ANR NaCaR : Flavien Charpentier (2019-2025)

Ana Maria Gomez ( Inserm UMR 1180 Signaling and Cardiovascular Pathophysiology, Université Paris-Sud) is the scientific leader and Flavien Charpentier is the partner 2 of the ANR funded project : Sodium calcium dependent arrhythmias.

Abstract

Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT), a severe genetic disorder, often results in sudden cardiac death (SCD) in individuals with structurally normal hearts. The malfunctioning of the ryanodine receptor type 2 (RyR2) and aberrant openings during diastole lead to elevated intracellular calcium concentration, triggering arrhythmias. While β-adrenergic blockers are the primary therapy, the addition of flecainide, a sodium channel blocker, is effective but poorly understood. The hypothesis of altered sodium homeostasis contributing to arrhythmogenicity in CPVT is explored in this project.
Long QT syndrome type 3 (LQTS3), a hereditary disorder, involves delayed repolarization, leading to a prolonged QT interval on the ECG and an increased risk of ventricular tachycardia and fibrillation. Mutations in the sodium channel Nav1.5 (SCN5A gene) are implicated. Our data suggest enhanced intracellular calcium concentration in LQTS3 mice, prompting the novel hypothesis that calcium handling alteration contributes to arrhythmogenicity in LQTS3.
 

Objectives

This project aims to uncover the mechanisms behind life-threatening ventricular arrhythmias leading SCD, which constitutes 15% of global casualties. Focusing on two adrenergically-induced syndromes, CPVT and LQTS3, the research seeks to explore the role of intracellular calcium and sodium in arrhythmogenesis. Beyond CPVT and LQT3, the research considers the broader implications for acquired cardiac diseases like heart failure, where arrhythmias contribute significantly to mortality. Understanding the fundamental mechanisms of CPVT and LQTS3 is expected to provide insights for developing effective antiarrhythmic