Isoproterenol Improves Hemodynamics And Right Ventricle-Pulmonary Artery Coupling After Heart Transplantation.

BACKGROUND: Right ventricular failure (RVF) is a major cause of early mortality after heart transplantation (HT). Isoproterenol has chronotropic, inotropic, and vasodilatory properties which might improve right ventricle function in this setting. We aimed to investigate the hemodynamic effects of isoproterenol on patients with post-HT RVF. METHODS: We conducted a one-year retrospective observational study including patients receiving isoproterenol and dobutamine for early RVF after HT. A comprehensive multiparametric hemodynamic evaluation was performed successively at three times: no isoproterenol, low doses: 0.025 µg/kg/min and high doses: 0.05 µg/kg/min (henceforth respectively called no-iso, low-iso and high-iso). RESULTS: From June 2022 to June 2023, 25 patients, median [IQR25-75] age 54 [38-61] years, were included. Before isoproterenol introduction, all patients received dobutamine and 15 (60%) were on veno-arterial extracorporeal membrane oxygenation. Isoproterenol significantly increased heart rate from 84 [77-99] (no-iso) to 91 [88-106] (low-iso) and 102 [90-122] bpm (high-iso, p<0.001). Similarly, cardiac index raised from 2.3 [1.4-3.1] to 2.7 [1.8-3.4] and 3 [1.9-3.7] l/min/m2 (p<0.001) with concomitant increase of indexed stroke volume (28 [17-34] to 31 [20-34] and 33 [23-35] mL/m2, p<0.05). Effective pulmonary arterial elastance and pressures were not modified by isoproterenol. Pulmonary vascular resistance tended to decrease from 2.9 (1.4-3.6) WU to 2.3 (1.3-3.5) WU, p=0.06. Right ventricular ejection fraction/systolic PAP evaluating RV-PA coupling increased after isoproterenol from 0.8 to 0.9 and 1 %.mmHg-1 (p=0.001). CONCLUSIONS: In post-HT RVF, isoproterenol exhibits chronotropic and inotropic effects, thereby improving RV-PA coupling and resulting in a clinically relevant increase in the cardiac index.

Perioperative Risk Factors of Acute Kidney Injury After Heart Transplantation and One-Year Clinical Outcomes: A Retrospective Cohort Study.

OBJECTIVES: This study aimed to identify perioperative risk factors of acute kidney injury after heart transplantation and to evaluate 1-year clinical outcomes. DESIGN: A retrospective single-center cohort study. SETTING: At a university hospital. PARTICIPANTS: All patients who underwent heart transplantation from January 2015 to December 2020. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The authors recorded acute kidney injury after heart transplantation. One-year mortality and renal function also were recorded. Risk factors of acute kidney injury were evaluated using a multivariate logistic regression model. Long-term survival was compared between patients developing acute kidney injury and those who did not, using a log-rank test. Among 209 patients included in this study, 134 patients (64% [95% CI (58; 71)]) developed posttransplantation acute kidney injury. Factors independently associated with acute kidney injury were high body mass index (odds ratio [OR]: 1.18 [1.02-1.38] per kg/m2; p = 0.030), prolonged duration of cold ischemic period (OR: 1.11 [1.01-1.24] per 10 minutes; p = 0.039), and high dose of intraoperative dobutamine support (OR: 1.24 [1.06-1.46] per µg/kg/min; p = 0.008). At 1 year, patients who developed postoperative acute kidney injury had higher mortality rates (20% v 8%, p = 0.015). Among 172 survivors at 1 year, 82 survivors (48%) had worsened their renal function compared with preheart transplantation. CONCLUSIONS: This study highlighted the high incidence of acute kidney injury after heart transplantation and its impact on patient outcomes. Risk factors such as body mass index, prolonged cold ischemic period duration, and level of inotropic support with dobutamine were identified, providing insights for preventive strategies.

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.

