The present study is the first to explore possible ion channel mechanisms that may predispose to arrhythmic risk in LQTS patients who do not exhibit the phenotypic QTc prolongation of the disease. We have shown that the S349W mutation exerts a relatively mild effect on the ion channel current, which is within the haploinsufficient range, explaining the lack of a significant prolongation of the corrected QT interval among all S349W mutation carriers. Despite this, however, the S349W mutation was associated with a high rate of cardiac events and SCD during the childhood and adolescence periods. Therefore, it is possible that the pronounced effect of the mutation on the voltage and time dependence of activation may explain the predisposition for arrhythmic events among S349W mutation carriers. These findings stress the importance of mutation-specific functional data for risk assessment in phenotype-negative LQTS.
The clinical course of patients with the congenital long QT syndrome was shown to be variable due to incomplete penetrance. It is influenced by age, genotype, gender, environmental factors, therapy, and possibly other modifier genes.1-6
Recent studies from the International LQTS Registry have assessed the risk for life-threatening events in LQTS patients,3-5
and these studies have consistently demonstrated that ECG and clinical risk factors, including the QTc and age-gender interactions, identify increased risk in the LQTS population. During childhood, affected males and patients with a prolonged QTc were shown to exhibit a higher risk for life threatening events,3
whereas after the onset of adolescence females and patients with a prolonged QTc were shown to exhibit a higher risk.4,5
These studies, however, included mainly phenotype-positive LQTS patients with a QTc ≥450 msec. Thus, it is possible that clinical and ECG factors have more limited applicability for risk assessment among phenotype-negative LQTS patients. Our findings extend prior data, and suggest that genetic information related to the functional effects of the LQTS mutations can be used to identify predisposition to arrhythmic risk in mutations that are associated with a relatively mild effect on the ion channel current and QTc duration.
A recent genotype-phenotype study from the International LQTS Registry has provided important information regarding the effect of the biophysical function of the channel mutations on the phenotypic manifestations and clinical course of LQTS patients.6
The study demonstrated that the biophysical function of KCNQ1 mutations, categorized according to dominant-negative (>50%) or haploinsufficiency (≤50%) reduction in cardiac repolarizing IKs potassium channel current, is an important determinant of outcome. Patients with dominant-negative ion channel dysfunction had more than a 2-fold increase in the risk of cardiac events compared with those who harbored mutations with haploinsufficiency effect.6
The present study consistently shows that the rate of cardiac events among carriers of haploinsufficent- KCNQ1 mutations is relatively low. However, in contrast to the previous report, we have demonstrated that the S349W
mutation, which exerts an effect comparable to haploisufficient currents on the IKs channel and on QTc duration, is associated with a high rate of cardiac events. Furthermore, carriers of the S349W
mutation were shown to experience SCD despite a normal ECG on baseline risk assessment. These findings suggest that additional ion channel mechanisms may predispose to ventricular tachyarrhythmias in high risk mutations that are associated with mild effects on the ion channel current and QTc duration. The S349W
mutation was shown to exert a pronounced effect on the channel activation, including the time constant and the voltage dependence of activation. In contrast, haploinsufficent channels did not affect either parameter of activation. Consistent with these findings, the cumulative probability of cardiac events during childhood and the adolescence period was significantly higher (58%) among carriers of the S349W
mutation as compared with QTc-matched KCNQ1 patients with haploinsufficient missense- and nonsense-mutations (21% and 25%, respectively).
Normal cardiac repolarization depends critically on the interplay of multiple ion mechanisms, and these provide some redundancy, or ‘reserve’, to protect against excessive QT prolongation by drugs. Accordingly, a genetic predisposition for reduced repolarization reserve has been suggested to play a role in patients with acquired long-QT syndrome with normal rest QTc durations who experience marked QT prolongation and torsades de pointes following exposure QT-prolonging drugs.16
Similarly, it is possible that patients with phenotype-negative congenital LQTS who harbor ion channel mutations that have a mild effect on current, but also affect channel activation, may be sensitive to drug-induced QT-prolongation despite the fact that the mutation has a relatively mild on ion channel current and QTc duration.
Our findings suggest that changes in the kinetics of activation of the IKs channel may predispose to arrhythmic risk in patients who harbor KCNQ1 mutations that are associated with a relatively mild effect on ion channel current and QTc duration. However, it is possible that additional mechanisms (including environmental, hormonal, the effect of modifier genes, and time-dependent changes in the phenotypic expression of LQTS) that were not explored in the present study may predispose to arrhythmic risk in phenotype-negative LQTS.
Changes in wild type and mutant subunit assembly may contribute to the functional changes caused by mutations, and the stoichiometry of functional channels may depend on the nature of the mutant subunit expressed. Channels formed by different combinations of wild type and mutant subunits co-exist, and contribute to the total macroscopic current. In this study we did not assess the contribution of each channel type to the total current. We assumed that channel assembly and wild-type and mutant subunit stoichiometry in the expression system reflected assembly of the channel in the native environment.
Study patients were not distributed in equivalent proportions among the different mutations (). Therefore, it is possible the association between mutation and risk may be biased by the inclusion of a higher frequency of symptomatic patients or their family members in the registry. To reduce a possible selection bias, we matched mutation categories by QTc duration. Thus, as seen in , no statistically significant differences in baseline characteristics (including the frequency of probands and a family history of SCD) were observed among the 3 categories of patients with the S349W mutation, missense mutations, and nonsense mutations, whereas the rate of cardiac events was significantly higher among patients with the S349W mutation.
Conclusions and clinical implications
In recent years there has been a substantial rise in the use of genetic testing for the identification of heritable cardiac arrhythmic disorders. This trend has resulted in a corresponding increase in the diagnosis of mutation-positive asymptomatic young individuals who undergo genetic testing due to a diagnosis of a genetic disorder in a symptomatic family member. Despite this progress, however, a significant barrier remains in the identification of silent carriers of mutations that predispose to ventricular tachyarrhythmias. Our study suggests that genetic data relating to the cellular expression of the ion channel mutation may explain predisposition to arrhythmic risk in LQTS patients who do not exhibit the phenotypic QTc prolongation of the disease. Carriers of the S349W mutation, which was shown to exert a relatively mild effect on the ion channel current but a pronounced effect on channel activation, experienced SCD at an early age despite having a normal ECG during baseline examination. These findings suggest that genetic functional data should be employed for risk assessment in LQTS patients who exhibit a normal-range QTc.