Abstract 11828: Follow-up of Genetically Confirmed Adult Long QT Syndrome Type 1 and 2 Patients: Clinical Course and Tools for Mutation-specific Risk Stratification

Abstract

Introduction: Long QT syndrome (LQTS) is an inherited cardiac disorder predisposing to sudden cardiac death (SCD). Research has been scarce on its clinical course in genetically confirmed patients not receiving β-blocker therapy. Also, applicability of specific mutations as a part of risk stratification calls for further investigation. Methods: The study population was drawn from the Finnish Inherited Cardiac Disorder Research Registry comprising 4000 molecularly tested subjects. The inclusion criteria were 1) genetically confirmed KCNQ1 or KCNH2 mutation, or non-carrier status of the family-specific LQTS mutation, and 2) the age of 18-40 years during the follow-up. A questionnaire was sent to the study subjects. Data of all deaths were obtained from Statistics Finland, and data of ICD and pacemaker implantations were acquired from Hospital discharge register (HDR). Results: A total of 2723 subjects fulfilled the inclusion criteria. Of them 14 died during the follow-up, 1495 (55%) responded to the inquiry, and additional 12 subjects with device therapy were drawn from the HDR. The final study population (n=1521) consisted of 867 LQTS mutation carriers (617 with KCNQ1 , 242 with KCNH2 , and seven with ≥1 mutation), and 654 non-carrier relatives. The total follow-up time including retrospectively collected data was 18.3±6.3 years. In mutation carriers, risk factors for cardiac events before initiation of β-blocker included LQT2 genotype (hazard ratio [HR]=2.1, p=0.002), female gender (HR=3.2, p<0.001), a cardiac event before the age of 18 years (HR=5.9, p<0.001), and QTc ≥500 ms (vs <470 ms, HR=2.7, p=0.01). LQT1 patients carrying the KCNQ1 D317N mutation were at higher risk (HR=3.0-3.9, p<0.001-0.03) compared to G589D, c.1129-2A>G and other KCNQ1 mutation carriers after adjusting for gender and QTc duration. KCNH2 c.453delC, L552S and R176W mutations associated with lower risk (HR=0.12-0.24, p<0.001) than other KCNH2 mutations. Of the seven SCDs four, and of the 14 aborted cardiac arrests three involved QT-prolonging drug. Conclusions: Specific mutations modulate the risk independently of gender and QTc duration. The avoidance of QT-prolonging drugs is fundamental in the prevention of potentially life-threatening cardiac events.