Abstract
The prolongation of the QT interval represents the main feature of the long QT syndrome (LQTS), a life-threatening genetic disease. The heterozygous SCN5A V411M mutation of the human sodium channel leads to a LQTS type 3 with severe proarrhythmic effects due to an increase in the late component of the sodium current (INaL). The two sodium blockers flecainide and ranolazine are equally recommended by the current 2015 ESC guidelines to treat patients with LQTS type 3 and persistently prolonged QT intervals. However, awareness of pro-arrhythmic effects of flecainide in LQTS type 3 patients arose upon the study of the SCN5A E1784K mutation. Regarding SCN5A V411M individuals, flecainide showed good results albeit in a reduced number of patients and no evidence supporting the use of ranolazine has ever been released. Therefore, we ought to compare the effect of ranolazine and flecainide in a SCN5A V411M model using an in-silico modeling and simulation approach. We collected clinical data of four patients. Then, we fitted four Markovian models of the human sodium current (INa) to experimental and clinical data. Two of them correspond to the wild type and the heterozygous SCN5A V411M scenarios, and the other two mimic the effects of flecainide and ranolazine on INa. Next, we inserted them into three isolated cell action potential (AP) models for endocardial, midmyocardial and epicardial cells and in a one-dimensional tissue model. The SCN5A V411M mutation produced a 15.9% APD90 prolongation in the isolated endocardial cell model, which corresponded to a 14.3% of the QT interval prolongation in a one-dimensional strand model, in keeping with clinical observations. Although with different underlying mechanisms, flecainide and ranolazine partially countered this prolongation at the isolated endocardial model by reducing the APD90 by 8.7 and 4.3%, and the QT interval by 7.2 and 3.2%, respectively. While flecainide specifically targeted the mutation-induced increase in peak INaL, ranolazine reduced it during the entire AP. Our simulations also suggest that ranolazine could prevent early afterdepolarizations triggered by the SCN5A V411M mutation during bradycardia, as flecainide. We conclude that ranolazine could be used to treat SCN5A V411M patients, specifically when flecainide is contraindicated.
Highlights
Mutations in genes encoding ion channels are regarded as the molecular basis of the congenital Long QT Syndrome (LQTS)
Our study showed that the druginduced attenuation of the APD90 prolongation caused by V411M was highly dependent on β4n and α4n
Our results show that both flecainide and ranolazine reduce the APD90 prolongation induced by the mutation for all the tested Basic Cycle Lengths (BCLs), flecainide’s APD90 reduction being higher than ranolazine’s (Figures 8A)
Summary
Mutations in genes encoding ion channels are regarded as the molecular basis of the congenital Long QT Syndrome (LQTS). Mutations in the SCN5A gene (LQTS type 3), which encodes the main protein of INa, and mutations in the genes encoding its regulatory proteins (LQTS 4, LQTS 9, LQTS 10 and LQTS 12) can cause LQTS as long as the mutations result in a gain-of-function of the late sodium current. High temperatures and/or the administration of flecainide could unmask the other phenotypes and trigger life-threatening arrhythmias (Makita et al, 2008; Abdelsayed et al, 2015). Basic research on these drugs has revealed that drug-channel interaction is complex and not just limited to a specific blockade of part of INa, the fast (INaf) or the late (INaL) components
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