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CLINICAL RESEARCH: ELECTROPHYSIOLOGY

Mutation site-specific differences in arrhythmic risk and sensitivity to sympathetic stimulation in the LQT1 form of congenital long QT syndrome

Multicenter study in Japan

Wataru Shimizu, MD, PhD^*,*, Minoru Horie, MD, PhD, Seiko Ohno, MD, Kotoe Takenaka, MD, Masato Yamaguchi, MD, PhD^||, Masami Shimizu, MD, PhD^||, Takashi Washizuka, MD, PhD^¶, Yoshifusa Aizawa, MD, PhD^¶, Kazufumi Nakamura, MD, PhD^#, Tohru Ohe, MD, PhD^#, Takeshi Aiba, MD, PhD^**, Yoshihiro Miyamoto, MD, PhD, Yasunao Yoshimasa, MD, PhD, Jeffrey A. Towbin, MD, Silvia G. Priori, MD, PhD and Shiro Kamakura, MD, PhD^*

^* Division of Cardiology, Department of Internal Medicine, National Cardiovascular Center, Suita, Japan
Laboratory of Molecular Genetics, National Cardiovascular Center, Suita, Japan
Department of Cardiopulmonary Medicine, Shiga University of Medical Science, Ohtsu, Japan
Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
^|| Molecular Genetics of Cardiovascular Disorders, Division of Cardiovascular Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan
^¶ Division of Cardiovascular Medicine, Niigata University Graduate School of Medical and Dental Science, Niigata, Japan
^# Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
^** Department of Cardiovascular Dynamics, Research Institute, National Cardiovascular Center, Suita, Japan
Department of Pediatrics (Cardiology), Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
Molecular Cardiology, Salvatore Maugeri Foundation, IRCCS, Pavia, Italy

Manuscript received February 9, 2004; revised manuscript received March 4, 2004, accepted March 11, 2004.

^* 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.
wshimizu{at}hsp.ncvc.go.jp

	Abstract

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OBJECTIVES: We sought to compare the arrhythmic risk and sensitivity to sympathetic stimulation of mutations located in transmembrane regions and C-terminal regions of the KCNQ1 channel in the LQT1 form of congenital long QT syndrome (LQTS).

BACKGROUND: The LQT1 syndrome is frequently manifested with variable expressivity and incomplete penetrance and is much more sensitive to sympathetic stimulation than the other forms.

METHODS: Sixty-six LQT1 patients (27 families) with a total of 19 transmembrane mutations and 29 patients (10 families) with 8 C-terminal mutations were enrolled from five Japanese institutes.

RESULTS: Patients with transmembrane mutations were more frequently affected based on electrocardiographic (ECG) diagnostic criteria (82% vs. 24%, p < 0.0001) and had more frequent LQTS-related cardiac events (all cardiac events: 55% vs. 21%, p = 0.002; syncope: 55% vs. 21%, p = 0.002; aborted cardiac arrest or unexpected sudden cardiac death: 15% vs. 0%, p = 0.03) than those with C-terminal mutations. Patients with transmembrane mutations had a greater risk of first cardiac events occurring at an earlier age, with a hazard ratio of 3.4 (p = 0.006) and with an 8% increase in risk per 10-ms increase in corrected Q-Tend. The baseline ECG parameters, including Q-Tend, Q-Tpeak, and Tpeak-end intervals, were significantly greater in patients with transmembrane mutations than in those with C-terminal mutations (p < 0.005). Moreover, the corrected Q-Tend and Tpeak-end were more prominently increased with exercise in patients with transmembrane mutations (p < 0.005).

CONCLUSIONS: In this multicenter Japanese population, LQT1 patients with transmembrane mutations are at higher risk of congenital LQTS-related cardiac events and have greater sensitivity to sympathetic stimulation, as compared with patients with C-terminal mutations.

Abbreviations and Acronyms   APD = action potential duration   DNA = deoxyribonucleic acid   ICl(Ca) = Ca2+-activated chloride current   IKr = fast component of the delayed rectifier potassium current   IKs = slow component of the delayed rectifier potassium current   INa-Ca = Na+/Ca2+ exchange current   LQTS = long QT syndrome   LZ = leucine zipper   PCR = polymerase chain reaction   TdP = torsade de pointes   Tpeak-end = interval between Tpeak and Tend

