Congenital long QT syndrome (LQTS) is an inherited arrhythmia syndrome characterized by a prolonged QT interval on the 12-lead ECG, torsades de pointes and a higher chance of sudden cardiac death. LQTS segregates in a Mendelian fashion, which includes Romano-Ward syndrome with an autosomal dominant pattern as well as a rare autosomal recessive pattern (Jervell and Lange-Nielsen syndrome). Since 1957 when Jervell and Lange-Nielsen reported the first familial LQTS with congenital deafness, progress in understanding the genetic and electrophysiological mechanisms of LQTS has tremendously improved diagnostic methods and treatments. In the meantime, it has become evident that LQTS may not always be explained by a single gene mutation, but seems to follow a more complex genetic model intertwined with genetic common polymorphisms that have a mild to moderate effect on disease expression. In this review, we summarize the characteristics of LQTS (mainly LQT1–3) and briefly describe the most recent advances in LQTS clinical diagnostics as well as genetics. (Circ J 2014; 78: 2827–2833)
Since the first description of a LQTS family in 1957,1
tremendous progress in understanding its pathogenesis, diagnosis and treatments has been achieved. This review will describe the recent update of the diagnostic scoring system in 2011, the expert consensus statement published in 2013 and new challenges in discovering genotype-phenotype relationship in LQTS. Because of limited space, our focus is mainly on the general concept of the most frequently encountered Romano-Ward syndrome (RWS; LQTS types 1–3). Details of minor LQTS subtypes are to be found elsewhere.2–4
The prevalence of congenital LQTS is reported to be approximately 1/2,000.5
Syncope is generally the most commonly encountered first episode in LQTS patients, and aborted cardiac arrest/sudden cardiac death (ACA/SCD) is rare (1–3%).6
Of the patients who eventually become symptomatic, 50% experience their first cardiac event by the age of 12, and 90% by the age of 40.7
LQTS is also known as an etiology of sudden infant death syndrome (SIDS)8
and in approximately 10% of SIDS cases the infant carried a mutation in a LQTS-causing gene.9
The most frequent LQTS subtypes are type 1 (LQT1), type 2 (LQT2) and type 3 (LQT3).10
The subdivision is based on the underlying genetic substrate, with the potassium channel genes,
KCNH2, and the sodium channel gene,
SCN5A, as the involved genes. Specific triggers of symptoms are known in these major LQTS subtypes. For example in LQT1, cardiac events occur during physical exertion or emotional stress, typically during swimming,11
whereas auditory stimulation such as an alarm clock or a telephone bell is a typical trigger for arrhythmic events in LQT2.12
Emotional stress, as well as the postpartum period, are also frequently observed triggers of arrhythmia in LQT2.11,13
More recently, a history of epilepsy has been reported to be more common with LQT2 (39%) than with other subtypes of LQTS (10%, P<0.001),14
is expressed in the brain as well.14
Obviously in such cases, the differential diagnosis of LQTS and epilepsy is important for treatment, because LQTS is often mistreated as epilepsy because of generalized seizures secondary to torsades de pointes. In LQT3, symptoms are most frequently observed during rest or at night.11,15
shows the LQTS diagnostic scoring system (updated in 2011), which includes symptoms, family history and ECG findings.16
Patients with a Schwartz score ≥3.5 points in the absence of a secondary cause for QT prolongation are diagnosed as LQTS.17
Typical LQTS cases can be readily diagnosed with this scoring system, whereas latent LQTS patients with normal QTc at rest, found in 36% of LQT1, 19% of LQT2 and 10% of LQT3, respectively,18
may show a non-diagnostic score of 1–3 points. In such cases, serial ECGs, 24-h Holter recordings, and an exercise or epinephrine test are recommended to reveal subclinical QT prolongation.19–21
Schwartz Score (Updated in 2011)16
| >480 ms
| 460–470 ms
| 450 (male) ms
| 4-min recovery QTc after exercise test ≥480 ms
| Torsades de pointes
| T-wave alternans
| Notched T wave in 3 leads
| Low heart rate for age
| With stress
| Without stress
| Congenital deafness
| A. Family members with definite LQTS
| B. Unexplained sudden cardiac death <age 30 among immediate family members
LQTS diagnostic criteria. QTc is calculated by Bazett’s formula where QTc=QT/. Low heart rate for age means resting heart rate below the 2nd percentile for age.
