The present study is the first to assess gender differences in the risk of life-threatening cardiac events in LQT2, and to relate gender-specific risk in this population to the location of the disease-causing mutation. We have shown that among patients with LQT2: 1) both men and women have a relatively low rate of ACA or SCD during childhood, whereas after the onset of adolescence and throughout adulthood women exhibit a significantly higher rate of life-threatening events as compared with men; 2) the risk of ACA or SCD in women is high regardless of the location of the disease-causing mutation in the KCNH2 channel, whereas pore-loop mutations identify increased risk for ACA or SCD in men; and 3) combined assessment of clinical and mutation-specific risk factors can be used for improved risk stratification for life-threatening cardiac events in patients with type-2 long QT syndrome.
In a prior study Zareba et al. assessed age-dependent gender differences in the risk of cardiac events (comprising mostly nonfatal syncopal episodes) among 533genotyped patients from the International LQTS Registry.7
The study included 209 LQT2 patients, and showed that in this population no significant gender-related difference in the risk of cardiac events were present duirng childhood, whereas in the age-range of 16 through 40 years LQT2 women had >3-fold higher risk of cardiac events as compared with men.7
Possibly due to sample size limitations, the study did not identify a significant gender-related risk difference when the more severe end point of a first life-threatening cardiac event was assessed. The present study comprises the largest LQT2 population reported to date of 1,166 patients. We have shown that after the onset of adolescence there is a pronounced increase in the risk of ACA or SCD among LQT2 women (resulting in a cumulative event rate of 26% by age 40 years), whereas the risk of ACA or SCD among LQT2 men remains significantly lower throughout follow-up (resulting in a cumulative event rate of 14% by age 40 years). These age-gender risk differences in the clinical course of LQT2 patients may be mediated by the opposing effects of male and female sex hormones on the potassium channel. Testosterone was found to shorten the action potential duration and the QT interval through enhancement of the IKr
and thus may be associated with QT shortening in males after childhood. In contrast, estrogen was shown to exhibit both acute and genomic effects on IKr
, including reduction in channel function and prolongation of ventricular repolarization.14,15
Thus, LQT2 women who harbor mutations impairing potassium channel activity may be specifically sensitive to estrogen activity that may result in an increase in the risk for arrhythmic events after the onset of adolesence.
Recent data from the International LQTS Registry show that the location of the mutation in the ion channel is an important determinant of arrhythmic risk in LQTS patients. In a study of 201 LQT2 subjects with a total of 44 different KCNH2
mutations, Moss et al showed that subjects harboring pore mutations exhibited a more severe clinical course and experienced a higher frequency of cardiac events, occurring at an earlier age, than did subjects with nonpore mutations.5
Consistent with these findings, in a more recent study, Shimizu et al. showed that mutations in the pore region were associated with a greater risk of cardiac events as compared with mutations located in other regions in the KCNH2
The pore region forms the potassium conductance pathway, and most mutations present in this region have a dominant-negative effects on IKr
,10 suggesting that the pore region is critical for channel function. The findings of the present study are consistent with the previous link of high cardiac risk to pore-domain mutations, and show that the presence of pore-loop mutations was independently associated with a significant 39% increase in the risk of ACA or SCD in the total LQT2 population. Our findings, however, extend prior data and show a differential effect of mutation-related risk between LQT2 men and women. Thus, among men the presence of pore-loop mutations was associated with >2-fold (p=0.01) increase in the risk of ACA or SCD, whereas women with pore-loop mutations did not display a significant increase in risk as compared with those with nonpore-loop mutations. Accordingly, by age 40 years the rate of life-threatening cardiac events among men with pore-loop mutations was >3-fold higher as compared with those with other mutations (28% vs. 8%, respectively), whereas the corresponding event rates among women were high regardless of mutation-location (35% and 23%, respectively). Possible mechanisms that may explain the observed gender-related differences include the fact that estrogen increases IKr
independently of mutation-location, thereby increasing arrhythymic risk even among women who carry lower-risk (nonpore) mutations in the KCNH2
channel. In contrast, the protective effects of testosterone on IKr
and ventricular repolarization in post-adolescent males result in a reduction in the risk of arrhytmic events among carriers of low-risk mutations, with a possible remaining residual risk in men who harbor higher risk mutations in the functionally more important pore-loop region.
In a prior study, Priori et al. proposed a risk stratification scheme for LQTS patients that is based on the LQTS genotype, QTc, and gender.16
This study, however, assessed a composite end point of cardiac events of any type, comprising mostly nonfatal symcopal episodes,16
whereas the large sample size of genotyped LQT2 patients in the present study facilitated for the first time the development of a risk stratification scheme for the end point of life-threatening cardiac events within the LQT2 population. We show that combined assessed of clinical and genetic data, related to mutation-location, can be used to identify risk groups of LQT2 patients with a significantly different risk of ACA or SCD and with a pronounced difference in the rate of ACA or SCD during follow-up. These findings suggest that risk stratification in long QT syndrome should combine clinical and mutation-related risk factors that are specific for each of the 3 main LQTS genotypes.
Prior data suggest that LQT2 patients expereince a relatively high rate of cardiac events during beta-blocker therapy.17
In the present study medical therapy with beta-blockers was associated with pronounced 61% reduction in the risk of ACA or SCD in the total LQT2 population. However, the present findings also suggest that careful follow-up, with consideration of ICD therapy for primary prevention, is warranted in high- and very-risk LQT2 patients. These patient subsets were shown to experience 3.5 to 5.3 events per 100 patient years (which correspond to a high rate of 1.5 to 2.1 life-threatening cardiac events per patient from birth through age 40 years) despite frequent usage of beta-blocker therapy (>80%).
We did not carry out expression studies to assess the effects of estrogen and testosterone on ion channel mutations by their location. Therefore, further studies are necessary to evaluate the mechanism related to the observed gender-specific risk related to mutation-location.
Due to sample size limitations we did not carry out comprehensive analysis of the relation between all function regions of the KCNH2 channel (including the PAS, CNBD, other C-terminus and N-terminus domains) and gender-specific risk. However, the results from the secondary analysis in which nonpore-loop mutations were further subcategorized into mutations in the transmembrane and C/N-terminus regions support the consistency of our findings.
Conclusions and Clinical Implications
The present study shows a distinct association between mutation characteristics and time-dependent differences in the clinical course of LQT2 patients. We have shown that after the onset of adolescence women with and without high risk mutations exhibit increased risk for life-threatening cardiac events, whereas the risk of ACA or SCD in men is increased only among carriers of the higher-risk pore-loop mutations. Thus, a comprehensive approach, that combines clinical and genetic data, should be employed for risk assessment and management of LQTS patients.