Abstract 4364773: Collagen Type XVIII Alpha Chain 1 Regulates the Progression to Heart Failure with Preserved Ejection Fraction

Introduction: Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome marked by reduced diastolic filling due to pathological cardiomyocyte and fibrotic remodeling. An overlooked feature of HFpEF is the elevation of oxidative stress, which drives endothelial cell (EC) dysfunction and vascular impairment. Delivery of endostatin (ES), a fragment of type XVIII Collagen alpha 1 (COL18α1) and a potent angiogenic inhibitor, improves recovery following myocardial infarction by attenuating oxidative stress and fibrosis. However, its role in the progression of HFpEF is unclear. This study investigates ES as a potential therapeutic strategy to rescue EC dysfunction in HFpEF. Hypothesis: COL18α1 deletion (COL18α1-/- or KO) will lead to maladaptive cardiac remodeling under pressure-overload-induced stress as evidenced by increased EC dysfunction, vascular density, and fibrosis, promoting an overall decline in cardiac function. Methods: COL18α1 KO and wildtype (WT) mice underwent transverse aortic constriction (TAC) surgery to promote the transition to HFpEF. Serial echocardiography (ECHO) was performed weekly to assess function. At 28 days post-TAC, hearts were harvested for immunohistochemical (IHC) analysis of fibrosis, cardiomyocyte size, and vascular density. In vitro studies were conducted using human coronary artery endothelial cells (HCAECs) treated with ES and pro-oxidative stress stimuli (TNF-α), followed by gene expression analysis to evaluate ES-mediated EC activation. Results: Following TAC surgery, mortality was significantly higher in KO mice compared to WT (p < 0.05). Left ventricular posterior wall thickness and diastolic dysfunction increased in KO mice relative to WT based on ECHO analysis up to 28 days post-TAC. Fibrosis, cardiomyocyte hypertrophy, and vascular density increased significantly in KO hearts (p < 0.05). In HCAECs, ES treatment attenuated expression of genes related to EC dysfunction and inflammation (ICAM1, CAV1; p < 0.05), particularly when compared to TNF-α treatment, indicating that ES may play a protective role during oxidative stress. Conclusion: These findings suggest that COL18α1 and ES deficiency exacerbate pathological remodeling and functional decline during pressure overload. ES has the potential to mitigate EC dysfunction and inflammation and may serve as a therapeutic option for patients with microvascular dysregulation and increased oxidative stress associated with the development of HFpEF.