Biochemistry (Moscow)

, Volume 83, Issue 12–13, pp 1437–1447 | Cite as

Cytomegalovirus Infection in Cardiovascular Diseases

  • A. M. LebedevaEmail author
  • A. V. Shpektor
  • E. Yu. Vasilieva
  • L. B. Margolis


Atherosclerosis underlies the development of many cardiovascular diseases that continue to hold a leading place among the causes of death in developed countries. The role of activated immune cells in atherosclerosis progression has been convincingly demonstrated, but the mechanism of their action remains poorly investigated. Since atherosclerosis is associated with chronic inflammatory response, involvement of viral and bacterial infections in atherogenesis has been examined. A special place among the infectious agents is held by human herpesviruses as the most common persistent viruses in human population coupled to chronic inflammation during atherosclerosis. We found that activation of cytomegalovirus (CMV, human herpesvirus 5) infection is associated with the emergence of acute coronary syndrome, which is in a good agreement with the data on productive CMV infection published elsewhere. In this review, we discuss the data obtained by us and other researchers regarding the role of cytomegalovirus infection and related potential mechanisms resulting in the expansion of atherosclerotic plaques during ischemic heart disease and stroke, including virus transfer to immune and endothelial cells via extracellular vesicles. In particular, the data presented in the review demonstrate that virus spreading in the vascular wall triggers immune system activation in atherosclerotic plaques and causes endothelial dysfunction. Moreover, productive CMV infection in patients with acute myocardial infarction correlates with the extent of endothelial dysfunction. The mechanisms described by us and other researchers may explain the role of CMV infection in atherosclerosis and development of ischemic heart disease.


atherosclerosis acute myocardial infarction stroke herpesvirus cytomegalovirus endothelial function 



acute myocardial infarction




extracellular vesicles


human her-pesvirus


human immunodeficiency virus


ischemic heart disease


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  1. 1.
    Libby, P., Okamoto, Y., Rocha, V. Z., and Folco, E. (2010) Inflammation in atherosclerosis: transition from theory to practice, Circ. J., 74, 213–220.CrossRefPubMedGoogle Scholar
  2. 2.
    Hartvigsen, K., Chou, M.–Y., Hansen, L. F., Shaw, P. X., Tsimikas, S., Binder, C. J., and Witztum, J. L. (2008) The role of innate immunity in atherogenesis, J. Lipid Res., 50, S388–S393.CrossRefPubMedGoogle Scholar
  3. 3.
    Andersson, J., Libby, P., and Hansson, G. K. (2010) Adaptive immunity and atherosclerosis, Clin. Immunol., 134, 33–46.CrossRefPubMedGoogle Scholar
  4. 4.
    Grivel, J.–C., Ivanova, O., Pinegina, N., Blank, P. S., Shpektor, A., Margolis, L. B., and Vasilieva, E. (2011) Activation of T lymphocytes in atherosclerotic plaques, Arterioscler. Thromb. Vasc. Biol., 31, 2929–2937.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Humphrey, L. L., Fu, R., Buckley, D. I., Freeman, M., and Helfand, M. (2008) Periodontal disease and coronary heart disease incidence: a systematic review and meta–analysis, J. Gen. Intern. Med., 23, 2079–2086.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Rosenfeld, M. E., and Campbell, L. A. (2011) Pathogens and atherosclerosis: update on the potential contribution of multiple infectious organisms to the pathogenesis of atherosclerosis, Thromb. Haemost., 106, 858–867.CrossRefPubMedGoogle Scholar
  7. 7.
    Mayr, M., Kiechl, S., Willeit, J., Wick, G., and Xu, Q. (2000) Infections, immunity, and atherosclerosis: associations of antibodies to Chlamydia pneumoniae, Helicobacter pylori, and cytomegalovirus with immune reactions to heat-shock protein 60 and carotid or femoral atherosclerosis, Circulation, 102, 833–839.PubMedGoogle Scholar
  8. 8.
    Espinola–Klein, C., Rupprecht, H. J., Blankenberg, S., Bickel, C., Kopp, H., Rippin, G., Victor, A., Hafner, G., Schlumberger, W., Meyer, J., and AtheroGene Investigators (2002) Impact of infectious burden on extent and long–term prognosis of atherosclerosis, Circulation, 105, 15–21.CrossRefPubMedGoogle Scholar
  9. 9.
    Haider, A. W., Wilson, P. W. F., Larson, M. G., Evans, J. C., Michelson, E. L., Wolf, P. A., O’Donnell, C. J., and Levy, D. (2002) The association of seropositivity to Helicobacter pylori, Chlamydia pneumoniae, and cytomegalovirus with risk of cardiovascular disease: a prospective study, J. Am. Coll. Cardiol., 40, 1408–1413.PubMedGoogle Scholar
  10. 10.
    Maniar, A., Ellis, C., Asmuth, D., Pollard, R., and Rutledge, J. (2013) HIV infection and atherosclerosis: evaluating the drivers of inflammation, Eur. J. Prev. Cardiol., 20, 720–728.CrossRefPubMedGoogle Scholar
  11. 11.
    Longenecker, C. T., Sullivan, C., and Baker, J. V. (2016) Immune activation and cardiovascular disease in chronic HIV infection, Curr. Opin. HIV AIDS, 11, 216–225.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Masia, M., Robledano, C., Ortiz de la Tabla, V., Antequera, P., Lopez, N., and Gutierrez, F. (2013) Increased carotid intima–media thickness associated with antibody responses to varicella–zoster virus and cytomegalovirus in HIV–infected patients, PLoS One, 8, e64327.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Hechter, R. C., Budoff, M., Hodis, H. N., Rinaldo, C. R., Jenkins, F. J., Jacobson, L. P., Kingsley, L. A., Taiwo, B., Post, W. S., Margolick, J. B., and Detels, R. (2012) Herpes simplex virus type 2 (HSV–2) as a coronary atherosclerosis risk factor in HIV–infected men: Multicenter AIDS Cohort Study, Atherosclerosis, 223, 433–436.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Stassen, F. R., Vega–Cordova, X., Vliegen, I., and Bruggeman, C. A. (2006) Immune activation following cytomegalovirus infection: more important than direct viral effects in cardiovascular disease? J. Clin. Virol., 35, 349–353.CrossRefPubMedGoogle Scholar
  15. 15.
