Successful treatment of gastric cancer 10 years after heart transplantation: A case report.

BACKGROUND: While survival rates among cardiac allograft recipients have improved, there has been a rise in post-transplant malignancies, with gastric cancer being less commonly reported. This study presented a successful treatment of gastric cancer in an individual 10 years after undergoing a heart transplant. CASE PRESENTATION: A 66-year-old Chinese man presented to the gastrointestinal clinic with a complaint of diagnosis of gastric cancer for 4 months and treated with neoadjuvant therapy for 1 month. He has undergone orthotopic heart transplantation 10 years earlier due to a myocardial infarction. Physical examination and laboratory tests did not reveal any significant abnormalities. Abdominal contrast-enhanced computed tomography (CT) imaging indicated a gastric mass near the greater curvature, with gastroscopy suggesting a carcinoma at the esophagogastric junction, Siewert III. An echocardiogram indicated left atrial enlargement with mild mitral and tricuspid regurgitation. The diagnosis suggested that his gastric cancer at the esophagogastric junction was a consequence of long-term immunosuppressive therapy. A multidisciplinary team (MDT) consultation recommended a proximal radical gastrectomy. Postoperatively, the patient received 4 cycles of adjuvant chemotherapy with XELOX combined with Herceptin, initiated a month after surgery. During the 1-year follow-up, the patient showed commendable recovery, with no signs of tumor recurrence or metastasis. CONCLUSION: This case underscores the potential risk of malignancy from immunosuppressive agents in transplant recipients. The successful management of this complex scenario underscores the indispensable role of an MDT approach in treating such unique and challenging cases.

Right Ventricular Function on Cardiovascular Magnetic Resonance Imaging and Long-Term Outcomes in Stable Heart Transplant Recipients.

BACKGROUND: In heart transplant recipients, right ventricular (RV) dysfunction may occur for a variety of reasons. Whether RV dysfunction in the stable phase after heart transplantation is associated with long-term adverse outcomes is unknown. We aimed to determine the long-term prognostic significance of RV dysfunction identified on cardiovascular magnetic resonance imaging (CMR) at least 1 year after heart transplantation. METHODS: In consecutive heart transplant recipients who underwent CMR for surveillance, we assessed 2 CMR measures of RV function: RV ejection fraction and RV global longitudinal strain (RVGLS). We investigated associations between RV dysfunction and a composite end point of death or major adverse cardiac events, including retransplantation, nonfatal myocardial infarction, coronary revascularization, and heart failure hospitalization. RESULTS: A total of 257 heart transplant recipients (median age, 59 years; 75% men) who had CMR at a median of 4.3 years after heart transplantation were included. Over a median follow-up of 4.4 years after the CMR, 108 recipients experienced death or major adverse cardiac events. In a multivariable Cox regression analysis adjusted for age, time since transplantation, indication for transplantation, cardiac allograft vasculopathy, history of rejection, and CMR covariates, RV ejection fraction was not associated with the composite end point, but RVGLS was independently associated with the composite end point with a hazard ratio of 1.08 per 1% worsening in RVGLS ([95% CI, 1.00-1.17]; P=0.046). RVGLS provided incremental prognostic value over other variables in multivariable analyses. The association was replicated in subgroups of recipients with normal RV ejection fraction and recipients with late gadolinium enhancement imaging. A similar association was seen with a composite end point of cardiovascular death or major adverse cardiac events. CONCLUSIONS: CMR feature tracking-derived RVGLS assessed at least 1 year after heart transplantation was independently associated with the long-term risk of death or major adverse cardiac events. Future studies should investigate its role in guiding clinical decision-making in heart transplant recipients.

A heart transplant center experience with basiliximab induction strategies: A double edged sword?

