Long QT Syndrome-Population Genetics and Cardiac Studies (LQTS)

To investigate the clinical, genetic and cardiologic aspects of the Long QT Syndrome, a predominantly hereditary disease with episodic malignant arrhythmias and sudden death, and a demonstrated gene linkage in a large pedigree.

Study Overview

• Status: Completed
• Conditions: Heart Diseases; Cardiovascular Diseases; Ventricular Arrhythmia; Long QT Syndrome

Detailed Description

BACKGROUND:

The Long QT Syndrome (LQTS) is an infrequently occurring disorder of unknown cause in which affected individuals have an unusual electrocardiographic repolarization abnormality and a propensity to syncope and fatal ventricular tachyarrhythmias. The first family with LQTS was described by Jervell and Lange-Nielsen in 1957. Three sudden deaths occurred in four deaf children with QT prolongation; two other children and the parents were healthy with normal hearing and normal electrocardiograms. The findings were interpreted as a pattern of autosomal recessive inheritance. Subsequent reports identified LQTS families with normal hearing (Romano-Ward Syndrome) having a pattern of occurrence suggesting autosomal dominant inheritance.

DESIGN NARRATIVE:

Beginning in 1985, patients and their unaffected relatives were longitudinally followed in this multicenter study to develop and validate widely applicable clinical criteria for stratifying the risk of life-threatening arrhythmias. A population of genetically deaf students was surveyed to identify additional families with the unique association of Long QT Syndrome and congenital deafness in order to expand the data base for genetic studies in the recessive form of the disorder, the Jervell and Lange-Nielsen Syndrome. Pedigrees of selected Long QT Syndrome families were recorded to better understand the inheritance of the dominant form of the disorder, the Romano-Ward Syndrome. Genetic studies were conducted using human leukocyte antigen and other protein markers in order to investigate the gene locus for the autosomal dominant form of the syndrome. A select group of 30 patients and 30 unaffected relatives had 24-hour Holter monitoring, treadmill exercise, Valsalva maneuver and handgrip stress tests to determine if the patients had a unique cardiovascular response to autonomic dysfunction.

The study was renewed in 1993. The renewal had six aims. The first examined genetic heterogeneity in LQTS by testing for Harvey-ras-1 gene linkage in the existing well-characterized LQTS families with evidence of a major gene by segregation analysis; in LQTS families that did not show Harvey-ras- 1 linkage, a search for other closely linked genetic markers was initiated. The second aim explored by segregation analysis the likelihood that a second gene coexisted with the Harvey-ras-1 gene to explain a more malignant disease process in some LQTS families than in others. The third established normal standards for six quantitative repolarization parameters on a healthy population (n=4,000) using digitized ECG recordings, and biomedical and statistical techniques with adjustment for age, gender, race, and heart rate. The fourth aim continued the existing LQTS registry with ongoing enrollment of new families and follow-up of new and existing LQTS pedigrees (n=370 families) in order to provide a central repository for this disorder, especially as it related to the natural history of this disorder and ongoing genetic analyses. The fifth aim investigated the static (12-lead ECG) and dynamic (24-hour Holter ECG) aspects of ventricular repolarization in LQTS families showing Harvey-ras gene linkage to upgrade the ECG categorization of delayed repolarization using the Harvey-ras- 1 marker as the gold standard to identify affected and unaffected individuals. The sixth aim continued the prospective longitudinal follow-up study of LQTS families to better understand the long-term clinical course of this disorder; time-dependent survivorship analyses were performed to evaluate the effects of various clinical features, repolarization severity (QTc length), Harvey-ras-I gene linkage, and therapeutic efficacy with antiadrenergic therapy (if data permits) on outcome event rates (syncope and sudden death) in the LQTS probands.

The study has been renewed several times to: expand the pedigrees of LQTS families and family members enrolled in the registry; identify new LQTS gene mutations and expand the number of gene-identified affected and unaffected members in LQTS families with known gene mutations; investigate phenotype-genotype relationships in 200 genotyped families involving 1,200 affected and unaffected family members regarding the clinical course of LQTS, T-wave repolarization, triggering factors for cardiac events, and co-morbidity associations, all by genotype. The study remains a multicenter project with six clinical centers, a genetic component involving four molecular genetic labs, a statistical genetic component, a biostatistical component, and a coordinating center.

• Study Type: Observational
• Enrollment (Actual): 2125

Contacts and Locations

Study Locations

• United States
  • New York
    • Rochester, New York, United States, 14642
      • University of Rochester

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 100 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

As of the 2013 closeout report, 1329 probands with clinical dx of LQTS and members of their extended families have been enrolled in the LQTS Registry. By ECG classification, this includes 3420 probands and affected family members, 3533 unaffected family members, and 2105 family members with borderline QTc. Of those, 2125 have had mutations identified.

Description

Probands are required to have clinical dx of LQTS. Family members are also invited to participate regardless of their dx.

