Ionic mechanisms of electrophysiological heterogeneity and conduction block in the infarct border zone.

The increased incidence of arrhythmia in the healing phase after infarction has been linked to remodeling in the epicardial border zone (EBZ). Ionic models of normal zone (NZ) and EBZ myocytes were incorporated into one-dimensional models of propagation to gain mechanistic insights into how ion channel remodeling affects action potential (AP) duration (APD) and refractoriness, vulnerability to conduction block, and conduction safety postinfarction. We found that EBZ tissue exhibited abnormal APD restitution. The remodeled Na(+) current (I(Na)) and L-type Ca(2+) current (I(Ca,L)) promoted increased effective refractory period and prolonged APD at a short diastolic interval. While postrepolarization refractoriness due to remodeled EBZ I(Na) was the primary determinant of the vulnerable window for conduction block at the NZ-to-EBZ transition in response to premature S2 stimuli, altered EBZ restitution also promoted APD dispersion and increased the vulnerable window at fast S1 pacing rates. Abnormal EBZ APD restitution and refractoriness also led to abnormal periodic conduction block patterns for a range of fast S1 pacing rates. In addition, we found that I(Na) remodeling decreased conduction safety in the EBZ but that inward rectifier K(+) current remodeling partially offset this decrease. EBZ conduction was characterized by a weakened AP upstroke and short intercellular delays, which prevented I(Ca,L) and transient outward K(+) current remodeling from playing a role in EBZ conduction in uncoupled tissue. Simulations of a skeletal muscle Na(+) channel SkM1-I(Na) injection into the EBZ suggested that this recently proposed antiarrhythmic therapy has several desirable effects, including normalization of EBZ effective refractory period and APD restitution, elimination of vulnerability to conduction block, and normalization of conduction in tissue with reduced intercellular coupling.

[1]  R. Robinson,et al.  Frequency dependent effects on Cai transients and cell shortening in myocytes that survive in the infarcted heart. , 1997, Cardiovascular research.

[2]  P. Boyden,et al.  Diminished Ca2+ and Ba2+ currents in myocytes surviving in the epicardial border zone of the 5-day infarcted canine heart. , 1995, Circulation research.

[3]  M. Janse,et al.  Electrophysiological mechanisms of ventricular arrhythmias resulting from myocardial ischemia and infarction. , 1989, Physiological reviews.

[4]  P. Boyden,et al.  Electrical remodeling in ischemia and infarction. , 1999, Cardiovascular research.

[5]  J. Pu,et al.  Ca(2+)-dependent outward currents in myocytes from epicardial border zone of 5-day infarcted canine heart. , 1997, The American journal of physiology.

[6]  R. Lazzara,et al.  Re‐entrant Ventricular Arrhythmias in the Late Myocardial Infarction Period: 4. Mechanism of Action of Lidocaine , 1977, Circulation.

[7]  J. Pu,et al.  Effects of Bay Y5959 on Ca2+ currents and intracellular Ca2+ in cells that have survived in the epicardial border of the infarcted canine heart. , 1999, Journal of cardiovascular pharmacology.

[8]  Yoram Rudy,et al.  Role of activated CaMKII in abnormal calcium homeostasis and I(Na) remodeling after myocardial infarction: insights from mathematical modeling. , 2008, Journal of molecular and cellular cardiology.

[9]  N. El-Sherif,et al.  Reentrant ventricular arrhythmias in the late myocardial infarction period. II. Burst pacing versus multiple premature stimulation in the induction of reentry. , 1984, Journal of the American College of Cardiology.

[10]  Stefan Wagner,et al.  Ca2+/calmodulin-dependent protein kinase II regulates cardiac Na+ channels. , 2006, The Journal of clinical investigation.

[11]  Y Rudy,et al.  Ionic mechanisms of propagation in cardiac tissue. Roles of the sodium and L-type calcium currents during reduced excitability and decreased gap junction coupling. , 1997, Circulation research.

[12]  P. Boyden,et al.  Abnormal Electrical Properties of Myocytes From Chronically Infarcted Canine Heart: Alterations in &OV0312;max and the Transient Outward Current , 1992, Circulation.

[13]  C. Cabo,et al.  Heterogeneous gap junction remodeling stabilizes reentrant circuits in the epicardial border zone of the healing canine infarct: a computational study. , 2006, American journal of physiology. Heart and circulatory physiology.

[14]  Nicholas S. Peters,et al.  Remodeling of Gap Junctional Channel Function in Epicardial Border Zone of Healing Canine Infarcts , 2003, Circulation research.

[15]  Yoram Rudy,et al.  Properties and ionic mechanisms of action potential adaptation, restitution, and accommodation in canine epicardium. , 2009, American journal of physiology. Heart and circulatory physiology.

[16]  Candido Cabo,et al.  Remodeling in Cells From Different Regions of the Reentrant Circuit During Ventricular Tachycardia , 2005, Circulation.