Examination of the genotype-phenotype correlation is important for the management and treatment of patients with congenital LQTS, especially in the LQT1, LQT2, and LQT3 forms, which constitute approximately two-thirds of genotyped LQTS (13). More recently, mutation site-specific differences in the severity of phenotype have been evaluated in each genotype. Moss et al. (14) have suggested that LQT2 patients with mutations in the pore region of the KCNH2 gene were at markedly increased risk of arrhythmia-related cardiac events, as compared with patients with non-pore mutations, in the International Long-QT Syndrome Registry. With regard to the LQT1 syndrome, Donger et al. (15) initially suggested that the missense mutation, R555C, located in the C-terminal region of the KCNQ1 gene was associated with a less severe phenotype than the mutations in the transmembrane regions. Since then, more than 20 mutations located in the C-terminal region of the KCNQ1 gene have been reported, but neither the severity nor the function of the mutations has been fully determined. In the present study, we compared the arrhythmic risk and sensitivity to sympathetic stimulation with exercise between LQT1 patients with mutations located in the transmembrane regions and those with mutations in the C-terminal regions of the KCNQ1 gene.

	Methods

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Patient population.   The study population consisted of 95 patients from 37 unrelated Japanese LQT1 families enrolled from five institutes in Japan: the National Cardiovascular Center, Kyoto University Graduate School of Medicine, Kanazawa University, Niigata University Graduate School of Medical and Dental Science, and Okayama University Graduate School of Medicine and Dentistry. The KCNQ1 mutations were confirmed in all patients by using standard genetic tests. Briefly, genomic deoxyribonucleic acid (DNA) was isolated from leukocyte nuclei by conventional methods. Screening for mutations of KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 was performed by using polymerase chain reaction (PCR)/single-strand conformation polymorphism or denatured high-performance liquid chromatography analyses. For aberrant PCR products, DNA sequencing was conducted with a DNA sequencer (3700 DNA Analyzer, PE Applied Biosystems, Foster City, California). If the patients had double mutations within the KCNQ1 gene or accompanying additional mutations in other genes, they were excluded from the present study. Genotyping of LQTS was reviewed and approved according to each Institutional Review Board's guideline, and written, informed consent was obtained from all patients. No patients were taking beta-blockers at the time of the baseline ECG and exercise treadmill test.

Clinical characterization.   Routine clinical and ECG parameters were usually obtained at the time of first admission to each institute for evaluation of LQTS, and thereafter at the time of at least yearly follow-up contact.

Clinical diagnosis
We evaluated two major clinical ECG criteria for diagnosing LQTS-affected individuals. The ECG diagnostic criteria of Keating et al. (16), included a corrected QT (QTc) interval 470 ms in asymptomatic individuals and a QTc interval >440 ms for males and >460 ms for females, were associated with one or more of the following: 1) stress-related syncope; 2) documented TdP; or 3) a family history of early sudden cardiac death. The LQTS was also diagnosed by the diagnostic criteria (score 4) of Schwartz et al. (17).

Baseline 12-lead ECG measurements
Baseline 12-lead ECG parameters included the RR, Q-Tend, Q-Tpeak, and Tpeak-end (Q-Tend – Q-Tpeak) intervals as an index of transmural dispersion of repolarization. The Q-Tend, Q-Tpeak, and Tpeak-end intervals were also corrected using Bazett's method. These parameters were measured manually in three leads (II, V₂, and V₅), with quantitative repolarization values reported for lead V₅, because the measurements were similar in all three leads. Q-Tend was defined as the interval between the QRS onset and the point at which an 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 fusing the first component appeared, it was included as part of the measurement of Q-Tend, but a normal U-wave, which was apparently separated from a T-wave, was not included. Q-Tpeak 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. Measurements were carried out by two investigators who were unaware of the subjects' genetic status. There were no significant differences in the measured data between the two (data not shown). In addition, TdP and T-wave alternans on the ECG were assessed.

Cardiac events, therapy, and follow-up
Congenital LQTS-related cardiac events were defined as syncope, aborted cardiac arrest, or unexpected sudden cardiac death without a known cause. Cardiac events, which brought the probands to medical attention but were secondary to apparent causes known to prolong repolarization, such as anti-arrhythmic drugs, electrolyte abnormalities, or bradycardia, were excluded from the analysis of congenital LQTS-related cardiac events. Such secondary cardiac events were documented in one patient with C-terminal mutation (hypokalemia 1) and one patient with transmembrane mutation (hypokalemia 1). Therapy, including beta-blockers, pacemakers, sympathectomy, and defibrillator, was also evaluated. Follow-up was censored at age 50 years to avoid the influence of coronary artery disease on cardiac events in the Japanese population.