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
None. This is an observational study.	By study end

Collaborators and Investigators

• Sponsor: University of Rochester
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Arthur Moss, University of Rochester

Publications and helpful links

General Publications

• 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 Apr;14(4):337-41. doi: 10.1046/j.1540-8167.2003.02545.x.
• Hobbs JB, Peterson DR, Moss AJ, McNitt S, Zareba W, Goldenberg I, Qi M, Robinson JL, Sauer AJ, Ackerman MJ, Benhorin J, Kaufman ES, Locati EH, Napolitano C, Priori SG, Towbin JA, Vincent GM, Zhang L. Risk of aborted cardiac arrest or sudden cardiac death during adolescence in the long-QT syndrome. JAMA. 2006 Sep 13;296(10):1249-54. doi: 10.1001/jama.296.10.1249.
• Zareba W, Moss AJ, Schwartz PJ, Vincent GM, Robinson JL, Priori SG, Benhorin J, Locati EH, Towbin JA, Keating MT, Lehmann MH, Hall WJ. Influence of the genotype on the clinical course of the long-QT syndrome. International Long-QT Syndrome Registry Research Group. N Engl J Med. 1998 Oct 1;339(14):960-5. doi: 10.1056/NEJM199810013391404.
• Zareba W, Moss AJ, Locati EH, Lehmann MH, Peterson DR, Hall WJ, Schwartz PJ, Vincent GM, Priori SG, Benhorin J, Towbin JA, Robinson JL, Andrews ML, Napolitano C, Timothy K, Zhang L, Medina A; International Long QT Syndrome Registry. Modulating effects of age and gender on the clinical course of long QT syndrome by genotype. J Am Coll Cardiol. 2003 Jul 2;42(1):103-9. doi: 10.1016/s0735-1097(03)00554-0.
• Schwartz PJ, Priori SG, Locati EH, Napolitano C, Cantu F, Towbin JA, Keating MT, Hammoude H, Brown AM, Chen LS, 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 Dec 15;92(12):3381-6. doi: 10.1161/01.cir.92.12.3381.
• Benhorin J, Taub R, Goldmit M, Kerem B, Kass RS, Windman I, Medina A. Effects of flecainide in patients with new SCN5A mutation: mutation-specific therapy for long-QT syndrome? Circulation. 2000 Apr 11;101(14):1698-706. doi: 10.1161/01.cir.101.14.1698.
• 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 Mar 10;80(5):805-11. doi: 10.1016/0092-8674(95)90359-3.
• 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 Apr 20;109(15):1826-33. doi: 10.1161/01.CIR.0000125523.14403.1E. Epub 2004 Mar 29.
• Weitkamp LR, Moss AJ: The Long QT (Romano-Ward) Syndrome Locus, LQT, is Probably Linked to the HLA Loci. Cytogenet Cell Genet, 40:775, 1985
• Locati E, Schwartz PJ, Moss AJ, Crampton RS: Long-Term Survival After Left Cervico-Thoracic Sympathectomy in High Risk Long QT Syndrome Patients With Refractory Ventricular Arrhythmias. J Am Coll Cardiol, 7:234A, 1986
• De Ambroggi L, Bertoni T, Locati E, Stramba-Badiale M, Schwartz PJ. Mapping of body surface potentials in patients with the idiopathic long QT syndrome. Circulation. 1986 Dec;74(6):1334-45. doi: 10.1161/01.cir.74.6.1334.
• Vincent GM. The heart rate of Romano-Ward syndrome patients. Am Heart J. 1986 Jul;112(1):61-4. doi: 10.1016/0002-8703(86)90678-2.
• Moss AJ. Prolonged QT-interval syndromes. JAMA. 1986 Dec 5;256(21):2985-7. No abstract available. Erratum In: JAMA 1987 Jan 23-20;257(4):487.
• Merri M, Benhorin J, Alberti M, Locati E, Moss AJ. Electrocardiographic quantitation of ventricular repolarization. Circulation. 1989 Nov;80(5):1301-8. doi: 10.1161/01.cir.80.5.1301.
• Benhorin J, Merri M, Alberti M, Locati E, Moss AJ, Hall WJ, Cui L. Long QT syndrome. New electrocardiographic characteristics. Circulation. 1990 Aug;82(2):521-7. doi: 10.1161/01.cir.82.2.521.
• Moss AJ. Clinical management of patients with the long QT syndrome: drugs, devices, and gene-specific therapy. Pacing Clin Electrophysiol. 1997 Aug;20(8 Pt 2):2058-60. doi: 10.1111/j.1540-8159.1997.tb03627.x.
• Zareba W, Moss AJ, le Cessie S, Locati EH, Robinson JL, Hall WJ, Andrews ML. Risk of cardiac events in family members of patients with long QT syndrome. J Am Coll Cardiol. 1995 Dec;26(7):1685-91. doi: 10.1016/0735-1097(95)60383-2.
• Weitkamp LR, Moss AJ, Lewis RA, Hall WJ, MacCluer JW, Schwartz PJ, Locati EH, Tzivoni D, Vincent GM, Robinson JL, et al. Analysis of HLA and disease susceptibility: chromosome 6 genes and sex influence long-QT phenotype. Am J Hum Genet. 1994 Dec;55(6):1230-41.
