Clinical and ECG characteristics of Caucasian and Japanese study patients are shown in . Gender distribution and baseline QTc duration were similar between the two ethnic groups. However, when the baseline QTc was analyzed by gender, Japanese male patients exhibited a significantly longer QTc duration as compared with their Caucasian counterparts. β-blocker therapy was administered to a similar proportion of Japanese and Caucasian patients, whereas ICD implantation occurred only in Caucasian LQT1 subjects.
Characteristics of Caucasian and Japanese LQT1 patients
The two ethnic groups exhibited significant differences in the frequencies of individual mutations () and their biophysical functional effects, with the higher-risk dominant negative mutations being significantly more frequent among Japanese patients than among Caucasians ().
Cardiac events during follow-up
A comparison of the frequency of cardiac events experienced between the two populations revealed a higher event rate among Japanese patients (). Notably, the frequency of presentation with ACA as a first cardiac event was significantly higher in Japanese patients as compared with Caucasians. Accordingly, the cumulative probability of a first cardiac event from birth through age 40 years was significantly higher among Japanese patients (67%) than among Caucasians (39%, p = 0.007; ). Furthermore, cardiac events occurred at a significantly earlier age in the former ethnic group. Thus, at age 10 years Japanese and Caucasians exhibited a respective cardiac event rate of 43% and 18% ().
Kaplan-Meier estimates of the probability of a first cardiac event from birth through age 40 years by ethnicity.
Comparison of event rates for the individual mutations showed a lower rate for mutations resulting in haploinsufficiency (G269S, A344A/sp, and delF340), and an increasing event rate for mutations with dominant negative ion current effects (R243C, G314S, and A341V; ). Accordingly, dominant negative mutation carriers exhibited a significantly greater probability of a first cardiac event than those with haploinsufficiency (), and this finding was consistent in both the Japanese (82% vs. 38%, respectively; p=0.001) and Caucasian (71% vs. 29%, respectively; p=0.001) groups.
Kaplan-Meier estimates of the probability of a first cardiac event from birth through age 40 years for the 6 individual KCNQ1 mutations included in the study.
Kaplan-Meier estimates of the probability of a first cardiac event from birth through age 40 years by the biophysical functional effect of the mutations.
Cox proportional hazards regression modeling demonstrated that Japanese ethnicity was associated with a marginally significant 81% increase in the risk of cardiac events as compared to Caucasian ethnicity, after adjustment for gender, QTc duration, and time-dependent β-blocker therapy (). However, the risk associated with ethnicity was no longer evident when the biophysical functional effect of the mutation was added to the multivariate model (). In this model a dominant negative mutation effect was shown to be the most powerful and significant predictor of outcome in study patients, and was associated with nearly a 4-fold increase in the risk of cardiac events during follow-up. The risk associated with dominant negative mutations was consistent for both Japanese and Caucasian patients (p-value for ethnicity × mutation effect interaction = 0.54).
Gender differences within ethnic groups
We have previously shown that in LQT1 patients the risk of cardiac events is affected by age and gender.20
We have therefore carried out a further exploratory analysis, in which the clinical course of males and females was compared and related to the biophysical functional effect of the mutations in the 2 ethnic groups. Overall, gender did not contribute significantly to outcome in study patients after adjustment for ethnicity or mutation effect (, respectively). However, when gender was related to the biophysical functional effect of the LQT1 mutations, dominant negative mutations were shown to exhibit a different gender effect in the 2 ethnic groups. The risk of cardiac events among Japanese males with dominant negative mutations was significantly higher than among Japanese females with the same mutations (HR = 3.46 [95% CI 1.06 − 11.27]; p = 0.03), whereas male and female Caucasians with dominant negative mutations exhibited a similar risk of cardiac events during follow-up (HR = 0.79 [95% CI 0.13 − 4.65]; p = 0.80).