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Lydie Ventéo, Thomas Bourlet, Fanny Renois, Fatima Douche-Aourik, Jean-François Mosnier, Geoffroy Lorain De la Grand Maison, Michel Pluot, Bruno Pozzetto, Laurent Andreoletti, Enterovirus-related activation of the cardiomyocyte mitochondrial apoptotic pathway in patients with acute myocarditis, European Heart Journal, Volume 31, Issue 6, March 2010, Pages 728–736, https://doi.org/10.1093/eurheartj/ehp489
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Abstract
We examined the impact of enterovirus (EV) cardiac replication activity on the endomyocardial mitochondrial pathway in patients with acute myocarditis.
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).
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.
- apoptosis
- cardiac myocytes
- myocarditis
- polymerase chain reaction
- enterovirus
- western blotting
- enzyme-linked immunosorbent assay
- immunohistochemistry
- mitochondria
- myocarditis, acute
- capsid
- cell death
- cytochrome c
- cytosol
- bcl2 gene
- in situ nick-end labeling
- ligation
- reverse transcriptase polymerase chain reaction
- rna, messenger
- up-regulation (physiology)
- heart
- bcl-2 protein
- caspase-9
- ventricular myocytes
Comments
Our cross sectional study evidenced 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 (1). These results confirmed previously published experimental demonstrating that the over-expression of pro-apoptotic mitochondrial Bax protein family proteins in cardiomyocytes of transgenic mice was identified as a causal mechanism of heart failure (2,3). Similarly, several clinical studies indicated that the number of apoptotic myocytes was related to the stage and severity of EV-related myocarditis. (1). Evidently, our study was not a clinical longitudinal study designed to determine the impact of EV infection onto the clinical outcome, but only to examine the impact of enterovirus (EV) cardiac replication activity on the endomyocardial mitochondrial pathway in patients with acute myocarditis. Whatever, we observed that the mean histological score of lesions was significantly higher in EV-positive than in EV-negative subgroup of patients (P = 0.03), whereas all of the clinical parameters were statistically equivalent between these two subgroups (1).These findings suggested that further multicentric clinical longitudinal studies would be necessary to assess the clinical impact of EV on apoptosis and on the potential evolution towards hypertrophic and dilated cardiomyopathies. In the manuscript published by Abbate et al. in 2009, no patient was detected as infected by EVs in cardiac tissues and therefore it is not possible to virologically, epidemiologically and clinically compare their study to ours (1,4). Finally, because some clinical and experimental studies have demonstrated that the EV-induced death of myocytes has a deleterious effect on ventricular haemodynamic and could cause sudden cardiac death by heart failure (2,3) our findings raised the possibility that inhibition of this cell death process may provide a novel target for treatments directed against common and lethal EV-induced myocarditis cases. Concerning the clinical practice, we agree that further collaborative experimental and clinical studies are necessary to validate the use of such therapeutic strategies to fight against severe EV induced myocarditis. The door is now open but the job remains to be done.
1. Venteo L, Bourlet T, Renois F, Douche-Aourik F, Mosnier JF, Maison GL, Pluot M, Pozzetto B, Andreoletti L. Enterovirus-related activation of the cardiomyocyte mitochondrial apoptotic pathway in patients with acute myocarditis. Eur Heart J. 2010;31:728-36.
2. Wencker D, Chandra M, Nguyen K, Miao W, Garantziotis S, Factor SM, Shirani J,Armstrong RC, Kitsis RN. A mechanistic role for cardiac myocyte apoptosis in heart failure. J Clin Invest 2003;10:1497-1504.
3. Kyto V, Saraste A, Saukko P, Henn V, Pulkki K, Vuorinen T, Voipio- Pulkki LM. Apoptotic cardiomyocyte death in fatal myocarditis. Am J Cardiol 2004;94:746-750.
4. Abbate A, Sinagra G, Bussani R, Hoke NN, Merlo M, Varma A, Toldo S, Salloum FN, Biondi-Zoccai GG, Vetrovec GW, Crea F, Silvestri F, Baldi A. Apoptosis in patients with acute myocarditis. Am J Cardiol. 2009;104:995-1000.
Conflict of Interest:
None declared
We read with interest the paper by Venteo and coll.[1] on the presence of apoptotic cardiomyocytes in the heart of patients suffering with acute viral myocarditis. The association of apoptosis with viral myocarditis is not novel. The authors speculate that apoptosis may be a mechanism by which the virus induces cell death, which is also likely the case. The authors also speculate that increased apoptosis may represent the link between acute myocarditis and progression to heart failure. This speculation is based on the observation that patients that died had greater apoptosis than those who survived. We believe that speculation that apoptosis may be responsible for the progression toward heart failure is unsupported. The study by Venteo and coll.[1] is indeed inappropriate to conclude on any cause-effect link, especially because the study represents a cross-section of the disease, and not information is given on the follow up. In this regard, we would like to call the attention of our very own study in which 16 patients with biopsy-proven myocarditis underwent serial echocardiograms to evaluate interval change in left ventricular ejection fraction [2]. Unexpectedly, an above median apoptotic rate predicted a full recovery in left ventricular function, whereas a lower apoptotic rate was associated with lack of recovery [2]. This highlights that the role of apoptosis in acute myocarditis may be more complex than it appears and apoptosis may represent a potential protective mechanism by which virus-infected are eliminated, and accordingly several studies have shown that viral persistence is a strong predictor of adverse outcome. This also shows that caution should be taken when interpreting results of cross-sectional studies as associations may be spurious. In conclusion, while may still remain undetermined whether apoptosis is friend or foe in acute myocarditis the call for clinical studies using antiapoptotic therapies (as envisioned by the authors) seems very premature.
Antonio Abbate, MD, PhD1; Rossan Bussani, MD2; Gianfranco Sinagra, MD2. 1 Virginia Commonwealth University, Richmond, VA, USA; 2 University of Trieste, Trieste, Italy
References:
1) Venteo L, Bourlet T, Renois F, et al. Enterovirus-related activation of the cardiomyocyte mitochondrial apoptotic pathway in patients with acute myocarditis. Eur Heart J 2010;31:728-736.
2) Abbate A, Sinagra G, Bussani R, et al. Apoptosis in patients with acute myocarditis. Am J Cardiol 2009;104:995-1000
Conflict of Interest:
None declared