Author + information
- Received August 19, 2002
- Revision received October 14, 2002
- Accepted October 31, 2002
- Published online February 19, 2003.
- Wataru Shimizu, MD, PhD*,* (, )
- Takashi Noda, MD*,
- Hiroshi Takaki, MD†,
- Takashi Kurita, MD, PhD*,
- Noritoshi Nagaya, MD, PhD*,
- Kazuhiro Satomi, MD*,
- Kazuhiro Suyama, MD, PhD*,
- Naohiko Aihara, MD*,
- Shiro Kamakura, MD, PhD*,
- Kenji Sunagawa, MD, PhD†,
- Shigeyuki Echigo, MD‡,
- Kazufumi Nakamura, MD, PhD§,
- Tohru Ohe, MD, PhD, FACC§,
- Jeffrey A Towbin, MD∥,
- Carlo Napolitano, MD, PhD¶ and
- Silvia G Priori, MD, PhD¶
- ↵*Reprint requests and correspondence:
Dr. Wataru Shimizu, Division of Cardiology, Department of Internal Medicine, National Cardiovascular Center, 5-7-1 Fujishiro-dai, Suita, Osaka 565-8565, Japan.
Objectives This study was designed to test the hypothesis that epinephrine infusion may be a provocative test able to unmask nonpenetrant KCNQ1mutation carriers.
Background The LQT1 form of congenital long QT syndrome is associated with high vulnerability to sympathetic stimulation and appears with incomplete penetrance.
Methods The 12-lead electrocardiographic parameters before and after epinephrine infusion were compared among 19 mutation carriers with a baseline corrected QT interval (QTc) of ≥460 ms (Group I), 15 mutation carriers with a QTc of <460 ms (Group II), 12 nonmutation carriers (Group III), and 15 controls (Group IV).
Results The mean corrected Q-Tend (QTce), Q-Tpeak (QTcp), and Tpeak-end (Tcp-e) intervals among 12-leads before epinephrine were significantly larger in Group I than in the other three groups. Epinephrine (0.1 μg/kg/min) increased significantly the mean QTce, QTcp, Tcp-e, and the dispersion of QTcp in Groups I and II, but not in Groups III and IV. The sensitivity and specificity of QTce measurements to identify mutation carriers were 59% (20/34) and 100% (27/27), respectively, before epinephrine, and the sensitivity was substantially improved to 91% (31/34) without the expense of specificity (100%, 27/27) after epinephrine. The mean QTce, QTcp, and Tcp-e before and after epinephrine were significantly larger in 15 symptomatic than in 19 asymptomatic mutation carriers in Groups I and II, and the prolongation of the mean QTce with epinephrine was significantly larger in symptomatic patients.
Conclusions Epinephrine challenge is a powerful test to establish electrocardiographic diagnosis in silent LQT1 mutation carriers, thus allowing implementation of prophylactic measures aimed at reducing sudden cardiac death.
Recent evidence has suggested that cardiac events associated with sympathetic stimulation are more common among the LQT1 form than the LQT2 or LQT3 forms of congenital long QT syndrome (LQTS) (1–4). LQT1 is one of the two most common genetic form of LQTS so far identified, and is frequently manifest with variable expressivity and incomplete penetrance (5). Because molecular diagnosis is still unavailable to many clinical centers, and it requires high costs and a long time to be performed, there is a strong need to devise clinical tools to improve the sensitivity of clinical tests to establish the diagnosis of LQTS. Infusion of catecholamines, such as epinephrine or isoproterenol, has been used to unmask patients with suspected LQTS (6). Recent clinical data from our group and others have demonstrated the differential response of dynamic QT interval to epinephrine infusion in LQT1, LQT2, and LQT3 syndrome and the paradoxical QT prolongation in LQT1 syndrome (7,8). The present study was prompted by the successful management of a 14-year-old boy who had been resuscitated from cardiac arrest during swimming and was referred to our hospital. His baseline 12-lead electrocardiogram (ECG) showed borderline corrected QT interval (QTc) (442 ms) (Fig. 1A), but epinephrine infusion prolonged the QTc remarkably (585 ms), leading to spontaneously terminating torsade de pointes (TdP) (Fig. 1B). The QTc interval was within normal range in his family members examined (parents and two sisters). Molecular screening for LQTS mutation was performed later, confirming the diagnosis of LQT1 syndrome. We designed a study to perform a systematic evaluation of the diagnostic value of epinephrine infusion in unmasking nonpenetrant mutation carriers with LQT1 syndrome.
