Abstract 4370032: Cardiac and renal expression of angiotensin II type 1 receptor and its association with fibrosis and heart function in ischemic heart failure rat models

Introduction: Despite the growing interest in the role of Angiotensin II type 1 receptor (AT 1 R) in left ventricular remodeling and heart failure, little is known about its association with heart function and fibrosis. This study evaluated temporal changes in myocardial and renal AT 1 R expression in ischemic heart failure rat models, and evaluated its potential as an early diagnostic marker for heart failure. Hypothesis: Upregulation of cardiac and renal AT 1 Rs occurs during early ventricular remodeling, prior to a reduction in left ventricular function as measured by echocardiography. Methods: Male Sprague-Dawley rats (n=55, 200-250g) were randomized and subjected to the following surgeries: Sham, Ischemia/Reperfusion (I/R, 20 min ligation) and Permanent Ligation (PL) of the left anterior descending artery. Heart function was assessed by weekly echocardiography for 12 weeks. AT 1 R expression and fibrosis levels in the heart (infarct and remote areas) and kidneys (cortex and medulla) were assessed at 2 hours, 1 and 3 days; 1, 3, 5, 7 and 12 weeks post-surgery using in vitro 125 I-[Sar 1 , Ile 8 ]-Angiotensin II autoradiography and picrosirius red staining, respectively. One-Way ANOVA, t-test and Pearson’s correlation tests were used for the association of AT 1 R, fibrosis and heart function. Results: Left ventricular ejection fraction was reduced by 19% (p<0.01) at 2 hours and 35% (p<0.0001) by week-7 in PL animals, while remaining unchanged in I/R. Compared to Shams, the highest increase (p<0.0001) in cardiac fibrosis in the infarcted area was observed at day-3 (+10,055%) in I/R and at day-1 (+17,850%) in PL. In Shams, renal cortex and medulla exhibited 50-fold higher (p<0.0001) AT 1 R levels compared to the heart. The highest increase (p<0.0001) in cardiac AT 1 R levels in I/R was at week-1 (+1,386%) and at day-3 (+1,100%) in PL. Infarct areas consistently had higher AT 1 R levels and fibrosis than remote areas. Renal AT 1 R expression and fibrosis remained unchanged across all groups. Cardiac AT 1 R levels strongly correlated with fibrosis in I/R (r=0.756, p<0.0001) and with LVEF in PL (r=-0.722, p<0.05). Conclusions: Cardiac AT 1 R expression reflects early cardiac remodeling and fibrosis in I/R animal models and may potentially be a more sensitive marker for detecting and studying at a molecular level cardiac remodeling than echocardiographic parameters. Unchanged renal AT 1 R expression indicates limited sensitivity of renal AT 1 R as a marker for heart failure detection.