Ranolazine as an Alternative Therapy to Flecainide for SCN5A V411M Long QT Syndrome Type 3 Patients.

Fecha de publicación: 17/12/2020 Fecha Ahead of Print: 17/12/2020

Autores de IIS La Fe

Esther Zorio Grima

Autor
Miguel Ángel Arnau Vives

Autor

Participantes ajenos a IIS La Fe

Cano J
Mazzanti A
Trenor B
Priori SG
Saiz J
Romero L

Grupos

Cardiopatías familiares, muerte súbita y mecanismos de enfermedad (CAFAMUSME)

Investigador Principal

Aitana Braza Boils
Grupo de Investigación Clínica y Traslacional en Cardiología

Investigador Principal

Esther Roselló Lletí

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.

Datos de la publicación

ISSN/ISSNe:: 1663-9812, 1663-9812
Tipo:: Article
Páginas:: 580481-580481
DOI:: 10.3389/fphar.2020.580481
Factor de Impacto:: 1,384 SCImago ℠
Cuartil:: Q1 SCImago ℠

Documentos

No hay documentos

Métricas

Filiaciones

Cano J:: Centro de Investigación e Innovación en Bioingeniería (CI2B), Universitat Politècnica de València, Valencia, España
Zorio E:: Unidad de Cardiopatías Familiares y Muerte Súbita, Servicio de Cardiología, Hospital Universitario y Politécnico La Fe, Valencia, España

Center for Biomedical Network Research on Cardiovascular Diseases (CIBERCV), Madrid, Spain
Mazzanti A:: Molecular Cardiology, IRCCS, Istituti Clinici Scientifici Maugeri, Pavia, Italy

Department of Molecular Medicine, University of Pavia, Pavia, Italy
Arnau MÁ:: Unidad de Cardiopatías Familiares y Muerte Súbita, Servicio de Cardiología, Hospital Universitario y Politécnico La Fe, Valencia, España
Trenor B:: Centro de Investigación e Innovación en Bioingeniería (CI2B), Universitat Politècnica de València, Valencia, España
Priori SG:: Molecular Cardiology, IRCCS, Istituti Clinici Scientifici Maugeri, Pavia, Italy

Department of Molecular Medicine, University of Pavia, Pavia, Italy
Saiz J:: Centro de Investigación e Innovación en Bioingeniería (CI2B), Universitat Politècnica de València, Valencia, España
Romero L:: Centro de Investigación e Innovación en Bioingeniería (CI2B), Universitat Politècnica de València, Valencia, España

Keywords

Long QT Syndrome, V411M, flecainide, in-silico model, ranolazine, sodium current channelopathy

Campos de estudio

Proyectos asociados

RED INVESTIGACION (RECAVA)

RD06/0014/0004 . INSTITUTO DE SALUD CARLOS III; FUNDACION PARA LA INV BIOMEDICA- HOSPITAL GREGORIO MARAÑON; FUNDACIÓN PARA LA INVESTIGACIÓN DEL HOSPITAL UNIVERSITARIO LA FE DE LA COMUNIDAD VALENCIANA . 2006