Eleven families affected with LQT1 syndrome were entered into the present study (six KCNQ1missense mutations, one splice mutation, and one deletion mutation). Among the eight mutations, five were in the core domain (six families) and three in the C-terminal domains (five families). Eleven families included 19 mutation carriers (seven families) with a prolonged QTc interval of ≥460 ms (Group I), 15 mutation carriers (seven families) with a normal or borderline QTc of <460 ms (Group II), and 12 nonmutation carriers (eight families) (Group III). Fifteen healthy volunteers were selected from doctors and nurses in our hospital and entered as controls (Group IV). LQTS-affected individuals were noted on the basis of electrocardiographic diagnostic criteria by Keating et al. (9), including a QTc ≥470 ms in asymptomatic individuals and a QTc >440 ms for men and >460 ms for women associated with one or more of the following: 1) stress-related syncope, 2) documented TdP, or 3) family history of early sudden cardiac death. The score of the LQTS was also calculated using the diagnostic criteria by Schwartz et al. (10).
Recording of standard 12-lead ECGs
Genotyping of LQTS was reviewed and approved by our Ethical Review Committee, and written informed consent was obtained from all patients, or their parents when the patients were <20 years of age. The epinephrine test was conducted as part of clinical evaluation of the LQTS. Standard 12-lead ECG was recorded with an FDX6521 (Fukuda Denshi Co., Tokyo, Japan) in the supine position without antiarrhythmic medications including beta-blockers. These electrocardiographic data were digitized using analog-digital converters with a sampling rate of 1,000 samples/s/channel.
Measurement of the electrocardiographic parameters was performed in a blinded fashion as to genotype status against five-averaged QRS complex by an offline computer using the analysis program developed by our institution. The Q-Tend interval was defined as the interval between the QRS onset and the point at which the isoelectric line intersected a tangential line drawn at the minimum first derivative (dV/dt) point of the positive T-wave or at the maximum dV/dt point of the negative T-wave. When a bifurcated or secondary T-wave (pathologic U-wave) appeared, it was included as part of the measurement of the Q-Tend interval, but a normal U-wave, which was apparently separated from a T-wave, was not included (11). The Q-Tpeak interval was defined as the interval between the QRS onset and the peak of the positive T-wave or the nadir of the negative T-wave. When the T-wave had a biphasic or a notched configuration, peak of the T-wave was defined as that of the dominant T deflection. The five QRS complexes were averaged first for each lead. Then, the Q-Tend, Q-Tpeak and Tpeak-end (Q-Tend minus Q-Tpeak) intervals, as an index of transmural dispersion of repolarization, were measured automatically from all 12-lead ECGs, corrected by Bazett’s method (corrected Q-Tend [QTce], corrected Q-Tpeak [QTcp], corrected Tpeak-end [Tcp-e]), and averaged among all 12-leads. As an index of spatial dispersion of repolarization, dispersion of the QTce and the QTcp was defined as the interval between the maximum and the minimum of the QTce and the QTcp among 12-leads, respectively.
