Resumen de Relación entre marcadores inflamatorios y escalas de riesgo cardiovascular

María Teresa de Jesús Gómez

• ANTECEDENTES: La aterosclerosis es un proceso inflamatorio crónico difuso y multisistémico que implica al sistema vascular, metabólico e inmunitario, que inicialmente cursa de forma silente pero termina manifestándose clínicamente de forma local o sistémica. Es responsable de la mayoría de los eventos cardiovasculares, que son actualmente la primera causa de mortalidad global a nivel mundial. La estimación del riesgo cardiovascular para poder prevenir la aparición de dichos eventos es fundamental. Disponemos de escalas de estratificación del riesgo cardiovascular poblacional que permiten guiar las actuaciones terapéuticas preventivas. OBJETIVOS: Sobre la hipótesis de que los niveles séricos de los marcadores inflamatorios se relacionan con la estimación del riesgo cardiovascular calculado por escalas se pretende: 1. Determinar la relación entre los niveles plasmáticos de marcadores inflamatorios: proteína C reactiva (PCR), Interferón gamma (IFN-¿), Interleucinas (IL-10, IL-13, IL1b, IL-2, IL-6, IL-5, e IL-4), Factor de necrosis tumoral alfa (TNF-¿), Moléculas de adhesión intercelular (ICAM-1, y VCAM-1) y anticuerpos frente a Proteína de choque Ac Hsp60 (Ac anti- Hsp 60 totales), en un grupo de pacientes sin evento cardiovascular diagnosticado y en un grupo de enfermos con enfermedad isquémica coronaria crónica. 2. Determinar si existe asociación entre el grado de control de factores de riesgo cardiovascular (PAS, colesterol total, colesterol LDL y HDL) según los criterios de la ATP III, incluyendo a la categoría de síndrome metabólico, con los niveles plasmáticos de los distintos marcadores inflamatorios. 3. Determinar el riesgo cardiovascular en pacientes sin evento cardiovascular diagnosticado, con las escalas de Framingham- Wilson (1998), Framingham D¿Agostino (2008), SCORE, REGICOR y DORICA y en los pacientes con enfermedad cardiaca isquémica crónica a través de la escala Framingham D¿Agostino (2000) para eventos subsecuentes. 4. Determinar si existe relación entre los niveles de marcadores inflamatorios y el riesgo cardiovascular estimado por las diferentes escalas. METODOLOGÍA. Se plantea un estudio seroepidemiológico, analítico, para comparar los niveles séricos de marcadores inflamatorios y el riesgo cardiovascular estimado por distintas escalas de riesgo cardiovascular en una muestra de pacientes con y sin enfermedad cardiovascular previa. La muestra estudiada fue de 425 pacientes como subanálisis de los proyectos proyectos FIS PI 031677 ¿Marcadores de Inflamación y de Activación Endotelial, e Infección por Chlamydophila Pneumoniae en Pacientes con Síndrome Coronario Agudo, y Enfermedad Isquémica Crónica del Corazón¿, a cargo de D. Jesús Esteban Hernández y el proyecto CAM 2005/00155/001 ¿Chlamydia Pneumoniae, proteínas de choque y enfermedad coronaria¿, a cargo de D. Jesús Mª San Román Montero. Los datos sociodemográficos y la información clínica se obtuvieron a partir de la historia clínica del paciente y mediante un formulario diseñado al efecto, y los datos analíticos a través de la extracción de una muestra de sangre. Los marcadores inflamatorios fueron analizados por ELISA y Citometría de Flujo. Los valores de riesgo cardiovascular de cada paciente fueron calculados mediante algoritmos de sintaxis SPSS según lo descrito en las publicaciones originales de cada escala CONCLUSIONES: A continuación enumero las conclusiones del estudio de acuerdo a los objetivos propuestos: 1. Se objetivaron diferencias significativas en los niveles séricos de algunos de los marcadores inflamatorios estudiados al comparar los pacientes con enfermedad vascular previa frente a aquellos sin enfermedad cardiovascular previa. El grupo de pacientes sin enfermedad cardiovascular presentaron niveles significativamente inferiores de Proteína C Reactiva y de IL5 y significativamente superiores de IL1b e IL6 a los de los pacientes con enfermedad previa. 2. Se objetivaron diferencias significativas en los niveles séricos de algunos de los marcadores inflamatorios estudiados al contrastarlos según los factores de riesgo y las categorías de control definidas en el Adult Treatment Panel III (ATP III), concretamente Hipertensión arterial, Perfil lipídico (c-LDL y c-HDL) y Síndrome metabólico. 2.1. Respecto a la Hipertensión arterial: pese a que la existencia del antecedente de Hipertensión arterial se asoció de forma significativa e independiente con un nivel elevado de VCAM1, no se detectó una asociación lineal significativa independiente entre el grado de control de la hipertensión arterial y niveles elevados de marcadores inflamatorios. 2.2. Respecto al perfil lipídico LDL, los niveles de IL1b, IL6 e IL13 fueron significativamente inferiores en las categorías de control del LDL-c definidas como Óptimo, Perióptimo y Borderline alto en comparación a las categorías Alto o Muy Alto. Sin embargo, ajustado al resto de los factores de riesgo, sólo se detectó como independiente de forma significativa una relación lineal inversa entre los niveles de c-LDL y los de VCAM1. 2.3. Respecto a los niveles de C-HDL, los niveles de PCR, IL 1b, IL6 y Ac Hsp60 fueron significativamente superiores en las pacientes con HDL-c menor de 40mg/dl. Se objetivó una relación lineal independiente al resto de los factores de riesgo entre tener HDL-c menor de 40 mg/dl y niveles elevados de PCR. 2.4. Respecto del Síndrome Metabólico, se detectaron niveles significativamente elevados de PCR, IFN-¿, IL-10, IL-2, TNF-¿ e IL-6 en los pacientes con Síndrome Metabólico, pero no se detectaron diferencias significativas en los pacientes con Síndrome Metabólico Premórbido. La condición de tener Síndrome Metabólico se asoció de forma significativa e independiente a tener niveles elevados de PCR y TNF-¿, y el ser diabético se asoció de forma significativamente e independiente a tener niveles elevados de Ac Hsp60. 3. Las escalas de riesgo cardiovascular aplicadas presentaron una correlación moderada a fuerte entre sí (Dorica, Regicor, Framingham) y débil ¿ moderada con la escala de mortalidad cardiovascular del Score. Se encontraron diferencias significativas en la clasificación de riesgo cardiovascular bajo, moderado, alto y muy alto entre las diversas escalas utilizadas. 