling have also provided further insight into the pathophysiology of CAV through the identification of novel biomarkers. Ultimately, these biomarkers may have a role in not only diagnosing CAV but also highlighting potential targets for disease-specific therapies. In this article, we review the current data for biomarkers in CAV and discuss future directions for biomarker identification.., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Primary graft dysfunction (PGD) is the leading cause of morbidity and mortality early after heart transplantation (HT). The International Consortium on PGD is a multicenter collaboration dedicated to identifying the clinical risk factors for PGD in the contemporary era of HT. The objectives of the current report were (1) to assess the incidence of severe PGD in an international cohort; (2) to evaluate the performance of the most strongly validated PGD risk tool, the RADIAL score, in a contemporary cohort; and (3) to redefine clinical risk factors for severe PGD in the current era of HT., Methods: This is a retrospective, observational study of consecutive adult HT recipients between 2010 and 2020 in 10 centers in the United States, Canada and Europe. Patients with severe PGD were compared to those without severe PGD (comprising those with no, mild and moderate PGD). The RADIAL score was calculated for each transplant recipient. The discriminatory power of the RADIAL score was evaluated using receiver operating characteristic (ROC) analysis, and its calibration was assessed by plotting the percentage of PGD predicted vs that which was observed. To identify clinical risk factors associated with severe PGD, we performed multivariable mixed-effects logistic regression modeling to account for among-center variability., Results: A total of 2746 patients have been enrolled in the registry to date, including 2015 (73.4%) from North America, and 731 (26.6%) from Europe; 215 participants (7.8%) met the criteria for severe PGD. There was an increase in the incidence of severe PGD over the study period (P value for trend by difference sign test = 0.004). The Kaplan-Meier estimate for 1-year survival was 75.7% (95% CI 69.4-80.9%) in patients with severe PGD as compared to 94.4% (95% CI 93.5-95.2%) in those without severe PGD (log-rank P value < 0.001). The RADIAL score performed poorly in our contemporary cohort and was not associated with severe PGD; it had an AUC of 0.53 (95% CI 0.48-0.58). In the multivariable regression model, acute preoperative dialysis (OR 2.41, 95% CI 1.31-4.43), durable left ventricular assist device support (OR 1.77, 95% CI 1.13-2.77), and total ischemic time (OR 1.20 for each additional hour, 95% CI 1.02-1.41) were associated with an increased risk of severe PGD., Conclusions: Our consortium has identified an increasing incidence of PGD in the modern transplant era. We identified contemporary risk factors for this early post-transplant complication, which confers a high mortality risk. These results may enable the identification of patients at high risk for developing severe PGD in order to inform peri-transplant donor and recipient management practices., Competing Interests: Disclosures None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Competing Interests: Declaration of competing interest Dr. Grodin receives consultancy fees from Alnylam, AstraZeneca, Alexion, Pfizer, Eidos/BridgeBio, and Sarepta.

Background: Cardiac metabolism is altered in heart failure and ischemia-reperfusion injury states. We hypothesized that metabolomic profiling during ex situ normothermic perfusion before heart transplantation (HT) would lend insight into myocardial substrate utilization and report on subclinical and clinical allograft dysfunction risk., Methods: Metabolomic profiling was performed on serial samples of ex situ normothermic perfusate assaying biomarkers of myocardial injury in lactate and cardiac troponin I (TnI) as well as metabolites (66 acylcarnitines, 15 amino acids, nonesterified fatty acids [NEFA], ketones, and 3-hydroxybutyrate). We tested for change over time in injury biomarkers and metabolites, along with differential changes by recovery strategy (donation after circulatory death [DCD] vs donation after brain death [DBD]). We examined associations between metabolites, injury biomarkers, and primary graft dysfunction (PGD). Analyses were performed using linear mixed models adjusted for recovery strategy, assay batch, donor-predicted heart mass, and time., Results: A total of 176 samples from 92 ex situ perfusion runs were taken from donors with a mean age of 35 (standard deviation 11.3) years and a median total ex situ perfusion time of 234 (interquartile range 84) minutes. Lactate trends over time differed significantly by recovery strategy, while TnI increased during ex situ perfusion regardless of DCD vs DBD status. We found fuel substrates were rapidly depleted during ex situ perfusion, most notably the branched-chain amino acids leucine/isoleucine, as well as ketones, 3-hydroxybutyrate, and NEFA (least squares [LS] mean difference from the first to last time point -1.7 to -4.5, false discovery rate q < 0.001). Several long-chain acylcarnitines (LCAC), including C16, C18, C18:1, C18:2, C18:3, C20:3, and C20:4, increased during the perfusion run (LS mean difference 0.42-0.67, q < 0.001). Many LCACs were strongly associated with lactate and TnI. The change over time of many LCACs was significantly different for DCD vs DBD, suggesting differential trends in fuel substrate utilization by ischemic injury pattern. Changes in leucine/isoleucine, arginine, C12:1-OH/C10:1-DC, and C16-OH/C14-DC were associated with increased odds of moderate-severe PGD. Neither end-of-run nor change in lactate or TnI was associated with PGD., Conclusions: Metabolomic profiling of ex situ normothermic perfusion solution reveals a pattern of fuel substrate utilization that correlates with subclinical and clinical allograft dysfunction. This study highlights a potential role for interventions focused on fuel substrate modification in allograft conditioning during ex situ perfusion to improve allograft outcomes., (Copyright © 2023. Published by Elsevier Inc.)

Purpose of Review: Heart transplantation (HT) remains the optimal therapy for patients living with end-stage heart disease. Despite recent improvements in peri-transplant management, the median survival after HT has remained relatively static, and complications of HT, including infection, rejection, and allograft dysfunction, continue to impact quality of life and long-term survival., Recent Findings: Omics technologies are becoming increasingly accessible and can identify novel biomarkers for, and reveal the underlying biology of, several disease states. While some technologies, such as gene expression profiling (GEP) and donor-derived cell-free DNA (dd-cfDNA), are routinely used in the clinical care of HT recipients, a number of emerging platforms, including pharmacogenomics, proteomics, and metabolomics, hold great potential for identifying biomarkers to aid in the diagnosis and management of post-transplant complications. Omics-based assays can improve patient and allograft longevity by facilitating a personalized and precision approach to post-HT care. The following article is a contemporary review of the current and future opportunities to leverage omics technologies, including genomics, transcriptomics, proteomics, and metabolomics in the field of HT., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Metabolic mechanisms underlying the heterogeneity of major adverse cardiovascular (CV) event (MACE) risk in individuals with type 2 diabetes mellitus (T2D) remain unclear. We hypothesized that circulating metabolites reflecting mitochondrial dysfunction predict incident MACE in T2D. Targeted mass-spectrometry profiling of 60 metabolites was performed on baseline plasma samples from the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS; discovery cohort) and Exenatide Study of Cardiovascular Event Lowering (EXSCEL; validation cohort) biomarker substudy cohorts. A principal components analysis metabolite factor comprising medium-chain acylcarnitines (MCACs) was associated with MACE in TECOS and validated in EXSCEL, with higher levels associated with higher MACE risk. Meta-analysis showed that long-chain acylcarnitines (LCACs) and dicarboxylacylcarnitines were also associated with MACE. Metabolites remained associated with MACE in multivariate models and favorably changed with exenatide therapy. A third cohort (Cardiac Catheterization Genetics [CATHGEN]) with T2D was assessed to determine whether these metabolites improved discriminative capability of multivariate models for MACE. Nine metabolites (MCACs and LCACs and 1 dicarboxylacylcarnitine) were associated with time to MACE in the CATHGEN cohort. Addition of these metabolites to clinical models minimally improved the discriminative capability for MACE but did significantly down reclassify risk. Thus, metabolites reporting on dysregulated mitochondrial fatty acid oxidation are present in higher levels in individuals with T2D who experience subsequent MACE. These biomarkers may improve CV risk prediction models, be therapy responsive, and highlight emerging risk mechanisms.