A bolus injection of epinephrine (0.1 μg/kg), an alpha + beta-adrenergic agonist, was immediately followed by continuous infusion (0.1 μg/kg/min). The 12-lead ECG was continuously recorded during sinus rhythm under baseline conditions and usually for 5 min under epinephrine infusion. The effect of epinephrine on both RR and QT intervals usually reached steady-state conditions 2 to 3 min after the start of epinephrine. Epinephrine infusion for more than 5 min was avoided, and electrocardiographic monitoring was continued for a further 5 min after epinephrine infusion for possible occurrence of TdP. The electrocardiographic data were collected under baseline conditions and at steady-state conditions of epinephrine (3 to 5 min after the start of epinephrine), and compared among the four groups. The epinephrine test was performed in a blinded fashion as to genotype status in 31 of 46 family members, because the 31 members were not genotyped at the epinephrine test.
Data are expressed as mean ± SD, except for those shown in the figures, which are expressed as mean ± SEM. Repeated-measures two-way analysis of variance followed by Scheffe’s test was used to compare measurements made before and after epinephrine, and to compare differences between the groups (STATISTICA, 98 edition, StatSoft Inc., Tulsa, Oklahoma). Repeated-measures one-way analysis of variance followed by Scheffe’s test were used to compare changes (Δ) of the measurements with epinephrine between the groups. Differences in frequencies were analyzed by the chi-square test. A two-sided p value <0.05 was considered significant.
Clinical and molecular diagnosis
Clinical characteristics of the four groups are shown in Table 1. All 19 Group I patients could be diagnosed as having LQTS by electrocardiographic diagnostic criteria; 18 patients had a score ≥4 (high probability of LQTS), and an average score of the 19 patients was 5.5 ± 1.3 points (range 3 to 7.5 points). One Group II patient could be diagnosed as having LQTS; all 15 Group II patients had a score ≤2 and an average score of 0.7 ± 0.7 points (range 0 to 2 points). All 12 Group III patients could not be diagnosed as having LQTS, and had a score ≤1 (0.7 ± 0.5 points). All 15 Group IV controls had a QTc of <440 ms and no symptoms. Therefore, the sensitivity and specificity for identifying mutation carriers among the family members and controls were 59% (20/34) and 100% (27/27), respectively, by using the electrocardiographic diagnostic criteria of Keating et al. (9). They were 53% (18/34) and 100% (27/27) when an LQTS score ≥4 was used (10), and 59% (20/34) and 100% (27/27) when a score ≥2 was used (Table 2). Average penetrance in the 11 LQT1 families was 59% (20/34). Among the 34 mutation carriers in Groups I and II, 15 patients were symptomatic (Group I, 14/19; Group II, 1/15) and 19 patients were asymptomatic.
Comparative influence of epinephrine in the four groups
Figure 2illustrates 12-lead ECGs under baseline conditions and during epinephrine infusion in Group I and Group II patients. In the Group I patients, both the mean QTce and QTcp were prolonged (516 ms, 431 ms) and the mean Tcp-e was increased (85 ms) under baseline conditions (Fig. 2A). Epinephrine produced a marked prolongation in the mean QTce (586 ms), but a mild prolongation in the mean QTcp (459 ms), resulting in a further increase in the mean Tcp-e (127 ms) (Fig. 2B). Although the baseline electrocardiographic parameters were normal in the Group II patients (Fig. 2C), epinephrine prolonged both the mean QTce (435→516 ms) and QTcp (362→420 ms), and increased the mean Tcp-e (73→96 ms) (Fig. 2D). Figure 3illustrates 12-lead ECGs under baseline conditions and during epinephrine infusion in Group III and Group IV patients. The Group III patient is an older brother of the Group II patient shown in Figures 2C and 2D. The baseline electrocardiographic parameters were normal (Figs. 3A and 3C), and no significant changes were produced by epinephrine in both group patients (Figs. 3B and 3D). Figures 4A through 4Eshow composite data of the electrocardiographic