A new large pre-clinical model of aging-related heart failure: a platform to develop new therapies for HFpEF

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Heart failure with preserved ejection fraction (HFpEF) is the predominant form of HF in the elderly and one of the largest unmet needs in cardiology. Cardiovascular aging is a complex process crafted by risk factors, biological variables (e.g., sex), and prevalent comorbidities like chronic kidney disease (CKD) that contribute to the development of HF. CKD is a disease that affects almost 40% of US adults ≥65 years and HFpEF is present in over 50% of CKD patients. However, limited knowledge about the impact of aging on CKD-HFpEF pathophysiology and the lack of models calls for efforts for new strategies to counteract the deterioration of cardiac function in CKD. We are uniquely qualified to address these needs since 1) We developed in juvenile pigs a model of CKD with left ventricular remodeling and diastolic dysfunction that recapitulates human HFpEF. 2) Cardiac dysfunction and remodeling in the CKD-HFpEF model show a significant reduction in cardiac vascular endothelial growth factor (VEGF) expression, in line with prior research on aging hearts. 3) We developed drug-delivery vectors based on elastin-like polypeptides (ELP) and showed their efficacy to deliver therapeutics to the kidney, including VEGF. In addition, we built a library of ELPs that based on their molecular weight can target different organs, including the heart. However, ELPs have never been used for cardiac therapies. 4) Unbiased analysis (published database) in the juvenile CKD-HFpEF model showed that cardiac abnormalities are associated with cardiac epigenetic and miRNA modifications of VEGF-related genes, altered angiogenic signaling, and cardiac microvascular rarefaction. The premise underlying this innovative R21 proposal is multi-fold: 1) We will develop the first model of HFpEF in normally aged pigs to recapitulate the phenotype of aging HFpEF in humans. This model will also foster the study of age and sex as biological variables in an unprecedented fashion. 2) We will test, for the first time, a therapeutic strategy to abate cardiac microvascular rarefaction, an important determinant of cardiac dysfunction in HFpEF by targeting VEGF angiogenic signaling using ELP-based therapeutic angiogenesis. Finally, we will set the foundation for new therapies in aging HFpEF by defining mechanisms of VEGF downregulation driven by cardiac microRNA (miRNA) and epigenetic modulation. Aim 1: Development of the first model of HFpEF in a normally aged swine. These studies will identify pathological pathways in aging HFpEF and offer a new suitable platform to guide the development of new therapeutic strategies in a translational fashion. Aim 2: Downregulation of VEGF signaling leads to cardiac microvascular rarefaction and HFpEF in aging. These studies will mechanistically define the role of VEGF in the normally aged heart and build the foundation for a new targeted therapy in aging HFpEF. By discerning mechanisms of altered cardiac signaling of VEGF-related genes, we will set the stage to explore new treatments. This proposal assures innovation by both developing a new model of aging HFpEF and by establishing the mechanistic foundation for new therapeutic strategies for HFpEF, which will result in a paradigm shift that aligns with the bench-to-bedside strategic mission of the NIH-NIA.