Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Inflammatory processes in cardiovascular disease: a route to targeted therapies

Nature Reviews Cardiology volume 14, pages 133–144 (2017)Cite this article

Subjects

A Corrigendum to this article was published on 16 March 2017

This article has been updated

Key Points

  • Inflammation and its failure to resolve are firmly established as central to the development and complications of several cardiovascular diseases

  • Targeting of inflammatory processes in experimental models has been demonstrated to be beneficial in attenuating myocardial and arterial injury, reducing disease progression, and promoting healing, but clinical translation has been disappointing

  • Current tools to measure 'inflammation' are nonspecific and represent downstream sequelae of biological processes, but provide little insight into disease state, site, or activation pathways

  • Contemporary molecular techniques (such as proteomics and gene-expression analysis) improve our ability to characterize underlying biological processes, and identify activation pathways as biomarkers and as a basis to develop new therapeutics

  • Noninvasive imaging tools enable the identification of activation of specific pathways and their sites, and can be used to monitor response to therapy

Abstract

Inflammatory processes are firmly established as central to the development and complications of cardiovascular diseases. Elevated levels of inflammatory markers have been shown to be predictive of future cardiovascular events. The specific targeting of these processes in experimental models has been shown to attenuate myocardial and arterial injury, reduce disease progression, and promote healing. However, the translation of these observations and the demonstration of clear efficacy in clinical practice have been disappointing. A major limitation might be that tools currently used to measure 'inflammation' are insufficiently precise and do not provide information about disease site and activity, or discriminate between functionally important activation pathways. The challenge, therefore, is to make measures of inflammation that are more meaningful, and which can guide specific targeted therapies. In this Review, we consider the roles of inflammatory processes in the related pathologies of atherosclerosis and acute myocardial infarction, by providing an evaluation of the known and emerging inflammatory pathways. We highlight contemporary techniques to characterize and quantify inflammation, and consider how they might be used to guide specific treatments. Finally, we discuss emerging opportunities in the field, including their current limitations and challenges that are the focus of ongoing study.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Biological pathways central to the pathogenesis of acute myocardial infarction (AMI).
Figure 2: Biological processes central to the pathogenesis of atherosclerosis.

Similar content being viewed by others

Change history

  • 16 March 2017

    In the version of this article initially published online and in print, there were some inaccuracies in Table 1. These errors have been corrected for the HTML and PDF versions of the article.

References

  1. Hansson, G. K. Inflammation, atherosclerosis, and coronary artery disease. N. Engl. J. Med. 352, 1685–1695 (2005).

    CAS  PubMed  Google Scholar 

  2. Frangogiannis, N. G. Regulation of the inflammatory response in cardiac repair. Circ. Res. 110, 159–173 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Libby, P. Inflammation and cardiovascular disease mechanisms. Am. J. Clin. Nutr. 83, 456S–460S (2006).

    Article  CAS  PubMed  Google Scholar 

  4. Biasucci, L. M. et al. Increasing levels of interleukin (IL)-1Ra and IL-6 during the first 2 days of hospitalization in unstable angina are associated with increased risk of in-hospital coronary events. Circulation 99, 2079–2084 (1999).

    Article  CAS  PubMed  Google Scholar 

  5. Valgimigli, M. et al. Tumor necrosis factor-α receptor 1 is a major predictor of mortality and new-onset heart failure in patients with acute myocardial infarction: the Cytokine-Activation and Long-Term Prognosis in Myocardial Infarction (C-ALPHA) study. Circulation 111, 863–870 (2005).

    Article  CAS  PubMed  Google Scholar 

  6. Ridker, P. M. Clinical application of C-reactive protein for cardiovascular disease detection and prevention. Circulation 107, 363–369 (2003).

    Article  PubMed  Google Scholar 

  7. Nahrendorf, M., Pittet, M. J. & Swirski, F. K. Monocytes: protagonists of infarct inflammation and repair after myocardial infarction. Circulation 121, 2437–2445 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Leuschner, F. et al. Therapeutic siRNA silencing in inflammatory monocytes in mice. Nat. Biotechnol. 29, 1005–1010 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Panizzi, P. et al. Impaired infarct healing in atherosclerotic mice with Ly-6Chi monocytosis. J. Am. Coll. Cardiol. 55, 1629–1638 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Moore, K. J., Sheedy, F. J. & Fisher, E. A. Macrophages in atherosclerosis: a dynamic balance. Nat. Rev. Immunol. 13, 709–721 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Bentzon, J. F., Otsuka, F., Virmani, R. & Falk, E. Mechanisms of plaque formation and rupture. Circ. Res. 114, 1852–1866 (2014).

    Article  CAS  PubMed  Google Scholar 

  12. Jia, H. et al. In vivo diagnosis of plaque erosion and calcified nodule in patients with acute coronary syndrome by intravascular optical coherence tomography. J. Am. Coll. Cardiol. 62, 1748–1758 (2013).

    Article  PubMed  Google Scholar 

  13. Prondzinsky, R. et al. Interleukin-6, -7, -8 and -10 predict outcome in acute myocardial infarction complicated by cardiogenic shock. Clin. Res. Cardiol. 101, 375–384 (2012).

    Article  CAS  PubMed  Google Scholar 

  14. Dimitrijevic, O., Stojcevski, B. D., Ignjatovic, S. & Singh, N. M. Serial measurements of C-reactive protein after acute myocardial infarction in predicting one-year outcome. Int. Heart J. 47, 833–842 (2006).

    Article  CAS  PubMed  Google Scholar 

  15. von Hundelshausen, P. & Weber, C. Platelets as immune cells: bridging inflammation and cardiovascular disease. Circ. Res. 100, 27–40 (2007).

    Article  CAS  PubMed  Google Scholar 

  16. Vinten-Johansen, J. Involvement of neutrophils in the pathogenesis of lethal myocardial reperfusion injury. Cardiovasc. Res. 61, 481–497 (2004).

    Article  CAS  PubMed  Google Scholar 

  17. Nahrendorf, M. et al. The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions. J. Exp. Med. 204, 3037–3047 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Nourshargh, S., Renshaw, S. A. & Imhof, B. A. Reverse migration of neutrophils: where, when, how, and why? Trends Immunol. 37, 273–286 (2016).

    Article  CAS  PubMed  Google Scholar 

  19. Yan, X. et al. Temporal dynamics of cardiac immune cell accumulation following acute myocardial infarction. J. Mol. Cell. Cardiol. 62, 24–35 (2013).

    Article  CAS  PubMed  Google Scholar 

  20. Martin, J. L., Mestril, R., Hilal-Dandan, R., Brunton, L. L. & Dillmann, W. H. Small heat shock proteins and protection against ischemic injury in cardiac myocytes. Circulation 96, 4343–4348 (1997).

