Genotype-phenotype correlation in the long-QT syndrome - Gene-specific triggers for life-threatening arrhythmias

Background-The congenital long-QT syndrome (LQTS) is caused by mutations on several genes, all of which encode cardiac ion channels. The progressive u nderstanding of the electrophysiological consequences of these mutations op ens unforeseen possibilities for genotype-phenotype correlation studies. Pr eliminary observations suggested that the conditions ("triggers") associate d with cardiac events may in large part be gene specific. Methods and Results-We identified 670 LQTS patients of known genotype (LQT1 , n = 371: LQT2, n = 234; LQT3, n = 65) who had symptoms (syncope, cardiac arrest, sudden death) and examined whether 3 specific triggers (exercise, e motion, and sleep/rest without arousal) differed according to genotype. LQT 1 patients experienced the majority of their events (62%) during exercise, and only 3% occurred during rest/sleep. These percentages were almost rever sed among LQT2 and LQT3 patients, who were less likely to have events durin g exercise (13%) and more likely to have events during rest/sleep (29% and 39%). Lethal and nonlethal events followed the same pattern. Corrected QT i nterval did not differ among LQT1, LQT2, and LQT3 patients (498, 497, and 5 06 ms, respectively). The percent of patients who were free of recurrence w ith beta -blocker therapy was higher and the death rate was lower among LQT 1 patients (81% and 4%, respectively) than among LQT2 (59% and 4%, respecti vely) and LQT3 (50% and 17%, respectively) patients. Conclusions-Life-threatening arrhythmias in LQTS patients tend to occur und er specific circumstances in a gene-specific manner. These data allow new i nsights into the mechanisms that relate the electrophysiological consequenc es of mutations on specific genes to clinical manifestations and offer the possibility of complementing traditional therapy with gene-specific approac hes.