Comparative evaluation of HERG currents and QT intervals following challenge with suspected torsadogenic and nontorsadogenic

Abstract word count: 243 Introduction word count: 75

Comparative evaluation of HERG currents and QT intervals following challenge with suspected torsadogenic and nontorsadogenic

ABSTRACT The purpose of the present study was to comparatively evaluate human HERG currents and QT intervals following challenge with suspected torsadogenic and nontorsadogenic drugs. Various concentrations of 14 different drugs were initially evaluated in terms of their relative potency to block I HERG in stably transfected human embryonic kidney cells. Four general categories of drugs were identified: high-potency blockers (IC 50 Ͻ 0.1 M) included lidoflazine, terfenadine, and haloperidol; moderatepotency blockers (0.1 M Ͻ IC 50 Ͻ 1 M) included sertindole, thioridazine, and prenylamine; low-potency blockers (IC 50 Ͼ 1 M) included propafenone, loratadine, pyrilamine, lovastatin, and chlorpheniramine; and ineffective blockers (IC 50 Ͼ 300 M) included cimetidine, pentamidine, and arsenic trioxide. All measurements were performed using similar conditions and tested acute drug effects only (Ͻ30 min of drug exposure per measurement). Since two of the drugs that were ineffective I HERG blockers, arsenic trioxide and pentamidine, have been associated with cardiac repolarization delays (QT interval lengthening) and torsades de pointes ventricular arrhythmias in patients, we chose to evaluate them further using the isolated perfused rabbit heart model. Neither arsenic trioxide nor pentamidine had any significant effect on QT intervals in this model, even at relatively high (micromolar) concentrations. Similar results were obtained for loratadine in this model. When the hearts were challenged with a known torsadogenic drug such as cisapride, significant QT lengthening was rapidly induced. These results demonstrate that arsenic trioxide and pentamidine are essentially devoid of direct acute effects on cardiac repolarization or inhibition of I HERG

Comparative Evaluation Of Herg Currents And Qt Intervals Following Challenge With Suspected Torsadogenic And Nontorsadogenic Drugs

The purpose of the present study was to comparatively evaluate human HERG currents and QT intervals following challenge with suspected torsadogenic and nontorsadogenic drugs. Various concentrations of 14 different drugs were initially evaluated in terms of their relative potency to block IHERG in stably transfected human embryonic kidney cells. Four general categories of drugs were identified: high-potency blockers (IC50 \u3c 0.1 μM) included lidoflazine, terfenadine, and haloperidol; moderate-potency blockers (0.1 μM \u3c IC50 \u3c 1 μM) included sertindole, thioridazine, and prenylamine; low-potency blockers (IC50 \u3e 1 μM) included propafenone, loratadine, pyrilamine, lovastatin, and chlorpheniramine; and ineffective blockers (IC50 \u3e 300 μM) included cimetidine, pentamidine, and arsenic trioxide. All measurements were performed using similar conditions and tested acute drug effects only (\u3c30 min of drug exposure per measurement). Since two of the drugs that were ineffective IHERG blockers, arsenic trioxide and pentamidine, have been associated with cardiac repolarization delays (QT interval lengthening) and torsades de pointes ventricular arrhythmias in patients, we chose to evaluate them further using the isolated perfused rabbit heart model. Neither arsenic trioxide nor pentamidine had any significant effect on QT intervals in this model, even at relatively high (micromolar) concentrations. Similar results were obtained for loratadine in this model. When the hearts were challenged with a known torsadogenic drug such as cisapride, significant QT lengthening was rapidly induced. These results demonstrate that arsenic trioxide and pentamidine are essentially devoid of direct acute effects on cardiac repolarization or inhibition of I HERG

Left atrial remodeling: Regional differences between paroxysmal and persistent atrial fibrillation

Background: The mechanisms underlying self-perpetuation of persistent atrial fibrillation (AF) are not well understood. To gain insight into these mechanisms, we conducted a study comparing left atrial (LA) electroanatomic maps obtained during sinus rhythm between patients with paroxysmal AF (PAF) and patients with persistent AF (PerAF). Methods: The study included 23 men with PAF (age, 56.3±12.1 years) and 13 men with PerAF (age, 54.3±13.4 years). LA voltage mapping was performed during sinus rhythm. The clinical and electroanatomic characteristics of the two groups were evaluated and analyzed statistically. Results: The bipolar voltages at the LA septum, roof, and posterior wall, right superior pulmonary vein (PV) and its antrum, right superior PV carina, and right inferior PV antrum were significantly lower in patients with PerAF than in those with PAF. The bipolar voltages in other parts of the LA did not differ statistically between the two groups. Conclusion: PAF and PerAF seem to be characterized by differences in the regional voltage in the LA and PVs. The LA structural remodeling of PerAF may initiate from the right PVs and their antra and LA septum, roof, and posterior wall