Cardiac Mechanics, Calcium Overload and Arrhythmogenesis

A. Ivanov1*, O. Petrov1, 2, L. Sidorov3

1 Institute of Cytology and Genetics SB RAS, Novosibirsk, Russia

2 Institute of Immunology and Physiology UB RAS, Yekaterinburg, Russia

3 Novosibirsk State University, Novosibirsk, Russia

* e-mail: ivanov@gmail.com

Key words: calcium overload, rhythm disturbances, cardiac mechanics

Motivation and Aim: It is well-known that Ca2+ overload may cause cardiac arrhythmia. However, possible contribution of the mechanical factors to the arrhythmia development in Ca2+-overloaded cardiomyocytes has been insufficiently addressed. Earlier we have developed a mathematical model of cardiomyocyte electro-mechanical function [1] that predicted a significant role of the intra- and extracellular mechanical factors in arrhythmogenesys. Model prediction was verified in experiments on papillary muscles from the right ventricle of guinea pigs overloaded with calcium [2].

Methods and Algorithms: We utilized the cellular model to study effects of the electromechanical coupling between cardiomyocytes in a 1D heterogeneous muscle strand formed of 90% of normal (N) cardiomyocytes and 10% of sub-critical (SC) cardiomyocytes with decreased Na+-K+ pump activity. Single SCcardiomyocytes did not demonstrate spontaneous activity during isometric contractions at a reference length. Regular fiber twitches at the reference initial cell length were induced by 1 bps electrical stimulation applied at an edge of the strand. Excitation spread along the tissue via electro-diffusional cell coupling followed by cell contractions and force development in the fiber.

Results: Mechanical interactions between N- and SC-cells in the tissue resulted in the spontaneous activity emerged in the SCzone between the regular stimuli. If the excitation wave spread from SC- to N-region, the SC-cells developed delayed after-dеpolarizations (DAD) that caused a slowly developing beat-to-beat decrease in the force of fiber contraction. If the excitation spread in opposite direction, DAD in the SC-cells induced reflected downward excitation waves capturing the normal region and followed by extrasystoles in the whole fiber.

Conclusion: The results obtained in the model suggest that ectopic activity may emerge in a sub-critical myocardial region, e.g. comprising cardiomyocytes with moderately depressed N+-K+ pump, due to its mechanical interactions in the myocardial tissue. Moreover, such ectopic zone may expand by capturing normal regions in myocardium via the electro-mechanical coupling between cardiomyocytes.

Acknowledgements: Supported by the RFBR (14-01-00885, 14-01-31134), by Presidium of UB RAS (12-M-14-2009, 12-П-4-1067) and by UrFU (Act 211 of RF Government #02.A03.21.0006).

References

Katsnelson L.B. et al. (2011) Contribution of mechanical factors to arrhythmogenesis in calcium overloaded cardiomyocytes: Model predictions and experiments. Progress in Biophysics and Molecular Biology. 107(1): 81-89.

Lashin S.A., Matushkin Yu.G. (2012) Haploid evolutionary constructor: new features and further challenges. In Silico. Biol. 11(3): 125-135.