    Article  CAS  PubMed  Google Scholar 

  21. Andrassy, M. et al. High-mobility group box-1 in ischemia-reperfusion injury of the heart. Circulation 117, 3216–3226 (2008).

    Article  CAS  PubMed  Google Scholar 

  22. Jiang, D. et al. Regulation of lung injury and repair by Toll-like receptors and hyaluronan. Nat. Med. 11, 1173–1179 (2005).

    Article  CAS  PubMed  Google Scholar 

  23. Schoneveld, A. H. et al. Atherosclerotic lesion development and Toll like receptor 2 and 4 responsiveness. Atherosclerosis 197, 95–104 (2008).

    Article  CAS  PubMed  Google Scholar 

  24. Beg, A. A. Endogenous ligands of Toll-like receptors: implications for regulating inflammatory and immune responses. Trends Immunol. 23, 509–512 (2002).

    Article  CAS  PubMed  Google Scholar 

  25. Frantz, S. et al. Toll4 (TLR4) expression in cardiac myocytes in normal and failing myocardium. J. Clin. Invest. 104, 271–280 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Oyama, J. et al. Reduced myocardial ischemia-reperfusion injury in toll-like receptor 4-deficient mice. Circulation 109, 784–789 (2004).

    Article  CAS  PubMed  Google Scholar 

  27. Riad, A. et al. Toll-like receptor-4 modulates survival by induction of left ventricular remodeling after myocardial infarction in mice. J. Immunol. 180, 6954–6961 (2008).

    Article  CAS  PubMed  Google Scholar 

  28. Satoh, M. et al. Activated toll-like receptor 4 in monocytes is associated with heart failure after acute myocardial infarction. Int. J. Cardiol. 109, 226–234 (2006).

    Article  PubMed  Google Scholar 

  29. Shishido, T. et al. Toll-like receptor-2 modulates ventricular remodeling after myocardial infarction. Circulation 108, 2905–2910 (2003).

    Article  CAS  PubMed  Google Scholar 

  30. Ruparelia, N. et al. Acute myocardial infarction activates distinct inflammation and proliferation pathways in circulating monocytes, prior to recruitment, and identified through conserved transcriptional responses in mice and humans. Eur. Heart J. 36, 1923–1934 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Takahashi, M. NLRP3 inflammasome as a novel player in myocardial infarction. Int. Heart J. 55, 101–105 (2014).

    Article  CAS  PubMed  Google Scholar 

  32. Mezzaroma, E. et al. The inflammasome promotes adverse cardiac remodeling following acute myocardial infarction in the mouse. Proc. Natl Acad. Sci. USA 108, 19725–19730 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Dreyer, W. J. et al. Kinetics of C5a release in cardiac lymph of dogs experiencing coronary artery ischemia-reperfusion injury. Circ. Res. 71, 1518–1524 (1992).

    Article  CAS  PubMed  Google Scholar 

  34. Birdsall, H. H. et al. Complement C5a, TGF-β1, and MCP-1, in sequence, induce migration of monocytes into ischemic canine myocardium within the first one to five hours after reperfusion. Circulation 95, 684–692 (1997).

    Article  CAS  PubMed  Google Scholar 

  35. Distelmaier, K. et al. Local complement activation triggers neutrophil recruitment to the site of thrombus formation in acute myocardial infarction. Thromb. Haemost. 102, 564–572 (2009).

    Article  CAS  PubMed  Google Scholar 

  36. Torzewski, J. et al. Complement-induced release of monocyte chemotactic protein-1 from human smooth muscle cells: a possible initiating event in atherosclerotic lesion formation. Arterioscler. Thromb. Vasc. Biol. 16, 673–677 (1996).

    Article  CAS  PubMed  Google Scholar 

  37. Lakshminarayanan, V. et al. Reactive oxygen intermediates induce monocyte chemotactic protein-1 in vascular endothelium after brief ischemia. Am. J. Pathol. 159, 1301–1311 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Sellak, H., Franzini, E., Hakim, J. & Pasquier, C. Reactive oxygen species rapidly increase endothelial ICAM-1 ability to bind neutrophils without detectable upregulation. Blood 83, 2669–2677 (1994).

    CAS  PubMed  Google Scholar 

  39. Shingu, M. et al. Activation of complement in normal serum by hydrogen peroxide and hydrogen peroxide-related oxygen radicals produced by activated neutrophils. Clin. Exp. Immunol. 90, 72–78 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Maekawa, N. et al. Improved myocardial ischemia/reperfusion injury in mice lacking tumor necrosis factor-α. J. Am. Coll. Cardiol. 39, 1229–1235 (2002).

    Article  CAS  PubMed  Google Scholar 

  41. Kurrelmeyer, K. M. et al. Endogenous tumor necrosis factor protects the adult cardiac myocyte against ischemic-induced apoptosis in a murine model of acute myocardial infarction. Proc. Natl Acad. Sci. USA 97, 5456–5461 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Saxena, A. et al. IL-1 induces proinflammatory leukocyte infiltration and regulates fibroblast phenotype in the infarcted myocardium. J. Immunol. 191, 4838–4848 (2013).

    Article  CAS  PubMed  Google Scholar 

  43. Miyao, Y. et al. Elevated plasma interleukin-6 levels in patients with acute myocardial infarction. Am. Heart J. 126, 1299–1304 (1993).

    Article  CAS  PubMed  Google Scholar 

  44. Dawn, B. et al. IL-6 plays an obligatory role in late preconditioning via JAK–STAT signaling and upregulation of iNOS and COX-2. Cardiovasc. Res. 64, 61–71 (2004).

    Article  CAS  PubMed  Google Scholar 

  45. Swirski, F. K. et al. Identification of splenic reservoir monocytes and their deployment to inflammatory sites. Science 325, 612–616 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Kim, E. J., Kim, S., Kang, D. O. & Seo, H. S. Metabolic activity of the spleen and bone marrow in patients with acute myocardial infarction evaluated by 18f-fluorodeoxyglucose positron emission tomograpic imaging. Circ. Cardiovasc. Imaging 7, 454–460 (2014).

    Article  PubMed  Google Scholar 

  47. Dutta, P. et al. Myocardial infarction accelerates atherosclerosis. Nature 487, 325–329 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Weinberger, T. & Schulz, C. Myocardial infarction: a critical role of macrophages in cardiac remodeling. Front. Physiol. 6, 107 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  49. Tsujioka, H. et al. Impact of heterogeneity of human peripheral blood monocyte subsets on myocardial salvage in patients with primary acute myocardial infarction. J. Am. Coll. Cardiol. 54, 130–138 (2009).

    Article  PubMed  Google Scholar 

  50. Horckmans, M. et al. Neutrophils orchestrate post-myocardial infarction healing by polarizing macrophages towards a reparative phenotype. Eur. Heart J. http://dx.doi.org/10.1093/eurheartj/ehw002 (2016).

