Sodium channel kinetic changes that produce Brugada syndrome or progressive cardiac conduction system disease

Some mutations of the sodium channel gene Na-V1.5 are multifunctional, causing combinations of LQTS, Brugada syndrome and progressive cardiac conduction system disease ( PCCD). The combination of Brugada syndrome and PCCD is uncommon, although they both result from a reduction in the sodium current. We hypothesize that slow conduction is sufficient to cause S-T segment elevation and undertook a combined experimental and theoretical study to determine whether conduction slowing alone can produce the Brugada phenotype. Deletion of lysine 1479 in one of two positively charged clusters in the III/IV inter-domain linker causes both syndromes. We have examined the functional effects of this mutation using heterologous expression of the wild-type and mutant sodium channel in HEK-293- EBNA cells. We show that Delta K1479 shifts the potential of half- activation, V-1/2m, to more positive potentials ( V-1/2m = -36.8 +/- 0.8 and -24.5 +/- 1.3 mV for the wild- type and Delta K1479 mutant respectively, n = 11, 10). The depolarizing shift increases the extent of depolarization required for activation. The potential of half- inactivation, V-1/2h, is also shifted to more positive potentials ( V1/2h = - 85 +/- 1.1 and - 79.4 +/- 1.2 mV for wild- type and Delta K1479 mutant respectively), increasing the fraction of channels available for activation. These shifts are quantitatively the same as a mutation that produces PCCD only, G514C. We incorporated experimentally derived parameters into a model of the cardiac action potential and its propagation in a one dimensional cable ( simulating endo-, mid-myocardial and epicardial regions). The simulations show that action potential and ECG changes consistent with Brugada syndrome may result from conduction slowing alone; marked repolarization heterogeneity is not required. The findings also suggest how Brugada syndrome and PCCD which both result from loss of sodium channel function are sometimes present alone and at other times in combination.