Estimation of Proarrhythmic Hazards by QT Prolongation/Shortening: QT Obsession?
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Estimation of Proarrhythmic Hazards by QT Prolongation/Shortening: QT Obsession?
Lnc M. Hondrgber,
MD, PbD Professor of Pharmacology, Catholic University Leuven, Belgium
Key Words QT prolongation; QT shortening; Proanhythmia; Tonade de points; Ventricular fibrillation Corrrspondrncr Address Dr Luc M. Hondeghem, Westlaan 85,88400 Oostende, Belgium (e-mail: Luc.Hondeghem@ ScreenQTcom). Paper presented on March 8, 2005, at the DlA EuroMeeting, "Medicine in Changing Times," Lisbon.
But, when associated with APD shortening, QT pdongation is frequently assOCiated with proarrhythmia increasts more steeply and fipruadythmia, induding torsade de pointa qumtly becomes v e n t i d a r fibrillation. For (TdP). At the same time, @ongation of action potentid b t i o n (APD) is widely necognued as hERG blockers that change the APD little or not aprimaryantimrtgrthmicmdanism.??tkpamat aU, praolftythmia incremes with increasing TZ?ZaD, while TRZaD remcction can lead to andax d t s jh linking an accidental associatiadythmic adion. In the absence of TRZaD, tion (APD prdongation) to the cause ofproar@ongation of the APD becomes increa9in9j. dythmia: trimrgulation,reverse use dependence, antimrtgrthmic. In condusion, (a) rejedion of and instabilij. of the d a c action potentid, which d t in dispersion (TRZaD). 'Ihus, prodrugs that lengthentheAPDwithoutTRlaDmay u n n m * l ywithhold safe and valuable themlofigation of APD can occur without TRlaD (antiarhythmic) or with TRlaD @mar&ythmic). peutic agents jh needy patients; @) acceptance of drugs that shorten the APD but possess Human ethab-go-go dated gene (hERG) TRlaL) may d t in pmadythmic agents. blockers me more often than not associated with TNaD and procarhythmia. When associafed These wid not be stopped by QT prorongation with prdongaton Of APD, theiravwe p r - tests, even when t h m .IIhus, bmtning drugs sddy on the QT intervalis wunterprrductive. hythmia dog increase and is f;equently Tdk?
Electropharmacology is plagued by a confusing paradox: Prolongation of APD was first described as antiarrhythmic (l),but later QT prolongation was frequently associated with proarrhythmia, especially torsade de pointes (TdP). In this article, I show how triangulation, reverse use dependence, instability, and dispersion (TRIaD) can resolve this paradox. It is concluded that safety testing based solely on QT prolongation leads to QT madness: eliminating safe agents while approving potentially dangerous drugs.
CLASS 111 It was then not surprising that when a drug (amiodarone)was found to markedly prolong action potential duration (APD) and effective refractory period (ERP) that it had antiarrhythmic properties. The excellent insights of Vaughan Williams and Singh (1,Z) became generally accepted as a new primary mechanism for antiarrhythmic action and became widely described in many articles and textbooks as class I11 action.
PARADOX LAMBDA Ever since the work of Dr. Gordon Moe and his colleagues, it has been recognized that cardiac wavelength (5= effective refractory period times condu
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