  51. Levick, S. P. et al. Cardiac mast cells: the centrepiece in adverse myocardial remodelling. Cardiovasc. Res. 89, 12–19 (2011).

    Article  CAS  PubMed  Google Scholar 

  52. Hofmann, U. et al. Activation of CD4+ T lymphocytes improves wound healing and survival after experimental myocardial infarction in mice. Circulation 125, 1652–1663 (2012).

    Article  CAS  PubMed  Google Scholar 

  53. Liuzzo, G. et al. Monoclonal T-cell proliferation and plaque instability in acute coronary syndromes. Circulation 101, 2883–2888 (2000).

    Article  CAS  PubMed  Google Scholar 

  54. Ammirati, E. et al. Expansion of T-cell receptor ζdim effector T cells in acute coronary syndromes. Arterioscler. Thromb. Vasc. Biol. 28, 2305–2311 (2008).

    Article  CAS  PubMed  Google Scholar 

  55. Zal, B. et al. Heat-shock protein 60-reactive CD4+CD28null T cells in patients with acute coronary syndromes. Circulation 109, 1230–1235 (2004).

    Article  CAS  PubMed  Google Scholar 

  56. Liuzzo, G. et al. Unusual CD4+CD28null T lymphocytes and recurrence of acute coronary events. J. Am. Coll. Cardiol. 50, 1450–1458 (2007).

    Article  CAS  PubMed  Google Scholar 

  57. Mor, A., Luboshits, G., Planer, D., Keren, G. & George, J. Altered status of CD4+CD25+ regulatory T cells in patients with acute coronary syndromes. Eur. Heart J. 27, 2530–2537 (2006).

    Article  CAS  PubMed  Google Scholar 

  58. Blancke, F. et al. Systemic inflammation and reperfusion injury in patients with acute myocardial infarction. Mediators Inflamm. 2005, 385–389 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  59. Kohsaka, S. et al. Systemic inflammatory response syndrome after acute myocardial infarction complicated by cardiogenic shock. Arch. Intern. Med. 165, 1643–1650 (2005).

    Article  PubMed  Google Scholar 

  60. Debrunner, M. et al. Proinflammatory cytokines in acute myocardial infarction with and without cardiogenic shock. Clin. Res. Cardiol. 97, 298–305 (2008).

    Article  CAS  PubMed  Google Scholar 

  61. Leuschner, F. et al. Angiotensin-converting enzyme inhibition prevents the release of monocytes from their splenic reservoir in mice with myocardial infarction. Circ. Res. 107, 1364–1373 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Majmudar, M. D. et al. Polymeric nanoparticle PET/MR imaging allows macrophage detection in atherosclerotic plaques. Circ. Res. 112, 755–761 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. 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 107, 499–511 (2003).

    Article  PubMed  Google Scholar 

  64. Johnson, B. D. et al. Serum amyloid A as a predictor of coronary artery disease and cardiovascular outcome in women: the National Heart, Lung, and Blood Institute-Sponsored Women's Ischemia Syndrome Evaluation (WISE). Circulation 109, 726–732 (2004).

    Article  CAS  PubMed  Google Scholar 

  65. Danesh, J. et al. C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. N. Engl. J. Med. 350, 1387–1397 (2004).

    Article  CAS  PubMed  Google Scholar 

  66. Haim, M., Boyko, V., Goldbourt, U., Battler, A. & Behar, S. Predictive value of elevated white blood cell count in patients with preexisting coronary heart disease: the Bezafibrate Infarction Prevention Study. Arch. Intern. Med. 164, 433–439 (2004).

    Article  PubMed  Google Scholar 

  67. Lee, C. D. et al. White blood cell count and incidence of coronary heart disease and ischemic stroke and mortality from cardiovascular disease in African-American and White men and women: atherosclerosis risk in communities study. Am. J. Epidemiol. 154, 758–764 (2001).

    Article  CAS  PubMed  Google Scholar 

  68. Berk, B. C., Weintraub, W. S. & Alexander, R. W. Elevation of C-reactive protein in “active” coronary artery disease. Am. J. Cardiol. 65, 168–172 (1990).

    Article  CAS  PubMed  Google Scholar 

  69. Ridker, P. M., Cushman, M., Stampfer, M. J., Tracy, R. P. & Hennekens, C. H. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N. Engl. J. Med. 336, 973–979 (1997).

    Article  CAS  PubMed  Google Scholar 

  70. Ridker, P. M., Cushman, M., Stampfer, M. J., Tracy, R. P. & Hennekens, C. H. Plasma concentration of C-reactive protein and risk of developing peripheral vascular disease. Circulation 97, 425–428 (1998).

    Article  CAS  PubMed  Google Scholar 

  71. Zacho, J. et al. Genetically elevated C-reactive protein and ischemic vascular disease. N. Engl. J. Med. 359, 1897–1908 (2008).

    Article  CAS  PubMed  Google Scholar 

  72. Hirschfield, G. M. et al. Transgenic human C-reactive protein is not proatherogenic in apolipoprotein E-deficient mice. Proc. Natl Acad. Sci. USA 102, 8309–8314 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Passlick, B., Flieger, D. & Ziegler-Heitbrock, H. W. Identification and characterization of a novel monocyte subpopulation in human peripheral blood. Blood 74, 2527–2534 (1989).

    CAS  PubMed  Google Scholar 

  74. Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci. USA 102, 15545–15550 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Deng, M. C. et al. Noninvasive discrimination of rejection in cardiac allograft recipients using gene expression profiling. Am. J. Transplant. 6, 150–160 (2006).

    Article  CAS  PubMed  Google Scholar 

  76. Golub, T. R. et al. Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. Science 286, 531–537 (1999).

    Article  CAS  PubMed  Google Scholar 

  77. van't Veer, L. J. et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature 415, 530–536 (2002).

    Article  CAS  Google Scholar 

  78. Bendall, S. C. et al. Single-cell mass cytometry of differential immune and drug responses across a human hematopoietic continuum. Science 332, 687–696 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Haas, B. et al. Proteomic analysis of plasma samples from patients with acute myocardial infarction identifies haptoglobin as a potential prognostic biomarker. J. Proteomics 75, 229–236 (2011).

    Article  CAS  PubMed  Google Scholar 

  80. Shah, S. H. & Newgard, C. B. Integrated metabolomics and genomics: systems approaches to biomarkers and mechanisms of cardiovascular disease. Circ. Cardiovasc. Genet. 8, 410–419 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Stegemann, C. et al. Lipidomics profiling and risk of cardiovascular disease in the prospective population-based Bruneck study. Circulation 129, 1821–1831 (2014).

