Skip to main content
SpringerLink
Log in

Inflammation and Atherosclerotic Cardiovascular Disease

  • Chapter
  • First Online:
ASPC Manual of Preventive Cardiology

Part of the book series: Contemporary Cardiology ((CONCARD))

  • 772 Accesses

Abstract

Atherogenesis is not a process that involves a progressive, passive uptake of lipid into the subendothelial space eventually resulting in the development of obstructive plaque and tissue ischemia. Atherosclerotic cardiovascular disease is a manifestation of chronic inflammation in the arterial wall. Inflammation is a highly orchestrated and synchronized physiological state that is activated when the endothelium becomes dysfunctional in the face of such risk factors as hyperlipidemia, hypertension, insulin resistance, diabetes mellitus, and smoking, among others. Endothelial dysfunction results in reduced nitric oxide production and an upregulation of a variety of adhesion molecules which promote the binding, rolling, and transmigration of inflammatory white blood cells into the subendothelial space. The white blood cells include monocytes, neutrophils, mast cells, and T helper cells. Chronic inflammation gives rise to a pro-oxidative, prothrombotic, and pro-growth (clonal expansion) state. Monocytes are converted to resident macrophages which scavenge oxidatively modified lipoprotein particles; with progressive lipid uptake and formation of lipid inclusion bodies, macrophages become macrophage-derived foam cells. Foam cells can coalesce to form fatty streaks. Fatty streaks can become atheromatous plaques as foam cells and necrotic debris accumulate in the setting of impaired efferocytosis. Chronically inflamed atheromatous plaque can undergo architectural changes that predispose to rupture as metalloproteinases thin the fibrous cap, with cholesterol crystal formation, hemorrhage into the base of the plaque from adventitial vasa vasora, and sudden torsional influences like vasospasm. Ruptured plaques activate platelets and thrombosis secondary to the sudden availability of tissue factor, exposed collagen, calcium, and adenosine-5′-diphosphate (ADP). The thrombus can lead to luminal occlusion and tissue ischemia. Inflammation can be turned on by prostaglandins, leukotrienes, cytokines, and interleukins. Inflammation can also be resolved via the activity of such interleukins as interleukin-4 and interleukin-10, as well as lipoxins, resolvins, and protectins. Atherosclerosis represents a maladaptive physiological response since inflammation is allowed to persist, ultimately resulting in acute vascular events within myocardium, the brain, and other tissues.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 49.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 64.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Scott A, Khan KM, Cook JL, Duronio V. What is “inflammation”? Are we ready to move beyond Celsus? Br J Sports Med. 2004;38:248–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Mayerl C, Lukasser M, Sedivy R, Niederegger H, Seiler R, Wick G. Atherosclerosis research from past to present—on the track of two pathologists with opposing views, Carl von Rokitansky and Rudolf Virchow. Virchows Arch. 2006;449:96–103.

    Article  PubMed  Google Scholar 

  3. Heidland A, Klassen A, Rutkowski P, Bahner U. The contribution of Rudolf Virchow to the concept of inflammation: what is still of importance? J Nephrol. 2006;19 Suppl 10:S102–9.

    PubMed  Google Scholar 

  4. Furie MB, Mitchell RN. Plaque attack: one hundred years of atherosclerosis in The American Journal of Pathology. Am J Pathol. 2012;180:2184–7.

    Article  PubMed  Google Scholar 

  5. Levine SA. Coronary thrombosis: its various clinical features. Medicine. 1929;8:245–418.

    Article  Google Scholar 

  6. Baker WF, Bick RL. Antiphospholipid antibodies in coronary artery disease: a review. Semin Thromb Hemost. 1994;20:27–45.

    Article  PubMed  Google Scholar 

  7. Alenghat FJ. The prevalence of atherosclerosis in those with inflammatory connective tissue disease by race, age, and traditional risk factors. Sci Rep. 2016;6:20303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Dave AJ, Fiorentino D, Lingala B, Krishnan E, Chung L. Atherosclerotic cardiovascular disease in hospitalized patients with systemic sclerosis: higher mortality than patients with lupus and rheumatoid arthritis. Arthritis Care Res. 2014;66:323–7.

    Article  Google Scholar 

  9. Carrizales-Sepulveda EF, Ordaz-Farias A, Vera-Pineda R, Flores-Ramirez R. Periodontal disease, systemic inflammation and the risk of cardiovascular disease. Heart Lung Circ. 2018;27:1327–34.

    Article  PubMed  Google Scholar 

  10. Wong BW, Meredith A, Lin D, McManus BM. The biological role of inflammation in atherosclerosis. Can J Cardiol. 2012;28:631–41.

    Article  PubMed  Google Scholar 

  11. Libby P. Inflammation in atherosclerosis. Nature. 2002;420:868–74.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  13. Deanfield JE, Halcox JP, Rabelink TJ. Endothelial function and dysfunction. Circulation. 2007;115:1285–95.

    Article  PubMed  Google Scholar 

  14. Pries AR, Kuebler WM. Normal endothelium. Handb Exp Pharmacol. 2006;176(1):1–40.

    Google Scholar 

  15. Okamoto T, Suzuki K. The role of gap junction-mediated endothelial cell-cell interaction in the crosstalk between inflammation and blood coagulation. Int J Mol Sci. 2017;18:2254.

    Article  PubMed Central  CAS  Google Scholar 

  16. Reglero-Real N, Colom B, Bodkin JV, Nourshargh S. Endothelial cell junctional adhesion molecules. Arterioscler Thromb Vasc Biol. 2016;36:2048–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Bhagyalakshmi A, Frangos JA. Mechanism of shear-induced prostacyclin production in endothelial cells. Biochem Biophys Res Commun. 1989;158:31–7.

    Article  CAS  PubMed  Google Scholar 

  18. Ozkor MA, Quyyumi AA. Endothelium-derived hyperpolarizing factor and vascular function. Cardiol Res Pract. 2011;2011:156146.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Suzuki Y, Yasui H, Brzoska T, Mogami H, Urano T. Surface-retained tPA is essential for effective fibrinolysis on vascular endothelial cells. Blood. 2011;118:3182–5.

    Article  CAS  PubMed  Google Scholar 

  20. Martin FA, Murphy RP, Cummins PM. Thrombomodulin and the vascular endothelium: insights into functional, regulatory, and therapeutic aspects. Am J Physiol Heart Circ Physiol. 2013;304:H1585–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Wang GR, Zhu Y, Halushka PV, Lincoln TM, Mendelsohn ME. Mechanism of platelet inhibition by nitric oxide: in vivo phosphorylation of thromboxane receptor by cyclic GMP-dependent protein kinase. Proc Natl Acad Sci U S A. 1998;95:4888–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Smith JB. Prostaglandins and platelet aggregation. Acta Med Scand Suppl. 1981;651:91–9.

