Regístrese
Buscar en
Revista Colombiana de Cardiología
Toda la web
Inicio Revista Colombiana de Cardiología Biomarcadores cardíacos: Presente y futuro
Información de la revista
Vol. 19. Núm. 6.
Páginas 300-311 (Noviembre - Diciembre 2012)
Compartir
Compartir
Descargar PDF
Más opciones de artículo
Vol. 19. Núm. 6.
Páginas 300-311 (Noviembre - Diciembre 2012)
DOI: 10.1016/S0120-5633(12)70151-1
Open Access
Biomarcadores cardíacos: Presente y futuro
Cardiac biomarkers: present and future
Visitas
15453
Eduardo Fernández1,
Autor para correspondencia
efernandezdaza@gmail.com

Correspondencia:
, Carlos García1,2, Rafael de la Espriella3, Carmelo R. Dueñas1,2, Fernando Manzur1,2
1 Universidad de Cartagena. Cartagena, Colombia
2 Nuevo Hospital Bocagrande. Cartagena, Colombia
3 Hospital General de Valencia. Valencia, España
Información del artículo

En la actualidad, las enfermedades cardiovasculares se consideran la pandemia más significativa del siglo XXI. Dentro de ellas, la enfermedad coronaria es la más prevalente y la que más morbi-mortalidad genera; en el caso particular de Colombia, es la principal causa de muerte en individuos mayores de 45 años. La característica silenciosa de esta enfermedad ha impulsado la investigación de moléculas que permitan su diagnóstico precoz y sirvan como predictores pronóstico tanto en la fase crónica como en la aguda.

Fruto de estas investigaciones, en los últimos treinta años se ha producido un avance importante en el desarrollo de biomarcadores cardiacos. Entre ellos están los recién desarrollados ensayos de troponinas ultrasensibles para diagnóstico temprano, la medición de la albúmina modificada por isquemia que cuenta con alto valor predictivo negativo para la detección de isquemia miocárdica, el ligando de CD40 soluble para la clasificación e individualización del tratamiento, la utilidad de la proteína C reactiva como marcador de riesgo de enfermedad coronaria y las diversas técnicas de alto rendimiento como la proteómica, que permite la detección de múltiples biomarcadores potenciales. A pesar de ello, aún no se dispone de evidencia suficiente para sustituir los marcadores que recomiendan las asociaciones científicas por los nuevos marcadores que se han ido desarrollando, y continúa el debate sobre qué combinación utilizar para alcanzar mayor rendimiento diagnóstico, pronostico y terapéutico. A continuación se revisan los avances actuales en biomarcadores cardiacos y su potencial integración a la práctica clínica habitual.

Palabras clave:
biomarcadores
cardiopatía isquémica
inflamación
infarto agudo del miocardio

Cardiovascular diseases are currently considered the most significant pandemic of the XXI century. Among them, coronary disease is the most prevalent and the one that generates more morbidity and mortality. In Colombia, is the main cause of death in individuals over 45 years. The silent characteristics of this disease has promoted research of molecules that allow early diagnosis and serve as predictors of prognosis both in chronic and acute phases.

As result of this research, there has been significant progress in the development of cardiac biomarkers in the last thirty years. Among them are the newly developed ultrasensitive troponin assays for an early diagnosis, measurement of ischemia modified albumin, which has high negative predictive value for the detection of myocardial ischemia, soluble CD40 ligand for classification and individualization of treatment, the usefulness of CRP as a risk marker for coronary heart disease and various high-throughput techniques such as proteomics, which allow the detection of multiple potential biomarkers. Despite this, there is still insufficient evidence for replacing the markers recommended by the scientific associations by new developed markers, and the debate about what combination to use in order to achieve higher performance diagnosis, prognosis and therapy, continues Here we review current advances in cardiac biomarkers and their potential integration into daily clinical practice.

Keywords:
biomarkers
ischemic heart disease
inflammation
acute myocardial infarction
El Texto completo está disponible en PDF
Bibliografía
[1.]
Organización Panamericana de la Salud. World Health Statistics 2007. Disponible en: www.paho.org.
[2.]
H. Kesteloot, S. Sans, D. Kromhout.
Dynamics of cardiovascular and all-cause mortality in Western and Eastern Europe between 1970 and 2000.
