A new quantitative description of intracellular Ca2+ dynamics in the model of rat ventricular myocyte

The paper presents a new description of intracellular Ca2+ dynamics in the model of rat ventricular myocyte. The principal modifications based on the recently published data comprise: formulation of the function of peripheral dyads, incorporation of peripheral and tubular intracellular subspaces, reformulation of inactivation properties of surface of tubular ICa and description of the function of exogenous Ca2+ buffer in the intracellular space

Effect of Ca 2+

We have used a previously published computer model of the rat cardiac ventricular myocyte to investigate the effect of changing the distribution of Ca2+ efflux pathways (SERCA, Na+/Ca2+ exchange, and sarcolemmal Ca2+ ATPase) between the dyad and bulk cytoplasm and the effect of adding exogenous Ca2+ buffers (BAPTA or EGTA), which are used experimentally to differentially buffer Ca2+ in the dyad and bulk cytoplasm, on cellular Ca2+ cycling. Increasing the dyadic fraction of a particular Ca2+ efflux pathway increases the amount of Ca2+ removed by that pathway, with corresponding changes in Ca2+ efflux from the bulk cytoplasm. The magnitude of these effects varies with the proportion of the total Ca2+ removed from the cytoplasm by that pathway. Differences in the response to EGTA and BAPTA, including changes in Ca2+-dependent inactivation of the L-type Ca2+ current, resulted from the buffers acting as slow and fast “shuttles,” respectively, removing Ca2+ from the dyadic space. The data suggest that complex changes in dyadic Ca2+ and cellular Ca2+ cycling occur as a result of changes in the location of Ca2+ removal pathways or the presence of exogenous Ca2+ buffers, although changing the distribution of Ca2+ efflux pathways has relatively small effects on the systolic Ca2+ transient

Effect of Transmural Differences in Excitation-Contraction Delay and Contraction Velocity on Left Ventricle Isovolumic Contraction: A Simulation Study

Recent studies have shown that left ventricle (LV) exhibits considerable transmural differences in active mechanical properties induced by transmural differences in electrical activity, excitation-contraction coupling, and contractile properties of individual myocytes. It was shown that the time between electrical and mechanical activation of myocytes (electromechanical delay: EMD) decreases from subendocardium to subepicardium and, on the contrary, the myocyte shortening velocity (MSV) increases in the same direction. To investigate the physiological importance of this inhomogeneity, we developed a new finite element model of LV incorporating the observed transmural gradients in EMD and MSV. Comparative simulations with the model showed that when EMD or MSV or both were set constant across the LV wall, the LV contractility during isovolumic contraction (IVC) decreased significantly (dp/dtmax⁡  was reduced by 2 to 38% and IVC was prolonged by 18 to 73%). This was accompanied by an increase of transmural differences in wall stress. These results suggest that the transmural differences in EMD and MSV play an important role in physiological contractility of LV by synchronising the contraction of individual layers of ventricular wall during the systole. Reduction or enhancement of these differences may therefore impair the function of LV and contribute to heart failure

Mathematical modelling of restitution processes in cardiac cells

The restitution processes in cardiac cells are difficult to analyse experimentally. An effective approach to their quantitative analysis is mathematical modelling. The quantification of the share of individual membrane channels in restitution processes is based on the evaluation of electrical charges transmitted across cellular membrane

Kvantitativní analýza iontově-koncentračních změn v tubulárním systému srdečních komorových buněk morčete

In this work, we explored the extent of ion concentration changes in the transverse-axial tubular system (TATS) of guinea pig ventricular cardiomyocyte. Computer simulations on a quantitative model revealed a decrease in relative Ca2+ depletion from 15.6 % to 7.1 % when the stimulation frequency increased from 1 Hz to 5 Hz. On the contrary, the relative K+ accumulation increased from 2.4 % to 3.4 %. The relative changes of tubular Na+ were negligible

Effect of modulation of ionic channel conductivities on restitution processes in cardiac cells (Computer modelling)

The restitution properties of cardiac action potential were shown to be important determinants of stability of reentrant arrhythmias. The restitution hypothesis states that steeply sloped restitution curves (relations between action potential duration and preceding diastolic interval) induce unstable wave propagation that results in wave break, the event that leads to fibrillation. In this contribution we try to explore the effect of modulation of membrane channel conductuvities on electrical restitu**n curves by means of computer modelling

Quantitative modelling of effect of transverse-axial tubular system on electrical activity of cardiac cells under low [K+]e

In this work, we explored quantitatively the effect of ion concentration changes in the restricted space of transverse-axial tubular system (TAT-system) on ventricular cell arrhythmogenesis under the conditions of low extracellular potassium concentration ([K+]e). The simulations were performed on a model that integrates the quantitative description of electrical activity of surface and tubular membrane with the quantitative description of dynamic changes of intracellular ion concentrations. The results predict that the TAT-system plays a significant protecting role in cellular arrhythmogenesis that arises from the enhancement of potassium concentration gradient between tubular and extracellular spaces at low level of [K+]e