(W1269) DIFFERENTIAL RESPONSE OF INDUCED PLURIPOTENT STEM CELL-DERIVED CARDIOMYOCYTES TO CHRONIC BETA-ADRENERGIC STIMULATION AND ELECTRICAL PACING IN A MODEL OF EXERCISE-INDUCED LONG QT SYNDROME

Abstract: Intense physical activity, while beneficial for cardiovascular health, has been linked to adverse cardiac outcomes in certain predisposed individuals. Exercise-induced long QT syndrome (exiLQTS) is a life-threatening condition identified by our group, characterized by QT interval prolongation and repolarization abnormalities on the ECG that resolve upon cessation of physical activity. To investigate the mechanisms underlying exiLQTS, we generated six human induced pluripotent stem cell-derived (hiPSC) lines from competitive athletes diagnosed with exiLQTS (cases) and healthy controls. Using perforated patch-clamp techniques, multielectrode arrays (MEA), and optical action potential measurements, we performed detailed electrophysiological characterizations of hiPSCs differentiated towards cardiomyocytes (hiPSC-CMs). To mimic beta-adrenergic stimulation taking place during physical activity, hiPSC-CMs were subjected to chronic treatment with a cell-permeable cAMP analog, dibutyryl cAMP (dbcAMP). Additionally, to simulate the sustained elevated heart rate during training, hiPSC-CMs underwent chronic 2 Hz electrical stimulation for 7 days. At baseline, field potential duration (FPD), single-cell action potential (AP) parameters, and AP rate-dependency were similar between groups, except for the spontaneous beat-to-beat interval, significantly longer in hiPSC-CMs derived from exiLQTS cases (2.4 ± 1.04 s) compared to controls (1.83 ± 0.99 s). Following chronic dbcAMP treatment, hiPSC-CMs from exiLQTS cases exhibited significantly prolonged corrected FPD compared to controls (323 ± 60 ms vs 259 ± 85 ms, p ≤ 0.001 at day 9). Chronic electrical tachypacing resulted in reduced AP duration (APD) in both groups; however, hiPSC-CMs from exiLQTS cases displayed longer APD values under these conditions (459 ± 147 ms vs 378 ± 125 ms, p = 0.017). Together, these findings support the feasibility of modeling exiLQTS using hiPSC-CMs and suggest the presence of molecular differences between the two groups. Additional pacing protocols and transcriptomic analyses will further enhance our understanding of this condition.

Funding Source: EU Horizon Europe (PREPARE, No. 101105561 to AK), PRIN 2022 PNRR H53D23007640001 to LC, Leducq Foundation grant 18CVD05 to PJS, Next Generation EU project No. H45E22001210006 to LS, EU Horizon 2020 (ERA-CVD - EMPATHY No. 298736 to LC).

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