Produção Nacional
Revisado por pares
Brain-derived neurotrophic factor is up regulated in chronic Chagas disease
2011; Elsevier BV; Volume: 149; Issue: 2 Linguagem: Inglês
10.1016/j.ijcard.2011.02.058
ISSN1874-1754
AutoresPatrícia Massara Martinelli, Manoel Otávio da Costa Rocha, Antônio Lúcio Teixeira, Maria Carmo Pereira Nunes, Elizabeth Ribeiro da Silva Camargos,
Tópico(s)Trypanosoma species research and implications
ResumoChagas disease is caused by the parasite Trypanosoma cruzi, and is a serious public health concern in Latin America. Chagasic chronic cardiomyopathy (CCC) is the most significant clinical manifestation of the disease, due to its potential severity. CCC is characterized by extreme clinical variability, making the prediction of the progress of cardiac dysfunction a challenge for many researchers [1Rocha M.O.C. Ribeiro A.L.P. Teixeira M.M. Clinical management of chronic chagasic cardiomyopathy.Front Biosc. 2003; 8: e44-e54Crossref PubMed Scopus (45) Google Scholar, 2Talvani A. Rocha M.O. Cogan J. et al.Brain natriuretic peptide and left ventricular dysfunction in chagasic cardiomyopathy.Mem Inst Oswaldo Cruz. 2004; 99: 645-649Crossref PubMed Scopus (30) Google Scholar]. Brain Derived Neurotrophic Factor (BDNF) is a neurotrophin first recognized by its action on neuronal targets [[3]Hennigan A. O'Callaghan R.M. Kelly A.M. Neurotrophins and their receptors: roles in plasticity, neurodegeneration and neuroprotection.Biochem Soc Trans. 2007; 35: 424-427Crossref PubMed Scopus (176) Google Scholar]. Growing evidence has implicated BDNF in several nonneuronal phenomena, and circulating levels of the factor have been proposed as a peripheral marker for a variety of disorders, including those pertaining to the cardiovascular system [4Teixeira A.L. Barbosa I.G. Diniz B.S. Kummer A. Circulating levels of brain-derived neurotrophic factor: correlation with mood, cognition and motor function.Biomark Med. 2010; 4: 871-887Crossref PubMed Scopus (116) Google Scholar, 5Ejiri J. Inoue N. Kobayashi S. et al.Possible role of brain-derived neurotrophic factor in the pathogenesis of coronary artery disease.Circulation. 2005; 112: 2114-2120Crossref PubMed Scopus (109) Google Scholar, 6Golden E. Emiliano A. Maudsley S. et al.Circulating brain-derived neurotrophic factor and indices of metabolic and cardiovascular health: data from the Baltimore Longitudinal Study of Aging.PLoS ONE. 2010; 5: 1-9Crossref Scopus (147) Google Scholar]. We assessed BDNF serum levels in chronic chagasic patients in order to correlate with the degree of cardiac dysfunction. Patients were recruited from an outpatient reference center for Chagas Disease treatment (Centro de Tratamento e Referência em Doenças Infecciosas e Parasitárias, in Belo Horizonte, MG, Brazil). Informed consent was obtained from all subjects. The protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by our institutional human ethics committee, protocol number 001/97. Healthy subjects formed the control group (C) which was comprised of 18 men and 8 women, aged 22–55 years (mean±SD=36.5±9.4 years). Chagasic patients where divided into 3 groups: asymptomatic (A), non-dilated cardiopathic (ND), and dilated cardiopathic (D). These 3 groups were segregated based on ventricular dysfunction and conduction defects, assessed by electrocardiogram (ECG) and echocardiogram tests. Group A was comprised of asymptomatic patients whose ECG showed no alteration or discrete or minor alterations. None of the patients in this group had conduction defects. Patients in group ND had considerable ECG alterations and were characterized by advanced conduction defects and/or severe arrhythmia, but with no ventricular enlargement. Group D included patients with signs of heart enlargement and global systolic dysfunction. The principal clinical characteristics of the chagasic patients are depicted in Table 1.Table 1Clinical data from control (healthy) and chagasic patients.Group CGroup AGroup NDGroup DNumber of patients26111529Age Mean±SD36.5±9.441.1±7.550.7±10.350.8±10.3 Range22–5528–5227–6036–70Male/female18/0810/0109/0621/08Ejection fraction (%) Mean±SD–64.5±6.559.3±8.6⁎p<0.05.41.6±9.5⁎⁎p<0.0001. Range49–7035–6718–56Left Ventricular Dilatation Index (mm) Mean±SD–50.0±5.253.3±4.762.4+4.9⁎⁎p<0.0001. Range42–6135–6754–74C = control subjects; A = asymptomatic chagasic patients; ND = non-dilated cardiopathic chagasic patients; D = dilated cardiopathic chagasic patients. p<0.05. p<0.0001. Open table in a new tab C = control subjects; A = asymptomatic chagasic patients; ND = non-dilated cardiopathic chagasic patients; D = dilated cardiopathic chagasic patients. BDNF serum levels were determined by ELISA (Enzyme Linked Immuno Sorbent Assay), using kit and protocol from R&D Systems (Minneapolis, MN, USA). Nonparametric Mann–Whitney and Spearman Rank correlation tests were performed, with significance levels at 0.001% and 0.05%. Serum levels of BDNF were significantly higher in all groups of chagasic patients when compared to those in the control group (median [interquartile range]; 597.6 [249.9–5964] pg/mL). Groups A and ND presented similar BDNF levels (5353 [2003–7054] pg/mL and 5782 [3163–7995] pg/mL, respectively). In contrast, Group D presented lower BDNF levels (3584 [1205–7309] pg/mL) than those of groups A and ND (Fig. 1a ). The Spearman Rank test showed a positive correlation between BDNF levels and ejection fraction (r=0.3137, p=0.0431), and a negative correlation between BDNF levels and ventricular dilatation index (r=−0.3146, p=0.0424) in chagasic patients (Fig. 1b and c). A role for BDNF has been established in the modulation of the heart autonomic nervous system [5Ejiri J. Inoue N. Kobayashi S. et al.Possible role of brain-derived neurotrophic factor in the pathogenesis of coronary artery disease.Circulation. 2005; 112: 2114-2120Crossref PubMed Scopus (109) Google Scholar, 7Slonimsky J.D. Yang B. Hinterneder J.M. Nokes E.B. Birren S.J. BDNF and CNTF regulate cholinergic properties of sympathetic neurons through independent mechanisms.Mol Cell Neurosci. 2003; 23: 648-660Crossref PubMed Scopus (32) Google Scholar]. Chagasic patients, even the asymptomatic ones, are considered to have dysautonomia which does not always manifest as an alteration of heart rate and atrioventricular conduction [8Machado C.R.S. Camargos E.R.S. Guerra L.B. Moreira M.C.V. Cardiac autonomic denervation in congestive Heart Failure: comparison of Chagas' heart disease with other dilated cardiomyopathy.Hum Pathol. 2000; 31: 3-10Abstract Full Text PDF PubMed Scopus (33) Google Scholar, 9Molina R.B.G. Matsubara B.B. Hueb J.C. et al.Dysautonomia and ventricular dysfunction in the indeterminate form of Chagas disease.Intern J Card. 2006; 113: 188-193Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar]. Thus, autonomic denervation could account for, at least partially, the high levels of BDNF observed in chagasic patients. Denervated cardiomyocytes could be among the cells contributing to the elevation of BDNF levels, since it is known that these cells secrete neurotrophic factors, including BDNF [10Hiltunen J.O. Laurikainen A. keva A.V. Meri S. Saarma M. Nerve growth factor and brain-derived neurotrophic factor mRNAs are regulated in distinct cell populations of rat heart after ischaemia and reperfusion.J Pathol. 2001; 194: 247-253Crossref PubMed Scopus (77) Google Scholar, 11Lommatzsch M. Braun A. Mannsfeldt A. et al.Abundant production of brain-derived neurotrophic factor by adult visceral epithelia. Implications for paracrine and target-derived neurotrophic functions.Am J Pathol. 1999; 155: 1183-1193Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar]. In some conditions of autonomic denervation, including T. cruzi infection, cardiomyocytes are stimulated to secrete neurotrophic factors, as demonstrated for Nerve Growth Factor and Glial Derived Neurotrophic Factor [12Martinelli P.M. Camargos E.R. Azevedo A.A. Chiari E. Morel G. Machado C.R. Cardiac NGF and GDNF expression during Trypanosoma cruzi infection in rats.Auton Neurosci. 2006; 130: 32-40Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar, 13Korsching S. Thoenen H. Treatment with 6-hydroxydopamine and colchicine decreases nerve growth factor levels in sympathetic ganglia and increases them in the corresponding target tissues.J Neurosc. 