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Genetic basis and molecular mechanism for idiopathic ventricular fibrillation


Ventricular fibrillation causes more than 300, 000 sudden deaths each year in the USA alone1,2. In approximately 5–12% of these cases, there are no demonstrable cardiac or non-cardiac causes to account for the episode, which is therefore classified as idiopathic ventricular fibrillation (IVF)3,4,5,6. A distinct group of IVF patients has been found to present with a characteristic electrocardiographic pattern7,8,9,10,11,12,13,14,15. Because of the small size of most pedigrees and the high incidence of sudden death, however, molecular genetic studies of IVF have not yet been done. Because IVF causes cardiac rhythm disturbance, we investigated whether malfunction of ion channels could cause the disorder by studying mutations in the cardiac sodium channel gene SCN5A. We have now identified a missense mutation, a splice-donor mutation, and a frameshift mutation in the coding region of SCN5A in three IVF families. We show that sodium channels with the missense mutation recover from inactivation more rapidly than normal and that the frameshift mutation causes the sodium channel to be non-functional. Our results indicate that mutations in cardiac ion-channel genes contribute to the risk of developing IVF.

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Figure 1: SCN5A missense mutation co-segregating with IVF in family K005.
Figure 2: SCN5A splicing mutation in K007 and intragenic deletion in K2823.
Figure 3: Voltage-dependence of activation and inactivation, and time course of recovery from inactivation.
Figure 4: The predicted secondary structure of the cardiac sodium channel and locations of mutations causing IVF and chromosome-3-linked long-QT syn.


  1. Kannel, W. B., Cupples, A. & D'Agostino, R. B. Sudden death risk in overt coronary heart disease: the Framingham study. Am. Heart J. 113, 799–804 (1987).

    Article  CAS  Google Scholar 

  2. Willich, al. Circadian variation in the incidence of sudden cardiac death in the Framingham heart study population. Am. J. Cardiol. 60, 801–806 (1987).

    Article  CAS  Google Scholar 

  3. Trappe, H. al. Prognosis of patients with ventricular tachycardia and ventricular fibrillation: role of the underlying etiology. J. Am. Coll. Cardiol. 12, 166–174 (1988).

    Article  CAS  Google Scholar 

  4. Viskin, S. & Belhassen, B. Idiopathic ventricular fibrillation. Am. Heart J. 120, 661–671 (1990).

    Article  CAS  Google Scholar 

  5. Wichter, T., Breithardt, G. & Borggrefe, M. in Cardiac Arrhythmia: Mechanism, Diagnosis, and Management (eds Podrid, P. J. & Kowey, P. R.) 1219–1238 (Williams & Wilkins, Maryland, 1995).

    Google Scholar 

  6. Martini, al. Ventricular fibrillation without apparent heart disease: description of six cases. Am. Heart. J. 118, 1203–1209 (1989).

    Article  CAS  Google Scholar 

  7. Brugada, J., Brugada, R. & Brugada, P. Right bundle branch block, ST segment elevation in leads V1–V3: a marker for sudden death in patients without demonstrable structural heart disease. Circulation 96, I151 (1997).

    Google Scholar 

  8. Brugada, P. & Brugada, J. Right bundle branch block, persistent ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome. A multicenter report. J. Am. Coll. Cardiol. 20, 1391–1396 (1992).

    Article  CAS  Google Scholar 

  9. Brugada, P. & Brugada, J. Further characterization of the syndrome of right bundle branch block, ST segment elevation, and sudden cardiac death. J. Cardiovasc. Electrophysiol. 8, 325–331 (1997).

    Article  CAS  Google Scholar 

  10. Brugada, J., Brugada, P. & Brugada, R. Ajmaline unmasks right bundle branch block-like and ST segment elevation in V1–V3 in patients with idiopathic ventricular fibrillation. PACE 19, 599 (1996).

    Google Scholar 

  11. Miyanuma, H., Sakurai, M. & Odaka, H. Two cases of idiopathic ventricular fibrillation with interesting electrocardiographic findings. Kokyu to Junkan 41, 287–291 (1993).

    CAS  PubMed  Google Scholar 

  12. Aizawa, al. Idiopathic ventricular fibrillation and bradycardia-dependent intraventricular block. Am. Heart J. 126, 1473–1474 (1993).

    Article  CAS  Google Scholar 

  13. Sumiyoshi, al. Acase of idiopathic ventricular fibrillation with incomplete right bundle branch block and persistent ST segment elevation. Jpn Heart J. 34, 661–666 (1993).

    Article  CAS  Google Scholar 

  14. Bjerregaard, P., Gussak, I., Kotar, S. L., Gessler, J. E. & Janosik, D. Recurrent syncope in a patient with prominent J wave. Am. Heart J. 127, 1426–1430 (1994).

