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European Heart Journal Advance Access originally published online on July 9, 2008
European Heart Journal 2008 29(20):2514-2525; doi:10.1093/eurheartj/ehn328
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that the original authorship is properly and fully attributed; the Journal, Learned Society and Oxford University Press are attributed as the original place of publication with correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org.

The Ser96Ala variant in histidine-rich calcium-binding protein is associated with life-threatening ventricular arrhythmias in idiopathic dilated cardiomyopathy

Demetrios A. Arvanitis1, Despina Sanoudou1,{dagger}, Fotis Kolokathis2,{dagger}, Elizabeth Vafiadaki1, Vasiliki Papalouka1, Aikaterini Kontrogianni-Konstantopoulos3, George N. Theodorakis5, Ioannis A. Paraskevaidis2, Stamatios Adamopoulos5, Gerald W. Dorn, II4, Dimitrios Th. Kremastinos2 and Evangelia G. Kranias1,6,*

1 Molecular Biology Division, Biomedical Research Foundation, Academy of Athens, Athens, Greece
2 Second Department of Cardiology, University of Athens, Attikon Hospital, Athens, Greece
3 Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland Baltimore, Baltimore, MD, USA
4 Center for Molecular Cardiovascular Research, College of Medicine, University of Cincinnati, Cincinnati, OH, USA
5 Second Department of Cardiology, Onassis Cardiac Surgery Center, Athens, Greece
6 Department of Pharmacology and Cell Biophysics, College of Medicine, University of Cincinnati, 231 Albert Sabin Way, Cincinnati, OH 45267-0575, USA

Received 20 December 2007; revised 13 June 2008; accepted 19 June 2008; online publish-ahead-of-print 9 July 2008.

* Corresponding author. Tel: +1 513 558 2377, Fax: +1 513 558 2269, Email: litsa.kranias{at}uc.edu

Aims: To investigate whether genetic variants of the histidine-rich calcium (HRC)-binding protein are associated with idiopathic dilated cardiomyopathy (DCM) and its progression.

Methods and results: We screened 123 idiopathic DCM patients and 96 healthy individuals by single-strand conformation polymorphism analysis and direct sequencing for genetic variants in HRC. Six polymorphisms were detected: Leu35Leu (A/G), Ser43Asn (G/A), Ser96Ala (T/G), Glu202_Glu203insGlu (–/GAG), Asp261del (GAT/–), and an in-frame insertion of 51 amino acids at His321. The analysis of their frequencies did not reveal any significant correlation with DCM development. However, the Ser96Ala polymorphism exhibited a statistically significant correlation with the occurrence of life-threatening ventricular arrhythmias. During a follow-up of 4.02 ± 2.4 years, the risk for ventricular arrhythmias was higher (HR, 9.620; 95% CI, 2.183–42.394; P = 0.003) in the Ala/Ala patients, compared with Ser/Ser homozygous patients. On multivariable Cox regression analysis, the Ser96Ala polymorphism was the only significant genetic arrythmogenesis predictor in DCM patients (HR, 4.191; 95% CI, 0.838–20.967; P = 0.018).

Conclusion: The Ser96Ala genetic variant of HRC is associated with life-threatening ventricular arrhythmias in idiopathic DCM and may serve as an independent predictor of susceptibility to arrhythmogenesis in the setting of DCM.

Key Words: Calcium • Sarcoplasmic reticulum • Prognosis • Defibrillation

{dagger} D.S. and F.K. contributed equally to this work.


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