The number of heart transplants performed annually in the United States and worldwide continues to increase, but there has been little change in graft longevity and patient survival over the past 2 decades. The reference standard for diagnosis of acute cellular and antibody-mediated rejection includes histologic and immunofluorescence evaluation of endomyocardial biopsy samples, despite invasiveness and high interrater variability for grading histologic rejection. Circulating biomarkers and molecular diagnostics have shown substantial predictive value in rejection monitoring, and emerging data support their use in diagnosing other posttransplant complications. The use of genomic (cell-free DNA), transcriptomic (mRNA and microRNA profiling), and proteomic (protein expression quantitation) methodologies in diagnosis of these posttransplant outcomes has been evaluated with varying levels of evidence. In parallel, growing knowledge about the genetically mediated immune response leading to rejection (immunogenetics) has enhanced understanding of antibody-mediated rejection, associated graft dysfunction, and death. Antibodies to donor human leukocyte antigens and the technology available to evaluate these antibodies continues to evolve. This review aims to provide an overview of biomarker and immunologic tests used to diagnose posttransplant complications. This includes a discussion of pediatric heart transplantation and the disparate rates of rejection and death experienced by Black patients receiving a heart transplant. This review describes diagnostic modalities that are available and used after transplant and the landscape of future investigations needed to enhance patient outcomes after heart transplantation., Competing Interests: Disclosures Dr deFilippi reports consulting for Abbott Diagnostics, FujiRebio, Ortho/Quidel, Roche Diagnostics, and Siemens Healthineers. Dr Khush is a CareDx scientific advisor, speaker, and grant recipient. Dr Shah reports unrelated grant support paid to Inova from Merck, Bayer, Roche, and Abbott and consulting for Natera, Merck, and Procyrion. The other authors report no relevant disclosures.

Despite treatment with contemporary medical therapies for chronic heart failure (HF), there has been an increase in the prevalence of patients progressing to more advanced disease. Patients progressing to and living at the interface of severe stage C and stage D HF are underrepresented in clinical trials, and there is a lack of high-quality evidence to guide clinical decision making. For patients with severe HF phenotypes, the medical therapies used for patients with less advanced stages of illness are often no longer tolerated or provide inadequate clinical stability. The limited data on these patients highlights the need to increase formal research characterizing this high-risk population. This review summarizes existing clinical trial data and incorporates our considerations for approaches to the medical management of patients advanced "beyond stage C" HF., Competing Interests: Disclosures The following relationships exist related to this manuscript: SR serves on the DSMB committee for Abbott and as a consultant for Medtronic. ADV reports research funding through his institution from the American Heart Association, Amgen, AstraZeneca, Bayer, Intra-Cellular Therapies, American Regent, the NHLBI, Novartis, and PCORI and also provides consulting services for Amgen, AstraZeneca, Bayer, CareDx, InnaMed, LivaNova, Mardil Medical, Novartis, Procyrion, scPharmaceuticals, Story Health, and Zoll and has received nonfinancial support from Abbott for educational activities., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose of Review: Historically, the selection criteria for heart transplant candidates has prioritized posttransplant survival while contemporary allocation policy is focused on improving waitlist survival. Donor scarcity has continued to be the major influence on transplant allocation policy. This review will address the opportunity of donation after circulatory determination of death (DCDD) and potential impact on future policy revisions., Recent Findings: In 2018, changes to U.S. heart allocation policy led to several intended and unintended consequences. Beneficial changes include reduced waitlist mortality and broader geographic sharing. Additional impacts include scarcer pathways to transplant for patients with a durable left ventricular assist device, increased reliance on status exceptions, and expanded use of temporary mechanical support. DCDD is anticipated to increase national heart transplant volumes by ∼30% and will impact waitlist management. Centers that offer DCDD procurement will have reduced waitlist times, reduced waitlist mortality, and higher transplant volumes., Summary: While DCDD will provide more transplant opportunities, donor organ scarcity will persist and influence allocation policies. Differential patient selection, waitlist strategy, and outcome expectations may indicate that allocation is adjusted based on the procurement options at individual centers. Future policy, which will consider posttransplant outcomes, may reflect that different procurement strategies may yield different outcomes., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Primary graft dysfunction (PGD), the leading cause of early mortality after heart transplantation, is more common following donation after circulatory death (DCD) than donation after brain death (DBD). We conducted a single-center, retrospective cohort study to compare the incidence, severity and outcomes of patients experiencing PGD after DCD compared to DBD heart transplantation., Methods and Results: Medical records were reviewed for all adult heart transplant recipients at our institution between March 2016 and December 2021. PGD was diagnosed within 24 hours after transplant according to modified International Society for Heart and Lung Transplant criteria. A total of 459 patients underwent isolated heart transplantation during the study period, 65 (14%) following DCD and 394 (86%) following DBD. The incidence of moderate or severe PGD in DCD and DBD recipients was 34% and 23%, respectively (P = 0.070). DCD recipients were more likely to experience severe biventricular PGD than DBD recipients (19% vs 7.4%; P = 0.004). Among patients with severe PGD, DCD recipients experienced shorter median (Q1, Q3) duration of post-transplant mechanical circulatory support (6 [4, 7] vs 9 [5, 14] days; P = 0.039), shorter median post-transplant hospital length of stay (17 [15, 29] vs 52 [26, 83] days; P = 0.004), and similar 60-day survival rates (100% [95% CI: 76.8%-100%] vs 80.0% [63.1%-91.6%]; P = 0.17) and overall survival (log-rank; P = 0.078) compared with DBD recipients., Conclusions: DCD heart transplant recipients were more likely to experience severe, biventricular PGD than DBD recipients. Despite this, DCD recipients with severe PGD spent fewer days on mechanical circulatory support and in the hospital than similar DBD patients. These findings suggest that patterns of graft dysfunction and recovery may differ between donor types, and they support the expansion of the heart-donor pool with DCD., Competing Interests: Disclosures ADD receives research funding from AstraZeneca, Amgen, the American Heart Association, Bayer, Luitpold Pharmaceuticals, Medtronic, the NHLBI, PCORI, and Novartis and consults with AstraZeneca, Bayer, LivaNova, Mardil Medical, Novartis, and Procyrion. JNS receives research funding from TransMedics and is the Principal Investigator of the OCS DCD Heart Trial. All other authors have no conflicts of interest to disclose., (Copyright © 2022 Elsevier Inc. All rights reserved.)

There is increasing evidence that HFpEF is a heterogeneous clinical entity and distinct molecular pathways may contribute to pathophysiology. Leveraging unbiased proteomics to identify novel biomarkers, this study seeks to understand the underlying molecular mechanisms of HFpEF. The discovery cohort consisted of HFpEF cases and non-HF controls from the CATHGEN study (N = 176); the validation cohort consisted of participants from the TECOS trial of patients with diabetes (N = 109). Proteins associated with HFpEF were included in a LASSO model to create a discriminative multi-protein model and assessed in the validation cohort. Survival models and meta-analysis were used to test the association of proteins with incident clinical outcomes, including HF hospitalization, mortality and HFpEF hospitalization in CATHGEN, TECOS and the Jackson Heart Study. In the derivation set, 190 proteins were associated with HFpEF in univariate analysis, of which 65 remained significant in the multivariate model. Twenty (30.8%) of these proteins validated in TECOS, including LCN2, U-PAR, IL-1ra, KIM1, CSTB and Gal-9 (OR 1.93-2.77, p < 0.01). LASSO regression yielded a 13-protein model which, when added to a clinical model inclusive of NT-proBNP, improved the AUC from 0.82 to 0.92 (p = 1.5 × 10 -4 ). Five proteins were associated with incident HF hospitalization, four with HFpEF hospitalization and eleven with mortality (p < 0.05). We identified and validated multiple circulating biomarkers associated with HFpEF as well as HF outcomes. These biomarkers added incremental discriminative capabilities beyond clinical factors and NT-proBNP., (© 2022. The Author(s).)

Background: Left ventricular assist device (LVAD) placement frequently leads to a reduction in the severity of functional mitral regurgitation (MR). However, a significant number of LVAD supported patients have residual MR. We sought to assess the impact of residual MR in LVAD patient outcomes., Methods: Patients in the INTERMACS registry who received a continuous flow LVAD between 2006 and 2017 without a prior mitral valve repair were included for analysis. Residual MR was defined as moderate or severe MR within the first 3 months device support. Baseline characteristics, echocardiographic and hemodynamic variables, and clinical outcomes were comparatively analyzed between those with or without residual MR., Results: A total of 8,364 patients were included in the study, of which 18.8% demonstrated residual MR. Younger age, female gender, and non-ischemic heart failure were predictors of residual MR, as were increased LVEDD, RV dysfunction, severe baseline MR or TR, and elevated right heart pressures. Concomitant mitral valve repair reduced the risk of residual MR. Those with residual MR demonstrated worse LV remodeling, more right ventricular dysfunction, and higher right heart pressures at almost all time points analyzed. Residual MR was associated with increased risk of right heart failure and renal failure, and a trend toward increased mortality on LVAD support., Conclusions: Residual MR is associated with worse clinical outcomes on LVAD support. Strategies to minimize MR including medical and device optimization as well as valve repair should be considered in LVAD patients with residual MR., (Copyright © 2022 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Heart transplantation remains the gold-standard therapy for end-stage heart failure; the expected median survival range is 12-13 years. More than 30,000 heart transplants have been performed globally in the past decade alone. With advances in medical and surgical therapies for heart failure, including durable left ventricular assist devices, an increasing number of patients are living with end-stage disease. Last year alone, more than 2500 patients were added to the heart-transplant waitlist in the United States. Despite recent efforts to expand the donor pool, including an increase in transplantation of hepatitis C-positive and extended-criteria donors, supply continues to fall short of demand. Donation after circulatory death (DCD), defined by irreversible cardiopulmonary arrest rather than donor brain death, is widely used in other solid-organ transplants, including kidney and liver, but has not been widely adopted in heart transplantation. However, resurging interest in DCD donation and the introduction of ex vivo perfusion technology has catalyzed recent clinical trials and the development of DCD heart-transplantation programs. Herein, we review the history of DCD heart transplantation, describe the currently used procurement protocols for it and examine clinical challenges and outcomes of such a procedure., (Copyright © 2022. Published by Elsevier Inc.)