4. Se detectaron diferencias significativas entre los niveles de marcadores inflamatorios y el riesgo cardiovascular estimado por las diferentes escalas: 4.1. En el grupo de pacientes sin evento cardiovascular previo se evidenciaron niveles significativamente superiores de PCR y Ac Hsp60 en las categorías de riesgo Alto o Muy Alto respecto a las categorías de Moderado o Bajo riesgo, según las escalas de estimación del riesgo cardiovascular de Framingham D¿Agostino, Framingham de Wilson, Framingham para eventos duros y DORICA. Igualmente se detectaron niveles significativamente superiores de ICAM1 y VCAM1 en las categorías Alto o Muy Alto riesgo respecto a las categorías de Moderado o Bajo riesgo, según las escalas de SCORE. 4.2. Las asociaciones descritas se mantuvieron significativas una vez ajustadas al tratamiento con estatinas y al índice de masa corporal pero no se encontró significación estadística al ajustar por los factores de riesgo cardiovascular habituales en la determinación del riesgo. 4.3. En el grupo de pacientes que habían sufrido un evento cardiovascular previo se detectaron niveles significativamente superiores de TNF-¿, IL-13, IL-4 e VCAM1 en las categorías Alto o Muy Alto riesgo respecto a las categorías de Moderado o Bajo riesgo, según las escalas de Framingham para eventos subsecuentes. 4.4. Se detectó una asociación significativa entre tener niveles elevados de TNF-¿ y presentar un elevado riesgo cardiovascular según la escala de Framingham para eventos subsecuentes, que fue independiente de estar tratado con estatinas o tener un IMC elevado, sin embargo, no se evidenció que esta asociación fuera independiente de los factores de riesgo cardiovascular. BIBLIOGRAFÍA: 1. WHO, World Health Statistics. 2011, (World Health Organization). 2. WHO. Enfermedades cardiovasculares. Nota de prensa 2011 [cited 2012 Febrero]; Available from: http://www.who.int/mediacentre/factsheets/fs317/es/index.html. 3. Beaglehole, R. and R. Bonita, Global public health: a scorecard. Lancet, 2008. 372(9654): p. 1988-96. 4. WHO, The global burden of disease: update 2004. 2008, Geneva: World Health Organization. 5. (IOM), I.o.M., Promoting Cardiovascular Health in the Developing World: A Critical Challenge to Achieve Global Health., B.B.K. Valentín Fuster, Editor. 2010, The National Academies Press: Washington, DC. 6. WHO, Global Health Observatory Map Gallery 2008, World Health Organization. 7. Network, E.H., Cardiovascular disease statistics. 2008. 8. Eurostat (2012) Circulatory diseases: main causes of death for persons aged 65 and more in Europe,2009. 9. Eurostat, Death due to ischaemic heart diseases, by gender http://epp.eurostat.ec.europa.eu/portal/page/portal/health/public_health/data_public_health/main_tables, Consultado el 07/03/2011. 10. (INE), I.N.d.E. Encuesta de Morbilidad Hospitalaria. Series europeas. http://www.ine.es/inebmenu/mnu_salud.htm Febrero 2012 08/02/2012. 11. (INE), I.N.d.E., Defunciones según la Causa de Muerte. Resultados Nacionales. 2012, Instituto Nacional de Estadística. 12. (INE), I.N.d.E., Defunciones según la Causa de Muerte. Resultados por comunidad autónoma de residencia 2012, Instituto Nacional de Estadística. 13. Capewell, S., C.E. Morrison, and J.J. McMurray, Contribution of modern cardiovascular treatment and risk factor changes to the decline in coronary heart disease mortality in Scotland between 1975 and 1994. Heart, 1999. 81(4): p. 380-6. 14. Unal, B., J.A. Critchley, and S. Capewell, Explaining the decline in coronary heart disease mortality in England and Wales between 1981 and 2000. Circulation, 2004. 109(9): p. 1101-7. 15. Smolina, K., et al., Determinants of the decline in mortality from acute myocardial infarction in England between 2002 and 2010: linked national database study. Bmj, 2012. 344: p. d8059. 16. Hardoon, S.L., et al., How much of the recent decline in the incidence of myocardial infarction in British men can be explained by changes in cardiovascular risk factors? Evidence from a prospective population-based study. Circulation, 2008. 117(5): p. 598-604. 17. Bandosz, P., et al., Decline in mortality from coronary heart disease in Poland after socioeconomic transformation: modelling study. Bmj, 2012. 344: p. d8136. 18. Palmieri, L., et al., Explaining the decrease in coronary heart disease mortality in Italy between 1980 and 2000. Am J Public Health, 2010. 100(4): p. 684-92. 19. Bjorck, L., et al., Modelling the decreasing coronary heart disease mortality in Sweden between 1986 and 2002. Eur Heart J, 2009. 30(9): p. 1046-56. 20. Flores-Mateo, G., et al., [Analyzing the coronary heart disease mortality decline in a mediterranean population: Spain 1988-2005]. Rev Esp Cardiol, 2011. 64(11): p. 988-96. 21. Wijeysundera, H.C., et al., Association of temporal trends in risk factors and treatment uptake with coronary heart disease mortality, 1994-2005. Jama, 2010. 303(18): p. 1841-7. 22. Hunink, M.G., et al., The recent decline in mortality from coronary heart disease, 1980-1990. The effect of secular trends in risk factors and treatment. Jama, 1997. 277(7): p. 535-42. 23. Ford, E.S., et al., Explaining the decrease in U.S. deaths from coronary disease, 1980-2000. N Engl J Med, 2007. 356(23): p. 2388-98. 24. WHO, Global health risk: Mortality and burden of disease attributable to selected major risks. Geneva: World Health Organization, 2009. 25. Lopez, A.D., et al., Measuring the Global Burden of Disease and Risk Factors, 1990-2001. 2006. 26. Yusuf, S., et al., Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet, 2004. 364(9438): p. 937-52. 27. Iqbal, R., et al., Dietary patterns and the risk of acute myocardial infarction in 52 countries: results of the INTERHEART study. Circulation, 2008. 118(19): p. 1929-37. 28. Kuulasmaa, K., et al., Estimation of contribution of changes in classic risk factors to trends in coronary-event rates across the WHO MONICA Project populations. Lancet, 2000. 355(9205): p. 675-87. 29. Ferrieres, J., The French paradox: lessons for other countries. Heart, 2004. 90(1): p. 107-11. 30. Masia, R., et al., High prevalence of cardiovascular risk factors in Gerona, Spain, a province with low myocardial infarction incidence. REGICOR Investigators. J Epidemiol Community Health, 1998. 52(11): p. 707-15. 31. Grau, M., et al., [Cardiovascular risk factors in Spain in the first decade of the 21st Century, a pooled analysis with individual data from 11 population-based studies: the DARIOS study]. Rev Esp Cardiol, 2011. 64(4): p. 295-304. 32. Baena-Diez, J.M., et al., [Risk factor treatment and control in relation to coronary disease risk in the Spanish population of the DARIOS Study]. Rev Esp Cardiol, 2011. 64(9): p. 766-73. 33. Fuster, V., et al., The pathogenesis of coronary artery disease and the acute coronary syndromes (1). N Engl J Med, 1992. 326(4): p. 242-50. 34. Ross, R., The pathogenesis of atherosclerosis--an update. N Engl J Med, 1986. 