Report of the 2022 Banff Heart Concurrent: Focus on non-human leukocyte antigen antibodies in rejection and the pathology of "mixed" rejection.

The Banff Heart Concurrent Session, held as part of the 16th Banff Foundation for Allograft Pathology Conference at Banff, Alberta, Canada, on September 21, 2022, focused on 2 major topics: non-human leukocyte antigen (HLA) antibodies and mixed rejection. Each topic was addressed in a multidisciplinary fashion with clinical, immunological, and pathology perspectives and future developments and prospectives. Following the Banff organization model and principles, the collective aim of the speakers on each topic was to • Determine current knowledge gaps in heart transplant pathology • Identify limitations of current pathology classification systems • Discuss next steps in addressing gaps and refining classification system.

Banff Human Organ Transplant Consensus Gene Panel for the Detection of Antibody Mediated Rejection in Heart Allograft Biopsies.

The molecular refinement of the diagnosis of heart allograft rejection based on whole-transcriptome analyses faces several hurdles that greatly limit its widespread clinical application. The targeted Banff Human Organ Transplant gene panel (B-HOT, including 770 genes of interest) has been developed to facilitate reproducible and cost-effective gene expression analysis of solid organ allografts. We aimed to determine in silico the ability of this targeted panel to capture the antibody-mediated rejection (AMR) molecular profile using whole-transcriptome data from 137 heart allograft biopsies (71 biopsies reflecting the entire landscape of histologic AMR, 66 non-AMR control biopsies including cellular rejection and non-rejection cases). Differential gene expression, pathway and network analyses demonstrated that the B-HOT panel captured biologically and clinically relevant genes (IFNG-inducible, NK-cells, injury, monocytes-macrophage, B-cell-related genes), pathways (interleukin and interferon signaling, neutrophil degranulation, immunoregulatory interactions, endothelial activation) and networks reflecting the pathophysiological mechanisms underlying the AMR process previously identified in whole-transcriptome analysis. Our findings support the potential clinical use of the B-HOT-gene panel as a reliable proxy to whole-transcriptome analysis for the gene expression profiling of cardiac allograft rejection.

Diuretic dose is a strong prognostic factor in ambulatory patients awaiting heart transplantation.

AIMS: The prognostic value of 'high dose' loop diuretics in advanced heart failure outpatients is unclear. We aimed to assess the prognosis associated with loop diuretic dose in ambulatory patients awaiting heart transplantation (HT). METHODS AND RESULTS: All ambulatory patients (n = 700, median age 55 years and 70% men) registered on the French national HT waiting list between 1 January 2013 and 31 December 2019 were included. Patients were divided into 'low dose', 'intermediate dose', and 'high dose' loop diuretics corresponding to furosemide equivalent doses of ≤40, 40-250, and >250 mg, respectively. The primary outcome was a combined criterion of waitlist death and urgent HT. N-terminal pro-B-type natriuretic peptide, creatinine levels, pulmonary capillary wedge pressure, and pulmonary pressures gradually increased with higher diuretic dose. At 12 months, the risk of waitlist death/urgent HT was 7.4%, 19.2%, and 25.6% (P = 0.001) for 'low dose', 'intermediate dose', and 'high dose' patients, respectively. When adjusting for confounders, including natriuretic peptides, hepatic, and renal function, the 'high dose' group was associated with increased waitlist mortality or urgent HT [adjusted hazard ratio (HR) 2.23, 1.33 to 3.73; P = 0.002] and a six-fold higher risk of waitlist death (adjusted HR 6.18, 2.16 to 17.72; P < 0.001) when compared with the 'low dose' group. 'Intermediate doses' were not significantly associated with these two outcomes in adjusted models (P > 0.05). CONCLUSIONS: A 'high dose' of loop diuretics is strongly associated with residual congestion and is a predictor of outcome in patients awaiting HT despite adjustment for classical cardiorenal risk factors. This routine variable may be helpful for risk stratification of pre-HT patients.

