Abstract 753: Exercise Capacity, Cardiac fibrosis and Left Ventricular Remodeling in a Rat Model of Chronic Pressure Overload: Serial Echocardiography, Pressure-Volume Analysis and Gene Expression Profiling

Abstract

Background: Pressure overload (PO) left ventricular (LV) hypertrophy is a known precursor of heart failure with preserved ejection fraction (EF). The aims of this study were to establish a reliable model of chronic PO in rats and verify the pathophysiological features of this model by evaluating cardiac function using serial echocardiography and a pressure-volume analysis. Methods: Constriction of the abdominal aorta was used to induce PO LV hypertrophy (n = 40) in rats. Twenty sham rats were compared with PO rats. Serial echo studies and exercise were performed at 2-week intervals, and invasive hemodynamic examination by a pressure-volume catheter system was performed 12 weeks after the procedure. The gene expression profiles of the left ventricle (LV) 12 weeks after the procedure were analyzed by DNA chip technology. Results: Serial echo revealed that the LV wall thickness began to increase after the PO and showed progressive increasing until the 8th week (LV septal wall thickness at 8 weeks 1.4mm±0.1mm for PO vs 0.6mm ±0.05mm for Sham, p <0.01). LV dimension was comparable increased until 14 th week (LV end-systolic dimension at 14 weeks, 4.91±0.50 mm 4.71±0.25 mm for PO vs Sham; LV end-diastolic dimension, 9.02±0.42 mm vs. 8.71±0.47 mm for PO vs Sham, p>0.05). The LV ejection fraction showed similar between groups until the 14th week (70.0±2.2% vs. 69.1±3.1% for PO vs. Sham). In hemodynamic analyses, the LV end-diastolic pressure and the end-diastolic pressure-volume relationship slope were greater in the PO group than sham group. When we compared LV remodeling and exercise capacity, cardiac fibrosis and exercise intolerance developed in the PO group but not in the sham group (exercise duration, 234.0 ± 80.3 vs. 597.8 ± 49.0 seconds, p < 0.05, respectively). Transcriptional profiling of cardiac apical tissues revealed that gene expression related to the cardiac fibrosis, cytoskeletal pathway and G-protein signaling genes were enriched in the PO group. Conclusions: We established a small animal model of chronic PO and verified its pathophysiological features. Cardiac fibrosis and cytoskeletal pathway were important pathways in the PO group and influenced exercise capacity. This model may provide a useful tool for future research on PO heart failure.