Does terfenadine‐induced ventricular tachycardia/fibrillation directly relate to its QT prolongation and Torsades de Pointes?

BACKGROUND AND PURPOSE Terfenadine has been reported to cause cardiac death. Hence, we investigated its pro‐arrhythmic potential in various in vitro models. EXPERIMENTAL APPROACH Pro‐arrhythmic effects of terfenadine were investigated in rabbit isolated hearts and left ventricular wedge preparations. Also, using whole‐cell patch‐clamp recording, we examined its effect on the human ether‐à‐go‐go‐related gene (hERG) current in HEK293 cells transfected with hERG and on the INa current in rabbit ventricular cells and human atrial myocytes. KEY RESULTS Terfenadine concentration‐ and use‐dependently inhibited INa in rabbit myocytes and in human atrial myocytes and also inhibited the hERG. In both the rabbit left ventricular wedge and heart preparations, terfenadine at 1 µM only slightly prolonged the QT‐ and JT‐intervals but at 10 µM, it caused a marked widening of the QRS complex, cardiac wavelength shortening, incidences of in‐excitability and non‐TdP‐like ventricular tachycardia/fibrillation (VT/VF) without prolongation of the QT/JT‐interval. At 10 µM terfenadine elicited a lower incidence of early afterdepolarizations versus non‐ Torsades de Pointes (TdP)‐like VT/VF (100% incidence), and did not induce TdPs. Although the concentration of terfenadine in the tissue‐bath was low, it accumulated within the heart tissue. CONCLUSION AND IMPLICATIONS Our data suggest that: (i) the induction of non‐TdP‐like VT/VF, which is caused by slowing of conduction via blockade of INa (like Class Ic flecainide), may constitute a more important risk for terfenadine‐induced cardiac death; (ii) although terfenadine is a potent hERG blocker, the risk for non‐TdP‐like VT/VF exceeds the risk for TdPs; and (iii) cardiac wavelength (λ) could serve as a biomarker to predict terfenadine‐induced VT/VF.