314(8): p. 488-500. 35. Ross, R., Atherosclerosis--an inflammatory disease. N Engl J Med, 1999. 340(2): p. 115-26. 36. Fuster, V., et al., Atherosclerotic plaque rupture and thrombosis. Evolving concepts. Circulation, 1990. 82(3 Suppl): p. II47-59. 37. Libby, P., et al., Inflammation in atherosclerosis: transition from theory to practice. Circ J, 2010. 74(2): p. 213-20. 38. Hansson, G.K. and P. Libby, The immune response in atherosclerosis: a double-edged sword. Nat Rev Immunol, 2006. 6(7): p. 508-19. 39. Caligiuri, G., et al., Protective immunity against atherosclerosis carried by B cells of hypercholesterolemic mice. J Clin Invest, 2002. 109(6): p. 745-53. 40. Hartvigsen, K., et al., The role of innate immunity in atherogenesis. J Lipid Res, 2009. 50 Suppl: p. S388-93. 41. Chou, M.Y., et al., Oxidation-specific epitopes are dominant targets of innate natural antibodies in mice and humans. J Clin Invest, 2009. 119(5): p. 1335-49. 42. Swirski, F.K., et al., Monocyte accumulation in mouse atherogenesis is progressive and proportional to extent of disease. Proc Natl Acad Sci U S A, 2006. 103(27): p. 10340-5. 43. Kannel, W.B., Some lessons in cardiovascular epidemiology from Framingham. Am J Cardiol, 1976. 37(2): p. 269-82. 44. Calabro, P., E. Golia, and E.T. Yeh, CRP and the risk of atherosclerotic events. Semin Immunopathol, 2009. 31(1): p. 79-94. 45. Ouchi, N., et al., Reciprocal association of C-reactive protein with adiponectin in blood stream and adipose tissue. Circulation, 2003. 107(5): p. 671-4. 46. Calabro, P., et al., Release of C-reactive protein in response to inflammatory cytokines by human adipocytes: linking obesity to vascular inflammation. J Am Coll Cardiol, 2005. 46(6): p. 1112-3. 47. Singh, P., et al., Leptin induces C-reactive protein expression in vascular endothelial cells. Arterioscler Thromb Vasc Biol, 2007. 27(9): p. e302-7. 48. Inoue, T., et al., Local release of C-reactive protein from vulnerable plaque or coronary arterial wall injured by stenting. J Am Coll Cardiol, 2005. 46(2): p. 239-45. 49. Hattori, Y., M. Matsumura, and K. Kasai, Vascular smooth muscle cell activation by C-reactive protein. Cardiovasc Res, 2003. 58(1): p. 186-95. 50. Verma, S., et al., A self-fulfilling prophecy: C-reactive protein attenuates nitric oxide production and inhibits angiogenesis. Circulation, 2002. 106(8): p. 913-9. 51. Pasceri, V., J.T. Willerson, and E.T. Yeh, Direct proinflammatory effect of C-reactive protein on human endothelial cells. Circulation, 2000. 102(18): p. 2165-8. 52. Zwaka, T.P., V. Hombach, and J. Torzewski, C-reactive protein-mediated low density lipoprotein uptake by macrophages: implications for atherosclerosis. Circulation, 2001. 103(9): p. 1194-7. 53. Klouche, M., et al., Atherogenic properties of enzymatically degraded LDL: selective induction of MCP-1 and cytotoxic effects on human macrophages. Arterioscler Thromb Vasc Biol, 1998. 18(9): p. 1376-85. 54. Li, L., et al., C-reactive protein enhances LOX-1 expression in human aortic endothelial cells: relevance of LOX-1 to C-reactive protein-induced endothelial dysfunction. Circ Res, 2004. 95(9): p. 877-83. 55. Wang, C.H., et al., C-reactive protein upregulates angiotensin type 1 receptors in vascular smooth muscle. Circulation, 2003. 107(13): p. 1783-90. 56. Wadham, C., et al., High-density lipoproteins neutralize C-reactive protein proinflammatory activity. Circulation, 2004. 109(17): p. 2116-22. 57. Kim, S.J., et al., Opsonization of apoptotic cells and its effect on macrophage and T cell immune responses. Ann N Y Acad Sci, 2003. 987: p. 68-78. 58. Yamashita, H., et al., Concentrations of interleukins, interferon, and C-reactive protein in stable and unstable angina pectoris. Am J Cardiol, 2003. 91(2): p. 133-6. 59. Yasojima, K., et al., Generation of C-reactive protein and complement components in atherosclerotic plaques. Am J Pathol, 2001. 158(3): p. 1039-51. 60. Szalai, A.J., et al., Complement-dependent acute-phase expression of C-reactive protein and serum amyloid P-component. J Immunol, 2000. 165(2): p. 1030-5. 61. Cirillo, P., et al., C-reactive protein induces tissue factor expression and promotes smooth muscle and endothelial cell proliferation. Cardiovasc Res, 2005. 68(1): p. 47-55. 62. Singh, U., S. Devaraj, and I. Jialal, C-reactive protein decreases tissue plasminogen activator activity in human aortic endothelial cells: evidence that C-reactive protein is a procoagulant. Arterioscler Thromb Vasc Biol, 2005. 25(10): p. 2216-21. 63. Verma, S., et al., C-reactive protein attenuates endothelial progenitor cell survival, differentiation, and function: further evidence of a mechanistic link between C-reactive protein and cardiovascular disease. Circulation, 2004. 109(17): p. 2058-67. 64. Ridker, P.M., et al., Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med, 1997. 336(14): p. 973-9. 65. Ridker, P.M., et al., C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med, 2000. 342(12): p. 836-43. 66. Blankenberg, S., et al., Contribution of 30 biomarkers to 10-year cardiovascular risk estimation in 2 population cohorts: the MONICA, risk, genetics, archiving, and monograph (MORGAM) biomarker project. Circulation, 2010. 121(22): p. 2388-97. 67. Ballantyne, C.M., et al., Lipoprotein-associated phospholipase A2, high-sensitivity C-reactive protein, and risk for incident coronary heart disease in middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) study. Circulation, 2004. 109(7): p. 837-42. 68. Pai, J.K., et al., Inflammatory markers and the risk of coronary heart disease in men and women. N Engl J Med, 2004. 351(25): p. 2599-610. 69. Koenig, W., et al., C-Reactive protein, a sensitive marker of inflammation, predicts future risk of coronary heart disease in initially healthy middle-aged men: results from the MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) Augsburg Cohort Study, 1984 to 1992. Circulation, 1999. 99(2): p. 237-42. 70. Danesh, J., et al., C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. N Engl J Med, 2004. 350(14): p. 1387-97. 71. Cushman, M., et al., C-reactive protein and the 10-year incidence of coronary heart disease in older men and women: the cardiovascular health study. Circulation, 2005. 112(1): p. 25-31. 72. Ridker, P.M., et al., Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med, 2002. 347(20): p. 1557-65. 73. Ridker, P.M., et al., C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events: an 8-year follow-up of 14 719 initially healthy American women. Circulation, 2003. 107(3): p. 391-7. 