Iori Nagaoka

Latent Genetic Backgrounds and Molecular Pathogenesis in Drug-induced Long QT Syndrome

Background—Drugs with IKr-blocking action cause secondary long-QT syndrome. Several cases have been associated with mutations of genes coding cardiac ion channels, but their frequency among patients affected by drug-induced long-QT syndrome (dLQTS) and the resultant molecular effects remain unknown. Methods and Results—Genetic testing was carried out for long-QT syndrome–related genes in 20 subjects with dLQTS and 176 subjects with congenital long-QT syndrome (cLQTS); electrophysiological characteristics of dLQTS-associated mutations were analyzed using a heterologous expression system with Chinese hamster ovary cells together with a computer simulation model. The positive mutation rate in dLQTS was similar to cLQTS (dLQTS versus cLQTS, 8 of 20 [40%] versus 91 of 176 [52%] subjects, P=0.32). The incidence of mutations was higher in patients with torsades de pointes induced by nonantiarrhythmic drugs than by antiarrhythmic drugs (antiarrhythmic versus others, 3 of 14 [21%] versus 5 of 6 [83%] subjects, P<0.05). When reconstituted in Chinese hamster ovary cells, KCNQ1 and KCNH2 mutant channels showed complex gating defects without dominant negative effects or a relatively mild decreased current density. Drug sensitivity for mutant channels was similar to that of the wild-type channel. With the Luo-Rudy simulation model of action potentials, action potential durations of most mutant channels were between those of wild-type and cLQTS. Conclusions—dLQTS had a similar positive mutation rate compared with cLQTS, whereas the functional changes of these mutations identified in dLQTS were mild. When IKr-blocking agents produce excessive QT prolongation (dLQTS), the underlying genetic background of the dLQTS subject should also be taken into consideration, as would be the case with cLQTS; dLQTS can be regarded as a latent form of long-QT syndrome.

Heart rate-dependent variability of cardiac events in type 2 congenital long-QT syndrome

AIMS We aimed to examine the validity of heart rate (HR) at rest before β-blocker therapy as a risk factor influencing cardiac events (ventricular fibrillation, torsades de pointes, or syncope) in long QT type 2 (LQT2) patients. METHODS AND RESULTS In 110 genetically confirmed LQT2 patients (45 probands), we examined the significance of variables [HR at rest, corrected QT (QTc), female gender, age of the first cardiac event, mutation site] as a risk factor for cardiac events. We also evaluated frequency of cardiac events in four groups classified by the combination of basal HR and QTc with cutoff values of 60 b.p.m. and 500 ms to estimate if these two electrocardiographic parameters in combination could be a good predictor of outcome (mean follow-up period: 50 ± 39 months). Logistic regression analysis revealed three predictors: HR < 60 b.p.m., QTc ≥ 500 ms, and female gender. When the study population was divided into four groups using the cutoff values of 60 b.p.m. for HR and 500 ms for QTc, the cumulative event-free survival by the Kaplan-Meier method was significantly higher in the group with HR ≥ 60 b.p.m. and QTc < 500 ms than in the group with HR < 60 b.p.m. and QTc < 500 ms or that with HR < 60 b.p.m. and QTc ≥ 500 m (P < 0.05). Irrespective of QTc interval, LQT2 patients with basal HR < 60 b.p.m. were at significantly higher risk. CONCLUSION The basal HR of < 60 b.p.m. is a notable risk factor for the prediction of life-threatening arrhythmias in LQT2 patients.

Genetic Background of Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy: Time to Start Asian Registry!

Arrhythmogenic right venticular dysplasia/cardiomyopathy (ARVD/C) is an inherited cardiomyopathy with a very low penetrance affecting the right ventricle (RV) and presenting palpitation and syncope due to ventricular tachycardia (VT) originating from RV. The VT can degenerate into ventricular fibrillation and sudden cardiac death. The genetic background of ARVD/C has recently been found to be heterogeneous, mainly resulting from cell adhesion abnormalities due to mutations in five different genes encoding members of the desmosome complex. In Asian countries, however, the genetic aspect of the disease has not been fully studied, although the clinical features of Asian ARVD/C patients are different from those in Western countries in the penetrance of phenotypes, relation to Brugada syndrome and link to RV outflow tract ventricular tachycardia. It is of urgent need to have a registry of Asian ARVD/C patients and to conduct a more detailed genetic survey on the candidate genes, including desomosomal ones.