parameters before and after epinephrine in the four groups. The mean QTce, QTcp, and Tcp-e before epinephrine were significantly larger in Group I than in the other three groups (Scheffe’s test value, p < 0.005, Figs. 4A to 4C). Epinephrine significantly increased all the electrocardiographic parameters except the dispersion of the QTce in Groups I and II (Scheffe’s test value, p < 0.05), but did not increase parameters in Groups III and IV. Therefore, all electrocardiographic parameters after epinephrine were significantly larger in Groups I and II (mutation carriers) than those in Groups III (nonmutation carriers) and IV (controls) (Scheffe’s test value, p < 0.05, Figs. 4A to 4E). The changes (Δ) in the mean QTce, QTcp, and Tcp-e with epinephrine were not different between Groups I and II, but they were significantly larger than those in Groups III and IV (Scheffe’s test value, p < 0.005, Figs. 5A to 5C). The changes in the dispersion of the QTce and the QTcp with epinephrine were not different among the four groups, except for the change in the dispersion of the QTcp between Groups I and III (Scheffe’s test value, p < 0.05, Figs. 5D and 5E). The sensitivity for differentiating mutation carriers from nonmutation carriers and controls was substantially improved by epinephrine test without the expense of specificity (100%, 27/27): 91% (31/34) by using the electrocardiographic diagnostic criteria or when an LQTS score ≥2 was used, and 74% (25/34) when a score ≥4 was used. An increase of mean QTce with epinephrine ≥30 ms also improved the sensitivity to 91% (31/34) without the expense of the specificity (Table 2, Fig. 5A). Even if we excluded the Group I patients who had a clear diagnosis of LQTS before epinephrine and analyzed the sensitivity only in Group II patients, the sensitivity was improved with the epinephrine test: from 7% (1/15) to 80% (12/15) by using the electrocardiographic diagnostic criteria, from 0% (0/15) to 40% (6/15) when an LQTS score ≥4 was used, from 13% (2/15) to 80% (12/15) when a score ≥2 was used, and to 87% (13/15) when an increase of mean QTce with epinephrine ≥30 ms was used (parenthesis in Table 2). The heart rate before and after epinephrine and the increases of heart rate were not different among the four groups (Figs. 4F and 5F).
Influence of epinephrine between symptomatic and asymptomatic mutation carriers
The electrocardiographic parameters and the heart rate before and after epinephrine were compared between 15 symptomatic patients and 19 asymptomatic mutation carriers in Groups I and II. The mean QTce, QTcp, and Tcp-e both before and after epinephrine were significantly greater in the 15 symptomatic patients than in the 19 asymptomatic mutation carriers (Scheffe’s test value, p < 0.05), whereas neither dispersion of the QTce nor dispersion of the QTcp were different between the two groups. Epinephrine significantly increased all the electrocardiographic parameters except the dispersion of the QTce in both symptomatic and asymptomatic mutation carriers (Scheffe’s test value, p < 0.05). Figure 6illustrates composite data of the changes (Δ) of the electrocardiographic parameters and the heart rate with epinephrine in the 15 symptomatic patients and the 19 asymptomatic mutation carriers. The prolongation of the mean QTce with epinephrine was significantly greater in the 15 symptomatic patients than in the 19 asymptomatic mutation carriers (Scheffe’s test value, p < 0.05), whereas the changes in the other parameters were not different between the two groups.
Spontaneously terminating TdP was induced by epinephrine infusion (2 min after the start of epinephrine) in one Group II patient (Fig. 1), and spontaneous premature ventricular contractions were induced in one Group I patient.
The present study demonstrates that epinephrine infusion is a provocative test that greatly increases the sensitivity of electrocardiographic diagnosis of LQT1 syndrome, one of the two most common variants of LQTS, thus providing clinicians with a powerful tool for improving appropriate diagnosis and management of LQTS.
