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Heart transplantation is advocated in selected patients with advanced heart failure in the absence of contraindications. Principal challenges in heart transplantation centre around an insufficient and underutilized donor organ pool, the need to individualize titration of immunosuppressive therapy, and to minimize late complications such as cardiac allograft vasculopathy, malignancy, and renal dysfunction. Advances have served to increase the organ donor pool by advocating the use of donors with underlying hepatitis C virus infection and by expanding the donor source to use hearts donated after circulatory death. New techniques to preserve the donor heart over prolonged ischaemic times, and enabling longer transport times in a safe manner, have been introduced. Mechanical circulatory support as a bridge to transplantation has allowed patients with advanced heart failure to avoid progressive deterioration in hepato-renal function while awaiting an optimal donor organ match. The management of the heart transplantation recipient remains a challenge despite advances in immunosuppression, which provide early gains in rejection avoidance but are associated with infections and late-outcome challenges. In this article, we review contemporary advances and challenges in this field to focus on donor recovery strategies, left ventricular assist devices, and immunosuppressive monitoring therapies with the potential to enhance outcomes. We also describe opportunities for future discovery to include a renewed focus on long-term survival, which continues to be an area that is under-studied and poorly characterized, non-human sources of organs for transplantation including xenotransplantation as well as chimeric transplantation, and technology competitive to human heart transplantation, such as tissue engineering., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Heart transplantation is the standard of therapy for patients with end-stage heart disease. Since the first human-to-human heart transplantation, performed in 1967, advances in organ donation, surgical techniques, organ preservation, perioperative care, immunologic risk assessment, immunosuppression agents, monitoring of graft function and surveillance of long-term complications have drastically increased recipient survival. However, there are yet many challenges in the modern era of heart transplantation in which immunosuppression may play a key role in further advances in the field. A fine-tuning of immune modulation to prevent graft rejection while avoiding side effects from over immunosuppression has been the vital goal of basic and clinical research. Individualization of drug choices and strategies, taking into account the recipient's clinical characteristics, underlying heart failure diagnosis, immunologic risk and comorbidities seem to be the ideal approaches to improve post-transplant morbidity and survival while preventing both rejection and complications of immunosuppression. The aim of the present review is to provide a practical, comprehensive overview of contemporary immunosuppression in heart transplantation. Clinical evidence for immunosuppressive drugs is reviewed and practical approaches are provided. Cardiac allograft rejection classification and up-to-date management are summarized. Expanding therapies, such as photophoresis, are outlined. Drug-to-drug interactions of immunosuppressive agents focused on cardiovascular medications are summarized. Special situations involving heart transplantation such as sarcoidosis, Chagas diseases and pediatric immunosuppression are also reviewed. The evolution of phamacogenomics to individualize immunosuppressive therapy is described. Finally, future perspectives in the field of immunosuppression in heart transplantation are highlighted., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

This article updates the Heart Failure Association of the European Society of Cardiology (ESC) 2007 classification of advanced heart failure and describes new diagnostic and treatment options for these patients. Recognizing the patient with advanced heart failure is critical to facilitate timely referral to advanced heart failure centres. Unplanned visits for heart failure decompensation, malignant arrhythmias, co-morbidities, and the 2016 ESC guidelines criteria for the diagnosis of heart failure with preserved ejection fraction are included in this updated definition. Standard treatment is, by definition, insufficient in these patients. Inotropic therapy may be used as a bridge strategy, but it is only a palliative measure when used on its own, because of the lack of outcomes data. Major progress has occurred with short-term mechanical circulatory support devices for immediate management of cardiogenic shock and long-term mechanical circulatory support for either a bridge to transplantation or as destination therapy. Heart transplantation remains the treatment of choice for patients without contraindications. Some patients will not be candidates for advanced heart failure therapies. For these patients, who are often elderly with multiple co-morbidities, management of advanced heart failure to reduce symptoms and improve quality of life should be emphasized. Robust evidence from prospective studies is lacking for most therapies for advanced heart failure. There is an urgent need to develop evidence-based treatment algorithms to prolong life when possible and in accordance with patient preferences, increase life quality, and reduce the burden of hospitalization in this vulnerable patient population., (© 2018 The Authors. European Journal of Heart Failure © 2018 European Society of Cardiology.)