With regard to the exercise test, the QT interval during the recovery phase is valuable in LQTS diagnostics.22,23
In 69 relatives of LQT1 and LQT2 probands who showed borderline to normal QTc at rest, Sy et al reported that a 4-min recovery QTc ≥445 ms discriminated LQTS gene carriers from non-carriers, and a 4-min recovery ≥480 ms showed 100% specificity.22
Horner et al reported from exercise testing of 243 patients that paradoxical QTc prolongation during the recovery phase (QTc ≥460 ms) distinguished LQTS, particularly LQT1, and ∆QTc ≥30 ms (QTc 3-min recovery minus the baseline supine QTc) showed a high sensitivity and specificity (83% and 93%, respectively).23
Importantly, both studies reported that exercise testing showed satisfactory results in distinguishing LQTS cases from innocent ones while on β-blockers, suggesting no need for a β-blocker washout.22,23
As another diagnostic method in LQTS, brisk movement from supine to upright has been reported.24
In that study, QTc was significantly increased by 89±47 ms in the LQTS group compared with 50±30 ms in the control group during maximal sinus tachycardia induced by standing up.24
To note, the QT interval measurement can vary according to physician and LQTS expertise.25
In addition, accurate measurement of the QTc interval at high heart rate (HR) is particularly challenging. In the case of children, by analyzing ECGs from a school-based screening program, Yoshinaga et al managed to appropriately diagnose genotype-positive LQTS cases with a QTc cut-off value (Bazett’s formula) ≥450 ms for HR <75 beats/min and ≥500 ms for HR ≥75 beats/min (94% in screened children), although it was not shown how many genotype-positive patients were missed by the use of these cut-off values.26
In any case, an expert eye on the QT interval (and ST-T morphology) remains a cornerstone of LQTS diagnostics.
In addition to the diagnostic criteria just mentioned, T wave morphology may help differentiate LQT1–3.27
Typically, a broad T wave is observed in LQT1 (Figure A), a biphasic T wave in LQT2 (Figure B) and a late-appearing T wave in LQT3, which has a narrow and tall shape, and appears at the very end of the QT interval (Figure C).27
ECGs of LQTS types 1–3, with the typical T wave of each subtype. (A) LQTS type 1 with typical broad-based T wave pattern. (B) LQTS type 2 with typical bifid T wave. (C) LQTS type 3 with late-onset peaked T wave.
Furthermore, genotyping is certainly important in the diagnosis and treatment of LQTS.17
Currently in Asia, LQTS genetic testing (candidate gene approach) is reimbursed in Korea (by Korean NIH for 13 LQTS genes) and in Japan (70% covered by the government public health insurance), but it remains at research level at least in Bangladesh, China, India, Taiwan and Thailand because of either high costs or lack of facilities for broad use (personal communication). Currently, in the era of next-generation sequencing, technological advances enable us to screen many more genes through disease-associated gene panels or even whole exome sequencing. However, with these methods, there are numerous rare “variants of unknown significance” reported with unknown risk associated with disease. Such variants remain elusive and await further research to establish genotype-phenotype relationships before they can used in the clinical setting.
Electrophysiological and Genetic Abnormalities in LQTS
The QT interval reflects repolarization of the ventricular action potentials orchestrated by various cardiac ion currents, including sodium, calcium and potassium currents.28
When a decreased potassium current (loss-of-function) or increased sodium or calcium current (gain-of-function) is caused by a mutation in an ion channel or axillary protein, a prolongation of the action potential duration occurs, which manifests on the 12-lead ECG as QT prolongation.
In 1995 and 1996, causal gene mutations of familial LQTS in 3 genes (KCNQ1,
SCN5A) were discovered.28–30
To date, mutations in 15 different genes have been reported in LQTS (Table 2),31–41
remain numerically the major genes in LQTS and comprise more than 90% of genotype-positive cases of LQTS.10
A causal mutation is found in approximately 75% of LQTS patients with a Schwartz score ≥4,42
but the genetic background of the other 25% of patients remain elusive.
Congenital LQTS Genes and Affected Ion Currents
||↓ Coordination of Ncx,
|Jervell and Lange-Nielsen
In approximately 85% of genotype-positive cases of LQTS, the patient carries a mutation inherited from one of the parents and in the remaining 15% a de novo mutation is pertinent.43
In genotyped LQTS patients, approximately 50% have no lifetime symptoms, and 10–50% of such patients show no apparent QT prolongation.44–46
Compound mutations (ie, ≥2 mutations) are found in 10% of genotype-positive patients47
and the clinical manifestation of disease in such patients is often more severe.48,49
As for minor LQTS subtypes with severe clinical phenotypes, mutations in
present as homozygous or compound heterozygous mutations in Jervell and Lange-Nielsen syndrome (J-LNS;
mutations are much more prevalent (90%) than
Calmodulin de novo mutations were reported in infant cases of recurrent cardiac arrest by means of exome sequencing in the parents-child trio.41
Genetic Modifiers of LQTS
Since the beginning of research into the genetic background in LQTS, linkage analysis and the candidate gene approach have been used, assuming LQTS to be a monogenic model. Later, it became evident from research into large LQTS families that LQTS actually shows incomplete penetrance with variable expressivity. In other words, different clinical phenotypes (sudden death, syncope, asymptomatic) are observed in family members carrying the same familial mutation, which may be caused by a more complex genetic model involving multiple genetic and environmental factors affecting disease development.