Low penetrance in the LQT1 syndrome
The hypothesis that electrocardiographic diagnosis could miss patients affected by LQTS had already been proposed before the genetic bases of the disease were known (12). These initial observations were based on the evidence that syncopal events could occur among family members with a “normal” QT interval. Several years later, Vincent et al. (13)reported that five (6%) of 82 mutation carriers from three LQT1 families had a normal QT interval. More recently, Priori et al. (5)have demonstrated a very low penetrance (38%, 9/24) in nine families with only one individual clinically affected with LQTS. In the present study, the average penetrance was 59% (20/34) among 11 LQT1 families. The sensitivity and specificity for identifying mutation carriers were 59% and 100% by using the electrocardiographic diagnostic criteria or when an LQTS score ≥2 was used, and they were 53% and 100% when a score ≥4 was used. Our data are in agreement with other reports demonstrating a 100% specificity and 53% sensitivity for diagnosis of high probability of LQTS (14). Overall, these findings strongly point to the need of novel tools to unveil nonpenetrant mutation carriers of LQTS.
Usefulness of epinephrine infusion in unmasking LQT1 mutation carriers
Provocative tests using catecholamine or exercise testing have long been considered to unmask some forms of congenital LQTS (6). Recent preliminary data by Ackerman et al. (8)have suggested the usefulness of an epinephrine test to unveil concealed LQT1 syndrome. This study provides systematic evaluation of the efficacy of epinephrine provocative challenge to unmask silent forms of LQTS in a group of genetically characterized individuals. Our data demonstrate that intravenous administration of epinephrine significantly improves the sensitivity of electrocardiographic diagnosis of LQTS in carriers of KCNQ1defects. Because KCNQ1is one of the two most common forms of congenital LQTS, this provocative challenge could be applied to a large number of individuals suspected to be affected by this variant of the disease. On the basis of current data, probands of congenital LQTS who had cardiac events during exercise and emotion (4), and particularly during swimming (2,3), have a high probability of being affected by KCNQ1genetic defects. Accordingly, all their family members become likely candidates for epinephrine provocative challenge. The identification of affected individuals with normal electrocardiographic phenotype is of major importance, as it would enable limiting exposure of these individuals to potentially dangerous conditions such as participation in competitive sports and use of drugs known to prolong repolarization, thus reducing the risk of life-threatening cardiac arrhythmias (15). However, it goes without saying that an epinephrine provocative test should only be done by cardiologists under enough preparation of intravenous beta-blockers as well as a direct cardioverter for unintentionally induced ventricular fibrillation. Darbar et al. (16)reported that the QTc was increased in lead II (but not in lead V3) by epinephrine infusion even in normal controls, and suggested that this was due to increasing calcium current as well as hypokalemia induced by epinephrine. In this study, the QTce was not prolonged by epinephrine in Group III (nonmutation carrier) and Group IV (controls), probably as a result of the measurement of averaged QTce among all 12-leads as well as too-short epinephrine infusion (<5 min) to induce hypokalemia (17).
Mechanism of influence of epinephrine in LQT1 mutation carriers
Both experimental and clinical studies have suggested a differential response of action potential duration (APD) and QT interval to sympathetic stimulation among LQT1, LQT2, and LQT3 (7,8,18). Persistent and paradoxical prolongation of APD and QT interval at steady-state conditions of catecholamines was reported in LQT1 syndrome. Under normal conditions, beta-adrenergic stimulation is expected to increase net outward repolarizing current, owing to larger increase of outward currents, including Ca2+-activated slow component of the delayed rectifier potassium current (IKs) and Ca2+-activated chloride current, than that of an inward current, Na+/Ca2+exchange current (INa-Ca), resulting in an abbreviation of APD and QT interval. A defect in IKsin the LQT1 syndrome could account for failure of beta-adrenergic stimulation to abbreviate APD and QT interval, resulting in a persistent and paradoxical QT prolongation under sympathetic stimulation (18). In LQT2 syndrome, catecholamines are reported to initially prolong but then abbreviate APD and QT interval, probably because of an initial augmentation of INa-Caand a subsequent stimulation of IKs. In contrast to the LQT1 and LQT2 syndromes, catecholamines are reported to constantly abbreviate APD and QT interval as a result of a stimulation of IKsin the LQT3 syndrome, because an inward late sodium current (INa) was augmented in this genotype. Taken together with the data in the present study, the epinephrine test may be applied not only for unmasking silent mutation carriers with LQT1 syndrome but also for predicting genotype.