Background: Historically, women have had less access to advanced heart failure therapies, including temporary and permanent mechanical circulatory support and heart transplantation (HT), with worse waitlist and post-transplant survival compared with men. This study evaluated for improvement in sex differences across all phases of HT in the 2018 allocation system., Methods and Results: The United Network for Organ Sharing registry was queried to identify adult patients (≥18 years) listed for HT from October 18, 2016, to October 17, 2018 (old allocation), and from October 18, 2018, to October 18, 2020 (new allocation). The outcomes of interest included waitlist survival, pretransplant use of temporary and durable mechanical circulatory support, rates of HT, and post-transplant survival. There were 15,629 patients who were listed for HT and included in this analysis; 7745 (2039 women, 26.3%) in the new and 7875 patients (2074 women, 26.3%) in the old allocation system. When compared with men in the new allocation system, women were more likely to have lower priority United Network for Organ Sharing status at time of transplant, and less likely to be supported by an intra-aortic balloon pump (27.1% vs 32.2%, P < .001), with no difference in the use of venoarterial extracorporeal membrane oxygenation (5.5% vs 6.3%, P = .28). Despite these findings, when transplantation was viewed in the context of risk for death or delisting, the cumulative incidence of transplant within 6 months of listing was higher in women than men in the new allocation system (62.4% vs 54.9%, P < .001) with no differences in post-transplant survival. When comparing women in the old with the new allocation system, the distance traveled for organ procurement was 187.5 ± 207.0 miles vs 272.8 ± 233.7 miles (P < .001)., Conclusions: Although the use of temporary mechanical circulatory support in women remains lower than in men in the new allocation system, more women are being transplanted with comparable waitlist and post-transplant outcomes as men. Broader sharing may be making its greatest impact on improving transplant opportunities for women., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose of Review: Due to the growing mismatch between donor supply and demand as well as unacceptably high transplant waitlist mortality, the heart organ allocation system was revised in October 2018. This review gives an overview of the changes in the new heart organ allocation system and its impact on heart transplant practice and outcomes in the United States., Recent Findings: The 2018 heart allocation system offers a 6-tiered policy and therefore prioritizes the sickest patients on the transplant waitlist. Patients supported with temporary mechanical circulatory support devices are prioritized as Status 1 or Status 2, resulting in increased utilization of this strategy. Patients supported with durable left ventricular assist devices have been prioritized as Status 3 or 4, which has resulted in decreased utilization of this strategy. Broader geographic sharing in the new heart allocation system has resulted in prolonged donor ischemic times. Overall, the new heart allocation system has resulted in significantly lower candidate waitlist mortality, shorter waitlist times, and higher incidence of transplantation., Summary: The new United Network for Organ Sharing allocation policy confers significant advantages over the prior algorithm, allowing for decreased waitlist times and improved waitlist mortality without major impact on posttransplant survival., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: Solid organ transplantation (SOT) has become a widely accepted therapy for end-stage disease across the spectrum of thoracic and abdominal organs. With contemporary advances in medical and surgical therapies in transplantation, candidates for SOT are increasingly older with a larger burden of comorbidities, including cardiovascular disease (CVD). CVD, in particular, is a leading cause of morbidity and mortality in SOT candidates with end-stage disease of noncardiac organs [1]., Recent Findings: Identification of coronary artery disease (CAD), heart failure, and valvular disease are important in noncardiac SOT to ensure both appropriate peri-transplant management and equitable organ allocation. Although the American College of Cardiology (ACC) and the American Heart Association (AHA) have published guidelines and recommendations for the perioperative cardiovascular evaluation of patients undergoing noncardiac surgery, the implications of both symptomatic and asymptomatic CVD differ in patients with end-stage organ failure being considered for SOT when compared to the general population., Summary: Herein, we review the epidemiology, diagnosis, and evidence for the management of CVD in kidney and liver transplantation, combining current guidelines from the 2012 ACC/AHA scientific statement on cardiac disease evaluation in SOT with more contemporary evidenced-based algorithms., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Clinical models to identify patients at high risk of primary graft dysfunction (PGD) after heart transplantation (HT) are limited, and the underlying pathophysiology of this common post-transplant complication remains poorly understood. We sought to identify whether pre-transplant levels of circulating proteins reporting on immune activation and inflammation are associated with incident PGD., Methods: The study population consisted of 219 adult heart transplant recipients identified between 2016 and 2020 at Duke University Medical Center, randomly divided into derivation (n = 131) and validation (n = 88) sets. PGD was defined using modified ISHLT criteria. Proteomic profiling was performed using Olink panels (n = 354 proteins) with serum samples collected immediately prior to transplantation. Association between normalized relative protein expression and PGD was tested using univariate and multivariable (recipient age, creatinine, mechanical circulatory support, and sex; donor age; ischemic time) models. Significant proteins identified in the derivation set (p < 0.05 in univariate models), were then tested in the validation set. Pathway enrichment analysis was used to test candidate biological processes. The predictive performance of proteins was compared to that of the RADIAL score., Results: Nine proteins were associated with PGD in univariate models in the derivation set. Of these, only CLEC4C remained associated with PGD in the validation set after Bonferroni correction (OR [95% CI] = 3.04 [1.74,5.82], p = 2.8 × 10 -4 ). Patterns of association were consistent for CLEC4C in analyses stratified by biventricular/left ventricular and isolated right ventricular PGD. Pathway analysis identified interferon-alpha response and C-type lectin signaling as significantly enriched biologic processes. The RADIAL score was a poor predictor of PGD (AUC = 0.55). CLEC4C alone (AUC = 0.66, p = 0.048) and in combination with the clinical covariates from the multivariable model (AUC = 0.69, p = 0.018) improved discrimination for the primary outcome., Conclusions: Pre-transplantation circulating levels of CLEC4C, a protein marker of plasmacytoid dendritic cells (pDCs), may identify HT recipients at risk for PGD. Further studies are needed to better understand the potential role pDCs and the innate immune response in PGD., (Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Introduction: Gastrointestinal bleeding (GIB) remains a common and vexing complication of left ventricular assist device (LVAD) support. Recent single-center analyses suggest that ACE inhibitors (ACEi)/angiotensin receptor blockers (ARB) and digoxin may prevent GIB in LVAD patients. Here we evaluate the effect of guideline-directed medical therapies (GDMT) for heart failure (HF) on rates of GIB through analysis of the INTERMACS registry database., Methods: Thirteen thousand seven hundred thirty-two patients who received a continuous-flow LVAD and were on antiplatelet therapy and anticoagulation with warfarin after 3 months of pump support were included in the analysis. GIB events following implant were assessed based on receipt of ACEi/ARB, beta-blockers (BB), mineralocorticoid receptor antagonist (MRA), amiodarone, digoxin, loop diuretics, and phosphiesterase-5 inhibitors (PDE5). Backwards stepwise cox regression was used to control for confounding of each drug class on each other, as well as for clinical variables like age, gender, renal function, HF etiology, and device strategy., Results: After 3 months of pump support medications used in LVAD patients were BB (65.0%), ACEi/ARB (51.7%), Amio (43.7%), MRA (37.9%), and loop diuretics (70.1%). In patients with available data, PDE and digoxin use were 18.2% and 16.9%, respectively. The overall incidence of GIB was 19.5% at 2 years of support. After adjustment for other clinical variables, loop diuretics (HR 1.274, p  < 0.001) and PDE5 (HR 1.241, p  < 0.001) use were associated with increased risk of GIB, while use of BB (HR 0.871, p  = 0.006) was associated with lower risk of GIB. ACEi/ARB (HR 1.002, p  = 0.971), Amio (HR 1.083, p  = 0.106), AA (HR 0.967, p  = 0.522) or digoxin (HR 1.087, p  = 0.169) did not affect GIB rates on LVAD support (Figure)., Conclusion: Despite recent reports, ACEi/ARB, MRA, Amio, and digoxin use does not appear to be associated with GIB during LVAD support. The heightened risk seen in those on loop diuretics may reflect venous congestion in these patients, while antiplatelet effects of PDE5 could drive the higher risk of GIB.

