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Inflammation and Cardiovascular Disease: From Pathogenesis to Therapeutic Target

  • Cardiovascular Disease and Stroke (P Perrone-Filardi and S Agewall, Section Editors)
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Abstract

Atherosclerosis represents the most common pathological substrate of coronary heart disease (CHD), and the characterization of the disease as a chronic low-grade inflammatory condition is now largely accepted. A number of mediators of inflammation have been widely studied, both as surrogate biomarkers and as causal agents, in the pathophysiological network of atherogenesis and plaque vulnerability. The epidemiological observation that biomarkers of inflammation are associated with clinical cardiovascular risk supports the theory that targeted anti-inflammatory treatment appears to be a promising strategy in reducing residual cardiovascular risk on the background of traditional medical therapy. A large number of randomized controlled trials have shown that drugs commonly used in cardiovascular disease (CVD), such as statins, may be effective in the primary and secondary prevention of cardiovascular events through an anti-inflammatory effect. Moreover, several anti-inflammatory drugs are being tested for their potential to reduce residual cardiovascular risk on the background of validated medical therapy for atherosclerotic disease. In this paper, we review relevant evidence with regard to the relationship between inflammation and CVD, from pathogenesis to therapeutic strategies.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Libby P, Ridker P, Maseri A. Inflammation and atherosclerosis. Circulation. 2002;105(9):1135–43.

    Article  CAS  PubMed  Google Scholar 

  2. Ross R. Atherosclerosis – an inflammatory disease. N Engl J Med. 1999;340:115–26.

    Article  CAS  PubMed  Google Scholar 

  3. Wong BW, Meredith A, Lin D, McManus BM. The biological role of inflammation in atherosclerosis. Can J Cardiol. 2012;28(6):631–41. doi:10.1016/j.cjca.2012.06.023. A recent comprehensive review on the biological basis of the involvement of inflammation in atherosclerosis.

    Article  PubMed  Google Scholar 

  4. Holman R, McGill HJ, Strong J, Geer J. The natural history of atherosclerosis: the early aortic lesions as seen in New Orleans in the middle of the of the 20th century. Am J Pathol. 1958;34:209–35.

    CAS  PubMed Central  PubMed  Google Scholar 

  5. Ross R. The pathogenesis of atherosclerosis–an update. N Engl J Med. 1986;314(8):488–500. doi:10.1056/NEJM198602203140806.

    Article  CAS  PubMed  Google Scholar 

  6. Tabas I, Williams K, Boren J. Subendothelial lipoprotein retention as the initiating process in atherosclerosis: update and therapeutic implications. Circulation. 2007;116:1832–44.

    Article  CAS  PubMed  Google Scholar 

  7. Chatzizisis Y, Coskun A, Jonas M, Edelman E, Feldman C, Stone P. Role of endothelial shear stress in the natural history of coronary atherosclerosis and vascular remodeling: molecular, cellular, and vascular behavior. J Am Coll Cardiol. 2007;49:2379–93.

    Article  CAS  PubMed  Google Scholar 

  8. Zalewski A, Macphee C. Role of lipoprotein-associated phospholipase A2 in atherosclerosis: biology, epidemiology, and possible therapeutic target. Arterioscler Thromb Vasc Biol. 2005;25(5):923–31. doi:10.1161/01.ATV.0000160551.21962.a7.

    Article  CAS  PubMed  Google Scholar 

  9. Berliner JA, Leitinger N, Tsimikas S. The role of oxidized phospholipids in atherosclerosis. J Lipid Res. 2009;50(Suppl):S207–12. doi:10.1194/jlr.R800074-JLR200.

    PubMed Central  PubMed  Google Scholar 

  10. Libby P, Ridker P. Inflammation and Atherothrombosis: From Population Biology and Bench Research to Clinical Practice. J Am Coll Cardiol. 2006;48:A33–46.

    Article  CAS  Google Scholar 

  11. Abela G. Cholesterol crystals piercing the arterial plaque and intima trigger local and systemic inflammation. Clin Lipidol. 2010;4:156–64.

    Article  Google Scholar 

  12. Rajamäki K, Lappalainen J, Oörni K, Välimäki E, Matikainen S, Kovanen PT, et al. Cholesterol crystals activate the NLRP3 inflammasome in human macrophages: a novel link between cholesterol metabolism and inflammation. PLoS One. 2010;5:e1175.

    Article  Google Scholar 

  13. Duewell P, Kono H, Rayner KJ, Sirois CM, Vladimer G, Bauernfeind FG, et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature. 2010;464(7293):1357–61. doi:10.1038/nature08938.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Martinon F, Burns K, Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell. 2002;10(2):417–26.