    Krebs, P., Scandella, E., Bolinger, B., Engeler, D., Miller, S., and Ludewig, B. (2007) Chronic immune reactivity against persisting microbial antigen in the vasculature exacerbates atherosclerotic lesion formation, Arterioscler. Thromb. Vasc. Biol., 27, 2206–2213.CrossRefPubMedGoogle Scholar
  16. 16.
    Sorlie, P. D., Nieto, F. J., Adam, E., Folsom, A. R., Shahar, E., and Massing, M. (2000) A prospective study of cytomegalovirus, herpes simplex virus 1, and coronary heart disease: the atherosclerosis risk in communities (ARIC) study, Arch. Intern. Med., 160, 2027–2032.PubMedGoogle Scholar
  17. 17.
    Kutikhin, A. G., Yuzhalin, A. E., and Brusina, E. B. (2013) The role of Epstein–Barr virus in atherosclerosis and related diseases, in Viruses and Atherosclerosis (part of the Springer Briefs in Immunology, Vol. 4, Springer, New York, NY, pp. 21–33).CrossRefGoogle Scholar
  18. 18.
    Xenaki, E., Hassoulas, J., Apostolakis, S., Sourvinos, G., and Spandidos, D. A. (2009) Detection of cytomegalovirus in atherosclerotic plaques and nonatherosclerotic arteries, Angiology, 60, 504–508.CrossRefPubMedGoogle Scholar
  19. 19.
    Nunez, J., Chilet, M., Sanchis, J., Bodi, V., Nunez, E., Minana, G., Tormo, N., Clari, M. A., Pellicer, M., Chorro, F. J., Llacer, A., and Navarro, D. (2010) Prevalence and prognostic implications of active cytomegalovirus infection in patients with acute heart failure, Clin. Sci. (Lond.), 119, 443–452.CrossRefGoogle Scholar
  20. 20.
    Nikitskaya, E. A., Grivel’, Zh.–Sh., Ivanova, O. I., Lebedeva, A. M., Shpektor, A. V., Margolis, L. B., and Vasil’eva, E. Yu. (2014) Examination of herpesvirus DNA prevalence in post–mortem coronary arteries from patients with acute myocardial infarction, Kreat. Kardiol., No. 4, 50–62.Google Scholar
  21. 21.
    Gredmark, S., Jonasson, L., Van Gosliga, D., Ernerudh, J., and Soderberg–Naucler, C. (2007) Active cytomegalovirus replication in patients with coronary disease, Scand. Cardiovasc. J., 41, 230–234.CrossRefPubMedGoogle Scholar
  22. 22.
    Nikitskaya, E., Lebedeva, A., Ivanova, O., Maryukhnich, E., Shpektor, A., Grivel, J., Margolis, L., and Vasilieva, E. (2016) Cytomegalovirus–productive infection is associated with acute coronary syndrome, J. Am. Heart Assoc., 5, e003759.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Gyorgy, B., Szabo, T. G., Pasztoi, M., Pal, Z., Misjak, P., Aradi, B., Laszlo, V., Pallinger, E., Pap, E., Kittel, A., Nagy, G., Falus, A., and Buzas, E. I. (2011) Membrane vesicles, current state–of–the–art: emerging role of extracellular vesicles, Cell. Mol. Life Sci., 68, 2667–2688.PubMedGoogle Scholar
  24. 24.
    Ahmed, W., Philip, P. S., Tariq, S., and Khan, G. (2014) Epstein–Barr virus–encoded small RNAs (EBERs) are present in fractions related to exosomes released by EBV–transformed cells, PLoS One, 9, e99163.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Jung, C., Sorensson, P., Saleh, N., Arheden, H., Ryden, L., and Pernow, J. (2012) Circulating endothelial and platelet derived microparticles reflect the size of myocardium at risk in patients with ST–elevation myocardial infarction, Atherosclerosis, 221, 226–231.CrossRefPubMedGoogle Scholar
  26. 26.
    Vagida, M., Arakelyan, A., Lebedeva, A., Grivel, J.–C., Shpektor, A., Vasilieva, E., and Margolis, L. (2017) Flow analysis of individual blood extracellular vesicles in acute coronary syndrome, Platelets, 28, 165–173.CrossRefPubMedGoogle Scholar
  27. 27.
    Gimbrone, M. A., and Garcia–Cardena, G. (2016) Endothelial cell dysfunction and the pathobiology of atherosclerosis, Circ. Res., 118, 620–636.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Jensen, H. A., and Mehta, J. L. (2016) Endothelial cell dysfunction as a novel therapeutic target in atherosclerosis, Expert Rev. Cardiovasc. Ther., 14, 1021–1033.CrossRefPubMedGoogle Scholar
  29. 29.
    Manchurov, V., Ryazankina, N., Khmara, T., Skrypnik, D., Reztsov, R., Vasilieva, E., and Shpektor, A. (2014) Remote ischemic preconditioning and endothelial function in patients with acute myocardial infarction and primary PCI, Am. J. Med., 127, 670–673.CrossRefPubMedGoogle Scholar
  30. 30.
    Fichtlscherer, S., Breuer, S., and Zeiher, A. M. (2004) Prognostic value of systemic endothelial dysfunction in patients with acute coronary syndromes: further evidence for the existence of the “vulnerable” patient, Circulation, 110, 1926–1932.CrossRefPubMedGoogle Scholar
  31. 31.
