Computational modeling supports induced pluripotent stem cell-derived cardiomyocytes reliability as a model for human LQT3

Long QT 3 (LQT3) is a specific LQT syndrome, induced by defects in the SCN5A gene, encoding for the Na⁺ channels. Its effect is a Na⁺ current (I_Na) gain-of-function, resulting in a sustained late current and in an action potential (AP) duration (APD) prolongation. In this paper we aim to develop a control and a LQT3 patient in silico action potential model of human induced pluripotent stem cell-derived cardiomyocytes (hiPSCCMs), based on experimental electrophysiological data. We aim to study how in vitro and in silico hiPSC-CMs can model this syndrome. We also provide a comparison with one state-of-the-art model of adult cardiac cell. The control model showed (simulations vs experiments) (i) AP amplitude: 94.0 vs 86.0+/-1.4 mV, (ii) maximum diastolic potential: -64.0 vs -61.4+/-1.4 mV, (iii) APD90: 458.3 vs 434.0+/-31.1 ms and (iv) rate of spontaneous beating: 67.6 vs 69.1+/-11.3 bpm. In simulations, the LQT3 INa induced the experimentally observed APD prolongation (APD90 +32.3%) and rate slowdown (-33.0%). By simulating the administration of 50 j.tM of mexiletine in the patient model, the effect of the mutation was partially compensated, resulting in an APD₉₀ shortening (-16.0%), in agreement with the experiments (-20%). Finally, by simulating a 5-fold I_Na late increment in the O´Hara-Rudy adult model we got APD prolongations similar to those reproduced by our LQT3 model, APD₃₀ (+30.9%), APD⁵⁰ (+ 33.6%), APD⁷⁰ (+ 34.1%) and APD₉₀ (+ 30.2%). Our results show that hiPSC-CMs and computational models derived from their electrophysiological traces represent in vitro and in silico models comparable to adult cardiomyocytes for LQT3, suitable for personalized studies on this pathology.