[Show abstract][Hide abstract] ABSTRACT: This study investigated the mechanisms underlying the propagation of cytoplasmic calcium waves and the genesis of systolic Ca(2+) alternans in cardiac myocytes lacking transverse tubules (t-tubules). These correspond to atrial cells of either small mammals or large mammals that have lost their t-tubules due to disease-induced structural remodeling (e.g., atrial fibrillation). A mathematical model was developed for a cluster of ryanodine receptors distributed on the cross section of a cell that was divided into 13 elements with a spatial resolution of 2 μm. Due to the absence of t-tubules, L-type Ca(2+) channels were only located in the peripheral elements close to the cell-membrane surface and produced Ca(2+) signals that propagated toward central elements by triggering successive Ca(2+)-induced Ca(2+) release (CICR) via Ca(2+) diffusion between adjacent elements. Under control conditions, the Ca(2+) signals did not fully propagate to the central region of the cell. However, with modulation of several factors responsible for Ca(2+) handling, such as the L-type Ca(2+) channels (Ca(2+) influx), SERCA pumps (sarcoplasmic reticulum (SR) Ca(2+) uptake), and ryanodine receptors (SR Ca(2+) release), Ca(2+) wave propagation to the center of the cell could occur. These simulation results are consistent with previous experimental data from atrial cells of small mammals. The model further reveals that spatially functional heterogeneity in Ca(2+) diffusion within the cell produced a steep relationship between the SR Ca(2+) content and the cytoplasmic Ca(2+) concentration. This played an important role in the genesis of Ca(2+) alternans that were more obvious in central than in peripheral elements. Possible association between the occurrence of Ca(2+) alternans and the model parameters of Ca(2+) handling was comprehensively explored in a wide range of one- and two-parameter spaces. In addition, the model revealed a spontaneous second Ca(2+) release in response to a single voltage stimulus pulse with SR Ca(2+) overloading and augmented Ca(2+) influx. This study provides what to our knowledge are new insights into the genesis of Ca(2+) alternans and spontaneous second Ca(2+) release in cardiac myocytes that lack t-tubules.
[Show abstract][Hide abstract] ABSTRACT: Volatile anaesthetics such as halothane, isoflurane and sevoflurane inhibit membrane currents contributing to the ventricular action potential. Transmural variation in the extent of current blockade induces differential effects on action potential duration (APD) in the endocardium and epicardium which may be pro-arrhythmic. Biophysical modelling techniques were used to simulate the functional impact of anaesthetic-induced blockade of membrane currents on APD and effective refractory period (ERP) in rat endocardial and epicardial cell models. Additionally, the transmural conduction of excitation waves in 1-dimensional cell arrays, the tissue's vulnerability to arrhythmogenesis and dynamic behaviour of re-entrant excitation in 2-dimensional cell arrays were studied. Simulated anaesthetic exposure reduced APD and ERP in both epicardial and endocardial cell models. The reduction in APD was greater in endocardial than epicardial cells, reducing transmural APD dispersion consistent with experimental data. However, the transmural ERP dispersion was augmented. All three anaesthetics increased the width of the tissue's vulnerable window during which a premature stimulus could induce unidirectional conduction block but only halothane reduced the critical size of ventricular substrates necessary to initiate and sustain re-entrant excitation. All three anaesthetics accelerated the rate of re-entrant excitation waves, but only halothane prolonged the lifespan of re-entry. These data illustrate in silico, that modest changes in ion channel conductance abbreviate rat ventricular APD and ERP, reduce transmural APD dispersion, but augment transmural ERP dispersion. These changes collectively enhance the propensity for arrhythmia generation and provide a substrate for re-entry circuits with a longer half life than in control conditions.
Journal of Theoretical Biology 01/2009; 257(2):279-91. · 2.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Mechanical contraction alternans of the heart is associated with fatal cardiac death. It is manifested by T-wave alternans in the ECG, and is thought to be possibly related to intracellular Ca<sup>2+</sup> transient alternans released from the sarcoplasmic reticulum (SR). However, it is unclear yet how beat-to-beat alternans of intracellular Ca<sup>2+</sup> transient is produced. In this study investigated the mechanism(s) underlying the genesis of intracellular Ca<sup>2+</sup> alternans produced at slow pacing rates by using a mathematical model of a spatially extended cardiac cell with a cluster of coupled ryanodine receptor (RyR) elements. It was shown that the intracellular Ca<sup>2+</sup> alternans was generated by propagating waves of Ca<sup>2+</sup> release and sustained through alternation of SR Ca<sup>2+</sup> content that has a stiff relationship with the Ca<sup>2+</sup> transient. This study provides novel and fundamental insights to understand mechanisms that may underlie intracellular Ca<sup>2+</sup> alternans without the need for refractoriness of L-type Ca or RyR channels under rapid pacing.
[Show abstract][Hide abstract] ABSTRACT: Mechanical alternans in cardiac muscle is associated with intracellular Ca(2+) alternans. Mechanisms underlying intracellular Ca(2+) alternans are unclear. In previous experimental studies, we produced alternans of systolic Ca(2+) under voltage clamp, either by partially inhibiting the Ca(2+) release mechanism, or by applying small depolarizing pulses. In each case, alternans relied on propagating waves of Ca(2+) release. The aim of this study is to investigate by computer modeling how alternans of systolic Ca(2+) is produced. A mathematical model of a cardiac cell with 75 coupled elements is developed, with each element contains L-type Ca(2+) current, a subspace into which Ca release takes place, a cytoplasmic space, sarcoplasmic reticulum (SR) release channels [ryanodine receptor (RyR)], and uptake sites (SERCA). Interelement coupling is via Ca(2+) diffusion between neighboring subspaces via cytoplasmic spaces and network SR spaces. Small depolarizing pulses were simulated by step changes of cell membrane potential (20 mV) with random block of L-type channels. Partial inhibition of the release mechanism is mimicked by applying a reduction of RyR open probability in response to full stimulation by L-type channels. In both cases, systolic alternans follow, consistent with our experimental observations, being generated by propagating waves of Ca(2+) release and sustained through alternation of SR Ca(2+) content. This study provides novel and fundamental insights to understand mechanisms that may underlie intracellular Ca(2+) alternans without the need for refractoriness of L-type Ca or RyR channels under rapid pacing.