    Vasilieva, E., Urazovskaya, I., Skrypnik, D., and Shpektor, A. (2009) Total occlusion of the infarct–related coronary artery correlates with brachial artery flow–mediated dilation in patients with ST–elevation myocardial infarction, Acute Card Care, 11, 155–159.CrossRefPubMedGoogle Scholar
  32. 32.
    Xu, Y., Arora, R. C., Hiebert, B. M., Lerner, B., Szwajcer, A., McDonald, K., Rigatto, C., Komenda, P., Sood, M. M., and Tangri, N. (2014) Non–invasive endothelial function testing and the risk of adverse outcomes: a systematic review and meta–analysis, Eur. Heart J. Cardiovasc. Imaging, 15, 736–746.CrossRefPubMedGoogle Scholar
  33. 33.
    Guazzi, M., Reina, G., Gripari, P., Tumminello, G., Vicenzi, M., and Arena, R. (2009) Prognostic value of flow–mediated dilatation following myocardial infarction, Int. J. Cardiol., 132, 45–50.CrossRefPubMedGoogle Scholar
  34. 34.
    Khoretonenko, M. V., Leskov, I. L., Jennings, S. R., Yurochko, A. D., and Stokes, K. Y. (2010) Cytomegalovirus infection leads to microvascular dysfunction and exacerbates hypercholesterolemia–induced responses, Am. J. Pathol., 177, 2134–2144.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Gombos, R. B., Brown, J. C., Teefy, J., Gibeault, R. L., Conn, K. L., Schang, L. M., and Hemmings, D. G. (2013) Vascular dysfunction in young, mid–aged and aged mice with latent cytomegalovirus infections, Am. J. Physiol. Heart Circ. Physiol., 304, H183–H194.CrossRefPubMedGoogle Scholar
  36. 36.
    Simmonds, J., Fenton, M., Dewar, C., Ellins, E., Storry, C., Cubitt, D., Deanfield, J., Klein, N., Halcox, J., and Burch, M. (2008) Endothelial dysfunction and cytomegalovirus replication in pediatric heart transplantation, Circulation, 117, 2657–2661.CrossRefPubMedGoogle Scholar
  37. 37.
    Grahame–Clarke, C., Chan, N. N., Andrew, D., Ridgway, G. L., Betteridge, D. J., Emery, V., Colhoun, H. M., and Vallance, P. (2003) Human cytomegalovirus seropositivity is associated with impaired vascular function, Circulation, 108, 678–683.CrossRefPubMedGoogle Scholar
  38. 38.
    Guetta, E., Guetta, V., Shibutani, T., and Epstein, S. E. (1997) Monocytes harboring cytomegalovirus: interactions with endothelial cells, smooth muscle cells, and oxidized low–density lipoprotein. Possible mechanisms for activating virus delivered by monocytes to sites of vascular injury, Circ. Res., 81, 8–16.PubMedGoogle Scholar
  39. 39.
    Skarman, P. J., Rahbar, A., Xie, X., and Soderberg–Naucler, C. (2006) Induction of polymorphonuclear leukocyte response by human cytomegalovirus, Microbes Infect., 8, 1592–1601.CrossRefPubMedGoogle Scholar
  40. 40.
    Adler, B., and Sinzger, C. (2009) Endothelial cells in HCMV infection: one host cell out of many or a crucial target for virus spread? Thromb. Haemost., 102, 1057–1063.CrossRefPubMedGoogle Scholar
  41. 41.
    Reinhardt, B., Mertens, T., Mayrbeyrle, U., Frank, H., Luske, A., Schierling, K., and Waltenberger, J. (2005) HCMV infection of human vascular smooth muscle cells leads to enhanced expression of functionally intact PDGF β–receptor, Cardiovasc. Res., 67, 151–160.CrossRefPubMedGoogle Scholar
  42. 42.
    Vliegen, I., Duijvestijn, A., Stassen, F., and Bruggeman, C. (2004) Murine cytomegalovirus infection directs macrophage differentiation into a pro–inflammatory immune phenotype: implications for atherogenesis, Microbes Infect., 6, 1056–1062.CrossRefPubMedGoogle Scholar
  43. 43.
    Smith, P. D., Saini, S. S., Raffeld, M., Manischewitz, J. F., and Wahl, S. M. (1992) Cytomegalovirus induction of tumor necrosis factor–alpha by human monocytes and mucosal macrophages, J. Clin. Invest., 90, 1642–1648.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Zhou, X., Stemme, S., and Hansson, G. K. (1996) Evidence for a local immune response in atherosclerosis. CD4+ T cells infiltrate lesions of apolipoprotein–E–deficient mice, Am. J. Pathol., 149, 359–366.PubMedPubMedCentralGoogle Scholar
  45. 45.
    Carlquist, J. F., Muhlestein, J. B., Horne, B. D., Hart, N. I., Lim, T., Habashi, J., Anderson, J. G., and Anderson, J. L. (2004) Cytomegalovirus stimulated mRNA accumulation and cell surface expression of the oxidized LDL scavenger receptor, CD36, Atherosclerosis, 177, 53–59.CrossRefPubMedGoogle Scholar
  46. 46.
    Kabanova, A., Marcandalli, J., Zhou, T., Bianchi, S., Baxa, U., Tsybovsky, Y., Lilleri, D., Silacci–Fregni, C., Foglierini, M., Fernandez–Rodriguez, B. M., Druz, A., Zhang, B., Geiger, R., Pagani, M., Sallusto, F., Kwong, P. D., Corti, D., Lanzavecchia, A., and Perez, L. (2016) Platelet–derived growth factor–a receptor is the cellular receptor for human cytomegalovirus gHgLgO trimer, Nat. Microbiol., 1, 16082.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Zhou, Y. F., Yu, Z. X., Wanishsawad, C., Shou, M., and Epstein, S. E. (1999) The immediate early gene products of human cytomegalovirus increase vascular smooth muscle cell migration, proliferation, and expression of PDGF β–receptor, Biochem. Biophys. Res. Commun., 256, 608–613.CrossRefPubMedGoogle Scholar
  48. 48.
