(Circulation. 1995;92:3373-3375.)
© 1995 American Heart Association, Inc.
Articles |
Long QT Syndrome Patients With Gene Mutations
From the College of Physicians and Surgeons of Columbia University, New York, NY.
Correspondence to Michael R. Rosen, MD, College of Physicians and Surgeons of Columbia University, Department of Pharmacology, PH 7 West 321, 630 W 168th St, New York, NY 10032.
Key Words: Editorials • genes • mexiletine • long QT syndrome
 |
Introduction |
|---|
 Top Introduction References |
|---|
In their article in this issue of Circulation, Schwartz and colleagues1 deliver not only an important message in the rapidly advancing field of long QT syndrome but an equally important message concerning the marriage of basic science and clinical medicine. Hence, the study affects our understanding of (1) the pathophysiology of this disease process, (2) the planning of appropriate medical care, and (3) the supportive roles of basic and clinical research in bettering the human condition.
The idiopathic long QT syndrome (LQTS) is an uncommon disease first reported formally by Jervell and Lange-Nielsen in 1957.2 The family they described was beset with the association of congenital deaf-mutism, long QT interval, and sudden death. Romano et al3 in 1963 and Ward4 in 1964 reported families in whom QT prolongation and sudden death occurred with an autosomal-dominant inheritance, contrasted with the autosomal-recessive pattern of the Jervell–Lange-Nielsen syndrome. Although the LQTS is by no means common (fewer than 500 families worldwide had been incorporated into an international registry by 19945 ), its role is magnified by the frequency of occurrence of syncope, life-threatening arrhythmias, and sudden death. Indeed, about 21% of symptomatic patients who are untreated die within a year of their first syncopal episode, and mortality climbs to about 50% in 10 years.6 Moreover, it is likely that the number of reported cases is only a fraction of those actually occurring.5
The disease threatens afflicted families both physically and psychologically, and its phenotypic heterogeneity has led to some difficulties in deciding who is or is not at risk of sudden death and how to prevent or treat the life-threatening arrhythmias. Heterogeneity is evidenced in part by the observations that 5% to 10% of gene carriers have no QT prolongation7 and that about 5% of family members of LQTS patients experience life-threatening arrhythmias or syncope despite having normal QT intervals themselves.8 These findings are consistent with variable penetrance of the LQTS gene(s) and/or the presence of modifier genes. Heterogeneity and a role for modifier genes are also supported by the observation that, despite its autosomal-dominant inheritance (which should ensure equal expression in males and females), Romano-Ward LQTS shows a clear predilection for females.8 9 10
Therapy of LQTS has been difficult. Initial, empirical therapy had, at best, random success. However, clinical investigators noted that a characteristic of many patients who have the disease is a triggering of lethal events by emotional or physical stress. This led to a significant body of work examining the role of the sympathetic nervous system in the pathogenesis of LQTS (see Reference 5 for summary). Specifically, it was proposed that dominance of the left sympathetic nerves might be the cause of the long QT interval and/or the lethal arrhythmias.11 Attempts to limit the triggering events for arrhythmias resulted in the use of ß-adrenergic blockade, successful in preventing new syncopal events in about 75% of patients,6 as well as left cardiac sympathetic denervation for those patients not protected by ß-blockade alone.12 In other patients, whose arrhythmias are clearly bradycardia or pause dependent, cardiac pacing has been an effective adjunct.13 14 Five-year mortality with these and other interventions is now <5%.5
This information, while indicative of diagnostic and therapeutic advancement, left important mechanistic and therapeutic questions unanswered. If a sympathetic imbalance lies at the root of LQTS, why, then, did successful treatment not result in normalization of the QT interval? Why, too, if Romano-Ward is a "single" syndrome, has there been so much variability in its phenotypic expression? And why has the range of responses to therapeutic interventions been inconsistent?
