Several important clinical implications emerge from the current study of LQTS patients: 1) resting heart rate is an independent predictor of life-threatening cardiac events in LQT1, but not LQT2 patients, with a statistically significant difference in heart rate-related risk between genotypes; 2) current formulae that correct the QT interval duration for heart rate have important limitations for risk assessment in LQT1 patients; and 3) risk stratification for life-threatening cardiac events in LQTS patients may be improved by incorporating a genotype-specific correction of the QT interval for heart rate.
The identification that genes responsible for LQTS encode different ion channels involved in the control of repolarization has led to important advancements in current knowledge regarding genotype-phenotype correlation in hereditary arrhythmogenic disorders. Data from the International LQTS Registry have shown that life-threatening arrhythmias in LQTS patients occur under specific circumstances and in a gene-specific manner.11
It has been shown that, despite the fact that LQT1 and LQT2 patients harbor mutations that affect the potassium channels, triggers for life-threatening cardiac events among carriers of these 2 genotypes are distinctly different. Patients with the LQT1 genotype have been consistently reported to have a high frequency of arrhythmic events during activities that are associated with increased sympathetic activity and faster heart rates, such as vigorous exercise and swimming, whereas patients with the LQT2 genotype have been shown to be at a relatively low risk during exercise.11, 20–22
The difference in heart rate-related risk between genotypes may reflect that different potassium currents are involved in these two LQTS genotypes. IKs
shortens ventricular repolarization with fast heart rates and catecholamines; in LQT1, there is a reduction in this compensatory response. Fast heart rates have been shown to lead to accumulation of IKs
, even in the absence adrenergic stimulation.13
Thus, impaired IKs
accumulation in LQT1 patients, as a result of malfunction of channels containing a mutant subunit, may contribute to reduced adaptation of action potential duration to increasing heart rates. This concept is supported by an experimental model for LQT1, in which IKs
blockade greatly enhances the probability of torsade de pointes in the presence of catecholamines, 23
and by the fact that LQT1 patients have an exaggerated QTc interval prolongation during physical activity.24
Our findings are consistent with previous observations regarding the effect of impaired IKs
function on the relationship between heart rate and the duration of ventricular repolarization in LQT1 patients. However, in contrast to previous studies that evaluated the QT – RR relationship during exercise testing, 24–25
we have shown that increasing resting heart rate is an independent risk factor for life-threatening cardiac events in LQT1 patients. In addition, Schwartz et al.12
and Brink et al.14
have previously reported that resting heart rate plays a significant modulating role on the risk for cardiac events among carriers of a specific KCNQ1 mutation (A341V); the present study extends these findings to a wide range of KCNQ1 mutation carriers.
Importantly, although the Bazett’s correction formula was identified in the present study as the best predictor of life-threatening events among known formulae for LQT1 patients, our data suggest that currently available QT correction for heart rate do not provide sufficient risk-assessment among carriers of the LQT1 genotype. We have shown that risk-assessment among carriers of this genotype can be improved by incorporating a genotype-specific QT correction formula that assumes a more linear relationship between the duration of ventricular repolarization and heart rate than that provided by QTc(b) or QTc(f). Our data demonstrate a significant heart rate x genotype interaction effect, indicating that the risk associated with resting heart rate is significantly different between LQT1 and LQT2 patients. Thus, in LQT2 patients, in whom IKs function is not affected, a QTc exponential formula of QT/RR0.2 appears to describe accurately the relationship between heart rate and ventricular repolarization, whereas in LQT1 patients risk stratification is improved by using a much stronger QT/RR0.8 correction formula. All models in the present study were adjusted for baseline and time-dependent risk factors and showed that 100msec increase in QTc [new] was associated with 2.9-fold (p=0.004) and 2.1-fold (p=0.013) increased risk for ACA/SCD among LQT1 an LQT2 patients respectively, in addition to the effects of gender, time dependent syncope, and beta blockers.
When a baseline ECG is assessed in a non-genotyped LQTS patient, we suggest using Bazett’s correction formula; however, an important implication for a patient who has been diagnosed as a carrier of the LQT1 genotype would be that the RR interval provides incremental prognostic information to mere assessment of QTc by Bazett’s correction formula. Thus, we recommend using the improved QT correction formulae when the specific genotype is known. It should be noted that any given value of QTc means something different for each correction formula as the scales are not identical. When using the new correction formulae, a threshold of QTc (new) of 550 ms was associated with the best model fit for predicting life threatening events.
In the present study we evaluated risk factors for LQTS-related life-threatening cardiac events during adolescence, a time-period that has been shown to be associated with the highest event rate in patients with this genetic disorder 7
and when heart rates are usually faster than 60 bpm. However, the phenotypic expression of LQTS has been shown to be age-dependent.7–8
Thus, it is possible that the risk associated with heart rate may be different in older LQTS patients. Further studies are needed to validate the current findings in different age-groups of affected LQTS patients.
Due to sample size limitations, we did not exclude patients treated with β-blockers; nevertheless, all multivariate models included adjustment for time-dependent β-blocker therapy. In a secondary analysis excluding patients treated with β-blockers, we observed consistent results regarding the QT-RR relationship and the suggested improved QT correction formulae among LQT1 and LQT2 patients. Our study is underpowered to assess the yield of the new formulae and event rates within fixed time-periods by dichotomizing survival time and is also underpowered to calculate the sensitivity and specificity of the new formulae.
The current study population, despite being the largest genotyped population to assess QT/RR relation to arrhythmic risk, is not sufficient for validation of specific correction formulae without validations in independent populations. The present study is an overall risk assessment, whereas in clinical practice risk assessment should be individualized since some lethal events can occur in LQT1 patients in the absence of rapid heart rate. QTc alone should not be viewed as a complete diagnostic test, as there are several other important and known risk factors.
Investigations of clinical aspects and basic causal mechanisms of the LQTS have provided novel and important insight into the fundamental nature of the electrical activity of the human heart and to the relationship between disturbances in ion flow and cardiac disease. Our findings suggest that an understanding of the genotype-phenotype relationship in this genetic disorder can lead to improved criteria for risk stratification for life-threatening arrhythmic events in affected patients.