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(Circulation. 1995;92:3381-3386.)
© 1995 American Heart Association, Inc.

Articles

Long QT Syndrome Patients With Mutations of the SCN5A and HERG Genes Have Differential Responses to Na⁺ Channel Blockade and to Increases in Heart Rate

Implications for Gene-Specific Therapy

Peter J. Schwartz, MD; Silvia G. Priori, MD; Emanuela H. Locati, MD; Carlo Napolitano, MD; Francesco Cantù, MD; Jeffrey A. Towbin, MD; Mark T. Keating, MD; Hicham Hammoude, MD; Arthur M. Brown, MD; Ling-Sing K. Chen, PhD; Thomas J. Colatsky, PhD

From the Cattedra di Cardiologia, Università degli Studi di Pavia, and IRCCS Policlinico S Matteo, Pavia, Italy (P.J.S.); Centro di Fisiologia Clinica e Ipertensione/Istituto di Clinica Medica Generale e Terapia Medica, Università degli Studi di Milano, Italy (P.J.S., S.G.P., E.H.L., C.N., F.C.); Phoebe Willingham Muzzy Pediatric Molecular Cardiology Laboratory, Baylor College of Medicine, Texas Children's Hospital, Houston (J.A.T.); Eccles Institute of Human Genetics and Howard Hughes Medical Institute, University of Utah, Salt Lake City (M.T.K.); Centre Hospitalier de Sainte-Ode, Belgium (H.H.); Case Western Reserve University, Rammelkamp Center, MetroHealth Campus, Cleveland, Ohio (A.M.B.); and Division of Cardiovascular and Metabolic Diseases, Wyeth-Ayerst Research, Princeton, NJ (L-S.K.C., T.J.C.).

Correspondence to Peter J. Schwartz, MD, Cattidra di Cardiologia, Università degli Studi di Pavia, Divisione di Cardiologia, Policlinico S. Matteo IRCCS, Piazzale Golgi, 2-27100 Pavia, Italy.

	Abstract

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Background The genes for the long QT syndrome (LQTS) linked to chromosomes 3 (LQT3) and 7 (LQT2) were identified as SCN5A, the cardiac Na⁺ channel gene, and as HERG, a K⁺ channel gene. These findings opened the possibility of attempting gene-specific control of ventricular repolarization. We tested the hypothesis that the QT interval would shorten more in LQT3 than in LQT2 patients in response to mexiletine and also in response to increases in heart rate.

Methods and Results Fifteen LQTS patients were studied. Six LQT3 and 7 LQT2 patients were treated with mexiletine, and its effects on QT and QT_c were measured. Mexiletine significantly shortened the QT interval among LQT3 patients (QT_c from 535±32 to 445±31 ms, P<.005) but not among LQT2 patients (QT_c from 530±79 to 503±60 ms, P=NS). LQT3 patients (n=7) shortened their QT interval in response to increases in heart rate much more than LQT2 patients (n=4) and also more than 18 healthy control subjects (9.45±3.3 versus 3.95±1.97 and 2.83±1.33, P<.05; data expressed as percent reduction in QT per 100-ms shortening in RR). Among these patients, there is also a trend for LQT2 patients to have syncope or cardiac arrest under emotional or physical stress and for LQT3 patients to have cardiac events either at rest or during sleep.

Conclusions This is the first study to demonstrate differential responses of LQTS patients to interventions targeted to their specific genetic defect. These findings also suggest that LQT3 patients may be more likely to benefit from Na⁺ channel blockers and from cardiac pacing because they would be at higher risk of arrhythmia at slow heart rates. Conversely, LQT2 patients may be at higher risk to develop syncope under stressful conditions because of the combined arrhythmogenic effect of catecholamines with the insufficient adaptation of their QT interval when heart rate increases.

Key Words: genes • mexiletine • long QT syndrome • death, sudden

	Introduction

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The long QT syndrome (LQTS) is an inherited disorder characterized, in its most typical form, by prolongation of the QT interval and by life-threatening arrhythmias that are usually enhanced by stressful conditions.^{1 2 3}

Critical advances have recently been made in the molecular genetics of LQTS. After the report of linkage on chromosome 11⁴ and conclusive demonstration of genetic heterogeneity,⁵ with subsequent mapping of genes to chromosomes 3, 7,⁶ and 4,⁷ the LQTS genes for chromosomes 3 (LQT3) and 7 (LQT2) were identified.The LQT3 gene was identified as SCN5A,⁸ the cardiac Na⁺ channel gene, while HERG,⁹ a K⁺ channel gene suggested to encode the major subunit of the I_Kr channel, the rapid component of the delayed rectifier I_K,¹⁰ was found to be the LQT2 gene. The abnormalities found on SCN5A involve a 9-bp deletion or two different point mutations,^{8 11} all affecting transmembrane domains III and IV in a region thought to be critically important for the inactivation of the Na⁺ current. The abnormalities found on HERG are likely to impair expression of I_Kr.