    CAS  PubMed  Google Scholar 

  23. Hadi HA, Carr CS, Al Suwaidi J. Endothelial dysfunction: cardiovascular risk factors, therapy, and outcome. Vasc Health Risk Manag. 2005;1:183–98.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Gimbrone MA Jr, Garcia-Cardena G. Endothelial cell dysfunction and the pathobiology of atherosclerosis. Circ Res. 2016;118:620–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Davignon J, Ganz P. Role of endothelial dysfunction in atherosclerosis. Circulation. 2004;109:III-27–32.

    Google Scholar 

  26. Zhang J, Alcaide P, Liu L, et al. Regulation of endothelial cell adhesion molecule expression by mast cells, macrophages, and neutrophils. PLoS One. 2011;6:e14525.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Su Y, Lei X, Wu L, Liu L. The role of endothelial cell adhesion molecules P-selectin, E-selectin and intercellular adhesion molecule-1 in leucocyte recruitment induced by exogenous methylglyoxal. Immunology. 2012;137:65–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Rao RM, Yang L, Garcia-Cardena G, Luscinskas FW. Endothelial-dependent mechanisms of leukocyte recruitment to the vascular wall. Circ Res. 2007;101:234–47.

    Article  CAS  PubMed  Google Scholar 

  29. Bombeli T, Schwartz BR, Harlan JM. Adhesion of activated platelets to endothelial cells: evidence for a GPIIbIIIa-dependent bridging mechanism and novel roles for endothelial intercellular adhesion molecule 1 (ICAM-1), alphavbeta3 integrin, and GPIbalpha. J Exp Med. 1998;187:329–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Harrison M, Smith E, Ross E, et al. The role of platelet-endothelial cell adhesion molecule-1 in atheroma formation varies depending on the site-specific hemodynamic environment. Arterioscler Thromb Vasc Biol. 2013;33:694–701.

    Article  CAS  PubMed  Google Scholar 

  31. Hamilos M, Petousis S, Parthenakis F. Interaction between platelets and endothelium: from pathophysiology to new therapeutic options. Cardiovasc Diagn Ther. 2018;8:568–80.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Lord MS, Cheng B, Farrugia BL, McCarthy S, Whitelock JM. Platelet factor 4 binds to vascular proteoglycans and controls both growth factor activities and platelet activation. J Biol Chem. 2017;292:4054–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Chistiakov DA, Melnichenko AA, Myasoedova VA, Grechko AV, Orekhov AN. Thrombospondins: a role in cardiovascular disease. Int J Mol Sci. 2017;18:1540.

    Article  PubMed Central  CAS  Google Scholar 

  34. Funayama H, Ikeda U, Takahashi M, et al. Human monocyte-endothelial cell interaction induces platelet-derived growth factor expression. Cardiovasc Res. 1998;37:216–24.

    Article  CAS  PubMed  Google Scholar 

  35. Mallat Z, Tedgui A. The role of transforming growth factor beta in atherosclerosis: novel insights and future perspectives. Curr Opin Lipidol. 2002;13:523–9.

    Article  CAS  PubMed  Google Scholar 

  36. Ed Rainger G, Chimen M, Harrison MJ, et al. The role of platelets in the recruitment of leukocytes during vascular disease. Platelets. 2015;26:507–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Totani L, Evangelista V. Platelet-leukocyte interactions in cardiovascular disease and beyond. Arterioscler Thromb Vasc Biol. 2010;30:2357–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Nickenig G, Harrison DG. The AT-1 type angiotensin receptor in oxidative stress and atherogenesis. Circulation. 2002;105:393–6.

    Article  CAS  PubMed  Google Scholar 

  39. Spiekermann S, Landmesser U, Dikalov S, et al. Electron spin resonance characterization of vascular xanthine and NAD(P)H oxidase activity in patients with coronary artery disease: relation to endothelium-dependent vasodilation. Circulation. 2003;107:1383–9.

    Article  CAS  PubMed  Google Scholar 

  40. Pueyo ME, Gonzalez W, Nicoletti A, Savoie F, Arnal J-F, Michel J-B. Angiotensin II stimulates endothelial vascular cell adhesion molecule-1 via nuclear factor-kappaB activation induced by intracellular oxidative stress. Arterioscler Thromb Vasc Biol. 2000;20:645–51.

    Article  CAS  PubMed  Google Scholar 

  41. Mueller C, Baudler S, Welzel H, Bohm M, Nickenig G. Identification of a novel redox-sensitive gene, Id3, which mediates angiotensin II-induced cell growth. Circulation. 2002;105:2423–8.

    Article  CAS  PubMed  Google Scholar 

  42. Liu J, Yang F, Yang XP, Jankowski M, Pagano PJ. NAD(P)H oxidase mediates angiotensin II-induced vascular macrophage infiltration and medial hypertrophy. Arterioscler Thromb Vasc Biol. 2003;23:776–82.

    Article  CAS  PubMed  Google Scholar 

  43. Goldin A, Beckman JA, Schmidt AM, Creager MA. Advanced glycation end products: sparking the development of diabetic vascular injury. Circulation. 2006;114:597–605.

    Article  CAS  PubMed  Google Scholar 

  44. Stirban A, Gawlowski T, Roden M. Vascular effects of advanced glycation endproducts: clinical effects and molecular mechanisms. Mol Metab. 2014;3:94–108.

    Article  CAS  PubMed  Google Scholar 

  45. Bierhaus A, Chevion S, Chevion M, et al. Advanced glycation end product-induced activation of NF-kappaB is suppressed by alpha-lipoic acid in cultured endothelial cells. Diabetes. 1997;46:1481–90.

    Article  CAS  PubMed  Google Scholar 

  46. Tan KC, Chow WS, Ai VH, Metz C, Bucala R, Lam KS. Advanced glycation end products and endothelial dysfunction in type 2 diabetes. Diabetes Care. 2002;25:1055–9.

    Article  CAS  PubMed  Google Scholar 

  47. Ren X, Ren L, Wei Q, Shao H, Chen L, Liu N. Advanced glycation end-products decreases expression of endothelial nitric oxide synthase through oxidative stress in human coronary artery endothelial cells. Cardiovasc Diabetol. 2017;16:52.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Krishnasamy S, Rajaraman B, Ravi V. et al. Association of advanced glycation end products (AGEs) with endothelial dysfunction, oxidative stress in gestational diabetes mellitus (GDM). Int J Diabetes Dev Ctries. 2020;40:276–82.

    Google Scholar 

  49. Hayden MR, Sowers JR, Tyagi SC. The central role of vascular extracellular matrix and basement membrane remodeling in metabolic syndrome and type 2 diabetes: the matrix preloaded. Cardiovasc Diabetol. 2005;4:9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Libby P, Ridker PM, Hansson GK. Inflammation in atherosclerosis: from pathophysiology to practice. J Am Coll Cardiol. 2009;54:2129–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Lieschke GJ, Burgess AW. Granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor. N Engl J Med. 1992;327:28–35.

