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Simvastatin Prevents Coronary Microvascular Remodeling in Renovascular Hypertensive Pigs

Xiang-Yang Zhu^*, Elena Daghini^*, Alejandro R. Chade^*, Claudio Napoli, Erik L. Ritman, Amir Lerman and Lilach O. Lerman^*,

Department of Internal Medicine, Divisions of ^* Hypertension and Nephrology and Cardiovascular Diseases, Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, Minnesota; and Research Center of Excellence in Cardiovascular Diseases and Departments of General Pathology and Medicine, University of Naples, Naples, Italy, and Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University, Boston, Massachusetts

Address correspondence to: Dr. Lilach O. Lerman, Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905. Phone: 507-284-4695; Fax: 507-266-9316; E-mail: lerman.lilach{at}mayo.edu

Received for publication September 7, 2006. Accepted for publication January 26, 2007.

Patients with hypertension and chronic kidney disease are at risk for cardiovascular diseases, possibly related to inflammation. Statins have beneficial anti-inflammatory effects on vascular structure regardless of cholesterol reduction. It was hypothesized that alterations in myocardial microvascular structure in swine renovascular hypertension (RVH) would be improved by simvastatin treatment. Three groups of pigs were studied after 12 wk: Normal (n = 7), RVH (n = 7), or RVH+simvastatin (RVH+S; 80 mg/d; n = 6). Left ventricular muscle mass and myocardial perfusion were determined in vivo using electron beam computed tomography, and myocardial samples then were scanned ex vivo using micro-computed tomography for measurement of the spatial density of myocardial microvessels (80 to 500 µm) in situ. Capillary density and myocardial expression of inflammatory and growth factors were determined in myocardial tissue. The effects of simvastatin on inflammation-induced tube formation were evaluated in vitro in human umbilical vein endothelial cells that were exposed to TNF-. RVH and RVH+S had similarly increased arterial pressure and serum creatinine. However, left ventricular hypertrophy was prevented by simvastatin, and myocardial perfusion was increased. Compared with normal, RVH showed increased spatial density of microvessels (169.6 ± 21 versus 107.7 ± 15.2 vessels/cm²; P < 0.05), which was decreased in RVH+S (72.5 ± 14.9 vessels/cm²), whereas capillary density remained similar to normal. RVH also increased myocardial expression of inflammatory and growth factors, which were reversed by simvastatin. Furthermore, simvastatin attenuated TNF-–induced angiogenesis in vitro. Simvastatin prevents myocardial microvascular remodeling and hypertrophy in experimental RVH independent of lipid lowering. This protective effect is partly mediated by blunted expression as well as angiogenic activity of inflammatory cytokines.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673