Modifier genes are common genetic variants found in more than 1% of affected individuals, which have an influence on susceptibility to disease. They have less effect on disease compared with a causal gene mutation, but by summing up the effects of such modifier genes, the disease severity varies. In LQTS, variants in the coding regions of LQTS-related genes such as
are known to influence the QT interval. Single nucleotide polymorphisms (SNPs) in non-coding regions (intron, 3’UTR) of
are also reported as an important QT-interval modifier.56,57
Furthermore, genome-wide association studies have revealed SNPs in
as a modulator of QT interval in LQTS patients,58,59
as well as in the general population.60
An effort to find any SNPs affecting QT interval of the Caucasian general population continues by larger international consortia.61
This field is expected to expand to further understand the complexity of genotype-phenotype relationship in LQTS. However, it remains currently at the research level, which requires careful interpretation by experts.62
Risk Assessment of Cardiac Events
The well-established parameters of risk stratification in LQTS patients are prolonged QTc interval ≥500 ms and a history of syncope.18
More detailed studies have revealed that the risk of a first cardiac event in males is higher in childhood before puberty, whereas in females, cardiac events occur during adolescence and the postpartum period.63,64
In adults between 18 and 40 years of age, the risks of experiencing any cardiac event are a history of ≥1 cardiac events before age 18 years, female sex, longer QTc interval (≥440 ms) and LQT2.65
For patients older than 40 years, LQT3 patients have significantly more cumulative lethal arrhythmic events (35%) than LQT1 (14%), LQT2 (24%) and genotype-negative patients (10%).66,67
Importantly, a family history of SCD in a first-degree relative is not a significant risk for ACA/SCD.68
LQTS patients with a normal QTc interval (≤440 ms) carry a lower risk of ACA/SCD compared with LQTS patients with QT prolongation (QTc >440 ms), but still show >10-fold risk of fatal arrhythmia compared with genotype- and phenotype-negative family members.69
Such “latent” cases of LQTS can be recapitulated by cellular electrophysiological studies and can give further insights to the mechanisms. For example, Wu et al used a heterozygous construct of
KCNQ1-G269S in CHO and HEK cells and showed that this mutation located in segment 5 of IKs
channel significantly disrupted upregulation of IKs
currents in response to protein kinase A (PKA) stimulation, which fits with the clinical characteristics of patients carrying
KCNQ1-G269S (borderline QT interval at rest and QT prolongation and syncope after exercise).70
More recent studies have shown that mutation location and type influence the variability of symptoms. In patients with LQT1, missense cytoplasmic-loop mutations have been reported to cause a longer QT interval at enrolment and an increased risk of ACA/SCD.71
As a specific mutation in
A341V, more than other
mutations (transmembrane or dominant-negative mutations), harbors the most severe phenotype.72–74
In LQT2 patients, the risk of ACA/SCD is higher in females regardless of mutation site compared with males.75
Among male subjects, patients with pore-loop mutations,75
especially missense mutations,76
show a higher incidence of ACA/SCD compared with non-pore-loop mutations.