    Article  CAS  PubMed  Google Scholar 

  15. Razani B, Feng C, Coleman T, Emanuel R, Wen H, Hwang S, et al. Autophagy links inflammasomes to atherosclerotic progression. Cell Metab. 2012;15(4):534–44. doi:10.1016/j.cmet.2012.02.011.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Cirillo P, Golino P, Calabro P, Cali G, Ragni M, De Rosa S, et al. C-reactive protein induces tissue factor expression and promotes smooth muscle and endothelial cell proliferation. Cardiovasc Res. 2005;68(1):47–55. doi:10.1016/j.cardiores.2005.05.010.

    Article  CAS  PubMed  Google Scholar 

  17. Bisoendial RJ, Kastelein JJ, Stroes ES. C-reactive protein and atherogenesis: from fatty streak to clinical event. Atherosclerosis. 2007;195(2):e10–8. doi:10.1016/j.atherosclerosis.2007.04.053.

    Article  CAS  PubMed  Google Scholar 

  18. Calabrò P, Cirillo P, Limongelli G, Maddaloni V, Riegler L, Palmieri R, et al. Tissue factor is induced by resistin in human coronary artery endothelial cells by the NF-ĸB-dependent pathway. J Vasc Res. 2011;48:59–66.

    Article  PubMed  Google Scholar 

  19. Tousoulis D, Psarros C, Demosthenous M, Patel R, Antoniades C, Stefanadis C. Innate and adaptiveinflammation as a therapeutic target in vascular disease: The emerging role of statins. J Am Coll Cardiol. 2014. doi:10.1016/j.jacc.2014.01.054. Very recent and comprehensive review on the role of the immune system in atherosclerosis and the role of statins in the modulation of the atherosclerotic process.

    Google Scholar 

  20. Paulson KE, Zhu SN, Chen M, Nurmohamed S, Jongstra-Bilen J, Cybulsky MI. Resident intimal dendritic cells accumulate lipid and contribute to the initiation of atherosclerosis. Circ Res. 2010;106(2):383–90. doi:10.1161/CIRCRESAHA.109.210781.

    Article  CAS  PubMed  Google Scholar 

  21. Zwaal RF, Comfurius P, Bevers EM. Surface exposure of phosphatidylserine in pathological cells. Cellular Mol Life Sci CMLS. 2005;62(9):971–88. doi:10.1007/s00018-005-4527-3.

    Article  CAS  Google Scholar 

  22. Schiro A, Wilkinson F, Weston R, Smyth J, Serracino-Inglott F, Alexander M. Endothelial microparticles as conveyors of information in atherosclerotic disease. Atherosclerosis. 2014;234:295–302.

    Article  CAS  PubMed  Google Scholar 

  23. Hulsmans M, De Keyzer D, Holvoet P. MicroRNAs regulating oxidative stress and inflammation in relation to obesity and atherosclerosis. FASEB J. 2011;25(8):2515–27. doi:10.1096/fj.11-181149. Interesting review on microRNAs, novel candidates as regulators of the complex signaling that regulates gene expression during inflammatory response and atherogenesis.

    Article  CAS  PubMed  Google Scholar 

  24. Chen LJ, Lim SH, Yeh YT, Lien SC, Chiu JJ. Roles of microRNAs in atherosclerosis and restenosis. J Biomed Sci. 2012;19(1):79. doi:10.1186/1423-0127-19-79.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Memoli B, Procino A, Calabrò P, Esposito P, Grandaliano G, Pertosa G, et al. Inflammation may modulate IL-6 and C-reactive protein gene expression in the adipose tissue: the role of IL-6 cell membrane receptor. Am J Physiol Endocrinol Metab. 2007;293:E1030–5.

    Article  CAS  PubMed  Google Scholar 

  26. Calabrò P, Golia E, Riegler L, Limongelli G, Golino P, Russo M, et al. Inflammation: The Link Between Obesity and Cardiovascular Risk. Current Cardiovascular Risk Reports. 2010;4:101–11.

    Article  Google Scholar 

  27. Calabro' P, Chang DW, Willerson JT, Yeh ET. Release of C-reactive protein in response to inflammatory cytokines by human adipocytes: linking obesity to vascular inflammation. J Am Coll Cardiol. 2005;46(6):1112–3. doi:10.1016/j.jacc.2005.06.017.

    Article  Google Scholar 

  28. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med. 1997;336(14):973–9. doi:10.1056/NEJM199704033361401.