BACKGROUND: The use of induction immunosuppression for heart transplantation (HT) is debated given the uncertain benefit and potential risks of infection and malignancy. METHODS: This is a retrospective single-center analysis of 475 consecutive HT recipients from 2003 to 2020 grouped by use of induction with basiliximab group (BG) and the no basiliximab group (NBG). Subgroup analysis by era compared pre-2016 standard-basiliximab (BX) induction and 2016-2020 with selective-BX use as part of a calcineurin-inhibitor-sparing regimen. RESULTS: When adjusted for confounders (sex, age, PRA, eGFR), the BG was less likely to have acute cellular rejection (ACR) (OR.42, p < .001), but had more antibody mediated rejection (AMR) (OR 11.7, p < .001) and more cardiac allograft vasculopathy (CAV) (OR 3.8, p = .04). There was no difference between BG and NBG in the incidence of malignancies or infections. When stratified by era (pre-2016 vs. 2016-2020), ACR remained less common in the BG than the NBG (36% vs. 50%, p = .045) groups, while AMR remained more common (9.7 vs. 0% p = .005). There was no significant difference in conditional survival comparing pre-and post-2016 NBG (HR 2.20 (95% CI.75-6.43); however, both pre-2016 BG and post-2016 BG have significantly higher mortality (HR 2.37 [95% CI 1.02-5.50) and HR 2.69 (95% CI 1.08-6.71), p = .045 and.03, respectively]. CONCLUSION: Basiliximab reduces the incidence of ACR but increases the risk of AMR, CAV, and may be associated with increased mortality. Mechanistic studies are needed to describe a potential T-cell-escape mechanism with enhanced humoral immunity.

Metabolic Syndrome and Heart Transplantation: An Underestimated Risk Factor?

Metabolic Syndrome (MetS), a multifactorial condition that increases the risk of cardio-vascular events, is frequent in Heart-transplant (HTx) candidates and worsens with immunosuppressive therapy. The aim of the study was to analyze the impact of MetS on long-term outcome of HTx patients. Since 2007, 349 HTx patients were enrolled. MetS was diagnosed if patients met revised NCEP-ATP III criteria before HTx, at 1, 5 and 10 years of follow-up. MetS was present in 35% of patients pre-HTx and 47% at 1 year follow-up. Five-year survival in patients with both pre-HTx (65% vs. 78%, p < 0.01) and 1 year follow-up MetS (78% vs 89%, p < 0.01) was worst. At the univariate analysis, risk factors for mortality were pre-HTx MetS (HR 1.86, p < 0.01), hypertension (HR 2.46, p < 0.01), hypertriglyceridemia (HR 1.50, p=0.03), chronic renal failure (HR 2.95, p < 0.01), MetS and diabetes at 1 year follow-up (HR 2.00, p < 0.01; HR 2.02, p < 0.01, respectively). MetS at 1 year follow-up determined a higher risk to develop Coronary allograft vasculopathy at 5 and 10 year follow-up (25% vs 14% and 44% vs 25%, p < 0.01). MetS is an important risk factor for both mortality and morbidity post-HTx, suggesting the need for a strict monitoring of metabolic disorders with a careful nutritional follow-up in HTx patients.

Role of Radiology in Assessment of Postoperative Complications of Heart Transplantation.

Heart transplantation is a pivotal treatment of end-stage heart failure, and recent advancements have extended median posttransplant life expectancy. However, despite the progress in surgical techniques and medical treatment, heart transplant patients still face complications such as rejection, infections, and drug toxicity. CT is a reliable tool for detecting most of these complications, whereas MR imaging is particularly adept at identifying pericardial pathologies and signs of rejection. Awareness of these nuances by radiologists, cardiologists, and surgeons is desired to optimize care, reduce morbidities, and enhance survival.

The Effects of Exercise on Cardiogenic Shock with an Intra-Aortic Balloon Pump: A Case Report. / Efeitos do Exercício em Choque Cardiogênico e Balão Intra-Aórtico: Um Relato de Caso.

This case report describes the exercise program on a hospitalized 54-year-old male patient with cardiogenic shock waiting for a heart transplant assisted by an intra-aortic balloon pump, a temporary mechanical circulatory support device. The temporary mechanical circulatory support device, an intra-aortic balloon pump, was placed in the left subclavian artery, enabling the exercise protocol. Measurements and values from Swan-Ganz catheter, blood sample, brain natriuretic peptide (NT-proBNP), and high-sensitivity C-reactive protein (hs-CRP), as well as the six-minute walk test (6MWT) and venous oxygen saturation (SvO2) were obtained before and after an exercise protocol. The exercise training protocol involved the use of an unloaded bed cycle ergometer once a day, for a maximum of 30 minutes, to the tolerance limit. No adverse events or events related to the dislocation of the intra-aortic balloon pump were observed during the exercise protocol. The exercise program resulted in higher SvO2 levels, with an increased 6MWT with lower Borg dyspnea scores (312 meters vs. 488 meters and five points vs. three points, respectively). After completing the ten-day exercise protocol, the patient underwent a non-complicated heart transplant surgery and a full recovery in the ICU. This study showed that exercise is a feasible option for patients with cardiogenic shock who are using an intra-aortic balloon pump and that it is well-tolerated with no reported adverse events.

