Arthur J. Moss and Peter J. Schwartz
Uncover the Secrets of Long-QT Syndrome
25th Anniversary of the International Long-QT Syndrome Registry : An Ongoing Quest to
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25th Anniversary of the International Long-QT
An Ongoing Quest to Uncover the Secrets of Long-QT Syndrome
Arthur J. Moss, MD; Peter J. Schwartz, MD
(LQTS), but it was quite different 25 years ago when the
minuscule knowledge about LQTS was paralleled only by the
minute number of investigators interested in what seemed to
be little more than a medical oddity. Partly by chance, the two
of us had actually and independently developed a rather
burning interest and curiosity for this often lethal hereditary
disorder that is spiced by several unique features.1–4We
joined forces with the goal of unraveling this mysterious
disease by establishing a prospective International Registry
for LQTS. The main objectives were those to gain insight into
the natural history, clinical course, and efficacy of current and
novel therapies. When molecular biology techniques matured
to the point of making possible the identification of disease-
causing genes and disease-causing mutations, what became
essential was the availability of numerous and well-
developed clinical pedigrees providing clear separation be-
tween “affected” and “nonaffected” individuals. This is what
the Registry was able to provide and where it played a
decisive role in sharing with molecular biologists the ideal
material for their analysis.
In 1979, when the Registry was established, it did not
escape us that this long-term project was likely to contribute
to a better understanding and management of LQTS. Quite
frankly, however, we did not anticipate the explosion of
knowledge that would result from the genetic and molecular
findings of the 1990s and the central role that the Registry,
with its well-defined clinical phenotypes and family pedi-
grees, would play in uncovering the secrets of this disorder.
Additionally, we could not have fathomed the now clear
evidence that LQTS indeed represents a paradigm for the
understanding of sudden cardiac death in more common
oday, it is exceptional to find a major cardiology con-
gress without a session devoted to the long-QT syndrome
Our primary objective with the International LQTS Registry
was to gain insight into the natural history and clinical course
of this hereditary repolarization disorder so that more effec-
tive therapy could be rendered to prevent the syncope and
sudden death events that frequently accompanied LQTS.
The International LQTS Registry has enhanced our knowl-
edge base of an infrequently occurring cardiac disorder, and
it has become a paradigm for studying such conditions. The
diagnostic criteria for LQTS have been established.5The
cardiologists associated with the Registry continue to offer
physicians from around the world an opportunity to obtain
advice on how to manage their LQTS patients. This exchange
between the Registry cardiologists and physicians became a
mutually beneficial interaction because these physicians also
contributed clinical data to the Registry by willingly com-
pleting enrollment and yearly follow-up data forms. This
approach allowed us to gather information on an impressive
number of patients and, of crucial importance for the subse-
quent genetic developments, on first- and second-degree
family relatives. Over the years, the growing knowledge in
LQTS was shared with the profession through scientific
publications, chapters in cardiology textbooks, personal com-
munications, and recently, an Internet-based virtual LQTS
Subsequently, similar types of registries were established
by interested investigators for other uncommon cardiac dis-
orders, including hypertrophic cardiomyopathy, arrhythmo-
genic right ventricular cardiomyopathy, and Brugada syn-
drome. It is gratifying to know that the International LQTS
Registry helped to pave the way for scientific progress in the
difficult field of uncommon diseases.
By the early 1990s, molecular biology had made impressive
progress. The new genetic techniques, especially linkage
analysis and detection of DNA sequence differences, were
offering a realistic potential for the identification of disease
genes and disease-causing mutations. There was only one
limiting step, and not a small one. These techniques, as
powerful as they were, still depended for their success on the
availability of well-developed clinical pedigrees. Carefully
From the Cardiology Unit of the Department of Medicine, University of Rochester Medical Center, Rochester, NY (A.J.M.), and the Department of
Cardiology, IRCCS Policlinico S. Matteo and University of Pavia, Pavia, Italy (P.J.S.).
Correspondence to Arthur J. Moss, MD, Heart Research Follow-up Program, Box 653, University of Rochester Medical Center, Rochester, NY 14642.
© 2005 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.orgDOI: 10.1161/01.CIR.0000157069.91834.DA
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studied large family trees with clear separation between
affected and nonaffected individuals were essential. This is
where the Registry, with its many large families and myriad
of small families together with a quantitative QTc diagnostic
marker and well-defined clinical phenotypes, played a deci-
sive role in offering molecular biologists ideal material on
which to perform their analyses.
It was on this background that Keating and associates made
their fundamental discoveries.6–10It seems fair to say that in
modern cardiology, few findings have had such fruitful
consequences as the identification of the first 3 LQTS genes
(KvLQT1 [LQT1], hERG [LQT2], and SCN5A [LQT3]).
Merit is often not disjointed from good luck. The first series
of genes identified with LQTS were all encoding cardiac ion
channels, and it is fortunate that techniques already existed
that allowed for functional evaluation of the mutant genes by
cellular expression studies. These studies provided the evi-
dence on how a specific mutation, by altering cardiac elec-
trophysiology and the balance between inward and outward
currents, was affecting the cardiac action potential, thus
explaining how these mutations result in the lengthening of
ventricular repolarization coded as QT prolongation.
