Abstract 116: T Cells Contribute To Diastolic Dysfunction And Cardiac Hypertrophy In A Preclinical Model Of Heart Failure With Preserved Ejection Fraction

Abstract

Introduction: Heart Failure with Preserved Ejection Fraction (HFpEF) is a prevalent cardiovascular syndrome with no curative therapies, characterized by diastolic dysfunction, preserved systolic function, and decreased expression of unfolded protein response (UPR) genes in the heart. Obesity and hypertension are risk factors for HFpEF and are intimately associated with systemic inflammation. However, the inflammatory mechanisms driving HFpEF remain largely unexplored. Hypothesis: We hypothesized that nitrosative stress induced by obesity and hypertension programs T cells to infiltrate the heart and drive cardiac pathology in HFpEF. Methods: Using a recently established model of HFpEF, we modeled obesity and hypertension in male C57/BL6 (wild-type, WT), T cell receptor alpha-deficient ( Tcra-/-), and Nur77-GFP reporter mice for T cell receptor engagement, using a high-fat diet (HFD) and L-NAME for 5 weeks, or standard chow (STD) as controls. Invasive hemodynamic analyses were used to assess cardiac function, and the heart and lymphoid organs were harvested to characterize immune cell populations by flow cytometry, histology, and gene expression of cardiac remodeling. Results: In WT mice, HFD/L-NAME induced significant cardiac infiltration of T cells alongside the hallmarks of HFpEF. HFD/L-NAME significantly expanded CD62 lo CD44 hi effector T cells in the mediastinal lymph nodes and spleen. Nur77-GFP mice revealed no antigen engagement by T cells in the heart, however, T cells sorted out of the lymphoid organs of HFpEF mice had significantly decreased gene expression of the UPR gene spliced X box-binding protein 1 (XBP1s) compared to controls, suggesting a T cell intrinsic dysregulation of the UPR, and T cell phenotypic changes independent of TCR engagement in the heart. Strikingly, Tcra-/- mice did not develop diastolic dysfunction or cardiomyocyte hypertrophy, demonstrating a novel role for T cells in this experimental model of HFpEF. Conclusions: We conclude diastolic dysfunction and cardiomyocyte hypertrophy in HFpEF is T cell dependent. Ongoing studies are determining whether the observed intrinsic T cell changes in XBP1s prime T cells for cardiac infiltration and effector function that results in diastolic dysfunction and HFpEF.