HANCOX under the conditions of this study, ivabradine showed clear antiarrhythmic effects in the pinacidil SQTS model. The findings in this paper are important in two respects: first, they provide further evidence that ivabradine can exert clear electrophysiological actions that are independent of I f /HCN channel inhibition; second, they provide proof-of-concept that, at least under the conditions of this study, ivabradine is antiarrhythmic against abbreviated ventricular repolarization. So, could the drug be beneficial in clinical SQTS? Possibly, yes, though further preclinical work is likely needed first. In particular, it would be useful to verify that submicromolar ivabradine concentrations closer to the clinical range produce similar effects to those seen here.Second, as the authors themselves note, one of the main SQT1 hERG mutations (N588K-hERG) significantly reduces the ability of ivabradine to block the channel 11 and so the drug is unlikely to be effective in forms of SQT1 in which hERG channel inactivation is markedly impaired. Third, the paced preparation used in this study eliminates the bradycardic effect of ivabradine on the sinoatrial node and this would not be the case in the clinical setting. The significance of this point is that some forms of SQTS are themselves associated with bradycardia. For instance, one study has reported that up to 75% of SQT2 cases and 9% of non-SQT2 cases also show sick sinus syndrome/bradycardia. 3 Ivabradine would be expected to exacerbate these and so should be avoided in such cases. Also, as has been commented by others, 1 heterogeneity of repolarization and abnormality of the QT-RR relationship are likely to be greatest at slow rates, and this may facilitate susceptibility to tachyarrhythmia. Thus, if ivabradine were to be pursued further as a potential treatment for the SQTS, it may be important to establish whether or not the drug's prolongation of PRR would suffice to offset any increased vulnerability associated with drug-induced bradycardia.
DISCLOSURENone.
ACKNOWLEDGEMENTSThe author thanks the British Heart Foundation for research funding on the SQTS.