Flecainide reduces Ca2+ spark and wave frequency via inhibition of the sarcolemmal sodium current

Abstract

AimsCa2+ waves are thought to be important in the aetiology of ventricular tachyarrhythmias. There have been conflicting results regarding whether flecainide reduces Ca2+ waves in isolated cardiomyocytes. We sought to confirm whether flecainide inhibits waves in the intact cardiomyocyte and to elucidate the mechanism.Methods and resultsWe imaged spontaneous sarcoplasmic reticulum (SR) Ca2+ release events in healthy adult rat cardiomyocytes. Variation in stimulation frequency was used to produce Ca2+ sparks or waves. Spark frequency, wave frequency, and wave velocity were reduced by flecainide in the absence of a reduction of SR Ca2+ content. Inhibition of INa via alternative pharmacological agents (tetrodotoxin, propafenone, or lidocaine) produced similar changes. To assess the contribution of INa to spark and wave production, voltage clamping was used to activate contraction from holding potentials of −80 or −40 mV. This confirmed that reducing Na+ influx during myocyte stimulation is sufficient to reduce waves and that flecainide only causes Ca2+ wave reduction when INa is active. It was found that Na+/Ca2+-exchanger (NCX)-mediated Ca2+ efflux was significantly enhanced by flecainide and that the effects of flecainide on wave frequency could be reversed by reducing [Na+]o, suggesting an important downstream role for NCX function.ConclusionFlecainide reduces spark and wave frequency in the intact rat cardiomyocyte at therapeutically relevant concentrations but the mechanism involves INa reduction rather than direct ryanodine receptor (RyR2) inhibition. Reduced INa results in increased Ca2+ efflux via NCX across the sarcolemma, reducing Ca2+ concentration in the vicinity of the RyR2.

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.…”

Effect of flecainide derivatives on sarcoplasmic reticulum calcium release suggests a lack of direct action on the cardiac ryanodine receptor

“…These data suggest that it is the charged form of flecainide that mediates this effect and corroborate and extend previous findings that flecainide suppresses Ca 2 + spark frequency (Sikkel et al ., 2013a). Taken together with the present investigations that confirmed a lack of effect of these concentrations of flecainide and QX‐FL on the physiologically relevant luminal‐to‐cytoplasmic ion flux through RyR2 channels and, in the case of QX‐FL, any inhibition of a potential charge‐compensating cytosolic‐to‐luminal K + flux (Figures 4, 5, 6), these data support the conclusion that the only mode of action underpinning flecainide's efficacy in CPVT patients is the inhibition of I Na (Liu et al ., 2011; Sikkel et al ., 2013a; Bannister et al ., 2015). In addition, our demonstration that QX‐FL is a Na + channel specific ligand, yet has identical effects to flecainide on Ca 2 + spark parameters (Supplementary Table) reinforces this conclusion.…”

The Direct Actions of Flecainide on the Human Cardiac Ryanodine Receptor

“…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.…”

“…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. 5 To date this issue remains unresolved. A detailed mechanistic view of the action of flecainide is essential to design new strategies to counter CPVT.…”