    Article  CAS  PubMed  Google Scholar 

  29. Calabro' P, Golia E, Yeh ET. CRP and the risk of atherosclerotic events. Semin Immunopathol. 2009;31(1):79–94. doi:10.1007/s00281-009-0149-4.

    Article  Google Scholar 

  30. Calabro P, Golia E, Yeh ET. Role of C-reactive protein in acute myocardial infarction and stroke: possible therapeutic approaches. Curr Pharm Biotechnol. 2012;13(1):4–16. A comprehensive review of the predictive role of CRP and therapeutic strategies in cardiovscular disease.

    Article  CAS  PubMed  Google Scholar 

  31. Emerging Risk Factors Collaboration, Kaptoge S, Di Angelantonio E, Pennells L, Wood AM, White IR, et al. C-reactive protein, fibrinogen, and cardiovascular disease prediction. N Engl J Med. 2012;367(14):1310–20. doi:10.1056/NEJMoa1107477. This recent study support the predictive role of CRP in cardiovascular disease.

    Article  PubMed  Google Scholar 

  32. American College of Cardiology Foundation, American Heart Association. ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2010;56(25):e50–103.

    Article  Google Scholar 

  33. Anderson TJ, Gregoire J, Hegele RA, Couture P, Mancini GB, McPherson R, et al. 2012 update of the Canadian Cardiovascular Society guidelines for the diagnosis and treatment of dyslipidemia for the prevention of cardiovascular disease in the adult. Can J Cardiol. 2013;29(2):151–67. doi:10.1016/j.cjca.2012.11.032.

    Article  PubMed  Google Scholar 

  34. Kaptoge S, Seshasai SR, Gao P, Freitag DF, Butterworth AS, Borglykke A, et al. Inflammatory cytokines and risk of coronary heart disease: new prospective study and updated meta-analysis. Eur Heart J. 2014;35(9):578–89. doi:10.1093/eurheartj/eht367. An interesting prospective study, and the associated updated meta-analysis confirms the role of inflammatory cytokines in cardiovascular risk prediction.

    Article  CAS  PubMed  Google Scholar 

  35. Tousoulis D, Antoniades C, Vasiliadou C, Kourtellaris P, Koniari K, Marinou K, et al. Effects of atorvastatin and vitamin C on forearm hyperaemic blood flow, asymmentrical dimethylarginine levels and the inflammatory process in patients with type 2 diabetes mellitus. Heart. 2007;93(2):244–6. doi:10.1136/hrt.2006.093112.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Wolfrum S, Jensen KS, Liao JK. Endothelium-dependent effects of statins. Arterioscler Thromb Vasc Biol. 2003;23(5):729–36. doi:10.1161/01.ATV.0000063385.12476.A7.

    Article  CAS  PubMed  Google Scholar 

  37. Ridker PM, Rifai N, Pfeffer MA, Sacks F, Braunwald E. Long-term effects of pravastatin on plasma concentration of C-reactive protein. The Cholesterol and Recurrent Events (CARE) Investigators. Circulation. 1999;100(3):230–5.

    Article  CAS  PubMed  Google Scholar 

  38. Albert MA, Danielson E, Rifai N, Ridker PM, Investigators P. Effect of statin therapy on C-reactive protein levels: the pravastatin inflammation/CRP evaluation (PRINCE): a randomized trial and cohort study. JAMA. 2001;286(1):64–70.

    Article  CAS  PubMed  Google Scholar 

  39. Ridker PM, Rifai N, Clearfield M, Downs JR, Weis SE, Miles JS, et al. Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events. N Engl J Med. 2001;344(26):1959–65. doi:10.1056/NEJM200106283442601.

    Article  CAS  PubMed  Google Scholar 

  40. Ridker PM, Cannon CP, Morrow D, Rifai N, Rose LM, McCabe CH, et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med. 2005;352(1):20–8. doi:10.1056/NEJMoa042378.

    Article  CAS  PubMed  Google Scholar 

  41. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med. 1995;333(20):1301–7. doi:10.1056/NEJM199511163332001.

    Article  CAS  PubMed  Google Scholar 

  42. Ascer E, Bertolami MC, Venturinelli ML, Buccheri V, Souza J, Nicolau JC, et al. Atorvastatin reduces proinflammatory markers in hypercholesterolemic patients. Atherosclerosis. 2004;177(1):161–6. doi:10.1016/j.atherosclerosis.2004.07.003.

    Article  CAS  PubMed  Google Scholar 

  43. Bulcao C, Ribeiro-Filho FF, Sanudo A, Roberta Ferreira SG. Effects of simvastatin and metformin on inflammation and insulin resistance in individuals with mild metabolic syndrome. Am J Cardiovasc Drugs. 2007;7(3):219–24.