LQTS and Drug-Induced QT Prolongation
In 1982,11we highlighted the role of drug-induced QT
prolongation in delayed ventricular repolarization disorders.
We pointed out that flagrant QT prolongation and syncope
can occur at ordinary therapeutic doses of quinidine and
raised the possibility that “quinidine therapy may exacerbate
an underlying repolarization abnormality, possibly a subclin-
ical forme fruste of idiopathic LQTS with incomplete
Concurrent with the advance in the molecular genetics of
LQTS and the realization that reduction in the IKrcurrent
involving mutations in the hERG gene was responsible for
LQT2, drug-induced QT prolongation involving terfenadine,
cisapride, and other medications surfaced with documented
torsade de pointes and sudden death. The similarity of
acquired drug-induced prolongation of ventricular repolariza-
tion with the LQT2 form of LQTS was appreciated. The
information acquired from the Registry about the cellular and
molecular mechanisms involved in ion channel currents
contributed to our enhanced understanding of drug-induced
Findings From the Registry
The Registry, with its expanding number of genotyped
families, has provided an opportunity to study the clinical
aspects and explore the genotype-phenotype relationships in
this unique cardiovascular disorder. The first publication of
findings from the Registry occurred in 1985 when we
highlighted the risk factors for cardiac events in 196 LQTS
patients.12By 1991, we expanded the prospective study of the
clinical course of this disorder to 1016 affected individuals in
328 LQTS families.13Important findings from the Registry
during the past decade have included the following: age- and
sex-related differences in the clinical manifestations of
LQTS14; influence of pregnancy on the risk for cardiac events
in LQTS15; ECG T-wave patterns in genetically distinct
forms of LQTS16; clinical course of LQTS by genotype17; the
spectrum of mutations in LQTS genes18; increased risk
associated with mutations in the pore region of the hERG
gene19; role played by physical exercise, emotions, arousal,
and rest/sleep as triggers and facilitators for syncope and
sudden cardiac death in LQT1, LQT2, and LQT320–22; effec-
tiveness of ?-blocker therapy, particularly in patients with
LQT1 and LQT2 genotypes23; potential gene-specific useful-
ness of sodium channel blockers (mexiletine and flecainide)
in the treatment of patients with the LQT3 mutations24,25;
life-saving benefit from the implanted defibrillator in high-
risk LQTS patients26; and left cardiac sympathetic denerva-
tion in the management of high-risk LQTS patients.27
We initially thought that the clinical benefit of left-sided
sympathectomy might have come from either a correction of
a hypothesized left-sided dominance of sympathetic innerva-
tion or, in the case of a yet undefined “myocardial abnormal-
ity” (subsequently found to be represented by the mutations
in cardiac ion channel genes), from removal of an arrhyth-
mogenic trigger. Our current view is that the second hypoth-
esis was correct and that the benefit of left cardiac sympa-
thetic denervation reflects primarily the interruption of the
major source of norepinephrine release at the ventricular
Key to the success of the International LQTS Registry was
our good fortune to have an outstanding group of committed
multidisciplinary investigators who have been associated
with the program through several decades.
All registries have limitations. From the beginning we pre-
specified the data to be collected, but the initial data collec-
tion reflected our limited understanding of the disorder. As
we gained more insight into LQTS and its clinical and genetic
heterogeneity, we expanded the type and extent of collected
data, especially during yearly follow-ups. Our experience
with sophisticated data management grew as the Registry
expanded. Early on we recognized the need for biostatistical
and statistical-genetic expertise. Although we collected pro-
spective data and based our primary analyses on prespecified
hypotheses, several of our important secondary studies in-
volved retrospective analyses with the need to control for
relevant covariates. The Registry utilized observational data,
with all the potential problems of bias. Because the time
origin was usually birth when doing clinical course studies,
we appreciated the need for proportional-hazard survivorship
analyses using time-dependent end points for syncope,
aborted cardiac arrest, and death. Randomized placebo-
controlled clinical trials are not practical when dealing with a
rare cardiac disorder with relatively infrequent cardiac events,
and therefore we learned to control for various types of bias
as best we could through statistical adjustment techniques
when evaluating the safety and efficacy of ?-blocker, left
cardiac sympathetic denervation, and implanted defibrillator
Challenges for the Future
Additional new genes and new genetic mechanisms need to
be uncovered, modifier genes that explain the variable ven-
March 8, 2005
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tricular repolarization duration and/or the variable severity of
clinical manifestations in individuals with the same mutation
have yet to be identified, gene-specific and mutation-specific
therapy is presently in its infancy, and the brain-heart con-
nection with regard to emotional triggers of cardiac events
needs more neurophysiologically based investigations. Our
quest for uncovering the secrets of LQTS continues.
This work was supported in part by research grants HL-33843 and
HL-51618 from the National Institutes of Health, Bethesda, Md.
1. Moss AJ, McDonald J. Unilateral cervicothoracic sympathetic gan-
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J Med. 1971;285:903–904.
