Psychosocial Risk and Health Behaviors as Predictors of Clinical Events in Patients Wait-Listed for a New Heart: Results from 7 Years of Follow-Up

We examined the long-term relationship of psychosocial risk and health behaviors on clinical events in patients awaiting heart transplantation (HTx). Psychosocial characteristics (e.g., depression), health behaviors (e.g., dietary habits, smoking), medical factors (e.g., creatinine), and demographics (e.g., age, sex) were collected at the time of listing in 318 patients (82% male, mean age = 53 years) enrolled in the Waiting for a New Heart Study. Clinical events were death/delisting due to deterioration, high-urgency status transplantation (HU-HTx), elective transplantation, and delisting due to clinical improvement. Within 7 years of follow-up, 92 patients died or were delisted due to deterioration, 121 received HU-HTx, 43 received elective transplantation, and 39 were delisted due to improvement. Adjusting for demographic and medical characteristics, the results indicated that frequent consumption of healthy foods (i.e., foods high in unsaturated fats) and being physically active increased the likelihood of delisting due improvement, while smoking and depressive symptoms were related to death/delisting due to clinical deterioration while awaiting HTx. In conclusion, psychosocial and behavioral characteristics are clearly associated with clinical outcomes in this population. Interventions that target psychosocial risk, smoking, dietary habits, and physical activity may be beneficial for patients with advanced heart failure waiting for a cardiac transplant.

Prognostic Significance of Feature-Tracking Right Ventricular Global Longitudinal Strain in Non-ischemic Dilated Cardiomyopathy

Aims: Left ventricular global longitudinal strain (GLS) by cardiac magnetic resonance feature tracking (CMR-FT) analysis has shown an incremental prognostic value compared to classical parameters in non-ischemic dilated cardiomyopathy (NICM). However, less is known about the role of right ventricular (RV) GLS. Our objective was to evaluate the prognostic impact of RV-GLS by CMR-FT analysis in a population of NICM patients.Methods: In this multicenter study, we examined NICM patients evaluated with a comprehensive CMR-FT study. Major cardiac events (MACEs) were considered as the study primary outcome measure and were defined as a composite of (a) cardiovascular death, (b) cardiac transplant or destination therapy ventricular assist device, (c) hospitalization for life-threatening ventricular arrhythmias or implantable cardiac defibrillator appropriate intervention. Heart failure (HF) related events, including hospitalizations and life-threatening arrhythmia-related events were considered as secondary end-points. Receiver operating time-dependent analysis were used to calculate the possible additional effect of RV-GLS to standard evaluation.Results: We consecutively enrolled 273 patients. During a median follow-up of 39 months, 41 patients (15%) experienced MACEs. RV-GLS and LV late gadolinium emerged as the strongest prognostic CMR-FT variables: their association provided an estimated 3-year MACEs rate of 29%. The addition of RV-GLS significantly improved the prognostic accuracy in predicting MACEs with respect to the standard evaluation including LGE (areas under the curve from 0.71 [0.66–0.82] to 0.76 [0.66–0.86], p = 0.03). On competing risk analysis, RV-GLS showed a significant ability to reclassify overall both HF-related and life-threatening arrhythmia-related events, regardless of LV and RV ejection fraction.Conclusions: In NICM patients, RV-GLS showed a significant prognostic role in reclassifying the risk of MACEs, incremental with respect to standard evaluation with standard prognostic parameters.

Myocardial inflammation and energetics by cardiac MRI: a review of emerging techniques

The role of inflammation in cardiovascular pathophysiology has gained a lot of research interest in recent years. Cardiovascular Magnetic Resonance has been a powerful tool in the non-invasive assessment of inflammation in several conditions. More recently, Ultrasmall superparamagnetic particles of iron oxide have been successfully used to evaluate macrophage activity and subsequently inflammation on a cellular level. Current evidence from research studies provides encouraging data and confirms that this evolving method can potentially have a huge impact on clinical practice as it can be used in the diagnosis and management of very common conditions such as coronary artery disease, ischaemic and non-ischaemic cardiomyopathy, myocarditis and atherosclerosis. Another important emerging concept is that of myocardial energetics. With the use of phosphorus magnetic resonance spectroscopy, myocardial energetic compromise has been proved to be an important feature in the pathophysiological process of several conditions including diabetic cardiomyopathy, inherited cardiomyopathies, valvular heart disease and cardiac transplant rejection. This unique tool is therefore being utilized to assess metabolic alterations in a wide range of cardiovascular diseases. This review systematically examines these state-of-the-art methods in detail and provides an insight into the mechanisms of action and the clinical implications of their use.