74. Pradhan, A.D. and P.M. Ridker, Do atherosclerosis and type 2 diabetes share a common inflammatory basis? Eur Heart J, 2002. 23(11): p. 831-4. 75. Ridker, P.M., et al., Development and validation of improved algorithms for the assessment of global cardiovascular risk in women: the Reynolds Risk Score. Jama, 2007. 297(6): p. 611-9. 76. Ridker, P.M., et al., C-reactive protein and parental history improve global cardiovascular risk prediction: the Reynolds Risk Score for men. Circulation, 2008. 118(22): p. 2243-51, 4p following 2251. 77. Ridker, P.M., et al., Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med, 2008. 359(21): p. 2195-207. 78. Pearson, T.A., 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, 2003. 107(3): p. 499-511. 79. Leon, M.L. and S.H. Zuckerman, Gamma interferon: a central mediator in atherosclerosis. Inflamm Res, 2005. 54(10): p. 395-411. 80. McLaren, J.E. and D.P. Ramji, Interferon gamma: a master regulator of atherosclerosis. Cytokine Growth Factor Rev, 2009. 20(2): p. 125-35. 81. Nakagawa, T., et al., Oxidized LDL increases and interferon-gamma decreases expression of CD36 in human monocyte-derived macrophages. Arterioscler Thromb Vasc Biol, 1998. 18(8): p. 1350-7. 82. Geng, Y.J. and G.K. Hansson, Interferon-gamma inhibits scavenger receptor expression and foam cell formation in human monocyte-derived macrophages. J Clin Invest, 1992. 89(4): p. 1322-30. 83. Wuttge, D.M., et al., CXCL16/SR-PSOX is an interferon-gamma-regulated chemokine and scavenger receptor expressed in atherosclerotic lesions. Arterioscler Thromb Vasc Biol, 2004. 24(4): p. 750-5. 84. Reiss, A.B., et al., Interferon-gamma impedes reverse cholesterol transport and promotes foam cell transformation in THP-1 human monocytes/macrophages. Med Sci Monit, 2004. 10(11): p. BR420-5. 85. Mead, J.R. and D.P. Ramji, The pivotal role of lipoprotein lipase in atherosclerosis. Cardiovasc Res, 2002. 55(2): p. 261-9. 86. Jonasson, L., et al., Interferon-gamma inhibits lipoprotein lipase in human monocyte-derived macrophages. Biochim Biophys Acta, 1990. 1053(1): p. 43-8. 87. Fong, L.G., T.S. Albert, and S.E. Hom, Inhibition of the macrophage-induced oxidation of low density lipoprotein by interferon-gamma. J Lipid Res, 1994. 35(5): p. 893-904. 88. Inagaki, Y., et al., Interferon-gamma-induced apoptosis and activation of THP-1 macrophages. Life Sci, 2002. 71(21): p. 2499-508. 89. Gimbrone, M.A., Jr., Vascular endothelium, hemodynamic forces, and atherogenesis. Am J Pathol, 1999. 155(1): p. 1-5. 90. Kleinbongard, P., G. Heusch, and R. Schulz, TNFalpha in atherosclerosis, myocardial ischemia/reperfusion and heart failure. Pharmacol Ther. 127(3): p. 295-314. 91. Bruunsgaard, H., M. Pedersen, and B.K. Pedersen, Aging and proinflammatory cytokines. Curr Opin Hematol, 2001. 8(3): p. 131-6. 92. McKellar, G.E., et al., Role for TNF in atherosclerosis? Lessons from autoimmune disease. Nat Rev Cardiol, 2009. 6(6): p. 410-7. 93. Bergh, N., et al., Influence of TNF-alpha and biomechanical stress on endothelial anti- and prothrombotic genes. Biochem Biophys Res Commun, 2009. 385(3): p. 314-8. 94. Neumann, P., N. Gertzberg, and A. Johnson, TNF-alpha induces a decrease in eNOS promoter activity. Am J Physiol Lung Cell Mol Physiol, 2004. 286(2): p. L452-9. 95. Gebhard, C., et al., Guggulsterone, an anti-inflammatory phytosterol, inhibits tissue factor and arterial thrombosis. Basic Res Cardiol, 2009. 104(3): p. 285-94. 96. Chia, S., et al., Intra-arterial tumor necrosis factor-alpha impairs endothelium-dependent vasodilatation and stimulates local tissue plasminogen activator release in humans. Arterioscler Thromb Vasc Biol, 2003. 23(4): p. 695-701. 97. Chappell, D., et al., TNF-alpha induced shedding of the endothelial glycocalyx is prevented by hydrocortisone and antithrombin. Basic Res Cardiol, 2009. 104(1): p. 78-89. 98. Goetze, S., et al., TNF-alpha-induced migration of vascular smooth muscle cells is MAPK dependent. Hypertension, 1999. 33(1 Pt 2): p. 183-9. 99. Branen, L., et al., Inhibition of tumor necrosis factor-alpha reduces atherosclerosis in apolipoprotein E knockout mice. Arterioscler Thromb Vasc Biol, 2004. 24(11): p. 2137-42. 100. Levine, B., et al., Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N Engl J Med, 1990. 323(4): p. 236-41. 101. Tuomisto, K., et al., C-reactive protein, interleukin-6 and tumor necrosis factor alpha as predictors of incident coronary and cardiovascular events and total mortality. A population-based, prospective study. Thromb Haemost, 2006. 95(3): p. 511-8. 102. de Vries, J.E., Immunosuppressive and anti-inflammatory properties of interleukin 10. Ann Med, 1995. 27(5): p. 537-41. 103. Frostegard, J., et al., Cytokine expression in advanced human atherosclerotic plaques: dominance of pro-inflammatory (Th1) and macrophage-stimulating cytokines. Atherosclerosis, 1999. 145(1): p. 33-43. 104. de Waal Malefyt, R., et al., Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. J Exp Med, 1991. 174(5): p. 1209-20. 105. Andersson, J., P. Libby, and G.K. Hansson, Adaptive immunity and atherosclerosis. Clin Immunol. 134(1): p. 33-46. 106. Cohen, S.B., et al., Interleukin-10 rescues T cells from apoptotic cell death: association with an upregulation of Bcl-2. Immunology, 1997. 92(1): p. 1-5. 107. Ramani, M., et al., Interleukin-10 inhibits endotoxin-induced tissue factor mRNA production by human monocytes. FEBS Lett, 1993. 334(1): p. 114-6. 108. Lee, Y.W., et al., Interleukin-4, Oxidative Stress, Vascular Inflammation and Atherosclerosis. Biomol Ther (Seoul). 18(2): p. 135-144. 109. Binder, C.J., et al., IL-5 links adaptive and natural immunity specific for epitopes of oxidized LDL and protects from atherosclerosis. J Clin Invest, 2004. 114(3): p. 427-37. 110. Sampi, M., et al., Plasma interleukin-5 levels are related to antibodies binding to oxidized low-density lipoprotein and to decreased subclinical atherosclerosis. J Am Coll Cardiol, 2008. 52(17): p. 1370-8. 111. Huang, J., et al., Role of endothelial lipase in atherosclerosis. Transl Res. 156(1): p. 1-6. 112. Xu, Q., et al., Serum soluble heat shock protein 60 is elevated in subjects with atherosclerosis in a general population. Circulation, 2000. 102(1): p. 14-20. 113. Elkind, M.S., et al., Interleukin-2 levels are associated with carotid artery intima-media thickness. Atherosclerosis, 2005. 180(1): p. 181-7. 114. Ridker, P.M., et al., Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation, 2000. 101(15): p. 1767-72. 115. Shah, P.K., Circulating markers of inflammation for vascular risk prediction: are they ready for prime time. Circulation, 2000. 101(15): p. 1758-9. 