Abstract P3063: Downregulation Of The T Cell Unfolded Protein Response Precedes T Cell Cardiac Infiltration In Experimental Heart Failure With Preserved Ejection Fraction

Introduction: Diastolic dysfunction in Heart Failure with Preserved Ejection Fraction (HFpEF) is associated with T cell systemic inflammation and downregulation of myocardial unfolded protein response (UPR) genes. The T cell UPR can modulate T cell effector function and immune responses, yet this is largely unexplored in HFpEF. Hypothesis: We hypothesized T cells contribute to cardiometabolic HFpEF and that metabolic and nitrosative stress-induced alterations of the T cell UPR modulate T cell activation and diastolic function. Methods: Male C57/BL6 (wild-type, WT) or T cell receptor alpha-deficient ( Tcra-/-) were fed a high-fat diet (HFD) and L-NAME for 1, 3, and 5 weeks, or standard chow (STD). We assessed diastolic function by invasive hemodynamic analyses. Immune cells were characterized in the heart and spleen by flow cytometry, and cardiac pathology was assessed by histology. The UPR gene expression was evaluated in splenic CD4 + T cells over time by qPCR. Results: Unlike WT mice, Tcra-/- mice fed HFD/L-NAME for 5 weeks did not develop diastolic dysfunction or cardiomyocyte hypertrophy, demonstrating a critical role for T cells in experimental cardiometabolic HFpEF. Indeed, cardiac CD4 + T cells were increased in WT mice fed HFD/L-NAME for 5 weeks compared to STD, concordant with an expansion of splenic CD44 hi CD62l lo interferon-gamma (IFNγ) + effector cells. Strikingly, splenic T cells also experienced downregulation of the UPR proteins activating transcription factor 4 ( Atf4 ), Atf6 , and X box-binding protein 1 ( Xbp1s/u ). We found that the Atf4 arm of the T cell UPR is the earliest responder to HFD/L-NAME, with observed downregulation of Atf4 and its downstream effector C/EBP homologous protein ( Chop ) as early as 3 weeks, prior to onset of diastolic dysfunction, followed by the subsequent downregulation of Atf6 and Xbp1s/u . Conclusions: T cells contribute to diastolic dysfunction and cardiomyocyte hypertrophy in experimental cardiometabolic HFpEF. Early modulation of T cell Atf4 precedes diastolic dysfunction, enhanced IFNγ + effector T cell activation, and global T cell UPR downregulation. Ongoing studies are focused on understanding the functional consequences of impaired T cell UPR in cardiometabolic HFpEF.

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