Questioning flecainide's mechanism of action in the treatment of catecholaminergic polymorphic ventricular tachycardia

Questioning flecainide's mechanism of action in the treatment of catecholaminergic polymorphic ventricular tachycardia Flecainide attenuates cardiac Ca 2+ cycling abnormalities in malignant catecholamine-triggered arrhythmias but its mechanism of action remains highly contentious. We read with interest the study of Yang et al. (2016) that used in silico predictions in an attempt to determine the relative contribution of block by flecainide of ryanodine receptor 2 (RyR2) and the Na + channel to the overall therapeutic effect of this drug in catecholaminergic polymorphic ventricular tachycardia (CPVT). Flecainide's actions were modelled by considering its inhibition of the Na + current (I Na) and RyR2 in combination and individually. The authors conclude that the effects of the drug on Na + channels are insufficient to explain its efficacy in CPVT, while its block of RyR2 alone was as effective as the combined block of I Na and RyR2. Our concerns about the usefulness of this approach are twofold: (1) Purported block of RyR2 by flecainide The blocking parameters used in Yang et al. (2016) are based on values reported in Hilliard et al. (2010) and subsequent publications from the same group. The major problem with the use of these parameters to model open channel block by flecainide of RyR2-mediated Ca 2+ release from the sarcoplasmic reticulum (SR) is that Hilliard et al. (2010) did not demonstrate block of this current, rather they reported partial block of K + movement in the opposite (cytosol to luminal) direction. To fully understand the problem it is necessary to outline some basic features of RyR2 channel structure and function. RyR2 provides a ligand-regulated pathway for the release of Ca 2+ from the cardiac SR to initiate myocyte contraction. In its open conformation Ca 2+ flows through the pore-forming region (PFR) of RyR2, down its concentration gradient, from the SR lumen to the cytosol. The key structural features of the RyR2 PFR, based on recent high-resolution cryo-electron microscopy investigations (Yan et al. 2014), are shown schematically in Fig. 1. Ca 2+ leaving the SR enters the luminal mouth of the open PFR before passing through a region equivalent to the selectivity filter of the more discriminating monovalent-selective channels and eventually into a large, water-filled, lumen lumen Ca 2+ Ca 2+ Ca 2+ K + K + K + lumen cytosol cytosol SR lumen A B C D F G E cytosol cytosol lumen lumen lumen cytosol cytosol cytosol Figure …