cardiac alternans?: insights from a human atrial model.

Despite the important role of electromechanical alternans in cardiac arrhythmogenesis, its molecular origin is not well understood. The appearance of calcium alternans has often been associated to fluctuations in the sarcoplasmic reticulum (SR) Ca loading. However, cytosolic calcium alternans observed without concurrent oscillations in the SR Ca content suggests an alternative mechanism related to a dysfunction in the dynamics of the ryanodine receptor (RyR2). We have investigated the effect of SR release refractoriness in the appearance of alternans, using a mathematical model of a single human atrial cell, based on the model by Nygren et al. (30), where we modified the dynamics of the RyR2 and of SR Ca release. The genesis of calcium alternans was studied stimulating the cell for different periods and values of the RyR2 recovery time from inactivation. At fast rates cytosolic calcium alternans were obtained without concurrent SR Ca content fluctuations. A transition from regular response to alternans was also observed, changing the recovery time from inactivation of the RyR2. This transition was found to be hysteretic, so for a given set of parameters different responses were observed. We then studied the relevance of RyR2 refractoriness for the generation of alternans, reproducing the same protocols as in recent experiments. In particular, restitution of Ca release during alternans was studied with a S1S2 protocol, obtaining a different response if the S2 stimulation was given after a long or a short release. We show that the experimental results can be explained by RyR2 refractoriness, arising from a slow RyR2 recovery from inactivation, stressing the role of the RyR2 in the genesis of alternans.

[1]  M. Egger,et al.  Sarcoplasmic Reticulum Ca2+ Refilling Controls Recovery From Ca2+-Induced Ca2+ Release Refractoriness in Heart Muscle , 2004, Circulation research.

[2]  J. García-Ojalvo,et al.  Effects of noise in excitable systems , 2004 .

[3]  D. Dobrev,et al.  Transverse tubules are a common feature in large mammalian atrial myocytes including human. , 2011, American journal of physiology. Heart and circulatory physiology.

[4]  M. Legato.  Ultrastructure of the Atrial, Ventricular, and Purkinje Cell, with Special Reference to the Genesis of Arrhythmias , 1973, Circulation.

[5]  H. Llewelyn Roderick,et al.  The spatial pattern of atrial cardiomyocyte calcium signalling modulates contraction , 2004, Journal of Cell Science.

[6]  M. Berridge,et al.  Predetermined recruitment of calcium release sites underlies excitation‐contraction coupling in rat atrial myocytes , 2001, The Journal of physiology.

[7]  Donald M Bers,et al.  Cardiac Alternans Do Not Rely on Diastolic Sarcoplasmic Reticulum Calcium Content Fluctuations , 2006, Circulation research.

[8]  M. Courtemanche,et al.  Ionic mechanisms underlying human atrial action potential properties: insights from a mathematical model. , 1998, The American journal of physiology.

[9]  Michael D. Stern,et al.  Local Control Model of Excitation–Contraction Coupling in Skeletal Muscle , 1997, The Journal of general physiology.

[10]  Jan D'hooge,et al.  Ultrastructural and Functional Remodeling of the Coupling Between Ca2+ Influx and Sarcoplasmic Reticulum Ca2+ Release in Right Atrial Myocytes From Experimental Persistent Atrial Fibrillation , 2009, Circulation research.

[11]  C. Soeller,et al.  Numerical simulation of local calcium movements during L-type calcium channel gating in the cardiac diad. , 1997, Biophysical journal.

[12]  Elizabeth M Cherry,et al.  Dynamics of human atrial cell models: restitution, memory, and intracellular calcium dynamics in single cells. , 2008, Progress in biophysics and molecular biology.

[13]  Sanjiv M. Narayan,et al.  Repolarization Alternans Reveals Vulnerability to Human Atrial Fibrillation , 2011, Circulation.

[14]  Michael D. Stern,et al.  Local Control Models of Cardiac Excitation–Contraction Coupling , 1999, The Journal of general physiology.

[15]  R. Haworth,et al.  Depletion of T-tubules and specific subcellular changes in sarcolemmal proteins in tachycardia-induced heart failure. , 2003, Cardiovascular research.

[16]  H. T. ter Keurs,et al.  Calcium and arrhythmogenesis. , 2007, Physiological reviews.

[17]  M. Diaz,et al.  Sarcoplasmic Reticulum Calcium Content Fluctuation Is the Key to Cardiac Alternans , 2004, Circulation research.

[18]  S Nattel,et al.  Effects of flecainide and quinidine on human atrial action potentials. Role of rate-dependence and comparison with guinea pig, rabbit, and dog tissues. , 1990, Circulation.

[19]  Won Tae Kim,et al.  Simulation of Ca2+-activated Cl− current of cardiomyocytes in rabbit pulmonary vein: implications of subsarcolemmal Ca2+ dynamics , 2006, Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences.

