Genotype-specific QT correction for heart rate and the risk of life-threatening cardiac events in adolescents with congenital long-QT syndrome

BACKGROUND A prolonged QT interval corrected for heart rate (QTc) is a major risk factor in patients with long QT syndrome (LQTS). However, heart rate-related risk in this genetic disorder differs among genotypes. OBJECTIVE This study hypothesized that risk assessment in LQTS patients should incorporate genotype-specific QT correction for heart rate. METHODS The independent contribution of 4 repolarization measures (the absolute QT interval, and Bazett's, Fridericia's, and Framingham's correction formulas) to the risk of aborted cardiac arrest or sudden cardiac death during adolescence, before and after further adjustment for the RR interval, was assessed in 727 LQTS type 1 and 582 LQTS type 2 patients. Improved QT/RR correction was calculated using a Cox model, dividing the coefficient on log(RR) by that on log(QT). RESULTS Multivariate analysis demonstrated that in LQTS type 1 patients 100-ms increments in the absolute QT interval were associated with a 3.3-fold increase in the risk of life-threatening cardiac events (P = .020), and 100-ms decrements in the RR interval were associated with a further 1.9-fold increase in the risk (P = .007), whereas in LQTS type 2 patients, resting heart rate was not a significant risk factor (hazard ratio 1.11; P = .51; P value for heart rate X genotype interaction = .036). Accordingly, analysis of an improved QT correction formula showed that patients with the LQTS type 1 genotype required a greater degree of QT correction for heart rate (improved QTc = QT/RR0.8) than LQTS type 2 patients (improved QTc = QT/RR0.2). CONCLUSION Our findings suggest that risk stratification for life-threatening cardiac events in LQTS patients can be improved by incorporating genotype-specific QT correction for heart rate.