• Malfatto G, Beria G, Sala S, Bonazzi O, Schwartz PJ. Quantitative analysis of T wave abnormalities and their prognostic implications in the idiopathic long QT syndrome. J Am Coll Cardiol. 1994 Feb;23(2):296-301. doi: 10.1016/0735-1097(94)90410-3.
• Zareba W, Moss AJ, le Cessie S, Hall WJ. T wave alternans in idiopathic long QT syndrome. J Am Coll Cardiol. 1994 Jun;23(7):1541-6. doi: 10.1016/0735-1097(94)90653-x.
• De Ferrari GM, Nador F, Beria G, Sala S, Lotto A, Schwartz PJ. Effect of calcium channel block on the wall motion abnormality of the idiopathic long QT syndrome. Circulation. 1994 May;89(5):2126-32. doi: 10.1161/01.cir.89.5.2126.
• Moss AJ. Measurement of the QT interval and the risk associated with QTc interval prolongation: a review. Am J Cardiol. 1993 Aug 26;72(6):23B-25B. doi: 10.1016/0002-9149(93)90036-c.
• Schwartz PJ, Moss AJ, Vincent GM, Crampton RS. Diagnostic criteria for the long QT syndrome. An update. Circulation. 1993 Aug;88(2):782-4. doi: 10.1161/01.cir.88.2.782. No abstract available.
• Moss AJ, Robinson JL. Clinical aspects of the idiopathic long QT syndrome. Ann N Y Acad Sci. 1992 Jan 27;644:103-11. doi: 10.1111/j.1749-6632.1992.tb31006.x. No abstract available.
• Moss AJ, Robinson J. Clinical features of the idiopathic long QT syndrome. Circulation. 1992 Jan;85(1 Suppl):I140-4.
• Merri M, Moss AJ, Benhorin J, Locati EH, Alberti M, Badilini F. Relation between ventricular repolarization duration and cardiac cycle length during 24-hour Holter recordings. Findings in normal patients and patients with long QT syndrome. Circulation. 1992 May;85(5):1816-21. doi: 10.1161/01.cir.85.5.1816.
• Nador F, Beria G, De Ferrari GM, Stramba-Badiale M, Locati EH, Lotto A, Schwartz PJ. Unsuspected echocardiographic abnormality in the long QT syndrome. Diagnostic, prognostic, and pathogenetic implications. Circulation. 1991 Oct;84(4):1530-42. doi: 10.1161/01.cir.84.4.1530.
• 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 Oct;84(4):1524-9. doi: 10.1161/01.cir.84.4.1524.
• Moss AJ, Schwartz PJ, Crampton RS, Tzivoni D, Locati EH, MacCluer J, Hall WJ, Weitkamp L, Vincent GM, Garson A Jr, et al. The long QT syndrome. Prospective longitudinal study of 328 families. Circulation. 1991 Sep;84(3):1136-44. doi: 10.1161/01.cir.84.3.1136.
• De Ambroggi L, Negroni MS, Monza E, Bertoni T, Schwartz PJ. Dispersion of ventricular repolarization in the long QT syndrome. Am J Cardiol. 1991 Sep 1;68(6):614-20. doi: 10.1016/0002-9149(91)90353-m.
• 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 Aug;84(2):503-11. doi: 10.1161/01.cir.84.2.503.
• Schwartz PJ, Zaza A, Locati E, Moss AJ. Stress and sudden death. The case of the long QT syndrome. Circulation. 1991 Apr;83(4 Suppl):II71-80.
• Moss AJ, Merri M, Benhorin J, Alberti M, Locati E. Multidimensional quantitation of ventricular repolarization. Static and dynamic characteristics. Ann N Y Acad Sci. 1990;601:31-5. doi: 10.1111/j.1749-6632.1990.tb37289.x. No abstract available.
• 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 Aug;92(2):799-803. doi: 10.1172/JCI116653.
• Rashba EJ, Zareba W, Moss AJ, Hall WJ, Robinson J, Locati EH, Schwartz PJ, Andrews M. Influence of pregnancy on the risk for cardiac events in patients with hereditary long QT syndrome. LQTS Investigators. Circulation. 1998 Feb 10;97(5):451-6. doi: 10.1161/01.cir.97.5.451.
• Locati EH, Zareba W, Moss AJ, Schwartz PJ, Vincent GM, Lehmann MH, Towbin JA, Priori SG, Napolitano C, Robinson JL, Andrews M, Timothy K, Hall WJ. Age- and sex-related differences in clinical manifestations in patients with congenital long-QT syndrome: findings from the International LQTS Registry. Circulation. 1998 Jun 9;97(22):2237-44. doi: 10.1161/01.cir.97.22.2237.
• Ali RH, Zareba W, Moss AJ, Schwartz PJ, Benhorin J, Vincent GM, Locati EH, Priori S, 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 Feb 15;85(4):457-61. doi: 10.1016/s0002-9149(99)90772-5.
• 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. Circulation. 2000 Feb 15;101(6):616-23. doi: 10.1161/01.cir.101.6.616.
• Benhorin J, Goldmit M, MacCluer JW, Blangero J, Goffen R, Leibovitch A, Rahat A, Wang Q, Medina A, Towbin J, Kerem B. Identification of a new SCN5A mutation, D1840G, associated with the long QT syndrome. Mutations in brief no. 153. Online. Hum Mutat. 1998;12(1):72. doi: 10.1002/(SICI)1098-1004(1998)12:13.0.CO;2-T.
