Abstract 2559: Slow Rate of Ion Channel Activation Identifies High Cardiac Risk for Type 1 Long QT Syndrome Patients With Moderate QTc Prolongation
Background: The current risk stratification for Long QT syndrome (LQTS) includes parameters such as age, gender and QT interval, but mutation-specific information is rarely used.
Objective: We investigated whether changes in ion channel characteristics (channel current, current activation rate, current deactivation rate, voltage dependence of activation and maximal conductance) caused by missense mutations linked to LQTS type 1 (LQT1) correlate with increased risk of cardiac events for carriers of the mutations.
Methods: 387 LQT1 patients carrying 17 different mutations from 4 LQTS registries were included. The electrophysiological parameters were obtained from expression of mutant ion channels in Xenopus laevis oocytes. Linear regression was used to test for correlation between ion channel characteristics and clinical phenotype and Cox proportional hazard regression was used to identify independent risk factors for cardiac events.
Results: Slower rate of current activation significantly increased the risk of cardiac events (Hazard ratio: 2.02) independent of clinical measures (gender, QTc and β-blocker treatment), whereas other ion channel characteristics did not affect the risk of cardiac events. In patients with QTc <500 ms, QTc did not predict cardiac risk (Fig 1A⇓). Nonetheless, slow activation kinetics was still an independent predictor for cardiac events in these patients (Hazard ratio: 2.10) (Fig 1B⇓).
Conclusion: Slower channel activation identifies high-risk LQT1 patients. Functional analysis of the mutant ion channel activation may become a novel tool for the cardiac risk stratification in LQTS, especially in patients with modest QTc prolongation.