Skip Navigation

European Heart Journal 2001 22(5):410-422; doi:10.1053/euhj.2000.2292
Copyright © 2001 by the European Society of Cardiology.
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (15)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Lande, G.
Right arrow Articles by Le Marec, H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lande, G.
Right arrow Articles by Le Marec, H.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Dynamic analysis of the QT interval in long QT1 syndrome patients with a normal phenotype

G. Landea,f1,f2, F. Kyndta,f1, I. Baróa, D. Chabannesa, P. Boisseaua, J.-C. Ponyb, D. Escandea and H. Le Marecc

a INSERM U533, Hôpital Hôtel-Dieu, Nantes, France
b Service de Cardiologie, Centre Hospitalier Universitaire de Rennes, Rennes, France
c Service de Cardiologie, Centre Hospitalier Universitaire de Nantes, Nantes, France

revised May 22, 2000; accepted May 24, 2000

Abstract

Aims In families with the long QT syndrome penetrance may be low: up to 70% of gene carriers may have a normal QTc interval. These patients require therapy, similar to that in those with longer QTc intervals, but identifying them, using molecular analysis, is difficult to apply on a large scale. A large French family affected by the long QT1 syndrome was followed-up over a 25-year period. In adult males but not in females, the QTc interval normalized after puberty. We aimed to find clinical criteria, based on ambulatory ECG recordings so that we could improve diagnosis in affected members with a normal QTc.

Methods and Results Linkage analysis and direct sequencing were an indicator of the long QT1 gene in our family. Reverse transcription-polymerase chain reaction analysis demonstrated abnormal transcripts in lymphocytes from silent gene carriers. The functional profile of mutated protein isoforms was investigated using the patch–clamp technique. Dynamic analysis of ventricular depolarization was conducted using Holter recordings in patients, and in sex- and age-matched controls. Circadian variations of the QTc interval and the QT/RR relationship were assessed. Sensitivity, specificity, and predictive values were evaluated for proposed clinical criteria. We found that dynamic analysis of the QT interval permitted individual diagnosis in mutation carriers even when the QTc interval was normal (adult males).

Conclusion Dynamic analysis of the QT interval is of diagnostic value in the long QT1 syndrome in patients with a normal phenotype. Clinical implications include improvement in screening and patient management.

Key Words: Long QT syndrome, KvLQT1, ambulatory ECG recording, QT dynamic

f1 Joint first co-authors.

f2 Correspondence: Dr Gilles Lande, INSERM U533, 1 rue Gaston Veil, B.P. 53508, 44093 Nantes Cedex 1, France.

