Redefining the molecular rejection states in 3230 heart transplant biopsies: Relationships to parenchymal injury and graft survival.

The first-generation Molecular Microscope (MMDx) system for heart transplant endomyocardial biopsies used expression of rejection-associated transcripts (RATs) to diagnose not only T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR) but also acute injury. However, the ideal system should detect rejection without being influenced by injury, to permit analysis of the relationship between rejection and parenchymal injury. To achieve this, we developed a new rejection classification in an expanded cohort of 3230 biopsies: 1641 from INTERHEART (ClinicalTrials.gov NCT02670408), plus 1589 service biopsies added to improve the power of the machine learning algorithms. The new system used 6 rejection classifiers instead of RATs and generated 7 rejection archetypes: No rejection, 48%; Minor, 24%; TCMR1, 2.3%; TCMR2, 2.7%; TCMR/mixed, 2.7%; early-stage ABMR, 3.9%; and fully developed ABMR, 16%. Using rejection classifiers eliminated cross-reactions with acute injury, permitting separate assessment of rejection and injury. TCMR was associated with severe-recent injury and late atrophy-fibrosis and rarely had normal parenchyma. ABMR was better tolerated, seldom producing severe injury, but in later biopsies was often associated with atrophy-fibrosis, indicating long-term risk. Graft survival and left ventricular ejection fraction were reduced not only in hearts with TCMR but also in hearts with severe-recent injury and atrophy-fibrosis, even without rejection.

Identifying High-Risk Patients for Severe Pulmonary Complications after Cardiosurgical Procedures as a Target Group for Further Assessment of Lung-Protective Strategies.

OBJECTIVES: It remains unclear whether intraoperative lung-protective strategies can reduce the rate of respiratory complications after cardiac surgery, partly because low-risk patients have been studied in the past. The authors established a screening model to easily identify a high-risk group for severe pulmonary complications (ie, pneumonia or acute respiratory distress syndrome) that may be the ideal target population for the assessment of the potential benefits of such measures. DESIGN: Retrospective observational trial. SETTING: Departments of cardiac surgery and cardiac anesthesia of a university hospital. PARTICIPANTS: Consecutive patients undergoing cardiac surgery on cardiopulmonary bypass and subsequent treatment at a dedicated cardiosurgical intensive care unit between January 2019 and March 2021. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of the 2,572 patients undergoing surgery, 84 (3.3%) developed pneumonia/acute respiratory distress syndrome that significantly affected the outcome (ie, longer ventilatory support [66% vs 11%], higher reintubation rate [39% vs 3%]), prolonged length of intensive care unit [33 ± 36 vs 4 ± 10 days] and hospital stay [10 ± 15 vs 6 ± 7 days], and higher in-hospital [43% vs 9%] as well as 30-day [7% vs 3%] mortality). The screening model for severe pulmonary complications included left ventricular ejection fraction <52%, EuroSCORE II (European System for Cardiac Operative Risk Evaluation II) >5.9, cardiopulmonary bypass time >123 minutes, left ventricular assist device or aortic repair surgery, and bronchodilatory therapy. A cutoff for the predicted risk of 2.5% showed optimal sensitivity and specificity, with an area under the receiver operating characteristic curve of 0.82. CONCLUSIONS: The authors suggest that future research on intraoperative lung-protective measures focuses on this high-risk population, primarily aiming to mitigate severe forms of postoperative pulmonary dysfunction associated with poor outcomes and increased resource consumption.

Disparities in donor heart acceptance between the USA and Europe: clinical implications.