O presente relato de caso descreve o programa de exercícios aplicado a um paciente do sexo masculino, de 54 anos, internado com choque cardiogênico, aguardando transplante cardíaco e assistido por balão intra-aórtico, um dispositivo de suporte circulatório mecânico temporário. O dispositivo de suporte circulatório mecânico temporário, um balão intra-aórtico, foi colocado na artéria subclávia esquerda, possibilitando o protocolo de exercícios. Antes e após um protocolo de exercícios, foram obtidos dados a partir de cateter de Swan-Ganz, amostra de sangue, peptídeo natriurético cerebral (NT-proBNP), proteína C reativa de alta sensibilidade (PCR-as), teste de caminhada de seis minutos (TC6min) e medição da saturação venosa de oxigênio (SvO2). O protocolo de treinamento físico envolveu a utilização de um cicloergômetro adaptado ao leito, sem carga, uma vez ao dia, por no máximo 30 minutos, até o limite da tolerância. Não foram observados eventos adversos tampouco relacionados ao deslocamento do balão intra-aórtico durante o protocolo de exercícios. O programa de exercícios resultou em maior SvO2 com aumento do TC6min e menores escores de dispneia de Borg (312 metros vs. 488 metros e cinco pontos vs. três pontos, respectivamente). Após completar o protocolo de exercícios de dez dias, o paciente foi submetido a uma cirurgia de transplante cardíaco sem complicações e recuperação total na UTI. O presente estudo demonstrou que o exercício é uma opção viável para pacientes com choque cardiogênico em uso de balão intra-aórtico e que é bem tolerado, além de não haver relatos de eventos adversos.

Exploring personalized treatment for cardiac graft rejection based on a four-archetype analysis model and bioinformatics analysis.

Heart transplantation is the gold standard for treating patients with advanced heart failure. Although improvements in immunosuppressive therapies have significantly reduced the frequency of cardiac graft rejection, the incidences of T cell-mediated rejection (TCMR) and antibody-mediated rejection remain almost unchanged. A four-archetype analysis (4AA) model, developed by Philip F. Halloran, illustrated this problem well. It provided a new dimension to improve the accuracy of diagnoses and an independent system for recalibrating the histology guidelines. However, this model was based on the invasive method of endocardial biopsy, which undoubtedly increased the postoperative risk of heart transplant patients. Currently, little is known regarding the associated genes and specific functions of the different phenotypes. We performed bioinformatics analysis (using machine-learning methods and the WGCNA algorithm) to screen for hub-specific genes related to different phenotypes, based Gene Expression Omnibus accession number GSE124897. More immune cell infiltration was observed with the ABMR, TCMR, and injury phenotypes than with the stable phenotype. Hub-specific genes for each of the four archetypes were verified successfully using an external test set (accession number GSE2596). Logistic-regression models based on TCMR-specific hub genes and common hub genes were constructed with accurate diagnostic utility (area under the curve > 0.95). RELA, NFKB1, and SOX14 were identified as transcription factors important for TCMR/injury phenotypes and common genes, respectively. Additionally, 11 Food and Drug Administration-approved drugs were chosen from the DrugBank Database for each four-archetype model. Tyrosine kinase inhibitors may be a promising new option for transplant rejection treatment. KRAS signaling in cardiac transplant rejection is worth further investigation. Our results showed that heart transplant rejection subtypes can be accurately diagnosed by detecting expression of the corresponding specific genes, thereby enabling precise treatment or medication.

Unraveling the Uncommon: A Case Report of Giant Cell Myocarditis and Examination of Existing Literature.