[20]  J. Cinca,et al.  Sarcoplasmic reticulum and L‐type Ca2+ channel activity regulate the beat‐to‐beat stability of calcium handling in human atrial myocytes , 2011, The Journal of physiology.

[21]  G. Billman,et al.  Shortened Ca2+ Signaling Refractoriness Underlies Cellular Arrhythmogenesis in a Postinfarction Model of Sudden Cardiac Death , 2012, Circulation research.

[22]  Topi Korhonen,et al.  Impact of Sarcoplasmic Reticulum Calcium Release on Calcium Dynamics and Action Potential Morphology in Human Atrial Myocytes: A Computational Study , 2011, PLoS Comput. Biol..

[23]  A Garfinkel,et al.  Model of intracellular calcium cycling in ventricular myocytes. , 2003, Biophysical journal.

[24]  Joshua T Maxwell,et al.  Refractoriness of sarcoplasmic reticulum Ca2+ release determines Ca2+ alternans in atrial myocytes. , 2012, American journal of physiology. Heart and circulatory physiology.

[25]  I. Marty,et al.  Different compartments of sarcoplasmic reticulum participate in the excitation-contraction coupling process in human atrial myocytes. , 1997, Circulation research.

[26]  Angelina Peñaranda,et al.  Dependency of Calcium Alternans on Ryanodine Receptor Refractoriness , 2013, PloS one.

[27]  A. Trafford,et al.  Differences in intracellular calcium homeostasis between atrial and ventricular myocytes. , 2009, Journal of molecular and cellular cardiology.

[28]  J. Clark,et al.  Mathematical model of an adult human atrial cell: the role of K+ currents in repolarization. , 1998, Circulation research.

[29]  D. Bers.  Calcium cycling and signaling in cardiac myocytes. , 2008, Annual review of physiology.

[30]  W Yuan,et al.  Fractional SR Ca release is regulated by trigger Ca and SR Ca content in cardiac myocytes. , 1995, The American journal of physiology.

[31]  A. Peñaranda,et al.  Calcium alternans produced by increased Sarcoplasmic Reticulum refractoriness , 2011, 2011 Computing in Cardiology.

[32]  A. Minajeva,et al.  Sarcoplasmic reticulum function in determining atrioventricular contractile differences in rat heart , 1997 .

[33]  Katherine A. Sheehan,et al.  Functional coupling between glycolysis and excitation—contraction coupling underlies alternans in cat heart cells , 2000, The Journal of physiology.

[34]  C. Unkel,et al.  Regional expression of phospholamban in the human heart. , 1999, Cardiovascular research.

[35]  Mathias Wilhelms,et al.  Benchmarking electrophysiological models of human atrial myocytes , 2013, Front. Physio..

[36]  J. Jalife,et al.  Human Atrial Action Potential and Ca2+ Model: Sinus Rhythm and Chronic Atrial Fibrillation , 2011, Circulation research.

[37]  Katherine A. Sheehan,et al.  Activation and propagation of Ca(2+) release during excitation-contraction coupling in atrial myocytes. , 2001, Biophysical journal.

[38]  P. Fletcher,et al.  Couplons in rat atria form distinct subgroups defined by their molecular partners , 2011, Journal of Cell Science.

[39]  Alan Garfinkel,et al.  Spark-Induced Sparks As a Mechanism of Intracellular Calcium Alternans in Cardiac Myocytes , 2010, Circulation research.

[40]  D. Euler.  Cardiac alternans: mechanisms and pathophysiological significance. , 1999, Cardiovascular research.

[41]  D. Dobrev,et al.  Role of IKur in Controlling Action Potential Shape and Contractility in the Human Atrium: Influence of Chronic Atrial Fibrillation , 2004, Circulation.

[42]  C. Carnes,et al.  'Ryanopathy': causes and manifestations of RyR2 dysfunction in heart failure. , 2013, Cardiovascular research.

[43]  Qince Li,et al.  Mechanisms by which cytoplasmic calcium wave propagation and alternans are generated in cardiac atrial myocytes lacking T-tubules-insights from a simulation study. , 2012, Biophysical journal.

[44]  Katherine A. Sheehan,et al.  Local calcium gradients during excitation–contraction coupling and alternans in atrial myocytes , 2003, The Journal of physiology.

[45]  D. Rosenbaum,et al.  Repolarization alternans: implications for the mechanism and prevention of sudden cardiac death. , 2003, Cardiovascular research.

[46]  A. Trafford,et al.  Characterization of an Extensive Transverse Tubular Network in Sheep Atrial Myocytes and its Depletion in Heart Failure , 2009, Circulation. Heart failure.

[47]  Donald M Bers,et al.  A mathematical treatment of integrated Ca dynamics within the ventricular myocyte. , 2004, Biophysical journal.