116. Cesari, M., et al., Inflammatory markers and onset of cardiovascular events: results from the Health ABC study. Circulation, 2003. 108(19): p. 2317-22. 117. Ikonomidis, I., et al., Multimarker approach in cardiovascular risk prediction. Dis Markers, 2009. 26(5-6): p. 273-85. 118. Martin-Ventura, J.L., et al., Biomarkers in cardiovascular medicine. Rev Esp Cardiol, 2009. 62(6): p. 677-88. 119. Ridker, P.M., et al., Plasma concentration of soluble intercellular adhesion molecule 1 and risks of future myocardial infarction in apparently healthy men. Lancet, 1998. 351(9096): p. 88-92. 120. Hwang, S.J., 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, 1997. 96(12): p. 4219-25. 121. Blankenberg, S., et al., Circulating cell adhesion molecules and death in patients with coronary artery disease. Circulation, 2001. 104(12): p. 1336-42. 122. Mulvihill, N.T., et al., Risk stratification in unstable angina and non-Q wave myocardial infarction using soluble cell adhesion molecules. Heart, 2001. 85(6): p. 623-7. 123. Empana, J.P., et al., Contribution of novel biomarkers to incident stable angina and acute coronary syndrome: the PRIME Study. Eur Heart J, 2008. 29(16): p. 1966-74. 124. Pockley, A.G., et al., Circulating heat shock protein 60 is associated with early cardiovascular disease. Hypertension, 2000. 36(2): p. 303-7. 125. Chen, W., et al., Human 60-kDa heat-shock protein: a danger signal to the innate immune system. J Immunol, 1999. 162(6): p. 3212-9. 126. Kol, A., et al., Chlamydial heat shock protein 60 localizes in human atheroma and regulates macrophage tumor necrosis factor-alpha and matrix metalloproteinase expression. Circulation, 1998. 98(4): p. 300-7. 127. Dybdahl, B., et al., Myocardial ischaemia and the inflammatory response: release of heat shock protein 70 after myocardial infarction. Heart, 2005. 91(3): p. 299-304. 128. Zhang, X., et al., Elevated heat shock protein 60 levels are associated with higher risk of coronary heart disease in Chinese. Circulation, 2008. 118(25): p. 2687-93. 129. Magnus, P. and R. Beaglehole, The real contribution of the major risk factors to the coronary epidemics: time to end the "only-50%" myth. Arch Intern Med, 2001. 161(22): p. 2657-60. 130. Hamburg, N.M., et al., Cross-sectional relations of digital vascular function to cardiovascular risk factors in the Framingham Heart Study. Circulation, 2008. 117(19): p. 2467-74. 131. Vasan, R.S., et al., Association of leukocyte telomere length with circulating biomarkers of the renin-angiotensin-aldosterone system: the Framingham Heart Study. Circulation, 2008. 117(9): p. 1138-44. 132. Marrugat, J., et al., [Relative validity of the 10-year cardiovascular risk estimate in a population cohort of the REGICOR study]. Rev Esp Cardiol, 2011. 64(5): p. 385-94. 133. Khot, U.N., et al., Prevalence of conventional risk factors in patients with coronary heart disease. Jama, 2003. 290(7): p. 898-904. 134. Marrugat, J., et al., Validity of an adaptation of the Framingham cardiovascular risk function: the VERIFICA Study. J Epidemiol Community Health, 2007. 61(1): p. 40-7. 135. Grau, M. and J. Marrugat, [Risk functions and the primary prevention of cardiovascular disease]. Rev Esp Cardiol, 2008. 61(4): p. 404-16. 136. Han, T.S., et al., Waist circumference action levels in the identification of cardiovascular risk factors: prevalence study in a random sample. Bmj, 1995. 311(7017): p. 1401-5. 137. Rosito, G.A., et al., Pericardial fat, visceral abdominal fat, cardiovascular disease risk factors, and vascular calcification in a community-based sample: the Framingham Heart Study. Circulation, 2008. 117(5): p. 605-13. 138. Anderson, K.M., et al., An updated coronary risk profile. A statement for health professionals. Circulation, 1991. 83(1): p. 356-62. 139. Levy, D., et al., Stratifying the patient at risk from coronary disease: new insights from the Framingham Heart Study. Am Heart J, 1990. 119(3 Pt 2): p. 712-7; discussion 717. 140. Gotto, A.M., Jr. and S.M. Grundy, Lowering LDL cholesterol: questions from recent meta-analyses and subset analyses of clinical trial DataIssues from the Interdisciplinary Council on Reducing the Risk for Coronary Heart Disease, ninth Council meeting. Circulation, 1999. 99(8): p. E1-7. 141. Grundy, S.M., et al., Diabetes and cardiovascular disease: a statement for healthcare professionals from the American Heart Association. Circulation, 1999. 100(10): p. 1134-46. 142. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). Jama, 2001. 285(19): p. 2486-97. 143. Alberti, K.G. and P.Z. Zimmet, Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med, 1998. 15(7): p. 539-53. 144. Balkau, B., A. Forhan, and E. Eschwege, Two hour plasma glucose is not unequivocally predictive for early death in men with impaired fasting glucose: more results from the Paris Prospective Study. Diabetologia, 2002. 45(9): p. 1224-30. 145. Grundy, S.M., et al., Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation, 2005. 112(17): p. 2735-52. 146. Alberti, K.G., et al., Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation, 2009. 120(16): p. 1640-5. 147. Simmons, R.K., et al., The metabolic syndrome: useful concept or clinical tool? Report of a WHO Expert Consultation. Diabetologia, 2010. 53(4): p. 600-5. 148. Laclaustra, M., et al., Metabolic syndrome and coronary heart disease among Spanish male workers: A case-control study of MESYAS. Nutr Metab Cardiovasc Dis, 2010. 149. Sattar, N., et al., Metabolic syndrome with and without C-reactive protein as a predictor of coronary heart disease and diabetes in the West of Scotland Coronary Prevention Study. Circulation, 2003. 108(4): p. 414-9. 150. Lean, M.E., T.S. Han, and C.E. Morrison, Waist circumference as a measure for indicating need for weight management. Bmj, 1995. 311(6998): p. 158-61. 151. Wannamethee, S.G., et al., Metabolic syndrome vs Framingham Risk Score for prediction of coronary heart disease, stroke, and type 2 diabetes mellitus. Arch Intern Med, 2005. 165(22): p. 2644-50. 152. Banegas, J.R., et al., Association between awareness, treatment, and control of hypertension, and quality of life among older adults in Spain. Am J Hypertens, 2006. 19(7): p. 686-93. 153. Kannel, W.B., D. McGee, and T. Gordon, A general cardiovascular risk profile: the Framingham Study. Am J Cardiol, 1976. 38(1): p. 46-51. 154. Anderson, K.M., et al., Cardiovascular disease risk profiles. Am Heart J, 1991. 121(1 Pt 2): p. 293-8. 155. Wilson, P.W., et al., Prediction of coronary heart disease using risk factor categories. Circulation, 1998. 97(18): p. 1837-47. 