    Article  CAS  PubMed  Google Scholar 

  82. Malik, Z. A. et al. Cardiac myocyte exosomes: stability, HSP60, and proteomics. Am. J. Physiol. Heart Circ. Physiol. 304, H954–H965 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Valadi, H. et al. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat. Cell Biol. 9, 654–659 (2007).

    Article  CAS  PubMed  Google Scholar 

  84. Muralidharan-Chari, V., Clancy, J. W., Sedgwick, A. & D'Souza-Schorey, C. Microvesicles: mediators of extracellular communication during cancer progression. J. Cell Sci. 123, 1603–1611 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Wickman, G. R. et al. Blebs produced by actin–myosin contraction during apoptosis release damage-associated molecular pattern proteins before secondary necrosis occurs. Cell Death Differ. 20, 1293–1305 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Wickman, G., Julian, L. & Olson, M. F. How apoptotic cells aid in the removal of their own cold dead bodies. Cell Death Differ. 19, 735–742 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Tans, G. et al. Comparison of anticoagulant and procoagulant activities of stimulated platelets and platelet-derived microparticles. Blood 77, 2641–2648 (1991).

    CAS  PubMed  Google Scholar 

  88. Taraboletti, G. et al. Shedding of the matrix metalloproteinases MMP-2, MMP-9, and MT1-MMP as membrane vesicle-associated components by endothelial cells. Am. J. Pathol. 160, 673–680 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Boulanger, C. M. et al. Circulating microparticles from patients with myocardial infarction cause endothelial dysfunction. Circulation 104, 2649–2652 (2001).

    Article  CAS  PubMed  Google Scholar 

  90. Deng, Z. B. et al. Adipose tissue exosome-like vesicles mediate activation of macrophage-induced insulin resistance. Diabetes 58, 2498–2505 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Mesri, M. & Altieri, D. C. Endothelial cell activation by leukocyte microparticles. J. Immunol. 161, 4382–4387 (1998).

    CAS  PubMed  Google Scholar 

  92. Martin, S. et al. Shed membrane particles from T lymphocytes impair endothelial function and regulate endothelial protein expression. Circulation 109, 1653–1659 (2004).

    Article  PubMed  Google Scholar 

  93. Quiat, D. & Olson, E. N. MicroRNAs in cardiovascular disease: from pathogenesis to prevention and treatment. J. Clin. Invest. 123, 11–18 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Zhang, Y. et al. Secreted monocytic miR-150 enhances targeted endothelial cell migration. Mol. Cell 39, 133–144 (2010).

    Article  CAS  PubMed  Google Scholar 

  95. Bye, A. et al. Circulating microRNAs predict future fatal myocardial infarction in healthy individuals — the HUNT study. J. Mol. Cell. Cardiol. 97, 162–168 (2016).

    Article  CAS  PubMed  Google Scholar 

  96. Yilmaz, A. et al. Imaging of myocardial infarction using ultrasmall superparamagnetic iron oxide nanoparticles: a human study using a multi-parametric cardiovascular magnetic resonance imaging approach. Eur. Heart J. 34, 462–475 (2013).

    Article  CAS  PubMed  Google Scholar 

  97. Alam, S. R. et al. Ultrasmall superparamagnetic particles of iron oxide in patients with acute myocardial infarction: early clinical experience. Circ. Cardiovasc. Imaging 5, 559–565 (2012).

    Article  PubMed  Google Scholar 

  98. Lee, W. W. et al. PET/MRI of inflammation in myocardial infarction. J. Am. Coll. Cardiol. 59, 153–163 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Jung, K. et al. Endoscopic time-lapse imaging of immune cells in infarcted mouse hearts. Circ. Res. 112, 891–899 (2013).

    Article  CAS  PubMed  Google Scholar 

  100. Wollenweber, T. et al. Characterizing the inflammatory tissue response to acute myocardial infarction by clinical multimodality noninvasive imaging. Circ. Cardiovasc. Imaging 7, 811–818 (2014).

    Article  PubMed  Google Scholar 

  101. Rischpler, C. et al. Prospective evaluation of 18F-fluorodeoxyglucose uptake in postischemic myocardium by simultaneous positron emission tomography/magnetic resonance imaging as a prognostic marker of functional outcome. Circ. Cardiovasc. Imaging 9, e004316 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  102. McAteer, M. A. et al. In vivo magnetic resonance imaging of acute brain inflammation using microparticles of iron oxide. Nat. Med. 13, 1253–1258 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. McAteer, M. A. et al. A leukocyte-mimetic magnetic resonance imaging contrast agent homes rapidly to activated endothelium and tracks with atherosclerotic lesion macrophage content. Arterioscler. Thromb. Vasc. Biol. 32, 1427–1435 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Akhtar, A. M. et al. In vivo quantification of VCAM-1 expression in renal ischemia reperfusion injury using non-invasive magnetic resonance molecular imaging. PLoS ONE 5, e12800 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Sahul, Z. H. et al. Targeted imaging of the spatial and temporal variation of matrix metalloproteinase activity in a porcine model of postinfarct remodeling: relationship to myocardial dysfunction. Circ. Cardiovasc. Imaging 4, 381–391 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  106. Ross, R. Atherosclerosis — an inflammatory disease. N. Engl. J. Med. 340, 115–126 (1999).

    Article  CAS  PubMed  Google Scholar 

  107. Choudhury, R. P., Lee, J. M. & Greaves, D. R. Mechanisms of disease: macrophage-derived foam cells emerging as therapeutic targets in atherosclerosis. Nat. Clin. Pract. Cardiovasc. Med. 2, 309–315 (2005).

    Article  CAS  PubMed  Google Scholar 

  108. Tabas, I., Williams, K. J. & Boren, J. Subendothelial lipoprotein retention as the initiating process in atherosclerosis: update and therapeutic implications. Circulation 116, 1832–1844 (2007).

    Article  CAS  PubMed  Google Scholar 

  109. van Furth, R. & Cohn, Z. A. The origin and kinetics of mononuclear phagocytes. J. Exp. Med. 128, 415–435 (1968).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Cybulsky, M. I. & Gimbrone, M. A. Jr. Endothelial expression of a mononuclear leukocyte adhesion molecule during atherogenesis. Science 251, 788–791 (1991).

    Article  CAS  PubMed  Google Scholar 

  111. Tacke, F. et al. Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques. J. Clin. Invest. 117, 185–194 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Combadiere, C. et al. Combined inhibition of CCL2, CX3CR1, and CCR5 abrogates Ly6Chi and Ly6Clo monocytosis and almost abolishes atherosclerosis in hypercholesterolemic mice. Circulation 117, 1649–1657 (2008).

