Heterogeneous Connexin43 distribution in heart failure is associated with dispersed conduction and enhanced susceptibility to ventricular arrhythmias
Heterogeneous Connexin43 distribution in heart failure is associated with dispersed conduction and enhanced susceptibility to ventricular arrhythmias
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DOI：
10.1093/eurjhf/hfq092
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发表时间：
2010-09-01
影响因子：
18.2
通讯作者：
van Rijen, Harold V. M.
中科院分区：
文献类型：
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作者：
Boulaksil, Mohamed;Winckels, Stephan K. G.;van Rijen, Harold V. M.
目的 心律失常性心源性猝死是充血性心力衰竭 (CHF) 患者死亡的主要原因。为了研究致心律失常易感性增加的决定因素，我们研究了 CHF 患者和慢性压力超负荷小鼠模型的心脏重塑和致心律失常性。 方法和结果 将记录有 (VT+) 和无 (VT-) 室性心律失常的 CHF 患者心肌活检的临床和（免疫）组织学数据与对照进行比较。在 CHF 患者中，射血分数降低，QRS 时限延长。细胞大小和间质纤维化增加，但心室肌中最丰富的间隙连接 Connexin43 (Cx43) 水平没有变化。除了 Cx43 的分布模式外，VT+ 和 VT- 患者之间没有发现差异，VT+ 患者的 Cx43 分布模式明显更加异质。对小鼠进行横向主动脉缩窄术（TAC）或假手术。第 16 周时，通过超声心动图测定心功能，并进行心外膜心室激活图测。横主动脉缩窄小鼠的缩短分数减少，QRS 时限延长。 44% TAC 和 0% 假小鼠中右心室传导速度降低，并诱导多态性室速。在有或没有心律失常的 TAC 小鼠中，间质纤维化增加，而 Cx43 数量没有变化。与 CHF 患者类似，TAC 小鼠中 Cx43 的异质分布与心律失常以及冲动传导的空间异质性显着相关。 结论 CHF 期间 Cx43 的异质表达与分散的冲动传导相关，可能是室性快速心律失常易感性增强的基础。
Aims Sudden arrhythmogenic cardiac death is a major cause of mortality in patients with congestive heart failure (CHF). To investigate determinants of the increased arrhythmogenic susceptibility, we studied cardiac remodelling and arrhythmogenicity in CHF patients and in a mouse model of chronic pressure overload.Methods and results Clinical and (immuno) histological data of myocardial biopsies from CHF patients with (VT+) and without (VT-) documented ventricular arrhythmia were compared with controls. In CHF patients, ejection fraction was decreased and QRS duration was increased. Cell size and interstitial fibrosis were increased, but Connexin43 (Cx43) levels, the most abundant gap junction in ventricular myocardium, were unchanged. No differences were found between VT+ and VT- patients, except for the distribution pattern of Cx43, which was significantly more heterogeneous in VT+. Mice were subjected to transverse aortic constriction (TAC) or sham operated. At 16 weeks, cardiac function was determined by echocardiography and epicardial ventricular activation mapping was performed. Transverse aortic constriction mice had decreased fractional shortening and prolonged QRS duration. Right ventricular conduction velocity was reduced, and polymorphic VTs were induced in 44% TAC and 0% sham mice. Interstitial fibrosis was increased and Cx43 quantity was unchanged in TAC mice with and without arrhythmias. Similar to CHF patients, heterogeneous Cx43 distribution was significantly associated with arrhythmias in TAC mice and with spatial heterogeneity of impulse conduction.Conclusion Heterogeneous Cx43 expression during CHF is associated with dispersed impulse conduction and may underlie enhanced susceptibility to ventricular tachyarrhythmias.