    Article  CAS  PubMed  Google Scholar 

  52. Libby P, Nahrendorf M, Swirski FK. Leukocytes link local and systemic inflammation in ischemic cardiovascular disease: an expanded “cardiovascular continuum”. J Am Coll Cardiol. 2016;67:1091–103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Vengrenyuk Y, Nishi H, Long X, 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. 2015;35:535–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Williams KJ, Tabas I. The response-to-retention hypothesis of early atherogenesis. Arterioscler Thromb Vasc Biol. 1995;15:551–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Loria V, Dato I, Graziani F, Biasucci LM. Myeloperoxidase: a new biomarker of inflammation in ischemic heart disease and acute coronary syndromes. Mediators Inflamm. 2008;2008:135625.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Brash AR. Lipoxygenases: occurrence, functions, catalysis, and acquisition of substrate. J Biol Chem. 1999;274:23679–82.

    Article  CAS  PubMed  Google Scholar 

  57. Veiraiah A. Hyperglycemia, lipoprotein glycation, and vascular disease. Angiology. 2005;56:431–8.

    Article  PubMed  Google Scholar 

  58. Moore KJ, Freeman MW. Scavenger receptors in atherosclerosis: beyond lipid uptake. Arterioscler Thromb Vasc Biol. 2006;26:1702–11.

    Article  CAS  PubMed  Google Scholar 

  59. Horvai A, Palinski W, Wu H, Moulton KS, Kalla K, Glass CK. Scavenger receptor A gene regulatory elements target gene expression to macrophages and to foam cells of atherosclerotic lesions. Proc Natl Acad Sci U S A. 1995;92:5391–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Febbraio M, Hajjar DP, Silverstein RL. CD36: a class B scavenger receptor involved in angiogenesis, atherosclerosis, inflammation, and lipid metabolism. J Clin Invest. 2001;108:785–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Mehta JL, Chen J, Hermonat PL, Romeo F, Novelli G. Lectin-like, oxidized low-density lipoprotein receptor-1 (LOX-1): a critical player in the development of atherosclerosis and related disorders. Cardiovasc Res. 2006;69:36–45.

    Article  CAS  PubMed  Google Scholar 

  62. Minami M, Kume N, Shimaoka T, et al. Expression of SR-PSOX, a novel cell-surface scavenger receptor for phosphatidylserine and oxidized LDL in human atherosclerotic lesions. Arterioscler Thromb Vasc Biol. 2001;21:1796–800.

    Article  CAS  PubMed  Google Scholar 

  63. Leibundgut G, Witztum JL, Tsimikas S. Oxidation-specific epitopes and immunological responses: translational biotheranostic implications for atherosclerosis. Curr Opin Pharmacol. 2013;13:168–79.

    Article  CAS  PubMed  Google Scholar 

  64. Lee S, Birukov KG, Romanoski CE, Springstead JR, Lusis AJ, Berliner JA. Role of phospholipid oxidation products in atherosclerosis. Circ Res. 2012;111:778–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Starosta V, Wu T, Zimman A, et al. Differential regulation of endothelial cell permeability by high and low doses of oxidized 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphocholine. Am J Respir Cell Mol Biol. 2012;46:331–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Bach RR. Tissue factor encryption. Arterioscler Thromb Vasc Biol. 2006;26:456–61.

    Article  CAS  PubMed  Google Scholar 

  67. Libby P, Theroux P. Pathophysiology of coronary artery disease. Circulation. 2005;111:3481–8.

    Article  PubMed  Google Scholar 

  68. Newby AC, Zaltsman AB. Fibrous cap formation or destruction — the critical importance of vascular smooth muscle cell proliferation, migration and matrix formation. Cardiovasc Res. 1999;41:345–60.

    Article  CAS  PubMed  Google Scholar 

  69. Löffek S, Schilling O, Franzke C-W. Biological role of matrix metalloproteinases: a critical balance. Eur Respir J. 2011;38:191–208.

    Article  PubMed  CAS  Google Scholar 

  70. Zimmer S, Grebe A, Latz E. Danger signaling in atherosclerosis. Circ Res. 2015;116:323–40.

    Article  CAS  PubMed  Google Scholar 

  71. Okamura Y, Watari M, Jerud ES, et al. The extra domain A of fibronectin activates Toll-like receptor 4. J Biol Chem. 2001;276:10229–33.

    Article  CAS  PubMed  Google Scholar 

  72. Johnson GB, Brunn GJ, Kodaira Y, Platt JL. Receptor-mediated monitoring of tissue well-being via detection of soluble heparan sulfate by Toll-like receptor 4. J Immunol. 2002;168:5233–9.

    Article  CAS  PubMed  Google Scholar 

  73. Bujo H, Saito Y. Modulation of smooth muscle cell migration by members of the low-density lipoprotein receptor family. Arterioscler Thromb Vasc Biol. 2006;26:1246–52.

    Article  CAS  PubMed  Google Scholar 

  74. Toth PP. Reverse cholesterol transport: high-density lipoprotein’s magnificent mile. Curr Atheroscler Rep. 2003;5:386–93.

    Article  PubMed  Google Scholar 

  75. Seimon TA, Nadolski MJ, Liao X, et al. Atherogenic lipids and lipoproteins trigger CD36-TLR2-dependent apoptosis in macrophages undergoing endoplasmic reticulum stress. Cell Metab. 2010;12:467–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Lin JH, Walter P, Yen TS. Endoplasmic reticulum stress in disease pathogenesis. Annu Rev Pathol. 2008;3:399–425.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. van der Krieken SE, Popeijus HE, Mensink RP, Plat J. CCAAT/enhancer binding protein beta in relation to ER stress, inflammation, and metabolic disturbances. Biomed Res Int. 2015;2015:324815.

    PubMed  PubMed Central  Google Scholar 

  78. Li Y, Bevilacqua E, Chiribau C-B, et al. Differential control of the CCAAT/enhancer-binding protein β (C/EBPβ) products liver-enriched transcriptional activating protein (LAP) and liver-enriched transcriptional inhibitory protein (LIP) and the regulation of gene expression during the response to endoplasmic reticulum stress. J Biol Chem. 2008;283:22443–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Tabas I. Consequences and therapeutic implications of macrophage apoptosis in atherosclerosis: the importance of lesion stage and phagocytic efficiency. Arterioscler Thromb Vasc Biol. 2005;25:2255–64.

    Article  CAS  PubMed  Google Scholar 

  80. Silvestre-Roig C, de Winther MP, Weber C, Daemen MJ, Lutgens E, Soehnlein O. Atherosclerotic plaque destabilization: mechanisms, models, and therapeutic strategies. Circ Res. 2014;114:214–26.

