Ischemic cardiomyopathy in pigs with two-vessel occlusion and viable, chronically dysfunctional myocardium

Abstract

Fallavollita, James A. and John M. Canty, Jr. Ischemic cardiomyopathy in pigs with two-vessel occlusion and viable, chronically dysfunctional myocardium. Am J Physiol Heart Circ Physiol 282: H1370-H1379, 2002; 10.1152/ajpheart.00138.2001.-A chronic left anterior descending coronary artery (LAD) stenosis leads to the development of hibernating myocardium with severe regional hypokinesis but normal global ventricular function after 3 mo. We hypothesized that two-vessel occlusion would accelerate the progression to hibernating myocardium and lead to global left ventricular (LV) dysfunction and heart failure. Pigs were instrumented with a fixed 1.5-mm constrictor on the proximal LAD and circumflex arteries. After 2 mo, there were no overt signs of right-heart failure and triphenyl tetrazolium chloride infarction was trivial (1.4 Ϯ 0.1% of the LV). Compared with shams, regional function [myocardial systolic excursion (⌬WT); 2.1 Ϯ 0.3 vs. 4.6 Ϯ 0.4 mm, P Ͻ 0.05] and resting perfusion (0.90 Ϯ 0.13 vs. 1.32 Ϯ 0.09 ml ⅐ min Ϫ1 ⅐ g Ϫ1 , P Ͻ 0.05) were reduced, consistent with hibernating myocardium. Pulmonary systolic (45.9 Ϯ 3.3 vs. 36.5 Ϯ 2.2 mmHg, P Ͻ 0.05) and wedge pressures (19.1 Ϯ 1.6 vs. 11.2 Ϯ 0.9 mmHg, P Ͻ 0.05) were increased with global ventricular dysfunction (ejection fraction 43 Ϯ 2 vs. 50 Ϯ 2%, P Ͻ 0.05). Early LV remodeling was present with increased cavity size and mass. Reductions in sarcoplasmic reticulum Ca 2ϩ -ATPase and phospholamban were confined to the dysfunctional LAD region with no change in calsequestrin. Thus combined stenoses of the LAD and circumflex arteries accelerate the development of hibernating myocardium and result in compensated heart failure. hibernating myocardium; stunned myocardium; pigs; collaterals; heart failure; ischemic cardiomyopathy ISCHEMIC CARDIOMYOPATHY is an increasingly prevalent cause of death and disability from cardiovascular disease (20). Unfortunately, major deficiencies exist in our understanding of how chronic coronary artery disease progresses to symptomatic left ventricular (LV) dysfunction due to the lack of experimental animal models where the progression of physiological, cellular, and molecular responses can be evaluated longitudinally. Although some patients develop heart failure due to muscle loss and replacement fibrosis in association with large or multiple myocardial infarcts (1, 6, 29), pathological studies support the view that many patients have global LV dysfunction, disproportionately severe in relationship to the amount of replacement fibrosis identified at postmortem exam (3, 31). Two of the factors that could contribute to this dissociation include a chronic depression in myocyte contractile function due to alterations in sarcoplasmic reticulum (SR) function and LV remodeling with diffuse interstitial connective tissue proliferation and myocyte cell dropout due to apoptosis (28). An additional explanation for the dissociation between the severity of LV dysfunction and fixed structural changes could be reversible contractile dysfunction arisi...

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