Rate-dependent force, intracellular calcium, and action potential voltage alternans are modulated by sarcomere length and heart failure induced-remodeling of thin filament regulation in human heart failure: A myocyte modeling study.
Rate-dependent force, intracellular calcium, and action potential voltage alternans are modulated by sarcomere length and heart failure induced-remodeling of thin filament regulation in human heart failure: A myocyte modeling study.
复制标题
速率依赖性力、细胞内钙和动作电位电压交替受肌节长度和心力衰竭诱导的人类心力衰竭细丝调节重塑的调节：一项心肌细胞建模研究。
DOI：
10.1016/j.pbiomolbio.2015.12.012
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发表时间：
2016
影响因子：
3.8
通讯作者：
Trayanova,NataliaA
中科院分区：
文献类型：
--
作者：
Zile,MelanieA;Trayanova,NataliaA
微伏T波电交替（MTWA）测试可识别心力衰竭患者在接近静息心率（<110次/分钟）时发生致命性室性心律失常的风险。由于压力交替与MTWA同时发生，并且具有更高的信噪比，因此它可能是心律失常的更好预测器，尽管其机制尚不清楚。因此，我们研究了力交替（FORCE-ALT），压力交替的细胞表现，和动作电位电压交替（APV-ALT），MTWA的细胞驱动程序之间的关系。我们的目标是揭示在衰竭的人类心肌细胞中APV-ALT和FORCE-ALT的联系机制，并研究这些交替之间的联系如何受到起搏频率和生理条件（如肌节长度和心力衰竭诱导的机械参数重塑）的影响。为了实现这一点，一个机械为基础的，强耦合的人机电肌细胞模型的构建。将肌浆网钙摄取电流（Iup）降低至27%以模拟人心力衰竭中的异常钙处理。结合机械重塑以模拟改变的细丝激活和横桥（XB）循环速率。动态起搏方案被用来研究细胞内钙浓度（[Ca]i）的发展，电压，和主动力交替在不同的起搏频率。FORCE-ALT仅发生在包含降低Iup的模拟中，表明细胞内钙浓度（CA-ALT）的交替可诱导FORCE-ALT。FORCE-ALT的幅度在临床相关起搏频率（<110 bpm）下最大，而APV-ALT最小。我们发现，FORCE-ALT，CA-ALT和APV-ALT的幅度被心力衰竭诱导的机械参数和肌节长度的重塑由于肌丝反馈的存在而改变。这些研究结果提供了重要的洞察心力衰竭诱导的电和机械交替之间的关系，以及它们是如何改变的生理条件在近静息心率。
Microvolt T-wave alternans (MTWA) testing identifies heart failure patients at risk for lethal ventricular arrhythmias at near-resting heart rates (<110 beats per minute). Since pressure alternans occurs simultaneously with MTWA and has a higher signal to noise ratio, it may be a better predictor of arrhythmia, although the mechanism remains unknown. Therefore, we investigated the relationship between force alternans (FORCE-ALT), the cellular manifestation of pressure alternans, and action potential voltage alternans (APV-ALT), the cellular driver of MTWA. Our goal was to uncover the mechanisms linking APV-ALT and FORCE-ALT in failing human myocytes and to investigate how the link between those alternans was affected by pacing rate and by physiological conditions such as sarcomere length and heart failure induced-remodeling of mechanical parameters. To achieve this, a mechanically-based, strongly coupled human electromechanical myocyte model was constructed. Reducing the sarcoplasmic reticulum calcium uptake current (Iup) to 27% was incorporated to simulate abnormal calcium handling in human heart failure. Mechanical remodeling was incorporated to simulate altered thin filament activation and crossbridge (XB) cycling rates. A dynamical pacing protocol was used to investigate the development of intracellular calcium concentration ([Ca]i), voltage, and active force alternans at different pacing rates. FORCE-ALT only occurred in simulations incorporating reduced Iup, demonstrating that alternans in the intracellular calcium concentration (CA-ALT) induced FORCE-ALT. The magnitude of FORCE-ALT was found to be largest at clinically relevant pacing rates (<110 bpm), where APV-ALT was smallest. We found that the magnitudes of FORCE-ALT, CA-ALT and APV-ALT were altered by heart failure induced-remodeling of mechanical parameters and sarcomere length due to the presence of myofilament feedback. These findings provide important insight into the relationship between heart-failure-induced electrical and mechanical alternans and how they are altered by physiological conditions at near-resting heart rates.