BACKGROUND AND AIMS: Given limited evidence and lack of consensus on donor acceptance for heart transplant (HT), selection practices vary widely across HT centres in the USA. Similar variation likely exists on a broader scale-across countries and HT systems-but remains largely unexplored. This study characterized differences in heart donor populations and selection practices between the USA and Eurotransplant-a consortium of eight European countries-and their implications for system-wide outcomes. METHODS: Characteristics of adult reported heart donors and their utilization (the percentage of reported donors accepted for HT) were compared between Eurotransplant (n = 8714) and the USA (n = 60 882) from 2010 to 2020. Predictors of donor acceptance were identified using multivariable logistic regression. Additional analyses estimated the impact of achieving Eurotransplant-level utilization in the USA amongst donors of matched quality, using probability of acceptance as a marker of quality. RESULTS: Eurotransplant reported donors were older with more cardiovascular risk factors but with higher utilization than in the USA (70% vs. 44%). Donor age, smoking history, and diabetes mellitus predicted non-acceptance in the USA and, by a lesser magnitude, in Eurotransplant; donor obesity and hypertension predicted non-acceptance in the USA only. Achieving Eurotransplant-level utilization amongst the top 30%-50% of donors (by quality) would produce an additional 506-930 US HTs annually. CONCLUSIONS: Eurotransplant countries exhibit more liberal donor heart acceptance practices than the USA. Adopting similar acceptance practices could help alleviate the scarcity of donor hearts and reduce waitlist morbidity in the USA.

Evaluation of perivascular fat attenuation with coronary CT angiography in cardiac transplantation patients: an imaging biomarker candidate for prediction of cardiac mortality and re-transplantation.

OBJECTIVES: In cardiac transplant recipients, non-invasive allograft surveillance for identifying patients at risk for graft failure remains challenging. The fat attenuation index (FAI) of the perivascular adipose tissue in coronary computed tomography angiography (CCTA) predicts outcomes in coronary artery disease in non-transplanted hearts; however, it has not been evaluated in cardiac transplant patients. METHODS: We followed 39 cardiac transplant patients with two or more CCTAs obtained between 2010 and 2021. We performed FAI measurements around the proximal 4 cm segments of the left anterior descending (LAD), right coronary artery (RCA), and left circumflex artery (LCx) using a previously validated methodology. The FAI was analyzed at a threshold of - 30 to - 190 Hounsfield units. RESULTS: FAI measurements were completed in 113 CCTAs, obtained on two same-vendor CT models. Within each CCTA, the FAI values between coronary vessels were strongly correlated (RCA and LAD R = 0.67 (p < 0.0001), RCA and LCx R = 0.58 (p < 0.0001), LAD and LCx R = 0.67 (p < 0.0001)). The FAIs of each coronary vessel between the patient's first and last CCTA completed at 120 kV were also correlated (RCA R = 0.73 (p < 0.0001), LAD R = 0.81 (p < 0.0001), LCx R = 0.55 (p = 0.0069). Finally, a high mean FAI value of all three coronary vessels at baseline (mean ≥ - 71 HU) was predictive of cardiac mortality or re-transplantation, however, not predictive of all cause-mortality. CONCLUSION: High baseline FAI values may identify a higher-risk cardiac transplant population; thus, FAI may support the implementation of CCTA in post-transplant surveillance. KEY POINT: • Perivascular fat attenuation measured with coronary CT is feasible in cardiac transplant patients and may predict cardiac mortality or need for re-transplantation.

Heart transplantation: focus on donor recovery strategies, left ventricular assist devices, and novel therapies.

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.

Medical decisions in organ donors and heart transplant candidates with history of COVID-19 infection: An international practice survey.

BACKGROUND: A growing proportion of transplant donors and recipients have a history of COVID-19 infection. This study sought to characterize clinical practice after recipient or donor COVID-19 infection. METHODS: An online survey was distributed to heart transplant clinicians through a professional society message board and social media. Responses were collected between September 29 and November 5, 2021. RESULTS: There were 222 health care professionals (68% transplant cardiologists, 22% transplant surgeons, 10% other) across diverse geographic regions who completed the survey. While there was significant variation in donor acceptance, as it relates to past and current COVID-19 infection, the respondents were fairly cautious: 28% would not typically accept a donor with a history of COVID-19 regardless of the infection course and > 80% would not accept donors who had evidence of myocardial dysfunction during past COVID-19 infection, or who died of COVID-19 or its complications. The timing of candidate reactivation on the waiting list after COVID-19 infection also varied and often diverged from scenarios addressed by social guidelines. Eighty-one percent of the respondents felt COVID-19 vaccine should be mandatory before transplant, but this rate varied by geographic region. CONCLUSION: Our results reflect evolving experience of the heart transplant field at a time of lack of high-quality evidence. In the absence of longer-term outcome data for donors and transplant candidates with history of COVID-19 infection, clinicians remain cautious; however, this approach will likely need to be refined as an increasing proportion of the population will continue to be infected with COVID-19.