Beta-blocker therapy is the first choice for LQTS.17
It dramatically decreases event rates, from 0.97 to 0.31 events per patient per year.77
Recurrent events were often seen in patients with a history of ACA or in patients who are non-compliant with β-blocker therapy.77
In LQT1 and LQT2, propranolol (2–4 mg·kg–1·day–1) and nadolol (1–1.5 mg·kg–1·day–1) have been shown to be much more effective than metoprolol in suppressing recurrent cardiac events.78
Therefore, metoprolol should probably not be prescribed in symptomatic LQTS patients.78,79
Atenolol, not included in the aforementioned study, appears to be less effective, according to a study performed in (only) 28 genotyped patients with a median follow-up of 46 months.80
Of the 3 major genotypes of LQTS, β-blocker therapy is extremely effective in LQT1 because of the prominent involvement of adrenergic stimulation in its pathogenesis.11,70
Pure β-blockers are less effective in LQT2 than LQT1, possibly because of α1A
Preliminary data recently extracted from >400 LQT3 patients showed that β-blocker therapy is also protective in LQT3.82
As adjunctive therapy, some drugs are used in a genotype-specific manner. For example, oral K+
supplements are considered especially in LQT2 patients because the underlying genetic defect is very sensitive to the serum potassium level.83–85
This holds true particularly when the serum potassium level is low (eg, with diarrhea). In LQT3, mexiletine in addition to β-blocker therapy may be considered in patients with a specific mutation.86
Of note, worsening of QT prolongation by mexiletine was reported in 1 individual with LQT3.87
Therefore, it is important in LQT3 patients to re-check the QT interval after mexiletine administration when the serum mexiletine level reaches the therapeutic level.79
Another drug, ranolazine, a FDA-approved anti-anginal agent, has recently drawn attention as an alternative choice to treat patients with LQTS because it blocks the late sodium current, INa late, (and to a minor extent the IKr
without proarrhythmic effects).88
There is so far only 1 clinical report, which includes a small number of patients, on the short-term effectiveness of ranolazine in LQT3.89
Cardiac events in LQTS patients are generally well controlled with β-blocker therapy. However, patients with a history of ACA, symptomatic patients in the first year of life, and patients with J-LNS carrying
mutations are at particularly high risk and therefore, special aids, including implantable cardioverter defibrillator (ICD) and left cardiac sympathetic denervation (LCSD) on top of β-blocker therapy may be deemed necessary because of the high recurrence rate of fatal arrhythmia.77,90
Besides medical treatment, life-style advice for patients is important.17
LCSD is a surgical procedure to ablate the lower two-thirds of the left stellate ganglion together with the thoracic ganglia T2–T4 to denervate cardiac sympathetic innervation to the heart.91
It is currently used as an adjunctive therapy in symptomatic patients who are refractory to β-blocker therapy. LCSD has been shown to reduce cardiac events significantly in LQTS with a rather high long-term cardiac-event-free survival (46%/5 years,91
59%/2 years92). In patients with a history of syncope, post-LCSD QTc <500 ms predicts efficacy of LCSD.91
However, those with persistent QTc prolongation (≥500 ms) have a high chance of SCD and need to be protected with an ICD. A known complication of this procedure is Horner’s syndrome, but in most cases, it is only transiently observed after the surgery and the patient recovers afterwards.91
Use of an ICD should be regarded as adjunctive therapy in LQTS. An ICD is recommended only for patients who have frequent syncopal episodes despite being on maximal doses of β-blocker (and eventually other additional pharmacological therapies) or at high risk of recurrent ACA/SCD,17
such as patients who have a history of ACA, symptomatic infant cases (<1 year of age) or those with J-LNS.52
Research on LQTS in the past 2 decades has broadened our knowledge of the mechanism as well as genotype-specific therapeutic options. An ongoing challenge is LQTS with normal to borderline QTc at rest. In such cases, diagnostic tests to detect maladaptation of the QT interval to HR are clinically important. Indeed, the updated scoring system in 2011 now includes QT interval of a recovery phase after exercise. In LQTS genetics, next-generation sequencing enables us to detect SNPs in coding/non-coding regions of (LQTS-related) genes that modify the QT interval. Currently, analysis and interpretation of results by next-generation sequencing remains at the research level while advances in the understanding of genotype-phenotype relationships, including LQTS causal genes as well as SNPs, are expected to guide us further to genetically-guided personalized treatment in the future.
We thank Dr Api Khong (Thailand), Dr Jie Wu (China), Dr Jyh-Ming Juang (Taiwan), Dr Laila Banu (Bangladesh), Dr Priya Chockalingam (India) and Dr Seil Oh (Korea) for providing information on LQTS genetic testing in their countries.
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.
Schwartz PJ, Ackerman MJ, George AL Jr, Wilde AA. Impact of genetics on the clinical management of channelopathies. J Am Coll Cardiol 2013; 62: 169–180.
Shimizu W, Horie M. Phenotypic manifestations of mutations in genes encoding subunits of cardiac potassium channels. Circ Res 2011; 109: 97–109.
Wilde AA, Brugada R. Phenotypical manifestations of mutations in the genes encoding subunits of the cardiac sodium channel. Circ Res 2011; 108: 884–897.
Schwartz PJ, Stramba-Badiale M, Crotti L, Pedrazzini M, Besana A, Bosi G, et al. Prevalence of the congenital long-QT syndrome. Circulation 2009; 120: 1761–1767.
Zareba W, Moss AJ, Schwartz PJ, Vincent GM, Robinson JL, Priori SG, et al. Influence of genotype on the clinical course of the long-QT syndrome: International Long-QT Syndrome Registry Research Group. N Engl J Med 1998; 339: 960–965.
Moss AJ, Schwartz PJ, Crampton RS, Tzivoni D, Locati EH, MacCluer J, et al. The long QT syndrome: Prospective longitudinal study of 328 families. Circulation 1991; 84: 1136–1144.
