Not Signed In -
Arrhythmia |
Arrhythmias; Atrial Fibrillation; Irregular Heartbeat; Tachycardia |
Clinical Trial: Long QT Syndrome-Population Genetics and Cardiac Studies
This study is no longer recruiting patients.
Purpose
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.
| Condition |
|---|
| Cardiovascular Diseases Heart Diseases Ventricular Arrhythmia Long QT Syndrome |
MedlinePlus related topics: Arrhythmia; Heart Diseases; Heart Diseases--Prevention; Vascular Diseases
Study Type: Observational
Study Design: Natural History
Study start: August 1985; Study completion: June 2007
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 familiy 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.
Eligibility
Genders Eligible for Study: Both
Criteria
Location Information
Arthur Moss, University of Rochester
Arthur Moss, University of Rochester
More Information
Publications
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.
Vincent GM: The Heart Rate of Romano-Ward Long QT Syndrome Patients. Circulation, 72(III):44, 1986
Moss AJ. Prolonged QT-interval syndromes. JAMA. 1986 Dec 5;256(21):2985-7. No abstract available.
Merri M, Benhorin J, Alberti M, Locati E, Moss AJ. Electrocardiographic quantitation of ventricular repolarization. Circulation. 1989 Nov;80(5):1301-8.
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.
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. Review.
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.
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.
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.
Schwartz PJ, Priori SG, Locati EH, Napolitano C, Cantu F, Towbin JA, Keating MT, Hammoude H, Brown AM, Chen LS. 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.
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.
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.
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. Review.
Schwartz PJ, Moss AJ, Vincent GM, Crampton RS. Diagnostic criteria for the long QT syndrome. An update. Circulation. 1993 Aug;88(2):782-4. Review. 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. No abstract available.
Moss AJ, Robinson J. Clinical features of the idiopathic long QT syndrome. Circulation. 1992 Jan;85(1 Suppl):I140-4. Review.
Moss AJ, Robinson JL. Long QT syndrome. Heart Dis Stroke. 1992 Sep-Oct;1(5):309-14. Review. No abstract available.
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.
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.
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.
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.
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.
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.
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. Review.
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. 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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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. No abstract available.
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 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.
Moss AJ. Management of patients with the hereditary long QT syndrome. J Cardiovasc Electrophysiol. 1998 Jun;9(6):668-74.
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.
Moss AJ. The long QT syndrome revisited: current understanding and implications for treatment. Pacing Clin Electrophysiol. 1997 Dec;20(12 Pt 1):2879-81. 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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Moss AJ. Long QT Syndrome. JAMA. 2003 Apr 23-30;289(16):2041-4. Review. No abstract available.
Moss AJ. T-wave patterns associated with the hereditary long QT syndrome. Card Electrophysiol Rev. 2002 Sep;6(3):311-5. Review.
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. 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 JL, 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.
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.
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.
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.
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. Epub 2004 Mar 29.
Record last reviewed: March 2005
Last Updated: March 18, 2005
Record first received: May 25, 2000
ClinicalTrials.gov Identifier: NCT00005176
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08
Source: ClinicalTrials.gov
Cache Date: April 9, 2005
Resources
- Am I at Risk? (American Heart Association)
- Ambulatory Monitors (Cleveland Clinic Foundation)
email this page
print this page
bookmark this page
feedback on this page
