Department of Biomedical Engineering, Zhejiang University, Hangzhou 310027, China.
J Mol Cell Cardiol. 2013 Mar;56:34-43. doi: 10.1016/j.yjmcc.2012.11.020. Epub 2012 Dec 7.
Heart failure (HF) is associated with susceptibility to sudden cardiac death. However, the underlying mechanism of electrical instability and mechanical dysfunction associated with HF remains poorly understood. In this study, a new canine ventricular cell model based on the Hund-Rudy dynamic (HRd) model and recently published experimental data was developed to investigate the electrical changes and calcium handling dysfunction in HF. Simulation results suggest that: 1) acute Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) over-expression (CaMKII-OE) affects the action potential (AP) profile, while AP prolongation is mainly caused by the down-regulation of K(+) currents; 2) enhanced late Na(+) current (I(NaL)) alone cannot adequately lead to [Na(+)] elevation in HF; 3) enhanced sarcoplasmic reticulum (SR) leak current (I(leak)) causes disturbed Ca(2+) handling and there is little contribution from Na(+)/Ca(2+) exchanger (NCX); 4) at high SR Ca(2+) load, a steeper fractional SR Ca(2+) release is observed in HF than that in control, causing alternans to occur more easily; and 5) I(leak) block restores the contraction and relaxation function, but cannot eliminate alternans. By inhibiting CaMKII, alternans is eliminated, but contractility is not improved. Partial CaMKII inhibition in combination with I(leak) block could augment mechanical function and depress alternans, suggesting a new possible therapeutic target for HF treatment.
心力衰竭（HF）与易发生心脏性猝死相关。然而，HF 相关的电不稳定性和机械功能障碍的潜在机制仍未被很好地理解。在这项研究中，基于 Hund-Rudy 动力学（HRd）模型和最近发表的实验数据，建立了一个新的犬心室细胞模型，用于研究 HF 中的电变化和钙处理功能障碍。模拟结果表明：1）急性 Ca(2+)/钙调蛋白依赖性蛋白激酶 II（CaMKII）过表达（CaMKII-OE）会影响动作电位（AP）形态，而 AP 延长主要是由于 K(+)电流下调引起的；2）增强的晚期 Na(+)电流（I(NaL)）单独不能充分导致 HF 中的 [Na(+)]升高；3）增强的肌浆网（SR）泄漏电流（I(leak)）导致 Ca(2+)处理紊乱，而 Na(+)/Ca(2+)交换体（NCX）的贡献较小；4）在高 SR Ca(2+)负荷下，HF 中的 SR 钙释放分数斜率比对照更大，更容易发生交替；5）I(leak)阻断恢复收缩和舒张功能，但不能消除交替。抑制 CaMKII 可消除交替，但不能改善收缩性。CaMKII 的部分抑制与 I(leak)阻断相结合可增强机械功能并抑制交替，提示 HF 治疗的一个新的可能治疗靶点。
