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

Mutations that slow the opening of potassium channels in the heart can predict risk for long QT syndrome, a heart arrhythmia that can cause sudden death. Keeping the Heart in Tune The decades-long, 24/7 beating of the human heart is sustained by a symphony of ion channels rhythmically opening and closing on cue. Hearts of those born with mutations in these channels can occasionally hit a bad note, which can cause heart palpitations or—sometimes—sudden death. This so-called long QT syndrome can be diagnosed from an electrocardiogram (ECG) and other clinical parameters, but the distance between the Q and the T waves of the ECG predicts disease well only when the gap is very long—more than 500 ms. Now, Jons et al. have found an electrical characteristic of the IKs channel—the mutation-specific rate at which it opens—that allows the accurate diagnosis of individuals with a QT interval less than 500 ms. Seventeen different mutations in the IKs channel were identified in a group of 387 patients with long QT syndrome. To scrutinize the details of these mutation-carrying channels, the authors expressed the mutated subunits in frog oocytes and then analyzed their function with electrophysiological electrodes and stimulation. The mutated channels carried about 30% less current and tended to activate (open) more slowly than the wild-type ones, but in contrast, the aberrant channels deactivated (closed) at the same rate as their normal counterparts. By using multivariate regression, the authors showed that the diminished amount of current contributed directly to the longer QT interval seen in these patients (and so did not add to the information provided by an ECG), but the slow activation was an independent parameter relative to the QT gap. Further, when the authors analyzed the clinical history of the patients carrying these mutations, they found that the extent of the slowing of channel activation correlated positively with episodes of cardiac dysfunction—syncope (loss of consciousness), cardiac arrest requiring defibrillation, and sudden death—before age 30. But would the slowing of activation of IKs channels really disturb the beating heart enough to cause these cardiac problems? The authors used a computer model to find out. This analysis revealed that beating heart cells that carry the slowly activating mutant channels exhibit prolonged action potentials, which would compromise the cell’s ability to recover from any early beats experienced by the heart. This impairment could trigger arrhythmias such as those seen in the patients. These results could ensure better care for some patients with long QT syndrome, particularly those with only modest increases in their QT intervals. Right now, such patients sometimes remain untreated. Screening patients for channel mutations that cause slower activation could help to identify those at greatest risk, allowing proper intervention to prevent the electrical dissonance that can lead to lethal cardiac arrhythmias. Inherited long QT syndrome (LQTS) 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 individuals with LQTS is estimated from clinical parameters such as age, gender, and the QT interval, measured from the electrocardiogram. Even though a number of different mutations can cause LQTS, mutation-specific information is rarely used clinically. LQTS type 1 (LQT1), one of the most common forms of LQTS, is caused by mutations in the slow potassium current (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 387 LQT1 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 (hazard ratio = 2.02), independent of the clinical parameters usually used for risk stratification. In patients with moderate QT prolongation (a QT interval less than 500 ms), slower activation was an independent predictor for cardiac events (syncope, aborted cardiac arrest, and sudden death) (hazard ratio = 2.10), whereas the length of the QT interval itself 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.