Cardiovascular disease is increased in HIV-infected patients. Cytokines such as osteoprotegerin are implicated in atherosclerosis. The aim of our study was to evaluate the role of osteoprotegerin in the development and progression of atherosclerosis in HIV infected subjects on suppressive antiretroviral treatment. We enrolled 76 patients; 35 HIV infected men on suppressive Highly Active Antiretroviral Therapy with Framingham score <10%; 21 HIV negative individuals matched for age, gender, and Framingham score, and 20 subjects with Framingham score >10% as control groups. HIV positive subjects underwent echocardiography, electrocardiography, and heart multidetector computed tomography, whereas in HIV negative subjects, tomography was only performed in case of any abnormalities either in echocardiography or electrocardiography. In HIV positive patients, computed tomography showed stenosis in 51.4% of the subjects. Osteoprotegerin plasma levels were higher in HIV-infected patients than those in healthy controls but lower than in HIV negative subjects with Framingham score >10%. Higher osteoprotegerin plasma levels were found in HIV positive patients with grade I stenosis than in patients with grade II/III stenosis. In conclusion, in HIV infected subjects with Framingham score <10%, osteoprotegerin plasma concentrations are associated with atherosclerosis, in particular at the early stage of the process. 1. Introduction Cardiovascular disease (CVD) is an emerging and significant cause of morbidity and mortality in HIV-infected patients [1]. HIV itself and antiretroviral drugs may contribute to the increased risk of CVD. In addition to traditional risk factors (age, smoking, dyslipidemia, and diabetes), chronic viral infection, immune activation, and inflammation play a central role in vascular damage and endothelial dysfunction [2]. Proinflammatory cytokines such as interleukin (IL)-6 and IL-1 are associated with development and progression of atherosclerosis [3–7]; furthermore, new soluble markers including osteoprotegerin (OPG) have been shown to be involved in this process. The OPG/RANK (receptor activator of NF-kappaB)/RANKL (receptor activator of NF-kappaB ligand), member of TNF superfamily, is a key regulatory system in bone remodelling by regulating development and activation of osteoclasts [8–11]. Recent studies showed the implication of the OPG/RANKL system in vascular disease, especially in vascular calcification, atherosclerosis and plaque formation [12–15]. There are few data about the relationship between OPG and cardiovascular disease in HIV
References
[1]
A. Hakeem, S. Bhatti, and M. Cilingiroglu, “The spectrum of atherosclerotic coronary artery disease in HIV patients,” Current Atherosclerosis Reports, vol. 12, no. 2, pp. 119–124, 2010.
[2]
B. Coll, S. Parra, C. Alonso-Villaverde et al., “The role of immunity and inflammation in the progression of atherosclerosis in patients with HIV infection,” Stroke, vol. 38, no. 9, pp. 2477–2484, 2007.
[3]
S. W. Worm and P. Hsue, “Role of biomarkers in predicting CVD risk in the setting of HIV infection?” Current Opinion in HIV and AIDS, vol. 5, no. 6, pp. 467–472, 2010.
[4]
O. Melander, C. Newton-Cheh, P. Almgren et al., “Novel and conventional biomarkers for prediction of incident cardiovascular events in the community,” Journal of the American Medical Association, vol. 302, no. 1, pp. 49–57, 2009.
[5]
G. Biasillo, M. Leo, R. della Bona, and L. M. Biasucci, “Inflammatory biomarkers and coronary heart disease: from bench to bedside and back,” Internal and Emergency Medicine, vol. 5, no. 3, pp. 225–233, 2010.
[6]
M. Guzmán-Fulgencio, J. Medrano, N. Rallón et al., “Soluble markers of inflammation are associated with framingham scores in HIV-infected patients on suppressive antiretroviral therapy,” Journal of Infection, vol. 63, no. 5, pp. 382–390, 2011.
[7]
A. C. Ross, N. Rizk, M. A. O'Riordan et al., “Relationship between inflammatory markers, endothelial activation markers, and carotid intima-media thickness in HIV-infected patients receiving antiretroviral therapy,” Clinical Infectious Diseases, vol. 49, no. 7, pp. 1119–1127, 2009.
[8]
X. Cheng, M. Kinosaki, R. Murali, and M. I. Greene, “The TNF receptor superfamily: role in immune inflammation and bone formation,” Immunologic Research, vol. 27, no. 2-3, pp. 287–294, 2003.
[9]
D. Stejskal, J. Bartek, R. Pastorková, V. R?zicka, I. Oral, and D. Horalík, “Osteoprotegerin, RANK, RANKL,” Biomedical Papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia, vol. 145, no. 2, pp. 61–64, 2001.
[10]
H. L. Wright, H. S. McCarthy, J. Middleton, and M. J. Marshall, “RANK, RANKL and osteoprotegerin in bone biology and disease,” Current Reviews in Musculoskeletal Medicine, vol. 2, no. 1, pp. 56–64, 2009.
[11]
B. F. Boyce and L. Xing, “Functions of RANKL/RANK/OPG in bone modeling and remodeling,” Archives of Biochemistry and Biophysics, vol. 473, no. 2, pp. 139–146, 2008.
[12]
L. C. Hofbauer and M. Schoppet, “Clinical implications of the osteoprotegerin/RANKL/RANK system for bone and vascular diseases,” Journal of the American Medical Association, vol. 292, no. 4, pp. 490–495, 2004.
[13]
S. Kiechl, P. Werner, M. Knoflach, M. Furtner, J. Willeit, and G. Schett, “The osteoprotegerin/RANK/RANKL system: a bone key to vascular disease,” Expert Review of Cardiovascular Therapy, vol. 4, no. 6, pp. 801–811, 2006.