Extracorporeal Photopheresis With Low-Dose Immunosuppression in High-Risk Heart Transplant Patients-A Pilot Study.

In severely ill patients undergoing urgent heart transplant (HTX), immunosuppression carries high risks of infection, malignancy, and death. Low-dose immunosuppressive protocols have higher rejection rates. We combined extracorporeal photopheresis (ECP), an established therapy for acute rejection, with reduced-intensity immunosuppression. Twenty-eight high-risk patients (13 with high risk of infection due to infection at the time of transplant, 7 bridging to transplant via extracorporeal membrane oxygenation, 8 with high risk of malignancy) were treated, without induction therapy. Prophylactic ECP for 6 months (24 procedures) was initiated immediately postoperatively. Immunosuppression consisted of low-dose tacrolimus (8-10 ng/ml, months 1-6; 5-8 ng/ml, >6 months) with delayed start; mycophenolate mofetil (MMF); and low maintenance steroid with delayed start (POD 7) and tapering in the first year. One-year survival was 88.5%. Three patients died from infection (POD 12, 51, 351), and one from recurrence of cancer (POD 400). Incidence of severe infection was 17.9% (n = 5, respiratory tract). Within the first year, antibody-mediated rejection was detected in one patient (3.6%) and acute cellular rejection in four (14.3%). ECP with reduced-intensity immunosuppression is safe and effective in avoiding allograft rejection in HTX recipients with risk of severe infection or cancer recurrence.

Single Donor Infusion of S-Nitroso-Human-Serum-Albumin Attenuates Cardiac Isograft Fibrosis and Preserves Myocardial Micro-RNA-126-3p in a Murine Heterotopic Heart Transplant Model.

Objectives: Cold ischemia and subsequent reperfusion injury are non-immunologic cornerstones in the development of graft injury after heart transplantation. The nitric oxide donor S-nitroso-human-serum-albumin (S-NO-HSA) is known to attenuate myocardial ischemia-reperfusion (I/R)-injury. We assessed whether donor preservation with S-NO-HSA affects isograft injury and myocardial expression of GATA2 as well as miR-126-3p, which are considered protective against vascular and endothelial injury. Methods: Donor C57BL/6 mice received intravenous (0.1 µmol/kg/h) S-NO-HSA (n = 12), or 0.9% saline (control, n = 11) for 20 min. Donor hearts were stored in cold histidine-tryptophan-α-ketoglutarate-N solution for 12 h and underwent heterotopic, isogenic transplantation, except 5 hearts of each group, which were analysed immediately after preservation. Fibrosis was quantified and expression of GATA2 and miR-126-3p assessed by RT-qPCR after 60 days or immediately after preservation. Results: Fibrosis was significantly reduced in the S-NO-HSA group (6.47% ± 1.76 vs. 11.52% ± 2.16; p = 0.0023; 12 h-S-NO-HSA-hHTX vs. 12 h-control-hHTX). Expression of miR-126-3p was downregulated in all hearts after ischemia compared to native myocardium, but the effect was significantly attenuated when donors received S-NO-HSA (1 ± 0.27 vs. 0.33 ± 0.31; p = 0.0187; 12 h-S-NO-HSA-hHTX vs. 12 h-control-hHTX; normalized expression to U6 snRNA). Conclusion: Donor pre-treatment with S-NO-HSA lead to reduced fibrosis and preservation of myocardial miR-126-3p and GATA2 levels in murine cardiac isografts 60 days after transplantation.

Perioperative Risk Factors for Intensive Care Unit Readmissions and Mortality After Cardiac Surgery.