Schwartz PJ, Stramba-Badiale M, Segantini A, Austoni P, Bosi G, Giorgetti R, et al. Prolongation of the QT interval and the sudden infant death syndrome. N Engl J Med 1998; 338: 1709–1714.
Arnestad M, Crotti L, Rognum TO, Insolia R, Pedrazzini M, Ferrandi C, et al. Prevalence of long-QT syndrome gene variants in sudden infant death syndrome. Circulation 2007; 115: 361–367.
Goldenberg I, Zareba W, Moss AJ. Long QT syndrome. Curr Probl Cardiol 2008; 33: 629–694.
Schwartz PJ, Priori SG, Spazzolini C, Moss AJ, Vincent GM, Napolitano C, et al. Genotype-phenotype correlation in the long-QT syndrome: Gene-specific triggers for life-threatening arrhythmias. Circulation 2001; 103: 89–95.
Wilde AA, Jongbloed RJ, Doevendans PA, Duren DR, Hauer RN, van Langen IM, et al. Auditory stimuli as a trigger for arrhythmic events differentiate HERG-related (LQTS2) patients from KVLQT1-related patients (LQTS1). J Am Coll Cardiol 1999; 33: 327–332.
Khositseth A, Tester DJ, Will ML, Bell CM, Ackerman MJ. Identification of a common genetic substrate underlying postpartum cardiac events in congenital long QT syndrome. Heart Rhythm 2004; 1: 60–64.
Johnson JN, Hofman N, Haglund CM, Cascino GD, Wilde AA, Ackerman MJ. Identification of a possible pathogenic link between congenital long QT syndrome and epilepsy. Neurology 2009; 72: 224–231.
Takigawa M, Kawamura M, Noda T, Yamada Y, Miyamoto K, Okamura H, et al. Seasonal and circadian distributions of cardiac events in genotyped patients with congenital long QT syndrome. Circ J 2012; 76: 2112–2118.
Schwartz PJ, Crotti L. QTc behavior during exercise and genetic testing for the long-QT syndrome. Circulation 2011; 124: 2181–2184.
Priori SG, Wilde AA, Horie M, Cho Y, Behr ER, Berul C, et al. Executive summary: HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes. Europace 2013; 15: 1389–1406.
Priori SG, Schwartz PJ, Napolitano C, Bloise R, Ronchetti E, Grillo M, et al. Risk stratification in the long-QT syndrome. N Engl J Med 2003; 348: 1866–1874.
Goldenberg I, Mathew J, Moss AJ, McNitt S, Peterson DR, Zareba W, et al. Corrected QT variability in serial electrocardiograms in long QT syndrome: The importance of the maximum corrected QT for risk stratification. J Am Coll Cardiol 2006; 48: 1047–1052.
Shimizu W, Ohe T, Kurita T, Shimomura K. Differential response of QTU interval to exercise, isoproterenol, and atrial pacing in patients with congenital long QT syndrome. Pacing Clin Electrophysiol 1991; 14: 1966–1970.
Shimizu W, Noda T, Takaki H, Nagaya N, Satomi K, Kurita T, et al. Diagnostic value of epinephrine test for genotyping LQT1, LQT2, and LQT3 forms of congenital long QT syndrome. Heart Rhythm 2004; 1: 276–283.
Sy RW, van der Werf C, Chattha IS, Chockalingam P, Adler A, Healey JS, et al. Derivation and validation of a simple exercise-based algorithm for prediction of genetic testing in relatives of LQTS probands. Circulation 2011; 124: 2187–2194.
Horner JM, Horner MM, Ackerman MJ. The diagnostic utility of recovery phase QTc during treadmill exercise stress testing in the evaluation of long QT syndrome. Heart Rhythm 2011; 8: 1698–1704.
Viskin S, Postema PG, Bhuiyan ZA, Rosso R, Kalman JM, Vohra JK, et al. The response of the QT interval to the brief tachycardia provoked by standing: A bedside test for diagnosing long QT syndrome. J Am Coll Cardiol 2010; 55: 1955–1961.
Viskin S. The QT interval: Too long, too short or just right. Heart Rhythm 2009; 6: 711–715.
Yoshinaga M, Kucho Y, Sarantuya J, Ninomiya Y, Horigome H, Ushinohama H, et al. Genetic characteristics of children and adolescents with long-QT syndrome diagnosed by school-based electrocardiographic screening programs. Circ Arrhythm Electrophysiol 2014; 7: 107–112.
Moss AJ, Zareba W, Benhorin J, Locati EH, Hall WJ, Robinson JL, et al. ECG T-wave patterns in genetically distinct forms of the hereditary long QT syndrome. Circulation 1995; 92: 2929–2934.
Curran ME, Splawski 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.