    Tanaka, K., Zou, J. P., Takeda, K., Ferrans, V. J., Sandford, G. R., Johnson, T. M., Finkel, T., and Epstein, S. E. (1999) Effects of human cytomegalovirus immediate–early proteins on p53–mediated apoptosis in coronary artery smooth muscle cells, Circulation, 99, 1656–1659.CrossRefPubMedGoogle Scholar
  49. 49.
    Straat, K., de Klark, R., Gredmark–Russ, S., Eriksson, P., and Soderberg–Naucler, C. (2009) Infection with human cytomegalovirus alters the MMP–9/TIMP–1 balance in human macrophages, J. Virol., 83, 830–835.CrossRefPubMedGoogle Scholar
  50. 50.
    Van de Berg, P. J., Yong, S.–L., Remmerswaal, E. B., van Lier, R. A., and ten Berge, I. J. (2012) Cytomegalovirus–induced effector T cells cause endothelial cell damage, Clin. Vaccine Immunol., 19, 772–779.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Lunardi, C., Dolcino, M., Peterlana, D., Bason, C., Navone, R., Tamassia, N., Tinazzi, E., Beri, R., Corrocher, R., and Puccetti, A. (2007) Endothelial cells’ activation and apoptosis induced by a subset of antibodies against human cytomegalovirus: relevance to the pathogenesis of atherosclerosis, PLoS One, 2, e473.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Popovic, M., Smiljanic, K., Dobutovic, B., Syrovets, T., Simmet, T., and Isenovic, E. R. (2012) Human cytomegalovirus infection and atherothrombosis, J. Thromb. Thrombolysis, 33, 160–172.CrossRefPubMedGoogle Scholar
  53. 53.
    Ghielmetti, M., Millard, A.–L., Haeberli, L., Bossart, W., Seebach, J. D., Schneider, M. K., and Mueller, N. J. (2009) Human CMV infection of porcine endothelial cells increases adhesion receptor expression and human leukocyte recruitment, Transplantation, 87, 1792–1800.CrossRefPubMedGoogle Scholar
  54. 54.
    Bolovan–Fritts, C. A., Trout, R. N., and Spector, S. A. (2007) High T–cell response to human cytomegalovirus induces chemokine–mediated endothelial cell damage, Blood, 110, 1857–1863.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Bentz, G. L., Jarquin–Pardo, M., Chan, G., Smith, M. S., Sinzger, C., and Yurochko, A. D. (2006) Human cytomegalovirus (HCMV) infection of endothelial cells promotes naive monocyte extravasation and transfer of productive virus to enhance hematogenous dissemination of HCMV, J. Virol., 80, 11539–11555.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Walker, J. D., Maier, C. L., and Pober, J. S. (2009) Cytomegalovirus–infected human endothelial cells can stimulate allogeneic CD4+ memory T cells by releasing antigenic exosomes, J. Immunol., 182, 1548–1559.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Rozmyslowicz, T., Majka, M., Kijowski, J., Murphy, S. L., Conover, D. O., Poncz, M., Ratajczak, J., Gaulton, G. N., and Ratajczak, M. Z. (2003) Platelet–and megakaryocyte–derived microparticles transfer CXCR4 receptor to CXCR4–null cells and make them susceptible to infection by X4–HIV, AIDS, 17, 33–42.CrossRefPubMedGoogle Scholar
  58. 58.
    Dargan, D. J., and Subak–Sharpe, J. H. (1997) The effect of herpes simplex virus type 1 L–particles on virus entry, replication, and the infectivity of naked herpesvirus DNA, Virology, 239, 378–388.PubMedGoogle Scholar
  59. 59.
    Ramakrishnaiah, V., Thumann, C., Fofana, I., Habersetzer, F., Pan, Q., de Ruiter, P. E., Willemsen, R., Demmers, J. A., Stalin Raj, V., Jenster, G., Kwekkeboom, J., Tilanus, H. W., Haagmans, B. L., Baumert, T. F., and van der Laan, L. J. (2013) Exosome–mediated transmission of hepatitis C virus between human hepatoma Huh7.5 cells, Proc. Natl. Acad. Sci USA, 110, 13109–13113.CrossRefPubMedGoogle Scholar
  60. 60.
    Wiley, R. D., and Gummuluru, S. (2006) Immature dendritic cell–derived exosomes can mediate HIV–1 trans infection, Proc. Natl. Acad. Sci. USA, 103, 738–743.CrossRefPubMedGoogle Scholar
  61. 61.
    Meckes, D. G., and Raab–Traub, N. (2011) Microvesicles and viral infection, J. Virol., 85, 12844–12854.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Suades, R., Padro, T., Alonso, R., Mata, P., and Badimon, L. (2013) Lipid–lowering therapy with statins reduces microparticle shedding from endothelium, platelets and inflammatory cells, Thromb. Haemost., 110, 366–377.CrossRefPubMedGoogle Scholar
  63. 63.
    Ponroy, N., Taveira, A., Mueller, N. J., and Millard, A.–L. (2015) Statins demonstrate a broad anti–cytomegalovirus activity in vitro in ganciclovir–susceptible and resistant strains, J. Med. Virol., 87, 141–153.CrossRefPubMedGoogle Scholar
  64. 64.
    Yi, L., Wang, J.–W., Zhao, R.–G., Tuo, H.–Z., Feng, Z.–J., and Wang, D.–X. (2010) Fluvastatin’s effect on atherogenesis in apolipoprotein–E knockout mice infected by cytomegalovirus, Zhonghua Shi Yan He Lin Chuang Bing Du Xue Za Zhi, 24, 433–435.PubMedGoogle Scholar
  65. 65.
