CPVT-associated calmodulin variants N53I and A102V dysregulate calcium signalling via different mechanisms

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited condition that can cause fatal cardiac arrhythmia. Human mutations in the Ca2+ sensor calmodulin (CaM) have been associated with CPVT susceptibility, suggesting that CaM dysfunction is a key driver of the disease. However, the detailed molecular mechanism remains unclear. Focusing on the interaction with the cardiac ryanodine receptor (RyR2), we determined the effect of CPVT-associated variants N53I and A102V on the structural characteristics of CaM and on Ca2+ fluxes in live cells. We provide novel data showing that binding of both Ca2+/CaM-N53I and Ca2+/CaM-A102V to RyR23583-3603 is decreased. Ca2+/CaM:RyR23583-3603 high-resolution crystal structures highlight subtle conformational changes for the N53I variant, with A102V being similar to wild-type. We show that co-expression of CaM-N53I or CaM-A102V with RyR2 in HEK293 cells significantly increased the duration of Ca2+ events, CaM-A102V exhibited a lower frequency of Ca2+ oscillations. In addition, we show that CaMKIIδ phosphorylation activity is increased for A102V, compared to CaM-WT. This paper provides novel insight into the molecular mechanisms of CPVT-associated CaM variants and will facilitate development of strategies for future therapies.

Sudden unexpected death after acute symptomatic seizures in a patient on mechanical ventilation

Background The mechanism of sudden unexpected death in epilepsy remains poorly understood. Seizure induced cardiac arrhythmia, central and obstructive apneas have been proposed as possible causes of death. Here we report a unique case of seizure related sudden unexpected death in a patient whose airway was fully protected by intubation and mechanic ventilation in the absence of fatal cardiac arrhythmia. Case presentation A 70-year-old woman was undergoing mechanical ventilation and video-electroencephalography (EEG) monitoring following two convulsive seizures with ictal hypoventilation and hypoxemia. Several hours after intubation, she suffered another generalized tonic clonic seizure lasted for 3 min and developed postictal generalized EEG suppression in the presence of stable vital signs with SpO2 > 90%. EEG suppression persisted throughout the postictal phase. There was a significant fluctuation of systolic blood pressure between 50 and 180 mmHg with several bouts of hypotension < 60 mmHg. She remained unresponsive after the convulsive seizure and died of diffuse cerebral edema 12 h later. Autopsy revealed no clear cause of death, except for possible hypoxic and ischemic injury leading to the diffuse cerebral edema. Conclusion Given the reliable periictal airway protection, neither seizure induced central apnea nor obstructive apnea appeared to be the direct cause of death in this unique case. In the absence of fatal cardiac arrhythmia, diffuse cerebral edema secondary to seizure-induced autonomic dysfunction, hypotension and hypoxemia might be the cause of death, highlighting the etiological heterogeneity of sudden unexpected death in epilepsy.