The clinical course of patients with 2 relatively common long QT syndrome type 3 mutations has not been well described. In the present study, we investigated the mutational-specific risk in patients with deletional (ΔKPQ) and missense (D1790G) mutations involving the SCN5A gene. The study population involved 50 patients with the ΔKPQ mutation and 35 patients with the D1790G mutation. The cumulative probability of a first cardiac event (syncope, aborted cardiac arrest, or long QT syndrome-related sudden death) was evaluated using the Kaplan-Meier method. The Cox proportional hazards survivorship model was used to determine the independent contribution of clinical and genetic factors to the first occurrence of cardiac events from birth through 40 years of age. The Andersen-Gill proportional intensity regression model was used to analyze the factors associated with recurrent syncope. Patients with a ΔKPQ mutation had a significantly greater probability of a first cardiac event from birth through 40 years of age (34%) than those with the D1790G mutation (20%; p <0.001). Multivariate analysis demonstrated an increased risk of cardiac events among ΔKPQ carriers compared to D1790G carriers (hazard ratio 2.42, p <0.0001) after adjustment for gender and QTc duration. Patients with ΔKPQ mutations also had an increased risk of recurrent syncope (hazard ratio 5.20, p <0.001). In conclusion, the clinical course of patients with long QT syndrome type with ΔKPQ mutations was shown to be more virulent than those with D1790G mutations, and this effect was independent of QTc duration. The findings highlight the importance of knowing the specific mutation in risk stratification of patients with long QT syndrome type 3.
The congenital long QT syndrome (LQTS) is an inherited disorder affecting the cardiac ion channels, with prolonged ventricular repolarization contributing to syncope, tachyarrhythmias, and sudden death. The long QT syndrome type 3 (LQT3) genotype, which includes a spectrum of different mutations, accounts for only 7% to 10% of patients with LQTS. Also, most studies have been restricted to case reports or small numbers of patients with limited follow-up. Patients with LQT3 have an increased risk of lethal cardiac events compared to patients with the long QT syndrome type 1 or type 2 forms of this disorder ; however, the reports to date have been limited. Most of these events typically occur when the patients are resting or asleep, presumably at a slow heart rate. β-Blocker therapy, the mainstay treatment of patients with long QT syndrome type 1 or 2, offers limited protection for patients with LQT3. The lack of long-term, clinical follow-up data involving patients with LQT3 and the concern about the high risk of sudden cardiac death have led many clinicians to consider an implantable defibrillator, even in the absence of symptoms. Within the International LQTS Registry, we identified 2 LQT3 mutations, D1790G and ΔKPQ, that have had detailed electrophysiologic study. The D1790G mutation exhibits a prolonged cardiac ventricular action potential owing to calcium-sensitive exchange modulation. The ΔKPQ mutation causes transitions from the inactivated state back to the open state with abnormal late entry of sodium into the myocardial cells. Sodium-channel blockers such as mexiletine, flecainide, and ranolazine have been shown to shorten the QTc interval in patients with D1790G and ΔKPQ mutations; however, the clinical efficacy of these drugs remains unknown in patients with these 2 mutations. In the present study, we investigated the clinical course, electrocardiographic phenotype, and treatment efficacy in patients with these 2 distinct LQT3 mutations.
Methods
The study population of 85 patients was drawn from the International LQTS Registry. The 85 patients included 50 affected subjects from 3 unrelated families carrying the ΔKPQ mutation and 35 from 2 unrelated families from Israel carrying the D1790G mutation. The patients carrying the D1790G mutation were either from a large multigenerational kindred originating from Tunisia or a family from Israel. The SCN5A mutations were identified using standard genetic tests performed in academic molecular-genetic laboratories. The University of Rochester institutional review board approved the LQTS Registry study, and all study participants or their guardians provided informed consent. The first recorded electrocardiogram obtained at patient enrollment in the Registry was used in the present analysis.
Subjects were included if they had a genetically confirmed D1790G or ΔKPQ mutation or if they were obligate carriers of the mutation. Family members who were untested for the D1790G or ΔKPQ mutation were included in the study sample if they had a QTc of ≥480 ms. Lead II of the baseline electrocardiogram was used for the analysis of T-wave measurements, which included QT onset, QT peak, T-wave duration, and T-wave amplitude.
Statistical analysis was performed using Statistical Analysis Systems, version 9.1.3, for Windows (SAS Institute, Cary, North Carolina). The cumulative probability of a first cardiac event (syncope, aborted cardiac arrest, or LQTS-related death) was assessed using the Kaplan-Meier method, with significance testing using the log-rank statistic. The Cox proportional hazards survivorship model was used to evaluate the independent contribution of clinical and genetic factors to the first occurrence of cardiac events from birth through the age of 40 years. In the analyses of the factors and outcomes associated with recurrent syncope, the end point intensity function was adjusted for covariate effects using the Andersen Gill proportional intensity regression model. This method is analogous to the proportional hazards method but examines the risk of repeated events and not just a first event.
Results
The clinical characteristics of the patients with ΔKPQ and D1790G mutations are listed in Table 1 . Patients with ΔKPQ mutations were more likely to be treated with β blockers, implanted defibrillators, left cervicothoracic sympathetic ganglionectomy, and pacemakers than were patients with D1790G mutations. Patients with D1790G mutations were primarily treated with flecainide. This medication was discontinued in 3 patients after new onset of a Brugada-type pattern on the electrocardiogram. Only 2 patients with the ΔKPQ mutation were treated with mexiletine. Among the patients with the ΔKPQ mutation, 3 experienced atrial fibrillation before the age of 25 years. Of the patients with the ΔKPQ mutation, 6 developed varying degrees of atrioventricular block during follow-up, including 3 patients with first-degree block, 1 with second-degree block, and 2 with third-degree heart block. None of the patients with D1790G mutations experienced atrial fibrillation or heart block.