Background: The role of cytokine gene polymorphism and its association with acute heart allograft rejection and cardiac allograft vasculopathy (CAV) is controversial. The role of growth factor gene polymorphism has never been investigated in heart allograft recipients., Methods: Seventy heart transplant recipients were studied. Mean age at transplant was 50.4 +/- 12.4 years (73% white, 91% male). Patients were followed for an average of 28 +/- 12 months. Cellular rejection episodes were determined based on criteria established by the International Society of Heart and Lung Transplantation. Angiography and intravascular ultrasound (IVUS) were performed annually. Cytokine and growth factor polymorphism data were analyzed using the single-nucleotide polymorphism polymerase chain reaction (SNP PCR) approach., Results: Patients who developed early CAV, documented by angiography, had increased frequency of the interferon-gamma high-producer phenotype, increased frequency of PDGF-286 AA, and decreased frequency of PDGF-1135 CC (p < 0.03, p < 0.03 and p = 0.01, respectively). Platelet-derived growth factor (PDGF) associations with early CAV were substantiated when vasculopathy was determined by IVUS. Additional associations were identified with vascular endothelial growth factor (VEGF) polymorphisms-1154 GG and -2578 AC (p < 0.03 and p = 0.01, respectively). Some of these associations translated to decreased patient survival, as indicated by Kaplan-Meier analysis. No significant association was identified between cytokine gene polymorphism (tumor necrosis factor-alpha, transforming growth factor-beta, interferon-gamma, interleukin-6 and interleukin-10) and acute cellular rejection episodes., Conclusions: These data suggest an association between PDGF and VEGF polymorphism and CAV. It is essential, however, due to the redundancy of the immune system and other confounding factors, that future studies be centrally conducted and include multiple programs, large cohorts of patients and properly chosen controls. Only then will we be able to identify the true association between cytokine and growth factor polymorphism and heart transplant outcome.

Background: The clinical significance of HLA-directed antibodies newly detected after transplantation (HT) is controversial., Methods: Seventy-one HT recipients consented to enroll. Mean follow-up time was 28 months (range 6-48). Panel reactive antibody (PRA) analysis was performed on posttransplant sera (2 weeks, 1, 2, 3, 6, and 12 months and annually thereafter) using Flow-PRA. A mean of 6.9+/-1.2 serum samples per patient were obtained. Severity of cellular rejection was measured using the ISHLT grading system. Coronary angiography and intravascular ultrasound (IVUS) studies were performed annually to evaluate severity of allograft vasculopathy., Results: Twenty-five recipients had newly detected HLA-directed antibodies during the first year postHT. HLA class I antibodies were detected in 18 patients (25.4%), and class II in 11 patients (15.5%). The majority of donor recipient pairs were HLA mismatched (4.6+/-1.2 of the six major HLA antigens). Only mismatches at HLA-A locus had significant association with de novo posttransplant antibody formation. Length of ischemia time was correlated with early and sustained presence of de novo HLA-directed antibodies postheart transplant. Importantly, an association between de novo HLA-directed antibodies and cellular rejection was notes (P=0.0002). De novo HLA class II directed antibodies are also associated with IVUS documented vasculopathy (P<0.002). Finally, death due to allograft failure is associated with the presence of de novo formed HLA class II directed antibodies (P=0.008)., Conclusions: Identifying the formation of de novo HLA-directed antibodies following heart transplantation may predict allograft outcome. This, in turn, may serve as a tool for individualization of immunosuppression protocols in heart transplant recipients.

