Arrhythmogenic potential of positive inotropic agents

The clinical use of positive inotropic agents has been associated with increased mortality, with proarrhythmia speculated to be a contributing factor. This study compares the arrhythmogenic potential of six positive inotropic agents representing different mechanistic classes: the β-adrenergic agonist dobutamine, the adenylyl cyclase activator forskolin, the phosphodiesterase-III inhibitor milrinone, the cardiac glycoside ouabain, and the sodium channel agonists DPI 201-106 and BDF 9148. These agents were studied in dogs with anterior myocardial infarction using lower and higher dose i. v. regimens targeted to elicit 20–40% and 70–90% increases in LV+dP/dt, respectively. Precipitation of new ventricular arrhythmia by programmed ventricular stimulation was observed in all treatment groups. Incidences of new arrhythmia were comparable in the lower dose regimens, ranging from 16.7% (3/18 animals with BDF 9148) to 31.6% (6/19 animals with DPI 201-106), and in the higher dose regimens, ranging from 10.0% (1/10 animals with milrinone) to 27.7% (5/18 animals with DPI 201-106). The overall incidence of new ventricular arrhythmia ranged from 27.3% (3/11 animals with ouabain) to 47.4% (9/19 animals with DPI 201-106). No differences were observed in underlying infarct size or time from infarction to electrophysiologic study between subgroups of animals in which new arrhythmias were precipitated vs. those remaining non-responsive in any treatment group. The positive inotropic agents tested displayed diverse total group effects on heart rate, electrocardiographic intervals including QTc and ventricular refractoriness. Within individual treatment comparisons revealed a general but not universal pattern of greater ventricular refractory period values in newly inducible vs. non-inducible subgroups in the DPI 201-106, BDF 9148 and ouabain (low and high dose); milrinone and dobutamine (high dose) treatment groups. These findings indicate that regardless of underlying cellular mechanisms of action, the six positive inotropic agents tested all displayed comparable proarrhythmic potentials unrelated to underlying infarct size and time from infarction. This observation suggests the general shared property of increased myocardial contractility, potentially adversely affecting myocardial oxygen balance, myocardial perfusion and electrical stability in the setting of previous myocardial infarction, to be a common underlying cause for arrhythmogenesis. Additionally, alterations in ventricular refractoriness and repolarization may contribute significantly to proarrhythmia with some positive inotropic interventions. Received: 20 July 1999, Returned for 1. revision: 16 September 1999, 1. Revision received: 26 October 1999, Returned for 2. revision: 24 November 1999, 2. Revision received: 22 December 1999, Accepted: 6 January 2000     

QT Interval prolongation and torsades de pointes due to a coadministration of ciprofloxacin and azimilide in a patient with implantable cardioverter-defibrillator

The presented case report describes a male patient with an implanted cardioverter-defibrillator (ICD) in whom a coadministration of ciprofloxacin and azimilide caused QT interval prolongation and multiple episodes of torsades de pointes (TdP) followed by ICD shocks (arrhythmic storm). The case highlights a not described drug interaction between azimilide and ciprofloxacin, which is believed to be the safest member of fluoroquinolones class.     

Exercise‐induced ventricular tachycardia in a case with hypertrophic cardiomyopathy taking cibenzoline

We report a 17‐year‐old woman with hypertrophic cardiomyopathy (HCM) successfully resuscitated from ventricular fibrillation while taking cibenzoline. During exercise–stress testing before implanting an implantable cardioverter–defibrillator, ventricular tachycardia was induced and thought to be a proarrhythmia due to the use‐dependent effect of the Na channel blockade with cibenzoline. In patients with arrhythmogenic substrates such as HCM, it is critical to pay attention to the proarrhythmic effects of class I antiarrhythmic drugs while increasing heart rate.     

