Ionic current abnormalities associated with prolonged action potentials in cardiomyocytes from diseased human right ventricles.

OBJECTIVES This study was designed to determine whether ionic currents in right ventricular myocytes from explanted human transplant recipient hearts are related to right ventricular histopathology and function. BACKGROUND Cardiac action potential duration (APD) is prolonged in ventricular tissues/cells from patients with heart failure, but the ionic mechanisms are not well documented. METHODS Membrane currents and transmembrane action potentials in myocytes from right ventricular epicardium of explanted human hearts were recorded using whole-cell patch clamp technique. Data from cells from right ventricles with severe histologic and functional abnormalities (abnormal histology group [AH]) and from right ventricles with preserved histology and function (relatively normal histology group [RNH]) were compared. RESULTS We found that APD at 50% (APD(50)) and 90% repolarization (APD(90)) were significantly longer in AH cells than in RNH cells. Early afterdepolarizations (EADs) were observed in 20% of AH cells and none of the RNH cells. Inwardly rectifying K(+) current (I(K1)) was decreased (both inward and outward components). Both transient outward K(+) current (I(to1)) and slowly delayed rectifier K(+) current (I(Ks)) were down-regulated in AH cells. L-type Ca(2+) (I(Ca.L)) was not altered in AH cells. CONCLUSIONS I(K1), I(to1), and I(Ks) are down-regulated in AH cells of human heart failure. This down-regulation contributes to APD prolongation that favors the occurrence of arrhythmogenic EADs and suggests a link between human cardiac histopathologic/functional abnormalities and arrhythmogenic ionic remodeling.

[1]  W. Crumb,et al.  Description of a nonselective cation current in human atrium. , 1995, Circulation research.

[2]  C Antzelevitch,et al.  I(NaCa) contributes to electrical heterogeneity within the canine ventricle. , 2000, American journal of physiology. Heart and circulatory physiology.

[3]  C. Antzelevitch,et al.  Characteristics of the delayed rectifier current (IKr and IKs) in canine ventricular epicardial, midmyocardial, and endocardial myocytes. A weaker IKs contributes to the longer action potential of the M cell. , 1995, Circulation research.

[4]  J. Bergin,et al.  Sudden cardiac death in heart failure. , 2000, The Journal of cardiovascular nursing.

[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]  P. Kowey,et al.  Increasing I(Ks) corrects abnormal repolarization in rabbit models of acquired LQT2 and ventricular hypertrophy. , 2002, American journal of physiology. Heart and circulatory physiology.

[7]  A. A. Armoundas,et al.  Ectopic expression of KCNE3 accelerates cardiac repolarization and abbreviates the QT interval. , 2002, The Journal of clinical investigation.

[8]  H A Fozzard,et al.  Afterdepolarizations and triggered activity. , 1992, Basic research in cardiology.

[9]  G. Rozanski,et al.  Electrophysiology of rabbit ventricular myocytes following sustained rapid ventricular pacing. , 1997, Journal of molecular and cellular cardiology.

[10]  M. Carrier,et al.  Transmural heterogeneity of action potentials and I to1 in myocytes isolated from the human right ventricle. , 1998, American journal of physiology. Heart and circulatory physiology.

[11]  D. Roden,et al.  Normalization of acquired QT prolongation in humans by intravenous potassium. , 1997, Circulation.

[12]  E. Erdmann,et al.  Alterations of K+ currents in isolated human ventricular myocytes from patients with terminal heart failure. , 1993, Circulation research.

[13]  Donald M Bers,et al.  Cellular Basis of Abnormal Calcium Transients of Failing Human Ventricular Myocytes , 2003, Circulation research.

[14]  H. Calkins,et al.  Beat-to-beat QT interval variability: novel evidence for repolarization lability in ischemic and nonischemic dilated cardiomyopathy. , 1997, Circulation.

