Immunosuppression Drug Mediated Cardiovascular Effects

Heart transplantation continues to be a life-saving therapy for patients with end-stage heart failure; yet the average long-term graft survival remains at only 12.5 years. Cardiac allograft vasculopathy (CAV) and cardiac graft dysfunction are both key contributors to long-term morbidity and mortality in the heart transplant population. Studies have suggested that immunosuppressive agents may modulate cardiovascular function, yet the mechanisms for this modulation is incompletely understood. The primary classes of immunosuppressive agents utilized post-heart transplantation are mammalian target of rapamycin inhibitors (e.g. sirolimus), calcineurin inhibitors (e.g. tacrolimus), and purine synthesis inhibitors (e.g. mycophenolate mofetil). Our prior findings indicate no discernible change to cell contraction or viability, but increased fibrosis and adverse remodeling in response to tacrolimus treatment. Using cardiac organoids; composed of human induced pluripotent stem cells (hiPSCs) derived cardiomyocytes, endothelial cells, and cardiac fibroblasts; we investigated the effects of these agents on the cardiovascular system using RNA-sequencing and proteomic analysis. Proteomic analysis of cardiac organoids was done using Luminex bead-array assay. Treatment with MPA coincided with a significant reduction of proinflammatory cytokines including the various interleukin-families and TNF-alpha/beta. Tacrolimus yielded mixed results on proteins associated with cardiac remodeling but indicated significant upregulation of proteins that have been implicated in CAV progression. In addition, RNA-sequencing findings revealed significant upregulation of genes associated with cardiac fibrosis and remodeling with tacrolimus treatment in comparison to sirolimus treatment. These findings correlate with functional profile observed on treatment of cardiac organoids. Our results provider further insight into the pathways by which differential immunosuppression drugs influence cardiovascular remodeling.