Abstract P2115: Differential Cardiac Remodeling Profile Of Immunosuppression Drugs

Introduction: Heart transplantation provides lifesaving therapy for patients with end-stage heart failure. The longevity of the therapy is limited by Cardiac Graft Dysfunction (CGD), which is an acquired cardiomyopathy affecting transplanted hearts associated with diastolic and/or systolic dysfunction. Some clinical risk factors for CGD have been identified, but none of them are easily modifiable. An unexplored potential contributor to CGD is the choice of immunosuppression agent used despite multiple clinical reports suggesting reduced adverse cardiac remodeling with mammalian target of rapamycin (mTOR) inhibitors compared to calcineurin inhibitors (CNI). This study examines mechanisms of differential cardiac remodeling effects of CNI versus mTOR inhibitors in a human cellular cardiac model. Methods/Results: We utilized 3D cardiac spheres composed of induced pluripotent stem cell-derived cardiomyocytes, cardiac fibroblasts, and endothelial cells (cardiac organoids). Cardiac organoids were treated with 5 days of vehicle, tacrolimus (CNI), or sirolimus (mTOR inhibitor). We did not observe a significant difference in surrogates of systolic or diastolic function in treated cardiac organoids. We pursued single cell-RNA sequencing of drug-treated cardiac organoids and identified gene expression changes consistent with increased extracellular matrix deposition and fibroblast activity in response to CNI treatment. In addition, CNI-treated cardiac organoids cellular composition was notable for increased proportion of fibroblasts and less cardiomyocytes compared to mTOR inhibitor-treated cardiac organoids. To validate gene expression changes observed, we treated cardiac fibroblasts with drugs and observed an increase in collagen production in response to CNI treatment and a reduction in fibroblast number and collagen production in response to mTOR inhibitor treatment. Furthermore, we observed increased ATP production in CNI-treated cardiac fibroblasts, but a reduction in mTOR-treated counterparts. Conclusion: We identify reduced extracellular matrix deposition and cardiac fibroblast proliferation in response to mTOR inhibitor as a potential mechanism for the more favorable remodeling profile observed clinically.