Investigating the Role of Macrophages in Heart Failure with Preserved Ejection Fraction

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CHALLENGE: Heart failure with preserved ejection fraction (HFpEF) is a complex clinical syndrome that presents with heart failure symptoms, unaltered left ventricular ejection fraction, and is associated with comorbidities including obesity, diabetes and metabolic syndrome. HFpEF accounts for ~50% of all heart failure (HF) and is characterized by diastolic dysfunction and extensive cardiac fibrosis. The pathophysiology of HFpEF is not well understood, and there are no evidence-based therapies to treat HFpEF. In pilot studies, we utilized two-independent HFpEF models – i) 2-hit HFpEF model of hypertension and high-fat diet in mice and ii) obese ZSF1 rats. Both HFpEF models exhibit diastolic dysfunction, obesity and glucose intolerance. In the mouse HFpEF model, we observed increased numbers of inflammatory cells in the heart. We also observed an increase in fibroblast differentiation into myofibroblasts, upregulation of extracellular matrix (ECM) genes and complement signaling in the hearts HFpEF mice. We hypothesize that exaggerated macrophage infiltration into the left ventricle (LV) mediates pathological cardiac remodeling in HFpEF by modulating cardiac fibroblast differentiation and function. GOAL: Here, we propose to investigate the mechanisms by which inflammatory macrophages cause cardiac remodeling in HFpEF at the cellular, molecular and functional levels. In Aim 1, we will investigate the mechanisms by which inflammatory macrophages mediate fibroblast differentiation. We will also assess the contribution of macrophages to cardiac remodeling and diastolic dysfunction in two independent HFpEF models by depleting macrophages with clodronate liposomes. In Aim 2, we will determine the effect of complement signaling on macrophage polarization. We will characterize cardiac macrophage populations in HFpEF models after complement depletion and examine the role of NLRP3 inflammasome activation in cardiac fibroblast function. The long-term goal of this study is to understand the molecular basis of inflammation-mediated cardiac remodeling in HFpEF. To facilitate my transition from a mentored postdoctoral fellowship to a stable independent research position, the K99 phase will be conducted as integrated mentored career development and research activities, and the R00 phase will be devoted to execution of the proposed research, establishing collaborations, and writing a DP2 and an R01 grant. INNOVATION: The proposed work pushes the envelope on multiple novel frontiers. It aims to uncover mechanisms at the molecular, cellular and functional levels of organization. It integrates two orthogonal fields – intercellular signaling in cardiovascular disease and regulation of fibroblast function by inflammatory signals. Our studies will for the first time characterize inflammatory signals that mediate fibroblast activation and cardiac remodeling in HFpEF. Understanding these mechanisms will help identify therapeutic targets to mitigate cardiac remodeling in HF.