156. Grundy, S.M., Primary prevention of coronary heart disease: integrating risk assessment with intervention. Circulation, 1999. 100(9): p. 988-98. 157. D'Agostino, R.B., et al., Primary and subsequent coronary risk appraisal: new results from the Framingham study. Am Heart J, 2000. 139(2 Pt 1): p. 272-81. 158. D'Agostino, R.B., Sr., et al., General cardiovascular risk profile for use in primary care: the Framingham Heart Study. Circulation, 2008. 117(6): p. 743-53. 159. Conroy, R.M., et al., Estimation of ten-year risk of fatal cardiovascular disease in Europe: the SCORE project. Eur Heart J, 2003. 24(11): p. 987-1003. 160. Marrugat, J., et al., [Coronary risk estimation in Spain using a calibrated Framingham function]. Rev Esp Cardiol, 2003. 56(3): p. 253-61. 161. Marrugat, J., et al., An adaptation of the Framingham coronary heart disease risk function to European Mediterranean areas. J Epidemiol Community Health, 2003. 57(8): p. 634-8. 162. Ramos, R., et al., [Comparison of population coronary heart disease risk estimated by the Framingham original and REGICOR calibrated functions]. Med Clin (Barc), 2003. 121(14): p. 521-6. 163. Marrugat, J., R. Elosua, and H. Marti, [Epidemiology of ischaemic heart disease in Spain: estimation of the number of cases and trends from 1997 to 2005]. Rev Esp Cardiol, 2002. 55(4): p. 337-46. 164. Aranceta, J., et al., [Tables of coronary risk evaluation adapted to the Spanish population: the DORICA study]. Med Clin (Barc), 2004. 123(18): p. 686-91. 165. Alvarez-Leon, E.E., et al., [Hospital resources and myocardial infarction case fatality. The IBERICA study]. Rev Esp Cardiol, 2004. 57(6): p. 514-23. 166. Tunstall-Pedoe, H., The Dundee coronary risk-disk for management of change in risk factors. Bmj, 1991. 303(6805): p. 744-7. 167. Jackson, R., Updated New Zealand cardiovascular disease risk-benefit prediction guide. Bmj, 2000. 320(7236): p. 709-10. 168. Tunstall-Pedoe, H., Cardiovascular Risk and Risk Scores: ASSIGN, Framingham, QRISK and others: how to choose. Heart, 2011. 97(6): p. 442-4. 169. Assmann, G., P. Cullen, and H. Schulte, Simple scoring scheme for calculating the risk of acute coronary events based on the 10-year follow-up of the prospective cardiovascular Munster (PROCAM) study. Circulation, 2002. 105(3): p. 310-5. 170. Lloyd-Jones, D.M., et al., Parental cardiovascular disease as a risk factor for cardiovascular disease in middle-aged adults: a prospective study of parents and offspring. Jama, 2004. 291(18): p. 2204-11. 171. Tzoulaki, I., et al., Inflammatory, haemostatic, and rheological markers for incident peripheral arterial disease: Edinburgh Artery Study. Eur Heart J, 2007. 28(3): p. 354-62. 172. Morrison, A.C., et al., Prediction of coronary heart disease risk using a genetic risk score: the Atherosclerosis Risk in Communities Study. Am J Epidemiol, 2007. 166(1): p. 28-35. 173. Newman, A.B., et al., Ankle-arm index as a predictor of cardiovascular disease and mortality in the Cardiovascular Health Study. The Cardiovascular Health Study Group. Arterioscler Thromb Vasc Biol, 1999. 19(3): p. 538-45. 174. Missiou, A., et al., Tumor necrosis factor receptor-associated factor 1 (TRAF1) deficiency attenuates atherosclerosis in mice by impairing monocyte recruitment to the vessel wall. Circulation, 2010. 121(18): p. 2033-44. 175. Fox, C.S., et al., Parental atrial fibrillation as a risk factor for atrial fibrillation in offspring. Jama, 2004. 291(23): p. 2851-5. 176. Daviglus, M.L., et al., Favorable cardiovascular risk profile in young women and long-term risk of cardiovascular and all-cause mortality. Jama, 2004. 292(13): p. 1588-92. 177. Fowkes, F.G., et al., Ankle-brachial index and extent of atherothrombosis in 8891 patients with or at risk of vascular disease: results of the international AGATHA study. Eur Heart J, 2006. 27(15): p. 1861-7. 178. Plaza Perez, I., et al., [Control of cholesterolemia in Spain, 2000. A tool for cardiovascular prevention]. Rev Esp Cardiol, 2000. 53(6): p. 815-37. 179. Sun, J., et al., Deficiency of antigen-presenting cell invariant chain reduces atherosclerosis in mice. Circulation, 2010. 122(8): p. 808-20. 180. The sixth report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Arch Intern Med, 1997. 157(21): p. 2413-46. 181. Eldrup, N., et al., Ankle brachial index, C-reactive protein, and central augmentation index to identify individuals with severe atherosclerosis. Eur Heart J, 2006. 27(3): p. 316-22. 182. Comin, E., et al., [Estimating cardiovascular risk in Spain using different algorithms]. Rev Esp Cardiol, 2007. 60(7): p. 693-702. 183. Marrugat, J. and J. Sala, [New instruments, same risks]. Rev Esp Cardiol, 2007. 60(5): p. 464-7. 184. Braunwald, E., Epilogue: what do clinicians expect from imagers? J Am Coll Cardiol, 2006. 47(8 Suppl): p. C101-3. 185. Taylor, A.J., C.N. Merz, and J.E. Udelson, 34th Bethesda Conference: Executive summary--can atherosclerosis imaging techniques improve the detection of patients at risk for ischemic heart disease? J Am Coll Cardiol, 2003. 41(11): p. 1860-2. 186. Naghavi, M., et al., From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part II. Circulation, 2003. 108(15): p. 1772-8. 187. Naghavi, M., et al., From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part I. Circulation, 2003. 108(14): p. 1664-72. 188. Naghavi, M., et al., From vulnerable plaque to vulnerable patient--Part III: Executive summary of the Screening for Heart Attack Prevention and Education (SHAPE) Task Force report. Am J Cardiol, 2006. 98(2A): p. 2H-15H. 189. Ridker, P.M., Clinical application of C-reactive protein for cardiovascular disease detection and prevention. Circulation, 2003. 107(3): p. 363-9. 190. Fernandez-Miranda, C., [New perspectives in the measurement of cardiovascular risk: explorations to detect subclinical atherosclerosis and inflammation markers]. Med Clin (Barc), 2007. 128(9): p. 344-51. 191. Folsom, A.R., et al., An assessment of incremental coronary risk prediction using C-reactive protein and other novel risk markers: the atherosclerosis risk in communities study. Arch Intern Med, 2006. 166(13): p. 1368-73. 192. Ridker, P.M., et al., C-reactive protein levels and outcomes after statin therapy. N Engl J Med, 2005. 352(1): p. 20-8. 193. Nissen, S.E., et al., Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N Engl J Med, 2005. 352(1): p. 29-38. 194. D'Agostino, R.B., Sr., et al., Validation of the Framingham coronary heart disease prediction scores: results of a multiple ethnic groups investigation. Jama, 2001. 286(2): p. 180-7. 195. Mancia, G., et al., [ESH/ESC 2007 Guidelines for the management of arterial hypertension]. Rev Esp Cardiol, 2007. 