Impact of Mechanical Circulatory Support and Microbiome Change on Outcomes in Heart Transplant Recipients

About This Grant

PROJECT SUMMARY/ABSTRACT Heart failure is a major cause of morbidity and mortality, with orthotopic heart transplant (OHT) considered the gold standard treatment for those eligible. As a result of improving mechanical circulatory support (MCS) technology, in 2018 the national heart allocation policy changed to prioritize candidates requiring temporary MCS (tMCS) (e.g., extracorporeal membrane oxygenation, intra-aortic balloon pump). This change resulted in a significant increase in tMCS use prior to OHT nationally. Throughout this period, infection remained a major cause of morbidity and mortality post-transplant, with bloodstream infections (BSI) being a particularly serious complication. In non-transplant patients, tMCS is associated with BSI, although no studies have specifically addressed this in the transplant population, which is unique due to need for high dose immunosuppression and different indications for tMCS use. To prevent BSI, we must understand the mechanisms by which tMCS contributes to BSI, which we hypothesize is due to changes in the gut and skin microbiome of OHT recipients. This occurs through the tMCS device disrupting skin integrity to alter the skin microbiome as well as tMCS altering gut perfusion, with related gut microbiome changes and translocation of dominant gut bacterial species. Additionally, BSI may impact post-OHT outcomes of graft function and mortality via infection and immune response as well as indirectly in changes to immunosuppression, which requires further exploration. In this study, we plan to address these knowledge gaps by studying a large retrospective and prospective cohort of OHT recipients. Specifically, we plan to determine the risk factors for post-transplant BSI in OHT recipients, with a focus on tMCS (AIM 1); define the impact of tMCS pre-transplant on the skin and gut microbiome of OHT recipients (AIM 2); and determine the association between early BSI and post-transplant outcomes of rejection, graft failure, and death (AIM 3). For Aims 1 and 3 we will collect retrospective data from a large cohort of OHT recipients, utilizing advanced statistical methods including time varying covariates and propensity matching to address the heterogeneity inherent in this population. Aim 2 will be accomplished through prospective pre- and post-transplant collection of biospecimens for microbiome analysis to evaluate changes and impact on infection. The results of this study will lead to paradigm shifts in how we think about tMCS before OHT and treat recipients after OHT to prevent infection, which may enhance organ allocation practices moving forward. The aims are combined with a robust training plan that includes formal education in biostatistics and epidemiology as well as microbiome analysis, formal benchmarks for progress including presentation at seminars and international conferences, and extensive research experience under the guidance of an expert mentoring and advisory team. This proposal will form a strong foundation for my continued development toward a career as an independent investigator with a research program focused on improving outcomes in OHT recipients.