Cardiac alternans induced by fibroblast-myocyte coupling: mechanistic insights from computational models.

Recent experimental studies have shown that fibroblasts can electrotonically couple to myocytes via gap junctions. In this study, we investigated how this coupling affects action potential and intracellular calcium (Ca(i)) cycling dynamics in simulated fibroblast-myocyte pairs and in two-dimensional tissue with random fibroblast insertions. We show that a fibroblast coupled with a myocyte generates a gap junction current flowing to the myocyte with two main components: an early pulse of transient outward current, similar to the fast transient outward current, and a later background current during the repolarizing phase. Depending on the relative prominence of the two components, fibroblast-myoycte coupling can 1) prolong or shorten action potential duration (APD), 2) promote or suppress APD alternans due to steep APD restitution (voltage driven) and also result in a novel mechanism of APD alternans at slow heart rates, 3) promote Ca(i)-driven alternans and electromechanically discordant alternans, and 4) promote spatially discordant alternans by two mechanisms: by altering conduction velocity restitution and by heterogeneous fibroblast distribution causing electromechanically concordant and discordant alternans in different regions of the tissue. Thus, through their coupling with myocytes, fibroblasts alter repolarization and Ca(i) cycling alternans at both the cellular and tissue scales, which may play important roles in arrhythmogenesis in diseased cardiac tissue with fibrosis.

[1]  A. Moreno,et al.  A Model of Electrical Conduction in Cardiac Tissue Including Fibroblasts , 2009, Annals of Biomedical Engineering.

[2]  C. Vásquez,et al.  Arrhythmogenic potential of activated fibroblasts , 2009 .

[3]  Matthew Gittinger,et al.  Heart failure enhances susceptibility to arrhythmogenic cardiac alternans. , 2009, Heart rhythm.

[4]  José Jalife,et al.  Electrotonic myofibroblast-to-myocyte coupling increases propensity to reentrant arrhythmias in two-dimensional cardiac monolayers. , 2008, Biophysical journal.

[5]  Henggui Zhang,et al.  Alternans of cardiac calcium cycling in a cluster of ryanodine receptors: a simulation study. , 2008, American journal of physiology. Heart and circulatory physiology.

[6]  Vincent Jacquemet,et al.  Loading effect of fibroblast-myocyte coupling on resting potential, impulse propagation, and repolarization: insights from a microstructure model. , 2008, American journal of physiology. Heart and circulatory physiology.

[7]  S. Nattel,et al.  Atrial fibrosis: mechanisms and clinical relevance in atrial fibrillation. , 2008, Journal of the American College of Cardiology.

[8]  J. Restrepo,et al.  A rabbit ventricular action potential model replicating cardiac dynamics at rapid heart rates. , 2007, Biophysical journal.

[9]  Vincent Jacquemet,et al.  Modelling cardiac fibroblasts: interactions with myocytes and their impact on impulse propagation. , 2007, Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology.

[10]  MicheleMiragoli,et al.  Myofibroblasts Induce Ectopic Activity in Cardiac Tissue , 2007 .

[11]  S. Landas,et al.  Spatial Distribution of Fibrosis Governs Fibrillation Wave Dynamics in the Posterior Left Atrium During Heart Failure , 2007, Circulation research.

[12]  Godfrey L. Smith,et al.  Evidence of intercellular coupling between co‐cultured adult rabbit ventricular myocytes and myofibroblasts , 2007, The Journal of physiology.

[13]  Godfrey L. Smith,et al.  Mapping of Epicardial Activation in a Rabbit Model of Chronic Myocardial Infarction: , 2007, Journal of cardiovascular electrophysiology.

[14]  W. Giles,et al.  A mathematical model of electrotonic interactions between ventricular myocytes and fibroblasts. , 2007, Biophysical journal.

[15]  Kenneth McDonald,et al.  Diastolic Heart Failure: Evidence of Increased Myocardial Collagen Turnover Linked to Diastolic Dysfunction , 2007, Circulation.

[16]  Peter Kohl,et al.  Cardiac myocyte-nonmyocyte electrotonic coupling: implications for ventricular arrhythmogenesis. , 2007, Heart rhythm.

[17]  Zhilin Qu,et al.  Nonlinear dynamics of cardiac excitation-contraction coupling: an iterated map study. , 2007, Physical review. E, Statistical, nonlinear, and soft matter physics.

[18]  Frank B. Sachse,et al.  Electrophysiological Modeling of Fibroblasts and their Interaction with Myocytes , 2007, Annals of Biomedical Engineering.

[19]  Thomas K Borg,et al.  Cardiac fibroblasts: friend or foe? , 2006, American journal of physiology. Heart and circulatory physiology.

[20]  G. Aurigemma,et al.  Contractile behavior of the left ventricle in diastolic heart failure: with emphasis on regional systolic function. , 2006, Circulation.

[21]  Stephan Rohr,et al.  Electrotonic Modulation of Cardiac Impulse Conduction by Myofibroblasts , 2006, Circulation research.

[22]  B. Hopenfeld.  Mechanism for action potential alternans: the interplay between L-type calcium current and transient outward current. , 2006, Heart rhythm.

[23]  Peter N. Jordan,et al.  Action potential morphology influences intracellular calcium handling stability and the occurrence of alternans. , 2006, Biophysical journal.

[24]  Peter Kohl,et al.  Electrical coupling of fibroblasts and myocytes: relevance for cardiac propagation. , 2005, Journal of electrocardiology.