Wang Q, Curran ME, Splawski I, Burn TC, Millholland JM, VanRaay TJ, et al. Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias. Nat Genet 1996; 12: 17–23.
Wang Q, Shen J, Splawski I, Atkinson D, Li Z, Robinson JL, et al. SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome. Cell 1995; 80: 805–811.
Splawski I, Shen J, Timothy KW, Lehmann MH, Priori S, Robinson JL, et al. Spectrum of mutations in long-QT syndrome genes: KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Circulation 2000; 102: 1178–1185.
Mohler PJ, Schott JJ, Gramolini AO, Dilly KW, Guatimosim S, duBell WH, et al. Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death. Nature 2003; 421: 634–639.
Plaster NM, Tawil R, Tristani-Firouzi M, Canun S, Bendahhou S, Tsunoda A, et al. Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen’s syndrome. Cell 2001; 105: 511–519.
Splawski I, Timothy KW, Sharpe LM, Decher N, Kumar P, Bloise R, et al. Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell 2004; 119: 19–31.
Vatta M, Ackerman MJ, Ye B, Makielski JC, Ughanze EE, Taylor EW, et al. Mutant caveolin-3 induces persistent late sodium current and is associated with long-QT syndrome. Circulation 2006; 114: 2104–2112.
Medeiros-Domingo A, Kaku T, Tester DJ, Iturralde-Torres P, Itty A, Ye B, et al. SCN4B-encoded sodium channel beta4 subunit in congenital long-QT syndrome. Circulation 2007; 116: 134–142.
Chen L, Marquardt ML, Tester DJ, Sampson KJ, Ackerman MJ, Kass RS. Mutation of an A-kinase-anchoring protein causes long-QT syndrome. Proc Natl Acad Sci USA 2007; 104: 20990–20995.
Ueda K, Valdivia C, Medeiros-Domingo A, Tester DJ, Vatta M, Farrugia G, et al. Syntrophin mutation associated with long QT syndrome through activation of the nNOS-SCN5A macromolecular complex. Proc Natl Acad Sci USA 2008; 105: 9355–9360.
Wu G, Ai T, Kim JJ, Mohapatra B, Xi Y, Li Z, et al. α-1-syntrophin mutation and the long-QT syndrome: A disease of sodium channel disruption. Circ Arrhythm Electrophysiol 2008; 1: 193–201.
Yang Y, Yang Y, Liang B, Liu J, Li J, Grunnet M, et al. Identification of a Kir3.4 mutation in congenital long QT syndrome. Am J Hum Genet 2010; 86: 872–880.
Crotti L, Johnson CN, Graf E, De Ferrari GM, Cuneo BF, Ovadia M, et al. Calmodulin mutations associated with recurrent cardiac arrest in infants. Circulation 2013; 127: 1009–1017.
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.
Barsheshet A, Brenyo A, Moss AJ, Goldenberg I. Genetics of sudden cardiac death. Curr Cardiol Rep 2011; 13: 364–376.
Ackerman MJ. The long QT syndrome: Ion channel diseases of the heart. Mayo Clin Proc 1998; 73: 250–269.
Moss AJ. Long QT Syndromes. Curr Treat Options Cardiovasc Med 2000; 2: 317–322.
Schwartz PJ. Clinical applicability of molecular biology: The case of the long QT syndrome. Curr Control Trials Cardiovasc Med 2000; 1: 88–91.
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.
Westenskow P, Splawski I, Timothy KW, Keating MT, Sanguinetti MC. Compound mutations: A common cause of severe long-QT syndrome. Circulation 2004; 109: 1834–1841.
Itoh H, Shimizu W, Hayashi K, Yamagata K, Sakaguchi T, Ohno S, et al. Long QT syndrome with compound mutations is associated with a more severe phenotype: A Japanese multicenter study. Heart Rhythm 2010; 7: 1411–1418.
Splawski I, Timothy KW, Vincent GM, Atkinson DL, Keating MT. Molecular basis of the long-QT syndrome associated with deafness. N Engl J Med 1997; 336: 1562–1567.
Schulze-Bahr E, Wang Q, Wedekind H, Haverkamp W, Chen Q, Sun Y, et al. KCNE1 mutations cause jervell and Lange-Nielsen syndrome. Nat Genet 1997; 17: 267–268.
Schwartz PJ, Spazzolini C, Crotti L, Bathen J, Amlie JP, Timothy K, et al. The Jervell and Lange-Nielsen syndrome: Natural history, molecular basis, and clinical outcome. Circulation 2006; 113: 783–790.
Nishio Y, Makiyama T, Itoh H, Sakaguchi T, Ohno S, Gong YZ, et al. D85N, a KCNE1 polymorphism, is a disease-causing gene variant in long QT syndrome. J Am Coll Cardiol 2009; 54: 812–819.