On the basis of these genetic findings and of preliminary experimental observations,¹² we have now assessed the response of the QT interval to mexiletine and to heart rate changes in LQT2 and in LQT3 patients. Specifically, we tested the hypotheses that mexiletine and physiologically induced increases in heart rate would shorten the QT interval more in LQT3 than in LQT2 patients. Preliminary data have been presented.¹³

	Methods

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Patient Population
The study was performed in 15 LQTS patients (6 male and 9 female; mean age, 20±12 years). Eight patients belong to three LQTS families genetically linked to chromosome 3 (LQT3), and 7 patients belong to two families linked to chromosome 7 (LQT2). The specific mutations were identified either by single-strand conformation polymorphism analyses or by DNA sequencing of the individual polymerase chain reaction DNA subclones by two of us (M.T.K. and L.K.C., respectively). The clinical features of the patients are shown in Tables 1 and 2. These patients are enrolled in the International Registry for LQTS^{14 15} and, with the exception of family F-01594, have all been referred to the University of Milan.

View this table: [in this window] [in a new window]   Table 1. Patient Characteristics

View this table: [in this window] [in a new window]   Table 2. Patient and Control Subject Characteristics

LQT3 group. Five patients belong to family F-00142, which has a high incidence of life-threatening arrhythmias. Among the four siblings of the proband (E.B.), two died suddenly (at ages 16 and 17 years, and both during sleep), and only one is not affected; his two sons are affected, and the one still asymptomatic is only 2 years old. This family has a 9-bp deletion on chromosome 3p21-24; this results in the deletion of three amino acids, Lys1505-Pro1506-Gln1507 (KPQ), in the coding sequence for the cytoplasmic linker between DIII and DIV of SCN5A, the cardiac Na⁺ channel gene.^{8 11}

Two patients belong to family F-11069. The proband (E.B.), whose only sister is also affected, experienced several cardiac arrests requiring resuscitation. Her symptoms are controlled by ß-blockade, left sympathetic denervation, and pacemaker. In this family, the KPQ deletion⁸ is associated with a recently described¹¹ point mutation consisting of an arginine-to-histidine substitution at position 1644 (R/H).

The last patient (A.S.) is the only symptomatic member in his family. He has the R/H point mutation on the SCN5A gene and has had multiple cardiac arrests during sleep or at rest despite full-dose ß-blockade. He is currently treated with ß-blockade and left sympathetic denervation; mexiletine produced a dramatic shortening of his QT interval, and it has now been added as chronic therapy with persistence of the QT interval shortening.

LQT2 group. Family F-02459 included three sisters and their mother. The mutation in this family leads to a G-to-A substitution at the splice donor site that begins after cDNA sequence 2775 (I. Splawski et al, unpublished data, 1995). The proband (S.H.) and both her two sisters have had syncope and cardiac arrest, always under conditions of emotional stress. The proband required ß-blockade, left cardiac sympathectomy, and a pacemaker to prevent the syncopal episodes.

Three patients belong to family F-01594. The proband (C.H.) and his sister had multiple syncope, always during emotional or physical stress. Their mother (Ca.H.) is apparently asymptomatic. In this family, an HERG missense mutation has been identified (I. Splawski et al, unpublished data, 1995).

Healthy Control Subjects
Eighteen healthy individuals (8 male, 10 female), mean age 26±3 years, underwent 24-hour Holter monitoring to provide data for comparison with the LQTS patients for the study on the effects of heart rate changes.

Acute Response to Mexiletine
Six LQT3 and four LQT2 patients underwent acute oral administration of mexiletine (6 to 8 mg/kg). Continuous ECG recording (leads D₂, V₂, and V₅) was performed for 30 minutes in control conditions (before mexiletine) and for 3 hours after mexiletine. Every 15 minutes, a 12-lead ECG was recorded and stored in digital format for subsequent analysis. QT, RR interval, and QT_c (according to Bazett's formula) were calculated by measurement of each interval with a digitizer (ACECAD 9000) connected to a personal computer. At least three QT and RR intervals were measured in V₂ every 15 minutes. Data were analyzed by comparing the mean QT_c obtained by measuring two samples taken 15 minutes apart in control conditions and at the expected mexiletine peak plasma concentration (at 2 hours).

