RESUMEN
BACKGROUND: T-peak to T-end (TPE) interval on the electrocardiogram is a measure of myocardial dispersion of repolarization and is associated with an increased risk of ventricular arrhythmias. The genetic factors affecting the TPE interval are largely unknown. OBJECTIVE: To identify common genetic variants that affect the duration of the TPE interval in the general population. METHODS: We performed a genome-wide association study on 1870 individuals of Finnish origin participating in the Health 2000 Study. The TPE interval was measured from T-peak to T-wave end in leads II, V(2), and V(5) on resting electrocardiograms, and the mean of these TPE intervals was adjusted for age, sex, and Cornell voltage-duration product. We sought replication for a genome-wide significant result in the 3745 subjects from the Framingham Heart Study. RESULTS: We identified a locus on 17q24 that was associated with the TPE interval. The minor allele of the common variant rs7219669 was associated with a 1.8-ms shortening of the TPE interval (P = 1.1 × 10(-10)). The association was replicated in the Framingham Heart Study (-1.5 ms; P = 1.3 × 10(-4)). The overall effect estimate of rs7219669 in the 2 studies was -1.7 ms (P = 5.7 × 10(-14)). The common variant rs7219669 maps downstream of the KCNJ2 gene, in which rare mutations cause congenital long and short QT syndromes. CONCLUSION: The common variant rs7219669 is associated with the TPE interval and is thus a candidate to modify repolarization-related arrhythmia susceptibility in individuals carrying the major allele of this polymorphism.
Asunto(s)
Sistema de Conducción Cardíaco/fisiopatología , Síndrome de QT Prolongado/genética , Polimorfismo de Nucleótido Simple , Canales de Potasio de Rectificación Interna/genética , Adulto , Pueblo Asiatico/genética , Metilación de ADN , Electrocardiografía , Técnicas Electrofisiológicas Cardíacas , Femenino , Finlandia , Secuencia Rica en GC/genética , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Short QT syndrome (SQTS) carries an increased risk for sudden cardiac death. However, only a short QT interval does not express the risk of ventricular arrhythmias. Thus, additional evaluation of the repolarization abnormality in SQTS patients is essential. In experimental models of SQTS, increased transmural dispersion of repolarization (TDR) and its electrocardiographic counterpart T-wave peak to T-wave end interval (TPE) appeared critical for induction of polymorphic ventricular tachycardia (PMVT). In a clinical study with acquired long QT syndrome patients, TPE/QT ratio > 0.28 indicated arrhythmia risk. We hypothesized that the TPE/QT ratio would be greater in SQTS patients than in control subjects. METHODS AND RESULTS: We compared the behavior of the electrocardiographic TDR in three seriously symptomatic SQTS patients of unknown genotype presenting baseline QTc values < 320 ms and in nine healthy age-matched control subjects. We determined QT and TPE intervals as well as TPE/QT ratio from 24-hour ECG recordings using a computer-assisted program. Diurnal average of TPE/QT ratio was 0.28 +/- 0.03 in SQTS patients and 0.21 +/- 0.02 in control subjects (P = 0.01). SQTS patients had also lesser capacity to change TPE intervals from steady-state conditions to abrupt maximal values than control subjects. CONCLUSION: SQTS patients have increased and autonomically uncontrolled electrocardiographic TDR. According to experimental SQTS models, the present results may in part explain increased vulnerability of SQTS patients to ventricular arrhythmias.
Asunto(s)
Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/genética , Electrocardiografía/métodos , Predisposición Genética a la Enfermedad , Sistema de Conducción Cardíaco/fisiopatología , Adolescente , Anciano de 80 o más Años , Estudios de Casos y Controles , Electrocardiografía Ambulatoria/métodos , Técnicas Electrofisiológicas Cardíacas/métodos , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Contracción Miocárdica/fisiología , Linaje , Probabilidad , Medición de Riesgo , Muestreo , Índice de Severidad de la Enfermedad , Estadísticas no Paramétricas , Síndrome , Remodelación Ventricular/fisiologíaRESUMEN
OBJECTIVES: In LQT1 subtype of inherited long QT syndrome, repolarization abnormalities originating from defective I(Ks) render patients vulnerable to ventricular arrhythmia during sudden sympathetic activation. Experimental studies show lower I(Ks) density and longer action potential duration in left (LV) than in right (RV) ventricle. We studied interventricular dispersion of repolarization in patients with I(Ks) defect during autonomic tests. DESIGN: We measured interventricular (difference of QT intervals between LV and RV type leads) and transmural electrocardiographic dispersion of repolarization from 25-lead electrocardiograms in nine asymptomatic KCNQ1 mutation carriers (LQT1) and eight controls during rest, Valsalva maneuver, mental stress, sustained handgrip and supine exercise. RESULTS: LQT1 carriers showed increased interventricular dispersion of repolarization (13+/-9 ms vs. 4+/-4 ms, p=0.03) during all tests. Valsalva strain increased the difference between the study groups. In LQT1 carriers, interventricular dispersion of repolarization correlated weakly with electrocardiographic transmural dispersion of repolarization. CONCLUSIONS: Asymptomatic KCNQ1 mutation carriers exhibit increased and by abrupt sympathetic activation augmented interventricular difference in electrocardiographic repolarization times. Interventricular and transmural repolarization dispersion behave similarly in patients with I(Ks) defect.