Department of Internal Medicine II, University Medical Center Regensburg, Regensburg, Germany.
Department of Cardiology and Pneumology, University Hospital, Georg-August University Goettingen, and DZHK (German Centre for Cardiovascular Research), partner site Goettingen, Goettingen, Germany.
ESC Heart Fail. 2019 Feb;6(1):154-163. doi: 10.1002/ehf2.12378. Epub 2018 Oct 30.
In hypertrophy and heart failure, the proarrhythmic persistent Na current (I ) is enhanced. We aimed to investigate the electrophysiological role of neuronal sodium channel Na 1.8 in human hypertrophied myocardium.
Myocardial tissue of 24 patients suffering from symptomatic severe aortic stenosis and concomitant significant afterload-induced hypertrophy with preserved ejection fraction was used and compared with 12 healthy controls. We performed quantitative real-time PCR and western blot and detected a significant up-regulation of Na 1.8 mRNA (2.34-fold) and protein expression (1.96-fold) in human hypertrophied myocardium compared with healthy hearts. Interestingly, Na 1.5 protein expression was significantly reduced in parallel (0.60-fold). Using whole-cell patch-clamp technique, we found that the prominent I was significantly reduced after addition of novel Na 1.8-specific blockers either A-803467 (30 nM) or PF-01247324 (1 μM) in human hypertrophic cardiomyocytes. This clearly demonstrates the relevant contribution of Na 1.8 to this proarrhythmic current. We observed a significant action potential duration shortening and performed confocal microscopy, demonstrating a 50% decrease in proarrhythmic diastolic sarcoplasmic reticulum (SR)-Ca leak and SR-Ca spark frequency after exposure to both Na 1.8 inhibitors.
We show for the first time that the neuronal sodium channel Na 1.8 is up-regulated on mRNA and protein level in the human hypertrophied myocardium. Furthermore, inhibition of Na 1.8 reduced augmented I , abbreviated the action potential duration, and decreased the SR-Ca leak. The findings of our study suggest that Na 1.8 could be a promising antiarrhythmic therapeutic target and merits further investigation.
在心肌肥厚和心力衰竭中，致心律失常的持续钠电流（I ）增强。本研究旨在探讨神经元钠通道 Na 1.8 在人肥厚心肌中的电生理作用。
本研究使用了 24 例因严重主动脉瓣狭窄伴射血分数保留的显著后负荷诱导性肥厚而出现症状的患者的心肌组织，并与 12 例健康对照进行了比较。我们进行了定量实时 PCR 和 Western blot，发现与健康心脏相比，人肥厚心肌中 Na 1.8 mRNA（2.34 倍）和蛋白表达（1.96 倍）显著上调。有趣的是，Na 1.5 蛋白表达也显著降低（0.60 倍）。使用全细胞膜片钳技术，我们发现在人肥厚心肌细胞中加入新型 Na 1.8 特异性阻滞剂 A-803467（30 nM）或 PF-01247324（1 μM）后，明显的 I 显著减少。这清楚地表明 Na 1.8 对这种致心律失常电流有重要贡献。我们观察到动作电位时程缩短，并进行共聚焦显微镜检查，结果显示在暴露于两种 Na 1.8 抑制剂后，致心律失常的舒张性肌浆网（SR）-Ca 渗漏和 SR-Ca 火花频率降低了 50%。
我们首次表明，神经元钠通道 Na 1.8 在人肥厚心肌中的 mRNA 和蛋白水平上均上调。此外，Na 1.8 抑制减少了增强的 I ，缩短了动作电位时程，并减少了 SR-Ca 渗漏。本研究结果表明，Na 1.8 可能是一种有前途的抗心律失常治疗靶点，值得进一步研究。
