LQTS Website Opening Materials
The long QT syndrome is a life threatening disease that represents a leading cause of
sudden cardiac death in the young 1. The ECG features of this disease are QTc
prolongation and T wave abnormalities at rest, and failure of the QTc to shorten
with exercise and epinephrine 2. Approximately 1 in 2500 healthy live births will
have an abnormally long QT interval and have genetic LQTS, transmitted via an
autosomal dominance inheritance pattern 1. This estimate suggests a prevalence of
12-15,000 Canadians with LQTS.
Based on historic case series of symptomatic untreated patients, one in five of these
patients would die within one year of their first episode of syncope, and 50% within
10 years 3-7. One of the characteristic features of LQTS is the marked heterogeneity
of patients, ranging from sudden death in infancy to lifelong asymptomatic disease
carriers. The same holds true for the ECG features that have been the trademark of
the disease, and have been heavily relied on for diagnosis and risk stratification. As
many as 40% of patients will have normal or non-diagnostic QT intervals at rest 8-11.
While these patients are at generally lower risk, one in ten will have an arrhythmic
event related to their disease before the age of 40. Furthermore, these patients are
at risk of fatal side effects from medications12. Exercise testing is very helpful in
unmasking evidence of failed QT shortening and propensity to QT mediated
arrhythmias 13-15.
Fortunately, with improved screening and therapy, the mortality rate in LQTS has
dropped dramatically 1. Lifestyle modifications such as avoidance of strenuous
exercise, swimming without supervision, and medications that can prolong the QT
interval are advocated for all patients. Beta-blocker therapy is the primary
treatment for LQTS, offering substantial protection from fatal cardiac events 16-19.
Patients who are intolerant or refractory to beta-blockers can be offered left cardiac
sympathetic denervation 20. Patients, who have cardiac events while on betablockers, who have suffered a cardiac arrest, or who are deemed sufficiently high
risk, can be offered an implantable cardioverter defibrillator (ICD)21-24. ICD therapy,
however, has lifelong implications, and complications are common and even
expected when the recipient has had the device for >20 years. The reader is directed
to the recent HRS/EHRA/APHRS guidelines on management of inherited
arrhythmia syndromes 25, 26.
While several higher risk categories have been defined including rare recessive
forms of disease, decisions regarding invasive management strategies are difficult
and risk stratification models in their current forms are difficult. In a report of an
academic tertiary center’s outcomes for primary prevention ICDs, 35% of patients
had ICD related morbidity, and none of these LQTS patients received appropriate
ICD treatment-related shocks27.
The majority of efforts at improving risk stratification in patients with LQTS have
focused on our rapidly improving understanding of genetics. Long QT is an
autosomal dominant condition with 13 associated reported genes responsible 28-31.
The reader is directed to the Canadian and HRS guidelines for genetic testing cited
below 21, 32. Consequently, LQTS has become one of the best-understood and
characterized monogenic diseases, serving as a model for the investigation of
genotype-phenotype interactions. This mechanistic basis and understanding of
disease has afforded clinicians an improved patient specific management strategy.
As an example, mutations that involve the transmembrane portion of the affected
ion channel in patients with type 1 LQTS predicted increased risk33. This resonates
with our current understanding of the pathophysiology of the disease, which is
defined by ion channel mutations driving ineffective transport of ions across the
transmembrane region and predisposing patients to lethal events. These data were
further supported by a second study from the International Registry, further honing
in on the region of interest considered to be critical to the sympathetic triggers of
patient events 34. When a Canadian group looked at phenotypic expression of these
C-loop mutations compared to non C-loop mutations, we were unable to replicate
the expected findings 35. This supports the role of a more population-based registry
to validate initial reports and develop a refined phenotype to correlate with
anticipated comprehensive genetic information. This is the basis for the proposed
Canadian Long QT Registry.
While attractive and timely, the efforts to precisely risk stratify patients using novel
genetic tools have been fraught with problems including unexpected or
unexplainable clinical findings or clinical courses, difficulty in corroborating
laboratory clinical findings with testable and reproducible human physiology, and
detailed characterization of rare forms of disease which have little impact on
population health 35, 36. The determinants of disease severity, in which family
members who carry an identical mutation can demonstrate polar extremes of
disease severity, remain largely unknown despite the apparent simplicity of a
monogenic disorder37. This phenotypic heterogeneity is of increasing clinical
consequence given the growing number of patients identified through cascade
screening that are genotype positive, phenotype negative, and have an ill-defined
prognosis. To look for new pathways that act independently or as cofactors in the
expression of disease experienced by individuals and families, there is a need to
better understand the phenotype, and correlate this improved characterization with
modern complex genomics.
