Use of Mutant-Specific Ion Channel Characteristics for Risk Stratification of Long QT Syndrome Patients

Inherited Long QT syndrome (LQT) is caused by mutations in ion channels that delay cardiac repolarization, increasing the risk of sudden death from ventricular arrhythmias. Currently, the risk of sudden death in subjects with LQT is estimated from clinical parameters such as age, gender and the QT interval (QTc ≥ 500 ms). Even though a number of mutations can cause LQT, mutation-specific information is rarely used. LQT type 1 is one of the most common forms of LQT and is caused by mutations in the IKs channel α-subunit, KCNQ1. We investigated whether mutation-specific changes in IKs function can predict cardiac risk in LQT1. By correlating the clinical phenotype of 319 LQT type 1 patients with the cellular electrophysiological characteristics caused by an array of mutations in KCNQ1, we found that channels with a decreased rate of current activation are associated with increased risk of cardiac events (HR = 2.02), independent of the clinical parameters usually used for risk stratification. In patients with moderate QT prolongation (QTc < 500 ms), slower activation was an independent predictor for cardiac events (syncope, aborted cardiac arrest and sudden death) (HR = 2.10), whereas QT interval was not. Our results indicate that genotype and biophysical phenotype analysis may be useful for risk stratification of LQT1 patients and suggest that slow channel activation is associated with an increased risk of cardiac events.