cardiac arrhythmias; action potential; cardiac conduction; restitution; alternans; reentry; computer modeling; microelectrode arrays; cardiac cell cultures; ion currents; systems theory
Azzarito M., Prudat Y., Marcu I. C., Kucera J. P., Ullrich N. D. (2016), Reduced excitability and intercellular coupling lead to slow conduction in cultures of stem cell-derived cardiomyocytes, in ACTA PHYSIOLOGICA
, 216(S707), P22-03.
Prudat Yann, Madhvani Roshni V, Angelini Marina, Borgstom Nils P, Garfinkel Alan, Karagueuzian Hrayr S, Weiss James N, de Lange Enno, Olcese Riccardo, Kucera Jan P (2016), Stochastic pacing reveals the propensity to cardiac action potential alternans and uncovers its underlying dynamics., in The Journal of physiology
, 594(9), 2537-53.
Ullrich Nina D., Prudat Yann, Marcu Irene C., Kucera Jan P. (2015), Altered electrical signal propagation and slowed conduction in mixed cultured strands of primary ventricular cells and stem cell-derived cardiomyocytes, in Europace
, 17(Suppl 3), P492.
Kucera Jan P, Prudat Yann, Marcu Irene C, Azzarito Michela, Ullrich Nina D (2015), Slow conduction in mixed cultured strands of primary ventricular cells and stem cell-derived cardiomyocytes., in Frontiers in cell and developmental biology
, 3, 58-58.
Prudat Yann, Kucera Jan P. (2014), Nonlinear Behavior of Conduction in Cardiac Tissue with Heterogeneous Expression of Connexin 43, in BIOPHYSICAL JOURNAL
, 106(2), 120-121.
Prudat Yann, Kucera Jan P (2014), Nonlinear behaviour of conduction and block in cardiac tissue with heterogeneous expression of connexin 43., in Journal of Molecular and Cellular Cardiology
, 76, 46-54.
Kucera Jan P (2014), What makes the heart rhythm so intricate?, in Heart Rhythm : the official journal of the Heart Rhythm Society
, 11(7), 1220-1.
Jousset Florian, Grand Teddy, Rohr Stephan, Kucera Jan P. (2013), Changes of Axial Resistance following Mechanical Strain Prevail Over Stretch-Activated Currents in the Modulation of Conduction Velocity in Cardiac Cell Strands, in BIOPHYSICAL JOURNAL
, 104(2), 283-284.
Sottas Valentin, Rougier Jean-Sébastien, Jousset Florian, Kucera Jan P, Shestak Anna, Makarov Leonid M, Zaklyazminskaya Elena V, Abriel Hugues (2013), Characterization of 2 genetic variants of Na(v) 1.5-arginine 689 found in patients with cardiac arrhythmias., in Journal of Cardiovascular Electrophysiology
, 24(9), 1037-46.
Abriel Hugues, de Lange Enno, Kucera Jan P, Loussouarn Gildas, Tarek Mounir (2013), Computational tools to investigate genetic cardiac channelopathies., in Frontiers in Physiology
, 4, 390-390.
Prudat Yann, Madhvani Roshni V., Borgstrom N. Peter, de Lange Enno, Olcese Riccardo, Kucera Jan P. (2013), The propensity to alternans can be quantified in cardiac cells using stochastic pacing, in Heart Rhythm
, 10(5S), P02-90.
Lemay Mathieu, de Lange Enno, Kucera Jan P (2012), Uncovering the dynamics of cardiac systems using stochastic pacing and frequency domain analyses., in PLoS Computational Biology
, 8(3), 1002399-1002399.
Kondratyev Aleksandar A, Didon Jean-Philippe, Hinnen-Oberer Helene, Lemay Mathieu, Kucera Jan P, Kléber Andre G (2012), Virtual sources and sinks during extracellular field shocks in cardiac cell cultures: effects of source-sink interactions between adjacent tissue boundaries., in Circulation. Arrhythmia and Electrophysiology
, 5(2), 391-9.