• Rosero SZ, Zareba W, Moss AJ, Robinson JL, Hajj Ali RH, Locati EH, Benhorin J, Andrews ML. Asthma and the risk of cardiac events in the Long QT syndrome. Long QT Syndrome Investigative Group. Am J Cardiol. 1999 Dec 15;84(12):1406-11. doi: 10.1016/s0002-9149(99)00586-x.
• Couderc JP, Zareba W, Burattini L, Moss AJ. Beat-to-Beat repolarization variability in LQTS patients with the SCN5A sodium channel gene mutation. Pacing Clin Electrophysiol. 1999 Nov;22(11):1581-92. doi: 10.1111/j.1540-8159.1999.tb00376.x.
• Moss AJ, Robinson JL, Gessman L, Gillespie R, Zareba W, Schwartz PJ, Vincent GM, Benhorin J, Heilbron EL, Towbin JA, Priori SG, Napolitano C, Zhang L, Medina A, Andrews ML, Timothy K. Comparison of clinical and genetic variables of cardiac events associated with loud noise versus swimming among subjects with the long QT syndrome. Am J Cardiol. 1999 Oct 15;84(8):876-9. doi: 10.1016/s0002-9149(99)00458-0.
• Chen Q, Zhang D, Gingell RL, Moss AJ, Napolitano C, Priori SG, Schwartz PJ, Kehoe E, Robinson JL, Schulze-Bahr E, Wang Q, Towbin JA. Homozygous deletion in KVLQT1 associated with Jervell and Lange-Nielsen syndrome. Circulation. 1999 Mar 16;99(10):1344-7. doi: 10.1161/01.cir.99.10.1344.
• Couderc JP, Zareba W, Burattini L, Konecki JA, Moss AJ. Beat-to-beat repolarization variability in amplitude and duration in LQTS patients with the SCN5A sodium channel gene mutation. J Electrocardiol. 1998;31 Suppl:134. doi: 10.1016/s0022-0736(98)90306-5. No abstract available.
• Moss AJ. Management of patients with the hereditary long QT syndrome. J Cardiovasc Electrophysiol. 1998 Jun;9(6):668-74. doi: 10.1111/j.1540-8167.1998.tb00952.x.
• Li H, Chen Q, Moss AJ, Robinson J, Goytia V, Perry JC, Vincent GM, Priori SG, Lehmann MH, Denfield SW, Duff D, Kaine S, Shimizu W, Schwartz PJ, Wang Q, Towbin JA. New mutations in the KVLQT1 potassium channel that cause long-QT syndrome. Circulation. 1998 Apr 7;97(13):1264-9. doi: 10.1161/01.cir.97.13.1264.
• Moss AJ. The long QT syndrome revisited: current understanding and implications for treatment. Pacing Clin Electrophysiol. 1997 Dec;20(12 Pt 1):2879-81. doi: 10.1111/j.1540-8159.1997.tb05455.x. No abstract available.
• 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 AA, Toivonen L, Zareba W, Robinson JL, Timothy KW, Corfield V, Wattanasirichaigoon D, Corbett C, Haverkamp W, Schulze-Bahr E, Lehmann MH, Schwartz K, Coumel P, Bloise R. Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias. Circulation. 2001 Jan 2;103(1):89-95. doi: 10.1161/01.cir.103.1.89.
• Splawski I, Shen J, Timothy KW, Lehmann MH, Priori S, Robinson JL, 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 Sep 5;102(10):1178-85. doi: 10.1161/01.cir.102.10.1178.
• Jiang C, Atkinson D, Towbin JA, Splawski I, Lehmann MH, Li H, Timothy K, Taggart RT, Schwartz PJ, Vincent GM, et al. Two long QT syndrome loci map to chromosomes 3 and 7 with evidence for further heterogeneity. Nat Genet. 1994 Oct;8(2):141-7. doi: 10.1038/ng1094-141.
• Benhorin J, Moss AJ, Bak M, Zareba W, Kaufman ES, Kerem B, Towbin JA, Priori S, Kass RS, Attali B, Brown AM, Ficker E. Variable expression of long QT syndrome among gene carriers from families with five different HERG mutations. Ann Noninvasive Electrocardiol. 2002 Jan;7(1):40-6. doi: 10.1111/j.1542-474x.2001.tb00137.x.
• Perkiomaki JS, Zareba W, Couderc JP, Moss AJ. Heart rate variability in patients with congenital long QT syndrome. Ann Noninvasive Electrocardiol. 2001 Oct;6(4):298-304. doi: 10.1111/j.1542-474x.2001.tb00122.x.
• Kimbrough J, Moss AJ, Zareba W, Robinson JL, Hall WJ, Benhorin J, Locati EH, Medina A, Napolitano C, Priori S, Schwartz PJ, Timothy K, Towbin JA, Vincent GM, Zhang L. Clinical implications for affected parents and siblings of probands with long-QT syndrome. Circulation. 2001 Jul 31;104(5):557-62. doi: 10.1161/hc3001.093501.
• Windle JR, Geletka RC, Moss AJ, Zareba W, Atkins DL. Normalization of ventricular repolarization with flecainide in long QT syndrome patients with SCN5A:DeltaKPQ mutation. Ann Noninvasive Electrocardiol. 2001 Apr;6(2):153-8. doi: 10.1111/j.1542-474x.2001.tb00100.x.
• Wang Z, Li H, Moss AJ, Robinson J, Zareba W, Knilans T, Bowles NE, Towbin JA. Compound heterozygous mutations in KvLQT1 cause Jervell and Lange-Nielsen syndrome. Mol Genet Metab. 2002 Apr;75(4):308-16. doi: 10.1016/S1096-7192(02)00007-0.
