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(Circulation. 2004;110:796-802.)
© 2004 American Heart Association, Inc.

Original Articles

Bradycardia Induces Angiogenesis, Increases Coronary Reserve, and Preserves Function of the Postinfarcted Heart

Li Lei, MD, PhD; Ruifeng Zhou, MD; Wei Zheng, MD; Lance P. Christensen, BS; Robert M. Weiss, MD; Robert J. Tomanek, PhD

From the Departments of Anatomy and Cell Biology (L.L., R.Z., W.Z., L.P.C., R.J.T.) and of Internal Medicine (R.M.W.) and the Cardiovascular Center (R.M.W., R.J.T.), University of Iowa Carver College of Medicine, and the Department of Veteran’s Affairs Medical Center (R.M.W.), Iowa City, Iowa. Dr Lei is currently with the Department of Internal Medicine, Yale University, New Haven, Conn.

Correspondence to Robert J. Tomanek, PhD, Department of Anatomy and Cell Biology, 1-402 Bowen Science Bldg, University of Iowa, Iowa City, IA 52242. E-mail robert-tomanek{at}uiowa.edu

Received April 13, 2004; revision received June 14, 2004; accepted June 24, 2004.

Background— We tested the hypothesis that induction of chronic bradycardia would trigger an upregulation of key growth factors and receptors, which would then lead to angiogenesis and improve coronary reserve in the left ventricle after myocardial infarction.

Methods and Results— Bradycardia was induced in rats by administering alinidine via osmotic pumps beginning 1 day after coronary artery ligation. Echocardiographic analysis was conducted before and after treatment. Morphometric analysis was used in perfusion-fixed hearts to document arteriolar and capillary growth. Western blots were used to evaluate growth factor and receptor changes. During the first week of treatment, vascular endothelial growth factor (VEGF), VEGF receptor 1 (Flt-1), and basic fibroblast growth factor proteins were higher in the treated group, whereas VEGF receptor 2 (Flk-1), angiopoietin-1, and angiopoietin-2 were not affected by treatment. After 3 weeks, VEGF protein remained elevated, and bradycardia was associated with a higher capillary length density in the border (40%) and remote (14%) regions and a higher arteriolar length density in the septum (62%), despite a greater increase in left ventricular mass. Although arteriolar length density increased in all size classes, the greatest increase occurred in the smallest (terminal) arterioles. This vascular growth was associated with a 23% greater coronary reserve. Echocardiography revealed a smaller increase in ventricular volume and a greater preservation of ejection fraction in rats treated with bradycardia.

Conclusions— Pharmacologic induction of bradycardia enhances vascularity and coronary reserve, preserves function of surviving myocardium, and therefore, is a noninvasive, therapeutic avenue that provides an alternative to gene therapy.

Key Words: growth substances • ischemia • capillaries • remodeling • echocardiography

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