Chronic Therapy With Mexiletine
Three patients (F-01594) were studied before and after initiation of chronic therapy with mexiletine (12 to 16 mg·kg^-1·d^-1). One patient (A.S.) was studied with acute oral drug testing and during chronic therapy.

Steady-State QT Adaptation to Heart Rate Changes
QT interval adaptation to heart rate changes was derived from exercise stress tests or Holter recordings (in children who would not perform the exercise stress test). The QT was manually measured with a digitizer, and only when RR intervals were stable (defined as RR changes <10% for at least 10 beats). The QT interval at the longest and shortest RR intervals and at as many other cycle lengths as possible was selected in each patient. To adjust for differences in baseline values of the QT and RR intervals among patients, we expressed the adaptation of QT interval to heart rate changes as the percentage of QT shortening divided by the difference between the respective RR intervals and multiplied by 100. This index describes the percent reduction of QT interval for each 100-ms shortening of the RR interval.

Statistical Analysis
Data were analyzed by paired and unpaired t tests, and a value of P<.05 was accepted as significant. The incidence of syncope or cardiac arrest according to situations such as sleep or rest and emotional or physical stress was calculated by the Fisher exact test. The QT interval shortening during heart rate increases among the three groups was calculated by ANOVA with Scheffé's test for post hoc analysis. Data are presented as mean±SD.

	Results

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Response of QT Interval to Mexiletine
Mexiletine significantly shortened the QT interval among LQT3 patients (QT_c from 535±32 to 445±31 ms, P<.005) but not among LQT2 patients (QT_c from 530±79 to 503±60 ms, P=NS). The respective reductions were 17±8% and 4±6% (P<.02). Among the LQT3 patients, all but one had a very marked QT shortening, whereas among the seven LQT2 patients, all but two had practically no change. The summary data and representative examples are shown in Figs 1 and 2. Of note, there was no difference between LQT3 and LQT2 as to the QT_c before the test (535±32 versus 530±79 ms, P=NS); furthermore, there was no correlation between the degree of shortening of the QT interval and its duration in basal conditions (r²=.24, P=.08).

View larger version (18K): [in this window] [in a new window]   Figure 1. Bar graph showing QTc values in control conditions and during acute oral drug testing with mexiletine in LQT3 (linked to chromosome 3, n=6) and in LQT2 (linked to chromosome 7, n=7) patients. Data are expressed as mean±SD.

View larger version (26K): [in this window] [in a new window]   Figure 2. Tracings showing examples of ECG changes in response to acute administration of mexiletine (top) and to heart rate increase during exercise (bottom) in LQTS patients. Top, ECG tracings obtained in control conditions and during mexiletine administration from two LQT3 patients. Mexiletine markedly shortened QTc in both patients. Bottom, ECG recordings from one LQT3 patient (left) and one LQT2 patient (right) at rest (slow heart rate) and during exercise (fast heart rate). The increase in heart rate shortened QTc in the LQT3 patient but not in the LQT2 patient. Time and voltage calibrations are the same for all tracings; brackets on the right side indicate 10 mV.

Response of QT Interval to Heart Rate Increases
The responses to increases in heart rate were markedly different among seven LQT3 and four LQT2 patients. Fig 3 shows the individual responses and the averages for the two LQTS groups and for the control group. LQT3 patients shortened their QT interval in response to increases in heart rate much more than LQT2 patients and more than the healthy control subjects (9.45±3.3 versus 3.95±1.97 and 2.83±1.33, P<.05; data expressed as percent reduction in QT per 100-ms shortening in RR).

View larger version (10K): [in this window] [in a new window]   Figure 3. Scatterplot showing individual and mean values (±SD) of the response to heart rate increase in control subjects (n=18) and in LQT3 (linked to chromosome 3, n=7) and LQT2 (linked to chromosome 7, n=4) patients. Data are expressed as percent QT shortening for each 100-ms reduction in RR interval. *P<.05 vs control subjects and LQT2.

Triggers for Cardiac Events
The conditions associated with the occurrence of the syncopal episodes or cardiac arrest among the patients in the two groups were quite different. All five symptomatic members of the LQT2 families had their life-threatening arrhythmias in conditions of emotional or physical stress. By contrast, all seven symptomatic LQT3 patients had their cardiac events either at rest or during sleep, even though one of them had cardiac arrest also during emotional stress (Table 3). Overall, the incidence of cardiac events occurring either at rest or during sleep is significantly (P<.02) higher in LQT3 than in LQT2 patients; conversely, the probability of having syncope or cardiac arrest during emotional stress is higher in LQT2 patients.