Validation of the clinical utility of microRNA as noninvasive biomarkers of cardiac allograft rejection: A prospective longitudinal multicenter study.

While studies have shown an association between microRNAs and cardiac rejection, the clinical relevance of a preidentified miRNA signature as a noninvasive biomarker has never been assessed in prospective multicentric unselected cohorts. To address this unmet need, we designed a prospective study (NCT02672683) including recipients from 11 centers between August 2016 to March 2018. The objective was to validate the association between 3 previously identified circulating microRNA (10a, 92a, 155) and the histopathological diagnosis of rejection. Both relative and absolute (sensitivity analysis) quantifications of microRNAs were performed. Overall, 461 patients were included (831 biopsies, 79 rejections). A per-protocol interim analysis (258 biopsies, 49 rejections) did not find any association between microRNA and rejection (microRNA 10a: odds ratio (OR) = 1.05, 95% confidence intervals (CI) = 0.87-1.27, p = 0.61; 92a: OR = 0.98, 95%CI = 0.87-1.10, p = 0.68; 155: OR = 0.91, 95%CI = 0.76-1.10, p = 0.33). These results were confirmed in the sensitivity analysis. The analysis of the remaining sera was stopped for futility. This study shows no clinical utility of circulating microRNAs 10a, 92a, and 155 monitoring in heart allograft recipients.

Intermediate-term outcomes of complement inhibition for prevention of antibody-mediated rejection in immunologically high-risk heart allograft recipients.

Allosensitization represents a major barrier to heart transplantation. We previously reported favorable 1-year outcomes of complement inhibition at transplant in highly sensitized recipients. We now report a longer follow-up. In this single-arm trial (NCT02013037), 20 patients with panel reactive antibodies ≥70% and preformed donor-specific antibodies received eculizumab during the first 2 months post-transplant. The primary end-point was antibody-mediated rejection ≥ pAMR2 and/or left ventricular dysfunction. The median follow-up was 4.8 years. Beyond the first year post-transplant, there were no episodes of pAMR2 or greater and no Left Ventricular (LV) dysfunction. There were 3 deaths, 1 episode of pAMR1, and 1 patient with minimal de novo cardiac allograft vasculopathy. Compared to a matched control group, we observed a nonstatistically significant benefit of eculizumab with a lower incidence of the primary end-point or death (primary end-point: hazard ratio = 0.50, 95% confidence interval = 0.15-1.67, and p = 0.26; mortality: hazard ratio = 0.51, 95% confidence interval = 0.13-2.07, and p = 0.35). Our results support the utility of complement inhibition for high-immunological-risk recipients. CLINICAL TRIAL REGISTRATION: ClinincalTrials.gov, NCT02013037. https://clinicaltrials.gov/ct2/show/NCT02013037?term=eculizumab&cond=heart+transplantation&draw=2&rank=1.

Sudden cardiac death after heart transplantation: a population-based study.

AIMS: The epidemiology of sudden cardiac death (SCD) after heart transplantation (HTx) remains imprecisely described. We aimed to assess the incidence and determinants of SCD in a large cohort of HTx recipients, compared with the general population. METHODS AND RESULTS: Consecutive HTx recipients (n = 1246, 2 centres) transplanted between 2004 and 2016 were included. We prospectively assessed clinical, biological, pathologic, and functional parameters. SCD was centrally adjudicated. We compared the SCD incidence beyond the first year post-transplant in this cohort with that observed in the general population of the same geographic area (registry carried out by the same group of investigators; n = 19 706 SCD). We performed a competing risk multivariate Cox model to identify variables associated with SCD. The annual incidence of SCD was 12.5 per 1,000 person-years [95% confidence interval (CI), 9.7-15.9] in the HTx recipients cohort compared with 0.54 per 1,000 person-years (95% CI, 0.53-0.55) in the general population (P < 0.001). The risk of SCD was markedly elevated among the youngest HTx recipients with standardized mortality ratios for SCD up to 837 for recipients ≤30 years. Beyond the first year, SCD was the leading cause of death. Five variables were independently associated with SCD: older donor age (P = 0.003), younger recipient age (P = 0.001) and ethnicity (P = 0.034), pre-existing donor-specific antibodies (P = 0.009), and last left ventricular ejection fraction (P = 0.048). CONCLUSION: HTx recipients, particularly the youngest, were at very high risk of SCD compared with the general population. The consideration of specific risk factors may help identify high-risk subgroups.

