Conduction remodeling in human end-stage nonischemic left ventricular cardiomyopathy.
Conduction remodeling in human end-stage nonischemic left ventricular cardiomyopathy.
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DOI：
10.1161/circulationaha.111.047274
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发表时间：
2012-04-17
期刊：
影响因子：
37.8
通讯作者：
Efimov IR
中科院分区：
文献类型：
--
作者：
Glukhov AV;Fedorov VV;Kalish PW;Ravikumar VK;Lou Q;Janks D;Schuessler RB;Moazami N;Efimov IR
已经从动物心力衰竭（HF）模型中推断出几种致心脏病的机制。然而，由于缺乏功能性的人类数据，这些假设的翻译是困难的。我们的目的是研究人类终末期非缺血性心肌病心律失常的电生理基础。我们光学映射冠状动脉灌注左心室楔形准备与终末期非缺血性心肌病（HF，n=10）和非衰竭的心脏（NF，n=10）。用免疫染色、蛋白质印迹和组织学分析研究分子重塑。HF引起动作电位时程（APD）不均一性延长，跨壁APD离散度（64±12 ms）较NF（129±15 ms）明显降低（P<0.005）。在衰竭心脏中，从内膜（39±3 cm/s）到心外膜（28±3 cm/s）的跨壁激活显著减慢，NF为49±2 cm/s，P=0.008，NF为40±2 cm/s，P=0.008。传导减慢可能是由于Cx43下调，Cx43与N-钙粘蛋白共定位减少（NF中为40±2% vs 52±5%，P=0.02），以及由于去磷酸化Cx43在心内膜下和心外膜下的上调而改变磷酸化Cx43亚型的分布。衰竭的心脏进一步表现出空间上不一致的传导速度交替，这导致不均匀的传播中断和由增加的间质纤维化链调节的波破裂（HF中的纤维组织含量为16.4± 7.7%，NF中为9.9±1.4%，P=0.02）。由Cx43表达的各向异性下调、Cx43磷酸化的减少和纤维化的增加导致的传导障碍可能是非缺血性心肌病患者中致炎性底物的关键组分。
Several arrhythmogenic mechanisms have been inferred from animal heart failure (HF) models. However, the translation of these hypotheses is difficult due to lack of functional human data. We aimed to investigate the electrophysiological substrate for arrhythmia in human end-stage non-ischemic cardiomyopathy. We optically mapped the coronary-perfused left ventricular wedge preparations from human hearts with end-stage non-ischemic cardiomyopathy (HF, n=10) and non-failing hearts (NF, n=10). Molecular remodeling was studied with immunostaining, Western blotting, and histological analyses. HF produced heterogeneous prolongation of action potential duration (APD) resulting in the decrease of transmural APD dispersion (64±12 ms vs 129±15 ms in NF, P<0.005). In the failing hearts, transmural activation was significantly slowed from the endocardium (39±3 cm/s versus 49±2 cm/s in NF, P=0.008) to the epicardium (28±3 cm/s versus 40±2 cm/s in NF, P=0.008). Conduction slowing was likely due to Cx43 downregulation, decreased colocalization of Cx43 with N-cadherin (40±2% versus 52±5% in NF, P=0.02), and an altered distribution of phosphorylated Cx43 isoforms by the upregulation of the dephosphorylated Cx43 in both the subendocardium and subepicardium layers. Failing hearts further demonstrated spatially discordant conduction velocity alternans which resulted in nonuniform propagation discontinuities and wavebreaks conditioned by strands of increased interstitial fibrosis (fibrous tissue content in HF 16.4±7.7 versus 9.9±1.4% in NF, P=0.02). Conduction disorder resulting from the anisotropic downregulation of Cx43 expression, the reduction of Cx43 phosphorylation, and increased fibrosis is likely to be a critical component of arrhythmogenic substrate in patients with non-ischemic cardiomyopathy.