Abstract 16820: Impaired KCNQ1/KCNE1 Channel Activation by Alpha-Adrenergic Receptor is Associated with Emotion/Arousal Triggered Events in Long QT Syndrome Type 1

Abstract

Background: Stimulation of the cardiac K + channel IKs (KCNQ1/KCNE1) is crucial in mediating the QT shortening at high adrenergic stimulation states, with mutations in the KCNQ1 subunit being linked to a high risk of cardiac events triggered by adrenergic stimulation. IKs is strongly regulated by β-adrenergic receptor (AR) stimulation, but little is known about the role of α 1 -AR-mediated regulation and relation to the LQT1 phenotype. Methods: We co-expressed wild-type and mutant KCNQ1/KCNE1 subunits together in HEK293T cells. A single cardiomyocyte model adapted from the Flaim-Giles-McCulloch model was used to simulate the effect of α 1 -AR and β-AR activation in action potential duration (APD). Mutation specific adrenergic-effects on APD were correlated to the cumulative rate for exercise and stress-triggered cardiac events (syncope, sudden death and aborted cardiac arrest) by age 40 for patients carrying the mutation. Results: Acute α 1 -AR activation strongly facilitated voltage dependence of IKs activation independently of β-AR stimulation (V 1/2 shift @ - 20 mV) via activation of cPKC. We measured the effect of β-AR-PKA and α 1 -AR-cPKC activation for 8 LQT1 associated mutations. For each mutant we introduced the current activation measured in a single cardiomyocyte model to simulate the overall effect of (α 1 + β1) AR stimulation. Mutant specific α 1 - and β- AR-mediated APD showed stronger correlation to the cumulative rate of emotion/arousal triggered cardiac events than β-AR alone (α+β: R 2 =0.94, β: R 2 =0.58), while β-AR activation alone showed a better correlation with exercised triggered event rate (α+β: R 2 =0.34, β: R 2 =0.74) for patients carrying these mutations. Conclusion: Our study suggests that acute α 1 -AR regulation of the voltage activation of IKs may be important for QT shortening in response to strong adrenergic stimulation in the flight and fight response. In addition, impaired α 1 -AR regulation may be linked to increased risk of sudden emotion/arousal triggered cardiac events in LQT1patients.