Ionic mechanisms limiting cardiac repolarization reserve in humans compared to dogs

•  Cardiac repolarization, through which heart‐cells return to their resting state after having fired, is a delicate process, susceptible to disruption by common drugs and clinical conditions. •  Animal models, particularly the dog, are often used to study repolarization properties and responses to drugs, with the assumption that such findings are relevant to humans. However, little is known about the applicability of findings in animals to man. •  Here, we studied the contribution of various ion‐currents to cardiac repolarization in canine and human ventricle. •  Humans showed much greater repolarization‐impairing effects of drugs blocking the rapid delayed‐rectifier current IKr than dogs, because of lower repolarization‐reserve contributions from two other important repolarizing currents (the inward‐rectifier IK1 and slow delayed‐rectifier IKs). •  Our findings clarify differences in cardiac repolarization‐processes among species, highlighting the importance of caution when extrapolating results from animal models to man.

[1]  J. Papp,et al.  Pharmacological block of the slow component of the outward delayed rectifier current (IKs) fails to lengthen rabbit ventricular muscle QTc and action potential duration , 2001, British journal of pharmacology.

[2]  J. Nerbonne,et al.  Molecular physiology of cardiac repolarization. , 2005, Physiological reviews.

[3]  M. Pfaffl,et al.  A new mathematical model for relative quantification in real-time RT-PCR. , 2001, Nucleic acids research.

[4]  L. Virág,et al.  Effects of SEA0400 and KB-R7943 on Na+/Ca2+ exchange current and L-type Ca2+ current in canine ventricular cardiomyocytes , 2005, Naunyn-Schmiedeberg's Archives of Pharmacology.

[5]  J. Papp,et al.  Interaction of different potassium channels in cardiac repolarization in dog ventricular preparations: role of repolarization reserve , 2002, British journal of pharmacology.

[6]  G. Robertson,et al.  hERG subunit composition determines differential drug sensitivity , 2011, British journal of pharmacology.

[7]  Michael J. Ackerman,et al.  Physiological Properties of hERG 1a/1b Heteromeric Currents and a hERG 1b-Specific Mutation Associated With Long-QT Syndrome , 2008, Circulation research.

[8]  S. Nattel,et al.  Ion Channel Subunit Expression Changes in Cardiac Purkinje Fibers: A Potential Role in Conduction Abnormalities Associated With Congestive Heart Failure , 2009, Circulation research.

[9]  M. Shattock,et al.  Regulation of the cardiac sodium pump , 2012, Cellular and Molecular Life Sciences.

[10]  Justus M.B. Anumonwo,et al.  Unique Kir2.x Properties Determine Regional and Species Differences in the Cardiac Inward Rectifier K+ Current , 2004, Circulation research.

[11]  Jonathan M Cordeiro,et al.  Comparison of K+ currents in cardiac Purkinje cells isolated from rabbit and dog. , 2007, Journal of molecular and cellular cardiology.

[12]  QTc Interval as a Guide to Select Those Patients With Congestive Heart Failure and Reduced Left Ventricular Systolic Function Who Will Benefit From Antiarrhythmic Treatment With Dofetilide , 2001 .

[13]  László Virág,et al.  Restricting Excessive Cardiac Action Potential and QT Prolongation: A Vital Role for IKs in Human Ventricular Muscle , 2005, Circulation.

[14]  S. Nattel,et al.  Differential distribution of Kir2.1 and Kir2.3 subunits in canine atrium and ventricle. , 2002, American journal of physiology. Heart and circulatory physiology.

[15]  Yoram Rudy,et al.  Simulation of the Undiseased Human Cardiac Ventricular Action Potential: Model Formulation and Experimental Validation , 2011, PLoS Comput. Biol..

[16]  Liudmila Polonchuk,et al.  Scientific review and recommendations on preclinical cardiovascular safety evaluation of biologics. , 2008, Journal of pharmacological and toxicological methods.

[17]  S Nattel,et al.  Differential distribution of inward rectifier potassium channel transcripts in human atrium versus ventricle. , 1998, Circulation.

[18]  D. Khananshvili,et al.  The peptide ”FRCRCFa”, dialysed intracellularly, inhibits the Na/Ca exchange in rabbit ventricular myocytes with high affinity , 1997, Pflügers Archiv.

[19]  S. Hohnloser,et al.  Drug therapy : Sotalol , 1994 .