    Article  CAS  PubMed  Google Scholar 

  113. Heidt, T. et al. Chronic variable stress activates hematopoietic stem cells. Nat. Med. 20, 754–758 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Ley, K., Miller, Y. I. & Hedrick, C. C. Monocyte and macrophage dynamics during atherogenesis. Arterioscler. Thromb. Vasc. Biol. 31, 1506–1516 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Robbins, C. S. et al. Local proliferation dominates lesional macrophage accumulation in atherosclerosis. Nat. Med. 19, 1166–1172 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Khallou-Laschet, J. et al. Macrophage plasticity in experimental atherosclerosis. PLoS ONE 5, e8852 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Schissel, S. L. et al. Rabbit aorta and human atherosclerotic lesions hydrolyze the sphingomyelin of retained low-density lipoprotein. Proposed role for arterial-wall sphingomyelinase in subendothelial retention and aggregation of atherogenic lipoproteins. J. Clin. Invest. 98, 1455–1464 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Barthwal, M. K. et al. Fluid-phase pinocytosis of native low density lipoprotein promotes murine M-CSF differentiated macrophage foam cell formation. PLoS ONE 8, e58054 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Shao, B. Z., Han, B. Z., Zeng, Y. X., Su, D. F. & Liu, C. The roles of macrophage autophagy in atherosclerosis. Acta Pharmacol. Sin. 37, 150–156 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Chan, K. F., Siegel, M. R. & Lenardo, J. M. Signaling by the TNF receptor superfamily and T cell homeostasis. Immunity 13, 419–422 (2000).

    Article  CAS  PubMed  Google Scholar 

  121. Ait-Oufella, H., Taleb, S., Mallat, Z. & Tedgui, A. Recent advances on the role of cytokines in atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 31, 969–979 (2011).

    Article  CAS  PubMed  Google Scholar 

  122. Gharavi, N. M. et al. Role of the Jak/STAT pathway in the regulation of interleukin-8 transcription by oxidized phospholipids in vitro and in atherosclerosis in vivo. J. Biol. Chem. 282, 31460–31468 (2007).

    Article  CAS  PubMed  Google Scholar 

  123. Michel, J. B., Virmani, R., Arbustini, E. & Pasterkamp, G. Intraplaque haemorrhages as the trigger of plaque vulnerability. Eur. Heart J. 32, 1977–1985 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  124. Hellings, W. E. et al. Composition of carotid atherosclerotic plaque is associated with cardiovascular outcome: a prognostic study. Circulation 121, 1941–1950 (2010).

    Article  PubMed  Google Scholar 

  125. Vink, A. et al. HIF-1α expression is associated with an atheromatous inflammatory plaque phenotype and upregulated in activated macrophages. Atherosclerosis 195, e69–e75 (2007).

    Article  CAS  PubMed  Google Scholar 

  126. Sluimer, J. C. & Daemen, M. J. Novel concepts in atherogenesis: angiogenesis and hypoxia in atherosclerosis. J. Pathol. 218, 7–29 (2009).

    Article  PubMed  Google Scholar 

  127. Parathath, S. et al. Hypoxia is present in murine atherosclerotic plaques and has multiple adverse effects on macrophage lipid metabolism. Circ. Res. 109, 1141–1152 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Ugocsai, P. et al. HIF-1beta determines ABCA1 expression under hypoxia in human macrophages. Int. J. Biochem. Cell Biol. 42, 241–252 (2010).

    Article  CAS  PubMed  Google Scholar 

  129. Folco, E. et al. Hypoxia but not inflammation augments glucose uptake in human macrophages J. Am. Coll. Cardiol. 58, 603–614 (2011).

    Article  CAS  PubMed  Google Scholar 

  130. Rong, J. X., Shapiro, M., Trogan, E. & Fisher, E. A. Transdifferentiation of mouse aortic smooth muscle cells to a macrophage-like state after cholesterol loading. Proc. Natl Acad. Sci. USA 100, 13531–13536 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Feil, S. et al. Transdifferentiation of vascular smooth muscle cells to macrophage-like cells during atherogenesis. Circ. Res. 115, 662–667 (2014).

    Article  CAS  PubMed  Google Scholar 

  132. Shankman, L. S. et al. KLF4-dependent phenotypic modulation of smooth muscle cells has a key role in atherosclerotic plaque pathogenesis. Nat. Med. 21, 628–637 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Allahverdian, S., Chehroudi, A. C., McManus, B. M., Abraham, T. & Francis, G. A. Contribution of intimal smooth muscle cells to cholesterol accumulation and macrophage-like cells in human atherosclerosis. Circulation 129, 1551–1559 (2014).

    Article  CAS  PubMed  Google Scholar 

  134. Vengrenyuk, Y. et al. Cholesterol loading reprograms the microRNA-143/145–myocardin axis to convert aortic smooth muscle cells to a dysfunctional macrophage-like phenotype. Arterioscler. Thromb. Vasc. Biol. 35, 535–546 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Williams, K. J., Feig, J. E. & Fisher, E. A. Rapid regression of atherosclerosis: insights from the clinical and experimental literature. Nat. Clin. Pract. Cardiovasc. Med. 5, 91–102 (2008).

    Article  CAS  PubMed  Google Scholar 

  136. Nissen, S. E. et al. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N. Engl. J. Med. 352, 29–38 (2005).

    Article  CAS  PubMed  Google Scholar 

  137. Ridker, P. M. et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N. Engl. J. Med. 359, 2195–2207 (2008).

    Article  CAS  PubMed  Google Scholar 

  138. Semaan, H. B. et al. Soluble VCAM-1 and E-selectin, but not ICAM-1 discriminate endothelial injury in patients with documented coronary artery disease. Cardiology 93, 7–10 (2000).

    Article  CAS  PubMed  Google Scholar 

  139. 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 96, 4219–4225 (1997).

    Article  CAS  PubMed  Google Scholar 

  140. Blann, A. D., Lip, G. Y., Beevers, D. G. & McCollum, C. N. Soluble P-selectin in atherosclerosis: a comparison with endothelial cell and platelet markers. Thromb. Haemost. 77, 1077–1080 (1997).

    Article  CAS  PubMed  Google Scholar 

  141. Swirski, F. K., Weissleder, R. & Pittet, M. J. Heterogeneous in vivo behavior of monocyte subsets in atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 29, 1424–1432 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Schlitt, A. et al. CD14+CD16+ monocytes in coronary artery disease and their relationship to serum TNF-α levels. Thromb. Haemost. 92, 419–424 (2004).

    Article  CAS  PubMed  Google Scholar 

  143. Poitou, C. et al. CD14dimCD16+ and CD14+CD16+ monocytes in obesity and during weight loss: relationships with fat mass and subclinical atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 31, 2322–2330 (2011).

