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

Background-Left ventricular (LV) remodeling after myocardial infarction (MI ) is associated with fibrosis, dilatation, and dysfunction. We postulated t hat 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 an d 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. Echocardiogram s were performed weekly with a 15-MHz linear transducer, and at 4 weeks, co llagen isoform determinations and in vivo hemodynamics were performed. At r andomization, 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 FG0 41 group, LV area in systole was less (P <0.05), the dP/dt(max) after isopr oterenol 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 incr eased 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 fibrosi s with a P4H inhibitor alters the pattern of LV enlargement and produces pa rtial recovery of LV function after MI.