Eur Heart J, 27 (2006), pp. 107-113
[3.]
Ministerio de la Protección Social. Informe sobre la situación de salud en Colombia–Indicadores de salud; 2007.
[4.]
Pinedo J, Egea K, Mazenett E. Perfil epidemiológico de Cartagena de Indias, año 2010. Alcaldía Mayor de Cartagena.
[5.]
F. Vivanco, J.L. Martín-Ventura, M.C. Duran, M.G. Barderas, L. Blanco-Colido, V.M. Dardé, et al.
Quest for novel cardiovascular biomarkers by proteomic analysis.
J Proteome Res, 4 (2005), pp. 1181-1191
[6.]
E.S. Lander, L.M. Linton, B. Birren, C. Nusbaum, M.C. Zody, J. Baldwin, et al.
International human genome sequencing consortium. Initial sequencing and analysis of the human genome.
Nature, 409 (2001), pp. n860-n921
[7.]
R. Vasan.
Biomarkers of cardiovascular disease: molecular basis and practical considerations.
Circulation, 113 (2006), pp. 2335-2362
[8.]
A. Clerico.
The increasing impact of laboratory medicine on clinical cardiology.
Clin Chem Lab Med, 41 (2003), pp. 871-883
[9.]
J. LaBaer.
So, you want to look for biomarkers.
J Proteome Res, 4 (2005), pp. 1053-1059
[10.]
M.S. Brown, J.L. Goldstein.
Lipoprotein metabolism in the macrophage.
Ann Rev Biochem, 52 (1983), pp. 223-261
[11.]
D. Steinberg, A. Lewis.
Conner memorial lecture: oxidative modification of LDL and atherogenesis.
Circulation, 95 (1997), pp. 1062-1071
[12.]
I. Jialal, S. Devaraj.
The role of oxidized low-density lipoprotein in atherogenesis.
J Nutr, 126 (1996), pp. S1053-S1057
[13.]
S. Chatterjee.
Role of oxidized human plasma low density lipoproteins in atherosclerosis: effects on smooth muscle cell proliferation.
Moll Cell Biochem, 111 (1992), pp. 143-147
[14.]
M. Imazu, K. Ono, F. Tadehara, et al.
Plasma levels of oxidized low density lipoprotein are associated with stable angina pectoris and modalities of acute coronary syndrome.
Int Heart J, 49 (2008), pp. 515-524
[15.]
S. Tsimikas, C. Bergmark, R.W. Beyer, et al.
Temporal increases in plasma markers of oxidized low-density lipoprotein strongly reflect the presence of acute coronary syndromes.
J Am Coll Cardiol, 41 (2003), pp. 360-370
[16.]
S. Tsimikas, H.K. Lau, K.R. Han, et al.
Percutaneous coronary intervention results in acute increases in oxidized phospholipids and lipoprotein(a): short-term and long-term immunologic responses to oxidized low-density lipoprotein.
Circulation, 109 (2004), pp. 3164-3170
[17.]
T. Sotirios, et al.
Oxidized phospholipids, Lp(a) lipoprotein, and coronary artery disease.
N Engl J Med, 353 (2005), pp. 46-57
[18.]
P. Libby, D.I. Simon.
Inflammation and thrombosis: the clot thickens.
Circulation, 103 (2001), pp. 1718-1720
[19.]
C. Heeschen, et al.
Pregnancy-associated plasma protein-A levels in patients with acute coronary syndromes: comparison with markers of systemic inflammation, platelet activation, and myocardial necrosis.
J Am Coll Cardiol, 45 (2005), pp. 229-237
[20.]
A. Bayes-Genis, C.A. Conover, M.T. Overgaard, et al.
Pregnancy-associated plasma protein A as a marker of acute coronary syndromes.
N Engl J Med, 345 (2001), pp. 1022-1029
[21.]
Mei WY, et al. Pregnancy-associated plasma protein predicts outcomes of percutaneous coronary intervention in patients with non-ST-elevation acute coronary syndrome. Heart Lung. 2010.
[22.]
L. You, et al.
A pilot study of the clinical relevance of the relationship between the serum level of pregnancy-associated plasma protein A and the degree of acute coronary syndrome.
J Int Med Res, 38 (2010), pp. 625-632
[23.]
