Cellular basis for the ECG features of the LQT1 form of the long-QT syndrome: effects of beta-adrenergic agonists and antagonists and sodium channel blockers on transmural dispersion of repolarization and torsade de pointes.

BACKGROUND This study examines the cellular basis for the phenotypic appearance of broad-based T waves, increased transmural dispersion of repolarization (TDR), and torsade de pointes (TdP) induced by beta-adrenergic agonists under conditions mimicking the LQT1 form of the congenital long-QT syndrome. METHODS AND RESULTS A transmural ECG and transmembrane action potentials from epicardial, M, and endocardial cells were recorded simultaneously from an arterially perfused wedge of canine left ventricle. Chromanol 293B, a specific IKs blocker, dose-dependently (1 to 100 micromol/L) prolonged the QT interval and action potential duration (APD90) of the 3 cell types but did not widen the T wave, increase TDR, or induce TdP. Isoproterenol 10 to 100 nmol/L in the continued presence of chromanol 293B 30 micromol/L abbreviated the APD90 of epicardial and endocardial cells but not that of the M cell, resulting in widening of the T wave and a dramatic accentuation of TDR. Spontaneous as well as programmed electrical stimulation (PES)-induced TdP was observed only after exposure to the IKs blocker and isoproterenol. Therapeutic concentrations of propranolol (0.5 to 1 micromol/L) prevented the actions of isoproterenol to increase TDR and to induce TdP. Mexiletine 2 to 20 micromol/L abbreviated the APD90 of M cells more than that of epicardial and endocardial cells, thus diminishing TDR and the effect of isoproterenol to induce TdP. CONCLUSIONS This experimental model of LQT1 indicates that a deficiency of IKs alone does not induce TdP but that the addition of beta-adrenergic influence predisposes the myocardium to the development of TdP by increasing transmural dispersion of repolarization, most likely as a result of a large augmentation of residual IKs in epicardial and endocardial cells but not in M cells, in which IKs is intrinsically weak. Our data provide a mechanistic understanding of the cellular basis for the therapeutic actions of beta-adrenergic blockers in LQT1 and suggest that sodium channel block with class IB antiarrhythmic agents may be effective in suppressing TdP in LQT1, as they are in LQT2 and LQT3, as well as in acquired (drug-induced) forms of the long-QT syndrome.

[1]  C Antzelevitch,et al.  Cellular and ionic mechanisms underlying erythromycin-induced long QT intervals and torsade de pointes. , 1996, Journal of the American College of Cardiology.

[2]  M. Sanguinetti,et al.  Coassembly of K(V)LQT1 and minK (IsK) proteins to form cardiac I(Ks) potassium channel. , 1996, Nature.

[3]  S. Priori,et al.  Long QT syndrome patients with mutations of the SCN5A and HERG genes have differential responses to Na+ channel blockade and to increases in heart rate. Implications for gene-specific therapy. , 1995, Circulation.

[4]  M Restivo,et al.  The electrophysiological mechanism of ventricular arrhythmias in the long QT syndrome. Tridimensional mapping of activation and recovery patterns. , 1996, Circulation research.

[5]  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.

[6]  S. Priori,et al.  Dispersion of the QT interval. A marker of therapeutic efficacy in the idiopathic long QT syndrome. , 1994, Circulation.

[7]  清水 渉,et al.  Early afterdepolarizations induced by isoproterenol in patients with congenital long QT syndrome , 1992 .

[8]  R. Harvey,et al.  Chloride conductance pathways in heart. , 1991, The American journal of physiology.

[9]  M. Sanguinetti,et al.  A mechanistic link between an inherited and an acquird cardiac arrthytmia: HERG encodes the IKr potassium channel , 1995, Cell.

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

[11]  R. Crampton Preeminence of the Left Stellate Ganglion in the Long Q-T Syndrome , 1979, Circulation.

[12]  M. Sanguinetti,et al.  Coassembly of KVLQT1 and minK (IsK) proteins to form cardiac IKS potassium channel , 1996, Nature.

[13]  M. Sanguinetti,et al.  Mutations in the hminK gene cause long QT syndrome and suppress lKs function , 1997, Nature Genetics.

[14]  Gan-XinYan,et al.  Cellular Basis for the Normal T Wave and the Electrocardiographic Manifestations of the Long-QT Syndrome , 1998 .

[15]  R. Lazzara,et al.  Role of Na+:Ca2+ Exchange Current in Cs+‐Induced Early Afterdepolarizations in Purkinje Fibers , 1994, Journal of cardiovascular electrophysiology.

[16]  D. Zipes The long QT interval syndrome. A Rosetta stone for sympathetic related ventricular tachyarrhythmias. , 1991, Circulation.

[17]  CharlesAntzelevitch,et al.  Sodium Channel Block With Mexiletine Is Effective in Reducing Dispersion of Repolarization and Preventing Torsade de Pointes in LQT2 and LQT3 Models of the Long-QT Syndrome , 1997 .

[18]  G. Landes,et al.  Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias , 1996, Nature Genetics.

[19]  Arthur J Moss,et al.  SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome , 1995, Cell.

[20]  C Antzelevitch,et al.  Cellular basis for QT dispersion. , 1998, Journal of electrocardiology.

[21]  W. Shimizu,et al.  Influence of Epinephrine, Propranolol, and Atrial Pacing on Spatial Distribution of Recovery Time Measured by Body Surface Mapping in Congenital Long QT Syndrome , 1997, Journal of cardiovascular electrophysiology.

[22]  A. Camm,et al.  Assessment of QT dispersion in symptomatic patients with congenital long QT syndromes. , 1992, The American journal of cardiology.

[23]  M Restivo,et al.  Electrophysiological mechanism of the characteristic electrocardiographic morphology of torsade de pointes tachyarrhythmias in the long-QT syndrome: detailed analysis of ventricular tridimensional activation patterns. , 1997, Circulation.

[24]  A. Moss,et al.  The Long QT Syndrome: Prospective Longitudinal Study of 328 Families , 1991, Circulation.

[25]  A. Zygmunt Intracellular calcium activates a chloride current in canine ventricular myocytes. , 1994, The American journal of physiology.

[26]  Jacques Barhanin,et al.  KvLQT1 and IsK (minK) proteins associate to form the IKS cardiac potassium current , 1996, Nature.

[27]  W. Allan,et al.  Long QT Syndrome , 1998, Pediatrics.

[28]  A. Moss,et al.  ECG T-wave patterns in genetically distinct forms of the hereditary long QT syndrome. , 1995, Circulation.

[29]  J. Towbin,et al.  Improvement of repolarization abnormalities by a K+ channel opener in the LQT1 form of congenital long-QT syndrome. , 1998, Circulation.

[30]  E. Green,et al.  A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome , 1995, Cell.

[31]  H. Hirao,et al.  Frequency-dependent electrophysiologic properties of ventricular repolarization in patients with congenital long QT syndrome. , 1996, Journal of the American College of Cardiology.

[32]  P. Schwartz,et al.  Idiopathic long QT syndrome: progress and questions. , 1985, American heart journal.

[33]  A Malliani,et al.  Electrical alternation of the T-wave: clinical and experimental evidence of its relationship with the sympathetic nervous system and with the long Q-T syndrome. , 1975, American heart journal.

[34]  R Lazzara,et al.  Multiple mechanisms in the long-QT syndrome. Current knowledge, gaps, and future directions. The SADS Foundation Task Force on LQTS. , 1996, Circulation.

[35]  J. Jalife,et al.  Cardiac Electrophysiology: From Cell to Bedside , 1990 .