Swan Heikki, Amarouch Mohamed Yassine, Leinonen Jaakko, Marjamaa Annukka, Kucera Jan P, Laitinen-Forsblom Päivi J, Lahtinen Annukka M, Palotie Aarno, Kontula Kimmo, Toivonen Lauri, Abriel Hugues, Widen Elisabeth, A Gain-of-Function Mutation of the SCN5A Gene Causes Exercise-Induced Polymorphic Ventricular Arrhythmias., in Circulation. Cardiovascular Genetics
Cardiac arrhythmias are frequent in heart disease and represent an important cause of morbidity and mortality. Despite a wealth of advances in understanding arrhythmias from the level of the ion channel to the level of the whole organ, many challenges remain in both research and clinical practice to obtain an integrated picture of how arrhythmogenic mechanisms interact. Our general aim is to further the integrative understanding of cardiac electrical function. This knowledge is primordial to develop new diagnostic, prognostic and therapeutic approaches to arrhythmias.This proposal is built upon our previous achievements obtained by combining experiments, computer simulations of the action potential (AP) and innovative approaches based on systems theory. This combination is our expertise and we plan to further benefit from it in our new projects.Project A: New algorithms to characterize and predict alternans using frequency-domain analyses of cardiac restitution.Alternans designates the alternation of AP parameters (AP duration (APD), calcium transient) from beat to beat. It leads to dispersion of refractoriness and thus precipitates conduction block and severe reentrant arrhythmias. Alternans results from complex interactions between membrane potential, ion currents and intracellular calcium cycling. The genesis of alternans is linked with cardiac restitution and memory, two notions describing the dependence of AP parameters on the previous diastolic interval (DI), or on several previous DIs and APDs, respectively. However, the understanding of all these interactions is far from complete and efforts are still needed to design approaches for a reliable assessment of the propensity to alternans and its mechanisms.In previous work, we laid the fundament of a novel approach to evaluate restitution in the frequency domain by means of Fourier analysis and transfer functions, which opens new ways to quantify the propensity to alternans and to explore its mechanisms. The aim of this new project is to extend this framework by combining it with a mathematical method called eigenmode analysis in order to design experimental protocols and algorithms for a reliable prediction of alternans that should be superior to those developed so far. These protocols will first be evaluated and optimized using computer models of the AP and then tested and validated in various experimental settings (cardiac cell cultures, and, in collaboration, single cells and whole organ). Further hypotheses are that alternans can be predicted by monitoring other parameters than membrane potential or APD (e.g., calcium transient, mechanical parameters), and that the cause of alternans can be identified in this way. Such identification is important to anticipate in vitro and in vivo the effects of classical antiarrhythmic drugs and of new agents that may be developed in the future to target the cellular calcium handling system.Project B: Does supernormal conduction lead to alternans during reentry?The dependence of conduction velocity (CV) on the previous DI (CV restitution) is an important factor in arrhythmogenesis. It determines conditions promoting reentrant arrhythmias and influences the spatiotemporal dynamics of reentry. Normally, CV depends on the recovery of the sodium current from inactivation, and premature APs propagate slower than normally paced APs. However, under conditions favoring supernormal excitability (e.g., decreased extracellular potassium concentration), there is a range of DIs at which premature APs propagate faster than normally paced APs, a phenomenon called supernormal conduction. While the effects of normal CV restitution on reentry dynamics have been well described, the effects of supernormal conduction have scarcely been studied, and our aim is to investigate these effects.We showed previously that supernormal conduction is intrinsically unstable and potentiates alternans. Our hypothesis is that supernormal conduction induced by low extracellular potassium destabilizes reentry and leads to the formation of alternating or more complex excitation patterns, in particular in the case of two reentrant wavefronts in a circuit and in the case of spiral waves. We will test this hypothesis using a cardiac cell culture model with reduced gap junctional coupling permitting to accommodate two wavefronts in tissue rings and monolayers, and in corresponding computer simulations. Our study will contribute to understand the arrhythmogenic effects of hypokalemia, a common electrolyte abnormality in clinical practice, and provide new insights into dynamics related to supernormal conduction and alternans.