Objective: Coronary endothelial dysfunction may be an early marker for cardiac allograft vasculopathy (CAV) in orthotopic heart transplant recipients. We used serial studies to evaluate changes in coronary endothelial function in patients with and without clinically evident CAV., Background: In serial studies with intravascular ultrasound (IVUS) and Doppler flow wire measurements, we previously demonstrated that annual decrements in coronary endothelial function are associated with progressive intimal thickening., Methods: We studied 45 patients annually, beginning at transplantation until pre-specified end-points (angiographic CAV or cardiac death) were reached. At each study, we measured coronary endothelial function using intracoronary infusions of adenosine, acetylcholine, and nitroglycerin. We simultaneously recorded IVUS images and Doppler velocities., Results: Of the 45 patients studied, 9 reached end-points during the study (6 had CAV and 3 died). The mean annual change in area response to acetylcholine was -4.5% +/- 3.0% in patients who reached end-points and -0.9% +/- 1.5% in those who did not (p = 0.04). The mean annual decrement in flow response to acetylcholine was greater in patients who reached end-points (-31% +/- 11% vs -5% +/- 5%, p = 0.08). Responses to adenosine and nitroglycerin did not differ., Conclusions: When serial responses were evaluated, patients with end-points had more rapid decreases in endothelial function. The rate of disease progression may be more important than the absolute degree of intimal thickening in early CAV. These data implicate endothelial dysfunction in the development of clinically significant vasculopathy and suggest that serial studies of endothelial function may provide important prognostic information about the development of CAV after heart transplantation.

Background: No studies have analyzed quality of life (QOL) from before to after heart transplantation in patients with a left ventricular assist device (LVAD). Therefore, the purpose of this longitudinal, multi-site study was to compare QOL outcomes of patients listed for heart transplantation who required a left ventricular assist device (LVAD) at 3 months after implantation of an LVAD vs 3 months after heart transplantation., Methods: A non-random sample of 40 patients (predominantly middle-aged, married, white men), who had paired data at both 3 months after LVAD implantation and 3 months after heart transplantation, were investigated. Patients completed self-report questionnaires (with acceptable reliability and validity) at both time periods, including the Quality of Life Index, Rating Question Form, Heart Failure Symptom Checklist, Sickness Impact Profile, LVAD Stressor Scale (completed only after LVAD implant), Heart Transplant Stressor Scale (completed only after heart transplant) and Jalowiec Coping Scale. Descriptive analyses and comparative analyses using paired t-tests were performed with statistical significance set at 0.01., Results: Patients were significantly more satisfied with their lives overall and with their health and functioning at 3 months after heart transplantation as compared with 3 months after LVAD implantation. Mobility, self-care ability, physical ability and overall functional ability improved from 3 months after LVAD implant to 3 months after heart transplant. There was significantly less symptom distress after LVAD implant as compared with after heart transplant for the neurologic, dermatologic and physical sub-scales. Work/school/financial stress was significantly lower after heart transplant vs after LVAD implant. In contrast, 2 other areas of stress were significantly lower after LVAD implant vs after heart transplant: self-care stress and hospital/clinic-related stress., Conclusions: Differences were found in QOL outcomes at 3 months after LVAD implant as compared with 3 months after heart transplant. Our findings point out specific areas of concern with respect to QOL after LVAD implant and post-transplant, some of which are amenable to health-care provider interventions.

