Selective inhibition of matrix metalloproteinase species favorably modifies left ventricular remodeling post myocardial infarction

Background: A contributory mechanism for left ventricular (LV) dilation post myocardial infarction (MI) is increased expression and activation of the matrix metalloproteinases (MMPs). Animal models have demonstrated that broad spectrum pharmacological MMP inhibition (MMPI) can attenuate the adverse remodeling process post-MI. Over 20 MMP species have been identified with many playing critical roles in normal physiological processes. Thus, identification of a more focused MMPI profile which can achieve favorable effects on LV remodeling post-MI is warranted. For example, the interstitial collagenase MMP-1, matrilysin (MMP-7), and stromelysin (MMP-3) play important roles in non-cardiac related biological processes. Methods and Results: The effects of selective MMPI were examined in a pig MI model (30 kg, circumflex ligation) assigned to the following groups: MMPI 1/7 sparing (PGE-530742:10 mg/kg-PO/TID, n = 11); MMPI 1/3/7 sparing (1 mg/kg-PO/TID, n = 11), MI Only (no treatment, n = 11), and Control (n = 11). MMPI was started 3 days before MI and dosing determined by pharmacokinetics and MMP bioassays in order to develop MMPI sparing effects. At 10 days post-MI, LV end-diastolic volume (LVEDV) and ejection fraction LVEF were measured by ventriculography. MI size was 47±3% and similar in all MMPI groups. LVEDV increased (82±3 vs 56±3 mL, p<0.05) and LVEF decreased (62±2 vs 71±2 %, P,0.05) in the MI only group compared to controls. LVEDV was reduced from untreated MI values with MMPI 1/7 or MMPI 1/3/7 sparing (67±3 and 69±3 mL, respectively, p<0.05), but remained increased from controls (p<0.05). With MMPI 1/7 or MMPI 1/3/7, LVEF was not different from control (66±3, 68±3%). Conclusion: Thus, broad-spectrum MMP inhibition is not necessary to modulate post-MI remodeling. Moreover, the present study demonstrated that MMP-1, MMP-3, and MMP-7 activity are not likely to contribute to post-MI LV remodeling. Development of an MMP species-specific pharmacological inhibitory profile that attenuates adverse LV remodeling post MI holds therapeutic promise.