Role of ageing and coronary atherosclerosis in the development of cardiac fibrosis in the rabbit

Objective: Myocardial fibrosis contributes to the impairing of cardiac function and characterizes ageing, but is also a consequence of atherosclerotic ischemic disease. Since atherosclerosis is a slow progressive disease, which prevails in elderly populations, the aim of this study was to distinguish the contribution of ageing and atherosclerosis to cardiac fibrosis. Methods: Coronary atherosclerosis was induced in 5-6-year-old rabbits by a hyperlipemic diet for 9 months. Left ventricular (LV) coltagen was quantified by densitometric analysis after Sirius-Red staining; an immunohistochemical investigation of the interstitium was also performed. Results: Atherosclerosis was associated to a marked increase of left ventricular interstitial collagen with the appearance of fibrotic foci and a decrease of coronary vessel endothelial nitric oxide synthase (eNOS) expression. In fibrotic foci, abundant macrophages co-localized with transforming growth factor beta-1 (TGFbeta-1)-positive myofibroblasts and vascular cell adhesion molecule-1 (VCAM-1) positive microvessels (52.3 +/- 3.9%). In normocholesterolemic rabbits, ageing resulted in a fourfold increase of myocardial interstitial collagen, with alpha-smooth muscle actin and TGFbeta-1 negative fibroblasts and VCAM-1 positive microvessels (19.4 +/- 1.2%) without macrophages, suggesting a role of endothelial dysfunction in age-related fibrosis. Conclusions: There is a distinct difference between ageing and coronary atherosclerosis-induced cardiac fibrosis, although the effects may be cumulative. In the cascade of events leading to myocardial remodeling, reparative fibrosis with TGFbeta-1-positive myofibroblasts and interstitial inflammation were the major findings in atherosclerotic old rabbits, whereas with ageing alone, interstitial fibrosis with TGFbeta-1 negative fibroblasts and VCAM-I positive microvessels prevailed. (C) 2004 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.