Crotti L, Lundquist AL, Insolia R, Pedrazzini M, Ferrandi C, De Ferrari GM, et al. KCNH2-K897T is a genetic modifier of latent congenital long-QT syndrome. Circulation 2005; 112: 1251–1258.
Makielski JC, Ye B, Valdivia CR, Pagel MD, Pu J, Tester DJ, et al. A ubiquitous splice variant and a common polymorphism affect heterologous expression of recombinant human SCN5A heart sodium channels. Circ Res 2003; 93: 821–828.
Duchatelet S, Crotti L, Peat RA, Denjoy I, Itoh H, Berthet M, et al. Identification of a KCNQ1 polymorphism acting as a protective modifier against arrhythmic risk in long-QT syndrome. Circ Cardiovasc Genet 2013; 6: 354–361.
Amin AS, Giudicessi JR, Tijsen AJ, Spanjaart AM, Reckman YJ, Klemens CA, et al. Variants in the 3’ untranslated region of the KCNQ1-encoded Kv7.1 potassium channel modify disease severity in patients with type 1 long QT syndrome in an allele-specific manner. Eur Heart J 2012; 33: 714–723.
Crotti L, Monti MC, Insolia R, Peljto A, Goosen A, Brink PA, et al. NOS1AP is a genetic modifier of the long-QT syndrome. Circulation 2009; 120: 1657–1663.
Tomas M, Napolitano C, De GL, Bloise R, Subirana I, Malovini A, et al. Polymorphisms in the NOS1AP gene modulate QT interval duration and risk of arrhythmias in the long QT syndrome. J Am Coll Cardiol 2010; 55: 2745–2752.
Arking DE, Pfeufer A, Post W, Kao WH, Newton-Cheh C, Ikeda M, et al. A common genetic variant in the NOS1 regulator NOS1AP modulates cardiac repolarization. Nat Genet 2006; 38: 644–651.
Arking DE, Pulit SL, Crotti L, van der Harst P, Munroe PB, Koopmann TT, et al. Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization. Nat Genet 2014; 46: 826–836.
Giudicessi JR, Ackerman MJ. Genetic testing in heritable cardiac arrhythmia syndromes: Differentiating pathogenic mutations from background genetic noise. Curr Opin Cardiol 2013; 28: 63–71.
Locati EH, Zareba W, Moss AJ, Schwartz PJ, Vincent GM, Lehmann MH, et al. Age- and sex-related differences in clinical manifestations in patients with congenital long-QT syndrome: Findings from the International LQTS Registry. Circulation 1998; 97: 2237–2244.
Rashba EJ, Zareba W, Moss AJ, Hall WJ, Robinson J, Locati EH, et al. Influence of pregnancy on the risk for cardiac events in patients with hereditary long QT syndrome: LQTS Investigators. Circulation 1998; 97: 451–456.
Sauer AJ, Moss AJ, McNitt S, Peterson DR, Zareba W, Robinson JL, et al. Long QT syndrome in adults. J Am Coll Cardiol 2007; 49: 329–337.
Goldenberg I, Moss AJ, Bradley J, Polonsky S, Peterson DR, McNitt S, et al. Long-QT syndrome after age 40. Circulation 2008; 117: 2192–2201.
Moss AJ, Goldenberg I. Importance of knowing the genotype and the specific mutation when managing patients with long QT syndrome. Circ Arrhythm Electrophysiol 2008; 1: 213–226.
Goldenberg I, Moss AJ, Peterson DR, McNitt S, Zareba W, Andrews ML, et al. Risk factors for aborted cardiac arrest and sudden cardiac death in children with the congenital long-QT syndrome. Circulation 2008; 117: 2184–2191.
Goldenberg I, Horr S, Moss AJ, Lopes CM, Barsheshet A, McNitt S, et al. Risk for life-threatening cardiac events in patients with genotype-confirmed long-QT syndrome and normal-range corrected QT intervals. J Am Coll Cardiol 2011; 57: 51–59.
Wu J, Naiki N, Ding WG, Ohno S, Kato K, Zang WJ, et al. A molecular mechanism for adrenergic-induced long QT syndrome. J Am Coll Cardiol 2014; 63: 819–827.
Barsheshet A, Goldenberg I, Uchi J, Moss AJ, Jons C, Shimizu W, et al. 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.
Brink PA, Crotti L, Corfield V, Goosen A, Durrheim G, Hedley P, et al. Phenotypic variability and unusual clinical severity of congenital long-QT syndrome in a founder population. Circulation 2005; 112: 2602–2610.
Crotti L, Spazzolini C, Schwartz PJ, Shimizu W, Denjoy I, Schulze-Bahr E, et al. 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.
