Abstract 5497: Chronic Stenosis of the Proximal Left Anterior Descending Coronary Artery in Juvenile Rats Results in a Critical Impairment in Coronary Flow Reserve and Leads to the Development of Hibernating Myocardium without Necrosis

Abstract

Background: Previous studies in adult rats have shown that a chronic coronary artery stenosis can produce variable degrees of heart failure and global LV dysfunction with concomitant fibrosis and necrosis. In contrast, placement of a fixed LAD stenosis in juvenile swine leads to the gradual development of hibernating myocardium with regional dysfunction in the absence of infarction. We hypothesized that a similar approach could be used to produce hibernating myocardium in growing rats. Methods: Sprague-Dawley rat pups (3 wk old, 40±2g, n=24) were instrumented with a 200μm stenosis using an 8 – 0 suture around the proximal LAD and compared to sham controls (n=7). At 12-wks post-instrumentation (399±6g), ejection fraction (EF) and regional wall thickening (%WT) were determined by echocardiography and myocardial perfusion was measured using fluorescent microspheres (n=8). Histology was used to assess necrosis, fibrosis and regional myocyte loss. Results: Mortality was low (16%) and survivors (n=20) had no gross evidence of infarction. LAD end-diastolic wall thickness was normal (1.2 ± 0.04 vs. 1.2 ± 0.04 mm in controls, p=ns) and EF was preserved (65 ± 2% vs.70±1% in controls, p=0.07). After 12 weeks, LAD %WT was significantly reduced (49 ± 5% vs. 74 ± 5% in remote, p<0.01). In LAD subendocardium, vasodilated flow was decreased (3.1 ± 0.7 vs.7.1±1.2 ml/min/g in remote, p<0.01) with a critical impairment in coronary flow reserve (adenosine/rest 1.2 ± 0.3 vs.1.8 ± 0.2 in remote, p<0.05). Although fibrosis and necrosis were absent, regional myocyte nuclear density in LAD subendocardium decreased (489 ± 27 vs. 628 ± 24 nuclei per mm 2 in remote, p<0.01) and relative reductions were closely correlated with LAD flow reserve (r =0.76, p<0.05) and LAD %WT (r =0.54, P<0.05). Conclusion: Like swine, a chronic LAD stenosis in growing rats leads to a critical impairment in coronary flow reserve with reduced regional myocardial perfusion, wall thickening and regional myocyte loss without infarction. Our findings establish a model of hibernating myocardium in rodents, facilitating high-throughput studies to identify novel mechanisms and therapies for chronic ischemic LV dysfunction.