Moe Gordon W, Laurent Gabriel, Doumanovskaia Liia, Konig Andrea, Hu Xudong, Dorian Paul
Division of Cardiology, St. Michael's Hospital, Toronto, Ontario, Canada.
J Card Fail. 2008 Nov;14(9):768-76. doi: 10.1016/j.cardfail.2008.07.229. Epub 2008 Aug 22.
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.
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.
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.
心房结构重塑发生于进展性心力衰竭（HF）过程中，是心房颤动（AF）发生发展的重要基础。基质金属蛋白酶（MMPs）在细胞外重塑中发挥作用，近期研究表明HF时心房MMP活性增加。在HF背景下，MMP活性增加是否直接导致心房重塑和AF尚不清楚。本研究探讨了MMP抑制在HF进展过程中对心房结构重塑和AF易感性的影响。
三组犬（每组n = 5）——对照正常犬（对照组）以及10只接受房室同步起搏（SAVP）2周以诱导HF的犬，将后者随机分为接受安慰剂治疗（SAVP-安慰剂组）或MMP抑制剂PGE-7113313（一种保留MMP-1的MMP抑制剂，6 mg/kg，口服，每日2次）治疗（SAVP-MMPi组）并进行研究。与SAVP-安慰剂组相比，SAVP-MMPi组犬的AF诱发率（诱发AF发作的猝发刺激时间百分比：1.7±2.9秒 vs. 23±19秒，均值±标准差，P <.05）和维持率（AF持续时间：253 [105至326] vs. 1932 [1296至2724]秒，中位数[第25 - 75四分位数]，P <.05）更低。与对照组相比，SAVP-MMPi组犬心房肌细胞横截面积、胶原面积分数和MMP-9活性的增加幅度显著小于SAVP-安慰剂组。然而，左心房腔大小和功能的变化无显著差异。
MMP抑制后AF易感性降低，同时心肌细胞肥大和纤维化减轻，这一独特发现表明，在进展性HF过程中，心房MMP活性升高有助于心房结构重塑和AF的发生发展。