BACKGROUND Idiopathic giant cell myocarditis (IGCM) is an uncommon and frequently fatal type of myocarditis. It primarily affects young individuals and has the potential to result in heart failure and life-threatening arrhythmias. IGCM seems to be dependent on activation of CD4-positive T lymphocytes and can show improvement with treatment aimed at reducing T-cell function. We present a case of a 65-year-old patient who presented with features of acute heart failure refractory to guideline-directed medical therapy (GDMT), due to IGCM. A review of the natural history and treatment of IGCM is also presented. CASE REPORT A 65-year-old woman with multiple comorbidities was admitted to our hospital for ventricular tachycardia in the setting of progressive non-ischemic heart failure, unresponsive to GDMT. This led to further investigation, including an endomyocardial biopsy, which revealed inflammatory infiltration, with multinucleated giant cells and lymphocytes in the absence of granuloma formation, prompting a diagnosis of IGCM. An implantable cardioverter-defibrillator (ICD) was placed for secondary prevention of sudden cardiac death and the patient was initiated on combined immunosuppressive therapy. Owing to numerous comorbidities, she was determined to be unsuitable for a heart transplant. Unfortunately, she eventually died from complications secondary to the disease. CONCLUSIONS IGCM remains a challenging clinical diagnosis with a poor long-term outcome without heart transplantation. This case highlights the importance of considering atypical causes of heart failure in patients who do not respond to conventional therapies. Early recognition and appropriate management, involving medical and interventional approaches, are crucial in improving outcomes for patients with IGCM.

Routine screening for HLA Antibodies in Heart Transplant patients-Does it affect clinical decision making?

BACKGROUND: We aimed to assess outcomes in patients with and without donor specific antibodies (DSA) and to evaluate the relationship between DSA presence and graft function, cardiac allograft vasculopathy (CAV), and mortality. METHODS: The study population comprises 193 consecutive long-term heart transplanted (HTx) patients who underwent DSA surveillance between 2016 and 2022. The patients were prospectively screened for CAV through serial coronary angiograms, graft function impairment through serial echocardiograms, and cardiac biomarkers. The patients were followed from the first DSA measurement until death, 5 years follow-up or right censuring on the 30th of June 2023. RESULTS: DSAs were detected in 50 patients using a cut-off at MFI ≥1000 and 45 patients using a cut-off at ≥2000 MFI. The median time since HTx was 9.0 years [3.0-14.4]. DSA positive patients had poorer graft function and higher values of NT-proBNP and troponin T, and more prevalent CAV than DSA negative patients. In total, 25 patients underwent endomyocardial biopsies due to DSA presence while another eight patients underwent endomyocardial biopsies for other reasons. Histological antibody mediated rejection (AMR) signs were seen in three biopsies. During a median follow-up of five years [4.7-5], a total of 41 patients died. Mortality rates did not differ between DSA positive and DSA negative patients (HR 1.2, 95% CI .6-2.4). DSA positive patients were more likely to experience CAV progression than DSA negative patients (HR 2.7, 95% CI 1.5-4.8) CONCLUSIONS: Routine screening reveals DSA in approximately 25% of long-term HTx patients but is rarely related to histopathological AMR signs. DSA presence was associated with poorer graft function and more prevalent and progressive CAV. However, DSA positive patients had similar survival rates to DSA negative patients.

Cardiac allograft vasculopathy in heart transplant recipients from hepatitis C viremic donors.

BACKGROUND: Recent studies suggest the transplantation of Hepatitis C (HCV) hearts from viremic donors is associated with comparable 1 year survival to nonviremic donors. Though HCV viremia is a known risk factor for accelerated atherosclerosis, data on cardiac allograft vasculopathy (CAV) outcomes are limited. We compared the incidence of CAV in heart transplant recipients from HCV viremic donors (nucleic acid amplification test positive; NAT+) compared to non-HCV infected donors (NAT-). METHODS: We retrospectively reviewed annual coronary angiograms with intravascular ultrasound from April 2017 to August 2020 at two large cardiac transplant centers. CAV was graded according to ISHLT guidelines. Maximal intimal thickness (MIT) ≥ 0.5 mm was considered significant for subclinical disease. RESULTS: Among 270 heart transplant recipients (mean age 54; 77% male), 62 patients were transplanted from NAT+ donors. CAV ≥ grade 1 was present in 8.8% of the NAT+ versus 16.8% of the NAT- group at 1 year, 20% versus 28.8% at 2 years, and 33.3% versus 41.5% at 3 years. After adjusting for donor age, donor smoking history, recipient BMI, recipient, hypertension, and recipient diabetes, NAT+ status did not confer increased risk of CAV (HR.80; 95% CI.45-1.40, p = 0.43) or subclinical IVUS disease (HR.87; 95% CI.58-1.30, p = 0.49). Additionally, there was no difference in the presence of rapidly progressive lesions on IVUS. CONCLUSION: Our data show that NAT+ donors conferred no increased risk for early CAV or subclinical IVUS disease following transplantation in a cohort of heart transplant patients who were treated for HCV, suggesting the short-term safety of this strategy to maximize the pool of available donor hearts.