[25]  D. Rosenbaum,et al.  Molecular correlates of repolarization alternans in cardiac myocytes. , 2005, Journal of molecular and cellular cardiology.

[26]  David M. Harris,et al.  Alterations in Early Action Potential Repolarization Causes Localized Failure of Sarcoplasmic Reticulum Ca2+ Release , 2005, Circulation research.

[27]  Joshua I. Goldhaber,et al.  Action Potential Duration Restitution and Alternans in Rabbit Ventricular Myocytes: The Key Role of Intracellular Calcium Cycling , 2005, Circulation research.

[28]  C. Long,et al.  The cardiac fibroblast: therapeutic target in myocardial remodeling and failure. , 2005, Annual review of pharmacology and toxicology.

[29]  T. Borg,et al.  Structural and functional characterisation of cardiac fibroblasts. , 2005, Cardiovascular research.

[30]  C. Vásquez,et al.  Modeling fibroblast-mediated conduction in the ventricle , 2004, Computers in Cardiology, 2004.

[31]  Sander Verheule,et al.  Increased Vulnerability to Atrial Fibrillation in Transgenic Mice With Selective Atrial Fibrosis Caused by Overexpression of TGF-β1 , 2004, Circulation research.

[32]  Peter Kohl,et al.  Spatially and temporally distinct expression of fibroblast connexins after sheep ventricular infarction. , 2004, Cardiovascular research.

[33]  I. LeGrice,et al.  Fibroblast Network in Rabbit Sinoatrial Node: Structural and Functional Identification of Homogeneous and Heterogeneous Cell Coupling , 2004, Circulation research.

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

[35]  Andrew L Wit,et al.  Cell Coupling Between Ventricular Myocyte Pairs From Connexin43-Deficient Murine Hearts , 2003, Circulation research.

[36]  P. Kohl.  Heterogeneous cell coupling in the heart: an electrophysiological role for fibroblasts. , 2003, Circulation research.

[37]  M. Miragoli,et al.  Coupling of Cardiac Electrical Activity Over Extended Distances by Fibroblasts of Cardiac Origin , 2003, Circulation research.

[38]  R. Ramirez,et al.  Regulation of cardiac excitation–contraction coupling by action potential repolarization: role of the transient outward potassium current (Ito) , 2003, The Journal of physiology.

[39]  R. Ramirez,et al.  Modulation of Ca2+ Release in Cardiac Myocytes by Changes in Repolarization Rate: Role of Phase-1 Action Potential Repolarization in Excitation-Contraction Coupling , 2002 .

[40]  R. Ramirez,et al.  Modulation of Ca(2+) release in cardiac myocytes by changes in repolarization rate: role of phase-1 action potential repolarization in excitation-contraction coupling. , 2002, Circulation research.

[41]  Shien-Fong Lin,et al.  Spatial Heterogeneity of Calcium Transient Alternans During the Early Phase of Myocardial Ischemia in the Blood-Perfused Rabbit Heart , 2001, Circulation.

[42]  M. Diaz,et al.  Integrative Analysis of Calcium Cycling in Cardiac Muscle , 2000, Circulation research.

[43]  R. Winslow,et al.  Role of the Calcium-Independent Transient Outward Current Ito1 in Shaping Action Potential Morphology and Duration , 2000, Circulation research.

[44]  A. Garfinkel,et al.  Mechanisms of Discordant Alternans and Induction of Reentry in Simulated Cardiac Tissue , 2000, Circulation.

[45]  M. Rosen,et al.  Effects of the renin-angiotensin system on the current I(to) in epicardial and endocardial ventricular myocytes from the canine heart. , 2000, Circulation research.

[46]  C Antzelevitch,et al.  Ionic mechanisms responsible for the electrocardiographic phenotype of the Brugada syndrome are temperature dependent. , 1999, Circulation research.

[47]  A Garfinkel,et al.  Spatiotemporal heterogeneity in the induction of ventricular fibrillation by rapid pacing: importance of cardiac restitution properties. , 1999, Circulation research.

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

[49]  D. Rosenbaum,et al.  Mechanism linking T-wave alternans to the genesis of cardiac fibrillation. , 1999, Circulation.

[50]  A. Kamkin,et al.  Mechanically Induced Potentials in Fibroblasts from Human Right Atrium , 1999, Experimental physiology.

[51]  K. Weber,et al.  Extracellular matrix remodeling in heart failure: a role for de novo angiotensin II generation. , 1997, Circulation.

[52]  P Kohl,et al.  Mechanosensitive fibroblasts in the sino‐atrial node region of rat heart: interaction with cardiomyocytes and possible role , 1994, Experimental physiology.

[53]  J. Ruskin,et al.  Electrical alternans and vulnerability to ventricular arrhythmias. , 1994, The New England journal of medicine.

[54]  C. Antzelevitch,et al.  Differences in the Electrophysiological Response of Canine Ventricular Epicardium and Endocardium to Ischemia Role of the Transient Outward Current , 1993, Circulation.

[55]  M. Rook,et al.  Differences in gap junction channels between cardiac myocytes, fibroblasts, and heterologous pairs. , 1992, The American journal of physiology.

[56]  C. Luo,et al.  A model of the ventricular cardiac action potential. Depolarization, repolarization, and their interaction. , 1991, Circulation research.

[57]  L. Girardier,et al.  Homo- and heterocellular junctions in cell cultures: an electrophysiological and morphological study. , 1969, Progress in Brain Research.