    Article  CAS  PubMed  Google Scholar 

  44. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto Jr AM, Kastelein JJ, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359(21):2195–207. doi:10.1056/NEJMoa0807646.

    Article  CAS  PubMed  Google Scholar 

  45. Ridker P. Targeting inflammatory pathways for the treatment of cardiovascular disease. Eur Heart J. 2014;35:540–3.

    Article  PubMed  Google Scholar 

  46. Ridker PM, Thuren T, Zalewski A, Libby P. Interleukin-1beta inhibition and the prevention of recurrent cardiovascular events: rationale and design of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS). Am Heart J. 2011;162(4):597–605. doi:10.1016/j.ahj.2011.06.012.

    Article  CAS  PubMed  Google Scholar 

  47. Ridker P, Howard C, Walter V, Everett B, Libby P, Hensen J, et al. Effects of interleukin-1beta inhibition with canakinumab on hemoglobin A1c, lipids, C-reactive protein, interleukin-6, and fibrinogen: a phase IIb randomized, placebo-controlled trial. Circulation. 2012;126:2739–48.

    Article  CAS  PubMed  Google Scholar 

  48. Hurlimann D, Forster A, Noll G, Enseleit F, Chenevard R, Distler O, et al. Antitumor necrosis factor-alpha treatment improves endothelial function in patients with rheumatoid arthritis. Circulation. 2002;106:2184–7.

    Article  PubMed  Google Scholar 

  49. Ridker P, Lüscher T. Anti-inflammatory therapies for cardiovascular disease. Eur Heart J. 2014 (A complete review of the ongoing evaluation of direct antinflmmatory strategies in cardiovascular disease).

  50. Everett BM, Pradhan AD, Solomon DH, Paynter N, Macfadyen J, Zaharris E, et al. Rationale and design of the Cardiovascular Inflammation Reduction Trial: a test of the inflammatory hypothesis of atherothrombosis. Am Heart J. 2013;166(2):199–207. doi:10.1016/j.ahj.2013.03.018.

    Article  PubMed Central  PubMed  Google Scholar 

  51. Reiss AB, Rahman MM, Chan ES, Montesinos MC, Awadallah NW, Cronstein BN. Adenosine A2A receptor occupancy stimulates expression of proteins involved in reverse cholesterol transport and inhibits foam cell formation in macrophages. J Leukoc Biol. 2004;76(3):727–34. doi:10.1189/jlb.0204107.

    Article  CAS  PubMed  Google Scholar 

  52. Bulgarelli A, Martins Dias AA, Caramelli B, Maranhao RC. Treatment with methotrexate inhibits atherogenesis in cholesterol-fed rabbits. J Cardiovasc Pharmacol. 2012;59(4):308–14. doi:10.1097/FJC.0b013e318241c385.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

Supported by a grant from the Italian Ministry for Education, University and Research (FIRB RBFR12W5V5) to Paolo Calabrò

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Conflict of Interest

Enrica Golia, Giuseppe Limongelli, Francesco Natale, Fabio Fimiani, Valeria Maddaloni, Ivana Pariggiano, Renatomaria Bianchi, Mario Crisci, Ludovica D’Acierno, Roberto Giordano, Gaetano Di Palma, Marianna Conte, Paolo Golino, Maria Giovanna Russo, Raffaele Calabrò, and Paolo Calabrò each declare that they have no conflict of interest.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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Authors and Affiliations

  1. Division of Cardiology, Cardio-thoracic and Respiratory Sciences Department, Second University of Naples, AO Dei Colli-Monaldi Hospital, 80131, Naples, Italy

    Enrica Golia, Giuseppe Limongelli, Francesco Natale, Fabio Fimiani, Valeria Maddaloni, Ivana Pariggiano, Renatomaria Bianchi, Mario Crisci, Ludovica D’Acierno, Roberto Giordano, Gaetano Di Palma, Marianna Conte, Maria Giovanna Russo, Raffaele Calabrò & Paolo Calabrò

  2. Division of Cardiology, Cardio-thoracic and Respiratory Sciences Department, Second University of Naples, AO S. Anna e S. Sebastiano, Caserta, Italy

    Paolo Golino

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  1. Enrica Golia
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Golia, E., Limongelli, G., Natale, F. et al. Inflammation and Cardiovascular Disease: From Pathogenesis to Therapeutic Target. Curr Atheroscler Rep 16, 435 (2014). https://doi.org/10.1007/s11883-014-0435-z

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