
Despite substantive advances in the understanding of underlying molecular mechanisms, inherited arrhythmias remain a major cause of morbidity and mortality, including sudden cardiac death. Long QT and Brugada Syndromes (LQTS and BrS), in particular, contribute to these statistics and often go undetected until a catastrophic event occurs. Many of the cardiac voltage-gated sodium channel (NaV1.5) mutations underlying LQTS and BrS have been characterized biophysically. Although the defective channel properties account, in most cases, for the possibility of arrhythmogenesis, the events that trigger these pathophysiological behaviors remain unknown. Using a combination of experimental approaches to study ionic and gating currents, and computer modeling, we studied three NaV1.5 mutations and found that one associated with LQT3 and BrS, E1784K, is acutely sensitive to changes in extracellular pH, temperature, and cytosolic calcium.

Despite substantive advances in the understanding of underlying molecular mechanisms, inherited arrhythmias remain a major cause of morbidity and mortality, including sudden cardiac death. Long QT and Brugada Syndromes (LQTS and BrS), in particular, contribute to these statistics and often go undetected until a catastrophic event occurs. Many of the cardiac voltage-gated sodium channel (NaV1.5) mutations underlying LQTS and BrS have been characterized biophysically. Although the defective channel properties account, in most cases, for the possibility of arrhythmogenesis, the events that trigger these pathophysiological behaviors remain unknown. Using a combination of experimental approaches to study ionic and gating currents, and computer modeling, we studied three NaV1.5 mutations and found that one associated with LQT3 and BrS, E1784K, is acutely sensitive to changes in extracellular pH, temperature, and cytosolic calcium.