References

  1. Romano C, Gemme G, Pongiglione R. Aritmie cardiache rare dell'eta pediatria. Clin Pediatr. 1963;45:656–683
  2. Ward OC. A new familial cardiac syndrome in children. J Irish Med Ass. 1964;54:103–106
  3. Wang Q, Curran ME, Splawski I. Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias. Nat Genet. 1996;12:17–23[CrossRef][ISI][Medline]
  4. Rautaharju PM, Zhou SH, Wong S. Sex differences in the evolution of the electrocardiographic QT interval with age. Can J Cardiol. 1992;8:690–695[ISI][Medline]
  5. Lehmann MH, Timothy KW, Frankovich D. Age-gender influence on the rate-corrected QT interval and the QT-heart rate relation in families with genotypically characterized long QT syndrome. J Am Coll Cardiol. 1997;29:93–99[Abstract]
  6. Roden DM, Lazzara R, Rosen M, Schwartz PJ, Towbin J, Vincent GM. Multiple mechanisms in the long-QT syndrome. Current knowledge, gaps, and future directions. The SADS Foundation Task Force on LQTS. Circulation. 1996;94:1996–2012[Abstract/Free Full Text]
  7. Donger C, Denjoy I, Berthet M. KVLQT1 C-terminal missense mutation causes a forme fruste long-QT syndrome. Circulation. 1997;96:2778–2781[Abstract/Free Full Text]
  8. Priori SG, Napolitano C, Schwartz PJ. Low penetrance in the long-QT syndrome: clinical impact. Circulation. 1999;99:529–533[Abstract/Free Full Text]
  9. Schwartz PJ, Moss AJ, Vincent GM, Crampton RS. Diagnostic criteria for the long QT syndrome. An update. Circulation. 1993;88:782–784[Free Full Text]
  10. Locati EH, Zareba W, Moss AJ. 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[Abstract/Free Full Text]
  11. Vincent GM, Timothy K, Fox J, Zhang L. Long QT syndrome patients with normal to borderline prolonged QTc intervals are at risk for syncope, cardiac arrest and sudden death (Abstr). Circulation. 1999;18:I–245
  12. Pony JC, Mattheyses M, Daubert JC, Fourdilis M, Gouffault J. Le syndrome QT long-syncope familial. Deux observations de syndrome de Romano et Ward. Arch Mal Coeur Vaiss. 1977;70:1105–1114[ISI][Medline]
  13. Lathrop GM, Lalouel JM. Easy calculations of lod scores and genetic risks on small computers. Am J Hum Genet. 1984;36:460–465[ISI][Medline]
  14. Jiang C, Atkinson D, Towbin JA. Two long QT syndrome loci map to chromosomes 3 and 7 with evidence for further heterogeneity. Nat Genet. 1994;8:141–147[CrossRef][ISI][Medline]
  15. Schott JJ, Charpentier F, Peltier S. Mapping of a gene for long QT syndrome to chromosome 4q25-27. Am J Hum Genet. 1995;57:1114–1122[ISI][Medline]
  16. Gyapay G, Morissette J, Vignal A. The 1993–94 Genethon human genetic linkage map. Nat Genet. 1994;7:246–339[CrossRef][ISI][Medline]
  17. Grunebaum L, Cazenave JP, Camerino G. Carrier detection of Hemophilia B by using a restriction site polymorphism associated with the coagulation Factor IX gene. J Clin Invest. 1984;73:1491–1495[ISI][Medline]
  18. Splawski I, Shen J, Timothy KW, Vincent GM, Lehmann MH, Keating MT. Genomic structure of three long QT syndrome genes: KVLQT1, HERG, and KCNE1. Genomics. 1998;51:86–97[CrossRef][ISI][Medline]
  19. Demolombe S, Barò I, Pereon Y. A dominant negative isoform of the long QT syndrome 1 gene product. J Biol Chem. 1998;273:6837–6843[Abstract/Free Full Text]
  20. Mohammad-Panah R, Demolombe S, Riochet D. Hyperexpression of recombinant CFTR in heterologous cells alters its physiological properties. Am J Physiol. 1998;274:C310–8[ISI][Medline]
  21. Barhanin J, Lesage F, Guillemare E, Fink M, Lazdunski M, Romey G. KvLQT1 and lsK (minK) proteins associate to form the IKs cardiac potassium current. Nature. 1996;384:78–80[CrossRef][Medline]
  22. Lepeschkin E, Surawicz B. The measurement of the QT interval of the electrocardiogram. Circulation. 1952;6:378–388[ISI][Medline]
  23. Bazett HC. An analysis of the time relations of the electyrocardiograms. Am Heart J. 1920;7:353–370
  24. Fridericia LS. Die Systolendauer im Elektrokardiogramm bei normalen Menschen und bei Herzkranken. Acta Med Scand. 1920;53:469–486
  25. Lande G, Funck-Brentano C, Ghadanfar M, Escande D. Steady-state versus non-steady-state QT-RR relationships in 24-hour Holter recordings. Pacing Clin Electrophysiol. 2000;23:293–302[CrossRef][Medline]
  26. Badilini F, Maison-Blanche P, Childers R, Coumel P. QT interval analysis on ambulatory electrocardiogram recordings: a selective beat averaging approach. Med Biol Eng Comput. 1999;37:71–79[ISI][Medline]
  27. Dickhuth HH, Bluemner E, Auchschwelk W, Zehnder M, Irmer M, Meinertz T. The relationship between heart rate and QT interval during atrial stimulation. Pacing Clin Electrophysiol. 1991;14:793–799[CrossRef][Medline]