Objective: The objective of this study was to describe the profiles and outcomes of a cohort of advanced heart failure patients on ambulatory inotropic therapy (AIT)., Background: With the growing burden of patients with end-stage heart failure, AIT is an increasingly common short or long-term option, for use as bridge to heart transplant (BTT), bridge to ventricular assist device (BTVAD), bridge to decision regarding advanced therapies (BTD) or as palliative care. AIT may be preferred by some patients and physicians to facilitate hospital discharge. However, counseling patients on risks and benefits is critically important in the modern era of defibrillators, durable mechanical support and palliative care., Methods: We retrospectively studied a cohort of 241 patients on AIT. End points included transplant, VAD implantation, weaning of inotropes, or death. The primary outcomes were survival on AIT and ability to reach intended goal if planned as BTT or BTVAD. We also evaluated recurrent heart failure hospitalizations, incidence of ventricular arrhythmias (VT/VF) and indwelling line infections. Unintended consequences of AIT, such reaching unintended end point (e.g. VAD implantation in BTT patient) or worse than expected outcome after LVAD or HT, were recorded., Results: Mean age of the cohort was 60.7 ± 13.2 years, 71% male, with Class III-IV heart failure (56% non-ischemic). Average ejection fraction was 19.4 ± 10.2%, pre-AIT cardiac index was 1.5 ± 0.4 L/min/m 2 and 24% had prior ventricular arrhythmias. Overall on-AIT 1-year survival was 83%. Hospitalizations occurred in 51.9% (125) of patients a total of 174 times for worsening heart failure, line complication or ventricular arrhythmia. In the BTT cohort, only 42% were transplanted by the end of follow-up, with a 14.8% risk of death or delisting for clinical deterioration. For the patients who were transplanted, 1-year post HT survival was 96.7%. In the BTVAD cohort, 1-year survival after LVAD was 90%, but with 61.7% of patients undergoing LVAD as INTERMACS 1-2. In the palliative care cohort, only 24.5% of patients had a formal palliative care consult prior to AIT., Conclusions: AIT is a strategy to discharge advanced heart failure patients from the hospital. It may be useful as bridge to transplant or ventricular assist device, but may be limited by complications such as hospitalizations, infections, and ventricular arrhythmias. Of particular note, it appears more challenging to bridge to transplant on AIT in the new allocation system. It is important to clarify the goals of AIT therapy upfront and continue to counsel patients on risks and benefits of the therapy itself and potential unintended consequences. Formalized, multi-disciplinary care planning is essential to clearly define individualized patient, as well as programmatic goals of AIT., (Copyright © 2021. Published by Elsevier Inc.)

Background: Whether differences in circulating long chain acylcarnitines (LCAC) are seen in heart failure (HF) patients with and without diabetes mellitus (DM), and whether these biomarkers report on exercise capacity and clinical outcomes, remains unknown. The objective of the current study was to use metabolomic profiling to identify biomarkers that report on exercise capacity, clinical outcomes, and differential response to exercise in HF patients with and without DM., Methods: Targeted mass spectrometry was used to quantify metabolites in plasma from participants in the heart failure: a controlled trial investigating outcomes of exercise training (HF-ACTION) trial. Principal components analysis was used to identify 12 uncorrelated factors. The association between metabolite factors, diabetes status, exercise capacity, and time to the primary clinical outcome of all-cause mortality or all-cause hospitalization was assessed., Results: A total of 664 participants were included: 359 (54%) with DM. LCAC factor levels were associated with baseline exercise capacity as measured by peak oxygen consumption (beta 0.86, p  =  2 × 10 -7 , and were differentially associated in participants with and without DM (beta 1.58, p  =  8  ×  10 -8 vs. 0.67, p  =  9  ×  10 -4 , respectively; p value for interaction  =  0.012). LCAC levels changed to a lesser extent in participants with DM after exercise (mean ∆ 0.09, p  =  0.24) than in those without DM (mean ∆ 0.16, p  =  0.08). In univariate and multivariate modeling, LCAC factor levels were associated with time to the primary outcome (multivariate HR 0.80, p  =  2.74  ×  10 -8 ), and were more strongly linked to outcomes in diabetic participants (HR 0.64, p  =  3.21  ×  10 -9 v. HR 0.90, p  =  0.104, p value for interaction  =  0.001). When analysis was performed at the level of individual metabolites, C16, C16:1, C18, and C18:1 had the greatest associations with both exercise capacity and outcomes, with higher levels associated with worse outcomes. Similar associations with time to the primary clinical outcome were not found in a control group of patients without HF from the CATHeterization GENetics (CATHGEN) study., Conclusions: LCAC biomarkers are associated with exercise status and clinical outcomes differentially in HF patients with and without DM. Impaired fatty acid substrate utilization and mitochondrial dysfunction both at the level of the skeletal muscle and the myocardium may explain the decreased exercise capacity, attenuated response to exercise training, and poor clinical outcomes seen in patients with HF and DM. Trial Registration clinicaltrials.gov Identifier: NCT00047437., (© 2021. The Author(s).)

CRP is an established inflammatory biomarker with prognostic value in patients with chronic heart failure, yet its role in continuous-flow left ventricular assist device (LVAD) patients is largely unknown. 5,183 patients from the INTERMACS registry who underwent durable LVAD between 2008 and 2017 and had preimplant CRP levels were included. The sample was stratified into two groups based on preimplant CRP levels: CRP of 0-10 mg/L (low) and >10 mg/L (high). Kaplan-Meier survival estimates were used to assess outcomes at 2 years after LVAD implantation, with log-rank testing used to compare groups. Cox proportional hazard models were used for multivariable adjustment. Patients with high preimplant CRP were younger, more likely to be INTERMACS class I, and had a higher need for temporary mechanical circulatory support before LVAD implant compared to those with lower CRP levels (all P < 0.001). The high CRP group had higher WBC counts and BNP levels (all P < 0.001). After adjustment, higher CRP (>10 mg/L) was associated with greater risk of mortality, RV failure, and stroke postimplant (P < 0.001). In addition, elevated postimplant CRP level at 3 months was associated with increased mortality and stroke on LVAD support (P < 0.001). CRP is a predictor of death and complications on LVAD support. Future studies are necessary to explore the mechanisms underlying this finding and the potential role of antiinflammatory therapies in this population., Competing Interests: Disclosures: The authors have no conflicts of interest to report., (Copyright © ASAIO 2021.)