Answers have come as the result of imagination and of major breakthroughs in molecular genetics and in electrophysiology. Imagination compounded with advances in our understanding of the roles of ion channels in repolarization led to hypotheses implicating an abnormality in a repolarizing K+ channel and/or a depolarizing Ca2+ channel as possible causes of the syndrome.5 15 16 The duration of repolarization might be increased and early afterdepolarizations leading to triggered arrhythmias might be induced by prolonged opening of channels carrying inward current (eg, Ca2+) or delayed or incomplete opening of channels carrying outward current (eg, K+). The most likely respective candidates were the L-type Ca2+ channel, ICaL, and the delayed rectifier, IK.5
Breakthroughs that brought hypotheses to reality commenced with a report in 1991 in which the LQTS phenotype was linked with a marker on chromosome 11 (at 11p15.5).17 The marker on chromosome 11 is related to the gene encoding the ras oncogene, which in turn has been implicated in sympathetic receptor-effector coupling and ion channel modulation.18 This finding was met with great excitement because it offered a chance to unify sympathetic neural abnormalities with the function of an ion channel. However, this potential linkage of gene and disease did not bear fruit in any pathogenetic sense because the chromosome 11p15.5 locus was subsequently reported to lie outside the ras locus,19 because the ion channel most likely associated with receptor-effector coupling here was primarily atrial in its distribution,20 and because a number of families with LQTS were found to have disease not linked to 11p15.5.19 20 21 22 23
More recent advances have related to chromosomes 7 and 3. The chromosome 7 story epitomizes the relationship of doing science for science's sake to the answering of a specific clinical question. Initially, research having no focus on LQTS resulted in the cloning of K+ channels from a drosophila mutant called "shaker."24 A mutant cloned in 1991 was named eag (for ether-à-go-go, reflecting movement patterns of the fruitflies under ether),25 and in 1994, an eag-related gene (referred to as HERG) was cloned and localized to chromosome 7 in human hippocampus.26 The subsequent localization of HERG to 7q35-36,27 previously identified as linked to LQTS,22 23 and its demonstration in human heart mRNA27 heightened interest in a HERG mutation that might contribute to delayed repolarization. It has recently been shown that the ion current associated with HERG is closely related to the IKr (rapidly activating component of the IK) current in human heart.28 The abnormality, then, lies in a K+ channel whose function is reduced, thereby prolonging the action potential plateau and the QT interval. Mexiletine, which primarily blocks Na+ channels,29 would be expected to exert little or no effect on the QT interval. This is precisely what Schwartz et al1 found. The other intervention used by Schwartz et al1 was exercise to increase heart rate. To the extent that increasing heart rate increases K+ accumulation in intercellular clefts,30 thereby increasing transmembrane K+ conductance and accelerating repolarization, the QT shortening seen in the chromosome 7 group was expected to be—and turned out to be—not unlike that in control subjects.1
However, the chromosome 3 group associated with Na+ channel dysfunction is the more exciting focus of the study by Schwartz et al.1 The cardiac-specific isoform of the Na+ channel was initially cloned from rat heart31 and, in 1992, from human heart.32 The human heart Na+ channel gene (SCNSA) has been localized to chromosome 3p21.33 This is the same region as the linkage in a subset of LQTS families.22 The hypothesis relating to this channel was that its delayed inactivation would lead to persistent inward Na+ current and prolongation of the action potential plateau. Mexiletine, which decreases inward Na+ current29 and shortens the action potential, would be expected to—and, in fact, did1 —have a profound effect here, decreasing the QT interval. That increases in exercise-induced heart rate shortened the QT interval more than in control subjects is a bit surprising, but the explanation provided by the authors and related to longer open time for Na+ channels is logical and may be borne out by further experimentation.
One major implication of the study is that two very different forms of disease, having completely different genotypic determinants yet showing an identical phenotype, can be segregated by a simple clinical test. This can be the oral administration of mexiletine or, by extension, the IV administration of lidocaine. In their "clinical implications" section, Schwartz et al1 indicate that somewhat different patterns of onset of arrhythmias characterize chromosome 7 patients (tending toward situations of stress) and chromosome 3 patients (tending toward rest or sleep). Moreover, the former group is said to be more likely to benefit from simple ß-blocker therapy. If, in the detailed study now needed, the results of this paper with respect to mexiletine- and rate-induced changes in QT intervals are borne out, then we shall gain a simple yet powerful means of making a diagnosis more readily applicable to planning therapy than is now possible.
Finally, the implications of the work by Schwartz et al1 and by others in the LQTS area go beyond the idiopathic LQTS itself. For example, some have wondered whether acquired LQTS (eg, induced by drugs) might be a variant on the congenital LQTS in the sense of reflecting a subclinical abnormality in a specific channel or channels that requires exposure to pharmacological agents for its phenotypic expression.34 Yet a preliminary report indicates that neither the HERG nor SCN5A mutations occurring in congenital LQTS are found in patients with acquired LQTS.34 And so we may ask whether other chromosomal anomalies are involved here. Additional questions remain, as well: for example, for the congenital LQTS, are there other anomalies? And what is it that determines the excess expression of LQTS, an autosomal-dominant disease, in female patients? And how can the information used in studies such as these be applied to modulation of the duration of the QT interval and/or the effective refractory period in a way that would have therapeutic application?