• Perkiomaki JS, Zareba W, Nomura A, Andrews M, Kaufman ES, Moss AJ. Repolarization dynamics in patients with long QT syndrome. J Cardiovasc Electrophysiol. 2002 Jul;13(7):651-6. doi: 10.1046/j.1540-8167.2002.00651.x.
• Moss AJ. Long QT Syndrome. JAMA. 2003 Apr 23-30;289(16):2041-4. doi: 10.1001/jama.289.16.2041. No abstract available.
• Moss AJ. T-wave patterns associated with the hereditary long QT syndrome. Card Electrophysiol Rev. 2002 Sep;6(3):311-5. doi: 10.1023/a:1016301730302.
• Kupershmidt S, Yang T, Chanthaphaychith S, Wang Z, Towbin JA, Roden DM. Defective human Ether-a-go-go-related gene trafficking linked to an endoplasmic reticulum retention signal in the C terminus. J Biol Chem. 2002 Jul 26;277(30):27442-8. doi: 10.1074/jbc.M112375200. Epub 2002 May 20.
• Zareba W, Moss AJ, Sheu G, Kaufman ES, Priori S, Vincent GM, Towbin JA, Benhorin J, Schwartz PJ, Napolitano C, Hall WJ, Keating MT, Qi M, Robinson J, Andrews ML; International LQTS Registry, University of Rochester, Rochester, New York. Location of mutation in the KCNQ1 and phenotypic presentation of long QT syndrome. J Cardiovasc Electrophysiol. 2003 Nov;14(11):1149-53. doi: 10.1046/j.1540-8167.2003.03177.x.
• Ning L, Moss A, Zareba W, Robinson J, Rosero S, Ryan D, Qi M. Denaturing high-performance liquid chromatography quickly and reliably detects cardiac ion channel mutations in long QT syndrome. Genet Test. 2003 Fall;7(3):249-53. doi: 10.1089/109065703322537287.
• Ning L, Moss AJ, Zareba W, Robinson J, Rosero S, Ryan D, Qi M. Novel compound heterozygous mutations in the KCNQ1 gene associated with autosomal recessive long QT syndrome (Jervell and Lange-Nielsen syndrome). Ann Noninvasive Electrocardiol. 2003 Jul;8(3):246-50. doi: 10.1046/j.1542-474x.2003.08313.x.
• Moss AJ, Schwartz PJ. 25th anniversary of the International Long-QT Syndrome Registry: an ongoing quest to uncover the secrets of long-QT syndrome. Circulation. 2005 Mar 8;111(9):1199-201. doi: 10.1161/01.CIR.0000157069.91834.DA. No abstract available.
• Goldenberg I, Bradley J, Moss A, McNitt S, Polonsky S, Robinson JL, Andrews M, Zareba W; International LQTS Registry Investigators. Beta-blocker efficacy in high-risk patients with the congenital long-QT syndrome types 1 and 2: implications for patient management. J Cardiovasc Electrophysiol. 2010 Aug 1;21(8):893-901. doi: 10.1111/j.1540-8167.2010.01737.x. Epub 2010 Mar 5.
• Horr S, Goldenberg I, Moss AJ, O-Uchi J, Barsheshet A, Connelly H, Gray DA, Zareba W, Lopes CM. Ion channel mechanisms related to sudden cardiac death in phenotype-negative long-QT syndrome genotype-phenotype correlations of the KCNQ1(S349W) mutation. J Cardiovasc Electrophysiol. 2011 Feb;22(2):193-200. doi: 10.1111/j.1540-8167.2010.01852.x.
• Moss AJ. Sex hormones and ventricular tachyarrhythmias in LQTS: new insights regarding antiarrhythmic therapy. Heart Rhythm. 2012 May;9(5):833-4. doi: 10.1016/j.hrthm.2012.01.014. Epub 2012 Jan 20. No abstract available.
• Goldenberg I, Thottathil P, Lopes CM, Moss AJ, McNitt S, O-Uchi J, Robinson JL, Zareba W, Ackerman MJ, Kaufman ES, Towbin JA, Vincent M, Barsheshet A. Trigger-specific ion-channel mechanisms, risk factors, and response to therapy in type 1 long QT syndrome. Heart Rhythm. 2012 Jan;9(1):49-56. doi: 10.1016/j.hrthm.2011.08.020. Epub 2011 Aug 24.
• Barsheshet A, Moss AJ, McNitt S, Polonsky S, Lopes CM, Zareba W, Robinson JL, Ackerman MJ, Benhorin J, Kaufman ES, Towbin JA, Vincent GM, Qi M, Goldenberg I. Risk of syncope in family members who are genotype-negative for a family-associated long-QT syndrome mutation. Circ Cardiovasc Genet. 2011 Oct;4(5):491-9. doi: 10.1161/CIRCGENETICS.111.960179. Epub 2011 Aug 10.
• Migdalovich D, Moss AJ, Lopes CM, Costa J, Ouellet G, Barsheshet A, McNitt S, Polonsky S, Robinson JL, Zareba W, Ackerman MJ, Benhorin J, Kaufman ES, Platonov PG, Shimizu W, Towbin JA, Vincent GM, Wilde AA, Goldenberg I. 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 Oct;8(10):1537-43. doi: 10.1016/j.hrthm.2011.03.049. Epub 2011 Mar 25.
