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Ventricular arrhythmias and sudden death in patients taking ibrutinib

Benjamin L. Lampson, Lijian Yu, Robert J. Glynn, Jacqueline C. Barrientos, Eric D. Jacobsen, Versha Banerji, Jeffrey A. Jones, Renata Walewska, Kerry J. Savage, Gregory F. Michaud, Javid J. Moslehi and Jennifer R. Brown

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  • RE: Ibrutinib and short-coupled variant of torsade de pointes
    • Joachim Alexandre, Clinical pharmacology CHU Caen, France
    • Other Contributors:
      • Joe-Elie Salem, Clinical pharmacology
      • Christian Funck-Brentano, Clinical pharmacology
      • Paul Milliez, Cardiology

    We appreciated the letter by Lampson et al. 1 regarding the ventricular arrhythmogenicity of ibrutinib. As pointed out by the authors, ibrutinib was already known to induce atrial fibrillation (AF) but was considered exempt of effect on ventricular repolarization without any impact on QTc interval. Interestingly, the authors described polymorphic ventricular tachycardia including normal QTc interval, without any short-long-short–coupling patterns before the start of episodes, occurring without any underlying cardiac disease. This ECG description corresponds to the short-coupled variant of torsade de pointes first described in 1994 which has the particularity of a short coupling ventricular premature beat initiating ventricular tachycardia 2. Beyond semantics, this distinct form of torsade de pointes has a particular pathophysiology that could help understand ibrutinib arrhythmogenicity. Although the underlying mechanism remains uncertain, it appears that sarcoplasmic reticulum Ca2+ leak plays a major role. Recently, cardiac ryanodine receptor (RyR2) variant with reduced Ca2+ release was associated to short-coupled variant of torsade de pointes 3. It was recently shown that ibrutinib could increase de risk of AF by inhibiting cardiac PI3K-Akt signaling 4. Since cardiac PI3K-Akt signaling was previously linked to the β-adrenergic receptors-cAMP- Calmodulin-dependent protein kinase (CaMKII)-RyR2 pathway to modulate sarcoplasmic reticulum Ca2+ leak 5, it seems reasonable to a...

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    Conflict of Interest:
    None declared.