Detection of proarrhythmia in the female rabbit heart: blinded validation

INTRODUCTION: Reliable detection of drug-induced proarrhythmia, especially the potential for polymorphic ventricular tachycardia, is of great importance in the development of new compounds that are safe for the heart and was evaluated in a blinded study. METHODS AND RESULTS: In 142 female rabbits, the monophasic action potential was used to determine intraventricular conduction, action potential duration (APD), triangulation (APD30 to APD90), reverse use-dependence, instability and presence of chaotic behavior, early afterdepolarizations, torsades de pointes (TdP), and ventricular fibrillation. In addition, 31 coded drugs were tested in a blinded fashion in another 150 hearts. Prototype cardiovascular agents [quinidine (IA), lidocaine (IB), flecainide (IC), propranolol (II), sotalol (IIIB), amiodarone (IIIAB) and verapamil (IV)] were correctly characterized in terms of their effects upon conduction and APD. Agents documented in clinical practice to have proarrhythmic potential (droperidol, sotalol, mibefradil, bepridil, lidoflazine, ketanserin, sertindole, terfenadine, haloperidol, astemizole, cisapride, ziprasidone, lubeluzole, dofetilide, quinidine, ibutilide) were identified as such. Pimozide is reported to rarely produce TdP and was also found to elicit Class III action with few adverse effects. Equally important, agents believed not to be proarrhythmic (two solvents, atenolol, propranolol, fenoximone, cetirizine, verapamil, sildenafil, lidocaine, diltiazem) were identified as having no proarrhythmic activity. CONCLUSION: The SCREENIT method properly characterized and quantified prototype cardiovascular drugs and correctly identified proarrhythmic noncardiovascular agents of various mechanisms, but it did not produce false-positive results.     

Physician-induced torsade de pointes--therapeutic implications

Torsade de pointes (TdP) is a clinico-electrocardiographic syndrome characterized by an abnormally prolonged QT interval and the occurrence of potentially life-threatening ventricular tachyarrhythmias. Two mayor causes can be distinguished: congenital and acquired long QT syndrome. Whereas the former has recently been identified as an ion channelopathy, the mechanisms underlying acquired long QT syndrome are far from being understood. It has been suggested that patients with the acquired form of the disease may suffer from a clinically hidden form of the congenital variant. However, recent studies have yielded only a small number of individual cases in whom genetic analyses revealed the presence of an ion channel gene mutation.Since acquired long QT syndrome is most often induced by drugs prolonging myocardial repolarization, it is largely an iatrogenic disease. In order to prevent unwitting exposure to risk, physicians prescribing agents that may prolong repolarization need to be aware of the typical clinico-electrocardiographic characteristics of drug-induced TdP, and its diagnosis and management. A clearer delineation of the risk factors predisposing to abnormal prolongation of repolarization, and a more precise quantification of the torsadogenic potency of individual drugs appear mandatory in order to prevent or at least minimize the occurrence of this potentially fatal adverse effect of certain drugs.     

Block of HERG-carried K+ currents by the new repolarization delaying agent H 345/52

INTRODUCTION: The aim of this study was to analyze the block of HERG-carried membrane currents caused by H 345/52, a new antiarrhythmic compound with low proarrhythmic activity, in transfected mouse fibroblasts. METHODS AND RESULTS: Using the whole-cell configuration of the voltage patch clamp technique, it was demonstrated that H 345/52 concentration-dependently blocked HERG-carried currents with an IC50 of 230 nM. H 345/52 preferentially bound to the open channel with unusually rapid kinetics and was trapped by channel closure. Voltage-independent behavior of H 345/52 was observed during both square-pulse and action potential clamp protocols. In contrast, the Class III agents dofetilide (10 nM) and almokalant (250 nM) demonstrated significant membrane potential-dependent effects during square-pulse clamp protocols. When using action potential clamp protocols, voltage dependence was seen with dofetilide but not with almokalant. Mathematical simulations of human ventricular action potentials predicted that the different voltage-dependent behaviors would not produce marked variations in action potential duration prolongation patterns. CONCLUSION: We propose that block of IKr is the principal mechanism by which H 345/52 delays repolarization in human myocardium. The voltage independence of HERG/IKr block is unlikely to underlie the low proarrhythmic potential, and ancillary effects on other membrane currents must be considered.     

Non-investigational antiarrhythmic drugs: long-term use and limitations

Background: Long-term use of antiarrhythmic drugs is less important today as curative catheter ablation often is more appropriate, and the use of implantable cardioverter-defibrillators is an option. Many patients, however, still prefer, or are merely offered drug treatment. Objectives: To review current literature on conventional antiarrhythmic drugs in the intervention and device era, with focus on efficacy, side effects, drug interactions and pro arrhythmic problems in adult patients. Results/conclusion: Antiarrhythmic drugs are still justified in patients who prefer this treatment or who cannot be cured by catheter ablation owing to technical problems or lack of treatment capacity. Another main use of these drugs is adjunctive treatment after unsuccessful catheter ablation or when arrhythmias frequently recur in a patient with an implanted device. Drug interactions owing to treatment for comorbidity represent a serious challenge.