European Heart Journal Advance Access originally published online on March 27, 2007
European Heart Journal 2007 28(9):1117-1127; doi:10.1093/eurheartj/ehm022
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Myocardial production of chromogranin A in human heart: a new regulatory peptide of cardiac function
1 Cardiology Department, Catholic University of the Sacred Heart, Largo A. Gemelli 8, 00168 Rome, Italy
2 Oncology Department and ITT Network Research, Unit of Molecular Neuroscience, San Raffaele Scientific Institute, Milan, Italy
3 Cell Biology, University of Calabria, Rende, Italy
4 Pharmaco-Biology Department, University of Calabria, Rende, Italy
5 Cardio-Thoracic and Vascular Department, San Raffaele Scientific Institute, Milan, Italy
Received 28 June 2006; revised 6 February 2007; accepted 15 February 2007; online publish-ahead-of-print 27 March 2007.
* Corresponding author. Tel: +39 (0) 6 30154187; fax: +39 (0) 6 3055535. E-mail address: mauriziopieroni{at}yahoo.com
See page 1052 for the editorial comment on this article (doi:10.1093/eurheartj/ehm047)
Aims: High chromogranin-A (CgA) levels were observed in patients with heart failure but its source remained uncertain. We evaluated whether CgA is produced by myocardium and might affect myocardial function.
Methods and results: We measured plasma CgA levels and performed immunohistochemistry with anti-CgA antibodies on myocardial biopsies in 40 patients with dilated cardiomyopathy (DCM) and 20 patients with hypertrophic cardiomyopathy (HCM). Surgical myocardial specimens from DCM and HCM patients were used for PCR and ELISA. The presence of CgA-derived fragments in plasma was evaluated by gel-filtration HPLC and their effects on cardiac performance assessed in isolated perfused rat heart. All patients showed increased CgA plasma levels (DCM 153.7 ± 158.5 ng/mL; HCM 150.2 ± 86.7 ng/mL vs. 64.1 ± 17.9 ng/mL of controls) with a positive correlation between CgA and left ventricular end-diastolic pressure (DCM, R = 0.86; HCM, R = 0.83), and plasma brain natriuretic peptide (BNP) levels (DCM, R = 0.88; HCM, R = 0.85) (P < 0.001). Immunohistochemistry showed cytoplasmic expression of CgA and co-localization with BNP in all patients, but not in controls. PCR detected CgA mRNA in both pathologic and normal myocardium, while ELISA showed a significant amount of CgA only in pathologic myocardium (>0.5 µg/g of tissue); gel-filtration HPLC of plasma samples identified immunoreactive N-terminal CgA fragments containing vasostatin-1. Administration of vasostatin-1 to perfused rat heart produced negative inotropic and lusitropic effects counteracting isoproterenol actions.
Conclusion: We demonstrate for the first time that CgA is produced by human myocardium and exerts negative inotropic and lusitropic effects on mammalian heart. CgA may represent a key player in neuroendocrine regulation of cardiac function and a potential therapeutic target in heart failure.
Key Words: Chromogranin A • Heart failure • Natriuretic peptides • Endomyocardial biopsy
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