The long QT syndrome. Prospective longitudinal study of 328 families.

Abstract

BACKGROUND The Long QT Syndrome (LQTS) is an infrequently occurring familial disorder in which affected individuals have electrocardiographic QT interval prolongation and a propensity to ventricular tachyarrhythmic syncope and sudden death. We prospectively investigated the clinical characteristics and the long-term course of 3,343 individuals from 328 families in which one or more members were identified as affected with LQTS (QTc greater than 0.44 sec1/2). METHODS AND RESULTS The first member of a family to be identified with LQTS, the proband, was usually brought to medical attention because of a syncopal episode during childhood or teenage years. Probands (n = 328) were younger at first contact (age 21 +/- 15 years), more likely to be female (69%), and had a higher frequency of preenrollment syncope or cardiac arrest with resuscitation (80%), congenital deafness (7%), a resting heart rate less than 60 beats/min (31%), QTc greater than or equal to 0.50 sec1/2 (52%), and a history of ventricular tachyarrhythmia (47%) than other affected (n = 688) and unaffected (n = 1,004) family members. Arrhythmogenic syncope often occurred in association with acute physical, emotional, or auditory arousal. The syncopal episodes were frequently misinterpreted as a seizure disorder. By age 12 years, 50% of the probands had experienced at least one syncopal episode or death. The rates of postenrollment syncope (one or more episodes) and probable LQTS-related death (before age 50 years) for probands (n = 235; average follow-up 54 months per patient) were 5.0% per year and 0.9% per year, respectively; these event rates were considerably higher than those observed among affected and unaffected family members. CONCLUSIONS Among 232 probands and 1,264 family members with prospective follow-up, three factors made significant independent contributions to the risk of subsequent syncope or probable LQTS-related death before age 50 years, whichever occurred first (Cox hazard ratio; 95% confidence limits): 1) QTc (1.052; 1.017, 1.088), 2) history of cardiac event (3.1; 1.3, 7.2), and 3) heart rate (1.017; 1.004, 1.031). The findings from this prospective longitudinal study highlight the clinical features, risk factors, and course of LQTS.

Incidence, Diagnosis, and Management of QT Prolongation Induced by Cancer Therapies: A Systematic Review

“…A prolonged QTc increases the risk of a potentially lethal ventricular arrhythmia called TdP (Figure 4A). Most of the data on the risk of TdP in relation to QTc prolongation are from large registries of patients with congenital long QT syndromes 193, 194. These data show that each 10‐ms increase in QTc contributes approximately a 5% to 7% increase in risk for cardiac events, including syncope, cardiac arrest, and/or death.…”

Epidemiology of Sudden Cardiac Death: Clinical and Research Implications

“…The relatively rare monogenic, long QT syndromes have long constituted a human model for the causative association between prolonged repolarization and increased risk of sudden cardiac death (67)(68)(69)(70). However the Rotterdam study reported that QTc interval was independently associated with sudden cardiac death even in a cohort of unrelated individuals (71).…”

25th Anniversary of the International Long-QT Syndrome Registry

“…12 By 1991, we expanded the prospective study of the clinical course of this disorder to 1016 affected individuals in 328 LQTS families. 13 Important findings from the Registry during the past decade have included the following: age-and sex-related differences in the clinical manifestations of LQTS 14 ; influence of pregnancy on the risk for cardiac events in LQTS 15 ; ECG T-wave patterns in genetically distinct forms of LQTS 16 ; clinical course of LQTS by genotype 17 ; the spectrum of mutations in LQTS genes 18 ; increased risk associated with mutations in the pore region of the hERG gene 19 ; role played by physical exercise, emotions, arousal, and rest/sleep as triggers and facilitators for syncope and sudden cardiac death in LQT1, LQT2, and LQT3 20 -22 ; effectiveness of ␤-blocker therapy, particularly in patients with LQT1 and LQT2 genotypes 23 ; potential gene-specific usefulness of sodium channel blockers (mexiletine and flecainide) in the treatment of patients with the LQT3 mutations 24,25 ; life-saving benefit from the implanted defibrillator in highrisk LQTS patients 26 ; and left cardiac sympathetic denervation in the management of high-risk LQTS patients. 27 We initially thought that the clinical benefit of left-sided sympathectomy might have come from either a correction of a hypothesized left-sided dominance of sympathetic innervation or, in the case of a yet undefined "myocardial abnormality" (subsequently found to be represented by the mutations in cardiac ion channel genes), from removal of an arrhythmogenic trigger.…”