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Clinical Aspects of Type 3 Long-QT Syndrome: An International Multicenter Study
Arthur A M Wilde1, Arthur J Moss2, Elizabeth S Kaufman2
1From AMC Heart Centre, Department of Clinical and Experimental Cardiology (A.A.M.W., C.R.B.) and Department of Clinical Genetics (N.H., M.A.), Academic Medical Center, Amsterdam, The Netherlands; Cardiology Division of the Department of Medicine (A.J.M., C.L., W.Z., I.G., J.L.R., M.L.A., S.M., B.P.), the Department of Biostatistics (D.R.P.), and the Department of Pathology (M.Q.), University of Rochester School of Medicine and Dentistry, Rochester, NY; Heart and Vascular Research Center, MetroHealth Campus of Case Western Reserve University, Cleveland, OH (E.S.K.); Department of Cardiovascular Medicine, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan (W.S.); Department of Cardiology Bikur Cholim Hospital, Jerusalem, Israel (J.B.); Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH (J.A.T.); IRCCS Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milan, Italy (C.P. L.C., P.J.S.); Department of Cardiology, Gentofte University Hospital, Copenhagen, Denmark (J.K.K.); Departments of Medicine, Pediatrics, and Molecular Pharmacology & Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, MN (D.J.T., M.J.A.); Division of Arrhythmia and Electrophysiology, Department of Cardiovascular Medicine (W.S.) and Department of Preventive Cardiology (Y.M.), National Cerebral and Cardiovascular Center, Suita, Japan; Department of Molecular Medicine, University of Pavia, Italy (L.C.); Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, Jeddah, Kingdom of Saudi Arabia (A.A.M.W.); and Department of Cardiovascular, Neural and Metabolic Sciences, San Luca Hospital IRCCS Istituto Auxologico Italiano, Milan, Italy (L.C., P.J.S.). a.a.wilde@amc.nl.
Insights
Risk stratification for Long QT Syndrome type 3 (LQT3) identified prolonged QTc and syncope as key risks. Beta-blocker therapy significantly reduced cardiac events in females with LQT3.
Area of Science:
- Cardiology
- Genetics
- Pharmacology
Background:
- Risk stratification for Long QT Syndrome type 3 (LQT3) in a large population is lacking.
- Previous studies have not evaluated clinical, genetic, and treatment factors in LQT3 patients.
Purpose of the Study:
- To investigate risk factors for cardiac events in LQT3 patients.
- To assess the effectiveness of beta-blocker therapy in LQT3 patients.
Main Methods:
- Analysis of clinical, electrocardiographic, and genetic data from 406 LQT3 patients.
- Cox regression analysis to identify predictors of cardiac events (CEs).
- Evaluation of time-dependent beta-blocker therapy in LQT3 patients.
Main Results:
- 30% of 391 LQT3 patients experienced at least one CE.
- Increased QTc duration and prior syncope were associated with higher CE risk.
- Beta-blocker therapy reduced CEs by 83% in females (P=0.015) but not conclusively in males.
Conclusions:
- Prolonged QTc and syncope are significant risk factors for life-threatening CEs in LQT3.
- Beta-blocker therapy is effective in reducing CEs in female LQT3 patients.
- Further research is needed to determine beta-blocker efficacy in male LQT3 patients due to limited events.
Background:
Risk stratification in patients with type 3 long-QT syndrome (LQT3) by clinical and genetic characteristics and effectiveness of β-blocker therapy has not been studied previously in a large LQT3 population.
Methods:
The study population included 406 LQT3 patients with 51 sodium channel mutations; 391 patients were known to be event free during the first year of life and were the focus of our study. Clinical, electrocardiographic, and genetic parameters were acquired for patients from 7 participating LQT3 registries. Cox regression analysis was used to evaluate the independent contribution of clinical, genetic, and therapeutic factors to the first occurrence of time-dependent cardiac events (CEs) from age 1 to 41 years.
Results:
Of the 391 patients, 118 (41 males, 77 females) patients (30%) experienced at least 1 CE (syncope, aborted cardiac arrest, or long-QT syndrome-related sudden death), and 24 (20%) suffered from LQT3-related aborted cardiac arrest/sudden death. The risk of a first CE was directly related to the degree of QTc prolongation. Cox regression analysis revealed that time-dependent β-blocker therapy was associated with an 83% reduction in CEs in females (P=0.015) but not in males (who had many fewer events), with a significant sex × β-blocker interaction (P=0.04). Each 10-ms increase in QTc duration up to 500 ms was associated with a 19% increase in CEs. Prior syncope doubled the risk for life-threatening events (P<0.02).
Conclusions:
Prolonged QTc and syncope predispose patients with LQT3 to life-threatening CEs. However, β-blocker therapy reduces this risk in females; efficacy in males could not be determined conclusively because of the low number of events.
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