View this table: [in this window] [in a new window]   Table 3. Factors Associated With Cardiac Events

	Discussion

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This study provides the first demonstration of differential responses by LQTS patients to interventions targeted according to their specific genetic defect. In LQT3 patients, marked shortening of the QT interval was produced by the Na⁺ channel blocker mexiletine and by exercise-induced increases in heart rate. By contrast, in most LQT2 patients, the QT interval did not shorten after mexiletine and adapted significantly less to increases in heart rate. The presence of a control group unmasked the surprising finding that whereas the modest QT adaptation of LQT2 patients to heart rate increases is within a normal range, the QT shortening of LQT3 patients is actually accentuated.

These observations have wide-ranging implications. They indicate the feasibility of assessing the potential value of interventions based on a pathophysiological approach to the alterations produced by the various gene mutations. If confirmed in a larger population, these preliminary findings will also provide the rationale for a differential and gene-specific therapeutic strategy for patients affected by LQTS.

Rationale for the Study
The identification of the mutations on SCN5A and on HERG made it logical to hypothesize that interference with the Na⁺ inward current and enhancement of the repolarizing K⁺ currents might have been useful in LQTS patients with SCN5A and HERG mutations, respectively. Although both defects result in a prolonged QT interval, the cellular basis for the repolarization delay is distinctly different. In LQT3 patients, excess inward current (I_Na) maintains the plateau at a depolarized level, whereas in LQT2 patients, a reduction in outward current (I_Kr) prevents the plateau from terminating early.

We focused on LQT3 patients, who have mutations on SCN5A, because the intervention to be tested is available and suitable for chronic treatment. The KPQ deletion⁸ and the two point mutations¹¹ found on SCN5A involve a region thought to be important for fast inactivation of the Na⁺ channel.⁸ The KPQ deletion actually results in multiple and intermittent reopenings of the mutant channels, giving rise to a small Na⁺ inward current.¹⁶ The two point mutations also increase Na⁺ current, but to a lesser degree because they increase only the number of brief dispersed openings without producing long-lasting bursts of channel openings (R. Dumaine et al, unpublished data, 1995). Furthermore, the increased inward current produced by all three mutations in oocytes is blocked by mexiletine, thus providing a molecular explanation for the clinical observations reported here.

When the present clinical study was initiated, we also attempted to reproduce the defects of SCN5A and of HERG at the cellular level. By exposing guinea pig ventricular myocytes to anthopleurin, a toxin that interferes with the inactivation of I_Na, and to dofetilide, a selective blocker of I_Kr, we obtained marked prolongation of the action potential.¹² This mimicked the alterations thought to be present in LQT3 and in LQT2 patients, respectively. The cells treated with anthopleurin shortened action potential duration (APD) with either mexiletine or rapid pacing; by contrast, the cells treated with dofetilide failed to shorten APD with mexiletine and only slightly reduced APD with pacing.

The results in LQTS patients with SCN5A and HERG present amazing similarities to those in isolated myocytes. This suggests that the mutations present in the two LQTS groups do indeed produce responses expected to occur with alterations in the inactivation of the Na⁺ channel or in the activation of I_Kr. Thus, the present data provide a link between the genetic findings, the reproduction of the abnormalities at molecular (Reference 16 and R. Dumaine et al, unpublished data, 1995) and at cellular¹² levels, and the clinical responses in the affected patients according to the specific mutation.

Effect of Na⁺ Channel Blockade
Mexiletine is a Na⁺ channel blocker similar to lidocaine but available for oral use; it may modestly shorten the QT interval in normal individuals.¹⁷ We tested the hypothesis that mexiletine would shorten the QT interval in the LQT3 patients in whom an excessive Na⁺ inward current appears to prolong repolarization. As predicted, all LQT3 patients but one had a significantly shortened QT interval after mexiletine; conversely, in all LQT2 patients but two, mexiletine did not shorten the QT interval.

