action potential; cardiac conduction; ion currents; computer modeling; stretchable microelectrode arrays; ephaptic conduction; sodium channels; gap junctions; cardiac cell cultures; cardiac arrhythmias; mechano-electrical coupling; conduction velocity; conduction block
Simone Stefano Andrea De, Moyle Sarah, Buccarello Andrea, Dellenbach Christian, Kucera Jan Pavel, Rohr Stephan (2020), The role of membrane capacitance in cardiac impulse conduction: an optogenetic study with non-excitable cells coupled to cardiomyocytes, in Frontiers in Physiology
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Alijevic Omar, Bignucolo Olivier, Hichri Echrak, Peng Zhong, Kucera Jan P., Kellenberger Stephan (2020), Slowing of the time course of acidification decreases the acid-sensing ion channel 1a current amplitude and modulates action potential firing in neurons, in Frontiers in Cellular Neuroscience
, 14, 41.
Vermij Sarah Helena, Abriel Hugues, Kucera Jan Pavel (2019), Modeling depolarization delay, sodium currents, and electrical potentials in cardiac transverse tubules, in Frontiers in Physiology
, 10, 1487.
Kucera Jan P. (2019), A modelling framework for the allosteric interactions between sodium channels provides insight into the negative dominance of certain cardiac sodium channel mutations, in Acta Physiologica
, 227(S719), OS 03-08.
Arrhythmias are frequent in the diseased heart. Reentrant arrhythmias represent an important factor of morbidity and mortality. They can precipitate heart failure, lead to stroke and cause sudden death. Disorders of action potential (AP) propagation, factors favoring conduction block and phenomena susceptible to trigger spontaneous excitations or to alter the rate of the sinoatrial node are mechanistically involved in arrhythmogenesis.In Project A, we will investigate how these factors are modulated by homogeneous and heterogeneous cardiac tissue deformation (strain). In Project B, we will investigate how the sodium (Na+) current (INa), an essential current for AP propagation, is influenced by the formation of Na+ channel dimers and by the distribution of Na+ channels and gap junctions in intercalated discs. Both projects involve a multidisciplinary approach (electrophysiological recordings, in vitro models, biomedical engineering and in silico models) and are a logical follow-up of our previous work.A: How does homogeneous and heterogeneous cardiac tissue strain influence conduction, spontaneous activity, and beat rate variability?Deformation of cardiac tissue influences its electrophysiological properties. This mechano-electrical feedback involves stretch-activated channels in myocytes and/or (myo)fibroblasts, modulation of ion channel function and changes in tissue resistance and capacitance. A deep understanding of how these phenomena influence arrhythmogenesis requires experiments in which strain can be applied to cardiac tissue in a reliably controlled manner while continuously recording its electrical activity. Using our recently developed platform based on cardiac cell cultures grown on stretchable microelectrode arrays in combination with mathematical modeling, we will 1) investigate the kinetic properties of stretch-activated processes and how they influence cardiac conduction, 2) determine whether heterogeneous cardiac tissue strain can cause local conduction delays or block, 3) investigate how cardiac tissue strain influences spontaneous excitations and beat rate variability. Our principal hypotheses are that stretch induces dynamic changes for which new modeling approaches are needed and that sites exposed to the largest strain are the most prone to exhibit conduction disturbances or to cause spontaneous excitations. Our study will contribute to understand how mechanical phenomena influence arrhythmia mechanisms.B: Modeling the interactions between Na+ channels mediated by a-a interactions and extracellular potentials in confined nanodomainsRecent studies showed that Na+ channels form dimers because their a subunits are linked together and that the gating of one channel influences the gating of the other. In addition, our recent work indicates that the previously reported clustering of Na+ channels in intercalated discs exerts major effects on excitation and conduction due to ephaptic interactions caused by large negative extracellular potentials in the intercellular cleft. Therefore, we will 1) implement new modeling concepts in which we will consider pairs of Na+ channels that interact allosterically as the functional units underlying INa and 2) develop high-resolution 3D finite element models of the intercalated disc to address the hypothesis that Na+ channel clustering in nanodomains near gap junction plaques influences cellular excitation and intercellular AP transmission. The models incorporating a-a interactions between Na+ channels will be validated using recordings of single/paired Na+ channel currents, and the intercalated disc models will integrate structural super-resolution microscopy data. Our models will bridge the gap between modeling the single channel and understanding the electrical behavior of the whole cell, and our work will contribute to a better understanding of cardiac electrical excitation at the subcellular scale.Expected value: The insights from both projects are expected to be valuable for both physiologists and cardiologists to better understand arrhythmia mechanisms, with the prospect to devise better approaches for the management of cardiac patients.