T-type calcium current contributes to escape automaticity and governs the occurrence of lethal arrhythmias after atrioventricular block in mice.

BACKGROUND: When complete atrioventricular block (AVB) occurs, infranodal escape rhythms are essential to prevent bradycardic death. The role of T-type Ca(2+) channels in pacemaking outside the sinus node is unknown. We investigated the role of T-type Ca(2+) channels in escape rhythms and bradycardia-related ventricular tachyarrhythmias after AVB in mice. METHODS AND RESULTS: Adult male mice lacking the main T-type Ca(2+) channel subunit Cav3.1 (Cav3.1(-/-)) and wild-type (WT) controls implanted with ECG telemetry devices underwent radiofrequency atrioventricular node ablation to produce AVB. Before ablation, Cav3.1(-/-) mice showed sinus bradycardia (mean±SEM; RR intervals, 148±3 versus 128±2 ms WT; P<0.001). Immediately after AVB, Cav3.1(-/-) mice had slower escape rhythms (RR intervals, 650±75 versus 402±26 ms in WT; P<0.01) but a preserved heart-rate response to isoproterenol. Over the next 24 hours, mortality was markedly greater in Cav3.1(-/-) mice (19/31; 61%) versus WT (8/26; 31%; P<0.05), and Torsades de Pointes occurred more frequently (73% Cav3.1(-/-) versus 35% WT; P<0.05). Escape rhythms improved in both groups during the next 4 weeks but remained significantly slower in Cav3.1(-/-). At 4 weeks after AVB, ventricular tachycardia was more frequent in Cav3.1(-/-) than in WT mice (746±116 versus 214±78 episodes/24 hours; P<0.01). Ventricular function remodeling was similar in Cav3.1(-/-) and WT, except for smaller post-AVB fractional-shortening increase in Cav3.1(-/-). Expression changes were seen post-AVB for a variety of genes; these tended to be greater in Cav3.1(-/-) mice, and overexpression of fetal and profibrotic genes occurred only in Cav3.1(-/-). CONCLUSIONS: This study suggests that T-type Ca(2+) channels play an important role in infranodal escape automaticity. Loss of T-type Ca(2+) channels worsens bradycardia-related mortality, increases bradycardia-associated adverse remodeling, and enhances the risk of malignant ventricular tachyarrhythmias complicating AVB.

Torsades de pointes following acute myocardial infarction: evidence for a deadly link with a common genetic variant.

BACKGROUND: Although QT prolongation following myocardial infarction (MI) is generally moderate, cases with marked QT prolongation leading to life-threatening torsades de pointes (TdP) have been described. OBJECTIVE: To investigate the genetic substrate of this phenomenon. METHODS: We studied 13 patients who developed TdP in the subacute phase of MI (2-11 days) and a group of 133 ethnically matched controls with uncomplicated MI. Long QT syndrome genes and the KCNH2-K897T polymorphism were screened by using denaturing high-performance liquid chromatography plus direct sequencing and a specific TaqMan assay, respectively. RESULTS: Two of the 13 patients (15%) who presented with QT prolongation and TdP were found to carry long QT syndrome mutations (KCNH2-R744X and SCN5A-E446K). Nine of the remaining 11 patients (82%) carried the KCNH2-K897T polymorphism, which was present in 35% of the controls (P = .0035). Thus, patients with an acute MI carrying the KCNH2-K897T polymorphism had an 8-fold greater risk of experiencing TdP compared with controls (95% confidence interval = 2-40). CONCLUSIONS: Our data suggest that the common K897T polymorphism is associated with an increased risk of TdP developing in the subacute phase of MI. Our findings support the concept that the electrical remodeling associated with this healing phase of MI may unmask a genetic substrate predisposing to a time-limited development of life-threatening arrhythmias. They also provide the first line of evidence in support of the hypothesis that a common polymorphism, previously described as a modifier of the severity of LQTS, may increase the risk of life-threatening arrhythmias in a much more prevalent cardiac disease such as myocardial infarction.

hERG subunit composition determines differential drug sensitivity.

BACKGROUND AND PURPOSE: The majority of human ether-a-go-go-related gene (hERG) screens aiming to minimize the risk of drug-induced long QT syndrome have been conducted using heterologous systems expressing the hERG 1a subunit, although both hERG 1a and 1b subunits contribute to the K+ channels producing the repolarizing current I(Kr) . We tested a range of compounds selected for their diversity to determine whether hERG 1a and 1a/1b channels exhibit different sensitivities that may influence safety margins or contribute to a stratified risk analysis. EXPERIMENTAL APPROACH: We used the IonWorks™ plate-based electrophysiology device to compare sensitivity of hERG 1a and 1a/1b channels stably expressed in HEK293 cells to 50 compounds previously shown to target hERG channels. Potency was determined as IC50 values (µM) obtained from non-cumulative, eight-point concentration-effect curves of normalized data, fitted to the Hill equation. To minimize possible sources of variability, compound potency was assessed using test plates arranged in alternating columns of cells expressing hERG 1a and 1a/1b. KEY RESULTS: Although the potency of most compounds was similar for the two targets, some surprising differences were observed. Fluoxetine (Prozac) was more potent at blocking hERG 1a/1b than 1a channels, yielding a corresponding reduction in the safety margin. In contrast, E-4031 was a more potent blocker of hERG 1a compared with 1a/1b channels, as previously reported, as was dofetilide, another high-affinity blocker. CONCLUSIONS AND IMPLICATIONS: The current assays may underestimate the risk of some drugs to cause torsades de pointes arrhythmia, and overestimate the risk of others.

