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From the Cardiology Unit, Department of Medicine (E.H.L., W.Z., A.J.M.,
J.L.R., M.A.), and the Department of Biostatistics (W.J.H.), University of
Rochester, NY; the Institute of Clinica Medica Generale e Terapia Medica,
IRCCS, University of Milan, Italy (E.H.L., P.J.S., S.G.P., C.N.); the
Department of Cardiology, University of Pavia, and Policlinico San Matteo,
IRCCS, Pavia, Italy (P.J.S., S.G.P., C.N.); the Department of Medicine, LDS
Hospital, University of Utah, Salt Lake City (G.M.V., K.T.); the Arrhythmia
Center, Sinai Hospital, Detroit, Mich (M.H.L.); and the Department of
Pediatric Cardiology, Phoebe Willingham Muzzy Pediatric Molecular Cardiology
Laboratory, Baylor College of Medicine, Texas Children's Hospital,
Houston (J.A.T.).
Correspondence to Dr Emanuela H. Locati, Sezione di Cardiologia, Dipartimento di Medicina Clinica, Patologia e Farmacologia, Università degli Studi di Perugia, Via Eugubina, 42, 06122 Perugia, Italy. E-mail heilbron{at}edisons.it
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 (QTc >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 QTc
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.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Age- and Sex-Related Differences in Clinical Manifestations in Patients With Congenital Long-QT Syndrome
Findings From the International LQTS Registry
Key Words: long-QT syndrome • genes • sex • syncope • death, sudden
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