OBJECTIVE: The aim of this study was to identify perioperative risk factors associated with intensive care unit readmission and in-hospital death after cardiac surgery. DESIGN: Retrospective analysis using a multivariate regression model to identify independent risk factors for intensive care unit [ICU] readmission and in-hospital mortality. SETTING: The study was carried out in a single tertiary-care hospital. PARTICIPANTS: This was an analysis of 2,789 adult patients. INTERVENTIONS: All patients underwent cardiac surgery and were admitted to the intensive care unit perioperatively at the General Hospital Vienna. MEASUREMENTS AND MAIN RESULTS: Among the 2,789 patients included in the analysis, 167 (6%) were readmitted to the intensive care unit during the same hospital stay. Preoperative risk factors associated with ICU readmission included end-stage renal failure (odds ratio [OR] 2.80, 95% CI: 1.126-6.964), arrhythmia (OR 1.59, 95% CI: 1.019-2.480), chronic obstructive pulmonary disease (OR 1.51, 95% CI: 1.018-2.237), age >80 (OR 2.55, 95% CI: 1.189-5.466), and European System for Cardiac Operative Risk Evaluation II >8 (OR 1.40, 95% CI: 1.013-1.940). Readmitted patients were more likely to die than nonreadmitted patients (OR 5.3, 95% CI: 3.284-8.558). In-hospital mortality in readmitted patients was 19.2%, whereas that in the nonreadmitted study population was 5.1%. CONCLUSION: Preoperative risk assessment is crucial for identifying cardiac surgery patients at risk of ICU readmission and in-hospital death. The potentially modifiable risk factors pinpointed by this study call for the optimization of care before surgery and after ICU discharge.

Safety and image quality of cardiovascular magnetic resonance imaging in patients with retained epicardial pacing wires after heart transplantation.

BACKGROUND: Temporary epicardial pacing wires, implemented in patients during heart transplantation, are routinely removed before discharge. However, in some cases, these wires may remain in situ and are often considered as a contraindication for cardiovascular magnetic resonance (CMR) imaging in the future. Therefore, we aimed to provide data about safety and image quality of CMR in these patients. METHODS: This is a report on a subpopulation out of 88 patients after heart transplantation that were included in a prospective cohort study and underwent multiple CMR in their post-transplant course. During CMR, patients were monitored by electrocardiogram and all examinations were observed by a physician to document potential adverse events. Additionally, image quality was assessed by an imaging specialist. RESULTS: Nineteen of 88 patients included had temporary pacing wires in situ. These patients underwent a total of 51 CMR studies. No major adverse event and only one single, mild sensory event could be documented. All CMR studies showed preserved diagnostic image quality. Temporary pacing wires were visible in 100% of HASTE and cine sequences. In less than 50% of the examinations, temporary pacing wires were also visible in T1 and T2 mapping, short tau inversion recovery (STIR), and late gadolinium enhancement (LGE) sequences, without any impairment of image quality. CONCLUSIONS: With a low event rate of only one mild adverse event during 51 CMR examinations (2%), CMR appears to be safe in patients with retained temporary epicardial pacing wires after heart transplantation. Moreover, image quality was not impaired by the presence of pacing wires.

The adapted Heart Donor Score.

The Heart Donor Score (HDS) predicts donor organ discard for medical reasons and survival after heart transplantation (HTX) in the Eurotransplant allocation system. Our aim was to adapt the HDS for application in the United Network for Organ Sharing (UNOS) registry. To adjust for differences between the Eurotransplant and UNOS registries, the "adapted HDS" was created (aHDS) by exclusion of the covariates "valve function," "left-ventricular hypertrophy," and exclusion of "drug abuse" from the variable "compromised history." Two datasets were analyzed to evaluate associations of the aHDS with donor organ discard (n = 70 948) and survival (n = 19 279). The aHDS was significantly associated with donor organ discard [odds ratio 2.72, 95% confidence interval (CI) 2.68-2.76, P < 0.001; c-statistic: 0.937). The score performed comparably in donors <60 and ≥60 years of age. The aHDS was a significant predictor of survival as evaluated by univariate Cox proportional hazards analysis (hazard ratio 1.04, 95% CI 1.01-1.07, P = 0.023), although the association lost significance in a multivariable model. The aHDS predicts donor organ discard. Negative effects of most aHDS components on survival are likely eliminated by highly accurate donor selection processes.

Mass Spectrometry-Based Redox and Protein Profiling of Failing Human Hearts.