  28. Altman DG, Gardner MJ. Calculating confidence intervals for regression and correlation. Br Med J. 1988;296:1238–1242[ISI][Medline]
  29. Chouabe C, Neyroud N, Guicheney P, Lazdunski M, Romey G, Barhanin J. Properties of KvLQT1 K+ channel mutations in Romano–Ward and Jervell and Lange-Nielsen inherited cardiac arrhythmias. EMBO J. 1997;16:5472–5479[CrossRef][ISI][Medline]
  30. Mohammad-Panah R, Demolombe S, Neyroud N. Mutations in a dominant-negative isoform correlates with phenotype in inherited cardiac arrhythmias. Am J Hum Genet. 1999;64:1015–1023[CrossRef][ISI][Medline]
  31. Hashiba K. Sex differences in phenotypic manifestation and gene transmission in the Romano–Ward syndrome. Ann NY Acad Sci. 1992;644:142–156[ISI][Medline]
  32. Hashiba K. Hereditary QT prolongation syndrome in Japan: genetic analysis and pathological findings of the conducting system. Jpn Circ J. 1978;42:1133–1150[Medline]
  33. Zareba W, Moss AJ, Le Cessie S. Risk of cardiac events in family members of patients with long QT syndrome. J Am Coll Cardiol. 1995;26:1685–1691[Abstract]
  34. Stramba-Badiale M, Locati EH, Martinelli A, Courville J, Schwartz PJ. Gender and the relationship between ventricular depolarisation and cardiac cycle length during 24-h Holter recordings. Eur Heart J. 1997;18:1000–1006[Abstract/Free Full Text]
  35. Makkar RR, Fromm BS, Steinman RT, Meissner MD, Lehmann MH. Female gender as a risk factor for torsades de pointes associated with cardiovascular drugs. JAMA. 1993;270:2590–2597[Abstract]
  36. Lehmann MH, Hardy S, Archibald D, Quart B, MacNeil DJ. Sex difference in risk of torsade de pointes with d,l-sotalol. Circulation. 1996;94:2535–2541[Abstract/Free Full Text]
  37. Drici MD, Burklow TR, Haridasse V, Glazer RI, Woosley RL. Sex hormones prolong the QT interval and downregulate potassium channel expression in the rabbit heart. Circulation. 1996;94:1471–1474[Abstract/Free Full Text]
  38. Li H, Chen Q, Moss AJ. New mutations in the KVLQT1 potassium channel that cause long-QT syndrome. Circulation. 1998;97:1264–1269[Abstract/Free Full Text]
  39. Murray A, Donger C, Fenske C. Splicing mutations in KCNQ1: A mutation hot spot at codon 344 that produces In frame transcripts. Circulation. 1999;100:1077–1084[Abstract/Free Full Text]
  40. Roden DM. Taking the ‘idio’ out of ‘idiosyncratic’: predicting torsades de pointes [editorial]. Pacing Clin Electrophysiol. 1998;21:1029–1034[CrossRef][Medline]
  41. Roden DM, Woosley RL, Primm RK. Incidence and clinical features of the quinidine-associated long QT syndrome: implications for patient care. Am Heart J. 1986;111:1088–1093[CrossRef][ISI][Medline]
  42. Hohnloser SH, Woosley RL. Sotalol. N Engl J Med. 1994;331:31–38[Free Full Text]
  43. Stambler BS, Wood MA, Ellenbogen KA, Perry KT, Wakefield LK, VanderLugt JT. Efficacy and safety of repeated intravenous doses of ibutilide for rapid conversion of atrial flutter or fibrillation. Ibutilide Repeat Dose Study Investigators. Circulation. 1996;94:1613–1621[Abstract/Free Full Text]
  44. Bexton RS, Vallin HO, Camm AJ. Diurnal variation of the QT interval—influence of the autonomic nervous system. Br Heart J. 1986;55:253–258[Abstract/Free Full Text]
  45. Browne KF, Prystowsky E, Heger JJ, Chilson DA, Zipes DP. Prolongation of the Q-T interval in man during sleep. Am J Cardiol. 1983;52:55–59[CrossRef][ISI][Medline]
  46. Hirao H, Shimizu W, Kurita T. Frequency-dependent electrophysiologic properties of ventricular depolarisation in patients with congenital long QT syndrome. J Am Coll Cardiol. 1996;28:1269–1277[Abstract]
  47. Merri M, Moss AJ, Benhorin J, Locati EH, Alberti M, Badilini F. Relation between ventricular depolarisation duration and cardiac cycle length during 24-hour Holter recordings. Findings in normal patients and patients with long QT syndrome. Circulation. 1992;85:1816–1821[Abstract/Free Full Text]
  48. Neyroud N, Maison-Blanche P, Denjoy I. Diagnostic performance of QT interval variables from 24-h electrocardiography in the long QT syndrome. Eur Heart J. 1998;19:158–165[Abstract/Free Full Text]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 CirculationHome page
A. D. Krahn, M. Gollob, R. Yee, L. J. Gula, A. C. Skanes, B. D. Walker, and G. J. Klein
Diagnosis of Unexplained Cardiac Arrest: Role of Adrenaline and Procainamide Infusion
Circulation, October 11, 2005; 112(15): 2228 - 2234.
[Abstract] [Full Text] [PDF]

