Selective matrix metalloproteinase inhibition attenuates progression of left ventricular dysfunction and remodeling...

Area of Science:

• Cardiovascular Research
• Pharmacology
• Biochemistry

Background:

• Matrix metalloproteinases (MMPs) are implicated in the progression of left ventricular (LV) dysfunction and adverse remodeling in heart failure (HF).
• Selective MMP inhibition presents a potential therapeutic strategy for managing HF progression.

Purpose of the Study:

• To investigate the long-term effects of a selective MMP inhibitor, PG-530742 (PG), on the progression of LV dysfunction and remodeling in a canine model of chronic heart failure.
• To determine the dose-dependent efficacy of PG in preventing adverse cardiac remodeling and improving LV function.

Main Methods:

• Chronic heart failure was induced in 24 dogs via sequential intracoronary microembolizations.
• Dogs were randomized to 3 months of high-dose (HD) PG (3.5 mg/kg), low-dose (LD) PG (0.2 mg/kg), or placebo (PL).
• Hemodynamic and echocardiographic measurements, alongside histological analysis of cardiac tissue and mRNA expression of MMPs, were performed before and after treatment.

Main Results:

• High-dose PG treatment significantly increased LV ejection fraction and reduced LV end-systolic and end-diastolic volumes.
• HD-PG therapy led to significant reductions in replacement fibrosis, interstitial fibrosis, and myocyte cross-sectional area compared to placebo.
• Reduced mRNA expression of selective MMPs was observed in the LV tissue of HD-PG treated dogs, but not in LD-PG treated dogs.

Conclusions:

• Long-term monotherapy with high-dose selective MMP inhibitor PG-530742 effectively prevents adverse LV remodeling and the progression of global LV dysfunction in dogs with moderate heart failure.
• The findings suggest a dose-dependent therapeutic effect of MMP inhibition in mitigating heart failure progression.
• Selective MMP inhibition warrants further investigation as a potential treatment for heart failure.