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

• Published in: Circulation (New York, N.Y.) Vol. 104; no. 18; pp. 2216 - 2221
• Main Authors: NWOGU, John I, GEENEN, David, BEAN, Maurice, BRENNER, Mitchell C, XINFAN HUANG, BUTTRICK, Peter M
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 30.10.2001; American Heart Association, Inc
• Subjects: Animals; Biological and medical sciences; Cardiovascular system; Collagen - biosynthesis; Dilatation, Pathologic - etiology; Dilatation, Pathologic - physiopathology; Dilatation, Pathologic - prevention & control; Disease Models, Animal; Echocardiography; Enzyme Inhibitors - blood; Enzyme Inhibitors - pharmacology; Female; Fibrosis - pathology; Fibrosis - prevention & control; Heart Ventricles - diagnostic imaging; Heart Ventricles - drug effects; Heart Ventricles - pathology; Heart Ventricles - physiopathology; Hemodynamics - drug effects; Hydroxyproline - metabolism; Medical sciences; Miscellaneous; Myocardial Infarction - complications; Myocardial Infarction - drug therapy; Myocardial Infarction - physiopathology; Pharmacology. Drug treatments; Procollagen-Proline Dioxygenase - antagonists & inhibitors; Procollagen-Proline Dioxygenase - metabolism; Proline - metabolism; Rats; Rats, Wistar; Recovery of Function - drug effects; Stroke Volume - drug effects; Ventricular Function, Left - drug effects; Infarct; Rat; Treatment efficiency; Rodentia; Cardiovascular disease; Exploration; Biosynthesis; Remodeling; Coronary heart disease; Myocardial disease; Left ventricle; Vertebrata; Chemotherapy; Mammalia; Functional recovery; Treatment; Animal; Collagen; Myocardium; Inhibitor; Left ventricle performance
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/hc4301.097193

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.