Congenital long QT syndrome: Severe Torsades de pointes provoked by epinephrine in a digenic mutation carrier

Congenital Long QT Syndrome (LQTS) is a potentially lethal cardiac channelopathy characterized by prolongation of the corrected QT (QTc) interval on the surface electrocardiogram. The hallmark phenotypic features are syncope, seizure or sudden death, however most of the mutation carriers are asymptomatic and their risk for arrhythmias such as Torsade de pointes (TdP) are low. We report a case of Long QT syndrome with a corrected QT of 520 ms. For symptom – arrhythmia correlation a loop recorder was implanted with no documented arrhythmias. Epinephrine testing was performed for clinical risk stratification leading to Torsades de pointes during recovery phase which required defibrillation. Genetic testing discovered two pathogenic heterozygous mutations in two different LQT genes (SCN5A and KCNQ1). We propose a calcium homeostasis mechanism for the interaction of both mutations that exaggerated the phenotype, while each mutation by itself is causing a relatively modest phenotype.     

Availability of human induced pluripotent stem cell-derived cardiomyocytes in assessment of drug potential for QT prolongation

Field potential duration (FPD) in human-induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs), which can express QT interval in an electrocardiogram, is reported to be a useful tool to predict K⁺ channel and Ca^2 + channel blocker effects on QT interval. However, there is no report showing that this technique can be used to predict multichannel blocker potential for QT prolongation. The aim of this study is to show that FPD from MEA (Multielectrode array) of hiPS-CMs can detect QT prolongation induced by multichannel blockers.     

Q-T延长致尖端扭转型室性心动过速的急诊治疗

报告18例由Q－T延长所致尖端扭转型室性心动过速的急诊治疗。根据发病前的精神状态和心电监护中于发作前、中、后心电图变化，可将其分为间歇依赖型和肾上腺素能神经依赖型两种类型。根据不同类型分别采用异丙肾上腺素，利多卡因，β－受体阻滞剂，补充钾盐、镁盐及埋值心脏临时起搏器，电除颤复律术等措施，18例均恢复窦性心律。需特别指出，心律平治疗1例本病时，病情恶化为室颤，立即采用电除颤复律术才获抢救成功。     

Proarrhythmia risk prediction using human induced pluripotent stem cell-derived cardiomyocytes

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are expected to become a useful tool for proarrhythmia risk prediction in the non-clinical drug development phase. Several features including electrophysiological properties, ion channel expression profile and drug responses were investigated using commercially available hiPSC-CMs, such as iCell-CMs and Cor.4U-CMs. Although drug-induced arrhythmia has been extensively examined by microelectrode array (MEA) assays in iCell-CMs, it has not been fully understood an availability of Cor.4U-CMs for proarrhythmia risk. Here, we evaluated the predictivity of proarrhythmia risk using Cor.4U-CMs. MEA assay revealed linear regression between inter-spike interval and field potential duration (FPD). The hERG inhibitor E?4031 induced reverse-use dependent FPD prolongation. We next evaluated the proarrhythmia risk prediction by a two-dimensional map, which we have previously proposed. We determined the relative torsade de pointes risk score, based on the extent of FPD with Fridericia's correction (FPDcF) change and early afterdepolarization occurrence, and calculated the margins normalized to free effective therapeutic plasma concentrations. The drugs were classified into three risk groups using the two-dimensional map. This risk-categorization system showed high concordance with the torsadogenic information obtained by a public database CredibleMeds. Taken together, these results indicate that Cor.4U-CMs can be used for drug-induced proarrhythmia risk prediction.     

Efficacy of Ventricular Pacing in the Treatment of an Arrhythmic Storm Associated with a Congenital Long QT Mutation

Long QT syndrome in the infant with 2:1 atrioventricular block is a malignant form of disease associated with frequent torsade de pointes in some cases. Those patients that do not respond to antiarrhythmic therapy are particularly challenging to manage. Ventricular pacing in this patient population has been shown to reduce arrhythmic events. We report a case of a newborn with frequent torsade de pointes requiring defibrillation and cardiopulmonary resuscitation with immediate shortening of the QTc interval with ventricular pacing and subsequent resolution of torsade de pointes.     

Drug monitoring of a case of citalopram overdosage

Selective serotonin reuptake inhibitors are widely prescribed drugs without recognized cardiovascular risk. We report the case of a 54-year-old patient who developed QTc interval prolongation, followed by ventricular fibrillation episodes, 10 hours after admission to the ICU, in the setting of a citalopram overdose. Citalopram plasma values dropped from 5.88 to 0.34?mg/L at 9 days postadmission. The patient was treated by oral activated charcoal, and final outcome was favorable.     

A benefit–risk assessment of class III antiarrhythmic agents

The prevalence of arrhythmia in the population is increasing as more people survive for longer with cardiovascular disease. It was once thought that antiarrhythmic therapy could save life, however, it is now evident that antiarrhythmic therapy should be administrated with the purpose of symptomatic relief. Since many patients experience a decrease in physical performance as well as a diminished quality of life during arrhythmia there is still a need for antiarrhythmic drug therapy. The development of new antiarrhythmic agents has changed the focus from class I to class III agents since it became evident that with class I drug therapy the prevalence of mortality is considerably higher. This review focuses on the benefits and risks of known and newer class III antiarrhythmic agents. The benefits discussed include the ability to maintain sinus rhythm in persistent atrial fibrillation patients, and reducing the need for implantable cardioverter defibrillator shock/antitachycardia therapy, since no class III antiarrhythmic agents have proven survival benefit. The risks discussed mainly focus on pro-arrhythmia as torsade de pointes ventricular tachycardia.     

Modulation of the late sodium current by ATX-II and ranolazine affects the reverse use-dependence and proarrhythmic liability of IKr blockade

BACKGROUND AND PURPOSE

Drug-induced torsades de pointes (TdP) often occurs during bradycardia due to reverse use-dependence. We tested the hypothesis that inhibition or enhancement of late sodium current (I_Na,L) could modulate the drug-induced reverse use-dependence in QT and T_p-e (an index of dispersion of repolarization), and therefore the liability for TdP.

EXPERIMENTAL APPROACH

Arterially perfused rabbit left ventricular wedge preparations were used. Action potentials from the endocardium were recorded simultaneously with a transmural ECG. The effects of Anemonia sulcata toxin (ATX-II) (an I_Na,L enhancer), d,l-sotalol, clarithromycin and ranolazine (an I_Na,L blocker) on rate-dependent changes in QT, T_p-e and proarrhythmic events were tested, either alone or in combination. Rate-dependent QT and T_p-e slopes and TdP score (a combined index of TdP liability) were calculated at control and during drug infusion.

KEY RESULTS

ATX-II (30 nM) and sotalol (300 µM) caused a marked increase in QT and T_p-e intervals, steeper QT-basic cycle length (BCL) and T_p-e-BCL slopes (i.e. reverse use-dependence), and TdP. Addition of ranolazine (15 µM) to ATX-II or sotalol significantly attenuated QT-BCL, T_p-e-BCL slopes and the increased TdP scores. In contrast, clarithromycin (100 µM) moderately prolonged QT and T_p-e without causing R-on-T extrasystole or TdP, but addition of ATX-II (1 nM) to clarithromycin markedly amplified the QT-BCL and T_p-e-BCL slopes and further increased TdP score.

CONCLUSION AND IMPLICATIONS

Modulation of I_Na,L altered drug-induced reverse use-dependence related to QT as well as T_p-e, indicating that inhibition of I_Na,L can markedly reduce the TdP liability of agents that prolong QT intervals.