Oxidative stress contributes to detrimental functional decline of the myocardium, leading to the impairment of the antioxidative defense, dysregulation of redox signaling, and protein damage. In order to precisely dissect the changes of the myocardial redox state correlated with oxidative stress and heart failure, we subjected left-ventricular tissue specimens collected from control or failing human hearts to comprehensive mass spectrometry-based redox and quantitative proteomics, as well as glutathione status analyses. As a result, we report that failing hearts have lower glutathione to glutathione disulfide ratios and increased oxidation of a number of different proteins, including constituents of the contractile machinery as well as glycolytic enzymes. Furthermore, quantitative proteomics of failing hearts revealed a higher abundance of proteins responsible for extracellular matrix remodeling and reduced abundance of several ion transporters, corroborating contractile impairment. Similar effects were recapitulated by an in vitro cell culture model under a controlled oxygen atmosphere. Together, this study provides to our knowledge the most comprehensive report integrating analyses of protein abundance and global and peptide-level redox state in end-stage failing human hearts as well as oxygen-dependent redox and global proteome profiles of cultured human cardiomyocytes.

Molecular-level HLA mismatch is associated with rejection and worsened graft survival in heart transplant recipients - a retrospective study.

The aim was to evaluate the association of molecular-level human leukocyte antigen (HLA) mismatching with post-transplant graft survival, rejection, and cardiac allograft vasculopathy (CAV). We retrospectively analyzed all primary cardiac transplant recipients between 01/1984-06/2016. 1167 patients fulfilled inclusion criteria and had HLA typing information available. In 312 donor-recipient pairs, typing at serological split antigen level was available. We used the Epitope MisMatch Algorithm to calculate the number of amino acid differences in antibody-verified HLA eplets (amino acid mismatch load (AAMM)) between donor and recipient. Patients with a higher HLA-DR AAMM load had inferior 1-year graft survival (hazard ratio [HR], 1.14; 95% confidence interval [CI], 1.01-1.28). The HLA-AB AAMM load showed no impact on graft survival. In the subgroup with available split-level information, we observed an inferior graft survival for a higher HLA-DR AAMM load 3 months after transplantation (HR, 1.22; 95% CI, 1.04-1.44) and a higher risk for rejection for an increasing HLA-AB (HR, 1.70; 95% CI, 1.29-2.24) and HLA-DR (HR, 1.32; 95% CI, 1.09-1.61) AAMM load. No impact on the development of CAV was found. Molecular-level HLA mismatch analysis could serve as a tool for risk stratification after heart transplantation and might take us one step further into precision medicine.

Donation after circulatory death today: an updated overview of the European landscape.

Donation after circulatory death (DCD) has become an accepted practice in many countries and remains a focus of intense interest in the transplant community. The present study is aimed at providing a description of the current situation of DCD in European countries. Specific questionnaires were developed to compile information on DCD practices, activities and post-transplant outcomes. Thirty-five countries completed the survey. DCD is practiced in 18 countries: eight have both controlled DCD (cDCD) and uncontrolled DCD (uDCD) programs, 4 only cDCD and 6 only uDCD. All these countries have legally binding and/or nonbinding texts to regulate the practice of DCD. The no-touch period ranges from 5 to 30 min. There are variations in ante and post mortem interventions used for the practice of cDCD. During 2008-2016, the highest DCD activity was described in the United Kingdom, Spain, Russia, the Netherlands, Belgium and France. Data on post-transplant outcomes of patients who receive DCD donor kidneys show better results with grafts obtained from cDCD versus uDCD donors. In conclusion, DCD is becoming increasingly accepted and performed in Europe, importantly contributing to the number of organs available and providing acceptable post-transplantation outcomes.

Transplanted stents: a case report.

BACKGROUND: An optimal donor work-up to exclude preexisting conditions is recommended, but urgency and technical equipment in donor centers must be considered. We report a case of two coronary stents present in the donor heart and the related long-term outcome. CASE PRESENTATION: A 59-year-old European male patient suffering from dilated cardiomyopathy with severely reduced left ventricular function and presenting with NYHA III underwent cardiac transplantation in 2004. At the one-year follow-up, during routine cardiac catheterization, two stents were found, one in the right coronary artery and one in the circumflex artery, in the patient's transplanted heart. As no stent implantation was performed since transplantation, these were present prior to transplantation and had been transplanted without causing clinical signs. One of the stents showed in-stent restenosis, and the patient received an additional stent 7 years after transplantation. The other stent still showed a good result, and no further intervention has been required so far. The patient is currently in good clinical condition. CONCLUSION: This is the first case report of favorable long-term stented coronary arteries prior to transplantation. This case highlights the importance of the donor work-up and meticulous palpation of the coronary arteries during donor evaluation.