Case ascertainment and estimated incidence of drug-induced long-QT syndrome: study in Southwest France.

AIMS: The aim of this study was to investigate the incidence and reporting rate of drug-induced long-QT syndrome (LQTS) in France [defined by evidence of torsades de pointes (TdP), QT prolongation and exposure to a relevant drug] and to assess feasibility of case collection for drug-induced LQTS. METHODS: A retrospective population-based study was carried out in Southwest France in five institutions: three main hospitals, one private clinic and one cardiac emergency unit, searched from 1 January 1999 to 1 January 2005 (population coverage of 614 000). The study population consisted of 861 cases with International Classification of Diseases-10 diagnostic codes for ventricular tachycardia (I147.2), ventricular fibrillation (I149.0) and sudden cardiac death (I146.1) from hospital discharge summaries, supplemented by cases reported to national or regional pharmacovigilance systems, and voluntary reporting by physicians, validated according to internationally defined criteria for drug-induced LQTS. RESULTS: Of 861 patients coded with arrhythmias or sudden cardiac death, there were 40 confirmed surviving acquired cases of drug-induced LQTS. We estimated that the incidence of those who survive to reach hospital drug-induced LQTS is approximately 10.9 per million annually in France (95% confidence interval 7.8, 14.8). CONCLUSIONS: Many cases of drug-induced LQTS may not survive before they reach hospital, as the reporting rate for drug-induced LQTS identified through the cardiology records and also reported to pharmacovigilance systems for the Midi-Pyrenees area is 3/40 (7.5%). Using the methods outlined it is possible to assemble cases to study genetic susceptibility to drug-induced LQTS and adapt these methods more widely.

Gender differences in autonomic modulation of ventricular repolarization in humans.

BACKGROUND: Gender differences in the incidence of ventricular arrhythmias have been reported and torsades de pointes associated with long QT syndrome are more common in women than men. Although increased sympathetic tone has an important role in vulnerability to arrhythmia, little is currently known regarding gender differences in the dynamic electrophysiological response to sympathetic stimulation. Therefore, we investigated whether there is a gender difference in humans with respect to the dynamic response of ventricular repolarization to beta-adrenergic stimulation and to autonomic blockade. METHODS: Twelve-lead ECGs were continuously recorded during isoproterenol infusion (protocol 1) and autonomic blockade with propranolol and atropine infusion (protocol 2) in 24 healthy volunteers (12 men, 23 +/- 2 years; 12 women, 23 +/- 5 years). QT (QTc) intervals were measured at the baseline and at a heart rate of 75, 100, and 120 beats/min. RESULTS: (1) The morphology of the T wave dynamically and transiently changed to bifid or biphasic during the acute phase of isoproterenol infusion. The incidence of these morphologic changes was higher in women than men (P < 0.05). (2) The QTc interval was initially prolonged and then shortened in both men and women during isoproterenol administration. However, QTc prolongation was significantly greater in women (0.44 +/- 0.02 to 0.55 +/- 0.03 sec) than men (0.42 +/- 0.03 to 0.51 +/- 0.04 sec; P < 0.05). (3) The QTc interval was significantly prolonged under autonomic blockade and the intrinsic QTc interval was longer in women than men (P < 0.05). CONCLUSION: While sympathetic stimulation and autonomic blockade modulated the dynamics of ventricular repolarization in both sexes, it was more pronounced in women. This gender difference may partially account for the susceptibility of women to arrhythmogenesis.

Torsade de pointes.

Torsade de pointes ventricular tachyarrhythmia in the long QT syndrome is a prime example of how molecular biology, ion channel, and cellular and organ physiology, coupled with clinical observations, promise to be the future paradigm for advancement of medical knowledge. Both the congenital and the acquired long QT syndrome are caused by abnormalities (intrinsic, acquired, or both) of the ionic currents underlying ventricular repolarization. In this review, the continually unraveling molecular biology of congenital long QT syndrome is discussed. The various pharmacologic agents associated with the acquired long QT syndrome are listed. Although it is difficult to predict which patients are at risk for torsade de pointes, careful assessment of the risk to benefit ratio is important before prescribing drugs known to cause QT prolongation. The in vivo electrophysiologic mechanism of torsade de pointes in the long QT syndrome is described, using as a paradigm the anthopleurin-A canine model, a surrogate for LQT3. The characteristic association of torsade de pointes with T-wave alternans and short-long cardiac sequences is discussed, with emphasis on electrophysiologic mechanisms. Finally, the expanding knowledge of genetic mutations other than long QT syndrome associated with polymorphic ventricular tachyarrhythmia is emphasized.