J. Lund, Q.P. Qin, T. Ilva, K. Pettersson, L.M. Voipio-Pulkki, P. Porela, K. Pulkki.
Circulating pregnancy-associated plasma protein a predicts outcome in patients with acute coronary syndrome but no troponin I elevation.
Circulation, 108 (2003), pp. 1924-1926
[24.]
P.M. Ridker, C.H. Hennekens, B. Roitman-Johnson, M.J. Stampfer, J. Allen.
Plasma concentration of soluble intercellular adhesion molecule 1 and risks of future myocardial infarction in apparently healthy men.
[25.]
S.J. Hwang, C.M. Ballantyne, R. Sharrett, et al.
Circulating adhesion molecules VCAM-1, ICAM-1, and E-selectin in carotid atherosclerosis and incident coronary heart disease cases: the atherosclerosis risk in communities (ARIC) study.
Circulation, 96 (1997), pp. 4219-4225
[26.]
I. Malik, J. Danesh, P. Whincup, V. Bhatia, O. Papacosta, M. Walker, et al.
Soluble adhesion molecules and prediction of coronary heart disease: a prospective study and metaanalysis.
[27.]
G. Luc, D. Arveiler, A. Evans, P. Amouyel, J. Ferrieres, J.M. Bard, et al.
Circulating soluble adhesion molecules ICAM-1 and VCAM-1 and incident coronary heart disease: the PRIME Study.
Atherosclerosis, 170 (2003), pp. 169-176
[28.]
A.S. Postadzhiyan, A.V. Tzontcheva, I. Kehayov, B. Finkov.
Circulating soluble adhesion molecules ICAM-1 and VCAM-1 and their association with clinical outcome, troponin T and C-reactive protein in patients with acute coronary syndromes.
Clin Biochem, 41 (2008), pp. 126-133
[29.]
S. Blankenberg, H.J. Rupprecht, C. Bickel, D. Peetz, G. Hafner, L. Tiret, et al.
Circulating cell adhesion molecules and death in patients with coronary artery disease.
Circulation, 104 (2001), pp. 1336-1342
[30.]
I. Malik, J. Danesh, P. Whincup, V. Bhatia, O. Papacosta, M. Walker, et al.
Soluble adhesion molecules and prediction of coronary heart disease: a prospective study and meta-analysis.
[31.]
G.K. Hansson.
Mechanisms of disease inflammation, atherosclerosis, and coronary artery disease.
N Engl J Med, 352 (2005), pp. 1685-1695
[32.]
A. Thomas, Pearson, A. George, R. Mensah, Wayne Alexander, et al.
Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the centers for disease control and prevention and the american heart association.
Circulation, 107 (2003), pp. 499-511
[33.]
G. Löfström.
Comparison between the reaction of acute phase serum with Pneumococcus C-polysaccharide and with Pneumococcus type 27.
Br J Exp Pathol, 25 (1944), pp. 21-26
[34.]
G. Liuzzo, L.M. Biasucci, J.R. Gallimore, et al.
The prognostic value of C-reactive protein and serum amyloid A protein in severe unstable angina.
N Engl J Med, 331 (1994), pp. 417-424
[35.]
D. Morrow, N. Rifai, E. Antman, et al.
C-reactive protein is a potent predictor of mortality independently and in combination with troponin T in acute coronary syndromes.
J Am Coll Cardiol, 31 (1998), pp. 1460-1465
[36.]
L.M. Biasucci, G. Liuzzo, R.L. Grillo, et al.
Elevated levels of C-reactive protein at discharge in patients with unstable angina predict recurrent instability.
Circulation, 99 (1999), pp. 855-860
[37.]
I. Kushner, M.L. Broder, D. Karp.
Control of the acute phase response. Serum Creactive protein kinetics after acute myocardial infarction.
J Clin Invest, 61 (1978), pp. 235-242
[38.]
P. Calabro, J.T. Willerson, E.T. Yeh.
Inflammatory cytokines stimulated C-reactive protein production by human coronary artery smooth muscle cells.
Circulation, 108 (2003), pp. 1930-1932
[39.]
K. Yasojima, C. Schwab, E.G. McGeer, P.L. McGeer.
Generation of C-reactive protein and complement components in atherosclerotic plaques.
Am J Pathol, 158 (2001), pp. 1039-1051
[40.]