    Article  CAS  PubMed  Google Scholar 

  81. Ravichandran KS. Beginnings of a good apoptotic meal: the find-me and eat-me signaling pathways. Immunity. 2011;35:445–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Norata GD, Marchesi P, Pulakazhi Venu VK, et al. Deficiency of the long pentraxin PTX3 promotes vascular inflammation and atherosclerosis. Circulation. 2009;120:699–708.

    Article  CAS  PubMed  Google Scholar 

  83. Ait-Oufella H, Kinugawa K, Zoll J, et al. Lactadherin deficiency leads to apoptotic cell accumulation and accelerated atherosclerosis in mice. Circulation. 2007;115:2168–77.

    Article  CAS  PubMed  Google Scholar 

  84. Thorp E, Cui D, Schrijvers DM, Kuriakose G, Tabas I. Mertk receptor mutation reduces efferocytosis efficiency and promotes apoptotic cell accumulation and plaque necrosis in atherosclerotic lesions of apoe-/- mice. Arterioscler Thromb Vasc Biol. 2008;28:1421–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Karunakaran D, Geoffrion M, Wei L, et al. Targeting macrophage necroptosis for therapeutic and diagnostic interventions in atherosclerosis. Sci Adv. 2016;2:e1600224.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Kojima Y, Weissman IL, Leeper NJ. The role of efferocytosis in atherosclerosis. Circulation. 2017;135:476–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Rajamaki K, Lappalainen J, Oorni K, et al. Cholesterol crystals activate the NLRP3 inflammasome in human macrophages: a novel link between cholesterol metabolism and inflammation. PLoS One. 2010;5:e11765.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Guo H, Callaway JB, Ting JP. Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat Med. 2015;21:677–87.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Bergsbaken T, Fink SL, Cookson BT. Pyroptosis: host cell death and inflammation. Nat Rev Microbiol. 2009;7:99–109.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Falck-Hansen M, Kassiteridi C, Monaco C. Toll-like receptors in atherosclerosis. Int J Mol Sci. 2013;14:14008–23.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Xu XH, Shah PK, Faure E, et al. Toll-like receptor-4 is expressed by macrophages in murine and human lipid-rich atherosclerotic plaques and upregulated by oxidized LDL. Circulation. 2001;104:3103–8.

    Article  CAS  PubMed  Google Scholar 

  92. Erridge C, Kennedy S, Spickett CM, Webb DJ. Oxidized phospholipid inhibition of toll-like receptor (TLR) signaling is restricted to TLR2 and TLR4: roles for CD14, LPS-binding protein, and MD2 as targets for specificity of inhibition. J Biol Chem. 2008;283:24748–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Billod JM, Lacetera A, Guzman-Caldentey J, Martin-Santamaria S. Computational approaches to toll-like receptor 4 modulation. Molecules. 2016;21(8):994.

    Article  PubMed Central  CAS  Google Scholar 

  94. Hansson GK, Libby P, Schonbeck U, Yan ZQ. Innate and adaptive immunity in the pathogenesis of atherosclerosis. Circ Res. 2002;91:281–91.

    Article  CAS  PubMed  Google Scholar 

  95. Hansson GK, Robertson AK, Soderberg-Naucler C. Inflammation and atherosclerosis. Annu Rev Pathol. 2006;1:297–329.

    Article  CAS  PubMed  Google Scholar 

  96. ten Broeke T, Wubbolts R, Stoorvogel W. MHC class II antigen presentation by dendritic cells regulated through endosomal sorting. Cold Spring Harb Perspect Biol. 2013;5:a016873.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Hao XR, Cao DL, Hu YW, et al. IFN-gamma down-regulates ABCA1 expression by inhibiting LXRalpha in a JAK/STAT signaling pathway-dependent manner. Atherosclerosis. 2009;203:417–28.

    Article  CAS  PubMed  Google Scholar 

  98. Oh SA, Li MO. TGF-beta: guardian of T cell function. J Immunol. 2013;191:3973–9.

    Article  CAS  PubMed  Google Scholar 

  99. Yin C, Mohanta SK, Srikakulapu P, Weber C, Habenicht AJ. Artery tertiary lymphoid organs: powerhouses of atherosclerosis immunity. Front Immunol. 2016;7:387.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Mohanta SK, Yin C, Peng L, et al. Artery tertiary lymphoid organs contribute to innate and adaptive immune responses in advanced mouse atherosclerosis. Circ Res. 2014;114:1772–87.

    Article  CAS  PubMed  Google Scholar 

  101. Luo S, Zhu R, Yu T, et al. Chronic inflammation: a common promoter in tertiary lymphoid organ neogenesis. Front Immunol. 2019;10:2938.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Campbell KA, Lipinski MJ, Doran AC, Skaflen MD, Fuster V, McNamara CA. Lymphocytes and the adventitial immune response in atherosclerosis. Circ Res. 2012;110:889–900.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Sheshachalam A, Srivastava N, Mitchell T, Lacy P, Eitzen G. Granule protein processing and regulated secretion in neutrophils. Front Immunol. 2014;5:448.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. Leclercq A, Houard X, Philippe M, et al. Involvement of intraplaque hemorrhage in atherothrombosis evolution via neutrophil protease enrichment. J Leukoc Biol. 2007;82:1420–9.

    Article  CAS  PubMed  Google Scholar 

  105. Singh U, Devaraj S, Jialal I. C-reactive protein stimulates myeloperoxidase release from polymorphonuclear cells and monocytes: implications for acute coronary syndromes. Clin Chem. 2009;55:361–4.

    Article  CAS  PubMed  Google Scholar 

  106. Soehnlein O. Multiple roles for neutrophils in atherosclerosis. Circ Res. 2012;110:875–88.

    Article  CAS  PubMed  Google Scholar 

  107. Döring Y, Drechsler M, Soehnlein O, Weber C. Neutrophils in atherosclerosis. Arterioscler Thromb Vasc Biol. 2015;35:288–95.

    Article  PubMed  CAS  Google Scholar 

  108. Pende A, Artom N, Bertolotto M, Montecucco F, Dallegri F. Role of neutrophils in atherogenesis: an update. Eur J Clin Invest. 2016;46:252–63.

    Article  PubMed  Google Scholar 

  109. Doring Y, Soehnlein O, Weber C. Neutrophil extracellular traps in atherosclerosis and atherothrombosis. Circ Res. 2017;120:736–43.

    Article  PubMed  CAS  Google Scholar 

  110. Fuchs TA, Abed U, Goosmann C, et al. Novel cell death program leads to neutrophil extracellular traps. J Cell Biol. 2007;176:231–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Martinelli S, Urosevic M, Daryadel A, et al. Induction of genes mediating interferon-dependent extracellular trap formation during neutrophil differentiation. J Biol Chem. 2004;279:44123–32.

    Article  CAS  PubMed  Google Scholar 

  112. Warnatsch A, Ioannou M, Wang Q, Papayannopoulos V. Inflammation. Neutrophil extracellular traps license macrophages for cytokine production in atherosclerosis. Science. 2015;349:316–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Massberg S, Grahl L, von Bruehl ML, et al. Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases. Nat Med. 2010;16:887–96.

