Mutation location effect on severity of phenotype during exercise testing in type 1 long-QT syndrome: impact of transmembrane and C-loop location

J Cardiovasc Electrophysiol. 2013 Sep;24(9):1015-20. doi: 10.1111/jce.12172. Epub 2013 May 20.

Abstract

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.

Keywords: LQT1; diagnosis; exercise; genetics; genotype; long-QT syndrome; phenotype.

Publication types

  • Multicenter Study

MeSH terms

  • Adolescent
  • Adult
  • Cell Membrane / genetics
  • Cohort Studies
  • Exercise Test / methods*
  • Female
  • Humans
  • KCNQ1 Potassium Channel / genetics*
  • Male
  • Middle Aged
  • Mutation, Missense / genetics*
  • Phenotype*
  • Retrospective Studies
  • Romano-Ward Syndrome / diagnosis*
  • Romano-Ward Syndrome / genetics*
  • Romano-Ward Syndrome / physiopathology
  • Young Adult

Substances

  • KCNQ1 Potassium Channel
  • KCNQ1 protein, human