[20]  P. Backx,et al.  Molecular dissection of the inward rectifier potassium current (IK1) in rabbit cardiomyocytes: evidence for heteromeric co‐assembly of Kir2.1 and Kir2.2 , 2003, The Journal of physiology.

[21]  M. Malik,et al.  QTc Interval as a Guide to Select Those Patients With Congestive Heart Failure and Reduced Left Ventricular Systolic Function Who Will Benefit From Antiarrhythmic Treatment With Dofetilide , 2001, Circulation.

[22]  B. Singh,et al.  A third class of anti‐arrhythmic action. Effects on atrial and ventricular intracellular potentials, and other pharmacological actions on cardiac muscle, of MJ 1999 and AH 3474 , 1970, British journal of pharmacology.

[23]  A. Varró,et al.  Potential therapeutic effects of Na+/Ca2+ exchanger inhibition in cardiac diseases. , 2009, Current medicinal chemistry.

[24]  László Virág,et al.  The role of the delayed rectifier component IKs in dog ventricular muscle and Purkinje fibre repolarization , 2000, The Journal of physiology.

[25]  S. Nattel,et al.  Functional expression of Kir2.x in human aortic endothelial cells: the dominant role of Kir2.2. , 2005, American journal of physiology. Cell physiology.

[26]  M. Lazdunski,et al.  Molecular and functional properties of two-pore-domain potassium channels. , 2000, American journal of physiology. Renal physiology.

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

[28]  C. Antzelevitch,et al.  Cellular basis for electrocardiographic and arrhythmic manifestations of Andersen-Tawil syndrome (LQT7). , 2006, Heart rhythm.

[29]  B. Surawicz.  Electrophysiologic substrate of torsade de pointes: dispersion of repolarization or early afterdepolarizations? , 1989, Journal of the American College of Cardiology.

[30]  K. Igarashi,et al.  Different intracellular polyamine concentrations underlie the difference in the inward rectifier K+ currents in atria and ventricles of the guinea‐pig heart , 2005, The Journal of physiology.

[31]  S. Nattel,et al.  Properties, Expression and Potential Roles of Cardiac K+ Channel Accessory Subunits: MinK, MiRPs, KChIP, and KChAP , 2003, The Journal of Membrane Biology.

[32]  Hua-rong Lu,et al.  Species Plays an Important Role in Drug‐Induced Prolongation of Action Potential Duration and Early Afterdepolarizations in Isolated Purkinje Fibers , 2001, Journal of cardiovascular electrophysiology.

[33]  José Jalife,et al.  The inward rectifier current (IK1) controls cardiac excitability and is involved in arrhythmogenesis. , 2005, Heart rhythm.

[34]  D. Roden.  Taking the “Idio” out of “Idiosyncratic”: Predicting Torsades de Pointes , 1998, Pacing and clinical electrophysiology : PACE.

[35]  Itsuo Kodama,et al.  Density and Kinetics of IKr and IKs in Guinea Pig and Rabbit Ventricular Myocytes Explain Different Efficacy of IKs Blockade at High Heart Rate in Guinea Pig and Rabbit: Implications for Arrhythmogenesis in Humans , 2001, Circulation.

[36]  C. Nichols,et al.  Inward rectifiers in the heart: an update on I(K1). , 2001, Journal of molecular and cellular cardiology.

[37]  Yoram Rudy,et al.  Subunit Interaction Determines IKs Participation in Cardiac Repolarization and Repolarization Reserve , 2005, Circulation.

[38]  D. Roden.  Long QT syndrome: reduced repolarization reserve and the genetic link , 2006, Journal of internal medicine.

[39]  Stanley Nattel,et al.  Molecular basis of species-specific expression of repolarizing K+ currents in the heart. , 2003, American journal of physiology. Heart and circulatory physiology.

[40]  S. Nattel,et al.  Barium block of Kir2 and human cardiac inward rectifier currents: evidence for subunit-heteromeric contribution to native currents. , 2003, Cardiovascular research.

[41]  C. Antzelevitch,et al.  Cellular basis for long QT, transmural dispersion of repolarization, and torsade de pointes in the long QT syndrome. , 1999, Journal of electrocardiology.

[42]  S. Olesen,et al.  Differential Expression of hERG1 Channel Isoforms Reproduces Properties of Native I Kr and Modulates Cardiac Action Potential Characteristics , 2010, PloS one.

[43]  D. Snyders,et al.  Class III antiarrhythmic agents have a lot of potential but a long way to go. Reduced effectiveness and dangers of reverse use dependence. , 1990, Circulation.