Published Online
on August 9, 2004

A more recent version of this article appeared on August 17, 2004

This Article Full Text (PDF) All Versions of this Article: 110/7/796    most recent 01.CIR.0000138933.85923.36v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lei, L. Articles by Tomanek, R. J. Search for Related Content PubMed PubMed Citation Articles by Lei, L. Articles by Tomanek, R. J. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB CLONIDINE Medline Plus Health Information Heart Attack Related Collections Structure Pacemaker Angiogenesis Acute myocardial infarction Other Vascular biology

Submitted on April 13, 2004
Revised on June 14, 2004
Accepted on June 24, 2004

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, and 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.

^* To whom correspondence should be addressed. E-mail: robert-tomanek{at}uiowa.edu.

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

This article has been cited by other articles:

				L. P. Christensen, R.-l. Zhang, W. Zheng, J. J. Campanelli, E. I. Dedkov, R. M. Weiss, and R. J. Tomanek Postmyocardial infarction remodeling and coronary reserve: effects of ivabradine and beta blockade therapy Am J Physiol Heart Circ Physiol, July 1, 2009; 297(1): H322 - H330. [Abstract] [Full Text] [PDF]

				D. Logeart, J.-P. Gueffet, F. Rouzet, F. Pousset, C. Chavelas, A. C. Solal, and G. Jondeau Heart rate per se impacts cardiac function in patients with systolic heart failure and pacing: a pilot study Eur J Heart Fail, January 1, 2009; 11(1): 53 - 57. [Abstract] [Full Text] [PDF]

				M. Maczewski and U. Mackiewicz Effect of metoprolol and ivabradine on left ventricular remodelling and Ca2+ handling in the post-infarction rat heart Cardiovasc Res, July 1, 2008; 79(1): 42 - 51. [Abstract] [Full Text] [PDF]

				D. Leosco, G. Rengo, G. Iaccarino, L. Golino, M. Marchese, F. Fortunato, C. Zincarelli, E. Sanzari, M. Ciccarelli, G. Galasso, et al. Exercise promotes angiogenesis and improves {beta}-adrenergic receptor signalling in the post-ischaemic failing rat heart Cardiovasc Res, May 1, 2008; 78(2): 385 - 394. [Abstract] [Full Text] [PDF]

				V. Ciobotaru, M. Heimburger, L. Louedec, C. Heymes, R. Ventura-Clapier, P. Bedossa, B. Escoubet, J.-B. Michel, J.-J. Mercadier, and D. Logeart Effect of Long-Term Heart Rate Reduction by If Current Inhibition on Pressure Overload-Induced Heart Failure in Rats J. Pharmacol. Exp. Ther., January 1, 2008; 324(1): 43 - 49. [Abstract] [Full Text] [PDF]

				E. I. Dedkov, W. Zheng, L. P. Christensen, R. M. Weiss, F. Mahlberg-Gaudin, and R. J. Tomanek Preservation of coronary reserve by ivabradine-induced reduction in heart rate in infarcted rats is associated with decrease in perivascular collagen Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H590 - H598. [Abstract] [Full Text] [PDF]

				S. Gizurarson, M. Lorentzon, T. Ramunddal, F. Waagstein, L. Bergfeldt, and E. Omerovic Effects of complete heart block on myocardial function, morphology, and energy metabolism in the rat Europace, June 1, 2007; 9(6): 411 - 416. [Abstract] [Full Text] [PDF]

				E. I. Dedkov, W. Zheng, and R. J. Tomanek Compensatory growth of coronary arterioles in postinfarcted heart: regional differences in DNA synthesis and growth factor/receptor expression patterns Am J Physiol Heart Circ Physiol, October 1, 2006; 291(4): H1686 - H1693. [Abstract] [Full Text] [PDF]

				K. G. Lamping, W. Zheng, D. Xing, L. P. Christensen, J. Martins, and R. J. Tomanek Bradycardia Stimulates Vascular Growth During Gradual Coronary Occlusion Arterioscler Thromb Vasc Biol, October 1, 2005; 25(10): 2122 - 2127. [Abstract] [Full Text] [PDF]

				D. Chalothorn, H. Zhang, J. A. Clayton, S. A. Thomas, and J. E. Faber Catecholamines augment collateral vessel growth and angiogenesis in hindlimb ischemia Am J Physiol Heart Circ Physiol, August 1, 2005; 289(2): H947 - H959. [Abstract] [Full Text] [PDF]

				E. I. Dedkov, L. P. Christensen, R. M. Weiss, and R. J. Tomanek Reduction of heart rate by chronic {beta}1-adrenoceptor blockade promotes growth of arterioles and preserves coronary perfusion reserve in postinfarcted heart Am J Physiol Heart Circ Physiol, June 1, 2005; 288(6): H2684 - H2693. [Abstract] [Full Text] [PDF]

				M. Simons Angiogenesis: Where Do We Stand Now? Circulation, March 29, 2005; 111(12): 1556 - 1566. [Full Text] [PDF]

				B. H. Annex and M. Simons Growth factor-induced therapeutic angiogenesis in the heart: protein therapy Cardiovasc Res, February 15, 2005; 65(3): 649 - 655. [Abstract] [Full Text] [PDF]

				W. Zheng, L. P. Christensen, and R. J. Tomanek Stretch induces upregulation of key tyrosine kinase receptors in microvascular endothelial cells Am J Physiol Heart Circ Physiol, December 1, 2004; 287(6): H2739 - H2745. [Abstract] [Full Text] [PDF]

				Minerva BMJ, August 28, 2004; 329(7464): 520 - 520. [Full Text] [PDF]