Association between vasoactive-inotropic score, morbidity and mortality after heart transplantation.

OBJECTIVES: The aim of this study was to evaluate the association between vasoactive-inotropic score (VIS), calculated in the 24 h after heart transplantation, and post-transplant mortality and morbidity. METHODS: This was an observational single-centre retrospective study. Patients admitted to surgical intensive care unit after transplantation, between January 2015 and December 2018, were reviewed consecutively. VISmax was calculated as dopamine+ dobutamine+ 100 × epinephrine + 100 × norepinephrine + 50 × levosimendan + 10 × milrinone (all in µg/kg/min) + 10 000 × vasopressin (units/kg/min), using the maximum dosing rates of vasoactive and inotropic medications in the 24 h after intensive care unit admission. The primary outcome was mortality at 1 year post-transplant. The secondary outcomes included length of stay, duration of mechanical ventilation and inotropic support and the occurrence of septic shock, ventilator-associated pneumonia, bloodstream infection or renal replacement therapy. RESULTS: A total of 151 patients underwent heart transplantation and admitted to intensive care unit. The median VISmax was 39.2 (interquartile range = 19.4-83.0). VISmax was independently associated with 1-year post-transplant mortality, as well as recipient age [hazard ratio (HR) = 1.004, P-value = 0.013], recipient gender (female to male: hazard ratio = 2.23, P-value = 0.047) and combined transplantation (hazard ratio = 2.85, P-value = 0.048). There was a significant association between VISmax and duration of mechanical ventilation (P-value < 0.001), length of stay (P-value = 0.002), duration of infused inotropes (P-value < 0.001), occurrence of bloodstream infections, septic shocks, ventilation-acquired pneumonia and renal replacement therapy. CONCLUSIONS: VISmax calculated during the first 24 h after postoperative intensive care unit admission in transplanted patients is independently associated with 1-year mortality. In addition, length of stay, duration of mechanical ventilation and infused inotropes increased with increasing VISmax.

Practical application of the French two-score heart allocation scheme: Insights from a high-volume heart transplantation centre.

BACKGROUND: In 2018, a cardiac allocation scheme based on an individual score considering the risk of death both on the waitlist and after heart transplantation was implemented in France. AIMS: To analyse the practical application of the pre- and post-transplant risk score in a French high-volume heart transplantation centre. METHODS: All consecutive adult patients listed for a first non-combined heart transplantation between 02 January 2018 and 30 June 2022 at our centre were included. Baseline characteristics of candidates and recipients were retrieved from the national CRISTAL registry. Both scores were calculated at listing and at transplant. RESULTS: Overall, 364 patients were included. During follow-up, 257 patients (70.6%) were transplanted, and 57 (15.6%) died or were removed from the waitlist. Post-transplant 3-month survival was 84.8%. Total bilirubin and natriuretic peptides had the most important weight in the pretransplant risk score. This score had a major impact on waitlist outcomes: quartile 1 was characterized by low access to heart transplantation (58.2%) and risk of death on the waitlist (9.9%) compared with quartile 4 (heart transplantation rate 74.1%, mortality on the waiting list>20%). According to the post-transplant risk score, a minimal number of candidates were considered ineligible for heart transplantation (<1%), but 12.4% were contraindicated to at least one donor category. The number of contraindicated donor categories had a significant impact on waitlist outcomes. Although adequately calibrated, the post-transplant score had a limited discrimination (area under the curve 0.65, 95% confidence interval 0.59-0.71). CONCLUSION: Our results highlight the major impact of pre- and post-transplantation risk scores on waitlist outcomes following the allocation scheme update.