    Khoretonenko, M. V., Brunson, J. L., Senchenkov, E., Leskov, I. L., Marks, C. R., and Stokes, K. Y. (2014) Platelets, acting in part via P–selectin, mediate cytomegalovirus–induced microvascular dysfunction, AJP Hear. Circ. Physiol., 307, H1745–H1753.Google Scholar
  66. 66.
    Wang, X., Li, Y., Huang, C., Zhang, R., Guo, H., Chen, H., and Wang, H. (2005) Changes of serum soluble Pselectin and tumor necrotic factor–alpha in patients with CMV induced acute coronary syndrome, Zhonghua Shi Yan He Lin Chuang Bing Du Xue Za Zhi, 19, 149–151.PubMedGoogle Scholar
  67. 67.
    Soroceanu, L., Akhavan, A., and Cobbs, C. S. (2008) Platelet–derived growth factor–a receptor activation is required for human cytomegalovirus infection, Nature, 455, 391–395.CrossRefPubMedGoogle Scholar
  68. 68.
    Rahbar, A., and Soderberg–Naucler, C. (2005) Human cytomegalovirus infection of endothelial cells triggers platelet adhesion and aggregation, J. Virol., 79, 2211–2220.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Neumann, F. J., Kastrati, A., Miethke, T., Pogatsa–Murray, G., Seyfarth, M., and Schomig, A. (2000) Previous cytomegalovirus infection and risk of coronary thrombotic events after stent placement, Circulation, 101, 11–13.CrossRefPubMedGoogle Scholar
  70. 70.
    Squizzato, A., Gerdes, V. E., and Buller, H. R. (2005) Effects of human cytomegalovirus infection on the coagulation system, Thromb. Haemost., 93, 403–410.CrossRefPubMedGoogle Scholar
  71. 71.
    Alfawaz, A. (2013) Cytomegalovirus–related corneal endotheliitis: a review article, Saudi J. Ophthalmol. Off. J. Saudi Ophthalmol. Soc., 27, 47–49.CrossRefGoogle Scholar
  72. 72.
    Fan, N.–W., Chung, Y.–C., Liu, Y.–C., Liu, C. J., Kuo, Y.–S., and Lin, P.–Y. (2016) Long–term topical ganciclovir and corticosteroids preserve corneal endothelial function in cytomegalovirus corneal endotheliitis, Cornea, 35, 596–601.CrossRefPubMedGoogle Scholar
  73. 73.
    Khairy, P., Rinfret, S., Tardif, J.–C., Marchand, R., Shapiro, S., Brophy, J., and Dupuis, J. (2003) Absence of association between infectious agents and endothelial function in healthy young men, Circulation, 107, 1966–1971.CrossRefPubMedGoogle Scholar
  74. 74.
    Oshima, T., Ozono, R., Yano, Y., Oishi, Y., Teragawa, H., Higashi, Y., Yoshizumi, M., and Kambe, M. (2005) Association of Helicobacter pylori infection with systemic inflammation and endothelial dysfunction in healthy male subjects, J. Am. Coll. Cardiol., 45, 1219–1222.CrossRefPubMedGoogle Scholar
  75. 75.
    Haarala, A., Kahonen, M., Lehtimaki, T., Aittoniemi, J., Jylhava, J., Hutri–Kahonen, N., Taittonen, L., Laitinen, T., Juonala, M., Viikari, J., Raitakari, O. T., and Hurme, M. (2012) Relation of high cytomegalovirus antibody titres to blood pressure and brachial artery flow–mediated dilation in young men: the cardiovascular risk in young Finns study, Clin. Exp. Immunol., 167, 309–316.CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Petrakopoulou, P., Kubrich, M., Pehlivanli, S., Meiser, B., Reichart, B., von Scheidt, W., and Weis, M. (2004) Cytomegalovirus infection in heart transplant recipients is associated with impaired endothelial function, Circulation, 110, II207–II212.CrossRefPubMedGoogle Scholar
  77. 77.
    Weis, M., Kledal, T. N., Lin, K. Y., Panchal, S. N., Gao, S. Z., Valantine, H. A., Mocarski, E. S., and Cooke, J. P. (2004) Cytomegalovirus infection impairs the nitric oxide synthase pathway: role of asymmetric dimethylarginine in transplant arteriosclerosis, Circulation, 109, 500–505.CrossRefPubMedGoogle Scholar
  78. 78.
    Prasad, A., Zhu, J., Halcox, J. P., Waclawiw, M. A., Epstein, S. E., and Quyyumi, A. A. (2002) Predisposition to atherosclerosis by infections: role of endothelial dysfunction, Circulation, 106, 184–190.CrossRefPubMedGoogle Scholar
  79. 79.
    DuRose, J. B., Li, J., Chien, S., and Spector, D. H. (2012) Infection of vascular endothelial cells with human cytomegalovirus under fluid shear stress reveals preferential entry and spread of virus in flow conditions simulating atheroprone regions of the artery, J. Virol., 86, 13745–13755.CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Hsich, E., Zhou, Y. F., Paigen, B., Johnson, T. M., Burnett, M. S., and Epstein, S. E. (2001) Cytomegalovirus infection increases development of atherosclerosis in apolipoprotein–E knockout mice, Atherosclerosis, 156, 23–28.CrossRefPubMedGoogle Scholar
  81. 81.
    Betjes, M. G. H., de Wit, E. E., Weimar, W., and Litjens, N. H. (2010) Circulating pro–inflammatory CD4posCD28null T cells are independently associated with cardiovascular disease in ESRD patients, Nephrol. Dial. Transplant., 25, 3640–3646.CrossRefPubMedGoogle Scholar
  82. 82.
