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Event Type
Research Presentation
Academic Department
Biology
Location
Dana Science Building, 2nd floor
Start Date
14-4-2023 1:30 PM
End Date
14-4-2023 3:00 PM
Description
Brugada Syndrome is a rare cardiac disease that leads to an increased risk of sudden cardiac death due to arrhythmias as a result of reduced sodium current due to mutations in genes such as SCN1B. Contemporary mouse models are criticized for their inability to produce an in vivo ECG phenotype consistent with human clinical presentation. Importantly, the same ex vivo mouse models can produce the human phenocopy when isolated edema is induced in hearts with the clinically relevant blood volume expander mannitol. Therefore, the purpose of this study is to test the hypothesis that sodium channel loss of function can be unmasked in vivo by the infusion of hyperosmotic solutions in mouse. Mice of both sexes heterozygous null for SCN1B (n=11, 20-30 weeks old) were retro-orbitally injected with 0.9% NaCl solution or 26.1 mg/mL mannitol dissolved in 0.9% NaCl solution. The ECG was measured in awake and ambulatory animals with the non-invasive ECGenie. The QRS duration, a measure of ventricular conduction, was significantly prolonged by 14.2% in heterozygous SCN1B mice after treatment with the osmotic agent mannitol compared to a non-significant 2.3% in the QRS duration of wild-type littermates. QTc significantly increased by 12.6% in the heterozygous SCN1B mice compared to a non-significant 2.3% increase in the QTc interval of the wild-type littermates. The change in QTc was not significantly different from the change in QRS duration in in the SCN1B heterozygous mice, suggesting that the QTc prolongation was a result of slowed ventricular conduction manifest as a prolonged QRS duration. Importantly, the clinically relevant osmotic agent mannitol can be used in mice in vivo to unmask a human phenocopy of sodium channel loss of function, and mannitol challenge may be a novel clinical challenge to unmask the Brugada Syndrome early in disease progression when some patients lack a diagnostic ECG. The corollary conclusion is that preventing cardiac edema could be a novel therapeutic strategy to reduce arrhythmias in patients with sodium channel loss of function.
Revealing Subclinical Sodium Channelopathies in an In Vivo Mouse Model Using Osmotic Manipulation
Dana Science Building, 2nd floor
Brugada Syndrome is a rare cardiac disease that leads to an increased risk of sudden cardiac death due to arrhythmias as a result of reduced sodium current due to mutations in genes such as SCN1B. Contemporary mouse models are criticized for their inability to produce an in vivo ECG phenotype consistent with human clinical presentation. Importantly, the same ex vivo mouse models can produce the human phenocopy when isolated edema is induced in hearts with the clinically relevant blood volume expander mannitol. Therefore, the purpose of this study is to test the hypothesis that sodium channel loss of function can be unmasked in vivo by the infusion of hyperosmotic solutions in mouse. Mice of both sexes heterozygous null for SCN1B (n=11, 20-30 weeks old) were retro-orbitally injected with 0.9% NaCl solution or 26.1 mg/mL mannitol dissolved in 0.9% NaCl solution. The ECG was measured in awake and ambulatory animals with the non-invasive ECGenie. The QRS duration, a measure of ventricular conduction, was significantly prolonged by 14.2% in heterozygous SCN1B mice after treatment with the osmotic agent mannitol compared to a non-significant 2.3% in the QRS duration of wild-type littermates. QTc significantly increased by 12.6% in the heterozygous SCN1B mice compared to a non-significant 2.3% increase in the QTc interval of the wild-type littermates. The change in QTc was not significantly different from the change in QRS duration in in the SCN1B heterozygous mice, suggesting that the QTc prolongation was a result of slowed ventricular conduction manifest as a prolonged QRS duration. Importantly, the clinically relevant osmotic agent mannitol can be used in mice in vivo to unmask a human phenocopy of sodium channel loss of function, and mannitol challenge may be a novel clinical challenge to unmask the Brugada Syndrome early in disease progression when some patients lack a diagnostic ECG. The corollary conclusion is that preventing cardiac edema could be a novel therapeutic strategy to reduce arrhythmias in patients with sodium channel loss of function.