1.
2.
Schwartz PJ, Crotti L, Insolia R. Long-qt syndrome: From genetics to
management. Circulation. Arrhythmia and electrophysiology. 2012;5:868-877
Ackerman MJ, Priori SG, Willems S, Berul C, Brugada R, Calkins H, Camm AJ,
Ellinor PT, Gollob M, Hamilton R, Hershberger RE, Judge DP, Le Marec H,
McKenna WJ, Schulze-Bahr E, Semsarian C, Towbin JA, Watkins H, Wilde A,
Wolpert C, Zipes DP, Heart Rhythm S, European Heart Rhythm A. Hrs/ehra
expert consensus statement on the state of genetic testing for the
channelopathies and cardiomyopathies: This document was developed as a
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
partnership between the heart rhythm society (hrs) and the european heart
rhythm association (ehra). Europace : European pacing, arrhythmias, and
cardiac electrophysiology : journal of the working groups on cardiac pacing,
arrhythmias, and cardiac cellular electrophysiology of the European Society of
Cardiology. 2011;13:1077-1109
Schwartz PJ. Idiopathic long qt syndrome: Progress and questions. American
heart journal. 1985;109:399-411
Sauer AJ, Moss AJ, McNitt S, Peterson DR, Zareba W, Robinson JL, Qi M,
Goldenberg I, Hobbs JB, Ackerman MJ, Benhorin J, Hall WJ, Kaufman ES,
Locati EH, Napolitano C, Priori SG, Schwartz PJ, Towbin JA, Vincent GM, Zhang
L. Long qt syndrome in adults. J Am Coll Cardiol. 2007;49:329-337
Jons C, Moss AJ, Goldenberg I, Liu J, McNitt S, Zareba W, Qi M, Robinson JL.
Risk of fatal arrhythmic events in long qt syndrome patients after syncope. J
Am Coll Cardiol. 2010;55:783-788
Wang Q, Shen J, Splawski I, Atkinson D, Li Z, Robinson JL, Moss AJ, Towbin JA,
Keating MT. Scn5a mutations associated with an inherited cardiac
arrhythmia, long qt syndrome. Cell. 1995;80:805-811
Schwartz PJ, Locati E. The idiopathic long qt syndrome: Pathogenetic
mechanisms and therapy. Eur Heart J. 1985;6 Suppl D:103-114
Priori SG, Napolitano C, Schwartz PJ. Low penetrance in the long-qt
syndrome: Clinical impact. Circulation. 1999;99:529-533
Tester DJ, Will ML, Haglund CM, Ackerman MJ. Effect of clinical phenotype on
yield of long qt syndrome genetic testing. J Am Coll Cardiol. 2006;47:764-768
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
Priori SG, Schwartz PJ, Napolitano C, Bloise R, Ronchetti E, Grillo M, Vicentini
A, Spazzolini C, Nastoli J, Bottelli G, Folli R, Cappelletti D. Risk stratification in
the long-qt syndrome. N Engl J Med. 2003;348:1866-1874
Vincent GM, Schwartz PJ, Denjoy I, Swan H, Bithell C, Spazzolini C, Crotti L,
Piippo K, Lupoglazoff JM, Villain E, Priori SG, Napolitano C, Zhang L. High
efficacy of beta-blockers in long-qt syndrome type 1: Contribution of
noncompliance and qt-prolonging drugs to the occurrence of beta-blocker
treatment "failures". Circulation. 2009;119:215-221
Sy RW, van der Werf C, Chattha IS, Chockalingam P, Adler A, Healey JS, Perrin
M, Gollob MH, Skanes AC, Yee R, Gula LJ, Leong-Sit P, Viskin S, Klein GJ, Wilde
AA, Krahn AD. Derivation and validation of a simple exercise-based algorithm
for prediction of genetic testing in relatives of lqts probands. Circulation.
2011;124:2187-2194
Wong JA, Gula LJ, Klein GJ, Yee R, Skanes AC, Krahn AD. Utility of treadmill
testing in identification and genotype prediction in long-qt syndrome. Circ
Arrhythm Electrophysiol. 2010;3:120-125
Chattha IS, Sy RW, Yee R, Gula LJ, Skanes AC, Klein GJ, Bennett MT, Krahn AD.
Utility of the recovery electrocardiogram after exercise: A novel indicator for
the diagnosis and genotyping of long qt syndrome? Heart Rhythm.
