Abstract 13466: Mutations in Cytoplasmic Loops are Associated with Increased Risk for Cardiac Events in Type-1 Long QT Syndrome
Background: Exercise and consequent β-adrenergic stimulation are the main triggers for cardiac events in type-1 Long QT syndrome (LQT1). Accordingly, β-blockers is the treatment of choice in LQT1, but its effectiveness is not uniform in this population. To identify patients who derive enhanced benefit from therapy, we evaluated a possible association between ion channel response to β-adrenergic stimulation and clinical response to β-blocker therapy.
Methods and Results: 860 LQT1 genotyped subjects with 100 different mutations from multinational LQTS registries were studied. Patients were categorized into carriers of missense mutations located in the C/N-terminus, membrane spanning (MS) and cytoplasmic loops (C-loops) domains, and non-missense mutations. After multivariate adjustment for clinical factors, the presence of C-loops mutations was associated with the highest risk for aborted cardiac arrest (ACA) or sudden cardiac death (SCD) (Figure; adjusted HR=3.27 compared with non-missense [p<0.001]). β-blocker therapy was associated with a significantly greater benefit among C-loops mutation patients (HR=0.12, p=0.02) than among all other patients (HR=0.82, p=0.68; p for interaction=0.045). Cellular expression studies showed that MS and C-loops mutations produced a similar decrease in current, but only C-loops mutations dramatically reduced channel activation in response to β-adrenergic stimulus.
Conclusions: Carriers of missense mutations located in the KCNQ1 C-loops exhibit the highest risk for fatal/near-fatal events in the LQT1 population independently of clinical risk factors, and show the greatest reduction in the risk of ACA or SCD with β-blocker therapy. Increased mutation burden during exercise caused by reduced channel activation can explain the increased clinical risk associated with C-loops mutations.
- © 2010 by American Heart Association, Inc.