S. Mora, K. Musunuru, R.S. Blumenthal.
The clinical utility of high-sensitivity C-reactive protein in cardiovascular disease and the potential implication of JUPITER on current practice guidelines.
Clin Chem, 55 (2009), pp. 219-228
[41.]
J. Danesh, J.G. Wheeler, G.M. Hirschfield, S. Eda, G. Eiriksdottir, A. Rumley, et al.
C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease.
N Engl J Med, 350 (2004), pp. 1387-1397
[42.]
N.R. Cook, J.E. Buring, P.M. Ridker.
The effect of including C-reactive protein in cardiovascular risk prediction models for women.
Ann Intern Med, 145 (2006), pp. 21-29
[43.]
D. Morrow, N. Rifai, E. Antman, D.L. Weiner, C.H. McCabe, C.P. Cannon, et al.
C-reactive protein is a potent predictor of mortality independently of and in combination with troponin T in acute coronary syndromes: a TIMI 11A substudy. Thrombolysis in myocardial infarction.
J Am Coll Cardiol, 31 (1998), pp. 1460-1465
[44.]
F.A. Fonseca, M.C. Izar, et al.
Primary prevention of vascular events in patients with high levels of C-reactive protein: the JUPITER study.
Expert Rev Cardiovasc Ther, 7 (2009), pp. 1041-1056
[45.]
H.G. Rus, R. Vlaicu, F. Niculescu.
Interleukin-6 and inteleukin-8 protein and gene expression in human arterial atherosclerotic wall.
Atherosclerosis, 127 (1996), pp. 263-271
[46.]
M. Cesari, B.W. Penninx, A.B. Newman, S.B. Kritchevsky, B.J. Nicklas, K. Sutton-Tyrrell, et al.
Inflammatory markers and onset of cardiovascular events: results from the Health ABC study.
Circulation, 108 (2003), pp. 2317-2322
[47.]
T. Abo, K. Kawate, K. Itoh, K. Kumagai.
Studies on the bioperiodicity of the immune response. Circadian rhythms of human T, B and K cell traffic in the peripheral blood.
J Immunol, 126 (1981), pp. 1360-1366
[48.]
G.J.M. Maestroni, A. Conti, W. Pierpaoli.
Pineal melatonin, its fundamental immunoregulatory role in aging and cancer.
Ann N Y Acad Sci, 521 (1988), pp. 140-148
[49.]
J.M. Guerrero, R.J. Reiter.
Melatonin-immune system relationship.
Curr Top Med Chem, 2 (2002), pp. 167-179
[50.]
A. Domínguez-Rodríguez, P. Abreu-González, M. García, J. Ferrer, A. de la Rosa, M. Vargas, et al.
Light/dark patterns of interleukin-6 in relation to the pineal hormone melatonin in patients with acute myocardial infarction.
Cytokine, 26 (2004), pp. 89-93
[51.]
U. Schonbeck, P. Libby.
The CD40/CDE154 receptor/ligand dyad.
Cell Moll Life Sci, 58 (2001), pp. 4-43
[52.]
C. Van Kooten, J. Banchereau.
CD40-CD40 ligand.
J Leukoc Biol, 67 (2000), pp. 2-17
[53.]
V. Henn, S. Steinbach, P. Buchner, P. Presek, R.A. Kroczek.
The inflammatory action of CD40 ligand (CD154) expressed on activated human platelets is temporally limited by coexpressed CD40.
Blood, 15 (2001), pp. 1047-1054
[54.]
U. Schonbeck, P. Libby.
CD40 signaling and plaque instability.
Circ Res, 89 (2001), pp. 1092-1103
[55.]
C. Heeschen, S. Dimmeler, C.W. Hamm, M.J. van den Brand, E. Boersma, A.M. Zeiher, et al.
Soluble CD40 ligand in acute coronary syndromes.
N Engl J Med, 348 (2003), pp. 1104-1111
[56.]
P. Andre, K.S. Prasad, C.V. Denis, M. He, J.M. Papalia, R.O. Hynes, et al.
CD40L stabilizes arterial thrombi by a beta3 integrin-dependent mechanism.
Nat Med, 8 (2002), pp. 247-252
[57.]
S. Baldus, C. Heeschen, T. Meinertz, A.M. Zeiher, J.P. Eiserich, T. Munzel, CAPTURE Investigators.
Myeloperoxidase serum levels predict risk in patients with acute coronary syndromes.