    Article  CAS  Google Scholar 

  15. Miyazaki, al. Autonomic and antiarrhythmic drug modulation of ST segment elevation in patients with Brugada syndrome. J. Am. Coll. Cardiol. 27, 1061–1070 (1996).

    Article  CAS  Google Scholar 

  16. Tung, R. T., Shen, W., Hammil, S. C. & Gersh, E. J. Idiopathic ventricular fibrillation in out-of-hospital cardiac arrest survivors. PACE 17, 1405–1411 (1994).

    Article  CAS  Google Scholar 

  17. Cobb, L. A. in Hurst's The Heart (eds Schlant, R. C. & Alexander, R. W.) 8th edn. 947–957 (McGraw Hill, New York, 1994).

    Google Scholar 

  18. Wang, Q., Li, Z., Shen, J. & Keating, M. T. Genomic organization of the human SCN5A gene encoding the cardiac sodium channel. Genomics 34, 9–16 (1996).

    Article  CAS  Google Scholar 

  19. Rogers, J. C., Qu, Y., Tanada, T. N., Scheuer, T. & Catterall, W. A. Molecular determinants of high affinity binding of α-scorpion toxin and sea anemone toxin in the S3–S4 extracellular loop in domain IV of the Na channel α subunit. J. Biol. Chem. 271, 15950–15962 (1996).

    Article  CAS  Google Scholar 

  20. Hoffman, E. P., Lehmann-Horn, F. & Rudel, R. Overexcited or inactive: ion channels in muscle disease. Cell 80, 681–686 (1995).

    Article  CAS  Google Scholar 

  21. Yang, N. & Horn, R. Evidence for voltage-dependent S4 movement in sodium channels. Neuron 15, 213–218 (1995).

    Article  CAS  Google Scholar 

  22. Shapiro, M. B. & Senapathy, P. RNA splice junctions of different classes of eukaryotes: sequence statistics and functional implications in gene expression. Nucleic Acids Res. 15, 7155–7174 (1987).

    Article  CAS  Google Scholar 

  23. Wang, al. SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome. Cell 80, 805–811 (1995).

    Article  CAS  Google Scholar 

  24. Wang, al. Cardiac sodium channel mutations in patients with long QT syndrome, an inherited cardiac arrhythmia. Hum. Mol. Genetics 4, 1603–1607 (1995).

    Article  CAS  Google Scholar 

  25. Bennett, P. B., Yazawa, K., Makita, N. & George, A. L. J Molecular mechanism for an inherited cardiac arrhythmia. Nature 376, 683–685 (1995).

    Article  ADS  CAS  Google Scholar 

  26. Dumaine, al. Multiple mechanisms of Na+ channel-linked long-QT syndrome. Circulation Res. 78, 916–992 ((1996).

    Article  CAS  Google Scholar 

  27. Stuhmer, al. Structural parts involved in activation and inactivation of the sodium channel. Nature 339, 597–603 (1989).

    Article  ADS  CAS  Google Scholar 

  28. Krishnan, S. C. & Antzelevitch, C. Sodium channel block produces opposite electrophysiological effects in canine ventricular epicardium and endocardium. Circulation Res. 69, 277–291 (1991).

    Article  CAS  Google Scholar 

  29. Krishnan, S. C. & Antzelevitch, C. Flecainide-induced arrhythmia in canine ventricular epicardium. Phase 2 reentry? Circulation 87, 562–572 (1992).

    Article  Google Scholar 

  30. Yan, G. X. & Antzelevitch, C. Cellular basis for the electrocardiographic J wave. Circulation 93, 372–379 (1996).

    Article  CAS  Google Scholar 

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We thank H. Hartmann for the wild-type SCN5A construct; M. Sanguinetti and P.Spector for help with electrophysiological analysis of the 1-bp deletion; and P. Szafranski, J. T. Bricker, M. Scheinman, A.L. Beaudet, A. Bradley and X. Qu for help and advice. This work ws supported by a Grant-In-Aid from the American Heart association, by the AHA, Northeast Ohio Affiliate (G.E.K.), and the Deutsche Forschungsgemeinschaft (E.S.-B.), and by grants from the NIH and Bristol-Myers Squibb (M.T.K.), The Texas Children's Hospital Foundation Chair in Pediatric Cardiac Research and NIH grants (J.A.T.), the Carolien Weiss Law Grant for Research in Molecular Medicine (Q.W.), the Abercrombie Cardiology Fund of Texas Children's Hospital (Q.W.), and a Scientist Development Award from the American Hearth Association (Q.W.).

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Correspondence to Qing Wang.

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Chen, Q., Kirsch, G., Zhang, D. et al. Genetic basis and molecular mechanism for idiopathic ventricular fibrillation. Nature 392, 293–296 (1998).

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