Atherosclerosis 185 (2006) 278–281 The combination of high dietary methionine plus cholesterol induces myocardial fibrosis in rabbits Anthony Zulli a,c,∗ , David L. Hare a,c , Brian F. Buxton b , M. Jane Black d a Vascular Laboratory, Department of Cardiology, University of Melbourne, Austin Health, Heidelberg, Australia b Department of Cardiac Surgery, University of Melbourne, Austin Health, Australia c Department of Medicine, University of Melbourne, Austin Health, Australia d Department of Anatomy and Cell Biology, Monash University, Clayton, Australia Received 18 April 2005; received in revised form 7 June 2005; accepted 21 June 2005 Available online 27 July 2005 Abstract Limited evidence suggests that myocardial fibrosis might be associated with dietary cardiovascular risk factors. Objective: To investigate the effects of high dietary cholesterol, methionine (the precursor to homocysteine), and the combination of the two diets on myocardial fibrosis. Methods: Rabbits were randomly allocated into four dietary groups for 12 weeks: control (Con), 1% methionine (Meth), 0.5% cholesterol (Chol) or 1% methionine plus 0.5% cholesterol (MethChol). Results: Myocardial fibrosis was not significantly increased in Chol or Meth. However, interstitial fibrosis increased by 85% (p = 0.03) and perivascular fibrosis 28-fold (p < 0.01) in the MethChol group compared to Con. Conclusions: These results suggest that high levels of dietary cholesterol or methionine alone do not significantly increase myocardial collagen content. However, the combination of the two diets does cause myocardial fibrosis. Therefore, excessive cholesterol and methionine intake may be an important pathogenic factor in the development of myocardial fibrosis. © 2005 Published by Elsevier Ireland Ltd. Keywords: Cholesterol; Homocysteine; Myocardial fibrosis 1. Introduction Myocardial fibrosis develops as a usual sequelae of aging in humans. This has detrimental effects on myocardial function, especially left ventricular diastolic filling. Cardiac fibrosis can be characterized into three main types: (a) interstitial fibrosis, whereby fibrillar collagen is thickened in intermuscular spaces previously devoid of collagen; (b) perivascular fibrosis, in which collagen accumulates within the adventitia of intramyocardial coronary arteries; and (c) replacement/reparative fibrosis, in which scarring follows cardiomyocyte cell loss after myocardial infarction [1]. ∗ Corresponding author. Tel.: 61 3 9496 2955; fax: 61 3 9497 4554. E-mail address: azulli@unimelb.edu.au (A. Zulli). Interstitial fibrosis (two- to three-fold rise in collagen type I) can increase the diastolic stiffness of the heart [2,3], and, after prolonged periods of collagen accumulation, can even produce systolic dysfunction with chamber dilation and impaired ejection fraction [4]. Microfibrosis can result in the isolation of cardiomyocyte groups by collagen, reduction in gap junctions in the heart, and thus electrical load variations that can trigger arrhythmias [5]. To date, there are no reports that have investigated the effects of high dietary methionine (the precursor to homocys- teine) or cholesterol on the development of myocardial fibro- sis. Furthermore, as methionine and cholesterol are found primarily in the same foods, such as meat, eggs, and milk, it is important to evaluate the effect of the combination of these two dietary components. 0021-9150/$ – see front matter © 2005 Published by Elsevier Ireland Ltd. doi:10.1016/j.atherosclerosis.2005.06.036