The Direct Actions of Flecainide on the Human Cardiac Ryanodine Receptor

Abstract

EditorialC atecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare but particularly disabling disease that manifests as spontaneous transition to VT associated with increased sympathetic activity. In 2 variants of this disease (CPVT1 and CPVT2), the abnormal electric activity of the heart is associated with genetic defects in the coding of either the ryanodine receptor (type 1) or a related sarcoplasmic reticulum (SR) protein, calsequestrin (type 2). For those cases (20%-30%) unresponsive to β-blocker treatment there were few options available to mitigate the risk of VT/VF (ventricular tachycardia/ventricular fibrillation). However, an article published by the Knollman group 1 in 2009 indicated that these individuals may respond to the class 1 antiarrhythmic drug flecainide, which has an anesthetic action via inhibition of I Na . The article provided evidence that in the case of CPVT, its antiarrhythmic action was not via inhibition of I Na , but instead via inhibition of the activity of the cardiac ryanodine receptor (RyR2) and subsequent reduction in the proarrhythmic release of Ca 2+ during diastole. This interpretation was supported by further work by the Knollman and his collaborators, 2,3 in particular, the demonstration of direct effects of flecainide and the related more potent local anesthetic R-propafenone 3 on SR Ca 2+ release in permeabilized cardiac muscle preparations. However, the interpretation of this result is controversial. Two independent groups 4,5 have failed to reproduce the effects of flecainide on RyR2 activity in either normal ventricular myocardium 5 or a mouse model of CPVT1. 4 The first group reported effects of flecainide that are entirely consistent with a direct action on the excitability of cardiac muscle via I Na , 4 whereas the second produced evidence that the antiarrhythmic effect is by depressed Na + influx through I Na and the subsequent effects on cytoplasmic Ca 2+ via the Na + /Ca 2+ exchanger. 5To date this issue remains unresolved. A detailed mechanistic view of the action of flecainide is essential to design new strategies to counter CPVT. RyR2 inhibition may be a suitable target for drug design, but the form of inhibition is unclear because a novel drug known to depress RyR2 (JTV 519) has been reported to be ineffective at suppressing the CPVT phenotype in some cases. 6 This makes a detailed analysis of the interaction of flecainide with RyR2, a priority for advancement in this area. Article, see p 1324In this issue, Bannister et al 8 present a detailed study of the action of flecainide on the isolated human cardiac ryanodine receptor. The authors show that flecainide can bind with the cytoplasmic face of isolated human cardiac ryanodine receptor 2 to reduce open probability (P o ) when cations (K + ) are conducted from cytoplasmic to luminal side of the channel. This block has a half maximal effect ≈20 μmol/L and is characterized by the appearance of a long-lasting subconductance state of ≈20% of maximal that supports the sustained conductance of cation...

Patient-Specific Drug Screening Using a Human Induced Pluripotent Stem Cell Model of Catecholaminergic Polymorphic Ventricular Tachycardia Type 2

“…21,[38][39][40][41][42][43][44] Our results support this concept by showing that flecainide, at clinically relevant concentrations, could significantly suppress baseline Ca 2+ -cycling abnormalities and protect against isoproterenol-induced arrhythmogenicity in the CPVT2-hiPSC-CMs. Finally, riluzole, a neuronal Na + channel blocker used for treatment of amyotrophic lateral sclerosis, which was recently shown to be antiarrhythmic in a mouse model of CPVT, 45 was also found beneficial in our CPVT2-hiPSC-CMs model.…”

“…21,[38][39][40][41][42][43][44] This was also manifested in our CPVT2 model ( Figure 3D), as application of flecainide significantly suppressed baseline arrhythmic activity in the CPVT2-hiPSC-CMs. Overall, flecainide (1 and 6 µmol/L) abolished Ca 2+ -cycling abnormalities in 26% and 57% of previously arrhythmic CPVT2-hiPSC-CMs, respectively ( Figures 3D and 4A).…”

“…Two main mechanisms were suggested (1) flecainide may increase triggered-activity threshold by directly blocking Na + channels 39,44,46 or (2) flecainide may stabilize SR thereby decreasing diastolic Ca 2+ leak. 38,40,[42][43][44] To provide mechanistic insights into the antiarrhythmic action of the tested pharmacological agents, we initially evaluated their ability to alter SOICR incidence in the CPVT2-hiPSC-CMs as a surrogate for SR stabilization. To provide additional information on their capacity to alter excitability or stabilize the SR, we also evaluated their effects on triggered activity and diastolic Ca 2+ -release events after pacing.…”

Catecholaminergic Polymorphic Ventricular Tachycardia

“…51 However, this suggested mechanism is opposed by others who have proposed a mechanism that can solely be attributed to the sodium channel-blocking properties of the drug or by interaction with other modulators of RyR2. [55][56][57][58] Left Cardiac Sympathetic Denervation (LCSD) LCSD is a surgical procedure in which the lower two-thirds of the left stellate ganglion, together with the thoracic ganglia T2-T4, are ablated, thereby interrupting the major source of norepinephrine release in the heart. 59, 60 The surgery can be subdivided into complete or partial LSCD and is considered partial whenever T1 or T4 is not ablated.…”

Therapeutic Strategies Targeting Inherited Cardiomyopathies

“…32,33 The mechanism by which flecainide prevents arrhythmias in patients with CPVT is not full elucidated. It may be a direct effect on the RyR2 receptor, 34,35 or it may act through its antagonistic activity on voltage gated sodium channels by increasing the threshold for triggered activity. 20,36,37 Finally, patients with calsequestrin associated CPVT (denoted CPVT2) may also benefit from flecainide by preventing exercise induced polymorphic VT. 38 While there is little controversy as to the beneficial effects of flecainide in patients with CPVT, the exact anti-arrhythmic mechanism has not been fully established.…”