Acute oxygenator occlusion in two cases of polycythemia vera: Bailout strategies.

Polycytemia vera (PV) is a rare myeloproliferative neoplasm associated with microcirculatory disturbances, thrombosis and bleeding. Patients suffering from PV have a high risk of perioperative adverse events, but the literature regarding on-pump procedures in PV patients is scarce. We report two cases of acute and severe oxygenator failure during cardiopulmonary bypass and present valid exit scenarios.

Assessment of sympathetic reinnervation after cardiac transplantation using hybrid cardiac PET/MRI: A pilot study.

BACKGROUND: Sympathetic reinnervation after heart transplantation (HTX) is a known phenomenon, which has an impact on patient heart rate variability and exercise capacity. The impact of reinnervation on myocardial structure has not been evaluated yet. PROPOSE: To evaluate the feasibility of simultaneous imaging of cardiac reinnervation and cardiac structure using a hybrid PET/MRI system. STUDY TYPE: Prospective / pilot study. SUBJECTS: Ten patients, 4-21 years after cardiac transplantation. FIELD STRENGTH/SEQUENCE: 3 T hybrid PET/MRI system. Cine SSFP, T1 mapping (modified Look-Locker inversion recovery sequence) pre/postcontrast as well as dynamic [11 C]meta-hydroxyephedrine ([11 C]mHED) PET. ASSESSMENT: All MRI and PET parameters were evaluated by experienced readers using dedicated postprocessing software packages for cardiac MRI and PET. For all parameters a 16-segment model for the left ventricle was applied. STATISTICAL TESTS: Mann-Whitney U-test; Spearman correlations. RESULTS: Thirty-six of 160 myocardial segments showed evidence of reinnervation by PET. On a segment-based analysis, mean native T1 relaxation times were nonsignificantly altered in segments with evidence of reinnervation (1305 ± 151 msec vs. 1270 ± 112 msec; P = 0.1), whereas mean extracellular volume (ECV) was significantly higher in segments with evidence of reinnervation (35.8 ± 11% vs. 30.9 ± 7%; P = 0.019). There were no significant differences in wall motion (WM) and wall thickening (WT) between segments with or without reinnervation (mean WM: 7.6 ± 4 mm vs. group B: 9.3 ± 7 mm [P = 0.13]; WT: 79 ± 63% vs. 94 ± 74% [P = 0.27]) under resting conditions. DATA CONCLUSION: The assessment of cardiac reinnervation using a hybrid PET/MRI system is feasible. Segments with evidence of reinnervation by PET showed nonsignificantly higher T1 relaxation times and a significantly higher ECV, suggesting a higher percentage of diffuse fibrosis in these segments, without impairment of rest WM and WT. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2019;50:1326-1335.

A case report of a 40-year-old woman with endomyocardial fibrosis in a non-tropical area: from initial presentation to high urgent heart transplantation.