Exercise treadmill testing
Forty-nine of the 95 patients were included for the analysis with exercise treadmill testing. All patients were in sinus rhythm, and none had atrioventricular or bundle branch block during the exercise testing. Exercise treadmill testing was performed using the standard Bruce protocol. Twelve-lead ECGs were recorded every 1 min from the baseline condition through the maximal exercise to the recovery phase for 8 min. The ECG measurements before exercise were obtained in the standing position before exercise, and those after exercise were usually obtained within 2 min after stopping exercise to avoid noise in the measurement.

Genetic characterization.   Genetic mutations of the KCNQ1 amino acid sequence were characterized by a specific location and coding effect (missense, splice site, frameshift, or deletion). The transmembrane regions were defined as six transmembrane segments (S1 to S6, amino acid residues 112 through 354), including cytoplasmic and extracellular linkers as well as the pore region. The pore region of the KCNQ1 channel was defined as the area extending from S5 to the mid-portion of S6 involving amino acid residues 301 through 320.

Statistical analysis.   Data are expressed as the mean value ± SD. Repeated measures two-way analysis of variance (ANOVA), followed by the Scheffé test, was used to compare data between mutations located in the transmembrane regions and those in the C-terminal regions, as well as to compare measurements made before and after exercise (STATISTICA, 1998 edition). Repeated measures one-way ANOVA, followed by the Scheffé test, was used to compare changes () in the measurements with exercise between the groups. Differences in frequencies were analyzed by the chi-square test. A two-sided p value <0.05 was considered to indicate significance. The cumulative probability of a first cardiac event was assessed by the Kaplan-Meier method and log-rank statistic. The multivariate Cox proportional hazards survivorship model (adjusting for mutation locations, age, and gender) was used to evaluate the independent contribution of clinical and genetic factors to first cardiac events from birth through to age 50 years. Clinical data were also compared between transmembrane mutations and C-terminal mutations for the probands and non-probands, separately. Because the non-probands (family members) in this study were mainly relatives in the first or second degree of the probands, the non-probands in each family were equally handled in the analysis.

	Results

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Genetic characteristics.   Table 1 illustrates the numbers of LQT1 patients by mutation and location (18–24). We identified 27 KCNQ1 mutations among the 95 LQT1 patients, with 19 mutations located in the transmembrane regions and eight mutations in the C-terminal regions. Four mutations were located at the pore region in the transmembrane domain. Twenty-three of the 27 mutations were missense mutations; 2 were frameshift mutations; 1 was a deletion mutation; and 1 was a splice mutation. Thirteen mutations (seven in the transmembrane regions and six in the C-terminal regions) were novel. Functional effects by cellular electrophysiologic tests have been reported in eight of the 27 mutations (Table 1).

View larger version (75K): [in this window] [in a new window]   Figure 1 Electrocardiographic parameters in lead V5 before and after exercise in LQT1 patients with mutations located in the transmembrane region (A341V, non-proband, 16-year-old male) (A and B) and in the C-terminal region (D611Y, non-proband, 16-year-old male) (C and D). The baseline corrected Q-Tend (cQ-Tend), Q-Tpeak (cQ-Tpeak), and Tpeak-end (cTpeak-end) intervals were greater in the patient with a transmembrane mutation than in the patient with a C-terminal mutation (A and C). Exercise produced more prominent increases in the cQ-Tend and cTpeak-end in the patient with a transmembrane mutation than in the patient with a C-terminal mutation (B and D).

View larger version (19K): [in this window] [in a new window]   Figure 2 (A) Kaplan-Meier cumulative cardiac event curves from birth through to age 50 years for a total of 95 patients with KCNQ1 mutations located in the transmembrane regions (n = 66) and C-terminal regions (n = 29). The difference in the clinical course by mutation location was significant (log-rank, p = 0.005), with a greater risk of first cardiac events in patients with transmembrane mutations than in those with C-terminal mutations. Kaplan-Meier cumulative cardiac event curves for 37 probands (B) and 58 non-probands (C) with transmembrane mutations and C-terminal mutations.

	Discussion

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The major findings of the present study are: 1) LQT1 patients with mutations located in the transmembrane regions are at a higher risk of congenital LQTS-related cardiac events than are patients with C-terminal mutations; and 2) LQT1 patients with transmembrane mutations had a greater sensitivity to sympathetic stimulation than did patients with C-terminal mutations.

