5 research outputs found
Effect of Active Smoking on Comparative Efficacy of Antithrombotic Therapy in Patients With Atrial Fibrillation
International audienc
Causes of Death and Influencing Factors in Patients with Atrial Fibrillation
International audienc
Progression of excitation-contraction coupling defects in doxorubicin cardiotoxicity
International audienc
RyR2R420Q catecholaminergic polymorphic ventricular tachycardia mutation induces bradycardia by disturbing the coupled clock pacemaker mechanism
International audienc
Impaired Binding to Junctophilin-2 and Nanostructural Alteration in CPVT Mutation
RATIONALE: Catecholaminergic polymorphic ventricular tachycardia is a rare disease, manifested by syncope or sudden death
in children or young adults under stress conditions. Mutations in the Ca2+ release channel/type 2 ryanodine receptor (RyR2)
gene account for about 60% of the identified mutations. Recently, we found and described a mutation in RyR2 N-terminal
domain, RyR2R420Q.
OBJECTIVE: To determine the arrhythmogenic mechanisms of this mutation.
METHODS AND RESULTS: Ventricular tachycardias under stress conditions were observed in both patients with catecholaminergic
polymorphic ventricular tachycardia and knock-in mice. During action potential recording (by patch-clamp in knock-in mouse
cardiomyocytes and by microelectrodes in mutant human induced pluripotent stem cell-derived cardiomyocytes), we observed
an increased occurrence of delayed afterdepolarizations under isoproterenol stimulation, associated with increased Ca2+ waves
during confocal Ca2+ recording in both mouse and human RyR2R420Q cardiomyocytes. In addition, Ca2+-induced Ca2+-release,
as well as a rough indicator of fractional Ca2+ release, were higher and Ca2+ sparks longer in the RyR2R420Q-expressing cells.
At the ultrastructural nanodomain level, we observed smaller RyR2 clusters and widened junctional sarcoplasmic reticulum
measured by gated stimulated emission depletion super-resolution and electronic microscopy, respectively. The increase in
junctional sarcoplasmic reticulum width might be due to the impairment of RyR2R420Q binding to junctophilin-2, as there were
less junctophilin-2 coimmunoprecipitated with RyR2R420Q. At the single current level, the RyR2R420Q channel dwells longer in
the open state at low intracellular Ca2+ ([Ca2+]i), but there is predominance of a subconductance state. The latter might be
correlated with an enhanced interaction between the N terminus and the core solenoid, a RyR2 interdomain association that
has not been previously implicated in the pathogenesis of arrhythmias and sudden cardiac death.
CONCLUSIONS: The RyR2R420Q catecholaminergic polymorphic ventricular tachycardia mutation modifies the interdomain
interaction of the channel and weakens its association with junctophillin-2. These defects may underlie both nanoscale
disarrangement of the dyad and channel dysfunction.
GRAPHIC ABSTRACT: An online graphic abstract is available for this article.This work was funded by Inserm and University Paris-Sud, and grants from ANR
(ANR-19-CE14-0031-01 to A.M. Gómez), LabEx LERMIT (ANR-10-LABX-33),
“Instituto de Salud Carlos III”; FEDER “Union Europea, Una forma de hacer Europa”
(PI18/01582), La Fe Biobank (PT17/0015/0043) and Memorial Nacho Barberá
to E. Zorio; Swiss National Science Foundation (SNSF grants no. 31003A 179325
and 310030 156375 to E. Niggli), British Heart Foundation (FS/15/30/31494)
to S. Zissimopoulos; Italian Telethon ONLUS Foundation (GGP19231) and Italian
MIUR (PRIN no. 2015ZZR4W3) to F. Protasi; National Institutes of Health
(NIH) grants to J. Ramos-Franco (R01GM111397) and H.H. Valdivia–A.M. Gómez
(2R01HL055438-22); and European Union H2020 (MSCA-RISE AMD-734931-
6) to A.M. Gómez. H.H. Valdivia was recipient of a Fullbright-Tockeville chair to work
on A.M. Gómez laboratory. J.L. Álvarez and C.R. Valdivia were recipient of a visiting
program Alambert from University Paris-Sud to work in A.M. Gómez laboratory. A.
Zahradnikova was recipient of a postdoctoral position from University Paris-Sud. R.
Rizzetto was recipient of a postdoctoral fellowship from CORDDIM (Région Ile de
France). L. Yin was recipient of the CSC (Chinese Scholarship council)