Targeting cardiac fibrosis: a new frontier in antiarrhythmic therapy?
Targeting cardiac fibrosis: a new frontier in antiarrhythmic therapy?
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针对心脏纤维化：抗心律失常治疗的新领域？
DOI：
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发表时间：
2011
期刊：
影响因子：
--
通讯作者：
H. Karagueuzian
中科院分区：
文献类型：
--
作者：
H. Karagueuzian
已知心脏纤维化可改变心脏传导并促进心脏再入。最近的证据表明，以间质胶原积累增加和肌成纤维细胞增殖增加为特征的纤维化也促进自动性增强和早期去极化（EADs），从而引起触发活动。纤维化因此成为致命心律失常管理的有效治疗靶点。虽然过氧化氢氧化应激(H（2)O(2)）在分离的大鼠和兔心室肌细胞中很容易促进EADs并触发其活性，但由于细胞间偶联引起的源-库不匹配，这种应激不能在偶联良好的非纤维化心脏中引起EADs。在老年纤维化心脏中触发的活动引起局灶性室性心动过速（VT），在出现空间不一致的动作电位持续时间交替导致波破、再入和VF后，在数秒内退化为心室颤动（VF）。在不同程度纤维化的二维组织中进行的计算机模拟显示，中度（但不是轻度或非常严重）纤维化促进了EADs和TA的发生。人体研究表明，心肌纤维化是心律失常的独立预测因子，包括持续性室性心动过速和室性心动过速。多种药物，包括torsemide，一种循环利尿剂，抑制心肌细胞外生成I型胶原分子的酶，肾素-血管紧张素-醛固酮系统（RAAS）的抑制剂，矿物皮质激素受体和内皮素受体，通过降低心肌硬度和改善心室功能来减少心脏纤维化。希望在不久的将来能够开发出有效的抗纤维化药物方案，以降低与纤维化相关的VT和VF的风险。
Cardiac fibrosis is known to alter cardiac conduction and promote reentry. Recent evidence indicates that fibrosis characterized by increased interstitial collagen accumulation and increased myofibroblast proliferation also promotes enhanced automaticity and early afterdepolarizations (EADs) causing triggered activity. Fibrosis then becomes an effective therapeutic target for the management of lethal cardiac arrhythmias. While oxidative stress with hydrogen peroxide (H(2)O(2)) is shown to readily promote EADs and triggered activity in isolated rat and rabbit ventricular myocytes however, this same stress fails to cause EADs in well-coupled, non-fibrotic hearts due to source-to-sink mismatches arising from cell-to-cell coupling. The triggered activity in the aged fibrotic hearts causes focal ventricular tachycardia (VT) that degenerates within seconds to ventricular fibrillation (VF) after the emergence of spatially discordant action potential duration alternans leading to wavebreak, reentry and VF. Computer simulations in 2D tissue incorporating variable degrees of fibrosis showed that intermediate (but not mild or very severe) fibrosis promoted EADs and TA. Human studies have shown that myocardial fibrosis was an independent predictor for arrhythmias including sustained VT and VF. A variety of drug classes including, torsemide, a loop diuretic, that inhibits the enzyme involved in the myocardial extracellular generation of collagen type I molecules and the inhibitors of the renin-angiotensin-aldosterone system (RAAS), the mineralocorticoid receptors and endothelin receptors reduce cardiac fibrosis with reduction of myocardial stiffness and improved ventricular function. It is hoped that in the near future effective antifibrotic drug regimen would be developed to reduce the risk of fibrosis related VT and VF.
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影响因子：
37.8
作者：
Pogwizd, SM;McKenzie, JP;Cain, ME
通讯作者：
Cain, ME
DOI：
10.1152/ajpheart.00579.2009
发表时间：
2009-11-01
影响因子：
4.8
作者：
Morita, Norishige;Sovari, Ali A.;Karagueuzian, Hrayr S.
通讯作者：
Karagueuzian, Hrayr S.
影响因子：
3.4
作者：
Xie, Yuanfang;Sato, Daisuke;Weiss, James N.
通讯作者：
Weiss, James N.
影响因子：
24
作者：
Morita, Norishige;Lee, Jong Hwan;Xie, Yuanfang;Sovari, Ali;Qu, Zhilin;Weiss, James N.;Karagueuzian, Hrayr S.
通讯作者：
Karagueuzian, Hrayr S.
DOI：
10.1016/s0735-1097(98)00184-3
发表时间：
1998-07-01
影响因子：
24
作者：
Wu, TJ;Ong, JJC;Chen, PS
通讯作者：
Chen, PS