Purpose: Primary graft dysfunction (PGD) is a leading cause of early mortality after heart transplant (HTx). To identify PGD incidence and impact on mortality, and to elucidate risk factors for PGD, we systematically reviewed studies using the ISHLT 2014 Consensus Report definition and reporting the incidence of PGD in adult HTx recipients., Methods: We conducted a systematic search in January 2020 including studies reporting the incidence of PGD in adult HTx recipients. We used a random effects model to pool the incidence of PGD among HTx recipients and, for each PGD severity, the mortality rate among those who developed PGD. For prognostic factors evaluated in ≥2 studies, we used random effects meta-analyses to pool the adjusted odds ratios for development of PGD. The GRADE framework informed our certainty in the evidence., Results: Of 148 publications identified, 36 observational studies proved eligible. With moderate certainty, we observed pooled incidences of 3.5%, 6.6%, 7.7%, and 1.6% and 1-year mortality rates of 15%, 21%, 41%, and 35% for mild, moderate, severe and isolated right ventricular-PGD, respectively. Donor factors (female sex, and undersized), recipient factors (creatinine, and pre-HTx use of amiodarone, and temporary or durable mechanical support), and prolonged ischemic time proved associated with PGD post-HTx., Conclusion: Our review suggests that the incidence of PGD may be low but its risk of mortality high, increasing with PGD severity. Prognostic factors, including undersized donor, recipient use of amiodarone pre-HTx and recipient creatinine may guide future studies in exploring donor and/or recipient selection and risk mitigation strategies., (Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Objectives: The purpose of this study was to compare outcomes between patients on extracorporeal membrane oxygenation (ECMO) bridged to left ventricular assist device (LVAD) versus heart transplantation (HT) using registry data., Background: Patients with heart failure supported with ECMO represent the highest priority in the new HT allocation system. For patients on ECMO, bridging to LVAD may be non-inferior compared with bridging to HT., Methods: Adult patients in the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) from 2006 to 2017 and United Network for Organ Sharing (UNOS) database from 2006 to June 2019 requiring ECMO were included. Cause-specific hazard models were created and cumulative incidence functions were calculated with mortality, transplantation, and re-transplantation as competing events., Results: A total of 906 patients received ECMO as bridge to VAD (n = 587, 64.8%) or as bridge to HT (n = 319, 35.2%). Patients bridged directly to HT were younger (age 46.3 ± 15.4 years vs. 52.1 ± 13.2 years; p < 0.001) and more likely to be female (93 [29.2%] vs. 139 [23.7%]; p = 0.022). Patients bridged directly to HT were more likely to have a nonischemic cardiomyopathy, restrictive physiologies, and allograft failure; (p < 0.05 for all). ECMO use increased over time in both UNOS and INTERMACS. There was no significant difference in mortality between groups (Gray's p = 0.581). This remained true even when the analysis was restricted to transplant-listed or eligible patients as well as patients with dilated phenotypes (excluding patients with congenital heart disease, restrictive phenotypes, and allograft failure)., Conclusions: There was no difference in mortality on pump support compared with posttransplant mortality among those bridged from ECMO to LVAD or HT., Competing Interests: Funding Support and Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Advanced heart failure therapies such as left ventricular assist device (LVAD) implantation require intricate follow-up and complex care. We sought to explore the burden of psychosocial risk factors among patients with LVAD and their impact on postimplant outcomes using the Interagency Registry for Mechanically Assisted Circulatory Support., Methods: Adult patients in the Interagency Registry for Mechanically Assisted Circulatory Support requiring durable LVAD between 2008 and 2017 were included. Individuals were determined to have psychosocial risk if they had one of the following: (1) limited social support; (2) limited cognition; (3) substance abuse (alcohol and drug); (4) severe psychiatric disease (including major depression and other major psychiatric diagnosis); and (5) repeated noncompliance. Univariate and multivariate Cox proportional hazard regression models were used to analyze predictors of survival and complications., Results: A total of 15 403 continuous-flow LVAD recipients were included. A total of 3163 (20.5%) had one or more psychosocial risk factors. The most prevalent psychosocial risk factor was substance abuse in 1941 (12.6%) recipients. Patients with psychosocial risk factors were significantly younger at LVAD implant, less likely to be White, and less likely to be female compared with those without psychosocial risk, P <0.001 for all. Patients with psychosocial risk were significantly more likely to receive an LVAD as destination therapy, P <0.001. In adjusted models, patients with psychosocial risk were at increased hazards for device-related infection, gastrointestinal bleeding, pump thrombosis, and readmission and reduced hazards for cardiac transplantation ( P <0.05 for all). There was no statistically significant difference in survival on pump support or stroke., Conclusions: Psychosocial risk is an important component of patient selection for advanced heart failure therapies. Addressing these specific components may help improve access to advanced therapies and post-LVAD outcomes.

Background: Monogenic diseases are individually rare but collectively common, and are likely underdiagnosed., Objectives: The purpose of this study was to estimate the prevalence of monogenic cardiovascular diseases (MCVDs) and potentially missed diagnoses in a cardiovascular cohort., Methods: Exomes from 8,574 individuals referred for cardiac catheterization were analyzed. Pathogenic/likely pathogenic (P/LP) variants associated with MCVD (cardiomyopathies, arrhythmias, connective tissue disorders, and familial hypercholesterolemia were identified. Electronic health records (EHRs) were reviewed for individuals harboring P/LP variants who were predicted to develop disease (G+). G+ individuals who did not have a documented relevant diagnosis were classified into groups of whether they may represent missed diagnoses (unknown, unlikely, possible, probable, or definite) based on relevant diagnostic criteria/features for that disease., Results: In total, 159 P/LP variants were identified; 2,361 individuals harbored at least 1 P/LP variant, of whom 389 G+ individuals (4.5% of total cohort) were predicted to have at least 1 MCVD. EHR review of 342 G+ individuals predicted to have 1 MCVD with sufficient EHR data revealed that 52 had been given the relevant clinical diagnosis. The remaining 290 individuals were classified as potentially having an MCVD as follows: 193 unlikely (66.6%), 50 possible (17.2%), 30 probable (10.3%), and 17 definite (5.9%). Grouping possible, probable, definite, and known diagnoses, 149 were considered to have an MCVD. Novel MCVD pathogenic variants were identified in 16 individuals., Conclusions: Overall, 149 individuals (1.7% of cohort) had MCVDs, but only 35% were diagnosed. These patients represents a "missed opportunity," which could be addressed by greater use of genetic testing of patients seen by cardiologists., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

In broad terms, "advanced" heart failure describes a clinical syndrome characterized by persistent or progressive symptoms and ventricular dysfunction despite guideline-directed medical therapy. Clinically the definition is often dependent upon iterative and integrated clinical assessments to identify patients with worsening status and reliance on specific therapies. This review examines current consensus definitions, highlights strategies for risk stratification and prognostication, and examines short- and long-term treatment strategies. Lastly, this paper explores future directions of research and development for the field., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Palliative care improves quality of life in patients with heart failure. Whether men and women with heart failure derive similar benefit from palliative care interventions remains unknown., Methods: In a secondary analysis of the PAL-HF trial (Palliative Care in Heart Failure), we analyzed differences in quality of life among men and women with heart failure and assessed for differential effects of the palliative care intervention by sex. Differences in clinical characteristics and quality-of-life metrics were compared between men and women at serial time points. The primary outcome was change in Kansas City Cardiomyopathy Questionnaire score between baseline and 24 weeks., Results: Among the 71 women and 79 men, there was a significant difference in baseline Kansas City Cardiomyopathy Questionnaire (24.5 versus 36.2, respectively; P =0.04) but not Functional Assessment of Chronic Illness Therapy-Palliative Care scale (115.7 versus 120.3; P =0.27) scores. Among those who received the palliative care intervention (33 women and 42 men), women's quality-of-life score remained lower than that of men after enrollment. Treated men's scores were significantly higher than those untreated (6-month Kansas City Cardiomyopathy Questionnaire, 68.0 [interquartile range, 52.6-85.7] versus 41.1[interquartile range, 32.0-78.3]; P =0.047), whereas the difference between treated and untreated women was not significantly different ( P =0.39). Rates of death and rehospitalization, as well as the composite end point, were similar between treated and untreated women and men., Conclusions: In the PAL-HF trial, women with heart failure experienced a greater symptom burden and poorer quality of life as compared with men. The change in treated men's Kansas City Cardiomyopathy Questionnaire score between baseline and 24 weeks was significantly higher than those untreated; this trend was not observed in women. Thus, there may be a sex disparity in response to palliative care intervention, suggesting that sex-specific approaches to palliative care may be needed to improve outcomes. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT0158960.

Background: Obesity remains a relative contraindication for heart transplantation, and hence, obese patients with advanced heart failure receive ventricular assist devices (VADs) either as a destination or "bridge to weight loss" strategy. However, impact of obesity on clinical outcomes after VAD implantation is largely unknown. We sought to determine the clinical outcomes of obese patients with body mass index (BMI) ≥ 35 kg/m 2 ) following contemporary VAD implantation., Methods: The Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) registry was queried for patients who underwent VAD implantation. Patients were categorized into BMI groups based on World Health Organization classification., Results: Of 17,095 patients, 2620 (15%) had a BMI ≥ 35 kg/m 2 . Obese patients were likely to be young, non-white, females with dilated cardiomyopathy and undergo device implantation as destination. Survival was similar amongst BMI groups (P = .058). Obese patients had significantly higher risk for infection (hazard ratio [HR]: 1.215; P = .001), device malfunction or thrombosis (HR: 1.323; P ≤ .001), cardiac arrhythmia (HR: 1.188; P = .001) and hospital readmissions (HR: 1.073; P = .022), but lower risk of bleeding (HR: 0.906; P = .018). Significant weight loss (≥10%) during VAD support was achieved only by a small proportion (18.6%) of patients with BMI ≥ 35 kg/m 2 . Significant weight loss rates observed in obese patients with VAD implantation as destination and bridge to transplant strategy were comparable. Obese patients with significant weight loss were more likely to undergo cardiac transplantation. Weight loss worsened bleeding risk without altering risk for infection, cardiac arrhythmia, and device complications., Conclusions: Obesity alone should not be considered a contraindication for VAD therapy in contemporary era. Given durability of heart transplantation, strategies should be developed to promote weight loss, which occurs infrequently in obese patients. Impact of weight loss on clinical outcome of obese patients warrants further investigation., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Continuous-flow left ventricular assist devices (CF-LVADs) are increasingly used in advanced heart failure patients. Recent studies suggest that low socioeconomic status (SES) predicts worst survival after heart transplantation. Both individual-level and neighborhood-level SES (nSES) have been linked to cardiovascular health; however, the impact of SES in CF-LVAD patients remains unknown. We hypothesized that SES is a major determinant of CF-LVAD candidacy and postimplantation outcomes. A retrospective chart review was conducted on 362 patients between February 2009 and May 2016. Neighborhood-level SES was measured using the American Community Survey data and the Agency for Healthcare Research and Quality SES index score. Individual-level SES was self reported. Kaplan-Meier survival analysis and multivariable Cox proportional hazards regression determined survival statistics. Patients in the highest SES tertile were older (58 ± 13 vs. 53 ± 14; p < 0.001), less likely to be black or Hispanic (26% vs. 70%; p < 0.001), more likely to be married (87% vs. 65%; p < 0.001), more likely to have private insurance (50% vs. 39%; p < 0.001), and more likely to have employment (29% vs. 15%; p < 0.001) compared with patients in the lowest tertile. Low nSES was associated with a decreased risk of death (hazard ratio [HR], 0.580; 95% confidence interval [CI], 0.347-0.970; p = 0.038) in comparison to the high nSES. However, after adjusting for baseline clinical morbidities, the relationship was no longer present. When selecting patients for a LVAD, SES should not be thought of as an immutable risk factor. Carefully selected low-SES patients could be safely implanted with CF-LVAD with outcomes comparable to high-SES patients.

