Histological remodeling in an ovine heart failure model resembles human ischemic cardiomyopathy

Abstract

Staged coronary embolization, causing myocardial microinfarctions, has been shown in dogs and sheep to cause chronic ischemic heart failure (HF) that resembles the hemodynamics of the human condition. However, its histopathological basis remains unclear. We examined the hypothesis that the ventricular remodeling seen in such sheep resembles the histopathology of human ischemic cardiomyopathy (ICM). Understanding the pathophysiology of this model will determine its place in the development of treatment strategies for HF. Global left ventricular (LV) damage resulting in HF was induced by staged coronary embolization in 11 sheep. Six others served as controls (normal control, NC). In HF sheep, the heart was harvested 6 months after LV ejection fraction (EF) had stabilized at <35%. Histopathological profiles were compared in biventricular transverse sections at midpapillary level using computed image analysis. LV end-diastolic volume increased in the HF group from 84.9±29 to 122.4±30.3 ml ( n=11, P<.05), but myocytes across the LV wall in noninfarcted zones decreased (435.7±38.2 NC; 297.8±48.4/unit area HF; n=11, P<.0001) as did myocyte nuclear density (990.5±51.5 NC; 677.5±121.1/mm 2 HF, n=11, P<.0001). In contrast, LV replacement and interstitial fibrosis increased as did myocyte diameter in noninfarcted zones: 0.1±0.1 to 6.2±4.5% ( P=.0049); 2.0±1.0 to 7.6±4.9% ( P=.0149); and 10.0±0.5 to 15.9±2.2 μm ( P<.0001), respectively. Although LV myocyte nuclear length increased (10.2±1.0 NC; 12.2±0.9 μm HF, n=11, P=.0006), right ventricular (RV) myocyte nuclear density and length did not alter. In this ovine chronic HF model, LV dilation and interstitial and myocyte remodeling resemble human ICM.