    Article  CAS  PubMed  Google Scholar 

  114. Senzel L, Gnatenko DV, Bahou WF. The platelet proteome. Curr Opin Hematol. 2009;16:329–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Blair P, Flaumenhaft R. Platelet alpha-granules: basic biology and clinical correlates. Blood Rev. 2009;23:177–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Gawaz M, Langer H, May AE. Platelets in inflammation and atherogenesis. J Clin Invest. 2005;115:3378–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Koupenova M, Clancy L, Corkrey HA, Freedman JE. Circulating platelets as mediators of immunity, inflammation, and thrombosis. Circ Res. 2018;122:337–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Romo GM, Dong JF, Schade AJ, et al. The glycoprotein Ib-IX-V complex is a platelet counterreceptor for P-selectin. J Exp Med. 1999;190:803–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Blann AD, Nadar SK, Lip GY. The adhesion molecule P-selectin and cardiovascular disease. Eur Heart J. 2003;24:2166–79.

    Article  CAS  PubMed  Google Scholar 

  120. Gkaliagkousi E, Ritter J, Ferro A. Platelet-derived nitric oxide signaling and regulation. Circ Res. 2007;101:654–62.

    Article  CAS  PubMed  Google Scholar 

  121. Alard JE, Ortega-Gomez A, Wichapong K, et al. Recruitment of classical monocytes can be inhibited by disturbing heteromers of neutrophil HNP1 and platelet CCL5. Sci Transl Med. 2015;7:317ra196.

    Article  PubMed  CAS  Google Scholar 

  122. Risitano A, Beaulieu LM, Vitseva O, Freedman JE. Platelets and platelet-like particles mediate intercellular RNA transfer. Blood. 2012;119:6288–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Gidlof O, van der Brug M, Ohman J, et al. Platelets activated during myocardial infarction release functional miRNA, which can be taken up by endothelial cells and regulate ICAM1 expression. Blood. 2013;121:3908–17, S1–26.

    Article  PubMed  CAS  Google Scholar 

  124. Laffont B, Corduan A, Ple H, et al. Activated platelets can deliver mRNA regulatory Ago2*microRNA complexes to endothelial cells via microparticles. Blood. 2013;122:253–61.

    Article  CAS  PubMed  Google Scholar 

  125. Laffont B, Corduan A, Rousseau M, et al. Platelet microparticles reprogram macrophage gene expression and function. Thromb Haemost. 2016;115:311–23.

    Article  PubMed  Google Scholar 

  126. Draznin B. Molecular mechanisms of insulin resistance: serine phosphorylation of insulin receptor substrate-1 and increased expression of p85α. The two sides of a coin. Diabetes. 2006;55:2392–7.

    Article  CAS  PubMed  Google Scholar 

  127. Solinas G, Becattini B. JNK at the crossroad of obesity, insulin resistance, and cell stress response. Mol Metab. 2017;6:174–84.

    Article  CAS  PubMed  Google Scholar 

  128. Boden G, Cheung P, Kresge K, Homko C, Powers B, Ferrer L. Insulin resistance is associated with diminished endoplasmic reticulum stress responses in adipose tissue of healthy and diabetic subjects. Diabetes. 2014;63:2977–83.

    Article  PubMed  PubMed Central  Google Scholar 

  129. Hotamisligil GS, Peraldi P, Budavari A, Ellis R, White MF, Spiegelman BM. IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. Science. 1996;271:665–8.

    Article  CAS  PubMed  Google Scholar 

  130. Yang Q, Graham TE, Mody N, et al. Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes. Nature. 2005;436:356–62.

    Article  CAS  PubMed  Google Scholar 

  131. Farjo KM, Farjo RA, Halsey S, Moiseyev G, Ma JX. Retinol-binding protein 4 induces inflammation in human endothelial cells by an NADPH oxidase- and nuclear factor kappa B-dependent and retinol-independent mechanism. Mol Cell Biol. 2012;32:5103–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Tabata M, Kadomatsu T, Fukuhara S, et al. Angiopoietin-like protein 2 promotes chronic adipose tissue inflammation and obesity-related systemic insulin resistance. Cell Metab. 2009;10:178–88.

    Article  CAS  PubMed  Google Scholar 

  133. Kwon H, Pessin JE. Adipokines mediate inflammation and insulin resistance. Front Endocrinol (Lausanne). 2013;4:71.

    Article  Google Scholar 

  134. Lettner A, Roden M. Ectopic fat and insulin resistance. Curr Diab Rep. 2008;8:185–91.

    Article  CAS  PubMed  Google Scholar 

  135. Iacobellis G, Sharma AM. Epicardial adipose tissue as new cardio-metabolic risk marker and potential therapeutic target in the metabolic syndrome. Curr Pharm Des. 2007;13:2180–4.

    Article  CAS  PubMed  Google Scholar 

  136. Rabkin SW. Epicardial fat: properties, function and relationship to obesity. Obes Rev. 2007;8:253–61.

    Article  CAS  PubMed  Google Scholar 

  137. Glagov S, Bassiouny HS, Giddens DP, Zarins CK. Pathobiology of plaque modeling and complication. Surg Clin North Am. 1995;75:545–56.

    Article  CAS  PubMed  Google Scholar 

  138. Greif M, Becker A, Ziegler FV, et al. Pericardial adipose tissue determined by dual source CT is a risk factor for coronary atherosclerosis. Arterioscler Thromb Vasc Biol. 2009;29:781–6.

    Article  CAS  PubMed  Google Scholar 

  139. Dey D, Wong ND, Tamarappoo B, et al. Computer-aided non-contrast CT-based quantification of pericardial and thoracic fat and their associations with coronary calcium and metabolic syndrome. Atherosclerosis. 2010;209:136–41.

    Article  CAS  PubMed  Google Scholar 

  140. Domouzoglou EM, Maratos-Flier E. Fibroblast growth factor 21 is a metabolic regulator that plays a role in the adaptation to ketosis. Am J Clin Nutr. 2011;93:901s-5.

    Article  PubMed  CAS  Google Scholar 

  141. Gormez S, Demirkan A, Atalar F, et al. Adipose tissue gene expression of adiponectin, tumor necrosis factor-alpha and leptin in metabolic syndrome patients with coronary artery disease. Intern Med. 2011;50:805–10.

    Article  CAS  PubMed  Google Scholar 

  142. Kotulak T, Drapalova J, Kopecky P, et al. Increased circulating and epicardial adipose tissue mRNA expression of fibroblast growth factor-21 after cardiac surgery: possible role in postoperative inflammatory response and insulin resistance. Physiol Res. 2011;60:757–67.