For patients bridged to transplant (BTT) with left ventricular assist devices (LVAD), data regarding the use of induction immunosuppressive therapy remain limited. The objectives of the current study were to describe the current trends and clinical consequences of IT in patients BTT with LVAD. The United Network of Organ Sharing database was queried to identify adult, single-organ heart transplant recipients who were BTT with LVAD between 2008 and 2018. Propensity score matching was then used to balance clinical covariates between those patient who did and did not receive IT. The primary outcomes of interest were graft survival, hospitalization for rejection and infection, and freedom from transplant coronary artery disease (TCAD). In the overall cohort, 49.1% (n = 3,978) received IT, with basiliximab being the most commonly used agent followed by antithymocyte globulin. After propensity score matching, 4,388 patients (2,194 without induction and 2,194 with induction) were identified. Between those who did and did not receive IT, there was no significant difference in graft survival, freedom from hospitalization for rejection, and freedom from hospitalization for infection. Patients who received IT experienced increased freedom from TCAD (p = 0.004) with unadjusted hazard ratio of 0.81 (95% Cardiac Index: 0.70-0.93). For freedom from TCAD, antithymocyte globulin was associated with better outcomes than basiliximab (80.2% vs. 73.1% at 5 years, log rank p value = 0.004). In a sensitivity analysis, there was no significant increase in hospitalization for infection in those patients with an infected LVAD before transplant. Use of induction therapy in patients BTT with LVAD appears to be safe and feasible, without a significant increase in the risk of infection or rejection, even in those patients with pretransplant device-related infections. IT, particularly antithymocyte globulin, was associated with increased time to development of TCAD. Routine use of IT in patients BTT with LVAD may be considered, and further randomized control trials are warranted to further support these data.

Donation after Circulatory Death (DCD) is an alternative to Donation after Brain death (DBD), and is a growing strategy for organ procurement in the United States(US). The purpose of this analysis was to review the number and quality of hearts in one United Network for Organ Sharing (UNOS) Region that were not utilized as a potential consequence of nonheart DCD donation. We retrospectively identified all successful US DCD solid organ donors from 1/2011 to 3/1/2017, defined an ideal heart donor by age and left ventricular ejection fraction (LVEF), and then reviewed the donor charts of unused hearts in New York and Vermont (UNOS Region 9). Of 8302 successful DCD donors across the United States, 5033 (61%) were between 18 and 49 years of age, and 872 had a screening echocardiogram, with 573 (66%) measuring an EF >50%. Of these 573 potential donors, 44 (7.7%) were from Region 9. Detailed donor chart review identified 36 ideal heart donors, 24 (66.7%) with anoxic brain injury. Trends in Region 9 DCD donation increased from 4 unused hearts in 2011, to 13 in 2016. In the context of severe organ scarcity, these data indicate that implementation of DCD heart transplantation in the United States would improve overall donation rates and provide a pathway to utilize these ideal donor hearts., (© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Bridge to transplantation (BTT) with left ventricular assist devices (LVADs) is a mainstay of therapy for heart failure in patients awaiting heart transplantation (HT). Criteria for HT listing do not differ between patients medically managed and those mechanically bridged to HT. The objectives of the present study were to evaluate the impact of BTT with LVAD on posttransplantation survival, to describe differences in causes of 1-year mortality in medically and mechanically bridged patients, and to evaluate differences in risk factors for 1-year mortality between those with and those without LVAD at the time of HT., Methods: Using the United Network of Organ Sharing database, we identified 5486 adult, single-organ HT recipients transplanted between 2008 and 2015. Patients were propensity matched for likelihood of LVAD at the time of HT. Kaplan-Meier survival estimates were used to assess the impact of BTT on 1- and 5-year mortality. Logistic regression analysis was used to evaluate the odds ratio of 1-year mortality for patients BTT with LVAD compared with those with medical management across clinically significant variables at various thresholds., Results: Early mortality was higher in mechanically bridged patients: 9.5% versus 7.2% mortality at 1 year (P<0.001). BTT patients incurred an increased risk of 1-year mortality with an estimated glomerular filtration rate of 40 to 60 mL·min -1 ·1.73 m -2 (odds ratio, 1.69; P=0.003) and <40 mL·min -1 ·1.73 m -2 (odds ratio, 2.16; P=0.005). A similar trend was seen in patients with a body mass index of 25 to 30 kg/m 2 (odds ratio, 1.88; P=0.024) and >30 kg/m 2 (odds ratio, 2.11; P<0.001). When patients were stratified by BTT status and the presence of risk factors, including age >60 years, estimated glomerular filtration rate <40 mL·min -1 ·1.73 m -2 , and body mass index >30 kg/m 2 , there were significant differences in 1-year mortality between medium- and high-risk medically and mechanically bridged patients, with 1-year mortality in high-risk BTT patients at 17.6% compared with 10.4% in high-risk medically managed patients., Conclusions: Bridge to HT with LVAD, although necessary because of organ scarcity and capable of improving wait list survival, confers a significantly higher risk of early posttransplantation mortality. Patients bridged with mechanical support may require more careful consideration for transplant eligibility after LVAD placement.

