Modeling of the long-QT syndrome type 1 and 2

Types 1 and 2 of the long-QT syndrome (LQTS₁ and LQTS₂) are caused by mutations in genes encoding the ion channels carrying the slow and rapid delayed rectifier potassium currents I_Ks and I_Kr, respectively. Electrocardiographic dispersion in repolarization varies between these subtypes of the long-QT syndrome. We studied transmural dispersion in repolarization in a computer model of LQTS₁ and LQTS₂. Transmural activation was simulated in a linear strand of 500 human ventricular cells (300 subendocardial, 150 M-cells, and 50 subepicardial cells) that were arranged transversally and coupled at low or high normal intercellular coupling conductance (2.5 and 7.0 μS, respectively). Missense mutations in LQTS₁ and LQTS₂ were simulated by setting I_Ks and I_Kr to 6.25% of the original value, respectively. To simulate truncating LQTS2 mutations, I_Kr was set to 50%. Repolarization moment was obtained by summation of the local activation time and the local action potential duration. Both at low and high normal intercellular coupling, the latest repolarization moments and the largest dispersion are found in the LQTS₂-missense simulation, whereas the earliest repolarization moments and the least dispersion are found in LQTS₁. This complies with our clinical data obtained from a group of 87 LQTS patients.