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Vol. 291, Issue 2, 799-811, November 1999
Cardiothoracic Surgery, Medical University of South Carolina,
Charleston, South Carolina
The progression of congestive heart failure (CHF) is left ventricular
(LV) myocardial remodeling. The matrix metalloproteinases (MMPs)
contribute to tissue remodeling and therefore MMP inhibition may serve
as a useful therapeutic target in CHF. Angiotensin converting enzyme
(ACE) inhibition favorably affects LV myocardial remodeling in CHF.
This study examined the effects of specific MMP inhibition, ACE
inhibition, and combined treatment on LV systolic and diastolic function in a model of CHF. Pigs were randomly assigned 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 treatment groups. LV fractional shortening fell by
nearly 2-fold with rapid pacing and increased in all treatment groups.
The circumferential fiber shortening-systolic stress relation was
reduced with rapid pacing and increased in the ACE inhibition and
combination groups. LV myocardial stiffness constant was unchanged in
the rapid pacing group, increased nearly 2-fold in the MMP inhibition
group, and was normalized in the ACE inhibition and combination
treatment groups. Increased MMP activation contributes to the LV
dilation and increased wall stress with pacing CHF and a contributory
downstream mechanism of ACE inhibition is an effect on MMP activity.
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