Paper
Background —Unexplained female predominance is observed in long-QT syndrome (LQTS), a congenital autosomal disorder with prolonged repolarization and syncope or sudden death due to ventricular tachyarrhythmias. Our objectives were to evaluate age- and sex-related differences in events among LQTS patients referred to the LQTS International Registry. Methods and Results —Age- and sex-related occurrence of events was analyzed in 479 probands (70% females) and 1041 affected family members (QT c >440 ms, 58% females). LQTS-gene mutations were identified in 162 patients: 69 LQT1 carriers ( KVLQT1 on 11p15.5), 62 LQT2 carriers ( HERG on 7q35-36), and 31 LQT3 carriers ( SCN5A on 3p21-24). Females predominated among 366 probands (71% females) and 230 symptomatic family members (62% females). Male probands were younger than females at first event (8±7 versus 14±10 years, P <0.0001) and had higher event rates by age 15 years than females (74% versus 51%, P <0.0001). Affected family members had similar findings. By Cox analysis adjusting for QT c duration, the hazard ratio for female probands of experiencing events by age 15 years was 0.48 ( P <0.001), and it was 1.87 ( P =0.09) by age 15 to 40 years. In female family members, the hazard ratio was 0.58 ( P <0.001) by age 15 years, and it was 3.25 ( P <0.001) by age 15 to 40 years. The event rate was higher in male than female LQT1 carriers (69% versus 32%, P =0.001). No age-sex difference in event rate was detected in LQT2 and LQT3 carriers. Conclusions —Among LQTS patients, the risk of cardiac events was higher in males until puberty and higher in females during adulthood. The same pattern was evident among LQT1 gene carriers. Unknown sex factors modulate QT duration and arrhythmic events, with preliminary evidence of gene-specific differences in age-sex modulation.