In closing, investigators from three countries, who are supported by a variety of funding sources, represent academia and industry, and specialize in clinical and basic research, all had a hand in the studies. As such, this article and the prior reports that provided its information base demonstrate clearly how the support of diverse basic and clinically oriented research leads to significant clinical advancement. The message is self-evident and is to be emphasized to all who question the relationship of research in basic science to clinical application and the value of clinical studies in identifying telling questions for basic investigation.
|
Footnotes |
|---|
The opinions expressed in this Editorial are not necessarily those of the Editor or of the American Heart Association.
|
References |
|---|
|
TopIntroductionReferences |
|---|
1. Schwartz PJ, Priori SG, Locati EH, Napolitano C, Cantu F, Towbin JA, Keating MT, Hammoude H, Brown AM, Chen L-SK, Colatsky TJ. 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. Circulation. 1995;92:3381-3386.
2. Jervell A, Lange-Nielsen F. Congenital deaf-mutism, functional heart disease with prolongation of the Q-T interval and sudden death. Am Heart J. 1957;54:59-68. [Medline] [Order article via Infotrieve]
3. Romano C, Gemme G, Pongiglione R. Aritmie cardiache rare in età pediatrica. Clin Pediatr. 1963;45:656-683.
4. Ward OC. A new familial cardiac syndrome in children. J Irish Med Assoc. 1964;54:103-106. [Medline] [Order article via Infotrieve]
5. Schwartz PJ, Locati EH, Napolitano C, Priori SG. The long QT syndrome. In: Zipes DP, Jalife J, eds. Cardiac Electrophysiology: From Cell to Bedside. 2nd ed. Philadelphia, PA: WB Saunders Co; 1995:788-811.
6. Schwartz PJ. Idiopathic long QT syndrome: progress and questions. Am Heart J. 1985;109:399-411. [Medline] [Order article via Infotrieve]
7. Vincent GM, Timothy KW, Leppert M, Keating M. The spectrum of symptoms and QT intervals in carriers of the gene for the long QT syndrome. N Engl J Med. 1992;327:846-852. [Abstract]
8.
Moss AJ, Schwartz PJ, Crampton RS, Tzivoni D, Locati
EH, MacCluer J, Hall WJ, Weitkamp L, Vincent GM, Garson A Jr, Robinson
JL, Benhorin J, Choi S. The long QT syndrome: prospective
longitudinal study of 328 families.
Circulation. 1991;84:1136-1144.
9. Hashiba K. Hereditary QT prolongation syndrome in Japan: genetic analysis and pathological findings of the conducting system. Jpn Circ J. 1978;42:1133-1150. [Medline] [Order article via Infotrieve]
10. Hashiba K. Some genetic analysis of the Romano-Ward syndrome: with special reference to the incidence of manifestations and its sex difference. In: Iwa T, Fontaine G, eds. Cardiac Arrhythmias: Recent Progress in Investigation and Management. Amsterdam, Netherlands: Elsevier Science Publishers BV; 1988:203-210.
11. Schwartz PJ, Periti M, Malliani A. The long Q-T syndrome. Am Heart J. 1975;89:378. [Medline] [Order article via Infotrieve]
12.
Schwartz PJ, Locati EH, Moss AJ, Crampton RS, Trazzi R,
Ruberti U. Left cardiac sympathetic denervation in the therapy
of congenital long QT syndrome: a worldwide report.
Circulation. 1991;84:503-511.
13. Edlar M, Griffin JC, Abbott JA, Benditt D, Bhandari A, Herre JM, Benson DW, Scheinman MM. Permanent cardiac pacing in patients with the long QT syndrome. J Am Coll Cardiol. 1987;10:600-607. [Abstract]
14.
Moss AJ, Liu JE, Gottlieb S, Locati EH, Schwartz PJ,
Robinson JL. Efficacy of permanent pacing in the management of
high-risk patients with long QT syndrome.
Circulation. 1991;84:1524-1529.
15.
Moss AG. Prolonged QT-interval syndrome.
JAMA. 1986;256:2985-2987.
