Abstract |
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.
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Authors | J I Nwogu, D Geenen, M Bean, M C Brenner, X Huang, P M Buttrick |
Journal | Circulation
(Circulation)
Vol. 104
Issue 18
Pg. 2216-21
(Oct 30 2001)
ISSN: 1524-4539 [Electronic] United States |
PMID | 11684634
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Enzyme Inhibitors
- Collagen
- Proline
- Procollagen-Proline Dioxygenase
- Hydroxyproline
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Topics |
- Animals
- Collagen
(biosynthesis)
- Dilatation, Pathologic
(etiology, physiopathology, prevention & control)
- Disease Models, Animal
- Echocardiography
- Enzyme Inhibitors
(blood, pharmacology)
- Female
- Fibrosis
(pathology, prevention & control)
- Heart Ventricles
(diagnostic imaging, drug effects, pathology, physiopathology)
- Hemodynamics
(drug effects)
- Hydroxyproline
(metabolism)
- Myocardial Infarction
(complications, drug therapy, physiopathology)
- Procollagen-Proline Dioxygenase
(antagonists & inhibitors, metabolism)
- Proline
(metabolism)
- Rats
- Rats, Wistar
- Recovery of Function
(drug effects)
- Stroke Volume
(drug effects)
- Ventricular Function, Left
(drug effects)
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