COMPUTATIONAL ANALYSIS OF THE NOVEL LQT3 MUTATIONS G1481V AND Q1491H IN MYOCARDIAL AND PURKINJE CELLS

Long QT Syndrome type 3 (LQT3) arises from mutations in SCNA5 gene encoding the Nav1.5 sodium channel. We studied two novel mutations (G1481V and Q1491H) found in infants who suffered sudden cardiac death. Using computational modeling, we incorporated experimental data into a Na⁺ Markovian model and simulated effects in rabbit cardiac cells. Both mutations caused tissue-specific effects, with Purkinje cells showing more severe action potential prolongation than myocardial cells. At slow heart rates, these mutations triggered early afterdepolarizations (EADs) and delayed afterdepolarizations (DADs) exclusively in Purkinje cells, with Q1491H displaying greater arrhythmogenic potential which was absent in myocardial cells. Enhanced late sodium current underlies these effects, especially in Purkinje cells with fewer repolarization reserves. Our findings suggest targeted therapies: late Na⁺ current blockers or Purkinje fiber ablation for patients with these mutations.