Session S63.2

Approaching the Mechanistic Insights towards the Genesis of Intracellular Calcium Transient Alternans: A Simulation Study

H Zhang*, T Tao, SC O'Neill

The University of Manchester
Manchester, UK

Mechanical contraction alternans is commonly observed in patients with heart failure, with which the force of heart contraction alternates between strong and weak leading to sudden cardiac death. Mechanical contraction alternans is manifested by T-wave alternans in the ECG, and is thought to be possibly related to intracellular Ca2+ transient alternans released from the sarcoplasmic reticulum (SR), the main source of Ca2+ responsible for cardiac contraction. However, it is unclear yet how beat-to-beat alternans of intracellular Ca2+ transient is produced.
The aim of this study was to investigate the mechanism(s) underlying the genesis of intracellular Ca2+ alternans. A mathematical model of a spatially extended cardiac cell has been developed. The cell has a length of 150 micrometer, which is discretized by a spatial resolution of 2 micrometer to form 75 coupled ryanodine receptor (RyR) elements. Each element has a cluster of unitary voltage-gated L-type Ca2+ channels, a subspace under the sarcolemma, a cytoplasmic space and a cluster of sarcolemma reticulum (SR) RyR channels. For each element, mathematical equations were developed to model Ca2+ cycling. Inter-element coupling is via Ca2+ diffusion from subspaces to cytoplasmic spaces and via network SR spaces. In simulations, two protocols were used to produce Ca2+ alternans, both of which used 100 ms depolarising pulses at 1 Hz from a holding potential of -40 mV to activate L-type channel opening. In the first protocol, the depolarising pulse was from -40 mV to 0 mV and the Ca2+ release mechanism was partially inhibited by increasing the threshold of RyR Ca2+ release (mimicking the decreased sensitivity of RyR by tetracaine as suggested by a previous experimental study). In the second approach L-type Ca channel openings was reduced by depolarising to only -20 mV and a random block of 40 out of 75 channels was applied, thus Ca2+ release was activated at only a few sites on the SR (mimicking a small depolarising pulse in a previous experimental study). In both cases systolic Ca2+ alternans was generated, which was consistent with previous experimental observations. From the modelling data, the relationship between the SR content and Ca2+ transient was analyzed for normal and alternans conditions. Effects of propagating Ca2+ diffusion waves in generating concordant and dis-concordant Ca2+ alternans in the cell was also analyzed. Our study suggested that the intracellular Ca2+ alternans was generated by propagating waves of Ca2+ release and sustained through alternation of SR Ca2+ content that has a stiff relationship with the Ca2+ transient. 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.

(Abstract Control Number: 128)