2010;7:906-911
16.
17.
18.
19.
20.
21.
22.
23.
Villain E, Denjoy I, Lupoglazoff JM, Guicheney P, Hainque B, Lucet V, Bonnet D.
Low incidence of cardiac events with beta-blocking therapy in children with
long qt syndrome. European heart journal. 2004;25:1405-1411
Monnig G, Kobe J, Loher A, Eckardt L, Wedekind H, Scheld HH, Haverkamp W,
Milberg P, Breithardt G, Schulze-Bahr E, Bocker D. Implantable cardioverterdefibrillator therapy in patients with congenital long-qt syndrome: A longterm follow-up. Heart rhythm : the official journal of the Heart Rhythm Society.
2005;2:497-504
Schwartz PJ, Spazzolini C, Priori SG, Crotti L, Vicentini A, Landolina M,
Gasparini M, Wilde AA, Knops RE, Denjoy I, Toivonen L, Monnig G, AlFayyadh M, Jordaens L, Borggrefe M, Holmgren C, Brugada P, De Roy L,
Hohnloser SH, Brink PA. Who are the long-qt syndrome patients who receive
an implantable cardioverter-defibrillator and what happens to them?: Data
from the european long-qt syndrome implantable cardioverter-defibrillator
(lqts icd) registry. Circulation. 2010;122:1272-1282
Horner JM, Kinoshita M, Webster TL, Haglund CM, Friedman PA, Ackerman
MJ. Implantable cardioverter defibrillator therapy for congenital long qt
syndrome: A single-center experience. Heart rhythm : the official journal of
the Heart Rhythm Society. 2010;7:1616-1622
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
Ackerman MJ, Priori SG, Willems S, Berul C, Brugada R, Calkins H, Camm AJ,
Ellinor PT, Gollob M, Hamilton R, Hershberger RE, Judge DP, Le Marec H,
McKenna WJ, Schulze-Bahr E, Semsarian C, Towbin JA, Watkins H, Wilde A,
Wolpert C, Zipes DP. Hrs/ehra expert consensus statement on the state of
genetic testing for the channelopathies and cardiomyopathies: This
document was developed as a partnership between the heart rhythm society
(hrs) and the european heart rhythm association (ehra). Europace.
2011;13:1077-1109
Nunn LM, Lambiase PD. Genetics and cardiovascular disease--causes and
prevention of unexpected sudden adult death: The role of the sads clinic.
Heart. 2011;97:1122-1127
Zipes DP, Camm AJ, Borggrefe M, Buxton AE, Chaitman B, Fromer M,
Gregoratos G, Klein G, Moss AJ, Myerburg RJ, Priori SG, Quinones MA, Roden
DM, Silka MJ, Tracy C, Smith SC, Jr., Jacobs AK, Adams CD, Antman EM,
Anderson JL, Hunt SA, Halperin JL, Nishimura R, Ornato JP, Page RL, Riegel B,
Priori SG, Blanc JJ, Budaj A, Camm AJ, Dean V, Deckers JW, Despres C,
Dickstein K, Lekakis J, McGregor K, Metra M, Morais J, Osterspey A, Tamargo
JL, Zamorano JL. Acc/aha/esc 2006 guidelines for management of patients
with ventricular arrhythmias and the prevention of sudden cardiac death: A
report of the american college of cardiology/american heart association task
force and the european society of cardiology committee for practice
guidelines (writing committee to develop guidelines for management of
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
patients with ventricular arrhythmias and the prevention of sudden cardiac
death). J Am Coll Cardiol. 2006;48:e247-346
Tang AS, Ross H, Simpson CS, Mitchell LB, Dorian P, Goeree R, Hoffmaster B,
Arnold M, Talajic M. Canadian cardiovascular society/canadian heart rhythm
society position paper on implantable cardioverter defibrillator use in
canada. Can J Cardiol. 2005;21 Suppl A:11-18
Priori SG, Wilde AA, Horie M, Cho Y, Behr ER, Berul C, Blom N, Brugada J,
Chiang CE, Huikuri H, Kannankeril P, Krahn A, Leenhardt A, Moss A, Schwartz
PJ, Shimizu W, Tomaselli G, Tracy C. Hrs/ehra/aphrs expert consensus
statement on the diagnosis and management of patients with inherited
primary arrhythmia syndromesexpert consensus statement on inherited
primary arrhythmia syndromes: Document endorsed by hrs, ehra, and aphrs
in may 2013 and by accf, aha, paces, and aepc in june 2013. Heart Rhythm.