    Article  CAS  PubMed  Google Scholar 

  143. Kremen J, Dolinkova M, Krajickova J, et al. Increased subcutaneous and epicardial adipose tissue production of proinflammatory cytokines in cardiac surgery patients: possible role in postoperative insulin resistance. J Clin Endocrinol Metab. 2006;91:4620–7.

    Article  CAS  PubMed  Google Scholar 

  144. Sade LE, Eroglu S, Bozbas H, et al. Relation between epicardial fat thickness and coronary flow reserve in women with chest pain and angiographically normal coronary arteries. Atherosclerosis. 2009;204:580–5.

    Article  CAS  PubMed  Google Scholar 

  145. Aydin H, Toprak A, Deyneli O, et al. Epicardial fat tissue thickness correlates with endothelial dysfunction and other cardiovascular risk factors in patients with metabolic syndrome. Metab Syndr Relat Disord. 2010;8:229–34.

    Article  CAS  PubMed  Google Scholar 

  146. Perseghin G, Lattuada G, De Cobelli F, et al. Increased mediastinal fat and impaired left ventricular energy metabolism in young men with newly found fatty liver. Hepatology. 2008;47:51–8.

    Article  CAS  PubMed  Google Scholar 

  147. Lin YK, Chen YJ, Chen SA. Potential atrial arrhythmogenicity of adipocytes: implications for the genesis of atrial fibrillation. Med Hypotheses. 2010;74:1026–9.

    Article  CAS  PubMed  Google Scholar 

  148. Wong CX, Ganesan AN, Selvanayagam JB. Epicardial fat and atrial fibrillation: current evidence, potential mechanisms, clinical implications, and future directions. Eur Heart J. 2016;38:1294–302.

    Google Scholar 

  149. Ambros V. The functions of animal microRNAs. Nature. 2004;431:350–5.

    Article  CAS  PubMed  Google Scholar 

  150. Creemers EE, Tijsen AJ, Pinto YM. Circulating microRNAs: novel biomarkers and extracellular communicators in cardiovascular disease? Circ Res. 2012;110:483–95.

    Article  CAS  PubMed  Google Scholar 

  151. Wang GK, Zhu JQ, Zhang JT, et al. Circulating microRNA: a novel potential biomarker for early diagnosis of acute myocardial infarction in humans. Eur Heart J. 2010;31:659–66.

    Article  PubMed  CAS  Google Scholar 

  152. Tijsen AJ, Creemers EE, Moerland PD, et al. MiR423-5p as a circulating biomarker for heart failure. Circ Res. 2010;106:1035–9.

    Article  CAS  PubMed  Google Scholar 

  153. Zampetaki A, Kiechl S, Drozdov I, et al. Plasma microRNA profiling reveals loss of endothelial miR-126 and other microRNAs in type 2 diabetes. Circ Res. 2010;107:810–7.

    Article  CAS  PubMed  Google Scholar 

  154. Fichtlscherer S, De Rosa S, Fox H, et al. Circulating microRNAs in patients with coronary artery disease. Circ Res. 2010;107:677–84.

    Article  CAS  PubMed  Google Scholar 

  155. Andreou I, Sun X, Stone PH, Edelman ER, Feinberg MW. miRNAs in atherosclerotic plaque initiation, progression, and rupture. Trends Mol Med. 2015;21:307–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Nicholls SJ, Hazen SL. Myeloperoxidase and cardiovascular disease. Arterioscler Thromb Vasc Biol. 2005;25:1102–11.

    Article  CAS  PubMed  Google Scholar 

  157. Koenig W, Twardella D, Brenner H, Rothenbacher D. Lipoprotein-associated phospholipase A2 predicts future cardiovascular events in patients with coronary heart disease independently of traditional risk factors, markers of inflammation, renal function, and hemodynamic stress. Arterioscler Thromb Vasc Biol. 2006;26:1586–93.

    Article  CAS  PubMed  Google Scholar 

  158. Leopold JA, Loscalzo J. Oxidative enzymopathies and vascular disease. Arterioscler Thromb Vasc Biol. 2005;25:1332–40.

    Article  CAS  PubMed  Google Scholar 

  159. Forstermann U, Xia N, Li H. Roles of vascular oxidative stress and nitric oxide in the pathogenesis of atherosclerosis. Circ Res. 2017;120:713–35.

    Article  PubMed  CAS  Google Scholar 

  160. Nowak WN, Deng J, Ruan XZ, Xu Q. Reactive oxygen species generation and atherosclerosis. Arterioscler Thromb Vasc Biol. 2017;37:e41–52.

    Article  CAS  PubMed  Google Scholar 

  161. Arulselvan P, Fard MT, Tan WS, et al. Role of antioxidants and natural products in inflammation. Oxid Med Cell Longev. 2016;2016:5276130.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  162. Esterbauer H, Gebicki J, Puhl H, Jürgens G. The role of lipid peroxidation and antioxidants in oxidative modification of LDL. Free Radic Biol Med. 1992;13:341–90.

    Article  CAS  PubMed  Google Scholar 

  163. Bochkov VN, Oskolkova OV, Birukov KG, Levonen AL, Binder CJ, Stockl J. Generation and biological activities of oxidized phospholipids. Antioxid Redox Signal. 2010;12:1009–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Binder CJ, Papac-Milicevic N, Witztum JL. Innate sensing of oxidation-specific epitopes in health and disease. Nat Rev Immunol. 2016;16:485–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Kirabo A, Fontana V, de Faria AP, et al. DC isoketal-modified proteins activate T cells and promote hypertension. J Clin Invest. 2014;124:4642–56.

    Article  PubMed  PubMed Central  Google Scholar 

  166. Herrema H, Nieuwdorp M, Groen AK. Microbiome and Cardiovascular Disease. Handb Exp Pharmacol. 2020. https://doi.org/10.1007/164_2020_356. Epub ahead of print. PMID: 32185503.

  167. Tilg H, Zmora N, Adolph TE, Elinav E. The intestinal microbiota fuelling metabolic inflammation. Nat Rev Immunol. 2020;20:40–54.

    Article  CAS  PubMed  Google Scholar 

  168. Hajishengallis G. Periodontitis: from microbial immune subversion to systemic inflammation. Nat Rev Immunol. 2015;15:30–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Emoto T, Yamashita T, Sasaki N, et al. Analysis of gut microbiota in coronary artery disease patients: a possible link between gut microbiota and coronary artery disease. J Atheroscler Thromb. 2016;23:908–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Lobo MG, Schmidt MM, Lopes RD, et al. Treating periodontal disease in patients with myocardial infarction: a randomized clinical trial. Eur J Intern Med. 2020;71:76–80.

    Article  PubMed  Google Scholar 

  171. Rath S, Heidrich B, Pieper DH, Vital M. Uncovering the trimethylamine-producing bacteria of the human gut microbiota. Microbiome. 2017;5:54.

