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 in 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 on atrial structural remodeling and AF vulnerability during HF progression. METHODS AND RESULTS: Three groups 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 SAVP-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 of the vulnerability to AF in conjunction 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.

Simultaneous right atrioventricular pacing: a novel model to study atrial remodeling and fibrillation in the setting of heart failure.

BACKGROUND: Atrial fibrillation (AF) is a common arrhythmia which contributes to morbidity and mortality in patients with heart failure (HF). Atrial remodeling is a key substrate for the development of AF in HF. However, experimental models that study AF in the setting of HF have important limitations. We evaluated a new dog model of atrial remodeling and AF. METHODS AND RESULTS: Twenty-two mongrel dogs were randomized into 2 groups: 14 dogs with simultaneous atrioventricular pacing (SAVP) for 2 weeks (220 beats/min, no AV delay) and 8 control dogs with no pacing. SAVP for 2 weeks induced marked changes in atrial mechanical function and conduction. Left atrial area fractional shortening decreased 61 +/- 17%, whereas left ventricular area fractional shortening decreased by 38 +/- 18% from baseline (both P < .05). Conduction slowed and conduction heterogeneity increased. AF was induced in 83% of SAVP dogs, lasting a median of 1600 seconds, versus no dogs with induced AF in the controls. SAVP significantly increased nonfibrillar collagen in the mid-myocardium of both atrial appendages and matrix metalloproteinase-9 activity. CONCLUSIONS: SAVP in dogs induces structural and electrical remodelling that form the substrate for reproducibly inducible AF. This novel model may be useful for studies of the pathophysiology and treatment of AF in heart failure.

Experimental studies of atrial fibrillation: a comparison of two pacing models.

Rapid ventricular pacing (RVP) is a well-established animal model of atrial fibrillation (AF). However, this model is limited by a high mortality rate and severe heart failure. The purpose of our study was to assess a new canine model of inducible AF. We performed acute, short-term, simultaneous atrioventricular pacing (SAVP) and RVP (in random order) in 14 dogs for 30 s. SAVP produced more echocardiographic pulmonary venous flow reversal, a greater increase in mean pulmonary capillary wedge pressure, and a significantly greater decrease in left atrial emptying function (-84.4 +/- 38.6% vs. -23.7 +/- 27.1%, P < 0.05) than RVP. Thirty dogs were randomized to three, longer-term, study groups: eight dogs in the control group (no pacing), eight dogs in the RVP group (2 wk at 240 beats/min followed by 3 wk at 220 beats/min), and fourteen dogs in the SAVP group (2 wk at 220 beats/min). SAVP induced less left ventricular dysfunction but more left atrial dysfunction than RVP. SAVP dogs had similar atrial effective refractory periods as RVP dogs but more heterogeneity in conduction and more AF inducibility (83% vs. 40%, P < 0.05) and maintenance (median 1,660 vs. 710 s, P < 0.05) than RVP dogs. SAVP induced more collagen turnover and was associated with a significantly greater increase in type III collagen in the atria compared with RVP dogs (6.9 +/- 1.5 vs. 4.8 +/- 1.6, respectively, P < 0.05 vs. 1.1 +/- 0.7 in unpaced control dogs). In conclusion, the SAVP model induced profound mechanical and substrate atrial remodeling and reproducible sustained AF. This new model is clinically relevant and may be useful for testing AF interventions.