[17]  R Lazzara,et al.  Re-entrant Ventricular Arrhythmias in the Late Myocardial Infarction Period: 3. Manifest and Concealed Extrasystolic Grouping , 1977, Circulation.

[18]  Edward J Ciaccio,et al.  Heterogeneous gap junction remodeling in reentrant circuits in the epicardial border zone of the healing canine infarct. , 2006, Cardiovascular research.

[19]  H. Jongsma,et al.  Modulating L-type calcium current affects discontinuous cardiac action potential conduction. , 1996, Biophysical journal.

[20]  Candido Cabo,et al.  Electrical remodeling of the epicardial border zone in the canine infarcted heart: a computational analysis. , 2003, American journal of physiology. Heart and circulatory physiology.

[21]  Chris Clausen,et al.  Epicardial Border Zone Overexpression of Skeletal Muscle Sodium Channel SkM1 Normalizes Activation, Preserves Conduction, and Suppresses Ventricular Arrhythmia: An In Silico, In Vivo, In Vitro Study , 2009, Circulation.

[22]  L. Maier.  Role of CaMKII for signaling and regulation in the heart. , 2009, Frontiers in bioscience.

[23]  Wen Dun,et al.  Diverse phenotypes of outward currents in cells that have survived in the 5-day-infarcted heart. , 2005, American journal of physiology. Heart and circulatory physiology.

[24]  Mark E. Anderson,et al.  Oxidized Calmodulin Kinase II Regulates Conduction Following Myocardial Infarction: A Computational Analysis , 2009, PLoS Comput. Biol..

[25]  Y Rudy,et al.  The Vulnerable Window for Unidirectional Block in Cardiac Tissue: , 1995, Journal of cardiovascular electrophysiology.

[26]  C. Cabo,et al.  Delayed rectifier K currents have reduced amplitudes and altered kinetics in myocytes from infarcted canine ventricle. , 2000, Cardiovascular research.

[27]  R. Robinson,et al.  Abnormalities in Ca(i)handling in myocytes that survive in the infarcted heart are not just due to alterations in repolarization. , 2000, Journal of molecular and cellular cardiology.

[28]  Shigeo Baba,et al.  Dynamic remodeling of K+ and Ca2+ currents in cells that survived in the epicardial border zone of canine healed infarcted heart. , 2004, American journal of physiology. Heart and circulatory physiology.

[29]  M. Allessie,et al.  Influences of anisotropic tissue structure on reentrant circuits in the epicardial border zone of subacute canine infarcts. , 1988, Circulation research.

[30]  N S Peters,et al.  Disturbed connexin43 gap junction distribution correlates with the location of reentrant circuits in the epicardial border zone of healing canine infarcts that cause ventricular tachycardia. , 1997, Circulation.

[31]  N. El-Sherif,et al.  Reentrant ventricular arrhythmias in the late myocardial infarction period in the dog. 13. Correlation of activation and refractory maps. , 1985, Circulation research.

[32]  A. Pollard,et al.  Transient outward current modulates discontinuous conduction in rabbit ventricular cell pairs. , 2001, Cardiovascular research.

[33]  C. Antzelevitch,et al.  Differential effects of the transient outward K(+) current activator NS5806 in the canine left ventricle. , 2009, Journal of molecular and cellular cardiology.

[34]  S. Rohr,et al.  Involvement of the calcium inward current in cardiac impulse propagation: induction of unidirectional conduction block by nifedipine and reversal by Bay K 8644. , 1997, Biophysical journal.

[35]  Stefan Wagner,et al.  Ca/Calmodulin Kinase II Differentially Modulates Potassium Currents , 2009, Circulation. Arrhythmia and electrophysiology.

[36]  R Lazzara,et al.  Re‐entrant Ventricular Arrhythmias in the Late Myocardial Infarction Period: 1. Conduction Characteristics in the Infarction Zone , 1977, Circulation.

[37]  Y Rudy,et al.  Ionic charge conservation and long-term steady state in the Luo-Rudy dynamic cell model. , 2001, Biophysical journal.

[38]  M. Janse,et al.  Experimental models of ventricular tachycardia and fibrillation caused by ischemia and infarction. , 1992, Circulation.

[39]  P. Ursell,et al.  Structural and Electrophysiological Changes in the Epicardial Border Zone of Canine Myocardial Infarcts during Infarct Healing , 1985, Circulation research.

[40]  Yoram Rudy,et al.  Rate Dependence and Regulation of Action Potential and Calcium Transient in a Canine Cardiac Ventricular Cell Model , 2004, Circulation.

[41]  C. Antzelevitch,et al.  Sodium channel block produces opposite electrophysiological effects in canine ventricular epicardium and endocardium. , 1991, Circulation research.

[42]  J. Pu,et al.  Alterations of Na+ currents in myocytes from epicardial border zone of the infarcted heart. A possible ionic mechanism for reduced excitability and postrepolarization refractoriness. , 1997, Circulation research.