Matrix Metalloproteinase Inhibition Attenuates Atrial Remodeling and Vulnerability to Atrial Fibrillation in a Canine Model of Heart Failure

Background: Atrial structural remodeling occurs in evolving heart failure (HF) and is an important substrate for the development of atrial fibrillation (AF). The matrix metalloproteinases (MMPs) play a role in extracellular remodeling. and recent studies have demonstrated increased atrial MMP activity ill HF. Whether increased MMP activity directly contributes to atrial remodeling and AF in the setting of HF remains unclear. The current study examined the effects of MMP inhibition oil atrial structural remodeling and AF vulnerability during HF progression. Methods and Results: Three of dogs (n = 5 each)-control normal dogs (controls) and 10 dogs subjected to simultaneous atrioventricular pacing (SAVP) for 2 weeks to induce HF and randomly assigned to treatment with placebo (SAVP-placebo) or a MMP inhibitor PGE-7113313, a MMp-1-sparing MMP inhibitor, 6 mg/kg orally twice daily (SAVP-MMPi)-were studied. SAVP-MMPi dogs had less AF inducibility (percent of burst attempts leading to AF episodes: 1.7 +/- 2.9 seconds vs. 23 +/- 19 seconds, mean +/- SD, P < .05) and maintenance (AF duration: 253 [105 to 326] vs. 1932 [1296 to 2724] seconds, median [25th-75th quartile] P < .05) than SAVP-placebo dogs. The SAVP-MMPi dogs had significantly smaller increases in atrial myocyte cross sectional area, collagen area fraction, and MMP-9 activity relative to controls than SAW-placebo. There were, however. no significant differences in the changes in chamber dimension and function in the left atrium. Conclusions: This unique finding of an attenuation oft lie vulnerability to AF in conjuction with reduced myocyte hypertrophy and fibrosis after MMP inhibition suggests that heightened MMP activity in the atria contributes to atrial structural remodeling and AF promotion during evolving HF. (J Cardiac Fail 2008:14:768-776)