Abstract Fri097: Pharmacological enhancement of SK channels increases repolarization reserve in congenital and acquired long QT type 2 syndrome

Introduction: Long QT syndrome type 2 (LQT2), induced by either genetic variations or drugs blocking the hERG channel, is associated with polymorphic ventricular tachycardia (pVT) and sudden cardiac death. Small conductance Ca 2+ -activated K + (SK) channels are directly gated by Ca 2+ and provide feedback from Ca 2+ to membrane voltage to accelerate cardiac repolarization, which may help mitigate LQT2. Goal: To show that pharmacological enhancement of SK channels normalizes prolonged action potential duration (APD) in LQT2. Methods: We used optical mapping of ex vivo hearts from a transgenic rabbit model of LQT2 and human induced pluripotent stem cell-derived ventricular cardiomyocyte (hiPSC-CM) microtissues as well as Ca 2+ imaging and patch clamp of isolated hiPSC-CMs. A six state I SK gating model combined with intrinsic rectification and divalent ion block was incorporated into the Mahajan rabbit AP model to investigate potential mechanisms of APD normalization. Results: We found that enhancing I SK with NS309 in LQT2 rabbit hearts consistently shortened ventricular APD (224 ± 8 ms vs. 176 ± 3 ms, p=0.007). By computational simulation, we found increasing levels of SK channel conductance (g SK ) shortened APD and reduced APD dispersion. Computer modeling indicates that increased Ca 2+ duration by prolonged APD augments I SK and lowers plateau V m to mask I Ks heterogeneity. Application of NS309, significantly shortened hiPSC-CM microtissue APD in an apamin-dependent manner (Figure 1) confirming that there were functional SK channels in our line of hiPSCs. The cardiotoxic drug, Cisapride (1 μM), increased hiPSC-CM microtissue APD by a mean of 62 ± 13% which was significantly reduced to 24 ± 7% above baseline APD (p=0.04) by adding 2 μM NS309. Conclusion: The Ca 2+ dependent gating of I SK allows it to directly feedback on the APD especially under reduced repolarization reserve and could be a potential therapeutic target for LQT2 patients.