Campos Fernando O, Shiferaw Yohannes, Prassl Anton J, Boyle Patrick M, Vigmond Edward J, Plank Gernot
Institute of Biophysics, Medical University of Graz, Graz, Austria.
Department of Physics, California State University, Northridge, CA, USA.
Cardiovasc Res. 2015 Jul 1;107(1):175-83. doi: 10.1093/cvr/cvv149. Epub 2015 May 12.
Premature ventricular complexes (PVCs) due to spontaneous calcium (Ca) release (SCR) events at the cell level can precipitate ventricular arrhythmias. However, the mechanistic link between SCRs and PVC formation remains incompletely understood. The aim of this study was to investigate the conditions under which delayed afterdepolarizations resulting from stochastic subcellular SCR events can overcome electrotonic source-sink mismatch, leading to PVC initiation.
A stochastic subcellular-scale mathematical model of SCR was incorporated in a realistic model of the rabbit ventricles and Purkinje system (PS). Elevated levels of diastolic sarcoplasmic reticulum Ca(2+) (CaSR) were imposed until triggered activity was observed, allowing us to compile statistics on probability, timing, and location of PVCs. At CaSR≥ 1500 µmol/L PVCs originated in the PS. When SCR was incapacitated in the PS, PVCs also emerged in the ventricles, but at a higher CaSR (≥1550 µmol/L) and with longer waiting times. For each model configuration tested, the probability of PVC occurrence increased from 0 to 100% within a well-defined critical CaSR range; this transition was much more abrupt in organ-scale models (∼50 µmol/L CaSR range) than in the tissue strand (∼100 µmol/L) or single-cell (∼450 µmol/L) models. Among PVCs originating in the PS, ∼68% were located near Purkinje-ventricular junctions (<1 mm).
SCR events overcome source-sink mismatch to trigger PVCs at a critical CaSR threshold. Above this threshold, PVCs emerge due to increased probability and reduced variability in timing of SCR events, leading to significant diastolic depolarization. Sites of lower electronic load, such as the PS, are preferential locations for triggering.
细胞水平上由自发性钙（Ca）释放（SCR）事件导致的室性早搏（PVC）可引发室性心律失常。然而，SCR与PVC形成之间的机制联系仍未完全明确。本研究的目的是探究随机亚细胞SCR事件导致的延迟后去极化能够克服电紧张性源 - 汇失配从而引发PVC的条件。
将一个随机亚细胞尺度的SCR数学模型纳入兔心室和浦肯野系统（PS）的真实模型中。施加升高的舒张期肌浆网Ca²⁺（CaSR）水平，直至观察到触发活动，从而使我们能够收集关于PVC的概率、发生时间和位置的统计数据。当CaSR≥1500 μmol/L时，PVC起源于PS。当PS中的SCR功能丧失时，PVC也会出现在心室中，但此时CaSR更高（≥1550 μmol/L）且等待时间更长。对于所测试的每种模型配置，在明确界定的临界CaSR范围内，PVC发生的概率从0增加到100%；这种转变在器官尺度模型（约50 μmol/L CaSR范围）中比在组织条（约100 μmol/L）或单细胞（约450 μmol/L）模型中更为突然。在起源于PS的PVC中，约68%位于浦肯野 - 心室交界处附近（<1 mm）。
SCR事件在临界CaSR阈值时克服源 - 汇失配以触发PVC。高于此阈值，由于SCR事件发生概率增加且时间变异性降低，导致显著的舒张期去极化，从而出现PVC。电负荷较低的部位，如PS，是触发的优先位置。