    Roizman, B., and Whitley, R. J. (2013) An inquiry into the molecular basis of HSV latency and reactivation, Annu. Rev. Microbiol., 67, 355–374.CrossRefPubMedGoogle Scholar
  83. 83.
    Gyorkey, F., Melnick, J. L., Guinn, G. A., Gyorkey, P., and DeBakey, M. E. (1984) Herpesviridae in the endothelial and smooth muscle cells of the proximal aorta in arteriosclerotic patients, Exp. Mol. Pathol., 40, 328–339.CrossRefPubMedGoogle Scholar
  84. 84.
    Yamashiroya, H. M., Ghosh, L., Yang, R., and Robertson, A. L. (1988) Herpesviridae in the coronary arteries and aorta of young trauma victims, Am. J. Pathol., 130, 71–79.PubMedPubMedCentralGoogle Scholar
  85. 85.
    Melnick, J. L., Hu, C., Burek, J., Adam, E., and DeBakey, M. E. (1994) Cytomegalovirus DNA in arterial walls of patients with atherosclerosis, J. Med. Virol., 42, 170–174.CrossRefPubMedGoogle Scholar
  86. 86.
    Nerheim, P. L., Meier, J. L., Vasef, M. A., Li, W.–G., Hu, L., Rice, J. B., Gavrila, D., Richenbacher, W. E., and Weintraub, N. L. (2004) Enhanced cytomegalovirus infection in atherosclerotic human blood vessels, Am. J. Pathol., 164, 589–600.CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Westphal, M., Lautenschlager, I., Backhaus, C., Loginov, R., Kundt, G., Oberender, H., Stamm, C., and Steinhoff, G. (2006) Cytomegalovirus and proliferative signals in the vascular wall of CABG patients, Thorac. Cardiovasc. Surg., 54, 219–226.CrossRefPubMedGoogle Scholar
  88. 88.
    Ibrahim, A. I., Obeid, M. T., Jouma, M. J., Moasis, G. A., Al–Richane, W. L., Kindermann, I., Boehm, M., Roemer, K., Mueller–Lantzsch, N., and Gartner, B. C. (2005) Detection of herpes simplex virus, cytomegalovirus and Epstein–Barr virus DNA in atherosclerotic plaques and in unaffected bypass grafts, J. Clin. Virol., 32, 29–32.PubMedGoogle Scholar
  89. 89.
    Shi, Y., and Tokunaga, O. (2002) Herpesvirus (HSV–1, EBV and CMV) infections in atherosclerotic compared with non–atherosclerotic aortic tissue, Pathol. Int., 52, 31–39.PubMedGoogle Scholar
  90. 90.
    Radke, P. W., Merkelbach–Bruse, S., Dorge, H., Naami, A., Vogel, G., Messmer, B. J., Handt, S., and Hanrath, P. (2001) Direct evidence of cytomegalovirus in coronary atheromas of patients with advance coronary heart artery disease, Med. Klin. (Munich), 96, 129–134.CrossRefGoogle Scholar
  91. 91.
    Horvath, R., Cerny, J., Benedik, J., Hokl, J., and Jelinkova, I. (2000) The possible role of human cytomegalovirus (HCMV) in the origin of atherosclerosis, J. Clin. Virol., 16, 17–24.CrossRefPubMedGoogle Scholar
  92. 92.
    Izadi, M., Zamani, M. M., Sabetkish, N., Abolhassani, H., Saadat, S. H., Taheri, S., and Dabiri, H. (2014) The probable role of cytomegalovirus in acute myocardial infarction, Jundishapur J. Microbiol., 7, e9253.PubMedPubMedCentralGoogle Scholar
  93. 93.
    Liu, R., Moroi, M., Yamamoto, M., Kubota, T., Ono, T., Funatsu, A., Komatsu, H., Tsuji, T., Hara, H., Hara, H., Nakamura, M., Hirai, H., and Yamaguchi, T. (2006) Presence and severity of Chlamydia pneumoniae and cytomegalovirus infection in coronary plaques are associated with acute coronary syndromes, Int. Heart J., 47, 511–519.CrossRefPubMedGoogle Scholar
  94. 94.
    Ridker, P. M., Hennekens, C. H., Stampfer, M. J., and Wang, F. (1999) Prospective study of herpes simplex virus, cytomegalovirus, and the risk of future myocardial infarction and stroke, Circulation, 98, 2796–2799.Google Scholar
  95. 95.
    Hagiwara, N., Toyoda, K., Inoue, T., Shimada, H., Ibayashi, S., Iida, M., and Okada, Y. (2007) Lack of association between infectious burden and carotid atherosclerosis in japanese patients, J. Stroke Cerebrovasc. Dis., 16, 145–152.CrossRefPubMedGoogle Scholar
  96. 96.
    Virok, D., Kis, Z., Kari, L., Barzo, P., Sipka, R., Burian, K., Nelson, D. E., Jackel, M., Kerenyi, T., Bodosi, M., Gonczol, E., and Endresz, V. (2006) Chlamydophila pneumoniae and human cytomegalovirus in atherosclerotic carotid plaques–combined presence and possible interactions, Acta Microbiol. Immunol. Hung., 53, 35–50.CrossRefPubMedGoogle Scholar
  97. 97.
    Adam, E., Melnick, J. L., and DeBakey, M. E. (1997) Cytomegalovirus infection and atherosclerosis, Cent. Eur. J. Public Health, 5, 99–106.PubMedGoogle Scholar
  98. 98.
    Nieto, F. J., Adam, E., Sorlie, P., Farzadegan, H., Melnick, J. L., Comstock, G. W., and Szklo, M. (1996) Cohort study of cytomegalovirus infection as a risk factor for carotid intimal–medial thickening, a measure of subclinical athero–sclerosis, Circulation, 94, 922–927.Google Scholar
  99. 99.