Mutation site-specific arrhythmic risk in LQT1 syndrome.   Moss et al. (14) have recently reported that the greater risk of arrhythmia-related cardiac events in LQT2 patients with pore mutations of the KCNH2 gene was consistent with the cellular electrophysiologic effects of the KCNH2 mutations, with pore mutations showing a greater negative effect on the rapidly activating component of the delayed rectifier potassium current (I_Kr) than non-pore mutations. Although the cellular electrophysiologic effects of a small percentage of known KCNQ1 mutations have been reported to be like those of KCNH2 mutations, several in vitro electrophysiologic studies have reported missense mutations with dominant-negative effects on I_Ks in the transmembrane regions of the KCNQ1 gene (18,19,25,26). However, Wang et al. (18) have suggested that the degree of I_Ks suppression by KCNQ1 transmembrane mutations evaluated in the heterologous expression system did not correlate with severity in the clinical phenotype in LQT1 patients. There have been fewer reports on the cellular electrophysiologic effects of the C-terminal mutations of the KCNQ1 gene. To the best of our knowledge, the electrophysiologic effects were examined in seven C-terminal mutations of the KCNQ1 gene (R555C, R533W, R539W, 544, G589D, T587M, and G643S) by French, Finland, and Japanese groups (19,20,24,27–30). All seven C-terminal mutations, except for 544 and T587M, when co-expressed with KCNE1, could produce functional heteromultimeric channels and showed only a mild reduction of I_Ks due to a rightward voltage shift in the activation process and/or acceleration of the deactivation kinetics. Neyroud et al. (28) have reported a homozygous deletion-insertion mutation in the C-terminal region of the KCNQ1 gene (544), causing a severe phenotype—the Jervell and Lange-Nielsen syndrome. However, the heterozygotes of 544 clinically displayed mild or no QT prolongation, with no symptoms, mainly due to the lower dominant-negative effects of the 544 mutant. More recently, Larsen et al. (31) have described a severe form of Romano-Ward syndrome associated with compound heterozygosity for two C-terminal mutations (R518X and A525T) in the KCNQ1 gene. Once again, none of the heterozygotes of the C-terminal mutations (R518X or A525T) had symptoms with minor or no QT prolongation. These previous reports on C-terminal mutations in the KCNQ1 gene indicate a less severe phenotype in C-terminal mutations than that in transmembrane mutations in LQT1 syndrome, concordant with the findings in the present study.

It is noteworthy that most of the first cardiac events occurred before age 15 years in the LQT1 patients with transmembrane mutations, whereas half of the LQT1 patients with C-terminal mutations had their first cardiac events after age 15 years. This tendency holds up regardless of whether the patient was a proband. Moreover, hypokalemia, which is known to prolong repolarization, unmasked the LQTS proband in a patient with C-terminal mutation in the present study. These findings suggest that careful follow-up is needed in LQT1 patients with C-terminal mutations, despite their less severe phenotype, by limiting exposure of these patients to QT prolonging conditions.

Although the difference in the clinical course based on mutation location was obvious in the non-probands, no significant difference was observed in the clinical course according to mutation location in the probands. This is not surprising, because probands are usually brought to medical attention by their first cardiac events, especially those with a less prolonged QT interval. There indeed may be no difference in cardiac events based on mutation location for probands. This is because other modifier genes may be contributing to the more severe phenotype, which leads to the individual receiving a label of "proband."

Zareba et al. (32) recently reported on 294 LQT1 patients in the International Long-QT Syndrome Registry and analyzed the QTc interval and cardiac event rates by mutation location. In contrast to the present study, they found no significant differences in QTc or risk of cardiac events when the patients were separated into those with transmembrane mutations and those with C-terminal mutations. However, only six transmembrane mutations were overlapped between the two studies (out of 31 transmembrane mutations in the Registry and 19 transmembrane mutations in this study). Moreover, no overlap was observed in the C-terminal mutations between the two studies (out of 11 C-terminal mutations in the Registry and 8 C-terminal mutations in this study). In transmembrane regions, the S4 to S5 loop (amino acid residues 221 through 300) and the S6 segment (amino acid residues 325 through 354) are known to be important for voltage-dependent I_Ks function (22); thus, a more severe phenotype is expected in mutations located in the S4 to S5 loop and the S6 segment than in the S2 to S3 loop (amino acid residues 148 through 220). The transmembrane mutations in the non-pore region in the present study were located in the S4 to S5 loop and the S6 segment, except for two mutations found in the S2 to S3 loop. This may affect the result that cardiac event rates were higher in patients with transmembrane mutations in the present study than those in the Registry. Interestingly, when the patients with transmembrane mutations in the present study were separated into those with pre-pore mutations and those with pore mutations, according to the definition by Zareba et al. (32), the patients with pore mutations had a longer corrected Q-Tend than did those with pre-pore mutations (data not shown). Overall, our data present evidence that mutation site-specific differences in arrhythmic risk exist, in contrast to findings previously reported from the Long-QT Syndrome Registry. Therefore, a larger patient population per mutation and a greater spectrum of KCNQ1 mutations by corroboration with other investigators are clearly needed to make a definitive conclusion about the mutation site-specific differences in arrhythmic risk in LQT1 syndrome.

