Genotype- and Mutation Site-Specific Differences in Arrhythmic Risk and Sensitivity to Sympathetic Stimulation in the Long QT Syndrome

Wataru Shimizu
National Cardiovascular Center, Suita, Japan

Congenital Long-QT (LQT) syndrome is a hereditary disorder characterized by a prolonged QT interval and polymorphic ventricular tachycardia (pVT) known as Torsade de Pointes, mainly as a result of increased sympathetic tone during exercise or mental stress. Genetic studies have identified 7 forms of congenital LQT syndrome, caused by mutations in potassium or sodium channel genes or in membrane adaptor located in chromosome 3, 4, 7, 11, 17, and 21. LQT-1, LQT-2, and LQT-3 syndromes comprise more than two-thirds of the genotyped patients. Therefore, genotype-phenotype coordination in the LQT-1, 2, and 3 syndromes are more clinically important for effective management and treatment of genotyped patients.

An international registry conducted by Schwartz and coworkers demonstrated differential triggers for cardiac events between the LQT 1, 2, and 3 syndromes. Exercise-related events seem to dominate the clinical picture in LQT1. Swimming is a specific trigger in LQT1. A sudden startle in the form of an auditory stimulus is a predominant trigger in LQT2, and more recently LQT2 females were shown to have a greater risk of cardiac events during the post-partum period than the other forms of LQT syndrome. In contrast, sleep-related events are seen more often in LQT3. Differential sensitivity of each genotype to sympathetic stimulation is considered the reason for the differential triggers for cardiac events.

Epinephrine for provocative testing

Provocative testing using epinephrine infusion or isoproterenol infusion has been used to unmask concealed forms of congenital LQT syndrome. In a study conducted by this group, a bolus injection of epinephrine (0.1 mcg/kg) was immediately followed by continuous infusion (0.1 mcg/kg/min). The 12-lead ECG was continuously recorded during sinus rhythm (SR) and the corrected QT-interval (QTc) was measured under baseline conditions. The peak epinephrine effect is seen usually 1-2 minutes after initiating the epinephrine when the heart rate is maximally increased, and a steady-state epinephrine effect is seen usually 3-5 minutes after initiating epinephrine.

In LQT1 patients, in their study, epinephrine dramatically prolonged the QTc interval at the peak epinephrine effect. Notably, the QTc remained prolonged during the steady-state epinephrine. The paradoxical prolongation of the QT interval was seen in this setting. In LQT2, the QTc interval was also prominently prolonged at the peak epinephrine effect but returned close to the baseline level during steady-state epinephrine. In LQT3, the QTc interval at the peak epinephrine effect was much less than that seen in LQT1 or 2, and the QTc was shortened to below the baseline level during steady-state epinephrine.

Based on their study results, the schema in Figure 1 illustrates the flow chart to predict each genotype of LQT1, 2, and 3 after epinephrine testing. A prolongation of the QTc interval (delta QTc) at steady-state epinephrine 35 ms was associated with LQT1, and a prolongation of the QTc interval 80 ms at the peak epinephrine level was associated with LQT2. Patients that do not meet either of these conditions after epinephrine testing were considered to be either controls or to have LQT3.

Prospective study of value of epinephrine testing

To test their hypothesis that epinephrine testing is useful for improving clinical ECG diagnosis and for predicting genotypes in the LQT1, 2, and 3 syndromes, they conducted a prospective study. In the study, there were 31 LQT1 patients, 23 LQT2 patients, 6 LQT3 patients, and 30 control patients. No significant differences were seen between the 4 groups for the clinical characteristics, except for the baseline QTc interval, which was significantly longer in the LQT2 and LQT3 patients than that in the LQT1 patients, but all were significantly longer than that in the control group.

Panel B illustrates the change of the mean QTC between baseline and the peak epinephrine effect. The delta mean QTC at peak was not different between LQT1 and LQT2, but both were significantly greater than those in the LQT3 and control groups. The delta mean QTc at peak of 80 ms differentiated LQT1 and LQT2 from LQT3 or control.

Panel C illustrates the mean change in QTc between baseline and steady-state epinephrine effect. The delta mean QTc at steady state was significantly greater only in LQT1 than in the other 3 groups. The delta mean QTc at steady state of 35 ms differentiated LQT1 from the other 3 groups.

The sensitivity for identifying LQT-1 mutation carriers among the LQT1 and the control groups was relatively low at 68% by ECG diagnostic criteria or for an LQT score 4. The specificity was always 100%. Thus, about one-third of LQT-1 mutation carriers will be missed by the ECG diagnostic criteria at baseline. The sensitivity was substantially improved with the steady-state epinephrine effect. The sensitivity was 87% by ECG criteria and 81% for an LQT score 4. In contrast, for the LQT2 and LQT3 groups, the sensitivity was relatively high, more than 80%, by ECG diagnostic criteria. The sensitivity was further increased by epinephrine steady-state in LQT2, however, the sensitivity was not changed with epinephrine in the LQT3 group.