60(9): p. 968 e1-94. 196. INE-CAM, Instituto Nacional de Estadística de Comunidad Autónoma de Madrid. 197. Grau, M., et al., [Cardiovascular risk factors in Spain in the first decade of the 21st Century, a pooled analysis with individual data from 11 population-based studies: the DARIOS study]. Rev Esp Cardiol. 64(4): p. 295-304. 198. Medrano, M.J., et al., [Cardiovascular risk factors in Spanish population: metaanalysis of cross-sectional studies]. Med Clin (Barc), 2005. 124(16): p. 606-12. 199. Sanchez, R.G., et al., [The EPICARDIAN project, a cohort study on cardiovascular diseases and risk factors among the elderly in Spain: methodological aspects and major demographic findings]. Rev Esp Salud Publica, 2004. 78(2): p. 243-55. 200. Novella, B., et al., [Ten-year incidence of fatal and non-fatal myocardial infarction in the elderly population of Madrid]. Rev Esp Cardiol, 2008. 61(11): p. 1140-9. 201. Coca, A., et al., [Treatment and control of cardiovascular risk in primary care in Spain. The PREVENCAT study]. Med Clin (Barc), 2006. 126(6): p. 201-5. 202. Lopez Suarez, A., et al., [Prevalence of obesity, diabetes, hypertension, hypercholesterolemia and metabolic syndrome in over 50-year-olds in Sanlucar de Barrameda, Spain]. Rev Esp Cardiol, 2008. 61(11): p. 1150-8. 203. Basterra-Gortari, F.J., et al., [Trends in obesity, diabetes mellitus, hypertension and hypercholesterolemia in Spain (1997-2003)]. Med Clin (Barc), 2007. 129(11): p. 405-8. 204. Banegas, J.R., et al., Blood pressure in Spain: distribution, awareness, control, and benefits of a reduction in average pressure. Hypertension, 1998. 32(6): p. 998-1002. 205. Banegas, J.R., et al., Hypertension magnitude and management in the elderly population of Spain. J Hypertens, 2002. 20(11): p. 2157-64. 206. Gutierrez-Misis, A., et al., Prevalence and incidence of hypertension in a population cohort of people aged 65 years or older in Spain. J Hypertens, 2011. 29(10): p. 1863-70. 207. Baena Diez, J.M., et al., [Cardiovascular disease epidemiology and risk factors in primary care]. Rev Esp Cardiol, 2005. 58(4): p. 367-73. 208. de Velasco, J.A., et al., [Risk factor prevalence and drug treatment in coronary patients at hospital discharge. Results of a national multicenter registry (3C Program)]. Rev Esp Cardiol, 2001. 54(2): p. 159-68. 209. De Velasco, J.A., et al., [New data on secondary prevention of myocardial infarction in Spain. Results of the PREVESE II study]. Rev Esp Cardiol, 2002. 55(8): p. 801-9. 210. Aros, F., et al., [Management of myocardial infarction in Spain in the year 2000. The PRIAMHO II study]. Rev Esp Cardiol, 2003. 56(12): p. 1165-73. 211. Martinez, M.A., et al., Metabolic syndrome: prevalence, associated factors, and C-reactive protein: the MADRIC (MADrid RIesgo Cardiovascular) Study. Metabolism, 2008. 57(9): p. 1232-40. 212. Fernandez-Berges, D., et al., Metabolic Syndrome in Spain: Prevalence and Coronary Risk Associated With Harmonized Definition and WHO Proposal. DARIOS Study. Rev Esp Cardiol, 2012. 213. Fernandez-Berges, D., et al., [Prevalence of metabolic syndrome estimated with the new World Health Organization recommendations. The HERMEX study]. Gac Sanit, 2011. 25(6): p. 519-24. 214. Alvarez-Sala, L.A., et al., [PREVENCAT study: control of cardiovascular risk in primary care]. Med Clin (Barc), 2005. 124(11): p. 406-10. 215. Babio, N., et al., Adherence to the Mediterranean diet and risk of metabolic syndrome and its components. Nutr Metab Cardiovasc Dis, 2009. 19(8): p. 563-70. 216. Gavrila, D., et al., Prevalence of metabolic syndrome in Murcia Region, a southern European Mediterranean area with low cardiovascular risk and high obesity. BMC Public Health, 2011. 11: p. 562. 217. Bernal-Lopez, M.R., et al., Why not use the HbA1c as a criterion of dysglycemia in the new definition of the metabolic syndrome? Impact of the new criteria in the prevalence of the metabolic syndrome in a Mediterranean urban population from Southern Europe (IMAP study. Multidisciplinary intervention in primary care). Diabetes Res Clin Pract, 2011. 93(2): p. e57-60. 218. Jover, A., et al., [Prevalence of metabolic syndrome and its components in patients with acute coronary syndrome]. Rev Esp Cardiol, 2011. 64(7): p. 579-86. 219. Seculi, E., et al., [Detection of cardiovascular risk factors in the reformed primary care network in Catalonia. Comparison between the years 1995 and 2000]. Aten Primaria, 2003. 31(3): p. 156-62. 220. Conthe, P., et al., Degree of control and delayed intensification of antihyperglycaemic treatment in type 2 diabetes mellitus patients in primary care in Spain. Diabetes Res Clin Pract, 2011. 91(1): p. 108-14. 221. Escobar, C., et al., [Diabetes mellitus in hypertensive population attended in Primary Care in Spain. Blood pressure and lipid control rates]. Rev Clin Esp, 2007. 207(5): p. 221-7. 222. Rodriguez, A., et al., Blood glucose control and quality of health care in non-insulin-treated patients with Type 2 diabetes in Spain: a retrospective and cross-sectional observational study. Diabet Med, 2011. 28(6): p. 731-40. 223. Llisterri Caro, J.L., et al., [Blood pressure control in Spanish hypertensive patients in Primary Health Care Centres. PRESCAP 2002 Study]. Med Clin (Barc), 2004. 122(5): p. 165-71. 224. Benitez, M., et al., [Control of blood pressure in a population of patients with hypertension and in a subgroup with hypertension and diabetes: relationship with characteristics of the health care center and the community]. Aten Primaria, 2001. 28(6): p. 373-80. 225. Mena Martin, F.J., et al., [Cardiovascular risk factors in diabetic patients. Cross-sectional study in general population: Hortega study]. An Med Interna, 2003. 20(6): p. 292-6. 226. Banegas, J.R., et al., Blood pressure control and physician management of hypertension in hospital hypertension units in Spain. Hypertension, 2004. 43(6): p. 1338-44. 227. Cottone, S., et al., C-reactive protein and intercellular adhesion molecule-1 are stronger predictors of oxidant stress than blood pressure in established hypertension. J Hypertens, 2007. 25(2): p. 423-8. 228. Parissis, J.T., et al., Plasma profiles of peripheral monocyte-related inflammatory markers in patients with arterial hypertension. Correlations with plasma endothelin-1. Int J Cardiol, 2002. 83(1): p. 13-21. 229. Mazzone, A., et al., Cigarette smoking and hypertension influence nitric oxide release and plasma levels of adhesion molecules. Clin Chem Lab Med, 2001. 39(9): p. 822-6. 230. Madej, A., et al., Plasma concentrations of adhesion molecules and chemokines in patients with essential hypertension. Pharmacol Rep, 2005. 