Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States of America; Department of Physiology, Biophysics Rush University Medical Center, Chicago, IL, United States of America.
Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States of America.
J Mol Cell Cardiol. 2021 Sep;158:72-81. doi: 10.1016/j.yjmcc.2021.05.012. Epub 2021 May 31.
Both gap junctional remodeling and interstitial fibrosis have been linked to impaired electrical conduction velocity (CV) and fatal ventricular arrhythmias in nonischemic heart failure (HF). However, the arrhythmogenic role of the ventricular gap junctional Cx43 in nonischemic HF remains in debate. Here, we assessed this in a newly developed arrhythmogenic canine model of nonischemic HF.
Nonischemic HF was induced in canines by combined aortic valve insufficiency and aortic constriction. Left ventricular (LV) myocardium from HF dogs showed similar pathological changes to that of humans. HF dogs had reduced LV function, widened QRS complexes, and spontaneous nonsustained ventricular tachycardia. CV was measured in intact LV epicardium with high-density grid mapping. Total (Cx43-T) and nonphosphorylated Cx43 (Cx43-NP) and histological interstitial fibrosis were assessed from these mapped LV tissues. Longitudinal CV, which was slowed in HF (49 ± 1 vs. 65 ± 2 cm/s in Ctl), was positively correlated with reduced total junctional Cx43 and negatively correlated with markedly increased junctional Cx43-NP (2-fold) in HF. Cx43 dephosphorylation in HF was associated with enhanced colocalization of PP2A at the level of Cx43. Unchanged action potential upstroke and transverse CV were associated with unaltered Cx43 lateralization and interstitial fibrosis in the nonischemic HF canine LV.
Our unique arrhythmogenic canine model of HF resembles human nonischemic HF (prior to the end stage). Cx43 remodeling occurs prior to the structural remodeling (with lack of fibrosis) in HF and it is crucial in slowed CV and ventricular arrhythmia development. Our findings suggest that altered Cx43 alone is arrhythmogenic and modulation of Cx43 has the anti-arrhythmic therapeutic potential for HF patients.
在非缺血性心力衰竭（HF）中，缝隙连接重塑和间质纤维化均与电传导速度（CV）受损和致命性室性心律失常有关。然而，非缺血性 HF 中心室缝隙连接 Cx43 的致心律失常作用仍存在争议。在这里，我们在新开发的非缺血性 HF 致心律失常犬模型中对此进行了评估。
通过主动脉瓣关闭不全和主动脉缩窄联合诱导犬发生非缺血性 HF。HF 犬的左心室（LV）心肌表现出与人相似的病理变化。HF 犬的 LV 功能降低，QRS 波群增宽，并出现自发性非持续性室性心动过速。通过高密度网格映射测量完整 LV 心外膜中的 CV。从这些映射的 LV 组织中评估总（Cx43-T）和非磷酸化 Cx43（Cx43-NP）以及组织学间质纤维化。在 HF 中，纵向 CV 减慢（HF 为 49±1cm/s，对照为 65±2cm/s），与总连接 Cx43 减少呈正相关，与 HF 中明显增加的连接 Cx43-NP（2 倍）呈负相关。HF 中 Cx43 的去磷酸化与 PP2A 在 Cx43 水平上的增强募集有关。不变的动作电位上升和横向 CV 与非缺血性 HF 犬 LV 中不变的 Cx43 侧向化和间质纤维化有关。
我们的 HF 致心律失常犬模型独特，类似于人类的非缺血性 HF（在终末期之前）。在 HF 中，Cx43 重塑发生在结构重塑（无纤维化）之前，它在 CV 减慢和室性心律失常发展中起着至关重要的作用。我们的研究结果表明，改变的 Cx43 本身是致心律失常的，并且 Cx43 的调节对 HF 患者具有抗心律失常的治疗潜力。