Outcome of Post Solid Organ Transplant Burkitt Lymphoma (PSOT-BL): A Report from the Pediatric PTLD Collaborative (PPC)

Background Post solid organ transplant Burkitt lymphoma (PSOT-BL) is a rare form of monomorphic post-transplant lymphoproliferative disease (M-PTLD). Outcome data in pediatric patients are limited and guidelines on optimal treatment in PSOT-BL are lacking. Methods Retrospective study and analysis of clinical characteristics, treatment, and outcome data from patients diagnosed with PSOT-BL at age ≤ 21 years (y) in 11 US pediatric transplant centers. Results We identified 28 patients transplanted between 1993-2016 who developed PSOT-BL. Median age at organ transplantation and at diagnosis of PSOT-BL was 2.9y (range, 0.1-14) and 7.5y (range, 7-17), respectively, with median interval from transplant to PSOT-BL diagnosis of 3.8y (range 2-7). Heart and liver were the most frequently transplanted organs (n=14, 11), while bowel, kidney, and lung were each transplanted in one patient. Immunosuppressive therapy at the time of PSOT-BL diagnosis was tacrolimus alone (n=9), or in combination with mycophenolate (n=7), azathioprine (n=6), cyclosporin (n=3), or prednisone (n=3). None were receiving an mTOR inhibitor at time of PSOT-BL diagnosis. Six, twelve, and ten patients corresponded to Murphy stages II, III, and IV, respectively. Lactate dehydrogenase was elevated in 23 patients (82%) and was > 2x upper limit of normal in 14 (50%). All tumors were pathologically consistent with BL; MYC FISH testing was positive in 10/10 tumors tested, while 21/23 tumors (90%) had detectable Epstein Barr Virus. Rituximab-containing regimens were given to 25/28 patients (93%). These treatment regimens were as follows: rituximab alone (n=2), low dose cyclophosphamide, prednisone, and rituximab (CPR) (n=10), Burkitt lymphoma specific therapy: (FAB/LMB chemotherapy (n=3) or FAB/LMB therapy with rituximab (n=8)), reduced dose FAB/LMB (n=2), diffuse large B-cell lymphoma (DLBCL) regimens including EPOCH-R (n=2) and R-CHOP (n=1). Treatment modifications/reductions were infrequent. Methotrexate dose modification and/or omission were required in four patients due to renal dysfunction (n=3) and ascites (n=1). Doxorubicin was electively eliminated in one cardiac transplant recipient due to concern for cardiotoxicity and dose-reduced in another due to prolonged myelosuppression. There was no treatment related mortality. There were two episodes of rejection, one was a liver rejection that was successfully treated without graft loss, the other occurred after achieving partial response (PR) to 3 cycles of CPR, required intensive immune suppression, and was followed by PTLD/DLBCL and death from PTLD progression. There were two additional cases of a second PTLD/DLBCL. One died of PTLD progression nine months after developing a second PTLD and the other is alive in complete remission (CR) 17 months after diagnosis of a second PTLD. Of the two patients treated with rituximab alone, one had no response and the other relapsed. Both were subsequently treated with BL chemotherapy and are alive in CR 15- and 7-years following BL diagnosis, respectively. For all study patients over a median of 6.8y follow-up (range, 0.5-17), 3-year event-free survival (EFS) was 73.5% and 3-year overall survival (OS) was 92.6%, see figure. Three patients died of Burkitt lymphoma (all had been treated with CPR, experienced treatment failure and required treatment escalation to intensive BL chemoimmunotherapy but died of progressive disease). Of the 11 patients who received Burkitt lymphoma intensive therapy, all are alive in CR. One had progressed on treatment but achieved CR with further treatment intensification. Another developed a second PTLD/DLBCL, with subsequent CR. Conclusion This collaborative study represents the largest pediatric series of PSOT-BL reported to date. In this study patients with PSOT-BL treated with intensive BL directed therapy appear to have comparable outcome to immunocompetent pediatric patients with BL. Figure 1 Figure 1. Disclosures Orjuela: ATARA Pharmaceuticals: Other: Scientific Advisory Board.

Renal replacement therapy in heart transplant recipients

Kidney injury in cardiac transplant recipients is one of the most severe complications affecting both short- and long-term transplant outcomes. The need for renal replacement therapy (RRT) is determined not only and not so much by the degree of renal dysfunction, as by the need for correction of fluid balance and metabolic disorders. These circumstances are associated with the specificity of extracorporeal renal replacement therapy in donor heart recipients. In this review, we discuss the problems of early versus delayed initiation of RRT, anticoagulation and vascular access, advantages and disadvantages of continuous and intermittent techniques. Special attention is paid to chronic kidney injury and peculiarities of kidney transplantation in heart recipients.

