Journal of Genetic Syndromes & Gene Therapy
Open Access

Temperature, pH and calcium: Arrhythmogenic triggers in mixed long QT3 and Brugada syndrome

Annual Congress on Rare Diseases & Orphan Drugs

October 26-27, 2016 Chicago, USA

Peter C Ruben, Colin H Peters and Mena Abdelsayed

Simon Fraser University, Canada

Posters & Accepted Abstracts: J Genet Syndr Gene Ther

Abstract :

Sudden cardiac death (SCD) is a major cause of mortality, afflicting more than a quarter million people annually in the United States. Although there are a number of causes for SCD, inherited genetic mutations account for a substantial proportion of deaths in victims under the age of 40 years. Rare forms of inheritable cardiac disease underlying SCD include Long-QT3 (LQT3) and Brugada syndromes (BrS1), both of which arise as a consequence of mutations in the SCN5a gene that encodes the cardiac voltagegated sodium channel, NaV1.5. A particularly rare NaV1.5 mutant, E1784K, is one of several mutants that cause mixed or overlap syndrome, which has the characteristics of both LQT3 and BrS1. We studied E1784K channels expressed in Xenopus oocytes and mammalian cells and found that several physiological factors, all of which are normal byproducts of intense exercise, exacerbate the biophysical defects caused by the mutation itself. Voltage clamp recordings of ionic and gating currents show changes in a range of biophysical properties in E1784K, compared to wild-type NaV1.5 channels, when temperature is raised, extracellular pH is reduced or cytosolic Ca++ is elevated. These biophysical changes are predicted to be arrhythmogenic. We incorporated our biophysical results into a ventricular action potential model and found that, at high heart rates, the effects of temperature, pH, or calcium are individually arrhythmogenic. These results lead us to the conclusion that catastrophic arrhythmias may be triggered by intense exercise in individuals carrying the SCN5a mutation underlying the E1784K form of mixed syndrome.

Biography :

Email: pruben@sfu.ca