Abstract Wed063: Murine Repetitive Pressure Overload Induces Eccentric Remodeling and Systolic Dysfunction

Background: Repetitive pressure overload (RPO) is a critical driver of maladaptive cardiac remodeling and heart failure. While porcine models of RPO have been shown to induce adaptive hypertrophy, the impact of RPO in a murine model remains unclear. We sought to establish a mouse model of RPO using chronic phenylephrine (PE) infusion and assess its effects on cardiac structure and function. Methods: A murine RPO model was developed using PE infusion through a surgically implanted vascular access button (VAB) to allow repeated administration and longitudinal hemodynamic assessment. Cardiac function was evaluated using echocardiography and closed-chest pressure-volume (PV) loop acquisition, and histological analyses were performed to assess myocardial remodeling. Mice were subjected to short-term pressure overload (SPO) or 2-week RPO, and left ventricular (LV) function, remodeling, and fibrosis were analyzed. Results: Compared to SPO, 2-week RPO mice exhibited increased preload accommodation, as evidenced by elevated left ventricular end-diastolic pressure (LVEDP) and a rightward shift in diastolic PV relationships. Despite increased LVEDP, diastolic stiffness was reduced, suggesting altered ventricular compliance. PE-induced pressure overload transiently decreased left ventricular ejection fraction (LVEF) in both SPO and RPO groups, with no protective effect of RPO against stretch-induced myocardial stunning. RPO was associated with increased cardiomyocyte apoptosis and elevated serum cardiac troponin I (cTnI), indicating ongoing myocyte injury. Structurally, RPO led to significant cardiomyocyte loss with compensatory hypertrophy of remaining myocytes. While total LV mass remained unchanged, RPO mice exhibited a trend toward decreased LV mass indexed to LV end-diastolic volume (LVEDV), indicative of eccentric remodeling and progressive systolic dysfunction. Additionally, interstitial fibrosis was significantly increased in RPO compared to SPO and control mice. Conclusions: Unlike large animal models of RPO, our murine model did not produce adaptive hypertrophy. Instead, chronic PE-induced RPO resulted in eccentric remodeling, myocardial injury, and progressive systolic dysfunction, closely resembling heart failure with reduced ejection fraction (HFrEF). This model provides new insights into the impact of chronic pressure overload on myocardial remodeling and may serve as a valuable tool for studying HFrEF progression.