    Article  CAS  PubMed  Google Scholar 

  144. Feig, J. E. et al. Reversal of hyperlipidemia with a genetic switch favorably affects the content and inflammatory state of macrophages in atherosclerotic plaques. Circulation 123, 989–998 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Lee, K. et al. Increased expression of fatty acid binding protein 4 and leptin in resident macrophages characterises atherosclerotic plaque rupture. Atherosclerosis 226, 74–81 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Puig, O. et al. A gene expression signature that classifies human atherosclerotic plaque by relative inflammation status. Circ. Cardiovasc. Genet. 4, 595–604 (2011).

    Article  CAS  PubMed  Google Scholar 

  147. Hulsmans, M. & Holvoet, P. MicroRNA-containing microvesicles regulating inflammation in association with atherosclerotic disease. Cardiovasc. Res. 100, 7–18 (2013).

    Article  CAS  PubMed  Google Scholar 

  148. Rautou, P. E. et al. Microparticles from human atherosclerotic plaques promote endothelial ICAM-1-dependent monocyte adhesion and transendothelial migration. Circ. Res. 108, 335–343 (2011).

    Article  CAS  PubMed  Google Scholar 

  149. Skajaa, T. et al. High-density lipoprotein-based contrast agents for multimodal imaging of atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 30, 169–176 (2010).

    Article  CAS  PubMed  Google Scholar 

  150. Ruehm, S. G., Corot, C., Vogt, P., Cristina, H. & Debatin, J. F. Ultrasmall superparamagnetic iron oxide-enhanced MR imaging of atherosclerotic plaque in hyperlipidemic rabbits. Acad. Radiol. 9 (Suppl. 1), S143–S144 (2002).

    Article  PubMed  Google Scholar 

  151. Tarkin, J. M., Joshi, F. R. & Rudd, J. H. PET imaging of inflammation in atherosclerosis. Nat. Rev. Cardiol. 11, 443–457 (2014).

    Article  CAS  PubMed  Google Scholar 

  152. Moon, S. H. et al. Carotid FDG uptake improves prediction of future cardiovascular events in asymptomatic individuals. JACC Cardiovasc. Imaging 8, 949–956 (2015).

    Article  PubMed  Google Scholar 

  153. Joshi, N. V. et al. 18F-fluoride positron emission tomography for identification of ruptured and high-risk coronary atherosclerotic plaques: a prospective clinical trial. Lancet 383, 705–713 (2014).

    Article  PubMed  Google Scholar 

  154. Nahrendorf, M. et al. Hybrid in vivo FMT-CT imaging of protease activity in atherosclerosis with customized nanosensors. Arterioscler. Thromb. Vasc. Biol. 29, 1444–1451 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Vinegoni, C. et al. Indocyanine green enables near-infrared fluorescence imaging of lipid-rich, inflamed atherosclerotic plaques. Sci. Transl Med. 3, 84ra45 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Lee, S. et al. Fully integrated high-speed intravascular optical coherence tomography/near-infrared fluorescence structural/molecular imaging in vivo using a clinically available near-infrared fluorescence-emitting indocyanine green to detect inflamed lipid-rich atheromata in coronary-sized vessels. Circ. Cardiovasc. Interv. 7, 560–569 (2014).

    Article  CAS  PubMed  Google Scholar 

  157. Ughi, G. J. et al. Clinical characterization of coronary atherosclerosis with dual-modality OCT and near-infrared autofluorescence imaging. JACC Cardiovasc. Imaging http://dx.doi.org/10.1016/j.jcmg.2015.11.020 (2016).

  158. Santos, R. et al. Dynamics of interferon-β modulated mRNA biomarkers in multiple sclerosis patients with anti-interferon-β neutralizing antibodies. J. Neuroimmunol. 176, 125–133 (2006).

    Article  CAS  PubMed  Google Scholar 

  159. Yang, Y., Blomme, E. A. & Waring, J. F. Toxicogenomics in drug discovery: from preclinical studies to clinical trials. Chem. Biol. Interact. 150, 71–85 (2004).

    Article  CAS  PubMed  Google Scholar 

  160. Cardilo-Reis, L. et al. Interleukin-13 protects from atherosclerosis and modulates plaque composition by skewing the macrophage phenotype. EMBO Mol. Med. 4, 1072–1086 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Fredman, G. et al. Targeted nanoparticles containing the proresolving peptide Ac2-26 protect against advanced atherosclerosis in hypercholesterolemic mice. Sci. Transl Med. 7, 275ra20 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Barrett, P. M. & Topol, E. J. Pharmacogenetics: point-of-care genetic testing — a new frontier explored. Nat. Rev. Cardiol. 9, 315–316 (2012).

    Article  CAS  PubMed  Google Scholar 

  163. Kobara, M. et al. Antibody against interleukin-6 receptor attenuates left ventricular remodelling after myocardial infarction in mice. Cardiovasc. Res. 87, 424–430 (2010).

    Article  CAS  PubMed  Google Scholar 

  164. Kleveland, O. et al. Effect of a single dose of the interleukin-6 receptor antagonist tocilizumab on inflammation and troponin T release in patients with non-ST-elevation myocardial infarction: a double-blind, randomized, placebo-controlled phase 2 trial. Eur. Heart J. 37, 2406–2413 (2016).

    Article  CAS  PubMed  Google Scholar 

  165. Toldo, S. et al. Interleukin-1β blockade improves cardiacremodelling after myocardial infarction without interrupting the inflammasome in the mouse. Exp. Physiol. 98, 734–745 (2013).

    Article  CAS  PubMed  Google Scholar 

  166. Hwang, M. W. et al. Neutralization of interleukin-1β in the acute phase of myocardial infarction promotes the progression of left ventricular remodeling. J. Am. Coll. Cardiol. 38, 1546–1553 (2001).

    Article  CAS  PubMed  Google Scholar 

  167. Abbate, A. et al. Anakinra, a recombinant human interleukin-1 receptor antagonist, inhibits apoptosis in experimental acute myocardial infarction. Circulation 117, 2670–2683 (2008).

    Article  CAS  PubMed  Google Scholar 

  168. Morton, A. C. et al. The effect of interleukin-1 receptor antagonist therapy on markers of inflammation in non-ST elevation acute coronary syndromes: the MRC-ILA Heart Study. Eur. Heart J. 36, 377–384 (2015).

    Article  CAS  PubMed  Google Scholar 

  169. Abbate, A. et al. Comparative safety of interleukin-1 blockade with anakinra in patients with ST-segment elevation acute myocardial infarction (from the VCU-ART and VCU-ART2 pilot studies). Am. J. Cardiol. 115, 288–292 (2015).

    Article  CAS  PubMed  Google Scholar 

  170. Sugano, M., Tsuchida, K., Hata, T. & Makino, N. In vivo transfer of soluble TNF-alpha receptor 1 gene improves cardiac function and reduces infarct size after myocardial infarction in rats. FASEB J. 18, 911–913 (2004).

