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(Circulation. 2001;104:2216.)
© 2001 American Heart Association, Inc.

Basic Science Reports

Inhibition of Collagen Synthesis With Prolyl 4-Hydroxylase Inhibitor Improves Left Ventricular Function and Alters the Pattern of Left Ventricular Dilatation After Myocardial Infarction

John I. Nwogu, MD; David Geenen, PhD; Maurice Bean, BS; Mitchell C. Brenner, PhD; Xinfan Huang, MD; Peter M. Buttrick, MD

From the Section of Cardiology, University of Illinois at Chicago, Chicago, Ill (J.I.N., D.G., M.B., P.M.B.), and Fibrogen Inc, South San Francisco, Calif (M.C.B., X.H.).

Correspondence to Peter Buttrick, MD, University of Illinois at Chicago, 840 S Wood St, M/C 787, Chicago, IL 60612. E-mail buttrick{at}uic.edu

Background— Left ventricular (LV) remodeling after myocardial infarction (MI) is associated with fibrosis, dilatation, and dysfunction. We postulated that prevention of fibrosis after MI with a prolyl 4-hydroxylase inhibitor (P4HI) would preserve LV function and attenuate LV enlargement.

Methods and Results— Adult female rats (200 to 250 g) had experimental MI and were then randomized to treatment with P4HI (MI-FG041, n=29) or vehicle (MI-control, n=29) 48 hours after MI for 4 weeks in 2 phases. Echocardiograms were performed weekly with a 15-MHz linear transducer, and at 4 weeks, collagen isoform determinations and in vivo hemodynamics were performed. At randomization, the infarct size and LV function and size were similar in MI-FG041 and MI-control but significantly different from shams (n=9). At week 4, the LV function in MI-FG041 was significantly better than in MI-controls (fractional shortening 21% versus 16%, P=0.01; fractional area change 30% versus 19%, P=0.002; ejection fraction 35% versus 23%, P=0.001). In the FG041 group, LV area in systole was less (P<0.05), the dP/dt_max after isoproterenol was higher (P<0.05), and types I and III collagen in noninfarcted LV were less than in MI-control. The hydroxyproline/proline ratio was increased by 64% in MI-control and reduced to the sham value in MI-FG041 rats. In the scar tissue, it was reduced by 24% in MI-FG041.

Conclusions— This study demonstrates that prevention of interstitial fibrosis with a P4H inhibitor alters the pattern of LV enlargement and produces partial recovery of LV function after MI.

Key Words: myocardial infarction • collagen • remodeling

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