Inhibition of collagen synthesis with prolyl 4-hydroxylase inhibitor improves left ventricular function and alters the pattern of left ventricular dilatation after myocardial infarction.

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.

• 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.)

Chemical References

• Enzyme Inhibitors
• Collagen
• Proline
• Procollagen-Proline Dioxygenase
• Hydroxyproline

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)