Primary graft failure (PGF) after heart transplantation (HT) is a devastating and unexpected event characterized by failure of the graft to adequately support recipient circulation necessitating high doses of vasopressors and inotropes and/or temporary mechanical circulatory support. Although it represents an increasingly common event in the current era, there remains a high degree of variability in prevalence, reported risk factors, and approach to this clinical entity. The purpose of the current review is to highlight preoperative considerations including known incidence and risk factors, perioperative issues involving the identification and management of PGF, and postoperative decisions related to weaning of mechanical circulatory support and titration of immunosuppressive therapy. Lastly, we highlight future directions in PGF research, involving basic and translational research, that have the potential to uncover novel strategies of risk stratification and treatment. CASE: Our patient is a 53-year-old man with end-stage non-ischemic dilated cardiomyopathy complicated by ventricular tachycardia (VT), post-capillary pulmonary hypertension, and renal insufficiency. After progressing to NYHA Class IV symptoms, he underwent implantation of a durable left ventricular assist device (LVAD) as bridge to transplant (BTT). On device support, he developed recurrent VT resulting in multiple defibrillator discharges and hospital admission for intravenous anti-arrhythmic therapy. He is subsequently upgraded to a higher status on the waiting list. A suitable donor is identified, with an appropriate predicted heart mass and an anticipated ischemic time of <4 hours. He is taken to the operating room, where at the time of anesthesia induction he develops vasodilatory shock, requiring high-dose vasopressors, and cardiopulmonary bypass (CPB) support for dissection. After surgical anastomosis, cross clamp removal and reperfusion, graft function is extremely poor, there is significant bradycardia requiring pacing, and the patient is unable to be weaned successfully from CPB. Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is initiated, and the patient is transferred to the intensive care unit. Retrospective flow crossmatch is negative. This patient is suffering from severe primary graft failure., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: This study examined sex-related differences in use and outcomes of continuous-flow left ventricular assist devices (CF-LVADs) among individuals awaiting heart transplantation using the United Network for Organ Sharing registry., Background: Advanced therapies for heart failure including CF-LVADs remain underused in women. There have been contradictory results regarding sex-specific outcomes. Many studies have been limited by small sample sizes or included pulsatile-flow devices., Methods: De-identified patient-level data were obtained from the United Network for Organ Sharing database. The database was queried to identify adult patients (≥18 years of age) who required mechanical circulatory support with HeartWare HVAD (Medtronic, Minneapolis, Minnesota), HeartMate II (Abbott, Lake Bluff, Illinois), or HeartMate 3 (Abbott) as bridge to heart transplantation between 2008 and 2018. Each patient was assigned a propensity score. The primary outcomes of interest were rates of transplantation and death., Results: A total of 13,305 patients (2,771 women, 20.8%) received support with CF-LVAD in the study period. There were significant sex disparities in CF-LVAD use in listed patients (29.9% men vs. 18.9% women in 2017). Female patients receiving CF-LVAD support had lower chances of heart transplantation (55.1% vs. 67.5%), increased risk of waitlist mortality (7.0% vs. 4.2%), and delisting for worsening clinical status (8.5% vs. 4.7%) at 2 years post-implantation (all p < 0.001). After adjusting for device type, sex was still a significant predictor of waitlist mortality (hazard ratio: 1.51; p < 0.001)., Conclusions: Durable mechanical circulatory support with CF-LVADs remains underused in women. When matched with similar male control subjects, women experienced higher mortality and lower rates of heart transplantation., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Red cell distribution width (RDW) measures the variance in size of circulating red blood cells and is a strong independent predictor of morbidity and mortality in cardiovascular disease and heart failure. Predictive power of RDW on mortality after continuous-flow left ventricular assist device (CF-LVAD) implantation remains largely unknown. Four hundred nine patients who underwent CF-LVAD implantation between April 2004 and December 2015 were retrospectively analyzed. The primary outcome of interest was 90 day mortality after CF-LVAD implantation. Median RDW before CF-LVAD implantation was 15.8%. Patients with elevated RDW (>15.8%) at baseline had significantly lower hemoglobin (10.6 ± 1.8 vs. 11.9 ± 2.1 mg/dl; p < 0.001), lower mean corpuscular volume (84.9 ± 7.7. vs. 88.7 ± 5.9; p < 0.001), higher blood urea nitrogen (BUN; 36.3 ± 21.8 vs. 30.1 ± 17.1; p < 0.001), lower albumin (3.4 ± 0.6 vs. 3.7 ± 0.5; p < 0.001), and higher total bilirubin levels (1.67 ± 2.21 vs. 1.29 ± 0.96). Red cell distribution width was independently predictive of 90 day mortality (odds ratio [OR], 1.16 for 1% increase; CI, 1.04-1.31; p = 0.010). Discriminatory power of RDW alone was comparable to model of end-stage liver disease excluding international normalized ratio (MELD-Xi) and HeartMate II risk scores. Mechanical unloading with CF-LVAD was associated with a reduction in RDW levels. These findings suggest that RDW, a simple and inexpensive test available through routine complete blood count, can be successfully used for mortality risk assessment in CF-LVAD candidates.

Combination of venoarterial extracorporeal membrane oxygenation (VA-ECMO) and a percutaneous microaxial left ventricular assist device (pLVAD), or "EC-VAD," has been reported in cases of left ventricular decompression with mixed results. We conducted a retrospective review of patients who received EC-VAD (n = 29) or isolated VA-ECMO therapy (ECMO-only; n = 196) for refractory cardiogenic shock between February 2011 and October 2014. Fourteen patients received VA-ECMO and then Impella pLVAD (E→EC-VAD), and 15 received the Impella pump then VA-ECMO (I→EC-VAD). E→EC-VAD patients demonstrated decreased pulmonary artery systolic (36.00 ± 16.84 mm Hg versus 30.63 ± 12.13 mm Hg; p = 0.049) and diastolic (24.25 ± 13.45 mm Hg versus 17.25 ± 7.96 mm Hg, p = 0.049) pressures by 24 hours post-EC-VAD implant. In the same period, I→EC-VAD patients demonstrated improved SvO2 (43.14 ± 16.75% versus 75.18 ± 13.88%, p = 0.043) and PaO2/FiO2 ratio (148.55 ± 67.69 mm Hg versus 374.51 ± 170.97 mm Hg, p = 0.043). Thirty-day survival rates were 42.9% in E→EC-VAD, 46.7% in I→EC-VAD, and 49.0% in ECMO-only (p = 0.913). Hemolysis occurred more in EC-VAD patients (44.83% versus 17.35% in ECMO-only, p = 0.002); however, there was no increased frequency of other adverse events including bleeding and lower limb ischemia. Despite increased hemolysis, combined use of VA-ECMO and pLVAD may improve or circumvent left ventricular distension in refractory cardiogenic shock while promoting adequate blood flow.

Background: Primary graft dysfunction (PGD) remains a significant cause of post-transplant morbidity and mortality. The exact mechanism and risk factors for this phenomenon remain unknown in the contemporary era., Methods: In this study we reviewed adult patients undergoing heart transplantation (HT) at our institution between 2009 and 2017. Severe PGD was defined as the need for mechanical circulatory support (MCS) within the first 24 hours after HT. Multivariate logistic regression analysis was used to identify risk factors for severe PGD, focusing on those bridged to transplant (BTT) with a continuous-flow left ventricular assist device (CF-LVAD)., Results: Fifty-six of 480 (11.7%) HT patients experienced severe PGD. Eighty percent of the severe PGD patients were BTT with a CF-LVAD (odds ratio [OR] 3.86, 95% confidence interval [CI] 1.94 to 7.68, p < 0.001). Among the BTT patients, significant associations between >1 year of CF-LVAD support (OR 2.48, 95% CI 1.14 to 5.40, p = 0.022), pre-HT creatinine (OR 3.35, 95% CI 1.42 to 7.92, p = 0.006), elevated central venous pressure/pulmonary capillary wedge pressure (CVP/PCWP) ratio (OR 3.32, 95% CI 1.04 to 10.60, p = 0.043), use of amiodarone before HT (OR 2.69, 95% CI 1.20 to 6.20, p = 0.022), and severe PGD were identified. RADIAL score did not accurately predict severe PGD in this contemporary cohort. Those patients who developed severe PGD had decreased 1-year post-transplant survival (78.3% vs 91.8%, p = 0.007)., Conclusions: Use of CF-LVAD as BTT is associated with an increased risk of severe PGD. Increased time on device support, renal dysfunction, right ventricular dysfunction as assessed by CVP/PCWP ratio, and pre-transplant amiodarone may identify those patients at high risk. Further research is warranted focusing on optimal timing of device implantation and transplantation, as well as the underlying mechanisms of PGD., (Copyright © 2018 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study sought to evaluate the impact of moderate to severe aortic insufficiency (AI) on outcomes in patients with continuous flow left ventricular assist devices (CF-LVADs)., Background: Development of worsening AI is a common complication of prolonged CF-LVAD support and portends poor prognosis in single-center studies. Predictors of worsening AI and its impact on clinical outcomes have not been examined in a large cohort., Methods: We conducted a retrospective analysis of patients with CF-LVAD in the INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) study. Development of significant AI was defined as the first instance of at least moderate AI. Primary outcomes of interest were survival after development of significant AI and time to adverse events, including device complications and rehospitalizations., Results: Among 10,603 eligible patients, 1,399 patients on CF-LVAD support developed moderate to severe AI. Prevalence of significant AI progressively increased over time. Predictors of worsening AI included older age, female sex, smaller body mass index, mild pre-implantation AI, and destination therapy strategy. Moderate to severe AI was associated with significantly higher left ventricular end-diastolic diameter, reduced cardiac output, and higher levels of brain natriuretic peptide. Significant AI was associated with higher rates of rehospitalization (32.1% vs. 26.6%, respectively, at 2 years; p = 0.015) and mortality (77.2% vs. 71.4%, respectively, at 2 years; p = 0.005), conditional upon survival to 1 year., Conclusions: Development of moderate to severe AI has a negative impact on hemodynamics, hospitalizations, and survival on CF-LVAD support. Pre- and post-implantation management strategies should be developed to prevent and treat this complication., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The pulmonary artery pulsatility index (PAPi), defined as the ratio of pulmonary artery pulse pressure to right atrial pressure, emerged as a powerful predictor of right ventricular (RV) failure in patients with acute inferior myocardial infarction and those undergoing left ventricular assist device placement; however, its prognostic utility in the advanced heart failure population remains largely unknown., Methods and Results: We comparatively analyzed PAPi with traditional indices of RV function including RV stroke work index and right atrial/pulmonary capillary wedge pressure ratio (RAP/PCWP) in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness trial. Median PAPi score was 2.35 in 190 patients. PAPi was significantly associated with clinical (jugular venous distention, ascites, edema), echocardiographic (right atrial size, vena cava size, tricuspid regurgitation velocity), and hemodynamic signs of RV failure (RAP, PCWP); all P < .05. In addition, PAPi was associated with the measures of left ventricular function, including ejection fraction, cardiac index, and PCWP (all P < .05). In Cox regression analysis, PAPi was an independent predictor of primary endpoint of death or hospitalization at 6 months (hazard ratio 0.91 [95% confidence interval 0.84-0.99], P = .022), whereas RA pressure, RV stroke work index, or RA/PCWP were not., Conclusions: PAPi serves as a marker of RV dysfunction and strongly predicts adverse clinical events in patients with advanced heart failure. Incorporating PAPi into existing risk models can substantially improve patient selection for advanced therapies and clinical outcomes in this population., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Continuous-flow left ventricular assist devices (CF-LVADs) have become a standard treatment choice in advanced heart failure patients. We hypothesized that practice patterns with regards to CF-LVAD utilization vary significantly among transplant centers and impact waitlist outcomes., Methods and Results: The United Network for Organ Sharing registry was queried to identify adult patients who were waitlisted for heart transplantation (HT) between 2008 and 2015. Each patient was assigned a propensity score based on likelihood of receiving a durable CF-LVAD before or while waitlisted. The primary outcomes of interest were death or delisting for worsening status and HT at 1 year. A total of 22 863 patients from 92 centers were identified. Among these, 9013 (39.4%) were mechanically supported. CF-LVAD utilization varied significantly between and within United Network for Organ Sharing regions. Freedom from waitlist death or delisting was significantly lower in propensity-score-matched patients who were mechanically supported versus medically managed (83.5% versus 79.2%; P <0.001). However, cumulative incidence of HT was also lower in mechanically supported patients (53.3% versus 63.6%; P <0.001). Congruous mechanical and medical bridging strategies based on clinical risk profile were associated with lower risk of death or delisting (hazard ratio, 0.88; P =0.027) and higher likelihood of HT (hazard ratio, 1.14; P <0.001)., Conclusions: CF-LVAD utilization may lower waitlist mortality at the expense of lower likelihood of HT. Decision to use CF-LVAD and timing of transition should be individualized based on patient-, center-, and region-level risk factors to achieve optimal outcomes., (© 2018 American Heart Association, Inc.)