[15]  Ronald A. Li,et al.  Dual gene therapy with SERCA1 and Kir2.1 abbreviates excitation without suppressing contractility. , 2002, The Journal of clinical investigation.

[16]  G. Steinbeck,et al.  Molecular basis of transient outward potassium current downregulation in human heart failure: a decrease in Kv4.3 mRNA correlates with a reduction in current density. , 1998, Circulation.

[17]  J. M. Di Diego,et al.  High [Ca2+]o-induced electrical heterogeneity and extrasystolic activity in isolated canine ventricular epicardium. Phase 2 reentry. , 1994, Circulation.

[18]  D. Mckinnon,et al.  Role of the Kv4.3 K+ channel in ventricular muscle. A molecular correlate for the transient outward current. , 1996, Circulation research.

[19]  M. Näbauer,et al.  Potassium channel down-regulation in heart failure. , 1998, Cardiovascular research.

[20]  M. Sanguinetti,et al.  Two components of cardiac delayed rectifier K+ current. Differential sensitivity to block by class III antiarrhythmic agents , 1990, The Journal of general physiology.

[21]  C. Lau,et al.  Transmural action potential and ionic current remodeling in ventricles of failing canine hearts. , 2002, American journal of physiology. Heart and circulatory physiology.

[22]  E. Marbán,et al.  Overexpression of a human potassium channel suppresses cardiac hyperexcitability in rabbit ventricular myocytes. , 1999, The Journal of clinical investigation.

[23]  G. Tomaselli,et al.  Electrophysiological remodeling in hypertrophy and heart failure. , 1999, Cardiovascular research.

[24]  R. Hullin,et al.  Increased availability and open probability of single L-type calcium channels from failing compared with nonfailing human ventricle. , 1998, Circulation.

[25]  C Antzelevitch,et al.  Clinical relevance of cardiac arrhythmias generated by afterdepolarizations. Role of M cells in the generation of U waves, triggered activity and torsade de pointes. , 1994, Journal of the American College of Cardiology.

[26]  D. Kass,et al.  Ionic mechanism of action potential prolongation in ventricular myocytes from dogs with pacing-induced heart failure. , 1996, Circulation research.

[27]  C. Luo,et al.  A dynamic model of the cardiac ventricular action potential. II. Afterdepolarizations, triggered activity, and potentiation. , 1994, Circulation research.

[28]  H N Sabbah,et al.  Novel, ultraslow inactivating sodium current in human ventricular cardiomyocytes. , 1998, Circulation.

[29]  Craig T. January,et al.  Early Afterdepolarizations: Mechanism of Induction and Block A Role for L‐Type Ca2+ Current , 1989, Circulation research.

[30]  U Ravens,et al.  L-type calcium currents of human myocytes from ventricle of non-failing and failing hearts and from atrium. , 1994, Journal of molecular and cellular cardiology.

[31]  H. Wellens,et al.  Progress in the understanding of cardiac early afterdepolarizations and torsades de pointes: time to revise current concepts. , 2000, Cardiovascular research.

[32]  J. Foell,et al.  Reduction in density of transverse tubules and L-type Ca(2+) channels in canine tachycardia-induced heart failure. , 2001, Cardiovascular research.

[33]  S Nattel,et al.  Evidence for two components of delayed rectifier K+ current in human ventricular myocytes. , 1996, Circulation research.

[34]  S. Komşuoğlu,et al.  Significance of QTc prolongation on ventricular arrhythmias in patients with left ventricular hypertrophy secondary to essential hypertension. , 1996, International journal of cardiology.

[35]  D. Beuckelmann,et al.  Simulation study of cellular electric properties in heart failure. , 1998, Circulation research.

[36]  P. Kowey,et al.  Left Ventricular Hypertrophy Decreases Slowly but Not Rapidly Activating Delayed Rectifier Potassium Currents of Epicardial and Endocardial Myocytes in Rabbits , 2001, Circulation.