Severity of SARS-CoV-2 Omicron variant infection in heart transplant recipients.

SARS-CoV-2 Omicron variant was first detected in France mid-November 2021 in wastewater treatment plants while cases started to increase at the beginning of December. The maximum incidence occurred in mid-January 2022. The Omicron wave spread rapidly throughout France in general population with lower case-fatality rate compared with previous waves. Little is known about infection with Omicron variant in heart transplant (HT) recipients. In this study, we examined incidence and mortality rate of COVID-19 in the general population and among 1,263 HT recipients during the period from June, 2021 to February, 2022, described characteristics of HT recipients infected with SARS-CoV-2 during Omicron (December 1st, 2021-February 7, 2022) and Delta (June 1st- November 30, 2021) periods, and compared hospital course of HT recipients with Omicron and Delta variant infection. Our findings contrast with the reported lower severity for Omicron variant infection compared with Delta variant infection in immunocompetent individuals.

Impact of the 2018 French two-score allocation scheme on the profile of heart transplantation candidates and recipients: Insights from a high-volume centre.

BACKGROUND: In 2018, a new cardiac allograft allocation scheme, based on an individual scoring system, considering the risk of death both on the waiting list and after heart transplantation, was implemented in France. AIM: To assess the impact of this new scheme on the profile of transplantation candidates and recipients. METHODS: In this single-centre retrospective study, we included consecutive patients listed and/or transplanted between 01 January 2012 and 30 September 2021 at La Pitié-Salpêtrière Hospital. Baseline characteristics of patients were retrieved from the national CRISTAL registry and were compared according to the type of allocation scheme (before or after 2018). RESULTS: A total of 1098 newly listed transplantation candidates and 855 transplant recipients were included. One-year mortality rates after listing and after transplantation were 12.4% and 20%, respectively. At listing, the proportion of candidates on inotropes significantly declined following the scheme update (26.3 versus 20.9%; P=0.038), reflecting a change in medical practice. At transplantation, recipients had worse kidney function (estimated glomerular filtration rate<60mL/min/1.73 m2: old scheme, 29.7%; new scheme, 46.4%; P<0.001) and were more likely to be on extracorporeal membrane oxygenation support (33.5% versus 28.1%; P=0.080) under the new scheme, reflecting the prioritization of more severe patients. Outcomes after transplantation were not significantly influenced by the allocation system. CONCLUSIONS: The implementation of the 2018 French allocation scheme had a limited impact on the profile of transplantation candidates, but selected more severe patients for transplantation without significant impact on outcomes after transplantation.

Clinical course of arrhythmogenic right ventricular cardiomyopathy with end-stage heart failure and outcome after heart transplantation.

BACKGROUND: Few data exist on the characteristics and outcomes of patients with arrhythmogenic right ventricular cardiomyopathy and advanced heart failure who undergo heart transplantation. AIM: To explore the pretransplant course and outcomes of patients with arrhythmogenic right ventricular cardiomyopathy after heart transplantation. METHODS: This observational retrospective monocentric study included all consecutive patients with arrhythmogenic right ventricular cardiomyopathy who underwent heart transplantation during a 13-year period (2006-2019) at Pitié-Salpêtrière University Hospital (Paris). RESULTS: A total of 23 patients with arrhythmogenic right ventricular cardiomyopathy underwent heart transplantation between 2006 and 2019. The median time from diagnosis to heart transplantation was 9 years, and the median age at transplantation was 50 years. At diagnosis, half of the patients had left ventricular dysfunction, 59% had extensive T-wave inversion and 43% had a history of sustained ventricular tachycardia. Only five patients were involved in intensive sport activity. Indications for heart transplantation were end-stage biventricular dysfunction in 13 patients, end-stage right ventricular heart failure in seven and electrical storm in three. Only three patients had pulmonary hypertension, and half of the patients had atrial arrhythmias. The survival rate 1 year after heart transplantation was 74% (95% confidence interval 53-88%). Eight patients experienced primary graft dysfunction needing extracorporeal membrane oxygenation. CONCLUSIONS: Patients with arrhythmogenic right ventricular cardiomyopathy who eventually needed heart transplantation mostly exhibited extended disease with biventricular dysfunction at diagnosis. Intensive sport activity did not seem to be a major determinant. Advanced heart failure usually occurred late in the course of the disease. Primary graft dysfunction after heart transplantation was frequent, and should be anticipated. Additional data are needed to identify the optimal timing for heart transplantation and predictors of end-stage heart failure in patients with arrhythmogenic right ventricular cardiomyopathy.

