Risk stratification in the long-QT syndrome.
BACKGROUND
Mutations in potassium-channel genes KCNQ1 (LQT1 locus) and KCNH2 (LQT2 locus) and the sodium-channel gene SCN5A (LQT3 locus) are the most common causes of the long-QT syndrome. We stratified risk according to the genotype, in conjunction with other clinical variables such as sex and the length of the QT interval.


METHODS
We evaluated 647 patients (386 with a mutation at the LQT1 locus, 206 with a mutation at the LQT2 locus, and 55 with a mutation at the LQT3 locus) from 193 consecutively genotyped families with the long-QT syndrome. The cumulative probability of a first cardiac event, defined as the occurrence of syncope, cardiac arrest, or sudden death before the age of 40 years and before the initiation of therapy, was determined according to genotype, sex, and the QT interval corrected for heart rate (QTc). Within each genotype we also assessed risk in the four categories derived from the combination of sex and QTc (<500 msec or > or =500 msec).


RESULTS
The incidence of a first cardiac event before the age of 40 years and before the initiation of therapy was lower among patients with a mutation at the LQT1 locus (30 percent) than among those with a mutation at the LQT2 locus (46 percent) or those with a mutation at the LQT3 locus (42 percent) (P<0.001 by Fisher's exact test). Multivariate analysis showed that the genetic locus and the QTc, but not sex, were independent predictors of risk. The QTc was an independent predictor of risk among patients with a mutation at the LQT1 locus and those with a mutation at the LQT2 locus but not among those with a mutation at the LQT3 locus, whereas sex was an independent predictor of events only among those with a mutation at the LQT3 locus.


CONCLUSIONS
The locus of the causative mutation affects the clinical course of the long-QT syndrome and modulates the effects of the QTc and sex on clinical manifestations. We propose an approach to risk stratification based on these variables.
Priori
Silvia G
SG
Department of Molecular Cardiology, Istituto di Ricovero e Cura a Carattere Scientifico Fondazione S. Maugeri, University of Pavia, Pavia, Italy. spriori@fsm.it.
Schwartz
Peter J
PJ
Napolitano
Carlo
C
Bloise
Raffaella
R
Ronchetti
Elena
E
Grillo
Massimiliano
M
Vicentini
Alessandro
A
Spazzolini
Carla
C
Nastoli
Janni
J
Bottelli
Georgia
G
Folli
Roberta
R
Cappelletti
Donata
D
D000328:Adult; D017668:Age of Onset; D018572:Disease-Free Survival; D004562:Electrocardiography; D005260:Female; D005838:Genotype; D006323:Heart Arrest / Q000235:genetics; D006801:Humans; D008133:Long QT Syndrome / Q000235:genetics*; D008297:Male; D015999:Multivariate Analysis; D009154:Mutation; D010641:Phenotype; D015221:Potassium Channels / Q000235:genetics; D018570:Risk Assessment / Q000379:methods*; D015222:Sodium Channels / Q000235:genetics
D015221:Potassium Channels; D015222:Sodium Channels