16. Schwartz PJ. Prevention of the arrhythmias in the long QT syndrome. In: Kulbertus HE, ed. Medical Management of Cardiac Arrhythmias. Edinburgh, UK: Churchill Livingston; 1985:153-161.
17.
Keating M, Atkinson D, Dunn C, Timothy K, Vincent GM,
Leppert M. Linkage of a cardiac arrhythmia, the long QT
syndrome, and the Harvey ras-1 gene.
Science. 1991;252:704-706.
18.
Martin GA, Yatani A, Clark R, Conroy L, Polakis P,
Brown AM, McCormick F. Gap domains responsible for
ras p21-dependent inhibition of muscarinic atrial
K+ channel currents. Science. 1992;255:192-194.
19. Curran M, Atkinson D, Timothy K, Vincent GM, Moss AJ, Leppert M, Keating M. Locus heterogeneity of autosomal dominant long QT syndrome. J Clin Invest. 1993;92:799-803.
20.
Dean JC, Cross S, Jennings K. Evidence of
genetic and phenotypic heterogeneity in the Romano-Ward
syndrome. J Med Genet. 1993;30:947-950.
21. Akimoto K, Matsuoka R, Kasanuki H, Takao A, Monma K, Hayakawa K, Hosoda S. Linkage analysis in a Japanese long QT syndrome family. Kokyuto Junkan. 1993;41:463-465.
22. Jiang C, Atkinson D, Towbin JA, Splawski I, Lehmann MH, Li H, Timothy K, Taggart RT, Schwartz PJ, Vincent GM, Moss AJ, Keating MT. Two long QT syndrome loci map to chromosomes 3 and 7 with evidence for further heterogeneity. Nat Genet. 1994;8:141-147. [Medline] [Order article via Infotrieve]
23. Schott J-J, Peltier S, Foley P, Drouin E, Bouheur J-B, Donnely P, Vergnaud G, Moisan J-P, Lemarec H, Pascal O. Mapping of a new gene for the long QT syndrome. Circulation. 1994;90(suppl I):I-605. Abstract.
24.
Papazian DM, Schwarz TL, Tempel BL, Jan YN, Jan
LY. Cloning of genomic and complementary DNA from Shaker, a
putative potassium channel gene from Drosophila.
Science. 1987;237:749-753.
25.
Warmke J, Drysdale R, Ganetzky B. A distinct
potassium channel polypeptide encoded by the Drosophila eag
locus. Science. 1991;252:1560-1562.
26.
Warmke JW, Ganetzky B. A family of potassium
channel genes related to eag in Drosophila and mammals.
Proc Natl Acad Sci U S A. 1994;91:3438-3442.
27. Curran ME, Spiawski I, Timothy KW, Vincent GM, Green ED, Keating MT. A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell. 1995;80:795-803. [Medline] [Order article via Infotrieve]
28. Sanguinetti MC, Jiang C, Curran ME, Keating MT. A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the Ikr potassium channel. Cell. 1995;81:299-307. [Medline] [Order article via Infotrieve]
29.
Hondeghem LM. Antiarrhythmic agents: modulated
receptor applications. Circulation. 1987;75:514-520.
30.
Kline RP, Kupersmith J. Effects of extracellular
potassium accumulation and sodium pump activation on automatic canine
Purkinje fibres. J Physiol (Lond). 1982;324:507-533.
31.
Rogart RB, Cribbs LL, Muglia LK, Kephart DD, Kaiser
MW. Molecular cloning of a putative
tetrodotoxin-resistant rat heart Na+ channel
isoform. Proc Natl Acad Sci U S A. 1989;86:8170-8174.
32.
Gellens ME, George AL, Chen L, Chahine M, Horn R,
Barchi RL, Kallen RG. Primary structure and functional
expression of the human cardiac tetrodotoxin-insensitive
voltage-dependent sodium channel. Proc Natl Acad Sci
U S A. 1992;89:554-558.
33. George AL Jr, Varkony TA, Drabkin HAK, Han J, Knops JF, Finley WH, Brown GB, Ward DC, Haas M. Assignment of the human heart tetrodotoxin-resistant voltage-gated Na+ channel alpha-subunit gene (SCN5A) to band 3p21. Cytogenet Cell Genet. 1995;68:67-70. [Medline] [Order article via Infotrieve]
34. Wei J, Wathen M, Murray K, Daw R, Roden D, George AL Jr. Absence of HERG and SCN5A mutations in acquired long QT syndrome. Circulation. 1995;92:I-275. Abstract.
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||