Résumé
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a severe genetic arrhythmia associated with dysfunction in more than 80% of the type 2 cardiac ryanodine receptor (RyR2). It is characterized by ventricular tachycardia induced by catecholamines, by SNA stimulation (i.e. sympathetic tone), which manifests as syncope or even sudden death in childhood. CPVT patients can also frequently develop neuro-psycho behavioral disorders, including autism.
Autism is a neurodevelopmental disorder characterized by difficulties with social interaction and communication, and by restricted and repetitive behavior. Autism appears from an early age. Research suggests that autism develops from a combination of genetic and nongenetic, or environmental, influences. The behavioral and cognitive features of autism are associated with pervasive abnormalities in the central nervous system (CNS).
As RyR2 is expressed in heart and brain, and based on our previous work, we hypothesize that leaky RyR2 in CPVT patients affects both the cardiomyocytes and neurons.
Using patient-specific induced pluripotent stem cell (hiPSC), we differentiate them into cardiomyocytes and neurons. We performed structural and functional characterizations of the control and CPVT cardiomyocytes and neurons by immunofluorescence, fluorescent confocal microscopy, IonOptix and video-edge capture was done.
From the different differentiation protocols, we are able to obtain ventricular cardiomyocytes and neurons from the CNS. CPVT cardiomyocytes exhibit calcium and contractile defects, leaky RyR2 which are typical of CPVT. Surprisingly, CPVT neurons exhibit impaired size, altered intracellular calcium handling, leaky RyR2 and neurotransmitter secretion.
From the same CPVT patient, we are able to obtain ventricular cardiomyocytes and CNS neurons. Our preliminary data demonstrate that CPVT cardiomyocytes and neurons exhibit defects including RyR2 leak and neuronal impairment reminiscent of autism. This demonstrates for the first time a potential role of RyR2 mediated calcium leak in autism.