Figure 3 illustrates the specificity, sensitivity, positive predictive value, and negative predictive value, and predictive accuracy based on delta QTc for genotype prediction. The delta mean QTc at steady-state epinephrine 35 ms differentiated LQT1 from the LQT2, LQT3 or control groups, with predictive values of more than 90%. Even when calculating the predictive values by delta QTc simply measured from the ECG lead V5, the predictive accuracy was still more than 80%. The delta mean QTc at peak epinephrine effect of 80 ms differentiated LQT2 from the LQT3 or control groups, with a 100% predictive value.

Thus, epinephrine infusion is a powerful test to improve clinical diagnosis of genotype-positive patients, especially in the LQT1 syndrome. The epinephrine test is also effective to predict the genotype of the LQT1, 2, and 3 syndromes.

Mutation site-specific study in Japanese patients with LQT-1 syndrome

More recently, mutation site-specific differences in clinical phenotype have been evaluated in each genotype. Moss and colleagues reported that LQT2 patients with mutations located in the pore region had a greater risk of cardiac events than those with none-pore lesion mutations including C-terminus or N-terminus.   This group examined the arrhythmic risk and sensitivity to sympathetic stimulation between a Japanese LQT1 population with transmembrane mutations and a population with C-terminal mutations. The study population comprised 95 LQT1 patients from 37 unrelated families collected from 5 Japanese institutions. Of the 95 study patients, 66 patients from 27 families had a total of 19 transmembrane mutations, and 29 patients from 10 families had 8 C-terminal mutations.

Comparisons were made for clinical ECG diagnosis, baseline 12-lead ECG measurements, cardiac events, therapy, cumulative event curves, and exercise treadmill testing (detailed in Figure 4). The exercise treadmill testing was conducted in 33 patients with transmembrane patients and 16 with C-terminal mutations.

Only 4 mutations were located in the pore region. Previous reports have shown that patients with C-terminal mutations have a milder clinical phenotype. Therefore, they compared patients with transmembrane mutations, including pore regions, and those with C-terminal mutations.

There were no differences between the 2 groups for gender, percentage of proband, and age at the ECG-recording. Patients with transmembrane mutations were more frequently diagnosed to have LQT syndrome. The LQT score, using the scoring by Schwartz and colleagues, was significantly higher in patients with transmembrane mutations. The baseline 12-lead ECG parameters, including QT end, QT peak, T peak to end interval reflecting transmural dispersion, both corrected and uncorrected, were significantly greater in patients with transmembrane mutations than those with C-terminal mutations. The frequency of T wave alternans was significantly higher in patients with transmembrane mutations.

The patients with transmembrane domain mutations versus those with C-terminal mutations had more frequent cardiac events (55% vs 21%, p=0.002), syncope (55% vs 21%, p=0.002), and aborted cardiac arrest or sudden cardiac death (15% vs zero, p=0.03). Therapy was more frequently initiated in patients with transmembrane domain mutations versus those with C-terminal mutations, including more beta blockers (45% vs 21%, p=0.02).

The Kaplan-Meier cumulative event curves showed a significant difference for all patients, with a higher risk of a first cardiac event in patients with transmembrane domain mutations than those with C-terminal mutations (0.65 vs 0.25, respectively, p=0.005). Most of the cardiac events in patients with transmembrane mutations occurred before 15 years of age, whereas the one-half of the patients with C-terminal mutations experienced cardiac events after 15 years of age.

Examining the ECG lead V5 before and after treadmill exercise testing showed that the baseline corrected QT, QT peak, and T peak to end were significantly greater in the patients with transmembrane mutation than in the patients with C-terminal mutation. Moreover, the corrected T peak to end was more prominently increased with exercise testing in patients with transmembrane mutations.

Changes in the 12-lead ECG parameters before and after exercise testing, showed that corrected QT end, QT peak, and T peak to end were significantly greater in patients with transmembrane mutations than with C-terminal mutations. The corrected QT end and T peak to end were significantly increased with exercise testing in both transmembrane mutations and C-terminal mutations. However, they were more prominently increased with exercise testing in the patients with transmembrane mutations.

Conclusion

Genotype prediction of the LQT1, 2, and 3 syndromes may be possible by the differential response of the QTc interval to epinephrine testing. The LQT1 patients with transmembrane mutations are at higher risk of cardiac events and have a greater sensitivity to sympathetic stimulation that the patients with C-terminal mutations.