BACKGROUND: Endomyocardial fibrosis (EMF) represents the most common cause of restrictive cardiomyopathy worldwide. Despite a high prevalence in tropical regions, it occasionally occurs in patients who have never visited these areas. While researches have proposed various possible triggers for EMF, etiology and pathogenesis remain largely unknown. Diagnosis is based on patient history, heart failure symptoms, and echocardiographic signs of restrictive ventricular filling, atrioventricular valve regurgitation and frequently apical thrombus. Following is a case report of an Austrian patient with EMF who eventually had to undergo a heart transplant. This case report strives to promote awareness for this in non-tropical areas uncommon but nevertheless detrimental disease. CASE PRESENTATION: A 40-year-old woman was presented at our emergency department with chest pain and fever up to 38.1° Celsius. Plasma troponin-T levels and inflammatory markers were slightly elevated, but the echocardiogram was without pathological findings. The patient was hospitalized on the suspicion of acute myocarditis and discharged soon after improvement. Eight months later, she was presented again with chest pain and symptoms of heart failure. The echocardiogram showed normal systolic left ventricular (LV) function with LV wall thickening and severe restrictive mitral regurgitation as well as aortic and tricuspid regurgitation. Coronary angiogram was normal but right heart catheterization showed pulmonary hypertension due to left heart disease. Further diagnostic workup with cardiac magnetic resonance imaging revealed subendocardial late enhancement and apical thrombus formation in the left ventricle compatible with the diagnosis of EMF. A comprehensive diagnostic workup showed no evidence of infection, systemic immunologic or hematological disease, in particular hypereosinophilic syndrome. After a multidisciplinary consideration of several therapeutic options, the patient was listed for heart transplantation. On the waiting list, she deteriorated rapidly due to progressive heart failure and finally underwent a heart transplantation. Histological examination confirmed the diagnosis of EMF. Six years after her heart transplantation, the patient was presented in an excellent clinical condition. CONCLUSIONS: Even in non-tropical regions, the diagnosis of EMF should always be considered in restrictive cardiomyopathy. Knowledge of the distinct phenotype of EMF facilitates diagnosis, but comprehensive workup and therapeutic management remain challenging and require a multidisciplinary approach.

The meaning of donor-specific antibodies after heart transplant.

PURPOSE OF REVIEW: Antibody-mediated rejection (AMR) is a major contributor of impaired long-term survival after heart transplantation (HTx). The presence of circulating donor-specific antihuman leukocyte antigen (HLA) antibodies (DSAs) is considered as a mandatory criterion for AMR after HTx. DSA are known prognostic biomarkers of outcome, for example, recipients with de-novo DSA have a three-fold increased risk of mortality. RECENT FINDINGS: Although the awareness of the impact and prognosis of DSA on the survival has been increased in the HTx community over the last decade, the management of DSA pre and posttransplant varies among centers and is mainly based on the experience of transplant physicians. Thus, firm consensus strategies for each HTx recipient should be established by a center advisory board of experts in the field of HLA genetics, transplantation immunology, and HTx to evaluate the immunological risk preoperatively and also continuously during the posttransplant course. Consequently, the recent advances of invasive and noninvasive diagnostic tools should be applied, according to the risk, laboratory findings, and clinical events of the recipient. Such individual strategy will result in tailored therapeutic options. SUMMARY: Novel standards for the management of DSA in HTx recipients on the basis of an interdisciplinary approach of experts will improve diagnostics for personalized medicine.

Cardioprotective cytokine interleukin-33 is up-regulated by statins in human cardiac tissue.

Interleukin (IL)-33 is a member of the IL-1 family and is able to act cardioprotective. The aim of this study was to investigate the regulation of IL-33 by 3-hydroxy-3-methylglutaryl-coenzyme-A (HMG-CoA) reductase inhibitors (statins) and bisphosphonates (BPs) in human cardiac tissue. The lipophilic fluvastatin, simvastatin, atorvastatin, and lovastatin as well as the nitrogenous BPs alendronate and ibandronate, but not hydrophilic pravastatin increased IL-33 mRNA and intracellular IL-33 protein levels in both human adult cardiac myocytes (HACM) and fibroblasts (HACF). Additionally, fluvastatin reduced soluble ST2 secretion from HACM. IL-33 was also up-regulated by the general inhibitor of prenylation perillic acid, a RhoA kinase inhibitor Y-27632, and by latrunculin B, but statin-induced IL-33 expression was inhibited by mevalonate, geranylgeranyl pyrophosphate (GGPP) and RhoA activator U-46619. The IL-33 promoter was 2.3-fold more accessible in statin-treated HACM compared to untreated cells (P = 0.037). In explanted hearts of statin-treated patients IL-33 protein was up-regulated as compared with the hearts of non-statin-treated patients (P = 0.048). As IL-33 was previously shown to exert cardioprotective effects, one could speculate that such up-regulation of IL-33 expression in human cardiac cells, which might happen mainly through protein geranylgeranylation, could be a novel mechanism contributing to known cardioprotective effects of statins and BPs.