Enhancement of Cardiac Store Operated Calcium Entry (SOCE) within Novel Intercalated Disk Microdomains in Arrhythmic Disease

Store-operated Ca2+ entry (SOCE), a major Ca2+ signaling mechanism in non-myocyte cells, has recently emerged as a component of Ca2+ signaling in cardiac myocytes. Though it has been reported to play a role in cardiac arrhythmias and to be upregulated in cardiac disease, little is known about the fundamental properties of cardiac SOCE, its structural underpinnings or effector targets. An even greater question is how SOCE interacts with canonical excitation-contraction coupling (ECC). We undertook a multiscale structural and functional investigation of SOCE in cardiac myocytes from healthy mice (wild type; WT) and from a genetic murine model of arrhythmic disease (catecholaminergic ventricular tachycardia; CPVT). Here we provide the first demonstration of local, transient Ca2+ entry (LoCE) events, which comprise cardiac SOCE. Although infrequent in WT myocytes, LoCEs occurred with greater frequency and amplitude in CPVT myocytes. CPVT myocytes also evidenced characteristic arrhythmogenic spontaneous Ca2+ waves under cholinergic stress, which were effectively prevented by SOCE inhibition. In a surprising finding, we report that both LoCEs and their underlying protein machinery are concentrated at the intercalated disk (ID). Therefore, localization of cardiac SOCE in the ID compartment has important implications for SOCE-mediated signaling, arrhythmogenesis and intercellular mechanical and electrical coupling in health and disease

Post-intervention Status in Patients With Refractory Myasthenia Gravis Treated With Eculizumab During REGAIN and Its Open-Label Extension

OBJECTIVE: To evaluate whether eculizumab helps patients with anti-acetylcholine receptor-positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension. METHODS: Patients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study. RESULTS: A total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1-4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected. CONCLUSION: Eculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population. CLINICALTRIALSGOV IDENTIFIER: REGAIN, NCT01997229; REGAIN open-label extension, NCT02301624. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo

Asymptotic Analysis of a bi-monomeric nonlinear Becker-Döring system

International audienceTo provide a mechanistic explanation of sustained then damped oscillations observed in a depolymerisation experiment, a bi-monomeric variant of the seminal Becker-D\"oring system has been proposed in~(Doumic, Fellner, Mezache, Rezaei, J. of Theor. Biol., 2019). When all reaction rates are constant, the equations are the following:\begin{align*}\frac{dv}{dt} & =-vw+v\sum_{j=2}^{\infty}c_{j}, \qquad\frac{dw}{dt} =vw-w\sum_{j=1}^{\infty}c_{j}, \\\frac{dc_{j}}{dt} & =J_{j-1}-J_{j}\ \ ,\ \ j\geq1\ \ ,\ \ \J_{j}=wc_{j}-vc_{j+1}\ \ ,\ \ j\geq1\ \ ,\ J_{0}=0,\end{align*}where $v$ and $w$ are two distinct unit species, and $c_i$ represents the concentration of clusters containing $i$ units. We study in detail the mechanisms leading to such oscillations and characterise the different phases of the dynamics, from the initial high-amplitude oscillations to the progressive damping leading to the convergence towards the unique positive stationary solution. We give quantitative approximations for the main quantities of interest: period of the oscillations, size of the damping (corresponding to a loss of energy), number of oscillations characterising each phase. We illustrate these results by numerical simulation, in line with the theoretical results, and provide numerical methods to solve the system

Asymptotic Analysis of a bi-monomeric nonlinear Becker-D{\"o}ring system

To provide a mechanistic explanation of sustained {then} damped oscillations observed in a depolymerisation experiment, a bi-monomeric variant of the seminal Becker-D\"oring system has been proposed in \cite{DFMR}. When all reaction rates are constant, the equations are the following: \begin{align*}\frac{dv}{dt} & =-vw+v\sum_{j=2}^{\infty}c_{j}, \qquad \frac{dw}{dt} =vw-w\sum_{j=1}^{\infty}c_{j}, \\ \frac{dc_{j}}{dt} & =J_{j-1}-J_{j}\ \ ,\ \ j\geq1\ \ ,\ \ \ J_{j}=wc_{j}-vc_{j+1}\ \ ,\ \ j\geq1\ \ ,\ J_{0}=0, \end{align*} where $v$ and $w$ are two distinct unit species, and $c_i$ represents the concentration of clusters containing $i$ units. We study in detail the mechanisms leading to such oscillations and characterise the different phases of the dynamics, from the initial high-amplitude oscillations to the progressive damping leading to the convergence towards the unique positive stationary solution. We give quantitative approximations for the main quantities of interest: period of the oscillations, size of the damping (corresponding to a loss of energy), number of oscillations characterising each phase. We illustrate these results by numerical simulation, in line with the theoretical results, and provide numerical methods to solve the system