    Jeong, S. J., Ku, N. S., Han, S. H., Choi, J. Y., Kim, C. O., Song, Y. G., and Kim, J. M. (2015) Anti–cytomegalovirus antibody levels are associated with carotid atherosclerosis and inflammatory cytokine production in elderly Koreans, Clin. Chim. Acta, 445, 65–69.CrossRefPubMedGoogle Scholar
  100. 100.
    Parrinello, C. M., Sinclair, E., Landay, A. L., Lurain, N., Sharrett, A. R., Gange, S. J., Xue, X., Hunt, P. W., Deeks, S. G., Hodis, H. N., and Kaplan, R. C. (2012) Cytomegalovirus immunoglobulin G antibody is associated with subclinical carotid artery disease among HIV–infected women, J. Infect. Dis., 205, 1788–1796.CrossRefPubMedPubMedCentralGoogle Scholar
  101. 101.
    Roberts, E. T., Haan, M. N., Dowd, J. B., and Aiello, A. E. (2010) Cytomegalovirus antibody levels, inflammation, and mortality among elderly Latinos over 9 years of follow–up, Am. J. Epidemiol., 172, 363–371.PubMedGoogle Scholar
  102. 102.
    Simanek, A. M., Dowd, J. B., Pawelec, G., Melzer, D., Dutta, A., and Aiello, A. E. (2011) Seropositivity to cytomegalovirus, inflammation, all–cause and cardiovascular disease–related mortality in the United States, PLoS One, 6, e16103.PubMedGoogle Scholar
  103. 103.
    Rabczynski, M., Fiodorenko–Dumas, Z., Mastej, K., Dumas, I., Adamiec, R., and Paprocka–Borowicz, M. (2015) A relationship between serological markers of chronic C. pneumoniae and CMV infection and hsp60 in patients with atherosclerotic carotid stenosis, Acta Biochim. Pol., 62, 89–95.CrossRefPubMedGoogle Scholar
  104. 104.
    Guech–Ongey, M., Brenner, H., Twardella, D., Hahmann, H., and Rothenbacher, D. (2006) Role of cytomegalovirus sero–status in the development of secondary cardiovascular events in patients with coronary heart disease under special consideration of diabetes, Int. J. Cardiol., 111, 98–103.CrossRefPubMedGoogle Scholar
  105. 105.
    Zhang, J., Liu, Y., Sun, H., Li, S., Xiong, H., Yang, Z., Xiang, G., and Jiang, X. (2015) High human cytomegalovirus IgG level is associated with increased incidence of diabetic atherosclerosis in type 2 diabetes mellitus patients, Med. Sci. Monit., 21, 4102–4110.CrossRefPubMedPubMedCentralGoogle Scholar
  106. 106.
    Gattone, M., Iacoviello, L., Colombo, M., Castelnuovo, A. D., Soffiantino, F., Gramoni, A., Picco, D., Benedetta, M., and Giannuzzi, P. (2001) Chlamydia pneumoniae and cytomegalovirus seropositivity, inflammatory markers, and the risk of myocardial infarction at a young age, Am. Heart J., 142, 633–640.Google Scholar
  107. 107.
    Pesonen, E., El–Segaier, M., Persson, K., Puolakkainen, M., Sarna, S., Ohlin, H., and Pussinen, P. J. (2009) Infections as a stimulus for coronary occlusion, obstruction, or acute coronary syndromes, Ther. Adv. Cardiovasc. Dis., 3, 447–454.CrossRefPubMedGoogle Scholar
  108. 108.
    Ji, Y.–N., An, L., Zhan, P., and Chen, X.–H. (2012) Cytomegalovirus infection and coronary heart disease risk: a meta–analysis, Mol. Biol. Rep., 39, 6537–6546.CrossRefPubMedGoogle Scholar
  109. 109.
    Strandberg, T. E., Pitkala, K. H., and Tilvis, R. S. (2009) Cytomegalovirus antibody level and mortality among community–dwelling older adults with stable cardiovascular disease, JAMA, 301, 380–382.CrossRefPubMedGoogle Scholar
  110. 110.
    Savva, G. M., Pachnio, A., Kaul, B., Morgan, K., Huppert, F. A., Brayne, C., Moss, P. A., and Medical Research Council Cognitive Function and Ageing Study (2013) Cytomegalovirus infection is associated with increased mortality in the older population, Aging Cell, 12, 381–387.CrossRefPubMedGoogle Scholar
  111. 111.
    Wang, G. C., Kao, W. H., Murakami, P., Xue, Q. L., Chiou, R. B., Detrick, B., McDyer, J. F., Semba, R. D., Casolaro, V., Walston, J. D., and Fried, L. P. (2010) Cytomegalovirus infection and the risk of mortality and frailty in older women: a prospective observational cohort study, Am. J. Epidemiol., 171, 1144–1152.CrossRefPubMedPubMedCentralGoogle Scholar
  112. 112.
    Timoteo, A., Ferreira, J., Paixao, P., Aguiar, C., Teles, R., Cardoso, E., Silva, J. A., Marques, T., and Seabra–Gomes, R. (2003) Serologic markers for cytomegalovirus in acute coronary syndromes, Rev. Port. Cardiol., 22, 619–31.PubMedGoogle Scholar
  113. 113.
    Epstein, S. E., Zhou, Y. F., and Zhu, J. (1999) Potential role of cytomegalovirus in the pathogenesis of restenosis and atherosclerosis, Am. Heart J., 138, S476–478.CrossRefPubMedGoogle Scholar
  114. 114.
    Al–Ghamdi, A., Jiman–Fatani, A. A., and El–Banna, H. (2011) Role of Chlamydia pneumoniae, Helicobacter pylori and cytomegalovirus in coronary artery disease, Pak. J. Pharm. Sci., 24, 95–101.PubMedGoogle Scholar
  115. 115.
