Biomedical subjects

Luc M Hondeghem

Publications and source records attributed to Luc M Hondeghem.

5 recordsLinked to original sources

PubMed2006

Thorough QT/QTc not so thorough: removes torsadogenic predictors from the T-wave, incriminates safe drugs, and misses profibrillatory drugs.

Drug-induced QT prolongation has such a strong correlation with torsade de pointes (TdP) that it comes to serve as a surrogate for TdP. As a result, drugs that prolong QT by as little as a few ms, even without any evidence of TdP, may get dropped from development or blocked from approval. However, measurement of QT with ms accuracy may be impossible to achieve. Worse, some drugs that lengthen the QT interval are not only not proarrhythmic, they may even be antiarrhythmic; while some that shorten the QT can be strongly proarrhythmic. Indeed, proarrhythmia related to repolarization disturbances is caused by triangulation, reverse use dependence, instability, and dispersion (TRIaD). When TRIaD is present with QT prolongation it commonly yields TdP, but when TRIaD is combined with QT shortening it preferentially leads to VF instead. While TdP is lethal in less than 20% of instances, VF is much more morbid. Worse, available evidence suggests that there is more death from drug-induced fibrillation than TdP. Thus, QT prolongation alone is not very useful. Instead, the T-wave should be used in alternate ways: extraction of TRIaD.

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PubMed2005

Refining detection of drug-induced proarrhythmia: QT interval and TRIaD.

QT interval prolongation is so frequently associated with torsades de pointes (TdP) that it has come to be recognized as a surrogate marker of this unique tachyarrhythmia. However, not only does TdP not always follow QT interval prolongation, but TdP can occur even in the absence of a prolonged QT interval. Worse still, even shortening of the QT interval may be associated with serious arrhythmias (particularly ventricular tachycardia [VT] and ventricular fibrillation [VF]). It appears increasingly probable that the distinction between various ventricular tachyarrhythmias may be arbitrary, and drug-induced TdP, polymorphic VT, VT, catecholaminergic polymorphic VT, and VF may represent discrete entities within a spectrum of drug-induced proarrhythmia. Although they are differentiated by the coupling interval and the duration of QT interval, they appear to share a common substrate: a set of disturbances of repolarization characterized by Triangulation, Reverse use dependency, electrical Instability of the action potential, and Dispersion (TRIaD). It is becoming increasingly evident that augmentation of TRIaD, rather than changes in the duration of QT interval, provides the proarrhythmic substrate. In contrast, when not associated with an increase of TRIaD, QT interval prolongation can be an antiarrhythmic property. Electrophysiologically, augmentation of TRIaD can be explained by inhibition of hERG (human ether-a-go-go related gene) channel. Because drug-induced disturbances in repolarization commonly result from inhibition of hERG channels or I(Kr), hERG blockade and the resulting prolongation of QT interval are important properties of a drug to be studied. However, these need only be a concern if associated with TRIaD. More significantly, TRIaD so often precedes prolongation of action potential duration or QT interval and ventricular tachyarrhythmias that it should be considered a marker of proarrhythmia until proven otherwise, even in the absence of QT interval prolongation. Detecting drug-induced augmentation of TRIaD may offer an additional, more sensitive, and accurate indicator of the broader proarrhythmic potential of a drug than may QT interval prolongation alone.

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PubMed2005

TRIad: foundation for proarrhythmia (triangulation, reverse use dependence and instability).

There exist both safe and dangerous prolongations of the QT interval. Proarrhythmia can be induced by triangulation of the cardiac action potential, reverse use dependence and instability, a set of three features termed TRIad. TRIad leads to dispersion (spatial, transmural and temporal), stalling of fast repolarization or even early after-depolarization (EAD). EAD can progress to Torsade de Pointes (TdP) especially in the presence of prolonged APD; as the QT interval shortens (e.g. by reverse use-dependence), the cardiac wavelength shortens and TdP can progress to ventricular fibrillation (VF). In the absence of TRIad and QT prolongation, chemicals exhibit on average neither pro- nor anti-arrhythmia. However, QT prolongation in the absence of TRIad becomes antiarrhythmic. Furthermore, this desirable effect increases as TRIad components are replaced by squaring of the action potential, use-dependent prolongation of APD and stabilization of the action potential. It is concluded that proarrhythmic characteristics of drugs can readily be recognized and that hope exists for an effective and safe class III antiarrhythmic agent after all.

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PubMed2003

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.

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PubMed2003

Blinded test in isolated female rabbit heart reliably identifies action potential duration prolongation and proarrhythmic drugs: importance of triangulation, reverse use dependence, and instability.

Drug-induced proarrhythmia is a rare but potentially lethal adverse drug reaction. To test whether the SCREENIT system (an automated computerized test apparatus), using an isolated perfused heart obtained from female rabbits, could correctly identify agents that lengthen the action potential duration (APD) and drugs known to induce proarrhythmia, 14 drugs (penicillin G, haloperidol, adriamycin, indapamide, verapamil, aspirin, lidocaine, clomipramine, propranolol, erythromycin, quinidine, terfenadine, amiodarone, and thioridazine) were coded and submitted for a blinded test. Of these drugs, eight are reported to induce QT prolongation in the clinic (adriamycin, clomipramine, quinidine, amiodarone, and thioridazine), while three do not lengthen and three shorten the QT. To test for reproducibility, four drugs were given in duplicate (haloperidol, aspirin, erythromycin, and terfenadine). The drug effects on monophasic APD, conduction, instability (index of variability of APD), triangulation (index of duration of fast repolarization), and reverse use dependence were measured at five drug concentrations (0.05, 0.15, 0.5, 1.5, and 5 mg/l). All 14 blinded drugs, in the concentrations used, were correctly identified as to their effects on APD and conduction. The drugs eliciting drug-induced proarrhythmia in patients were also identified as promoting instability, triangulation, and reverse use dependence in the rabbit heart. Importantly, none of the safe agents was labeled as proarrhythmic, and the results were very consistent between duplications. In conclusion, SCREENIT correctly identifies prolongation of APD, accurately separates safe agents form proarrhythmic drugs, and has highly reproducible results. Thus, the isolated perfused rabbit heart can be a valuable tool in a preclinical proarrhythmia test battery in drug development.

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