Alternans of cardiac calcium cycling in a cluster of ryanodine receptors: a simulation study
- 1 August 2008
- journal article
- research article
- Published by American Physiological Society in American Journal of Physiology-Heart and Circulatory Physiology
- Vol. 295 (2), H598-H609
- https://doi.org/10.1152/ajpheart.01086.2007
Abstract
Mechanical alternans in cardiac muscle is associated with intracellular Ca2+ alternans. Mechanisms underlying intracellular Ca2+ alternans are unclear. In previous experimental studies, we produced alternans of systolic Ca2+ under voltage clamp, either by partially inhibiting the Ca2+ release mechanism, or by applying small depolarizing pulses. In each case, alternans relied on propagating waves of Ca2+ release. The aim of this study is to investigate by computer modeling how alternans of systolic Ca2+ is produced. A mathematical model of a cardiac cell with 75 coupled elements is developed, with each element contains L-type Ca2+ 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 Ca2+ 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 Ca2+ release and sustained through alternation of SR Ca2+ content. This study provides novel and fundamental insights to understand mechanisms that may underlie intracellular Ca2+ alternans without the need for refractoriness of L-type Ca or RyR channels under rapid pacing.Keywords
This publication has 42 references indexed in Scilit:
- Termination of Cardiac Ca2+ Sparks: An Investigative Mathematical Model of Calcium-Induced Calcium ReleaseBiophysical Journal, 2002
- Mechanical alternans and restitution in failing SHHF rat left ventriclesAmerican Journal of Physiology-Heart and Circulatory Physiology, 2002
- A Mathematical Model of Action Potential Heterogeneity in Adult Rat Left Ventricular MyocytesBiophysical Journal, 2001
- Integrative Analysis of Calcium Cycling in Cardiac MuscleCirculation Research, 2000
- Simultaneous maps of optical action potentials and calcium transients in guinea‐pig hearts: mechanisms underlying concordant alternansThe Journal of Physiology, 2000
- Enhanced Ca 2+ Release and Na/Ca Exchange Activity in Hypertrophied Canine Ventricular MyocytesCirculation, 2000
- Functional coupling between glycolysis and excitation—contraction coupling underlies alternans in cat heart cellsThe Journal of Physiology, 2000
- Rapid Activation of the Cardiac Ryanodine Receptor by Submillisecond Calcium StimuliThe Journal of general physiology, 1999
- Reentrant and focal mechanisms underlying ventricular tachycardia in the human heart.Circulation, 1992
- Mechanical alternans during acidosis in ferret heart muscle.Circulation Research, 1991