Cyclophilin D Regulates the Nuclear Translocation of AIF, Cardiac Endothelial Cell Necroptosis and Murine Cardiac Transplant Injury

Ischemia-reperfusion injury (IRI) is an inevitable consequence of organ transplant procedure and associated with acute and chronic organ rejection in transplantation. IRI leads to various forms of programmed cell death, which worsens tissue damage and accelerates transplant rejection. We recently demonstrated that necroptosis participates in murine cardiac microvascular endothelial cell (MVEC) death and murine cardiac transplant rejection. However, MVEC death under a more complex IRI model has not been studied. In this study, we found that simulating IRI conditions in vitro by hypoxia, reoxygenation and treatment with inflammatory cytokines induced necroptosis in MVECs. Interestingly, the apoptosis-inducing factor (AIF) translocated to the nucleus during MVEC necroptosis, which is regulated by the mitochondrial permeability molecule cyclophilin D (CypD). Furthermore, CypD deficiency in donor cardiac grafts inhibited AIF translocation and mitigated graft IRI and rejection (n = 7; p = 0.002). Our studies indicate that CypD and AIF play significant roles in MVEC necroptosis and cardiac transplant rejection following IRI. Targeting CypD and its downstream AIF may be a plausible approach to inhibit IRI-caused cardiac damage and improve transplant survival.

Multicentre comparative analysis of long-term outcomes after aortic valve replacement in children

ObjectiveThe ideal valve substitute for surgical intervention of congenital aortic valve disease in children remains unclear. Data on outcomes beyond 10–15 years after valve replacement are limited but important for evaluating substitute longevity. We aimed to describe up to 25-year death/cardiac transplant by type of valve substitute and assess the potential impact of treatment centre. Our hypothesis was that patients with pulmonic valve autograft would have better survival than mechanical prosthetic.MethodsThis is a retrospective cohort study from the Pediatric Cardiac Care Consortium, a multi-institutional US-based registry of paediatric cardiac interventions, linked with the National Death Index and United Network for Organ Sharing through 2019. Children (0–20 years old) receiving aortic valve replacement (AVR) from 1982 to 2003 were identified. Kaplan-Meier transplant-free survival was calculated, and Cox proportional hazard models estimated hazard ratios for mechanical AVR (M-AVR) versus pulmonic valve autograft.ResultsAmong 911 children, the median age at AVR was 13.4 years (IQR=8.4–16.5) and 73% were male. There were 10 cardiac transplants and 153 deaths, 5 after transplant. The 25-year transplant-free survival post AVR was 87.1% for autograft vs 76.2% for M-AVR and 72.0% for tissue (bioprosthetic or homograft). After adjustment, M-AVR remained related to increased mortality/transplant versus autograft (HR=1.9, 95% CI=1.1 to 3.4). Surprisingly, survival for patients with M-AVR, but not autograft, was lower for those treated in centres with higher in-hospital mortality.ConclusionPulmonic valve autograft provides the best long-term outcomes for children with aortic valve disease, but AVR results may depend on a centre’s experience or patient selection.

Prediction of outcomes after heart transplantation by machine learning models

Background Models based on traditional statistics for the prediction of outcomes after heart transplantation (HT) have moderate accuracy. We sought to develop and validate state-of-the-art machine learning (ML) models to predict mortality and acute rejection after contemporary HT. Methods We included adult HT recipients from the UNOS database between 2010–2018 using solely pre-transplant clinical and laboratory variables. The study cohort was randomly split in a derivation and a validation cohort with a 3:1 ratio. An effective feature selection algorithm was used to identify strong predictors of 1-year mortality and rejection in the training cohort. Results were used to train the ML models, which were then internally tested using the validation cohort. LIME explainability analysis was used for the best performing ML model. A similar subgroup analysis was performed for 3- and 5-year survival. Results The study cohort comprised of 18,625 patients (53±13 years, 73% males). At 1-year after cardiac transplant, there were 2,334 (12.5%) deaths. Out of a total of 134 pre-transplant variables, 39 and 27 were selected as highly predictive of 1-year mortality and acute rejection respectively, and were used in the ML models. Areas under the curve for the prediction of 1-year survival were 0.689, 0.642, 0.649, 0.637, 0.526 for the Adaboost, Logistic Regression, Decision Tree, Support Vector Machine and K-nearest neighbor models respectively, whereas the IMPACT score had an AUC of 0.569. For the prediction of 1-year acute rejection, Adaboost achieved the highest predictive performance (AUC 0.629). LIME explainability analysis identified the relative impact of the 10 strongest predictors of 1-year mortality and acute rejection. Subgroup analysis using a similar methodology for 3- and 5-year survival yielded AUC of 0.609 and 0.610 using 31 and 91 selected variables respectively. Conclusion ML models created and validated using a contemporary cohort of the UNOS database showed improved accuracy in predicting survival and acute rejection after HT. FUNDunding Acknowledgement Type of funding sources: None.