Effects of Matrix Metalloproteinase Inhibition on Ventricular Remodeling Due to Volume Overload

Abstract

Background — Left ventricular (LV) hypertrophy and dilatation are important compensatory responses to chronic volume overload. Although LV function is initially preserved by these responses, the continued structural remodeling of the myocardium ultimately becomes maladaptive, leading to the development of heart failure. We have shown previously that increased myocardial matrix metalloproteinase (MMP) activity precedes LV dilatation induced by a chronic volume overload. Accordingly, this study focused on the effects of MMP inhibition therapy (PD 166793, 1 mg · kg −1 · d −1 ) on LV size and function in a rat model of volume overload–induced heart failure. Methods and Results — Rats were divided into the following groups: treated and untreated infrarenal abdominal aortocaval fistula and treated and untreated sham-operated (control). LV weights of both fistula groups were increased above that of the control group (868±79 mg; P ≤0.001); LV weights in the treated fistula group, however, were lower than in the untreated fistula group at 8 weeks (1447±186 versus 1715±279 mg, respectively; P ≤0.012). The marked ventricular dilatation seen in the untreated fistula group was significantly diminished in the treated fistula group, although the increase in LV compliance was similar in both treated and untreated fistula hearts. Conclusions — MMP inhibition significantly attenuates the myocardial remodeling associated with chronic volume overload, as evidenced by prevention of dilatation, a marked reduction in LV hypertrophy, and preservation of ventricular function.