Use of induction therapy post-heart transplantation: Clinical practice recommendations based on systematic review and network meta-analysis of evidence.

BACKGROUND: The use of induction therapy (IT) agents in the early post-heart transplant period remains controversial. The following recommendations aim to provide guidance on the use of IT agents, including Basiliximab and Thymoglobulin, as part of routine care in heart transplantation (HTx). METHODS: We recruited an international, multidisciplinary panel of 15 stakeholders, including patient partners, transplant cardiologists and surgeons, nurse practitioners, pharmacists, and methodologists. We commissioned a systematic review on benefits and harms of IT on patient-important outcomes, and another on patients' values and preferences to inform our recommendations. We used the GRADE framework to summarize our findings, rate certainty in the evidence, and develop recommendations. The panel considered the balance between benefits and harms, certainty in the evidence, and patient's values and preferences, to make recommendations for or against the routine post-operative use of Thymoglobulin or Basiliximab. RESULTS: The panel made recommendations on three major clinical problems in HTx: (1) We suggest against the routine post-operative use of Basiliximab compared to no IT, (2) we suggest against the routine use of Thymoglobulin compared to no IT, and (3) for those patients for whom IT is deemed desirable, we suggest for the use of Thymoglobulin as compared to Basiliximab. CONCLUSION: This report highlights gaps in current knowledge and provides directions for clinical research in the future to better understand the clinical utility of IT agents in the early post heart transplant period, leading to improved management and care.

COVID-19 infection in patients with history of pediatric heart transplant in Germany, Austria, and Switzerland.

COVID-19 is a heterogenous infection-asymptomatic to fatal. While the course of pediatric COVID-19 infections is usually mild or even asymptomatic, individuals after adult heart transplantation are at high risk of a severe infection. We conducted a retrospective, multicenter survey of 16 pediatric heart transplant centers in Germany, Austria and Switzerland to evaluate the risk of a severe COVID-19 infection after pediatric heart transplantation between 02/2020 and 06/2021. Twenty-six subjects (11 male) with a median age of 9.77 years at time of transplantation and a median of 4.65 years after transplantation suffered from COVID-19 infection. The median age at time of COVID-10 infection was 17.20 years. Fourteen subjects had an asymptomatic COVID-19 infection. The most frequent symptoms were myalgia/fatigue (n = 6), cough (n = 5), rhinitis (n = 5), and loss of taste (n = 5). Only one subject showed dyspnea. Eleven individuals needed therapy in an outpatient setting, four subjects were hospitalized. One person needed oxygen supply, none of the subjects needed non-invasive or invasive mechanical ventilation. No specific signs for graft dysfunction were found by non-invasive testing. In pediatric heart transplant subjects, COVID-19 infection was mostly asymptomatic or mild. There were no SARS-CoV-2 associated myocardial dysfunction in heart transplant individuals.

Sex-Linked Differences in Cardiac Atrophy After Mechanical Unloading Induced by Heterotopic Heart Transplantation.

No information is available about sex-related differences in unloading-induced cardiac atrophy. We aimed to compare the course of unloading-induced cardiac atrophy in intact (without gonadectomy) male and female rats, and in animals after gonadectomy, to obtain insight into the influence of sex hormones on this process. Heterotopic heart transplantation (HT((x)) was used as a model for heart unloading. Cardiac atrophy was assessed as the weight ratio of heterotopically transplanted heart weight (HW) to the native HW on days 7 and 14 after HTx in intact male and female rats. In separate experimental groups, gonadectomy was performed in male and female recipient animals 28 days before HT(x) and the course of cardiac atrophy was again evaluated on days 7 and 14 after HT(x). In intact male rats, HT(x) resulted in significantly greater decreases in whole HW when compared to intact female rats. The dynamics of the left ventricle (LV) and right ventricle (RV) atrophy after HT(x) was quite similar to that of whole hearts. Gonadectomy did not have any significant effect on the decreases in whole HW, LV, and RV weights, with similar results in male and female rats. Our results show that the development of unloading-induced cardiac atrophy is substantially reduced in female rats when compared to male rats. Since gonadectomy did not alter the course of cardiac atrophy after HTx, similarly in both male and female rats, we conclude that sex-linked differences in the development of unloading-induced cardiac atrophy are not caused by the activity of sex hormones.