    Article  CAS  PubMed  Google Scholar 

  171. Padfield, G. J. et al. Cardiovascular effects of tumour necrosis factor α antagonism in patients with acute myocardial infarction: a first in human study. Heart 99, 1330–1335 (2013).

    Article  CAS  PubMed  Google Scholar 

  172. Matsumura, S. et al. Targeted deletion or pharmacological inhibition of MMP-2 prevents cardiac rupture after myocardial infarction in mice. J. Clin. Invest. 115, 599–609 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Hudson, M. P. et al. Effects of selective matrix metalloproteinase inhibitor (PG-116800) to prevent ventricular remodeling after myocardial infarction: results of the PREMIER (Prevention of Myocardial Infarction Early Remodeling) trial. J. Am. Coll. Cardiol. 48, 15–20 (2006).

    Article  CAS  PubMed  Google Scholar 

  174. Ducharme, A. et al. Targeted deletion of matrix metalloproteinase-9 attenuates left ventricular enlargement and collagen accumulation after experimental myocardial infarction. J. Clin. Invest. 106, 55–62 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Cerisano, G. et al. Early short-term doxycycline therapy in patients with acute myocardial infarction and left ventricular dysfunction to prevent the ominous progression to adverse remodelling: the TIPTOP trial. Eur. Heart J. 35, 184–191 (2014).

    Article  CAS  PubMed  Google Scholar 

  176. Slagman, A. C. et al. Specific removal of C-reactive protein by apheresis in a porcine cardiac infarction model. Blood Purif. 31, 9–17 (2011).

    Article  CAS  PubMed  Google Scholar 

  177. Wang, K. et al. Recombinant soluble P-selectin glycoprotein ligand-Ig (rPSGL-Ig) attenuates infarct size and myeloperoxidase activity in a canine model of ischemia-reperfusion. Thromb. Haemost. 88, 149–154 (2002).

    Article  CAS  PubMed  Google Scholar 

  178. Tardif, J. C. et al. Effects of the P-selectin antagonist inclacumab on myocardial damage after percutaneous coronary intervention for non-ST-segment elevation myocardial infarction: results of the SELECT-ACS trial. J. Am. Coll. Cardiol. 61, 2048–2055 (2013).

    Article  CAS  PubMed  Google Scholar 

  179. Toldo, S. et al. Alpha-1 antitrypsin inhibits caspase-1 and protects from acute myocardial ischemia-reperfusion injury. J. Mol. Cell. Cardiol. 51, 244–251 (2011).

    Article  CAS  PubMed  Google Scholar 

  180. Abbate, A. et al. Effects of Prolastin C (Plasma-Derived Alpha-1 Antitrypsin) on the acute inflammatory response in patients with ST-segment elevation myocardial infarction (from the VCU-alpha 1-RT pilot study). Am. J. Cardiol. 115, 8–12 (2015).

    Article  CAS  PubMed  Google Scholar 

  181. Weisman, H. F. et al. Soluble human complement receptor type 1: in vivo inhibitor of complement suppressing post-ischemic myocardial inflammation and necrosis. Science 249, 146–151 (1990).

    Article  CAS  PubMed  Google Scholar 

  182. Investigators, A. A. et al. Pexelizumab for acute ST-elevation myocardial infarction in patients undergoing primary percutaneous coronary intervention: a randomized controlled trial. JAMA 297, 43–51 (2007).

    Article  Google Scholar 

  183. Arai, M. et al. An anti-CD18 antibody limits infarct size and preserves left ventricular function in dogs with ischemia and 48-hour reperfusion. J. Am. Coll. Cardiol. 27, 1278–1285 (1996).

    Article  CAS  PubMed  Google Scholar 

  184. Aversano, T., Zhou, W., Nedelman, M., Nakada, M. & Weisman, H. A chimeric IgG4 monoclonal antibody directed against CD18 reduces infarct size in a primate model of myocardial ischemia and reperfusion. J. Am. Coll. Cardiol. 25, 781–788 (1995).

    Article  CAS  PubMed  Google Scholar 

  185. Faxon, D. P. et al. The effect of blockade of the CD11/CD18 integrin receptor on infarct size in patients with acute myocardial infarction treated with direct angioplasty: the results of the HALT-MI study. J. Am. Coll. Cardiol. 40, 1199–1204 (2002).

    Article  CAS  PubMed  Google Scholar 

  186. Baran, K. W. et al. Double-blind, randomized trial of an anti-CD18 antibody in conjunction with recombinant tissue plasminogen activator for acute myocardial infarction: limitation of myocardial infarction following thrombolysis in acute myocardial infarction (LIMIT AMI) study. Circulation 104, 2778–2783 (2001).

    Article  CAS  PubMed  Google Scholar 

  187. Gurantz, D. et al. Etanercept or intravenous immunoglobulin attenuates expression of genes involved in post-myocardial infarction remodeling. Cardiovasc. Res. 67, 106–115 (2005).

    Article  CAS  PubMed  Google Scholar 

  188. Gullestad, L. et al. Intravenous immunogloblin does not reduce left ventricular remodelling in patients with myocardial dysfunction during hospitalization after acute myocardial infarction. Int. J. Cardiol. 168, 212–218 (2013).

    Article  PubMed  Google Scholar 

  189. O'Donoghue, M. L. et al. Effect of losmapimod on cardiovascular outcomes in patients hospitalized with acute myocardial infarction: a randomized clinical trial. JAMA 315, 1591–1599 (2016).

    Article  CAS  PubMed  Google Scholar 

  190. Elhage, R. et al. Differential effects of interleukin-1 receptor antagonist and tumor necrosis factor binding protein on fatty-streak formation in apolipoprotein E-deficient mice. Circulation 97, 242–244 (1998).

    Article  CAS  PubMed  Google Scholar 

  191. Ridker, P. M. et al. Interleukin-1β inhibition and the prevention of recurrent cardiovascular events: rationale and design of the Canakinuman Anti-inflammatory Thrombosis Outcomes Study (CANTOS). Am. Heart J. 162, 597–605 (2011).

    Article  CAS  PubMed  Google Scholar 

  192. Choudhury, R. P. et al. Arterial effects of canakinumab in patients with atherosclerosis and type 2 diabetes mellitus of glucose intolerance. J. Am. Coll. Cardiol. 68, 1769–1780 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Devlin, C. M., Kuriakose, G., Hirsch, E. & Tabas, I. Genetic alterations of IL-1 receptor antagonist in mice affect plasma cholesterol level and foam cell lesion size. Proc. Natl Acad. Sci. USA 99, 6280–6285 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Branen, L. et al. Inhibition of tumor necrosis factor-α reduces atherosclerosis in apolipoprotein E knockout mice. Arterioscler. Thromb. Vasc. Biol. 24, 2137–2142 (2004).

