Investigating Chamber-Dependent Cardiac Remodelling in a Murine Model of Heart Failure with Preserved Ejection Fraction

Abstract

Heart failure with preserved ejection fraction (HFpEF) is strongly associated with atrial fibrillation (AF), yet chamber-specific mechanisms remain poorly defined. This thesis characterizes a HFpEF model using high-fat diet, sucrose, and L-NAME (HFDLS), a combination that has not been explored in the CD1 mouse strain. Relative to normal-diet controls, HFDLS mice showed greater percent body-weight gain (45.9 to 70.8%), reduced exercise tolerance (408 to 276 m), and elevated mean arterial pressure (84.7 to 107.6 mmHg). Invasive hemodynamics demonstrated increased LV end-diastolic pressure (6.7 to 11.8 mmHg), consistent with impaired diastolic filling. Echocardiography confirmed preserved ejection fraction with concentric remodeling. Histological analysis revealed increased fibrosis in the left atrium (5.96 to 12.15%) and left ventricle (1.71 to 3.76%). Intracardiac electrophysiology showed significantly prolonged atrial arrhythmia duration (2.6 to 23.6 s), with unchanged ventricular refractoriness. F4/80⁺ immunostaining demonstrated increased macrophage density in both chambers. Overall, the model produced a modest HFpEF phenotype that will require further refinement to strengthen disease severity, but it nevertheless revealed clear atrial-dominant structural and electrical remodeling, establishing a platform to investigate TNFαmediated mechanisms linking HFpEF and AF. Keywords: Heart Failure with Preserved Ejection Fraction, Atrial Fibrillation, CD1 mouse strain, High-Fat diet+L-NAME+Sucrose