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Cardiovascular Research 2004 64(3):544-552; doi:10.1016/j.cardiores.2004.07.024
© 2004 by European Society of Cardiology
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Copyright © 2004, European Society of Cardiology

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

Augusto Orlandia,*, Arianna Francesconia, Marcella Marcellinib, Amedeo Ferlosioa and Luigi Giusto Spagnolia

aDepartment of Biopathology and Image Diagnostics, Anatomic Pathology Institute, Tor Vergata University of Rome, Via della Ricerca Scientifica, 00133 Rome, Italy
bSigma-Tau Research Laboratories, Pomezia (Rome), Italy

* Corresponding author. Tel.: +39 6 20903960; fax: +39 6 20902209. Email address: orlandi{at}uniroma2.it

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) collagen 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 (TGFβ-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 TGFβ-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 TGFβ-1-positive myofibroblasts and interstitial inflammation were the major findings in atherosclerotic old rabbits, whereas with ageing alone, interstitial fibrosis with TGFβ-1 negative fibroblasts and VCAM-1 positive microvessels prevailed.

KEYWORDS Ageing; Atherosclerosis; Extracellular matrix; Remodeling; Endothelial function

Time for primary review 22 days


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