Circulation, 108 (2003), pp. 1440-1445
[58.]
N. Varo, J.A. de Lemos, P. Libby, D.A. Morrow, S.A. Murphy, R. Unzo, et al.
Soluble CD40L: risk prediction after acute coronary syndromes.
Circulation, 108 (2003), pp. 1049-1052
[59.]
A.G. Semb, S. Van Wissen, T. Ueland, T. Smilde, T. Waehre, M.D. Tripp, et al.
Raised serum levels of soluble CD40 ligand in patients with familial hypercholesterolemia: down regulatory effect of statin therapy.
J Am Coll Cardiol, 41 (2003), pp. 275-279
[60.]
S. Kinlay, G.G. Schwartz, A.G. Olsson, N. Rifai, W.J. Sasiela, M. Szarek, et al.
Effect of atorvastatin on risk of recurrent cardiovascular events after an acute coronary syndrome associated with high soluble CD40 ligand in the myocardial ischemia reduction with aggressive cholesterol lowering (MIRACL) study.
Circulation, 110 (2004), pp. 386-391
[61.]
M. Weber, B. Rabenau, M. Stanisch, A. Elsaesser, V. Mitrovic, C. Heeschen, et al.
Influence of sample type and storage conditions on soluble CD40 ligand assessment.
Clin Chem, 52 (2006), pp. 888-891
[62.]
A.M. Halldorsdottir, J. Stroker, R. Porche-Sorbet, C.S. Eby.
Soluble CD40 ligand measurement inaccuracies attributable to specimen type, processing time, and ELISA method.
Clin Chem, 51 (2005), pp. 1054-1057
[63.]
S. Sugiyama, Y. Okada, G. Sukhova, R. Virmani, J. Heinecke, P. Lobby.
Macrophage myeloperoxidase regulation by granulocyte macrophage colony-stimulating factor in human atherosclerosis and implications in acute coronary syndromes.
Am J Pathol, 158 (2001), pp. 879-891
[64.]
S.J. Nicholls, S.L. Hazen.
The role of myeloperoxidase in the pathogenesis of coronary artery disease.
Jpn J Infect Dis, 57 (2004), pp. S21-S22
[65.]
M.L. Brennan, M.S. Penn, F. Van Lente, V. Nambi, M.H. Shishehbor, R.J. Aviles, et al.
Prognostic value of myeloperoxidase in patients with chest pain.
N Engl J Med, 349 (2003), pp. 1595-1604
[66.]
F.S. Apple, L.A. Pearce, A. Chung, R. Ler, M.A.M. Murakamim.
Multiple biomarker use for detection of adverse events in patients presenting with symptoms suggestive of acute coronary syndrome.
Clin Chem, 53 (2007), pp. 874-881
[67.]
E. Mothes, P. Faller.
Evidence that the principal CoII-binding site in human serum albumin is not at the N-terminus: implication on the albumin cobalt binding test for detecting myocardial ischemia.
Biochemistry, 46 (2007), pp. 2267-2274
[68.]
D. Bar-Or, G. Curtis, N. Rao, N. Bampos, E. Lau.
Characterization of the Co(2+) and Ni(2+) binding amino-acid residues of the N terminus of human albumin. An insight into the mechanism of a new assay for myocardial ischemia.
Eur J Biochem, 268 (2001), pp. 42-47
[69.]
K. Kazanis, et al.
Ischemia modified albumin, high-sensitivity c-reactive protein and natriuretic peptide in patients with coronary atherosclerosis.
Clinica Chimica Acta, 408 (2009),
[70.]
M.K. Sinha, D. Roy, D.C. Gaze, P.O. Collinson, J.C. Kask, Role of “Ischemia Modified Albumin”, a new biochemical marker of myocardial ischemia in the early diagnosis of acute coronary syndromes..
Emerg Med J, 21 (2004), pp. 29-34
[71.]
S. Anwaruddin, J.L. Januzzi Jr., A.L. Baggish, E.L. Lewandrowski, K.B. Lewandrowski.
Ischemia-modified albumin improves the usefulness of standard cardiac biomarkers for the diagnosis of myocardial ischemia in the emergency department setting.
