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(Circulation. 1999;100:981-987.)
© 1999 American Heart Association, Inc.

Basic Science Reports

Effects of Chronic Heparin Administration on Coronary Vascular Adaptation to Hypertension and Ventricular Hypertrophy in Sheep

Michael F. Flanagan, MD; Teruhiko Aoyagi, MD; Lucy W. Arnold, MD; Christine Maute, PhD; Alan M. Fujii, MD; Joseph Currier, MD; Dennis Bergau, MA; Henry B. Warren, VMD; Karel Rakusan, MD, PhD

From the Department of Pediatrics, Dartmouth Medical School, Hanover, NH (M.F.F., C.M.); the Department of Cardiology, Children's Hospital, Boston, Mass (M.F.F., T.A., L.W.A., A.M.F., J.C., D.B.); Harvard Medical School, Boston, Mass (H.B.W.); and the Department of Physiology, University of Ottawa, Ottawa, Ont, Canada (K.R.).

Correspondence to Michael F. Flanagan, MD, Pediatric Cardiology, Dartmouth-Hitchcock Medical Center, 1 Medical Center Dr, Lebanon, NH 03756. E-mail michael.f.flanagan{at}dartmouth.edu

Background—Hypertension decreases myocardial perfusion capacity in adults for several reasons, including insufficient coronary angiogenesis with left ventricular (LV) hypertrophy, arteriolar hypertrophy, and altered vasomotion. Heparin influences growth factors that promote angiogenesis and vasodilation and inhibit arteriolar wall thickening.

Methods and Results—Adult sheep were given heparin 200 U/kg body wt SC twice daily throughout 6 weeks of LV and coronary hypertension from a progressively constricted ascending aortic band (n=14). They were compared with untreated sheep with (n=13) and without (n=13) aortic stenosis. After 6 weeks, maximum myocardial perfusion was measured during adenosine infusion in the conscious state by the microsphere method. Sheep with aortic stenosis had less maximum coronary flow per gram, less conductance reserve, and thicker arteriolar walls in the LV and nonhypertrophied right ventricle. Capillary density decreased in the LV endomyocardium and remained unchanged in the right ventricle. Heparin-treated sheep had significant partial normalization of coronary conductance reserve and maximum perfusion in both ventricles and capillary density in the LV endomyocardium. Arteriolar wall thickness was unchanged. Compared with untreated sheep with aortic stenosis, in heparin-treated sheep LV FGF-2 protein increased 2-fold, whereas FGF-2 mRNA remained unchanged. VEGF mRNA and protein increased 3-fold and 1.4-fold, respectively, whereas TGF-ß₁ mRNA declined 3-fold.

Conclusions—Heparin administration during LV hypertension increases heparin-binding angiogenic factors FGF-2 and VEGF in the LV and ameliorates decreases in LV perfusion capacity and capillary density.

Key Words: heparin • angiogenesis • growth substances • hypertrophy • hypertension • microcirculation

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