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European Heart Journal Advance Access published online on November 19, 2009
European Heart Journal, doi:10.1093/eurheartj/ehp489
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org

Enterovirus-related activation of the cardiomyocyte mitochondrial apoptotic pathway in patients with acute myocarditis

Lydie Ventéo1,2, Thomas Bourlet3, Fanny Renois1, Fatima Douche-Aourik3, Jean-François Mosnier4, Geoffroy Lorain De la Grand Maison5, Michel Pluot2, Bruno Pozzetto3 and Laurent Andreoletti1,*

1 Laboratoire de Virologie médicale et moléculaire Hôpital Robert Debré, IFR 53/EA4303, CHU et Faculté de Médecine de Reims, Avenue du Général Koenig, 51092 REIMS Cedex, France
2 Service d'Anatomie Pathologique, Hôpital Robert Debré, IFR 53/EA-3798, CHU et Faculté de Médecine de Reims, France
3 Laboratoire de Bactériologie-Virologie, GIMAP, EA-3064 Centre Hospitalier Universitaire, Saint-Etienne, France
4 Service d'Anatomie Pathologique, Centre Hospitalier Universitaire, Nantes, France
5 Service d'Anatomie Pathologique et de Médecine Légale, Hôpital Raymond Poincaré, Garches, France

Received 5 February 2009; revised 11 September 2009; accepted 2 October 2009 * Corresponding author. Tel: +33 3 26 78 39 93, Fax: +33 3 26 78 41 34; Email: landreoletti{at}chu-reims.fr

Aims: We examined the impact of enterovirus (EV) cardiac replication activity on the endomyocardial mitochondrial pathway in patients with acute myocarditis.

Methods and results: Levels of apoptotic cardiomyocytes were determined by TUNEL and ligation-mediated polymerase chain reaction (PCR) assays and EV replication activity was assessed by immunostaining of EV VP1 capsid protein in ventricular myocytes of patients with acute myocarditis (n = 25), and healthy heart controls (n = 15). Ratio of cytosolic/mitochondrial cytochrome c concentrations was determined by ELISA assay, levels of active caspase-9 were determined by western blot analysis and Bax/Bcl2 mRNA ratio was assessed by real-time reverse transcription–polymerase chain reaction (RT–PCR) in the same cardiac tissues. Patients with EV-associated acute myocarditis (n = 15) exhibited a significantly higher number of apoptotic cardiomyocytes than those with non-EV-associated acute myocarditis (n = 10) and controls (n = 15) (P < 0.001). Endomyocardial ratio of cytosolic/mitochondrial cytochrome c concentrations and levels of active caspase-9 protein were significantly increased in EV than in non-EV-related myocarditis patients (P < 0.001). Moreover, Bax/Bcl2 mRNA ratio was significantly increased in EV than in non-EV-related myocarditis patients (P < 0.001).

Conclusion: Our findings evidence an EV-related activation of the cardiomyocyte mitochondrial apoptotic pathway in patients with acute myocarditis. Moreover, our results indicate that this EV-induced pro-apoptotic mechanism could be partly related to an up-regulation of Bax expression, and suggest that inhibition of this cell death process may constitute the basis for novel therapies.

Key Words: Enterovirus • Cardiomyocytes • Apoptosis • Cytochrome c • Caspase-9 protein • Acute myocarditis • End-stage dilated cardiomyopathy (DCM)


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