• Barsheshet A, Peterson DR, Moss AJ, Schwartz PJ, Kaufman ES, McNitt S, Polonsky S, Buber J, Zareba W, Robinson JL, Ackerman MJ, Benhorin J, Towbin JA, Vincent GM, Zhang L, Goldenberg I. Genotype-specific QT correction for heart rate and the risk of life-threatening cardiac events in adolescents with congenital long-QT syndrome. Heart Rhythm. 2011 Aug;8(8):1207-13. doi: 10.1016/j.hrthm.2011.03.009. Epub 2011 Mar 10.
• Couderc JP, Xia X, Peterson DR, McNitt S, Zhao H, Polonsky S, Moss AJ, Zareba W. T-wave morphology abnormalities in benign, potent, and arrhythmogenic I(kr) inhibition. Heart Rhythm. 2011 Jul;8(7):1036-43. doi: 10.1016/j.hrthm.2011.02.005. Epub 2011 Feb 9.
• Patrick CC, Goust JM, Virella G. Tolerance and autoimmunity. Immunol Ser. 1990;50:415-33. No abstract available.
• Liu JF, Jons C, Moss AJ, McNitt S, Peterson DR, Qi M, Zareba W, Robinson JL, Barsheshet A, Ackerman MJ, Benhorin J, Kaufman ES, Locati EH, Napolitano C, Priori SG, Schwartz PJ, Towbin J, Vincent M, Zhang L, Goldenberg I; International Long QT Syndrome Registry. Risk factors for recurrent syncope and subsequent fatal or near-fatal events in children and adolescents with long QT syndrome. J Am Coll Cardiol. 2011 Feb 22;57(8):941-50. doi: 10.1016/j.jacc.2010.10.025. Erratum In: J Am Coll Cardiol. 2011 Apr 19;57(16):1717.
• Goldenberg I, Horr S, Moss AJ, Lopes CM, Barsheshet A, McNitt S, Zareba W, Andrews ML, Robinson JL, Locati EH, Ackerman MJ, Benhorin J, Kaufman ES, Napolitano C, Platonov PG, Priori SG, Qi M, Schwartz PJ, Shimizu W, Towbin JA, Vincent GM, Wilde AA, Zhang L. 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 Jan 4;57(1):51-9. doi: 10.1016/j.jacc.2010.07.038.
• Zareba W. Counting mRNA in blood of LQTS - new direction? Kardiol Pol. 2011;69(5):430. No abstract available.
• Kim JA, Lopes CM, Moss AJ, McNitt S, Barsheshet A, Robinson JL, Zareba W, Ackerman MJ, Kaufman ES, Towbin JA, Vincent M, Goldenberg I. Trigger-specific risk factors and response to therapy in long QT syndrome type 2. Heart Rhythm. 2010 Dec;7(12):1797-805. doi: 10.1016/j.hrthm.2010.09.011. Epub 2010 Sep 17.
• Zhang T, Moss A, Cong P, Pan M, Chang B, Zheng L, Fang Q, Zareba W, Robinson J, Lin C, Li Z, Wei J, Zeng Q; Long QT International Registry Investigators; HVP-China Investigators; Qi M. LQTS gene LOVD database. Hum Mutat. 2010 Nov;31(11):E1801-10. doi: 10.1002/humu.21341.
• 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 Feb 23;55(8):783-8. doi: 10.1016/j.jacc.2009.11.042.
• Ouellet G, Moss AJ, Jons C, McNitt S, Mullally J, Fugate T, Goldenberg I, Zareba W, Robinson JL; Investigators from the U.S. Portion of the International Long QT Syndrome Registry. Influence of diabetes mellitus on outcome in patients over 40 years of age with the long QT syndrome. Am J Cardiol. 2010 Jan 1;105(1):87-9. doi: 10.1016/j.amjcard.2009.08.657. Epub 2009 Oct 23.
• Fugate T 2nd, Moss AJ, Jons C, McNitt S, Mullally J, Ouellet G, Goldenberg I, Zareba W, Robinson JL; U.S. portion of International Long QT Syndrome Registry Investigators. Long QT syndrome in African-Americans. Ann Noninvasive Electrocardiol. 2010 Jan;15(1):73-6. doi: 10.1111/j.1542-474X.2009.00342.x.
• Shimizu W, Moss AJ, Wilde AA, Towbin JA, Ackerman MJ, January CT, Tester DJ, Zareba W, Robinson JL, Qi M, Vincent GM, Kaufman ES, Hofman N, Noda T, Kamakura S, Miyamoto Y, Shah S, Amin V, Goldenberg I, Andrews ML, McNitt S. Genotype-phenotype aspects of type 2 long QT syndrome. J Am Coll Cardiol. 2009 Nov 24;54(22):2052-62. doi: 10.1016/j.jacc.2009.08.028.
• Spazzolini C, Mullally J, Moss AJ, Schwartz PJ, McNitt S, Ouellet G, Fugate T, Goldenberg I, Jons C, Zareba W, Robinson JL, Ackerman MJ, Benhorin J, Crotti L, Kaufman ES, Locati EH, Qi M, Napolitano C, Priori SG, Towbin JA, Vincent GM. Clinical implications for patients with long QT syndrome who experience a cardiac event during infancy. J Am Coll Cardiol. 2009 Aug 25;54(9):832-7. doi: 10.1016/j.jacc.2009.05.029.
• Lane RD, Reis HT, Peterson DR, Zareba W, Moss AJ. Happiness and stress alter susceptibility to cardiac events in Long QT Syndrome. Ann Noninvasive Electrocardiol. 2009 Apr;14(2):193-200. doi: 10.1111/j.1542-474X.2009.00295.x.
• Goldenberg I, Zareba W, Moss AJ. Long QT Syndrome. Curr Probl Cardiol. 2008 Nov;33(11):629-94. doi: 10.1016/j.cpcardiol.2008.07.002.
• Zareba W, Cygankiewicz I. Long QT syndrome and short QT syndrome. Prog Cardiovasc Dis. 2008 Nov-Dec;51(3):264-78. doi: 10.1016/j.pcad.2008.10.006.