    Article  PubMed  PubMed Central  Google Scholar 

  172. Schugar RC, Brown JM. Emerging roles of flavin monooxygenase 3 in cholesterol metabolism and atherosclerosis. Curr Opin Lipidol. 2015;26:426–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Koeth RA, Wang Z, Levison BS, et al. Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med. 2013;19:576–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Senthong V, Li XS, Hudec T, et al. Plasma trimethylamine N-oxide, a gut microbe–generated phosphatidylcholine metabolite, is associated with atherosclerotic burden. J Am Coll Cardiol. 2016;67:2620–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Senthong V, Wang Z, Fan Y, Wu Y, Hazen SL, Tang WH. Trimethylamine N-oxide and mortality risk in patients with peripheral artery disease. J Am Heart Assoc. 2016;5:e004237.

    PubMed  PubMed Central  Google Scholar 

  176. Fu Q, Zhao M, Wang D, et al. Coronary plaque characterization assessed by optical coherence tomography and plasma trimethylamine-N-oxide levels in patients with coronary artery disease. Am J Cardiol. 2016;118:1311–5.

    Article  CAS  PubMed  Google Scholar 

  177. Roncal C, Martínez-Aguilar E, Orbe J, et al. Trimethylamine-N-oxide (TMAO) predicts cardiovascular mortality in peripheral artery disease. Sci Rep. 2019;9:15580.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  178. Koh A, Molinaro A, Ståhlman M, et al. Microbially produced imidazole propionate impairs insulin signaling through mTORC1. Cell. 2018;175:947–961.e17.

    Article  CAS  PubMed  Google Scholar 

  179. Arrieta MC, Bistritz L, Meddings JB. Alterations in intestinal permeability. Gut. 2006;55:1512–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Doherty TM, Shah PK, Arditi M. Lipopolysaccharide, toll-like receptors, and the immune contribution to atherosclerosis. Arterioscler Thromb Vasc Biol. 2005;25:e38–9.

    Article  CAS  PubMed  Google Scholar 

  181. Ohira H, Tsutsui W, Fujioka Y. Are short chain fatty acids in gut microbiota defensive players for inflammation and atherosclerosis? J Atheroscler Thromb. 2017;24:660–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Le Poul E, Loison C, Struyf S, et al. Functional characterization of human receptors for short chain fatty acids and their role in polymorphonuclear cell activation. J Biol Chem. 2003;278:25481–9.

    Article  PubMed  CAS  Google Scholar 

  183. Yang G, Chen S, Deng B, et al. Implication of G protein-coupled receptor 43 in intestinal inflammation: a mini-review. Front Immunol. 2018;9:1434.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  184. Bolognini D, Tobin AB, Milligan G, Moss CE. The pharmacology and function of receptors for short-chain fatty acids. Mol Pharmacol. 2016;89:388–98.

    Article  CAS  PubMed  Google Scholar 

  185. Kida T, Tsubosaka Y, Hori M, Ozaki H, Murata T. Bile acid receptor TGR5 agonism induces NO production and reduces monocyte adhesion in vascular endothelial cells. Arterioscler Thromb Vasc Biol. 2013;33:1663–9.

    Article  CAS  PubMed  Google Scholar 

  186. Zhang D, Sun M, Samols D, Kushner I. STAT3 participates in transcriptional activation of the C-reactive protein gene by interleukin-6. J Biol Chem. 1996;271:9503–9.

    Article  CAS  PubMed  Google Scholar 

  187. Tillett WS, Francis T. Serological reactions in pneumonia with a non-protein somatic fraction of pneumococcus. J Exp Med. 1930;52:561–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. French D, Wu AHB. Chapter 9.12 - Cardiac markers. In: Wild D, editor. The immunoassay handbook. 4th ed. Oxford: Elsevier; 2013. p. 817–31.

    Chapter  Google Scholar 

  189. Sproston NR, Ashworth JJ. Role of C-reactive protein at sites of inflammation and infection. Front Immunol. 2018;9:754.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  190. Ridker PM. High-sensitivity C-reactive protein. Circulation. 2001;103:1813–8.

    Article  CAS  PubMed  Google Scholar 

  191. Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med. 2000;342:836–43.

    Article  CAS  PubMed  Google Scholar 

  192. 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;336:973–9.

    Article  CAS  PubMed  Google Scholar 

  193. Kuller LH, Tracy RP, Shaten J, Meilahn EN. Relation of C-reactive protein and coronary heart disease in the MRFIT nested case-control study. Multiple risk factor intervention trial. Am J Epidemiol. 1996;144:537–47.

    Article  CAS  PubMed  Google Scholar 

  194. Tracy RP, Lemaitre RN, Psaty BM, et al. Relationship of C-reactive protein to risk of cardiovascular disease in the elderly. Results from the cardiovascular health study and the rural health promotion project. Arterioscler Thromb Vasc Biol. 1997;17:1121–7.

    Article  CAS  PubMed  Google Scholar 

  195. Koenig W, Sund M, Frohlich M, et al. C-Reactive protein, a sensitive marker of inflammation, predicts future risk of coronary heart disease in initially healthy middle-aged men: results from the MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) Augsburg Cohort Study, 1984 to 1992. Circulation. 1999;99:237–42.

    Article  CAS  PubMed  Google Scholar 

  196. Danesh J, Whincup P, Walker M, et al. Low grade inflammation and coronary heart disease: prospective study and updated meta-analyses. BMJ. 2000;321:199–204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA. 2001;286:327–34.

    Article  CAS  PubMed  Google Scholar 

  198. Sattar N, Gaw A, Scherbakova O, et al. Metabolic syndrome with and without C-reactive protein as a predictor of coronary heart disease and diabetes in the west of Scotland coronary prevention study. Circulation. 2003;108:414–9.

    Article  CAS  PubMed  Google Scholar 

  199. Ridker PM, Bassuk SS, Toth PP. C-reactive protein and risk of cardiovascular disease: evidence and clinical application. Curr Atheroscler Rep. 2003;5:341–9.

    Article  PubMed  Google Scholar 

  200. Lane T, Wassef N, Poole S, et al. Infusion of pharmaceutical-grade natural human C-reactive protein is not proinflammatory in healthy adult human volunteers. Circ Res. 2014;114:672–6.

    Article  CAS  PubMed  Google Scholar 

  201. Noveck R, Stroes ES, Flaim JD, et al. Effects of an antisense oligonucleotide inhibitor of C-reactive protein synthesis on the endotoxin challenge response in healthy human male volunteers. J Am Heart Assoc. 2014;3:e001084.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  202. Ridker PM. A test in context: high-sensitivity C-reactive protein. J Am Coll Cardiol. 2016;67:712–23.

    Article  PubMed  Google Scholar 

  203. Pearson TA, Mensah GA, Alexander RW, et al. Markers of inflammation and cardiovascular disease. Circulation. 2003;107:499–511.

    Article  PubMed  Google Scholar 

  204. Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med. 2002;347:1557–65.