Effect of Heart Rate Increases
Increases in heart rate induced by physical activity produced strikingly different results in the two groups of patients. Whereas LQT2 patients had a rate of shortening similar to that of control individuals, LQT3 patients had a markedly shortened QT interval during increases in heart rate. This behavior of LQT3 patients closely mimicked that of myocytes pretreated with anthopleurin, which during fast pacing shortened APD more than control and than dofetilide-pretreated cells.¹² A potential explanation is based on the fact that anthopleurin modifies the voltage dependence of the open state of the Na⁺ channels by prolonging open time at plateau voltage.¹⁸ Thus, at slow rates, when the time spent at less negative potentials is increased, the excessive inward flow of Na⁺ would be accentuated and would thereby cause a greater APD prolongation; conversely, there would be a more rapid APD shortening at fast rates. Also, Na⁺ channel blockade by tetrodotoxin slows the restitution of cardiac APD, suggesting that increased inward Na⁺ current may indeed enhance shortening in response to fast heart rates.¹⁹

Clinical Correlates
The population under study included only very typical LQTS patients^{2 20} ; however, the two groups had distinctive clinical features. All five symptomatic LQT2 patients had their syncopal episodes under situations of emotional stress. By contrast, all the seven symptomatic LQT3 patients had their episodes either at rest or during sleep; only one of them had syncope both at rest and under stress. Interestingly, several LQT3 patients have performed competitive sports without any arrhythmic episodes. Despite the small size of the population, there is a significantly higher relative risk of developing syncope during a stressful situation for LQT2 patients and either at rest or during sleep for LQT3 patients. This finding raises the possibility that the triggers for life-threatening arrhythmias differ among LQTS patients according to the specific gene mutation involved.

Clinical Implications
The implications of the present data are too important to be accepted on the basis of a limited population. Should these results be confirmed in the large population of our International Registry,^{14 15} with more than 200 genotyped LQTS gene carriers, the following implications may become legitimate.

1. LQT3 patients are more likely to develop torsades de pointes as a result of early afterdepolarizations favored by slow heart rates^{3 21} than as a consequence of sympathetic activation. Indeed, during physical stress this group may be at a not particularly high risk because during the progressive sinus tachycardia, their QT intervals would markedly shorten. The situation might be different with emotional stress, which produces an abrupt release of norepinephrine that often precedes an adequate increase in heart rate. They might benefit less than other LQTS patients from ß-adrenergic blockade; however, - and ß-adrenergic activation favor the onset of early and delayed afterdepolarizations,^{22 23} and indeed, these patients are protected by left cardiac sympathetic denervation,²⁴ which markedly reduces release of norepinephrine at the ventricular level without reducing heart rate.²⁵ On the basis of the present results, these patients may benefit also from chronic therapy with mexiletine and from pacing.

2. LQT2 patients are more likely to be at risk for syncope or sudden death under stressful conditions, because the arrhythmogenic effect of catecholamines²⁶ would be enhanced by the lack of appropriate shortening of their QT interval when heart rate increases. Arousal during sleep²⁷ would be dangerous for them, as for the other LQTS patients. They are very likely to be protected by antiadrenergic therapy, either ß-blockade or left cardiac sympathetic denervation. They should also benefit from interventions able to increase K⁺ conductance, eg, K⁺ channel openers, increased [K]^o that would shorten the QT interval by increasing repolarizing currents.

The limited sample size advises against direct extrapolation of these potentially important distinctions between LQT2 and LQT3 patients to the entire LQTS population. At this time, we consider these clinical implications to be only working hypotheses that require further validation.

	Acknowledgments

 
The financial support of Telethon Italy (grants 396 and 748) is gratefully acknowledged. This study was also supported by NIH grants HL-51618, HL-46401, and HL-36930 and by BIOMED grant PL-950028. We are grateful to Pinuccia De Tomasi for editorial support.

Received July 31, 1995; revision received October 23, 1995; accepted November 1, 1995.

	References

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				V. A. Maltsev, N. Silverman, H. N. Sabbah, and A. I. Undrovinas Chronic heart failure slows late sodium current in human and canine ventricular myocytes: Implications for repolarization variability Eur J Heart Fail, March 1, 2007; 9(3): 219 - 227. [Abstract] [Full Text] [PDF]

				G. Thomas, I. S. Gurung, M. J. Killeen, P. Hakim, C. A. Goddard, M. P. Mahaut-Smith, W. H. Colledge, A. A. Grace, and C. L.-H. Huang Effects of L-type Ca2+ channel antagonism on ventricular arrhythmogenesis in murine hearts containing a modification in the Scn5a gene modelling human long QT syndrome 3 J. Physiol., January 1, 2007; 578(1): 85 - 97. [Abstract] [Full Text] [PDF]

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				W. Shimizu and C. Antzelevitch Effects of a K+ Channel Opener to Reduce Transmural Dispersion of Repolarization and Prevent Torsade de Pointes in LQT1, LQT2, and LQT3 Models of the Long-QT Syndrome Circulation, August 8, 2000; 102(6): 706 - 712. [Abstract] [Full Text] [PDF]

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