• Thottathil P, Acharya J, Moss AJ, Jons C, McNitt S, Goldenberg I, Zareba W, Kaufman E, Qi M, Robinson JL; International Long QT Syndrome Investigative Group. Risk of cardiac events in patients with asthma and long-QT syndrome treated with beta(2) agonists. Am J Cardiol. 2008 Oct 1;102(7):871-4. doi: 10.1016/j.amjcard.2008.05.029. Epub 2008 Jul 17.
• Sze E, Moss AJ, Goldenberg I, McNitt S, Jons C, Zareba W, Qi M, Robinson JL; International Long QT Syndrome Investigative Group. Long QT syndrome in patients over 40 years of age: increased risk for LQTS-related cardiac events in patients with coronary disease. Ann Noninvasive Electrocardiol. 2008 Oct;13(4):327-31. doi: 10.1111/j.1542-474X.2008.00250.x.
• Wu G, Ai T, Kim JJ, Mohapatra B, Xi Y, Li Z, Abbasi S, Purevjav E, Samani K, Ackerman MJ, Qi M, Moss AJ, Shimizu W, Towbin JA, Cheng J, Vatta M. alpha-1-syntrophin mutation and the long-QT syndrome: a disease of sodium channel disruption. Circ Arrhythm Electrophysiol. 2008 Aug;1(3):193-201. doi: 10.1161/CIRCEP.108.769224.
• Liu JF, Goldenberg I, Moss AJ, Shimizu W, Wilde AA, Hofman N, McNitt S, Zareba W, Miyamato Y, Robinson JL, Andrews ML. Phenotypic variability in Caucasian and Japanese patients with matched LQT1 mutations. Ann Noninvasive Electrocardiol. 2008 Jul;13(3):234-41. doi: 10.1111/j.1542-474X.2008.00226.x.
• Goldenberg I, Moss AJ. Long QT syndrome. J Am Coll Cardiol. 2008 Jun 17;51(24):2291-300. doi: 10.1016/j.jacc.2008.02.068.
• Kaufman ES, McNitt S, Moss AJ, Zareba W, Robinson JL, Hall WJ, Ackerman MJ, Benhorin J, Locati ET, Napolitano C, Priori SG, Schwartz PJ, Towbin JA, Vincent GM, Zhang L. Risk of death in the long QT syndrome when a sibling has died. Heart Rhythm. 2008 Jun;5(6):831-6. doi: 10.1016/j.hrthm.2008.02.029. Epub 2008 Mar 4.
• Goldenberg I, Moss AJ, Peterson DR, McNitt S, Zareba W, Andrews ML, Robinson JL, Locati EH, Ackerman MJ, Benhorin J, Kaufman ES, Napolitano C, Priori SG, Qi M, Schwartz PJ, Towbin JA, Vincent GM, Zhang L. Risk factors for aborted cardiac arrest and sudden cardiac death in children with the congenital long-QT syndrome. Circulation. 2008 Apr 29;117(17):2184-91. doi: 10.1161/CIRCULATIONAHA.107.701243. Epub 2008 Apr 21.
• Goldenberg I, Moss AJ, Bradley J, Polonsky S, Peterson DR, McNitt S, Zareba W, Andrews ML, Robinson JL, Ackerman MJ, Benhorin J, Kaufman ES, Locati EH, Napolitano C, Priori SG, Qi M, Schwartz PJ, Towbin JA, Vincent GM, Zhang L. Long-QT syndrome after age 40. Circulation. 2008 Apr 29;117(17):2192-201. doi: 10.1161/CIRCULATIONAHA.107.729368. Epub 2008 Apr 21.
• Vaglio M, Couderc JP, McNitt S, Xia X, Moss AJ, Zareba W. A quantitative assessment of T-wave morphology in LQT1, LQT2, and healthy individuals based on Holter recording technology. Heart Rhythm. 2008 Jan;5(1):11-8. doi: 10.1016/j.hrthm.2007.08.026. Epub 2007 Aug 28.
• Couderc JP, Vaglio M, Xia X, McNitt S, Wicker P, Sarapa N, Moss AJ, Zareba W. Impaired T-amplitude adaptation to heart rate characterizes I(Kr) inhibition in the congenital and acquired forms of the long QT syndrome. J Cardiovasc Electrophysiol. 2007 Dec;18(12):1299-305. doi: 10.1111/j.1540-8167.2007.00960.x. Epub 2007 Oct 4.
• 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 Nov 20;116(21):2366-75. doi: 10.1161/CIRCULATIONAHA.107.726950. Epub 2007 Nov 5.
• 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 long-QT syndrome by location, coding type, and biophysical function of mutations involving the KCNQ1 gene. Circulation. 2007 May 15;115(19):2481-9. doi: 10.1161/CIRCULATIONAHA.106.665406. Epub 2007 Apr 30.
• Daubert JP, Zareba W, Rosero SZ, Budzikowski A, Robinson JL, Moss AJ. Role of implantable cardioverter defibrillator therapy in patients with long QT syndrome. Am Heart J. 2007 Apr;153(4 Suppl):53-8. doi: 10.1016/j.ahj.2007.01.025.
• Seth R, Moss AJ, McNitt S, Zareba W, Andrews ML, Qi M, Robinson JL, Goldenberg I, Ackerman MJ, Benhorin J, Kaufman ES, Locati EH, Napolitano C, Priori SG, Schwartz PJ, Towbin JA, Vincent GM, Zhang L. Long QT syndrome and pregnancy. J Am Coll Cardiol. 2007 Mar 13;49(10):1092-8. doi: 10.1016/j.jacc.2006.09.054. Epub 2007 Feb 27.
• Treherne JM, Woodward SK, Varga ZM, Ritchie JM, Nicholls JG. Restoration of conduction and growth of axons through injured spinal cord of neonatal opossum in culture. Proc Natl Acad Sci U S A. 1992 Jan 1;89(1):431-4. doi: 10.1073/pnas.89.1.431.
