Matrix Metalloproteinase Inhibition Attenuates Atrial Remodeling and Vulnerability to Atrial Fibrillation in a Canine Model of Heart Failure
Matrix Metalloproteinase Inhibition Attenuates Atrial Remodeling and Vulnerability to Atrial Fibrillation in a Canine Model of Heart Failure
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DOI：
10.1016/j.cardfail.2008.07.229
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发表时间：
2008-11-01
影响因子：
6
通讯作者：
Dorian, Paul
中科院分区：
文献类型：
--
作者：
Moe, Gordon W.;Laurent, Gabriel;Dorian, Paul
背景：心房结构重塑发生在不断发展的心力衰竭（HF）中，是心房颤动（AF）发展的重要基础。基质金属蛋白酶（MMP）在细胞外重塑中发挥作用。最近的研究表明心力衰竭时心房 MMP 活性增加。心力衰竭时 MMP 活性增加是否直接导致心房重构和房颤尚不清楚。目前的研究检查了 MMP 抑制油对心力衰竭进展期间心房结构重塑和 AF 脆弱性的影响。方法和结果：三只狗（每只 n = 5）对照正常狗（对照）和 10 只狗接受同步房室起搏 (SAVP) 2 周以诱发心力衰竭，并随机分配接受安慰剂 (SAVP-安慰剂) 或 MMP 抑制剂治疗 研究了 PGE-7113313，一种保留 MMp-1 的 MMP 抑制剂，每天两次口服 6 mg/kg (SAVP-MMPi)。 SAVP-MMPi 犬的 AF 诱发性（导致 AF 发作的突发尝试百分比：1.7 +/- 2.9 秒与 23 +/- 19 秒，平均值 +/- SD，P < .05）和维持时间（AF 持续时间：253 [105 至 326] 与 1932 [1296 至 2724] 秒，中位数 [第 25-75 个四分位数] P < .05) 比 SAVP-安慰剂 狗。与对照组相比，SAVP-MMPi 狗的心房肌细胞横截面积、胶原面积分数和 MMP-9 活性的增加显着小于 SAW 安慰剂。然而，确实有。左心房的心室尺寸和功能的变化没有显着差异。结论：这一独特的发现往往导致房颤易感性减弱，同时抑制 MMP 后心肌细胞肥大和纤维化减少，表明心房中 MMP 活性的增强有助于心房结构重塑和房颤发展过程中的房颤促进。 (J 心脏衰竭 2008:14:768-776)
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)