Abstract Body: 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 Ca²⁺-activated K⁺ (SK) channels are directly gated by Ca²⁺ and provide feedback from Ca²⁺ 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 Ca²⁺ 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 Ca²⁺ 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 Ca²⁺ 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.