Clinical Prediction Model for Antibody-Mediated Rejection: A Strategy to Minimize Surveillance Endomyocardial Biopsies After Heart Transplantation.

BACKGROUND: In heart transplantation, antibody-mediated rejection (AMR) is a major contributor to patient morbidity and mortality. Multiple routine endomyocardial biopsies (EMB) remain the gold standard to detect AMR, but this invasive procedure suffers from many limitations. We aimed to develop and validate an AMR risk model to improve individual risk stratification of AMR. METHODS: Heart recipients from 2 referral transplant centers, Cedars-Sinai (US) and Pitié-Salpêtrière (France), were included from 2012 to 2019. Database included detailed clinical, immunologic, imaging, and histological parameters. The US cohort was randomly distributed in a derivation (2/3) and in a test set (1/3). The primary end point was biopsy-proven AMR. A mixed effect logistic regression model with a random intercept was applied to identify variables independently associated with AMR. Simulation analyzes were performed. RESULTS: The US and French cohorts comprised a total of 1341 patients, representing 12 864 EMB. Overall, 490 AMR episodes were diagnosed (3.8% of EMB). Among the 26 potential determinants of AMR, 5 variables showed independent association: time post-transplant (P<0.001), pretransplant sensitizing event (P=0.001), circulating donor-specific anti-human leukocyte antigen antibody (P=0.001), graft dysfunction (P=0.004), and prior history of definite AMR (P<0.001). In the US test set, the calibration and the discrimination of the model were accurate (area under the curve, 0.79 [95% CI, 0.78-0.81]). Those results were confirmed in the external validation cohort (area under the curve, 0.78 [95% CI, 0.77-0.79]) and reinforced by various sensitivity analyses. The model also showed good performance to predict overall cause of rejection. Simulation models revealed that the AMR risk model could safely reduce the number of EMB. CONCLUSIONS: Our results support the use of the AMR risk model as a clinical decision tool to minimize the number of routine EMB after heart transplantation.

A Review of Biomarkers of Cardiac Allograft Rejection: Toward an Integrated Diagnosis of Rejection.

Despite major advances in immunosuppression, allograft rejection remains an important complication after heart transplantation, and it is associated with increased morbidity and mortality. The gold standard invasive strategy to monitor and diagnose cardiac allograft rejection, based on the pathologic evaluation of endomyocardial biopsies, suffers from many limitations including the low prevalence of rejection, sample bias, high inter-observer variability, and international working formulations based on arbitrary cut-offs that simplify the landscape of rejection. The development of innovative diagnostic and prognostic strategies-integrating conventional histology, molecular profiling of allograft biopsy, and the discovery of new tissue or circulating biomarkers-is one of the major challenges of translational medicine in solid organ transplantation, and particularly in heart transplantation. Major advances in the field of biomarkers of rejection have paved the way for a paradigm shift in the monitoring and diagnosis of cardiac allograft rejection. We review the recent developments in the field, including non-invasive biomarkers to minimize the number of protocol endomyocardial biopsies and tissue biomarkers as companion tools of pathology to refine the diagnosis of cardiac rejection. Finally, we discuss the potential role of these biomarkers to provide an integrated bio-histomolecular diagnosis of cardiac allograft rejection.