Greater sensitivity to sympathetic stimulation in transmembrane mutations of the KCNQ1 gene.   The LQT1 syndrome is reported both clinically and experimentally to be the most sensitive to sympathetic stimulation among the seven forms of LQTS (9–12). Sympathetic stimulation is known to increase the net outward repolarizing current due to a larger increase in outward currents, including Ca²⁺-activated I_Ks and Ca²⁺-activated chloride current (I_Cl(Ca)), compared with the inward Na⁺/Ca²⁺ exchange current (I_Na-Ca), resulting in an abbreviation of action potential duration (APD) and QT interval under normal conditions. A defect in I_Ks in LQT1 syndrome could account for the failure of sympathetic stimulation to abbreviate the QT interval and APD, especially in the mid-myocardial regions, resulting in a paradoxical QT prolongation and an increase in transmural dispersion of repolarization reflecting an increase in the Tpeak-end interval under sympathetic stimulation (12). In fact, recent clinical studies have demonstrated that sympathetic stimulation with epinephrine infusion or exercise produced a more significant increase in Q-Tend and Tpeak-end intervals in LQT1 compared with LQT2 patients (33–35). More recently, the Q-Tend and Tpeak-end intervals both before and after epinephrine and prolongation of Q-Tend with epinephrine were reported to be greater in symptomatic than asymptomatic patients with LQT1 syndrome (9). In the present study, LQT1 patients with transmembrane mutations, who had more frequent LQTS-related cardiac events than those with C-terminal mutations, showed greater baseline Q-Tend and Tpeak-end intervals and a greater increase in both Q-Tend and Tpeak-end intervals with exercise than those with C-terminal mutations. The data in the present study may indicate a stricter exercise limit and a more aggressive use of beta-blockers in LQT1 patients with transmembrane mutations, but once again, we need to evaluate a larger patient population to make a definitive recommendation.

With regard to the sympathetic regulation of I_Ks, Marx et al. (36) have suggested that beta-adrenergic modulation of I_Ks required targeting of cyclic adenosine monophosphate (cAMP)-dependent protein kinase and protein phosphatase-1 to KCNQ1 through the targeting protein yotiao. The binding of protein kinase and protein phosphatase-1 to the KCNQ1 channel through yotiao is mediated by leucine zipper (LZ) motifs located in the C-terminal of the KCNQ1 gene (amino acid residues 588 to 616). They also reported that the G589D mutant channel located in the LZ motifs of the C-terminus prevented cAMP-dependent regulation of I_Ks, and thus may not respond to beta-adrenergic stimulation, resulting in a defect of APD shortening and further prolonging of the APD. The G589D mutation was not included among the C-terminal mutations of the present study. Two C-terminal mutations, R591H and D611Y, located in the LZ motifs were included in the present study. However, the prolongation of the QTc interval was mild in patients with the two mutations (Fig. 1). Further clinical evaluation will be required to conclude the role of LZ motifs in the C-terminus on sympathetic modulation of the I_Ks channel.

	Acknowledgments

 
We gratefully acknowledge the expert technical assistance of Naotaka Ohta and Ritsuko Yamamoto (Laboratory of Molecular Genetics, National Cardiovascular Center, Suita, Japan).

	Footnotes

 
Dr. Shimizu was supported in part by the Japanese Cardiovascular Research Foundation, Vehicle Racing Commemorative Foundation, Health Sciences Research Grants from the Ministry of Health, Labour, and Welfare, and a Research Grant for Cardiovascular Diseases (15C-6) from the Ministry of Health, Labour, and Welfare, Japan. Dr. Priori was supported by an educational grant from the Leducq Foundation. Dr. Towbin was supported by grants R01-HL33843 and R01-HL51618 from the National Institutes of Health, National Heart, Lung, and Blood Institute, Bethesda, Maryland.

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