    Adler, S. P., Hur, J. K., Wang, J. B., and Vetrovec, G. W. (1998) Prior infection with cytomegalovirus is not a major risk factor for angiographically demonstrated coronary artery atherosclerosis, J. Infect. Dis., 177, 209–212.CrossRefPubMedGoogle Scholar
  116. 116.
    Prince, H. E., and Lape–Nixon, M. (2014) Role of cytomegalovirus (CMV) IgG avidity testing in diagnosing primary CMV infection during pregnancy, Clin. Vaccine Immunol., 21, 1377–1384.CrossRefPubMedPubMedCentralGoogle Scholar
  117. 117.
    Yi, L., Wang, D.–X., and Feng, Z.–J. (2008) Detection of human cytomegalovirus in atherosclerotic carotid arteries in humans, J. Formos. Med. Assoc., 107, 774–781.CrossRefPubMedGoogle Scholar
  118. 118.
    Chen, R., Xiong, S., Yang, Y., Fu, W., Wang, Y., and Ge, J. (2003) The relationship between human cytomegalovirus infection and atherosclerosis development, Mol. Cell. Biochem., 249, 91–96.CrossRefPubMedGoogle Scholar
  119. 119.
    Lee, Y.–L., Liu, C.–E., Cho, W.–L., Kuo, C.–L., Cheng, W.–L., Huang, C.–S., and Liu, C.–S. (2014) Presence of cytomegalovirus DNA in leucocytes is associated with increased oxidative stress and subclinical atherosclerosis in healthy adults, Biomarkers, 19, 109–113.CrossRefPubMedGoogle Scholar
  120. 120.
    Hu, W., Liu, J., Niu, S., Liu, M., Shi, H., and Wei, L. (2001) Prevalence of CMV in arterial walls and leukocytes in patients with atherosclerosis, Chin. Med. J. (Engl.), 114, 1208–1210.Google Scholar
  121. 121.
    Halvorsen, D. S., Karlsen, J., Noto, A.–T. W., Mathiesen, E. B., Njolstad, I., Gutteberg, T. J., Vorland, L. H., and Hansen, J.–B. (2007) No detectable Chlamydia pneumoniae and cytomegalovirus DNA in leukocytes in subjects with echolucent and echogenic carotid artery plaques, Int. J. Cardiol., 117, 388–394.CrossRefPubMedGoogle Scholar
  122. 122.
    Schlitt, A., Blankenberg, S., Weise, K., Gartner, B. C., Mehrer, T., Peetz, D., Meyer, J., Darius, H., and Rupprecht, H. J. (2005) Herpesvirus DNA (Epstein–Barr virus, herpes simplex virus, cytomegalovirus) in circulating monocytes of patients with coronary artery disease, Acta Cardiol., 60, 605–610.PubMedGoogle Scholar
  123. 123.
    Smieja, M., Cronin, L., Levine, M., Goldsmith, C. H., Yusuf, S., and Mahony, J. B. (2001) Previous exposure to Chlamydia pneumoniae, Helicobacter pylori and other infections in Canadian patients with ischemic heart disease, Can. J. Cardiol., 17, 270–276.PubMedGoogle Scholar
  124. 124.
    Gerna, G., Percivalle, E., Baldanti, F., Sozzani, S., Lanzarini, P., Genini, E., Lilleri, D., and Revello, M. G. (2000) Human cytomegalovirus replicates abortively in polymorphonuclear leukocytes after transfer from infected endothelial cells via transient microfusion events, J. Virol., 74, 5629–5638.CrossRefPubMedPubMedCentralGoogle Scholar
  125. 125.
    Tanabe, K., Tokumoto, T., Ishikawa, N., Koyama, I., Takahashi, K., Fuchinoue, S., Kawai, T., Koga, S., Yagisawa, T., Toma, H., Ota, K., and Nakajima, H. (1997) Comparative study of cytomegalovirus (CMV) antigenemia assay, polymerase chain reaction, serology, and shell vial assay in the early diagnosis and monitoring of CMV infection after renal transplantation, Transplantation, 64, 1721–1725.PubMedGoogle Scholar
  126. 126.
    Gimeno, C., Solano, C., Latorre, J. C., Hernandez–Boluda, J. C., Clari, M. A., Remigia, M. J., Furio, S., Calabuig, M., Tormo, N., and Navarro, D. (2008) Quantification of DNA in plasma by an automated realtime PCR assay (cytomegalovirus PCR kit) for surveillance of active cytomegalovirus infection and guidance of preemptive therapy for allogeneic hematopoietic stem cell transplant recipients, J. Clin. Microbiol., 46, 3311–3318.CrossRefPubMedPubMedCentralGoogle Scholar
  127. 127.
    Lebedeva, A. M., Mariukhnich, E. V., Grievel, Z. S., Nikitskaya, E. A., Albakova, T. M., Albakova, R. M., Ryzhkova, E. V., Shpektor, A. V., Margolis, L. B., and Vasilieva, E. Y. (2018) Cytomegalovirus infection and endothelial function in patients with acute myocardial infarction, Kardiologiya, 17, 41–52.CrossRefGoogle Scholar
  128. 128.
    Firth, C., Harrison, R., Ritchie, S., Wardlaw, J., Ferro, C. J., Starr, J. M., Deary, I. J., and Moss, P. (2016) Cytomegalovirus infection is associated with an increase in systolic blood pressure in older individuals, QJM, 109, 595–600.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Pleiades Publishing, Inc. 2018

Authors and Affiliations

  • A. M. Lebedeva
    • 1
    Email author
  • A. V. Shpektor
    • 1
  • E. Yu. Vasilieva
    • 1
  • L. B. Margolis
    • 2
  1. 1.Department of Cardiology and Laboratory of Atherothrombosis, A. I. Evdokimov Moscow State University of Medicine and DentistryMinistry of Health of the Russian FederationMoscowRussia
  2. 2.Section on Intercellular Interactions, Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNational Institutes of HealthBethesdaUSA

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