Background: Differences in mortality are thought to exist between African Americans and Caucasians with heart failure. These differences may be due to a variety of factors, including differences in disease process, socioeconomic status, and access to health care. Additionally, little data exist on racial differences between these two groups after cardiac transplantation. This study examines a single center, urban experience in treating African Americans and Caucasians with heart failure and after cardiac transplantation. We hypothesize that treatment in a specialized, comprehensive heart failure/cardiac transplantation program results in similar survival between African Americans and Caucasians., Methods: We retrospectively reviewed the Rush Heart Failure and Cardiac Transplant Database from July 1994 to August 2000. Variables analyzed in the cardiomyopathy patients included survival (until death, placement of left ventricular assist device or cardiac transplantation), number of hospitalizations per year, length of stay per year, and utilization of outpatient resources. Follow-up period was from initial visit to death, transplantation, or implantation of left ventricular assist device. In those who underwent cardiac transplantation, we examined rejection rates (cellular and humoral), rejection burden, hospitalization data, and 5-year survival. A subgroup bridged to cardiac transplantation with a left ventricular device was also analyzed., Results: Seven hundred thirty-four cardiomyopathy patients were identified: 203 were African Americans and 531 were Caucasians. The etiology of cardiomyopathy was more commonly ischemic in Caucasians as compared to non-ischemic in African Americans (P <.01). African Americans had more admissions to the hospital per year compared with Caucasians, 1.2 +/- 2.1 versus.5 +/- 1.1 (P <.01) with longer length of stay per year, 1.4 +/- 25.2 days versus 4.4 +/- 14.3 days (P <.01). Utilization of outpatient resources was significantly higher in African Americans compared with Caucasians with more use of continuous inotropes (13% versus 6%, P <.01), intermittent inotropes (11% versus 5%, P <.01), and home nursing after hospital discharge (52% versus 32% of hospital discharges, P <.01). Survival by Kaplan-Meier analysis was comparable between the two groups (mean survival 1,470 +/- 72 days in African Americans versus 1521 +/- 46 days in Caucasians, log rank test [P =.6]). During this time, 30 African Americans and 73 Caucasians underwent cardiac transplantation. Fifty-three were bridged to transplantation with a left ventricular assist device (20 African Americans, 33 Caucasians). There were no differences in 5-year survival by Kaplan-Meier analysis despite higher peak preoperative panel reactive antibody levels in African Americans versus Caucasians (12% +/- 30% compared with 5% +/- 15%, P =.04), more overall treated rejection episodes per year in the African Americans (P <.01), as well as more posttransplant hospitalizations (2.2 +/- 1.2 times per year as compared with 1.7 +/- 2.1 times per year, P =.04)., Conclusion: Delivery of care to heart failure patients in a comprehensive, specialized program results in similar survival regardless of race despite higher utilization of inpatient and outpatient resources. The finding that, after cardiac transplantation, African Americans do not have higher mortality rates, despite having higher rates of rejection overall and more hospitalizations, further supports the hypothesis that optimal care can improve outcomes despite unfavorable baseline clinical characteristics.

Abstract Only a few randomized clinical trials have been performed so far in heart transplant recipients, mainly because of the relatively small number of heart transplants performed worldwide each year. The main focus of the few controlled trials that have been completed has been the prevention and treatment of heart allograft rejection. In the area of pharmacologic immunosuppression, both biological agents and drugs have been the subject of investigation. Among the biological agents, chimeric monoclonal antibodies directed against the interleukin (IL)-2 receptor, which have been found to be safe and effective in renal transplant recipients, are now undergoing the test of controlled trials in heart transplant recipients. Immunosuppressive drugs that have been studied in controlled trials include calcineurin inhibitors (such as the microemulsion formulation of cyclosporine and tacrolimus) and inhibitors of purine synthesis, such as mycophenolate mofetil. Non-pharmacologic prophylactic immunosuppression with photopheresis has also been tested in a prospective, multicenter, randomized trial. New immunosuppressive regimens, such as mycophenolate mofetil combined with a monoclonal antibody against the IL-2 receptor, are being tested with the aim to reduce or eliminate calcineurin inhibitors or corticosteroids. Although clinical approaches to the induction of tolerance have undergone preliminary clinical evaluation, the ability to induce tolerance to an allograft in humans remains an elusive goal.

Background: Ventricular assist devices (VADs) are commonly used to bridge patients to heart transplantation. Recipients of VADs may develop anti-human histocompatibility leukocyte antigen antibodies, as reflected by elevated panel-reactive antibodies (PRA). The purpose of this study was to evaluate the relationship between bridging with VAD before heart transplantation and development of cellular rejection, humoral rejection, and allograft vasculopathy after transplantation.Methods: Data on all patients who underwent cardiac transplantation between July 1994 and February 2001 at Rush Presbyterian St Luke’s Medical Center were retrospectively reviewed. Data collected included sex, age, etiology of cardiomyopathy, percentage panel reactive antibodies (by cytotoxic method), type and duration of mechanical circulatory support, transfusion history, rejection history (both cellular and humoral) after cardiac transplantation, and development of allograft vasculopathy. Cellular rejection was treated when International Society of Heart and Lung and Transplantation Grade 2 or greater in the first 12 months after transplant and Grade 3 or greater after 12 months and treated with intensification of immunosuppression. Humoral rejection was defined clinically as allograft dysfunction by echocardiography without evidence of cellular rejection on endomyocardial biopsy or allograft vasculopathy. Allograft vasculopathy was defined by presence of any degree of luminal narrowing or pruning of distal vessels by coronary arteriography. Statistical analyses were performed by chi-square test, Fisher’s exact test, and Wilcoxon rank sum test, as appropriate.Results: Ninety-eight patients underwent cardiac transplantation during the study period (87 men, mean age 49 years, 46 ischemic etiology). Of these, 48 were bridged with HeartMate VAD (20 patients received vented electric device, 28 received pneumatic device). Nineteen percent of VAD patients had a peak pretransplant PRA ≥10% vs 2% of patients without VAD (p = 0.014). PRA ≥10%, use of VAD, or duration of VAD support did not predict development of humoral rejection. Use of VAD did not predict development of cellular rejection or allograft vasculopathy. VAD use was not associated with sudden death after heart transplantation. In the entire group of 98 patients, neither humoral nor cellular rejection predicted development of allograft vasculopathy. Longer ischemic time correlated with increased cellular rejection and humoral rejection after transplantation (p = 0.01).Conclusions: Some patients bridged to cardiac transplantation with VADs have increased PRA before heart transplantation, but this does not appear to translate into increased risk of either humoral or cellular rejection after transplantation or development of allograft vasculopathy as detected by coronary angiography. [Copyright &y& Elsevier]