Home page
 Br J AnaesthHome page
P. D. Booker, S. D. Whyte, and E. J. Ladusans
Long QT syndrome and anaesthesia
Br. J. Anaesth., March 1, 2003; 90(3): 349 - 366.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
V. N. Batchvarov, A. Ghuran, P. Smetana, K. Hnatkova, M. Harries, P. Dilaveris, A. J. Camm, and M. Malik
QT-RR relationship in healthy subjects exhibits substantial intersubject variability and high intrasubject stability
Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2356 - H2363.
[Abstract] [Full Text] [PDF]

Home page
 Circ. Res.Home page
J. M. Nerbonne, C. G. Nichols, T. L. Schwarz, and D. Escande
Genetic Manipulation of Cardiac K+ Channel Function in Mice: What Have We Learned, and Where Do We Go From Here?
Circ. Res., November 23, 2001; 89(11): 944 - 956.
[Abstract] [Full Text] [PDF]

Home page
 Eur Heart J SupplHome page
D. Escande
Inhibition of repolarizing ionic currents by drugs
Eur. Heart J. Suppl., September 1, 2001; 3(suppl_K): K17 - K22.
[Abstract] [PDF]

Home page
 Cardiovasc ResHome page
G. Lande, S. Demolombe, A. Bammert, A. Moorman, F. Charpentier, and D. Escande
Transgenic mice overexpressing human KvLQT1 dominant-negative isoform Part II: Pharmacological profile
Cardiovasc Res, May 1, 2001; 50(2): 328 - 334.
[Abstract] [Full Text] [PDF]

Home page
 Eur Heart JHome page
P. E. Puddu, A. Criniti, and F Monti
Screening for drug-induced (acquired) long QT syndrome: is it time to apply new methods?
Eur. Heart J., March 1, 2001; 22(5): 363 - 369.
[PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
V. N. Batchvarov, A. Ghuran, P. Smetana, K. Hnatkova, M. Harries, P. Dilaveris, A. J. Camm, and M. Malik
QT-RR relationship in healthy subjects exhibits substantial intersubject variability and high intrasubject stability
Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2356 - H2363.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (15)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Lande, G.
Right arrow Articles by Le Marec, H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lande, G.
Right arrow Articles by Le Marec, H.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?