Department of Biomedical Engineering, Washington University in St. Louis, MO 63130, USA.
Circulation. 2012 Apr 17;125(15):1835-47. doi: 10.1161/CIRCULATIONAHA.111.047274. Epub 2012 Mar 12.
Several arrhythmogenic mechanisms have been inferred from animal heart failure models. However, the translation of these hypotheses is difficult because of the lack of functional human data. We aimed to investigate the electrophysiological substrate for arrhythmia in human end-stage nonischemic cardiomyopathy.
We optically mapped the coronary-perfused left ventricular wedge preparations from human hearts with end-stage nonischemic cardiomyopathy (heart failure, n=10) and nonfailing hearts (NF, n=10). Molecular remodeling was studied with immunostaining, Western blotting, and histological analyses. Heart failure produced heterogeneous prolongation of action potential duration resulting in the decrease of transmural action potential duration dispersion (64 ± 12 ms versus 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 connexin 43 (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 wave breaks conditioned by strands of increased interstitial fibrosis (fibrous tissue content in heart failure 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 nonischemic cardiomyopathy.
从动物心衰模型中已经推断出几种致心律失常机制。然而，由于缺乏功能性的人体数据，这些假说的转化非常困难。我们旨在研究人类终末期非缺血性心肌病中心律失常的电生理基质。
我们对来自终末期非缺血性心肌病（心衰，n=10）和非衰竭心脏（NF，n=10）的冠状灌注左心室楔形标本进行光学标测。通过免疫染色、Western blot 和组织学分析研究分子重构。心衰导致动作电位时程不均匀延长，导致跨壁动作电位时程离散度降低（心衰时为 64±12ms，NF 时为 129±15ms，P<0.005）。在心衰心脏中，从心内膜（心衰时为 39±3cm/s，NF 时为 49±2cm/s，P=0.008）到心外膜（心衰时为 28±3cm/s，NF 时为 40±2cm/s，P=0.008）的激活明显减慢。传导减慢可能是由于连接蛋白 43（Cx43）下调、Cx43 与 N-钙粘蛋白的共定位减少（心衰时为 40±2%，NF 时为 52±5%，P=0.02），以及通过在内外膜层上调去磷酸化的 Cx43 导致磷酸化 Cx43 同工型的分布改变所致。衰竭的心脏进一步显示出空间上不一致的传导速度交替，导致不均匀的传播不连续性和波中断，这是由间质纤维化增加的条带引起的（心衰时的纤维组织含量为 16.4±7.7%，NF 时为 9.9±1.4%，P=0.02）。
由于 Cx43 表达的各向异性下调、Cx43 磷酸化减少和纤维化增加导致的传导障碍，可能是缺血性心肌病患者心律失常基质的一个关键组成部分。