Am J Clin Pathol, 123 (2005), pp. 140-145
[72.]
L. Keating, J.R. Benger, R. Beetham, S. Bateman, S. Veysey, J. Kendall, et al.
The PRIMA study: presentation ischaemia modified albumin in the emergency department.
Emerg Med J, 23 (2006), pp. 764-768
[73.]
E. Zapico Muñiz, M. Santalo' Bel, J. Merce' Muntañola, J.A. Montiel, A. Martínez Rubio, J. Ordoñez Llanos.
Ischemia-modified albumin during skeletal muscle ischemia.
Clin Chem, 50 (2004), pp. 1063-1065
[74.]
Sinhg, et al.
Cardiac biomarkers – the old and the new: a review.
Coronary Artery Disease, 21 (2010), pp. 244-256
[75.]
E.G. Krause, G. Rabitzsch, F. Noll, J. Mair, B. Puschendorf.
Glycogen phosphorylase isoenzyme BB in diagnosis of myocardial ischaemic injury and infarction.
Mol Cell Biochem, (1996), pp. 160-161
[76.]
J. Mair.
Glycogen phosphorylase isoenzyme BB to diagnose ischaemic myocardial damage.
Clin Chim Acta, 272 (1998), pp. 79e86
[77.]
G. Rabitzsch, J. Mair, P. Lechleitner, et al.
Immunoenzymometric assay of human glycogen phosphorylase isoenzyme BB in diagnosis of ischemic myocardial injury.
Clin Chem, 41 (1995), pp. 966e78
[78.]
D. Peetz, F. Post, H. Schinzel, et al.
Glycogen phosphorylase BB in acute coronary syndromes.
Clin Chem Lab Med, 43 (2005), pp. 1351e8
[79.]
National Academy of Clinical Biochemistry.
National Academy of Clinical Biochemistry Laboratory medicine practice guidelines: Clinical characteristics and utilization of biochemical markers in acute coronary syndromes.
Clin Chem, 53 (2007), pp. 552-574
[80.]
J.L. Anderson, C.D. Adams, E.M. Antman, et al.
ACC/AHA 2007 guidelines for the management of patients with unstable angina/non ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction): developed in collab*oration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons: endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine.
Circulation, 116 (2007), pp. e148-e304
[81.]
J.P. Bassand, C.W. Hamm, D. Ardissino, et al.
Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes.
Eur Heart J, 28 (2007), pp. 1598-1660
[82.]
K. Wang, R.W. Asinger, H.J. Marriott.
ST segment elevation in conditions other than acute myocardial infarction.
N Engl J Med, 349 (2003), pp. 2128-2135
[83.]
A.R. Macrae, P.A. Kavsak, V. Lustig, et al.
Assessing the requirement for the 6-hour interval between specimens in the American Heart Association Classification of Myocardial Infarction in Epidemiology and Clinical Research Studies.
Clin Chem, 52 (2006), pp. 812-818
[84.]
Reichlin, Tobias, Hochholzer, Willibald, Bassetti.
Early diagnosis of myocardial infarction with sensitive cardiac troponin assay.
N Engl J Med, 361 (2009), pp. 858-867
[85.]
T. Keller, T. Zeller, D. Peetz, et al.
Sensitive troponin I assay in early diagnosis of acute myocardial infarction.
N Engl J Med, 361 (2009), pp. 868-877
Copyright © 2012. Sociedad Colombiana de Cardiología y Cirugía Cardiovascular
Opciones de artículo
Herramientas
es en pt
Política de cookies Cookies policy Política de cookies
Utilizamos cookies propias y de terceros para mejorar nuestros servicios y mostrarle publicidad relacionada con sus preferencias mediante el análisis de sus hábitos de navegación. Si continua navegando, consideramos que acepta su uso. Puede cambiar la configuración u obtener más información aquí. To improve our services and products, we use "cookies" (own or third parties authorized) to show advertising related to client preferences through the analyses of navigation customer behavior. Continuing navigation will be considered as acceptance of this use. You can change the settings or obtain more information by clicking here. Utilizamos cookies próprios e de terceiros para melhorar nossos serviços e mostrar publicidade relacionada às suas preferências, analisando seus hábitos de navegação. Se continuar a navegar, consideramos que aceita o seu uso. Você pode alterar a configuração ou obter mais informações aqui.