: BackgroundThe HeartMate vented electric left ventricular assist device has been approved for use as destination therapy. Thus, the study of quality-of-life outcomes, as well as morbidity and mortality, is imperative. The purpose of our study was to describe change with time (from 1 month to 1 year) in patients who received a HeartMate vented electric left ventricular assist device as a bridge to heart transplantation and to identify quality-of-life predictors of survival after left ventricular assist device implantation.: MethodsA nonrandom sample of 78 patients who received a HeartMate vented electric left ventricular assist device (primarily middle-aged, white married males) who had quality-of-life data at 1, 2, 3, 6, 9, or 12 months after implant was the subject of this report. The sample size decreased with time primarily because of heart transplantation. Patients completed the following booklets of questionnaires: Quality of Life Index, Rating Question Form, Heart Failure Symptom Checklist, and Sickness Impact Profile. Analyses included both descriptive analyses and modeling procedures (mixed-effects models and Cox proportional hazards models).: ResultsQuality-of-life outcomes were fairly good and stable from 1 month to 1 year after HeartMate vented electric left ventricular assist device implantation. Both positive and negative changes were detected in all quality-of-life domains (physical and occupational function, social interaction, somatic sensation, and psychological state) after left ventricular assist device insertion. Items from the physical domain of quality of life, specifically walking and dressing oneself, were significantly associated with the risk of dying after left ventricular assist device implantation.: ConclusionsIdentifying poor quality-of-life outcomes within 1 year after left ventricular assist device implantation provides direction to develop strategies to improve outcomes. Physical and occupational rehabilitation, psychosocial intervention, and monitoring symptom distress and physical disability may contribute to improved quality-of-life outcomes and survival after left ventricular assist device implantation. [Copyright &y& Elsevier]