    Article  CAS  PubMed  Google Scholar 

  195. Maki-Petaja, K. M. et al. Anti-tumor necrosis factor-α therapy reduces aortic inflammation and stiffness in patients with rheumatoid arthritis. Circulation 126, 2473–2480 (2012).

    Article  CAS  PubMed  Google Scholar 

  196. Davenport, P. & Tipping, P. G. The role of interleukin-4 and interleukin-12 in the progression of atherosclerosis in apolipoprotein E-deficient mice. Am. J. Pathol. 163, 1117–1125 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Papp, K. A. et al. Long-term safety of ustekinumab in patients with moderate-to-severe psoriasis: final results from 5 years of follow-up. Br. J. Dermatol. 168, 844–854 (2013).

    Article  CAS  PubMed  Google Scholar 

  198. Erbel, C. et al. Inhibition of IL-17A attenuates atherosclerotic lesion development in apoE-deficient mice. J. Immunol. 183, 8167–8175 (2009).

    Article  CAS  PubMed  Google Scholar 

  199. van de Kerkhof, P. C. et al. Secukinumab long-term safety experience: a pooled analysis of 10 phase II and III clinical studies in patients with moderate to severe plaque psoriasis. J. Am. Acad. Dermatol. 75, 83–98.e4 (2016).

    Article  CAS  PubMed  Google Scholar 

  200. Jagavelu, K. et al. Systemic deficiency of the MAP kinase-activated protein kinase 2 reduces atherosclerosis in hypercholesterolemic mice. Circ. Res. 101, 1104–1112 (2007).

    Article  CAS  PubMed  Google Scholar 

  201. Elkhawad, M. et al. Effects of p38 mitogen-activated protein kinase inhibition on vascular and systemic inflammation in patients with atherosclerosis. JACC Cardiovasc. Imaging 5, 911–922 (2012).

    Article  PubMed  Google Scholar 

  202. Bursill, C. A., Choudhury, R. P., Ali, Z., Greaves, D. R. & Channon, K. M. Broad-spectrum CC-chemokine blockade by gene transfer inhibits macrophage recruitment and atherosclerotic plaque formation in apolipoprotein E-knockout mice. Circulation 110, 2460–2466 (2004).

    Article  CAS  PubMed  Google Scholar 

  203. Dong, Z. M. et al. The combined role of P- and E-selectins in atherosclerosis. J. Clin. Invest. 102, 145–152 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Stahli, B. E. et al. Effects of P-selectin antagonist inclacumab in patients undergoing coronary artery bypass graft surgery: SELECT-CABG Trial. J. Am. Coll. Cardiol. 67, 344–346 (2016).

    Article  CAS  PubMed  Google Scholar 

  205. Park, J. G. et al. Evaluation of VCAM-1 antibodies as therapeutic agent for atherosclerosis in apolipoprotein E-deficient mice. Atherosclerosis 226, 356–363 (2013).

    Article  CAS  PubMed  Google Scholar 

  206. Fraser, H. et al. Varespladib (A-002), a secretory phospholipase A2 inhibitor, reduces atherosclerosis and aneurysm formation in ApoE−/− mice. J. Cardiovasc. Pharmacol. 53, 60–65 (2009).

    Article  CAS  PubMed  Google Scholar 

  207. Nicholls, S. J. et al. Varespladib and cardiovascular events in patients with an acute coronary syndrome: the VISTA-16 randomized clinical trial. JAMA 311, 252–262 (2014).

    Article  CAS  PubMed  Google Scholar 

  208. Wilensky, R. L. et al. Inhibition of lipoprotein-associated phospholipase A2 reduces complex coronary atherosclerotic plaque development. Nat. Med. 14, 1059–1066 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Investigators, S. et al. Darapladib for preventing ischemic events in stable coronary heart disease. N. Engl. J. Med. 370, 1702–1711 (2014).

    Article  CAS  Google Scholar 

  210. Nash, P., Whitty, A., Handwerker, J., Macen, J. & McFadden, G. Inhibitory specificity of the anti-inflammatory myxoma virus serpin, SERP-1. J. Biol. Chem. 273, 20982–20991 (1998).

    Article  CAS  PubMed  Google Scholar 

  211. Wesley, R. B. 2nd, Meng, X., Godin, D. & Galis, Z. S. Extracellular matrix modulates macrophage functions characteristic to atheroma: collagen type I enhances acquisition of resident macrophage traits by human peripheral blood monocytes in vitro. Arterioscler. Thromb. Vasc. Biol. 18, 432–440 (1998).

    Article  CAS  PubMed  Google Scholar 

  212. Imazio, M. et al. COlchicine for the Prevention of the Post-pericardiotomy Syndrome (COPPS): a multicentre, randomized, double-blind, placebo-controlled trial. Eur. Heart J. 31, 2749–2754 (2010).

    Article  CAS  PubMed  Google Scholar 

  213. Bulgarelli, A., Martins Dias, A. A., Caramelli, B. & Maranhao, R. C. Treatment with methotrexate inhibits atherogenesis in cholesterol-fed rabbits. J. Cardiovasc. Pharmacol. 59, 308–314 (2012).

    Article  CAS  PubMed  Google Scholar 

  214. Everett, B. M. et al. Rationale and design of the Cardiovascular Inflammation Reduction Trial: a test of the inflammatory hypothesis of atherothrombosis. Am. Heart J. 166, 199–207.e15 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors acknowledge funding from the British Heart Foundation Oxford Centre for Research Excellence (N.R., R.P.C.), Oxford NIHR Biomedical Research Centre (R.P.C.), and US National Institutes of Health (E.A.F.).

Author information

Authors and Affiliations

  1. Division of Cardiovascular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Headley Way, Oxford, OX3 9DU, UK

    Neil Ruparelia, Joshua T. Chai, Edward A. Fisher & Robin P. Choudhury

  2. Acute Vascular Imaging Centre, University of Oxford, John Radcliffe Hospital, Headley Way, Oxford, OX3 9DU, UK

    Joshua T. Chai & Robin P. Choudhury

  3. The Center for the Prevention of Cardiovascular Disease and the Division of Cardiology, Department of Medicine, New York University School of Medicine, New York, 10016, New York, USA

    Edward A. Fisher

Authors
  1. Neil Ruparelia
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joshua T. Chai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Edward A. Fisher
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Robin P. Choudhury
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All the authors researched data for the article, discussed its contents, and wrote, reviewed, and edited the manuscript before submission.

Corresponding author

Correspondence to Robin P. Choudhury.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ruparelia, N., Chai, J., Fisher, E. et al. Inflammatory processes in cardiovascular disease: a route to targeted therapies. Nat Rev Cardiol 14, 133–144 (2017). https://doi.org/10.1038/nrcardio.2016.185

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrcardio.2016.185

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing