Mutation Location Effect on Severity of Phenotype During Exercise Testing in Type 1 Long-QT Syndrome: Impact of Transmembrane and C-Loop Location

Mutation Location Effect on Severity Background Targeted mutation site‐specific differences have correlated C‐loop missense mutations with worse outcomes and increased benefit of beta‐blockers in LQT1. This observation has implicated the C‐loop region as being mechanistically important in the altered response to sympathetic stimulation known to put patients with LQT1 at risk of syncope and sudden cardiac death. Objective The objective of this study was to determine if there is mutation site‐specific response to sympathetic stimulation and beta‐blockers using exercise testing. Methods This study is a retrospective review of LQT1 patients undergoing exercise testing at 3 academic referral centers. Results A total of 123 patients (age 28 ± 17 years, 59 male) were studied including 34 patients (28%) with C‐loop mutations. There were no significant differences in supine, standing, peak exercise and 1‐minute recovery QTc duration between patients with C‐loop mutations and patients with alternate mutation sites. In 37 patients that underwent testing on and off beta‐blockers, beta‐blocker use was associated with a significant reduction in supine, standing and peak exercise QTc. This difference was not seen in the small group of patients (7/37) with C‐loop mutations. There was no difference in QTc at 1 and 4 minutes into recovery. Conclusions Genetically confirmed LQT1 patients in this study cohort with C‐loop mutations did not demonstrate the expected increase in QTc in response to exercise, or resultant response to beta‐blocker. The apparent increased risk of cardiac events associated with C‐loop mutation sites and the marked benefit received from beta‐blocker therapy are not reflected by exercise‐mediated effects on QTc in this study population.