Sudden cardiac death (SCD) can be caused by a number of reasons. Previous works have identified the genetic causes, such as alterations in the DNA sequence, for many of these diseases. We hypothesize that some patients may show genomic imbalances and changes in the gene copy number leading to genetic instability. To clarify this, we analysed DNA samples from SCD victims using comparative genomic hybridization (CGH), a molecular cytogenetic technique that permits the genome-wide screening of chromosomal imbalances, and telomere length measurement. DNA derived from peripheral blood and heart tissue of 14 SCD cases and six apparently healthy control individuals were subjected to CGH analysis. Telomere length measurements were done by the Southern blotting method. Eight out of 14 SCD cases exhibited changes in DNA/gene copy number. CGH analysis showed variation in the gene copy number of some of the genes associated with potassium (KCNAB1, KCNH2, and KCNA4) and calcium (RyR2, ATP2A2) ions which are involved in maintaining the ionic balance of the heart. Alterations in TERC and TERT genes were also detected in SCD victims. In nine SCD victims shorter telomeres were detected. This might have resulted from excessive cellular proliferation and/or oxidative stress in these individuals. Copy number changes observed and telomere shortening detected in SCD cases would possibly explain at least some of the causes of SCD at early ages in humans. Identification of biomarkers of SCD is of great importance and thus the present study will facilitate the identification of some of the biomarkers.

1.
Ackerman MJ: The long QT syndrome. Pediatr Rev 19:232–238 (1998).
2.
Atarashi H, Ogawa S, Harumi K, Sugimoto T, Inoue H, et al: Three-year follow-up of patients with right bundle branch block and ST segment elevation in the right precordial leads: Japanese Registry of Brugada Syndrome. Idiopathic Ventricular Fibrillation Investigators. J Am Coll Cardiol 37:1916–1920 (2001).
3.
Aviv A: Telomeres, sex, reactive oxygen species, and human cardiovascular aging. J Mol Med 80:689–695 (2002).
4.
Aviv A: Telomeres and human aging: facts and fibs. Sci Aging Knowledge Environ 2004:e43 (2004).
5.
Bauce B, Rampazzo A, Basso C, Bagattin A, Daliento L, et al: Screening for ryanodine receptor type 2 mutations in families with effort-induced polymorphic ventricular arrhythmias and sudden death: early diagnosis of asymptomatic carriers. J Am Coll Cardiol 40:341–349 (2002).
6.
Blackburn EH: Telomeres. Trends Biochem Sci 16:378–381 (1991).
7.
Brugada R, Hong K, Dumaine R, Cordeiro J, Gaita F, et al: Sudden death associated with short-QT syndrome linked to mutations in HERG. Circulation 109:30–35 (2004).
8.
Chimenti C, Kajstura J, Torella D, Urbanek K, Heleniak H, et al: Senescence and death of primitive cells and myocytes lead to premature cardiac aging and heart failure. Circ Res 93:604–613 (2003).
9.
Drifmeyer EB, Batts KB: The Brugada syndrome. Curr Sports Med Rep 4:83–87 (2005).
10.
Engelstein ED: Long QT syndrome: a preventable cause of sudden death in women. Curr Womens Health Rep 3:126–134 (2003a).
11.
Engelstein ED: Prevention and management of chronic heart failure with electrical therapy. Am J Cardiol 91:62F–73F (2003b).
12.
England SK, Uebele VN, Kodali J, Bennett PB, Tamkun MM: A novel K+ channel β-subunit (hKvβ1.3) is produced via alternative mRNA splicing. J Biol Chem 270:28531–28534 (1995).
13.
Fuster JJ, Andres V: Telomere biology and cardiovascular disease. Circ Res 99:1167–1180 (2006).
14.
Hastings R, Li NC, Lacy PS, Patel H, Herbert KE, et al: Rapid telomere attrition in cardiac tissue of the ageing Wistar rat. Exp Gerontol 39:855–857 (2004).
15.
Kearney MT, Fox KA, Lee AJ, Brooksby WP, Shah AM, et al: Predicting sudden death in patients with mild to moderate chronic heart failure. Heart 90:1137–1143 (2004).
16.
Newman JP, Banerjee B, Fang W, Poonepalli A, Balakrishnan L, et al: Short dysfunctional telomeres impair the repair of arsenite-induced oxidative damage in mouse cells. J Cell Physiol 214:796–809 (2008).
17.
Oexle K, Zwirner A: Advanced telomere shortening in respiratory chain disorders. Hum Mol Genet 6:905–908 (1997).
18.
Oh H, Wang SC, Prahash A, Sano M, Moravec CS, et al: Telomere attrition and Chk2 activation in human heart failure. Proc Natl Acad Sci USA 100:5378–5383 (2003).
19.
Oliver D, Lien CC, Soom M, Baukrowitz T, Jonas P, Fakler B: Functional conversion between A-type and delayed rectifier K+ channels by membrane lipids. Science 304:265–270 (2004).
20.
Poonepalli A, Balakrishnan L, Khaw AK, Low GK, Jayapal M, et al: Lack of poly(ADP-ribose) polymerase-1 gene product enhances cellular sensitivity to arsenite. Cancer Res 65:10977–10983 (2005).
21.
Priori SG, Napolitano C, Tiso N, Memmi M, Vignati G, et al: Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia. Circulation 103:196–200 (2001).
22.
Rubart M, Zipes DP: Mechanisms of sudden cardiac death. J Clin Invest 115:2305–2315 (2005).
23.
Serrano AL, Andres V: Telomeres and cardiovascular disease: does size matter? Circ Res 94:575–584 (2004).
24.
Takubo K, Izumiyama-Shimomura N, Honma N, Sawabe M, Arai T, et al: Telomere lengths are characteristic in each human individual. Exp Gerontol 37:523–531 (2002).
25.
von Zglinicki T: Role of oxidative stress in telomere length regulation and replicative senescence. Ann N Y Acad Sci 908:99–110 (2000).
26.
von Zglinicki T: Oxidative stress shortens telomeres. Trends Biochem Sci 27:339–344 (2002).
27.
Wichter T, Schulze-Bahr E, Eckardt L, Paul M, Levkau B, et al: Molecular mechanisms of inherited ventricular arrhythmias. Herz 27:712–739 (2002).
28.
Zipes DP, Wellens HJ: Sudden cardiac death. Circulation 98:2334–2351 (1998).
© 2008 S. Karger AG, Basel
2009
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.