tetrodotoxin and Death--Sudden--Cardiac

Topics: Action Potentials; Animals; Calcium Channel Blockers; Death, Sudden, Cardiac; Electrocardiography; Gallopamil; Heart Conduction System; Humans; Models, Biological; Myocardial Ischemia; Rabbits; Sodium Channel Blockers; Tachycardia, Ventricular; Tetrodotoxin; Ventricular Fibrillation

Dravet syndrome is a severe form of intractable pediatric epilepsy with a high incidence of SUDEP: Sudden Unexpected Death in epilepsy. Cardiac arrhythmias are a proposed cause for some cases of SUDEP, yet the susceptibility and potential mechanism of arrhythmogenesis in Dravet syndrome remain unknown. The majority of Dravet syndrome patients have de novo mutations in SCN1A, resulting in haploinsufficiency. We propose that, in addition to neuronal hyperexcitability, SCN1A haploinsufficiency alters cardiac electrical function and produces arrhythmias, providing a potential mechanism for SUDEP.. Postnatal day 15-21 heterozygous SCN1A-R1407X knock-in mice, expressing a human Dravet syndrome mutation, were used to investigate a possible cardiac phenotype. A combination of single cell electrophysiology and in vivo electrocardiogram (ECG) recordings were performed.. We observed a 2-fold increase in both transient and persistent Na(+) current density in isolated Dravet syndrome ventricular myocytes that resulted from increased activity of a tetrodotoxin-resistant Na(+) current, likely Nav1.5. Dravet syndrome myocytes exhibited increased excitability, action potential duration prolongation, and triggered activity. Continuous radiotelemetric ECG recordings showed QT prolongation, ventricular ectopic foci, idioventricular rhythms, beat-to-beat variability, ventricular fibrillation, and focal bradycardia. Spontaneous deaths were recorded in 2 DS mice, and a third became moribund and required euthanasia.. These data from single cell and whole animal experiments suggest that altered cardiac electrical function in Dravet syndrome may contribute to the susceptibility for arrhythmogenesis and SUDEP. These mechanistic insights may lead to critical risk assessment and intervention in human patients.

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Cardiac Electrophysiology; Death, Sudden, Cardiac; Disease Models, Animal; Epilepsies, Myoclonic; Heart Rate; Humans; Ion Channel Gating; Mice; Mice, Inbred C57BL; Mutation; Myocytes, Cardiac; NAV1.5 Voltage-Gated Sodium Channel; Pentylenetetrazole; Protein Biosynthesis; Telemetry; Tetrodotoxin; Transcription, Genetic

In order to clarify the effect of trauma and treatment as stresses on myocardia, we examined histological changes of myocardia in victims who received various kinds of traumata and treatments. We also undertook a histochemical study for calmodulin, which we found useful in the diagnosis of early ischemia. Those who died shortly after stab wounds, traffic accident or head injuries, showed mild cardiac lesions such as contraction bands or fragmentation and mild diffusion of calmodulin, a marker for necrosis. A case with hemorrhagic shock after a traffic accident, involving intense resuscitation for 2 h, showed severe cardiac lesions such as contraction bands, hydropic change and subendocardial hemorrhage along with severe diffusion of calmodulin. In most of the instant death cases after falls, severe contraction band necrosis and severe calmodulin diffusion were observed. Myocardia of victims, who died several days after head injuries or traffic accidents, generally demonstrated distinct diffusion of calmodulin as compared to the mild and non-specific lesions detected by hematoxylin-eosin (H&E) staining. In cases of long-term survival in a state of brain death, calmodulin staining was very low, which was not always associated with the severity of the lesions on H&E staining. In cases with intensive or extended treatment, it appeared to be difficult to determine the cause-effect relationship between trauma and cardiac lesions or to distinguish the lesions due to extrinsic factors from those of disease. In some cases, calmodulin intensely stained the areas with hydropic appearance or hypereosinophilia, which may be related to calcium overload.

Topics: Accidents, Traffic; Adolescent; Adult; Asphyxia; Brain Death; Calmodulin; Cause of Death; Craniocerebral Trauma; Death, Sudden, Cardiac; Female; Histocytochemistry; Humans; Immunoenzyme Techniques; Male; Myocardium; Resuscitation; Shock, Hemorrhagic; Tetrodotoxin; Wounds and Injuries; Wounds, Gunshot