Acetylsalicylic acid use and development of cardiac allograft vasculopathy: A national prospective study using highly automated 3-D optical coherence tomography analysis.

BACKGROUND: There is conflicting evidence on the role of acetylsalicylic acid (ASA) use in the development of cardiac allograft vasculopathy (CAV). METHODS: A nationwide prospective two-center study investigated changes in the coronary artery vasculature by highly automated 3-D optical coherence tomography (OCT) analysis at 1 month and 12 months after heart transplant (HTx). The influence of ASA use on coronary artery microvascular changes was analyzed in the overall study cohort and after propensity score matching for selected clinical CAV risk factors. RESULTS: In total, 175 patients (mean age 52 ± 12 years, 79% male) were recruited. During the 1-year follow-up, both intimal and media thickness progressed, with ASA having no effect on its progression. However, detailed OCT analysis revealed that ASA use was associated with a lower increase in lipid plaque (LP) burden (p = .013), while it did not affect the other observed pathologies. Propensity score matching of 120 patients (60 patient pairs) showed similar results, with ASA use associated with lower progression of LPs (p = .002), while having no impact on layered fibrotic plaque (p = .224), calcification (p = .231), macrophage infiltration (p = .197), or the absolute coronary artery risk score (p = .277). According to Kaplan-Meier analysis, ASA use was not associated with a significant difference in survival (p = .699) CONCLUSION: This study showed a benefit of early ASA use after HTx on LP progression. However, ASA use did not have any impact on the progression of other OCT-observed pathologies or long-term survival.

Right ventricular dysfunction in left ventricular assist device candidates: is it time to change our prospective?

The use of left ventricular assist devices (LVAD) has significantly increased in the last years, trying to offer a therapeutic alternative to heart transplantation, in light also to the significant heart donor shortage compared to the growing advanced heart failure population. Despite technological improvements in the devices, LVAD-related mortality is still fairly high, with right heart failure being one of the predominant predictors. Therefore, many efforts have been made toward a thorough right ventricular (RV) evaluation prior to LVAD implant, considering clinical, laboratory, echocardiographic, and invasive hemodynamic parameters. However, there is high heterogeneity regarding both which predictor is the strongest as well as the relative cut-off values, and a consensus has not been reached yet, increasing the risk of facing patients in which the distinction between good or poor RV function cannot be surely reached. In parallel, due to technological development and availability of mechanical circulatory support of the RV, LVADs are being considered even in patients with suboptimal RV function. The aim of our review is to analyze the current evidence regarding the role of RV function prior to LVAD and its evaluation, pointing out the extreme variability in parameters that are currently assessed and future prospective regarding new diagnostic tools. Finally, we attempt to gather the available information on the therapeutic strategies to use in the peri-operative phase, in order to reduce the incidence of RV failure, especially in patients in which the preoperative evaluation highlighted some conflicting results with regard to ventricular function.

Composite CYP3A (CYP3A4 and CYP3A5) phenotypes and influence on tacrolimus dose adjusted concentrations in adult heart transplant recipients.

CYP3A5 genetic variants are associated with tacrolimus metabolism. Controversy remains on whether CYP3A4 increased [*1B (rs2740574), *1 G (rs2242480)] and decreased function [*22 (rs35599367)] genetic variants provide additional information. This retrospective cohort study aims to address whether tacrolimus dose-adjusted trough concentrations differ between combined CYP3A (CYP3A5 and CYP3A4) phenotype groups. Heart transplanted patients (n = 177, between 2008 and 2020) were included and median age was 54 years old. Significant differences between CYP3A phenotype groups in tacrolimus dose-adjusted trough concentrations were found in the early postoperative period and continued to 6 months post-transplant. In CYP3A5 nonexpressers, carriers of CYP3A4*1B or *1 G variants (Group 3) compared to CYP3A4*1/*1 (Group 2) patients were found to have lower tacrolimus dose-adjusted trough concentrations at 2 months. In addition, significant differences were found among CYP3A phenotype groups in the dose at discharge and time to therapeutic range while time in therapeutic range was not significantly different. A combined CYP3A phenotype interpretation may provide more nuanced genotype-guided TAC dosing in heart transplant recipients.