2. Schwartz PJ, Malliani A. Electrical alternation of the T-wave: clinical and
experimental evidence of its relationship with the sympathetic nervous
system and with the long Q-T syndrome. Am Heart J. 1975;89:45–50.
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Towbin JA, Keating MT. SCN5A mutations associated with an inherited
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tional cloning of a novel potassium channel gene: KVLQT1 mutations
cause cardiac arrhythmias. Nat Genet. 1996;12:17–23.
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and malignant ventricular arrhythmias. Modern Concepts Cardiovasc
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J, Hall WJ, Weitkamp L, Vincent GM, Garson A Jr, Robinson JL,
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GM, Towbin JA, Priori SG, Napolitano C, Robinson JL, Andrews M,
Timothy K, Hall WJ. Age- and sex-related differences in clinical mani-
festations in patients with congenital long-QT syndrome: findings from
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15. Rashba EJ, Zareba W, Moss AJ, Hall WJ, Robinson J, Locati EH,
Schwartz PJ, Andrews M, for the LQTS Investigators. Influence of
pregnancy on the risk for cardiac events in patients with hereditary long
QT syndrome. Circulation. 1998;97:451–456.
16. Moss AJ, Zareba W, Benhorin J, Locati EH, Hall WJ, Robinson JL,
Schwartz PJ, Towbin JA, Vincent GM, Lehmann MH, Keating MT,
MacCluer JW, Timothy KW. ECG T-wave patterns in genetically distinct
forms of the hereditary long QT syndrome. Circulation. 1995;92:
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Benhorin J, Locati EH, Towbin JA, Keating MT, Lehmann MH, Hall WJ,
for the International Long-QT Syndrome Registry Research Group.
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Moss AJ, Schwartz PJ, Towbin JA, Vincent GM, Keating MT. Spectrum
of mutations in long-QT syndrome genes: KVLQT1, HERG, SCN5A,
KCNE1, and KCNE2. Circulation. 2000;102:1178–1185.
19. Moss AJ, Zareba W, Kaufman ES, Gartman E, Peterson DR, Benhorin J,
Towbin JA, Keating MT, Priori SG, Schwartz PJ, Vincent GM, Robinson
JL, Andrews ML, Feng C, Hall WJ, Medina A, Zhang L, Wang Z.
Increased risk of arrhythmic events in long-QT syndrome with mutations
in the pore region of the human ether-a-go-go–related gene potassium
channel. Circulation. 2002;105:794–799.
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Vincent GM, Benhorin J, Locati Heilbron E, Towbin JA, Priori SG,
Napolitano C, Zhang L, Medina A, Andrews ML, Timothy K. Com-
parison of clinical and genetic variables of cardiac events associated with
loud noise versus swimming among subjects with the long QT syndrome.
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Locati EH, Priori SG, Napolitano C, Towbin JA, Hall WJ, Robinson JL,
Andrews ML, Zhang L, Timothy K, Medina A. Clinical and genetic
variables associated with acute arousal and nonarousal-related cardiac
events among subjects with long QT syndrome. Am J Cardiol. 2000;85:
22. Schwartz PJ, Priori SG, Spazzolini C, Moss AJ, Vincent GM, Napolitano
C, Denjoy I, Guicheney P, Breithardt G, Keating MT, Towbin JA, Beggs
AH, Brink P, Wilde AAM, Toivonen L, Zareba W, Robinson JL, Timothy
KW, Corfield V, Wattanasirichaigoon D, Corbett C, Haverkamp W,
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23. Moss AJ, Zareba W, Hall WJ, Schwartz PJ, Crampton RS, Benhorin J,
Vincent GM, Locati EH, Priori SG, Napolitano C, Medina A, Zhang L,
Robinson JL, Timothy K, Towbin JA, Andrews ML. Effectiveness and
limitations of beta-blocker therapy in congenital long-QT syndrome.
24. Schwartz PJ, Priori SG, Locati EH, Napolitano C, Cantù F, Towbin AJ,
Keating MT, Hammoude H, Brown AM, Chen LK, 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:
25. Windle JR, Geletka RC, Moss AJ, Zareba W, Atkins DL. Normalization
of ventricular repolarization with flecainide in long QT syndrome patients
with SCN5A:?KPQ mutation. Ann Noninvasive Electrocardiol. 2001;6:
26. Zareba W, Moss AJ, Daubert JP, Hall WJ, Robinson JL, Andrews M.
Implantable cardioverter defibrillator in high-risk long QT syndrome
patients. J Cardiovasc Electrophysiol. 2003;14:337–341.
27. Schwartz PJ, Priori SG, Cerrone M, Spazzolini C, Odero A, Napolitano
C, Bloise R, De Ferrari GM, Klersy C, Moss AJ, Zareba W, Robinson JL,
Hall WJ, Brink PA, Toivonen L, Epstein AE, Li C, Hu D. Left cardiac
sympathetic denervation in the management of high-risk patients affected
by the long-QT syndrome. Circulation. 2004;109:1826–1833.
electrophysiology ? genetics
Moss and Schwartz International Long-QT Syndrome Registry
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