Moss AJ, Shimizu W, Wilde AA, Towbin JA, Zareba W, Robinson JL, et al. Clinical aspects of type-1 long-QT syndrome by location, coding type, and biophysical function of mutations involving the KCNQ1 gene. Circulation 2007; 115: 2481–2489.
Migdalovich D, Moss AJ, Lopes CM, Costa J, Ouellet G, Barsheshet A, et al. Mutation and gender-specific risk in type 2 long QT syndrome: Implications for risk stratification for life-threatening cardiac events in patients with long QT syndrome. Heart Rhythm 2011; 8: 1537–1543.
Shimizu W, Moss AJ, Wilde AA, Towbin JA, Ackerman MJ, January CT, et al. Genotype-phenotype aspects of type 2 long QT syndrome. J Am Coll Cardiol 2009; 54: 2052–2062.
Moss AJ, Zareba W, Hall WJ, Schwartz PJ, Crampton RS, Benhorin J, et al. Effectiveness and limitations of beta-blocker therapy in congenital long-QT syndrome. Circulation 2000; 101: 616–623.
Chockalingam P, Crotti L, Girardengo G, Johnson JN, Harris KM, van der Heijden JF, et al. Not all beta-blockers are equal in the management of long QT syndrome types 1 and 2: Higher recurrence of events under metoprolol. J Am Coll Cardiol 2012; 60: 2092–2099.
Schwartz PJ, Crotti L, Insolia R. Long-QT Syndrome: From Genetics to Management. Circ Arrhythm Electrophysiol 2012; 5: 868–877.
Chatrath R, Bell CM, Ackerman MJ. Beta-blocker therapy failures in symptomatic probands with genotyped long-QT syndrome. Pediatr Cardiol 2004; 25: 459–465.
Zankov DP, Yoshida H, Tsuji K, Toyoda F, Ding WG, Matsuura H, et al. Adrenergic regulation of the rapid component of delayed rectifier K+ current: Implications for arrhythmogenesis in LQT2 patients. Heart Rhythm 2009; 6: 1038–1046.
Wilde A, Kaufman E, Shimizu W, Moss A, Benhorin J, Lopes CM, et al. Sodium channel mutations, risk of cardiac events, and efficacy of beta-blocker therapy in type 3 long QT syndrome. Heart Rhythm 2012; 9: S321.
Sanguinetti MC, Jurkiewicz NK. Role of external Ca2+ and K+ in gating of cardiac delayed rectifier K+ currents. Pflugers Arch 1992; 420: 180–186.
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.
Etheridge SP, Compton SJ, Tristani-Firouzi M, Mason JW. A new oral therapy for long QT syndrome: Long-term oral potassium improves repolarization in patients with HERG mutations. J Am Coll Cardiol 2003; 42: 1777–1782.
Ruan Y, Liu N, Bloise R, Napolitano C, Priori SG. Gating properties of SCN5A mutations and the response to mexiletine in long-QT syndrome type 3 patients. Circulation 2007; 116: 1137–1144.
Ruan Y, Denegri M, Liu N, Bachetti T, Seregni M, Morotti S, et al. Trafficking defects and gating abnormalities of a novel SCN5A mutation question gene-specific therapy in long QT syndrome type 3. Circ Res 2010; 106: 1374–1383.
Antzelevitch C, Burashnikov A, Sicouri S, Belardinelli L. Electrophysiologic basis for the antiarrhythmic actions of ranolazine. Heart Rhythm 2011; 8: 1281–1290.
Moss AJ, Zareba W, Schwarz KQ, Rosero S, McNitt S, Robinson JL. Ranolazine shortens repolarization in patients with sustained inward sodium current due to type-3 long-QT syndrome. J Cardiovasc Electrophysiol 2008; 19: 1289–1293.
Horigome H, Nagashima M, Sumitomo N, Yoshinaga M, Ushinohama H, Iwamoto M, et al. Clinical characteristics and genetic background of congenital long-QT syndrome diagnosed in fetal, neonatal, and infantile life: A nationwide questionnaire survey in Japan. Circ Arrhythm Electrophysiol 2010; 3: 10–17.
Schwartz PJ, Priori SG, Cerrone M, Spazzolini C, Odero A, Napolitano C, et al. Left cardiac sympathetic denervation in the management of high-risk patients affected by the long-QT syndrome. Circulation 2004; 109: 1826–1833.
Olde Nordkamp LR, Driessen AH, Odero A, Blom NA, Koolbergen DR, Schwartz PJ, et al. Left cardiac sympathetic denervation in the Netherlands for the treatment of inherited arrhythmia syndromes. Neth Heart J 2014; 22: 160–166.