[14]
P. Collin-Osdoby, “Regulation of vascular calcification by osteoclast regulatory factors RANKL and osteoprotegerin,” Circulation Research, vol. 95, no. 11, pp. 1046–1057, 2004.
[15]
A. van Campenhout and J. Golledge, “Osteoprotegerin, vascular calcification and atherosclerosis,” Atherosclerosis, vol. 204, no. 2, pp. 321–329, 2009.
[16]
S. M. Grundy, H. B. Brewer Jr., J. I. Cleeman, S. C. Smith Jr., and C. Lenfant, “Definition of metabolic syndrome: Report of the National Heart, Lung, and Blood Institute/American Heart Association Conference on Scientific Issues Related to Definition,” Circulation, vol. 109, no. 3, pp. 433–438, 2004.
[17]
C. R. Hamilton-Craig, D. Friedman, and S. Achenbach, “Cardiac computed tomography-evidence, limitations and clinical application,” Heart Lung and Circulation, vol. 21, no. 2, pp. 70–81, 2012.
[18]
G. D'Ettorre, M. Francone, M. Mancone et al., “Significant coronary stenosis detected by coronary computed angiography in asymptomatic HIV infected subjects,” Journal of Infection, vol. 64, no. 1, pp. 82–88, 2012.
[19]
M. D. Cerqueira, N. J. Weissman, V. Dilsizian et al., “Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart. A statement for healthcare professionals from the Cardiac Imaging Committee of the Council on Clinical Cardiology of the American Heart Association,” The international journal of cardiovascular imaging, vol. 18, no. 1, pp. 539–542, 2002.
[20]
W. G. Austen, J. E. Edwards, R. L. Frye et al., “A reporting system on patients evaluated for coronary artery disease. Report of the Ad Hoc Committee for Grading of Coronary Artery Disease, Council on Cardiovascular Surgery, American Heart Association,” Circulation, vol. 5, pp. 15–40, 1975.
[21]
S. B. King 3rd, S. C. Smith Jr., D. A. Morrison, et al., “Focused update of the ACC/AHA/SCAI, 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association task force on practice guidelines: 2007 Writing group to review new evidence and update the ACC/AHA/SCAI, 2005 guideline update for percutaneous coronary intervention, writing on behalf of the 2005 writing committee,” Circulation, vol. 117, pp. 261–295, 2008.
[22]
M. R. Patel, G. J. Dehmer, J. W. Hirshfeld, P. K. Smith, and J. A. Spertus, “ACCF/SCAI/STS/AATS/AHA/ASNC appropriateness criteria for coronary revascularization. A Report by the American College of Cardiology Foundation Appropriateness Criteria Task Force, Society for Cardiovascular Angiography and Interventions, Society of Thoracic Surgeons, American Association for Thoracic Surgery, American Heart Association, and the American Society of Nuclear,” Journal of the American College of Cardiology, vol. 53, no. 6, pp. 530–553, 2009.
[23]
J. Lo, S. Abbara, L. Shturman et al., “Increased prevalence of subclinical coronary atherosclerosis detected by coronary computed tomography angiography in hiv-infected men,” AIDS, vol. 24, no. 2, pp. 243–253, 2010.
[24]
M. W. Lorenz, C. Stephan, A. Harmjanz et al., “Both long-term HIV infection and highly active antiretroviral therapy are independent risk factors for early carotid atherosclerosis,” Atherosclerosis, vol. 196, no. 2, pp. 720–726, 2008.
[25]
S. G. Deeks, “Immune dysfunction, inflammation, and accelerated aging in patients on antiretroviral therapy,” Topics in HIV Medicine, vol. 17, no. 4, pp. 118–123, 2009.
[26]
W. Lieb, P. Gona, M. G. Larson et al., “Biomarkers of the osteoprotegerin pathway: clinical correlates, subclinical disease, incident cardiovascular disease, and mortality,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 30, no. 9, pp. 1849–1854, 2010.
[27]
B. J. Bennett, M. Scatena, E. A. Kirk et al., “Osteoprotegerin inactivation accelerates advanced atherosclerotic lesion progression and calcification in older ApoE-/- mice,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 26, no. 9, pp. 2117–2124, 2006.
[28]
F. Montecucco, S. Steffens, and F. Mach, “The immune response is involved in atherosclerotic plaque calcification: could the RANKL/RANK/OPG system be a marker of plaque instability?” Clinical & Developmental Immunology, vol. 2007, Article ID 75805, 8 pages, 2007.
[29]
A. Quercioli, G. Luciano Viviani, F. Dallegri, F. MacH, and F. Montecucco, “Receptor activator of nuclear factor kappaB ligand/osteoprotegerin pathway is a promising target to reduce atherosclerotic plaque calcification,” Critical Pathways in Cardiology, vol. 9, no. 4, pp. 227–230, 2010.
[30]
A. Vik, E. B. Mathiesen, J. Brox et al., “Serum osteoprotegerin is a predictor for incident cardiovascular disease and mortality in a general population: The Troms? Study,” Journal of Thrombosis and Haemostasis, vol. 9, no. 4, pp. 638–644, 2011.
[31]
M. Schoppet, A. M. Sattler, J. R. Schaefer, M. Herzum, B. Maisch, and L. Hofbauer, “Increased osteoprotegerin serum levels in men with coronary artery disease,” Journal of Clinical Endocrinology and Metabolism, vol. 88, no. 3, pp. 1024–1028, 2003.
[32]
J. J. Hwang, J. Wei, S. Abbara, S. K. Grinspoon, and J. Lo, “Receptor activator of nuclear factor-κB ligand (RANKL) and its relationship to coronary atherosclerosis in HIV patients,” Journal of Acquired Immune Deficiency Syndromes, vol. 61, no. 3, pp. 359–363, 2012.