Waitlist Outcomes in Candidates With Rare Causes of Heart Failure After Implementation of the 2018 French Heart Allocation Scheme.

BACKGROUND: In 2018, an algorithm-based allocation system for heart transplantation (HT) was implemented in France. Its effect on access to HT of patients with rare causes of heart failure (HF) has not been assessed. METHODS: In this national study, including adults listed for HT between 2018 and 2020, we analyzed waitlist and posttransplant outcomes of candidates with rare causes of HF (restrictive cardiomyopathy [RCM], hypertrophic cardiomyopathy, and congenital heart disease). The primary end point was death on the waitlist or delisting for clinical deterioration. Secondary end points included access to HT and posttransplant mortality. The cumulative incidence of waitlist mortality estimated with competing risk analysis and incidence of transplantation were compared between diagnosis groups. The association of HF cause with outcomes was determined by Fine-Gray or Cox models. RESULTS: Overall, 1604 candidates were listed for HT. At 1 year postlisting, 175 patients met the primary end point and 1040 underwent HT. Candidates listed for rare causes of HF significantly differed in baseline characteristics and had more frequent score exceptions compared with other cardiomyopathies (31.3%, 32.0%, 36.4%, and 16.7% for patients with hypertrophic cardiomyopathy, RCM, congenital heart disease, and other cardiomyopathies). The cumulative incidence of death on the waitlist and probability of HT were similar between diagnosis groups (P=0.17 and 0.40, respectively). The adjusted risk of death or delisting for clinical deterioration did not significantly differ between candidates with rare and common causes of HF (subdistribution hazard ratio (HR): hypertrophic cardiomyopathy, 0.51 [95% CI, 0.19-1.38]; P=0.18; RCM, 1.04 [95% CI, 0.42-2.58]; P=0.94; congenital heart disease, 1.82 [95% CI, 0.78-4.26]; P=0.17). Similarly, the access to HT did not significantly differ between causes of HF (hypertrophic cardiomyopathy: HR, 1.18 [95% CI, 0.92-1.51]; P=0.19; RCM: HR, 1.19 [95% CI, 0.90-1.58]; P=0.23; congenital heart disease: HR, 0.76 [95% CI, 0.53-1.09]; P=0.14). RCM was an independent risk factor for 1-year posttransplant mortality (HR, 2.12 [95% CI, 1.06-4.24]; P=0.03). CONCLUSIONS: Our study shows equitable waitlist outcomes among HT candidates whatever the indication for transplantation with the new French allocation scheme.

Failing to Make the Grade: Conventional Cardiac Allograft Rejection Grading Criteria Are Inadequate for Predicting Rejection Severity.

BACKGROUND: Cardiac allograft rejection is the leading cause of early graft failure and is a major focus of postheart transplant patient care. While histological grading of endomyocardial biopsy samples remains the diagnostic standard for acute rejection, this standard has limited diagnostic accuracy. Discordance between biopsy rejection grade and patient clinical trajectory frequently leads to both overtreatment of indolent processes and delayed treatment of aggressive ones, spurring the need to investigate the adequacy of the current histological criteria for assessing clinically important rejection outcomes. METHODS: N=2900 endomyocardial biopsy images were assigned a rejection grade label (high versus low grade) and a clinical trajectory label (evident versus silent rejection). Using an image analysis approach, n=370 quantitative morphology features describing the lymphocytes and stroma were extracted from each slide. Two models were constructed to compare the subset of features associated with rejection grades versus those associated with clinical trajectories. A proof-of-principle machine learning pipeline-the cardiac allograft rejection evaluator-was then developed to test the feasibility of identifying the clinical severity of a rejection event. RESULTS: The histopathologic findings associated with conventional rejection grades differ substantially from those associated with clinically evident allograft injury. Quantitative assessment of a small set of well-defined morphological features can be leveraged to more accurately reflect the severity of rejection compared with that achieved by the International Society of Heart and Lung Transplantation grades. CONCLUSIONS: Conventional endomyocardial samples contain morphological information that enables accurate identification of clinically evident rejection events, and this information is incompletely captured by the current, guideline-endorsed, rejection grading criteria.