Genetic mutations and arrhythmia: simulation from DNA to electrocardiogram

In the past two decades, mutations in cardiac ion channels have been shown to underlie a number of rare inherited cardiac arrhythmias. Defects in cardiac Na(+) channels can disrupt channel gating and cause electrical abnormalities that increase susceptibility to cardiac arrhythmia. Dozens of mutations have been identified in the gene SCN5A, which encodes the alpha subunit of the cardiac Na(+) channel, and have been causally linked to a wide spectrum of cardiac arrhythmic disorders. An important step in understanding genetically based arrhythmias is to clarify the relationship between molecular defects and the disruption of the delicate balance of dynamic interactions at the cell, tissue, and organ levels. Here, we provide an overview of cardiac Na(+) channel mutations that are associated with inherited arrhythmia syndromes. We also address pros and cons of current methodologies used to understand how specific genetic defects disrupt channel-gating kinetics and underlie cardiac arrhythmia. Finally, we discuss effects of mutations on predictability and efficacy of treatment with Na(+) channel-blocking drugs.