57(6): p. 878-81. 231. Kuklinska, A.M., et al., High-sensitivity C-reactive protein and total antioxidant status in patients with essential arterial hypertension and dyslipidemia. Adv Med Sci, 2009. 54(2): p. 225-32. 232. Magen, E., et al., Resistant arterial hypertension is associated with higher blood levels of complement C3 and C-reactive protein. J Clin Hypertens (Greenwich), 2008. 10(9): p. 677-83. 233. Preston, R.A., et al., Effects of severe, uncontrolled hypertension on endothelial activation: soluble vascular cell adhesion molecule-1, soluble intercellular adhesion molecule-1 and von Willebrand factor. J Hypertens, 2002. 20(5): p. 871-7. 234. Hu, F.B., et al., Inflammatory markers and risk of developing type 2 diabetes in women. Diabetes, 2004. 53(3): p. 693-700. 235. Han, T.S., et al., Prospective study of C-reactive protein in relation to the development of diabetes and metabolic syndrome in the Mexico City Diabetes Study. Diabetes Care, 2002. 25(11): p. 2016-21. 236. Mojahedi, M.J., et al., Elevated serum C-reactive protein level and microalbuminuria in patients with type 2 diabetes mellitus. Iran J Kidney Dis, 2009. 3(1): p. 12-6. 237. Choudhary, N. and R.S. Ahlawat, Interleukin-6 and C-reactive protein in pathogenesis of diabetic nephropathy: new evidence linking inflammation, glycemic control, and microalbuminuria. Iran J Kidney Dis, 2008. 2(2): p. 72-9. 238. Ray, I., et al., A study of the association of micro-albuminuria and C-reactive protein (CRP) in normotensive diabetic and hypertensive diabetic patients. J Indian Med Assoc, 2011. 109(6): p. 428-9. 239. Schram, M.T., et al., Markers of inflammation are cross-sectionally associated with microvascular complications and cardiovascular disease in type 1 diabetes--the EURODIAB Prospective Complications Study. Diabetologia, 2005. 48(2): p. 370-8. 240. Duvnjak, L. and M. Duvnjak, The metabolic syndrome - an ongoing story. J Physiol Pharmacol, 2009. 60 Suppl 7: p. 19-24. 241. Vykoukal, D. and M.G. Davies, Vascular biology of metabolic syndrome. J Vasc Surg, 2011. 54(3): p. 819-31. 242. Devaraj, S., U. Singh, and I. Jialal, Human C-reactive protein and the metabolic syndrome. Curr Opin Lipidol, 2009. 20(3): p. 182-9. 243. Ishikawa, S., et al., Metabolic syndrome and C-reactive protein in the general population: JMS Cohort Study. Circ J, 2007. 71(1): p. 26-31. 244. Glund, S. and A. Krook, Role of interleukin-6 signalling in glucose and lipid metabolism. Acta Physiol (Oxf), 2008. 192(1): p. 37-48. 245. el-Mesallamy, H., S. Suwailem, and N. Hamdy, Evaluation of C-reactive protein, endothelin-1, adhesion molecule(s), and lipids as inflammatory markers in type 2 diabetes mellitus patients. Mediators Inflamm, 2007. 2007: p. 73635. 246. Takeuchi, N., et al., The effect of cigarette smoking on soluble adhesion molecules in middle-aged patients with Type 2 diabetes mellitus. Diabet Med, 2002. 19(1): p. 57-64. 247. Thorand, B., et al., Elevated markers of endothelial dysfunction predict type 2 diabetes mellitus in middle-aged men and women from the general population. Arterioscler Thromb Vasc Biol, 2006. 26(2): p. 398-405. 248. Hoogeveen, R.C., et al., Circulating oxidised low-density lipoprotein and intercellular adhesion molecule-1 and risk of type 2 diabetes mellitus: the Atherosclerosis Risk in Communities Study. Diabetologia, 2007. 50(1): p. 36-42. 249. Pauciullo, P., et al., Tumor necrosis factor-alpha is a marker of familial combined hyperlipidemia, independently of metabolic syndrome. Metabolism, 2008. 57(4): p. 563-8. 250. Calan, M., et al., Examination of adhesion molecules, homocysteine and hs-CRP in patients with polygenic hypercholesterolemia and isolated hypertriglyceridemia. Intern Med, 2011. 50(15): p. 1529-35. 251. Benitez, M.B., et al., Endothelial and leukocyte adhesion molecules in primary hypertriglyceridemia. Atherosclerosis, 2008. 197(2): p. 679-87. 252. Libby, P., et al., Lipid lowering improves endothelial functions. Int J Cardiol, 2000. 74 Suppl 1: p. S3-S10. 253. Frohlich, M., et al., Independent association of various smoking characteristics with markers of systemic inflammation in men. Results from a representative sample of the general population (MONICA Augsburg Survey 1994/95). Eur Heart J, 2003. 24(14): p. 1365-72. 254. Petrescu, F., S.C. Voican, and I. Silosi, Tumor necrosis factor-alpha serum levels in healthy smokers and nonsmokers. Int J Chron Obstruct Pulmon Dis, 2010. 5: p. 217-22. 255. Diez-Pina, J.M., et al., Tumor necrosis factor alpha as a marker of systemic and local inflammation in "healthy" smokers. Int J Gen Med, 2009. 2: p. 9-14. 256. Hamer, M., et al., Objectively measured secondhand smoke exposure and risk of cardiovascular disease: what is the mediating role of inflammatory and hemostatic factors? J Am Coll Cardiol, 2010. 56(1): p. 18-23. 257. Jefferis, B.J., et al., Secondhand smoke (SHS) exposure is associated with circulating markers of inflammation and endothelial function in adult men and women. Atherosclerosis, 2010. 208(2): p. 550-6. 258. Flouris, A.D., et al., Cardiorespiratory and immune response to physical activity following exposure to a typical smoking environment. Heart, 2010. 96(11): p. 860-4. 259. Flouris, A.D., et al., Acute and short-term effects of secondhand smoke on lung function and cytokine production. Am J Respir Crit Care Med, 2009. 179(11): p. 1029-33. 260. Reichert, V., et al., A pilot study to examine the effects of smoking cessation on serum markers of inflammation in women at risk for cardiovascular disease. Chest, 2009. 136(1): p. 212-9. 261. St-Pierre, A.C., et al., Inflammatory markers and long-term risk of ischemic heart disease in men A 13-year follow-up of the Quebec Cardiovascular Study. Atherosclerosis, 2005. 182(2): p. 315-21. 262. Park, C.S., et al., Relation between C-reactive protein, homocysteine levels, fibrinogen, and lipoprotein levels and leukocyte and platelet counts, and 10-year risk for cardiovascular disease among healthy adults in the USA. Am J Cardiol, 2010. 105(9): p. 1284-8. 263. de Ruijter, W., et al., Use of Framingham risk score and new biomarkers to predict cardiovascular mortality in older people: population based observational cohort study. Bmj, 2009. 338: p. a3083. 264. Sattar, N., et al., C-reactive protein and prediction of coronary heart disease and global vascular events in the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). Circulation, 2007. 115(8): p. 981-9. 265. Bahadursingh, S., et al., C-reactive protein: adjunct to cardiovascular risk assessment. West Indian Med J, 2009. 58(6): p. 551-5.