Sodium calcium dependent arrhythmias – NaCaR

The main objective of this project is to elucidate the mechanisms of life-threatening ventricular arrhythmias involved in sudden cardiac death (SCD), which accounts for about 15% of casualties worldwide. SCD may happen in a diseased heart, but also in structurally normal hearts where a channelopathy, i.e., a genetic disease affecting ion channel, is most often at the origin of the lethal tachyarrhythmia. We will focus on two adrenergically-induced syndromes: Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) and Long QT syndrome type 3 (LQTS3). CPVT is a severe genetic disease manifested by syncope or SCD in children and young adults during physical or emotional stress and in the absence of structural heart disease. Most of the identified CPVT causative mutations are in the gene coding for the intracellular Ca2+ release channel, the ryanodine receptor type 2 (RyR2). Other CPVT-related mutations affect RyR2 regulatory proteins, indicating that CPVT is related to RyR2 malfunctioning. Aberrant openings of the RyR2 during diastole produce an elevation in [Ca2+]i that is rapidly extruded by the electrogenic sodium/calcium exchanger producing delayed after depolarizations, which are at the origin of triggered activity and arrhythmogenesis in CPVT. When ß-adrenergic blockers (first therapeutic option) do not confer enough protection, the Na+ channel blocker flecainide is added with good efficiency, although with a narrow therapeutic window. While a direct effect of flecainide on the RyR2 has been invoked as the mechanism of action, this is controversial. Thus we hypothesize that alteration in Na+ homeostasis contributes to arrhythmogenity in CPVT. This is a completely unexplored mechanism.
LQTS is a severe hereditary disorder of cardiac electrical activity. It is caused by delayed repolarization in ventricular cardiomyocytes, which results in a prolonged QT interval on the ECG and an increased susceptibility to polymorphic ventricular tachycardia and ventricular fibrillation. Mutations in genes encoding ion channels or their accessory subunits are linked to different types of LQT syndrome. Mutations in the Na+ channel Nav1.5, (SCN5A gene), which impair its inactivation, inducing the so called late Na+ current, are involved in LQTS3. Interestingly, our recently published data show that intracellular Ca2+ is enhanced in LQT3 mice (Scn5a+/?QKP) cardiomyocytes probably by the sodium/calcium exchanger activity extruding excess Na+. Thus we formulate the novel hypothesis that Ca2+ handling alteration contributes to arrhythmogenicity in LQTS3.
Gathering a group of international recognized experts, we propose an original and multidisciplinary project focused in the key role of [Ca2+]i and [Na+]i in the genesis of life-threatening arrhythmias, using both knock-in mice and rabbit models of CPVT or LQTS3, and cardiomyocytes differentiated from induced pluripotent stem cells derived from patients exhibiting the same mutations. Beyond the rare diseases CPVT and LQT3, Ca2+ and Na+ mishandling have been evidenced in acquired cardiac diseases like heart failure, where cardiac arrhythmias account for half of the mortality. The new knowledge obtained in these rare diseases may also yield benefits for common diseases in which the affected channel may show altered expression and/or function such as in heart failure, where SCD accounts for about half of the deaths. Thus elucidating CPVT and LQTS fundamental mechanisms will deliver essential knowledge to provide a solid rationale for new and effective antiarrhythmic therapies.