Background: Patients with restrictive cardiomyopathy (RCM) and hypertrophic cardiomyopathy (HCM) generally are considered poor candidates for mechanical circulatory support devices (MCSDs) and often not able to be bridged mechanically to heart transplantation. This study characterized MCSD utilization and transplant waitlist outcomes in patients with RCM/HCM under the current allocation system and discusses changes in the era of the new donor allocation system., Methods and Results: Patients waitlisted from 2006 to 2016 in the United Network for Organ Sharing registry were stratified by RCM/HCM versus other diagnoses. MCSD utilization and waitlist duration were analyzed by propensity score models. Waitlist outcomes were assessed by cumulative incidence functions with competing events. Predictors of waitlist mortality or delisting for worsening status in patients with RCM/HCM were identified by proportional hazards model. Of 30 608 patients on the waitlist, 5.1% had RCM/HCM. Patients with RCM/HCM had 31 fewer waitlist days ( P <0.01) and were ≈26% less likely to receive MCSD ( P <0.01). Cumulative incidence of waitlist mortality was similar between cohorts; however, patients with RCM/HCM had higher incidence of heart transplantation. Predictors of waitlist mortality or delisting for worsening status in patients with RCM/HCM without MCSD support included estimated glomerular filtration rate <60 mL/min per 1.73 m 2 , pulmonary capillary wedge pressure >20 mm Hg, inotrope use, and subjective frailty., Conclusions: Patients with RCM/HCM are less likely to receive MCSD but have similar waitlist mortality and slightly higher incidence of transplantation compared with other patients. The United Network for Organ Sharing RCM/HCM risk model can help identify patients who are at high risk for clinical deterioration and in need of expedited heart transplantation., (© 2018 American Heart Association, Inc.)

Despite significant advances in the medical management of heart transplant (HT) recipients, perioperative complications, including vasoplegia, remain a significant contributor to morbidity and mortality. This is a retrospective review of patients who received HT at our institution between 2012 and 2015. Mean systemic vascular resistance (SVR) was calculated during the bypass run. Vasoplegia was defined as a mean SVR <800 dynes s/cm despite a high pressor requirement (>1,500 μg neosynephrine bolused). The primary outcome of interest was 30 day post-transplant survival. There were 138 patients included in the current study. A total of 16% (n = 22) patients were identified as having developed on-cardiopulmonary bypass vasoplegia. Vasoplegic patients had a significantly higher body mass index (BMI) (30.1 ± 5.0 vs. 26.5 ± 4.7; p = 0.005) and were more likely to be male (95.5% vs. 66.4%; p = 0.004). Use of continuous-flow left ventricular assist device (CF-LVAD) as bridge-to-transplant (BTT) was prevalent among vasoplegic patients (81.8% vs. 57.8%; p = 0.033). These patients had significantly decreased survival at 30 and 60 days (86.4% vs. 99.1% at 30 days; 77.3% vs. 92.8% at 60 days). Bridge-to-transplant with CF-LVAD was an independent predictor of on-cardiopulmonary bypass (CPB) vasoplegia. On-CPB vasoplegia complicated 16% of HTs in the current study and was associated with increased mortality. Bridge-to-transplant with CF-LVAD was an independent predictor of this phenomenon.

Short-term ventricular assist devices (ST-VADs) have been effective in treating the patients with refractory cardiogenic shock. Membrane oxygenators (MOs) can be added to the circuit for concomitant, profound refractory hypoxia. This study reports the outcomes of combined therapy in this portion of patients. This is a retrospective review of 166 patients who received an ST-biventricular assist device (BiVAD) or right ventricular assist device (RVAD) for cardiogenic shock between November 2007 and November 2014. An MO was added to the RVAD for profound hypoxia refractory to maximized ventilation. Patients were divided into two groups: 33 with (MO-VAD [MV]) and 133 without (VAD only [VO]) an MO. Survival to discharge and adverse events were compared between groups. More MV than VO patients were intubated (93.9% vs. 59.4%; p < 0.001) and on veno-arterial extracorporeal membrane oxygenator (VA-ECMO) (72.7% vs. 19.5%; p < 0.001) before implantation. Survival to discharge (51.5% MV vs. 52.6% VO; p = 0.515) and 1 year survival (54.4% MV vs. 48.6% VO; p = 0.955) were not significantly different. MV patients had more prolonged intubation (69.7% vs. 37.6%; p < 0.001), tracheostomies (39.4% vs. 16.5%; p = 0.008), and a higher risk for bleeding (p = 0.037). Patients suffering from cardiogenic shock with refractory hypoxia requiring combined ST-VAD and MO therapy appear to achieve similar mid-term survival despite increased risk for early complications.

Left ventricular distention (LVD) during venoarterial extracorporeal membrane oxygenation (VA-ECMO) support is increasingly recognized but seldom reported in the literature. The current study defined LVD as not present (LVD-); subclinical (LVD+, evidence of pulmonary edema on chest radiograph AND pulmonary artery diastolic blood pressure greater than 25 mm Hg within the first 2 hours of intensive care unit admission); or clinical (LVD++, need for decompression of the left ventricle immediately following VA-ECMO initiation). Among 226 VA-ECMO device runs, 121 had sufficient data to define LVD retrospectively. Nine patients (7%) developed LVD++ requiring immediate decompression, and 27 patients (22%) met the definition of LVD+. Survival to discharge was similar among groups (LVD++: 44%, LVD+: 41%, LVD-: 44%). However, myocardial recovery appeared inversely related to the degree of LVD (LVD++: 11%, LVD+: 26%, LVD-: 40%). When death or transition to device was considered as a composite outcome, event-free survival was diminished in LVD++ and LVD+ patients compared with LVD-. Multivariable analysis identified cannulation of VA-ECMO during extracorporeal cardiopulmonary resuscitation (ECPR) as a risk factor for decompression (odds ratio [OR]: 3.64, confidence interval [CI]: 1.21-10.98; p = 0.022). Using a novel definition of LVD, the severity LVD was inversely related to the likelihood of myocardial recovery. Survival did not differ between groups. Extracorporeal cardiopulmonary resuscitation was associated with need for mechanical intervention.