2013:e75-e106
Priori SG, Wilde AA, Horie M, Cho Y, Behr ER, Berul C, Blom N, Brugada J,
Chiang CE, Huikuri H, Kannankeril P, Krahn A, Leenhardt A, Moss A, Schwartz
PJ, Shimizu W, Tomaselli G, Tracy C. Executive summary: Hrs/ehra/aphrs
expert consensus statement on the diagnosis and management of patients
with inherited primary arrhythmia syndromes. Heart Rhythm. 2013
Olde Nordkamp LR, Wilde AA, Tijssen JG, Knops RE, van Dessel PF, de Groot
JR. The icd for primary prevention in patients with inherited cardiac
diseases: Indications, use, and outcome: A comparison with secondary
prevention. Circulation. Arrhythmia and electrophysiology. 2013;6:91-100
Krahn AD, Sanatani S, Gardner MJ, Arbour L. Inherited heart rhythm disease:
Negotiating the minefield for the practicing cardiologist. Can J Cardiol.
2013;29:122-125
Hendrix A, Borleffs CJ, Vink A, Doevendans PA, Wilde AA, van Langen IM, van
der Smagt JJ, Bots ML, Mosterd A. Cardiogenetic screening of first-degree
relatives after sudden cardiac death in the young: A population-based
approach. Europace. 2011;13:716-722
Goldenberg I, Zareba W, Moss AJ. Long qt syndrome. Curr Probl Cardiol.
2008;33:629-694
Tester DJ, Will ML, Haglund CM, Ackerman MJ. Compendium of cardiac
channel mutations in 541 consecutive unrelated patients referred for long qt
syndrome genetic testing. Heart Rhythm. 2005;2:507-517
Gollob MH, Blier L, Brugada R, Champagne J, Chauhan V, Connors S, Gardner
M, Green MS, Gow R, Hamilton R, Harris L, Healey JS, Hodgkinson K,
Honeywell C, Kantoch M, Kirsh J, Krahn A, Mullen M, Parkash R, Redfearn D,
Rutberg J, Sanatani S, Woo A. Recommendations for the use of genetic testing
in the clinical evaluation of inherited cardiac arrhythmias associated with
sudden cardiac death: Canadian cardiovascular society/canadian heart
rhythm society joint position paper. Can J Cardiol. 2011;27:232-245
Moss AJ, Shimizu W, Wilde AA, Towbin JA, Zareba W, Robinson JL, Qi M,
Vincent GM, Ackerman MJ, Kaufman ES, Hofman N, Seth R, Kamakura S,
Miyamoto Y, Goldenberg I, Andrews ML, McNitt S. Clinical aspects of type-1
34.
35.
36.
37.
long-qt syndrome by location, coding type, and biophysical function of
mutations involving the kcnq1 gene. Circulation. 2007;115:2481-2489
Barsheshet A, Goldenberg I, J OU, Moss AJ, Jons C, Shimizu W, Wilde AA,
McNitt S, Peterson DR, Zareba W, Robinson JL, Ackerman MJ, Cypress M, Gray
DA, Hofman N, Kanters JK, Kaufman ES, Platonov PG, Qi M, Towbin JA,
Vincent GM, Lopes CM. Mutations in cytoplasmic loops of the kcnq1 channel
and the risk of life-threatening events: Implications for mutation-specific
response to beta-blocker therapy in type 1 long-qt syndrome. Circulation.
2012;125:1988-1996
Laksman ZW, Hamilton RM, Chockalingam P, Ballantyne E, Stephenson EA,
Gross GJ, Gula LJ, Klein GJ, Wilde AA, Krahn AD. Mutation location effect on
severity of phenotype during exercise testing in type 1 long-qt syndrome:
Impact of transmembrane and c-loop location. J Cardiovasc Electrophysiol.
2013
Crotti L, Spazzolini C, Schwartz PJ, Shimizu W, Denjoy I, Schulze-Bahr E,
Zaklyazminskaya EV, Swan H, Ackerman MJ, Moss AJ, Wilde AA, Horie M,
Brink PA, Insolia R, De Ferrari GM, Crimi G. The common long-qt syndrome
mutation kcnq1/a341v causes unusually severe clinical manifestations in
patients with different ethnic backgrounds: Toward a mutation-specific risk
stratification. Circulation. 2007;116:2366-2375
Amin AS, Pinto YM, Wilde AA. Long qt syndrome: Beyond the causal mutation.
The Journal of physiology. 2013