• Couderc JP, McNitt S, Xia J, Zareba W, Moss AJ. Repolarization morphology in adult LQT2 carriers with borderline prolonged QTc interval. Heart Rhythm. 2006 Dec;3(12):1460-6. doi: 10.1016/j.hrthm.2006.08.009. Epub 2006 Aug 10.
• Tan HL, Bardai A, Shimizu W, Moss AJ, Schulze-Bahr E, Noda T, Wilde AA. Genotype-specific onset of arrhythmias in congenital long-QT syndrome: possible therapy implications. Circulation. 2006 Nov 14;114(20):2096-103. doi: 10.1161/CIRCULATIONAHA.106.642694. Epub 2006 Nov 6.
• Goldenberg I, Moss AJ, Zareba W, McNitt S, Robinson JL, Qi M, Towbin JA, Ackerman MJ, Murphy L. Clinical course and risk stratification of patients affected with the Jervell and Lange-Nielsen syndrome. J Cardiovasc Electrophysiol. 2006 Nov;17(11):1161-8. doi: 10.1111/j.1540-8167.2006.00587.x. Epub 2006 Aug 14.
• Zareba W. Genotype-specific ECG patterns in long QT syndrome. J Electrocardiol. 2006 Oct;39(4 Suppl):S101-6. doi: 10.1016/j.jelectrocard.2006.05.017. Epub 2006 Sep 11.
• Goldenberg I, Mathew J, Moss AJ, McNitt S, Peterson DR, Zareba W, Benhorin J, Zhang L, Vincent GM, Andrews ML, Robinson JL, Morray B. 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 Sep 5;48(5):1047-52. doi: 10.1016/j.jacc.2006.06.033. Epub 2006 Jul 7.
• Karp JM, Moss AJ. Dental treatment of patients with long QT syndrome. J Am Dent Assoc. 2006 May;137(5):630-7. doi: 10.14219/jada.archive.2006.0259.
• Goldenberg I, Moss AJ, Maron BJ, Dick AW, Zareba W. Cost-effectiveness of implanted defibrillators in young people with inherited cardiac arrhythmias. Ann Noninvasive Electrocardiol. 2005 Oct;10(4 Suppl):67-83. doi: 10.1111/j.1542-474X.2005.00070.x.
• Goldenberg I, Moss AJ, Zareba W. Sudden cardiac death without structural heart disease: update on the long QT and Brugada syndromes. Curr Cardiol Rep. 2005 Sep;7(5):349-56. doi: 10.1007/s11886-005-0088-1.
• Zareba W, Moss AJ. Long QT syndrome in children. J Electrocardiol. 2001;34 Suppl:167-71. doi: 10.1054/jelc.2001.28863.
• Zhang L, Timothy KW, Vincent GM, Lehmann MH, Fox J, Giuli LC, Shen J, Splawski I, Priori SG, Compton SJ, Yanowitz F, Benhorin J, Moss AJ, Schwartz PJ, Robinson JL, Wang Q, Zareba W, Keating MT, Towbin JA, Napolitano C, Medina A. Spectrum of ST-T-wave patterns and repolarization parameters in congenital long-QT syndrome: ECG findings identify genotypes. Circulation. 2000 Dec 5;102(23):2849-55. doi: 10.1161/01.cir.102.23.2849.
• Moss AJ. Long QT Syndromes. Curr Treat Options Cardiovasc Med. 2000 Aug;2(4):317-322. doi: 10.1007/s11936-996-0005-y.
• Burattini L, Zareba W, Rashba EJ, Couderc JP, Konecki J, Moss AJ. ECG features of microvolt T-wave alternans in coronary artery disease and long QT syndrome patients. J Electrocardiol. 1998;31 Suppl:114-20. doi: 10.1016/s0022-0736(98)90302-8.
• Zareba W, Moss AJ, Konecki J. TU wave area-derived measures of repolarization dispersion in the long QT syndrome. J Electrocardiol. 1998;30 Suppl:191-5. doi: 10.1016/s0022-0736(98)80074-5.
• Zareba W, Moss AJ. Dispersion of repolarization. Relation to heart rate and repolarization duration. J Electrocardiol. 1995;28 Suppl:202-6. doi: 10.1016/s0022-0736(95)80057-3.
• Moss AJ, Robinson JL. The long-QT syndrome Genetic considerations. Trends Cardiovasc Med. 1992 May-Jun;2(3):81-3. doi: 10.1016/1050-1738(92)90010-P.
• Moss AJ, Robinson JL. Long QT syndrome. Heart Dis Stroke. 1992 Sep-Oct;1(5):309-14. No abstract available.

Study record dates

Study Major Dates

• Study Start: August 1, 1985
• Primary Completion (Actual): April 1, 2013
• Study Completion (Actual): April 1, 2013

Study Registration Dates

• First Submitted: May 25, 2000
• First Submitted That Met QC Criteria: May 25, 2000
• First Posted (Estimate): May 26, 2000

Study Record Updates

• Last Update Posted (Estimate): October 22, 2015
• Last Update Submitted That Met QC Criteria: October 20, 2015
• Last Verified: October 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Disease; Congenital Abnormalities; Arrhythmias, Cardiac; Cardiac Conduction System Disease; Heart Defects, Congenital; Cardiovascular Abnormalities; Heart Diseases; Cardiovascular Diseases; Syndrome; Long QT Syndrome
• Other Study ID Numbers: 1053; R01HL033843-16 (U.S. NIH Grant/Contract)