Symptomatic versus asymptomatic mutation carriers
In this study, the mean QTce, QTcp, and Tcp-e under the baseline conditions were significantly greater in the 15 symptomatic patients than in the 19 asymptomatic mutation carriers, consistent with previous large family studies without molecular diagnosis (12,19). Moreover, the epinephrine-induced prolongation of the mean QTce was significantly larger in the 15 symptomatic patients. This indicates a higher vulnerability of ventricular repolarization to sympathetic stimulation in symptomatic patients, although unknown factors may influence this phenomenon. The data also suggest that the epinephrine test may detect high-risk mutation carriers by the degree of QTc prolongation. In reverse, epinephrine-induced QTc prolongation was smaller in asymptomatic mutation carriers, indicating that the epinephrine test does not exert as great an effect to unveil mutation carriers in asymptomatic family members. However, epinephrine-induced prolongation of the mean QTce was >30 ms in all but two asymptomatic mutation carriers, and was clearly greater than those in either nonmutation carriers or normal controls. Prospective study using 30-ms cutoff with epinephrine challenge will be needed in order to conclude the diagnostic value of the epinephrine test.
Dispersion of repolarization
The mean QTce was the most sensitive parameter to epinephrine; however, the mean Tcp-e was also increased by epinephrine only in the mutation carriers, suggesting that sympathetic stimulation increases transmural dispersion of repolarization (20), leading to arrhythmogenesis in the LQTS with KCNQ1defects. In contrast, the dispersion of the QTce, as an index of spatial dispersion of repolarization, was not significantly increased by epinephrine in Groups I and II (mutation carriers), and the changes in the dispersion of the QTce with epinephrine were not different among the four groups. These data may be explained by a recent elegant study using computer simulation conducted by Burnes et al. (21), in which they suggested that regional heterogeneity of repolarization was not reflected in QT dispersion recorded from the body surface ECG.
First, the numbers of families and of individuals in the present study are relatively small, and all patients are the same ethnic origin (Japanese). Because the issue of ethnicity as a modulator of genetically determined disease is receiving increasing attention, our data may or may not be applicable to other ethnicities.
Second, although peak of the T-wave was defined as that of the dominant T deflection when the T-wave had a biphasic or a notched configuration, it is still unclear which peak of the biphasic or notched T-wave reflects the repolarization of epicardial action potential. Further basic studies will be needed to conclude the cellular basis for complex T-waves.
Third, we used Bazett’s formula for correction of heart rate. Bazett’s formula is derived from normal individuals, and its use at higher heart rate is likely to lead to an overestimation of the QTc, thus contributing to the increase in sensitivity, which should be taken into account to interpret data in this kind of study.
We are indebted to Drs. Peter J. Schwartz and Arthur J. Moss for their critical review and insightful comments for the manuscript. We gratefully acknowledge the expert statistical assistance of Nobuo Shirahashi, Novartis Parma Co., and Yasuko Tanabe.
☆ Dr. Shimizu was supported in part by Japanese Cardiovascular Research Foundation, Vehicle Racing Commemorative Foundation, and Health Sciences Research Grants from the Ministry of Health, Labour and Welfare, Japan. Molecular genetics performed in the laboratory of Dr. Priori was supported by an educational grant of the Leducq Foundation.
- action potential duration
- slow component of the delayed rectifier potassium current
- sodium current
- Na+/Ca2+exchange current
- long QT syndrome
- corrected QT interval
- corrected Q-Tend interval
- corrected Q-Tpeak interval
- corrected interval between Tpeak and Tend
- torsade de pointes
- Received August 19, 2002.
- Revision received October 14, 2002.
- Accepted October 31, 2002.
- American College of Cardiology Foundation
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