1985; 5: 1058-1061Crossref PubMed Google Scholar, 14Martinelli P.M. Camargos E.R. Morel G. Tavares C.A. Nagib P.R. Machado C.R. Rat heart GDNF: effect of chemical sympathectomy.Histochem Cell Biol. 2002; 118: 337-343Crossref PubMed Scopus (19) Google Scholar]. It is important to consider that in chagasic patients with severe cardiomyopathy there is an appreciated fibrosis [8Machado C.R.S. Camargos E.R.S. Guerra L.B. Moreira M.C.V. Cardiac autonomic denervation in congestive Heart Failure: comparison of Chagas' heart disease with other dilated cardiomyopathy.Hum Pathol. 2000; 31: 3-10Abstract Full Text PDF PubMed Scopus (33) Google Scholar, 15Rossi M.A. Fibrosis and inflammatory cells in human chronic chagasic myocarditis: scanning electron microscopy and immunohistochemical observations.Int J Cardiol. 1998; 66: 183-194Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar]. This could result in a decrease in the number of cardiomyocytes available for BDNF synthesis, and explain, at least partially, the lower serum levels of BDNF in patients with dilated cardiomyopathy. Inflammatory cells could be another important source of BDNF in chagasic patients, as these cells are considered a major source of BDNF and this neurotrophin production is increased upon antigen stimulation [[16]Kerschensteiner M. Gallmeier E. Behrens L. et al.Activated human T cells, B cells, and monocytes produce brain-derived neurotrophic factor in vitro and in inflammatory brain lesions: a neuroprotective role of inflammation?.J Exp Med. 1999; 189: 865-870Crossref PubMed Scopus (834) Google Scholar]. Finally, we cannot discard other possible sources of circulating BDNF such as vascular smooth muscle cells which can secrete BDNF [[5]Ejiri J. Inoue N. Kobayashi S. et al.Possible role of brain-derived neurotrophic factor in the pathogenesis of coronary artery disease.Circulation. 2005; 112: 2114-2120Crossref PubMed Scopus (109) Google Scholar]. Vasculopathy is well established as another phenomenon associated to CCC [[17]Rossi M.A. Tanowitz H.B. Malvestio L.M. et al.Coronary microvascular disease in chronic Chagas cardiomyopathy including an overview on history, pathology, and other proposed pathogenic mechanisms.PLoS Negl Trop Dis. Aug. 31. 2010; 4 (pii: e674.)Crossref PubMed Scopus (65) Google Scholar], and T. cruzi infection results in smooth muscle cell activation and proliferation [[18]Hassan G.S. Mukherjee S. Nagajyothi F. et al.Trypanosoma cruzi infection induces proliferation of vascular smooth muscle cells.Infect Immun. Jan. 2006; 74: 152-159Crossref PubMed Scopus (30) Google Scholar]. Thus, these cells could contribute to the BDNF levels found in the blood of chagasic patients. In conclusion elevated levels of serum BDNF are associated with Chagas disease. More, there is a significant correlation between serum BDNF levels and two clinical variables routinely used to evaluate cardiac function, ventricle enlargement and low ejection fraction. The underlying mechanism as to how remains unclear, but a relationship between BDNF serum levels and both cardiac autonomic denervation and inflammatory processes is supported. Although not directly associated to the severity of disease, serum BDNF levels could, to some degree, predict the evolution of patients to the dilated form of the disease. To confirm this, a longitudinal study involving a greater number of chagasic patients in varying stages of the disease is necessary. This work was supported by the Foundation for Research Support in the State of Minas Gerais (Fundação de Amparo à Pesquisa do Estado de Minas Gerais—FAPEMIG) and the National Council of Scientific and Technological Development (Conselho Nacional de Desenvolvimento Científico e Tecnológico—CNPq) . The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [[19]Shewan L.G. Coats A.J. Ethics in the authorship and publishing of scientific articles.Int J Cardiol. 2010; 144: 1-2Abstract Full Text Full Text PDF Scopus (699) Google Scholar].
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