Zile Melanie A, Trayanova Natalia A
Institute for Computational Medicine and Department of Biomedical Engineering at Johns Hopkins University, 3400 N Charles St, 208 Hackerman Hall, Baltimore, MD 21218, USA.
Prog Biophys Mol Biol. 2017 Nov;130(Pt B):418-428. doi: 10.1016/j.pbiomolbio.2017.06.015. Epub 2017 Jun 22.
Patients with hypertrophic cardiomyopathy (HCM), a disease associated with sarcomeric protein mutations, often suffer from sudden cardiac death (SCD) resulting from arrhythmia. In order to advance SCD prevention strategies, our understanding of how sarcomeric mutations in HCM patients contribute to enhanced arrhythmogenesis needs to be improved. Early afterdepolarizations (EADs) are an important mechanism underlying arrhythmias associated with HCM-SCD. Although the ionic mechanisms underlying EADs have been studied in general, whether myofilament protein dynamics mechanisms also underlie EADs remains unknown. Thus, our goals were to investigate if myofilament protein dynamics mechanisms underlie EADs and to uncover how those mechanisms are affected by pacing rate, sarcomere length (SL), and different levels of HCM-induced myofilament remodeling. To achieve this, a mechanistically-based bidirectionally coupled human electrophysiology-force myocyte model under the conditions of HCM was constructed. HCM ionic remodeling included a reduced repolarization reserve, while HCM myofilament modeling involved altered thin filament activation. We found that the mechanoelectric feedback (MEF) on calcium dynamics in the bidirectionally coupled model, via Troponin C buffering of cytoplasmic Ca, was the myofilament mechanism underlying EADs. Incorporating MEF diminished the degree of repolarization reserve reduction necessary for EADs to emerge and increased the frequency of EAD occurrence, especially at faster pacing rates. Longer SLs and enhanced thin filament activation diminished the effects of MEF on EADs. Together these findings demonstrate that myofilament protein dynamics mechanisms play an important role in EAD formation.
肥厚型心肌病（HCM）患者常因肌节蛋白突变而患病，他们经常因心律失常而突发心源性猝死（SCD）。为了推进SCD预防策略，我们需要加深对HCM患者肌节突变如何导致心律失常增强的理解。早期后去极化（EADs）是与HCM-SCD相关心律失常的重要潜在机制。尽管已对EADs的离子机制进行了总体研究，但肌丝蛋白动力学机制是否也是EADs的潜在机制仍不清楚。因此，我们的目标是研究肌丝蛋白动力学机制是否是EADs的潜在机制，并揭示这些机制如何受起搏频率、肌节长度（SL）以及不同程度的HCM诱导的肌丝重塑的影响。为实现这一目标，构建了一个基于机制的双向耦合人电生理-力心肌细胞模型，该模型处于HCM条件下。HCM离子重塑包括复极储备减少，而HCM肌丝建模涉及细肌丝激活改变。我们发现，在双向耦合模型中，通过肌钙蛋白C对细胞质Ca的缓冲作用，对钙动力学的机械电反馈（MEF）是EADs的肌丝机制。纳入MEF可降低EADs出现所需的复极储备减少程度，并增加EADs的发生频率，尤其是在较快的起搏频率下。更长的SL和增强的细肌丝激活可减弱MEF对EADs的影响。这些发现共同表明，肌丝蛋白动力学机制在EADs形成中起重要作用。
