Angiotensin-converting enzyme and matrix metalloproteinase inhibition withdeveloping heart failure: Comparative effects on left ventricular functionand geometry

The progression of congestive heart failure (CHF) is left ventricular (LV) myocardial remodeling. The matrix metalloproteinases (MMPs) contribute to t issue remodeling and therefore MMP inhibition may serve as a useful therape utic target in CHF. Angiotensin converting enzyme (ACE) inhibition favorabl y affects LV myocardial remodeling in CHF. This study examined the effects of specific MMP inhibition, ACE inhibition, and combined treatment on LV sy stolic and diastolic function in a model of CHF. Pigs were randomly assigne d to five groups: 1) rapid atrial pacing (240 beats/min) for 3 weeks (n = 8 ); 2) ACE inhibition (fosinopril, 2.5 mg/kg b.i.d. orally) and rapid pacing (n = 8); 3) MMP inhibition (PD166793 2 mg/kg/day p.o.) and rapid pacing (n = 8); 4) combined ACE and MMP inhibition (2.5 mg/kg b.i.d. and 2 mg/kg/day , respectively) and rapid pacing (n = 8); and 5) controls (n = 9). LV peak wall stress increased by 2-fold with rapid pacing and was reduced in all tr eatment groups. LV fractional shortening fell by nearly 2-fold with rapid p acing and increased in all treatment groups. The circumferential fiber shor tening-systolic stress relation was reduced with rapid pacing and increased in the ACE inhibition and combination groups. LV myocardial stiffness cons tant was unchanged in the rapid pacing group, increased nearly 2-fold in th e MMP inhibition group, and was normalized in the ACE inhibition and combin ation treatment groups. Increased MMP activation contributes to the LV dila tion and increased wall stress with pacing CHF and a contributory downstrea m mechanism of ACE inhibition is an effect on MMP activity.