BACKGROUND: An interatrial shunt may provide an autoregulatory mechanism to decrease left atrial pressure and improve heart failure (HF) symptoms and prognosis. METHODS: Patients with symptomatic HF with any left ventricular ejection fraction (LVEF) were randomized 1:1 to transcatheter shunt implantation versus a placebo procedure, stratified by reduced (≤40%) versus preserved (>40%) LVEF. The primary safety outcome was a composite of device-related or procedure-related major adverse cardiovascular or neurological events at 30 days compared with a prespecified performance goal of 11%. The primary effectiveness outcome was the hierarchical composite ranking of all-cause death, cardiac transplantation or left ventricular assist device implantation, HF hospitalization, outpatient worsening HF events, and change in quality of life from baseline measured by the Kansas City Cardiomyopathy Questionnaire overall summary score through maximum 2-year follow-up, assessed when the last enrolled patient reached 1-year follow-up, expressed as the win ratio. Prespecified hypothesis-generating analyses were performed in patients with reduced and preserved LVEF. RESULTS: Between October 24, 2018, and October 19, 2022, 508 patients were randomized at 94 sites in 11 countries to interatrial shunt treatment (n=250) or a placebo procedure (n=258). Median (25th and 75th percentiles) age was 73.0 years (66.0, 79.0), and 189 patients (37.2%) were women. Median LVEF was reduced (≤40%) in 206 patients (40.6%) and preserved (>40%) in 302 patients (59.4%). No primary safety events occurred after shunt implantation (upper 97.5% confidence limit, 1.5%; P <0.0001). There was no difference in the 2-year primary effectiveness outcome between the shunt and placebo procedure groups (win ratio, 0.86 [95% CI, 0.61–1.22]; P =0.20). However, patients with reduced LVEF had fewer adverse cardiovascular events with shunt treatment versus placebo (annualized rate 49.0% versus 88.6%; relative risk, 0.55 [95% CI, 0.42–0.73]; P <0.0001), whereas patients with preserved LVEF had more cardiovascular events with shunt treatment (annualized rate 60.2% versus 35.9%; relative risk, 1.68 [95% CI, 1.29–2.19]; P =0.0001; P interaction<0.0001). There were no between-group differences in change in Kansas City Cardiomyopathy Questionnaire overall summary score during follow-up in all patients or in those with reduced or preserved LVEF. CONCLUSIONS: Transcatheter interatrial shunt implantation was safe but did not improve outcomes in patients with HF. However, the results from a prespecified exploratory analysis in stratified randomized groups suggest that shunt implantation is beneficial in patients with reduced LVEF and harmful in patients with preserved LVEF. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03499236. [ABSTRACT FROM AUTHOR]

Rejection remains the Achilles heel of orthotopic cardiac transplantation (OHT). Reliable non-invasive markers of rejection are desirable for timely therapy and to reduce risks and costs. Changes in atrial electrophysiology may precede ventricular changes during acute rejection. Although P wave duration in the signal-averaged ECG reflects atrial conduction, the feasibility of such measurement and the range of its values in OHT patients in absence of rejection is uncertain. This study compared the filtered P wave duration in 15 hypertensive OHT patients free of rejection with that in 15 age-matched hypertensive controls. All OHT patients had biatrial anastomoses. Two electrophysiologists interpreted the tracings independently. Three tracings (2 OHT, 1 control) could not be interpreted by either reader. An adequate P wave signal-averaged ECG was obtained in the remaining patients, despite the frequent presence of dissociated P waves (recipient and donor atria) on standard ECG in OHT patients. There was good interobserver agreement in the measurement of filtered P wave duration (r = 0.91; P < 0.0001). Conclusions: The filtered P wave duration was significantly shorter in the OHT patients (112 ± 15 ms versus 128 ±14 ms; P = 0.008). Filtered P wave duration can be measured in most OHT. Filtered P wave duration is shorter in OHT patients than in hypertensive controls, possibly as a result of the reduced mass of the truncated donor atria. Further studies are needed to determine whether the signal-averaged P wave can be useful to predict acute cardiac rejection. [ABSTRACT FROM AUTHOR]

: Background:Quality of life (QOL) outcomes after left ventricular assist device (LVAD) implantation from before to after hospital discharge have been examined only in a very small sample of patients. The purposes of this study are to describe change in QOL from before to after hospital discharge in LVAD patients and to determine whether being discharged with an LVAD predicts better QOL than being hospitalized with an LVAD.: Methods:A non-random sample of 62 LVAD patients (approximately 50 years old, male, white, married, fairly well-educated) completed self-report questionnaires at ≥2 timepoints post-implant. The questionnaires (Quality of Life Index, Rating Question Form, Heart Failure Symptom Checklist, Sickness Impact Profile, LVAD Stressor Scale, Jalowiec Coping Scale), which were collated into booklets, had acceptable reliability and validity. Longitudinal analyses were performed in 2 steps using 1-sample t-tests and linear mixed effects modeling.: Results:Perception of QOL and health status were fairly good both before and after discharge of LVAD patients. Discharge predicted increased satisfaction with socioeconomic areas of life; decreased overall and psychologic stress and stress related to family and friends, self-care and work/school/finances; and decreased physical and self-care disability.: Conclusions:QOL outcomes improved from before to after hospital discharge in LVAD patients awaiting heart transplantation. As LVADs potentially become available as destination therapy, in addition to being successful bridges to heart transplantation, QOL outcomes will become more important to study. [Copyright &y& Elsevier]