Sodium channel haploinsufficiency and structural change in ventricular arrhythmogenesis

Abstract

Normal cardiac excitation involves orderly conduction of electrical activation and recovery dependent upon surface membrane, voltage-gated, sodium (Na+) channel α-subunits (Nav1.5). We summarize experimental studies of physiological and clinical consequences of loss-of-function Na+ channel mutations. Of these conditions, Brugada syndrome (BrS) and progressive cardiac conduction defect (PCCD) are associated with sudden, often fatal, ventricular tachycardia (VT) or fibrillation. Mouse Scn5a+/- hearts replicate important clinical phenotypes modelling these human conditions. The arrhythmic phenotype is associated not only with the primary biophysical change but also with additional, anatomical abnormalities, in turn dependent upon age and sex, each themselves exerting arrhythmic effects. Available evidence suggests a unified binary scheme for the development of arrhythmia in both BrS and PCCD. Previous biophysical studies suggested that Nav1.5 deficiency produces a background electrophysiological defect compromising conduction, thereby producing an arrhythmic substrate unmasked by flecainide or ajmaline challenge. More recent reports further suggest a progressive decline in conduction velocity and increase in its dispersion particularly in ageing male Nav1.5 haploinsufficient compared to WT hearts. This appears to involve a selective appearance of slow conduction at the expense of rapidly conducting pathways with changes in their frequency distributions. These changes were related to increased cardiac fibrosis. It is thus the combination of the structural and biophysical changes both accentuating arrhythmic substrate that may produce arrhythmic tendency. This binary scheme explains the combined requirement for separate, biophysical and structural changes, particularly occurring in ageing Nav1.5 haploinsufficient males in producing clinical arrhythmia.