    Article  CAS  PubMed  Google Scholar 

  205. Morrow DA, de Lemos JA, Sabatine MS, et al. Clinical relevance of C-reactive protein during follow-up of patients with acute coronary syndromes in the aggrastat-to-zocor trial. Circulation. 2006;114:281–8.

    Article  CAS  PubMed  Google Scholar 

  206. Ridker PM, Cannon CP, Morrow D, et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med. 2005;352:20–8.

    Article  CAS  PubMed  Google Scholar 

  207. Bohula EA, Giugliano RP, Cannon CP, et al. Achievement of dual low-density lipoprotein cholesterol and high-sensitivity C-reactive protein targets more frequent with the addition of ezetimibe to simvastatin and associated with better outcomes in IMPROVE-IT. Circulation. 2015;132:1224–33.

    Article  CAS  PubMed  Google Scholar 

  208. Ridker PM, Rifai N, Clearfield M, 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;344:1959–65.

    Article  CAS  PubMed  Google Scholar 

  209. Ridker PM, Danielson E, Fonseca FAH, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359:2195–207.

    Article  CAS  PubMed  Google Scholar 

  210. Kaptoge S, Di Angelantonio E, Lowe G, et al. C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. Lancet. 2010;375:132–40.

    Article  PubMed  CAS  Google Scholar 

  211. Quispe R, Michos ED, Martin SS, et al. High-sensitivity C-reactive protein discordance with atherogenic lipid measures and incidence of atherosclerotic cardiovascular disease in primary prevention: the ARIC study. J Am Heart Assoc. 2020;9:e013600.

    Article  PubMed  PubMed Central  Google Scholar 

  212. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;139:e1082–143.

    PubMed  Google Scholar 

  213. Gonçalves I, Edsfeldt A, Ko NY, et al. Evidence supporting a key role of Lp-PLA2-generated lysophosphatidylcholine in human atherosclerotic plaque inflammation. Arterioscler Thromb Vasc Biol. 2012;32:1505–12.

    Article  PubMed  CAS  Google Scholar 

  214. Kolodgie FD, Burke AP, Skorija KS, et al. Lipoprotein-associated phospholipase A2 protein expression in the natural progression of human coronary atherosclerosis. Arterioscler Thromb Vasc Biol. 2006;26:2523–9.

    Article  CAS  PubMed  Google Scholar 

  215. Silva IT, Mello AP, Damasceno NR. Antioxidant and inflammatory aspects of lipoprotein-associated phospholipase A(2) (Lp-PLA(2)): a review. Lipids Health Dis. 2011;10:170.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Garza CA, Montori VM, McConnell JP, Somers VK, Kullo IJ, Lopez-Jimenez F. Association between lipoprotein-associated phospholipase A2 and cardiovascular disease: a systematic review. Mayo Clin Proc. 2007;82:159–65.

    Article  CAS  PubMed  Google Scholar 

  217. Koenig W, Khuseyinova N, Lowel H, Trischler G, Meisinger C. Lipoprotein-associated phospholipase A2 adds to risk prediction of incident coronary events by C-reactive protein in apparently healthy middle-aged men from the general population: results from the 14-year follow-up of a large cohort from southern Germany. Circulation. 2004;110:1903–8.

    Article  CAS  PubMed  Google Scholar 

  218. Ballantyne CM, Hoogeveen RC, Bang H, et al. Lipoprotein-associated phospholipase A2, high-sensitivity C-reactive protein, and risk for incident coronary heart disease in middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) study. Circulation. 2004;109:837–42.

    Article  CAS  PubMed  Google Scholar 

  219. Corson MA. Darapladib: an emerging therapy for atherosclerosis. Ther Adv Cardiovasc Dis. 2010;4:241–8.

    Article  CAS  PubMed  Google Scholar 

  220. Serruys PW, Garcia-Garcia HM, Buszman P, et al. Effects of the direct lipoprotein-associated phospholipase A(2) inhibitor darapladib on human coronary atherosclerotic plaque. Circulation. 2008;118:1172–82.

    Article  CAS  PubMed  Google Scholar 

  221. O’Donoghue ML, Braunwald E, White HD, et al. Effect of darapladib on major coronary events after an acute coronary syndrome: the SOLID-TIMI 52 randomized clinical trial. JAMA. 2014;312:1006–15.

    Article  PubMed  CAS  Google Scholar 

  222. White HD, Held C, Stewart R, et al. Darapladib for preventing ischemic events in stable coronary heart disease. N Engl J Med. 2014;370:1702–11.

    Article  CAS  PubMed  Google Scholar 

  223. Aratani Y. Myeloperoxidase: its role for host defense, inflammation, and neutrophil function. Arch Biochem Biophys. 2018;640:47–52.

    Article  CAS  PubMed  Google Scholar 

  224. Ndrepepa G. Myeloperoxidase – a bridge linking inflammation and oxidative stress with cardiovascular disease. Clin Chim Acta. 2019;493:36–51.

    Article  CAS  PubMed  Google Scholar 

  225. Shao B, Oda MN, Oram JF, Heinecke JW. Myeloperoxidase: an oxidative pathway for generating dysfunctional high-density lipoprotein. Chem Res Toxicol. 2010;23:447–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. Nicholls SJ, Hazen SL. Myeloperoxidase, modified lipoproteins, and atherogenesis. J Lipid Res. 2009;50(Suppl):S346–51.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  227. Undurti A, Huang Y, Lupica JA, Smith JD, DiDonato JA, Hazen SL. Modification of high density lipoprotein by myeloperoxidase generates a pro-inflammatory particle. J Biol Chem. 2009;284:30825–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. Metzler KD, Fuchs TA, Nauseef WM, et al. Myeloperoxidase is required for neutrophil extracellular trap formation: implications for innate immunity. Blood. 2011;117:953–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. Kutter D, Devaquet P, Vanderstocken G, Paulus JM, Marchal V, Gothot A. Consequences of total and subtotal myeloperoxidase deficiency: risk or benefit? Acta Haematol. 2000;104:10–5.

    Article  CAS  PubMed  Google Scholar 

  230. Brennan ML, Penn MS, Van Lente F, et al. Prognostic value of myeloperoxidase in patients with chest pain. N Engl J Med. 2003;349:1595–604.

    Article  CAS  PubMed  Google Scholar 

  231. Baldus S, Heeschen C, Meinertz T, et al. Myeloperoxidase serum levels predict risk in patients with acute coronary syndromes. Circulation. 2003;108:1440–5.

    Article  CAS  PubMed  Google Scholar 

  232. Mocatta TJ, Pilbrow AP, Cameron VA, et al. Plasma concentrations of myeloperoxidase predict mortality after myocardial infarction. J Am Coll Cardiol. 2007;49:1993–2000.

    Article  CAS  PubMed  Google Scholar 

  233. Ridker PM, Everett BM, Pradhan A, et al. Low-dose methotrexate for the prevention of atherosclerotic events. N Engl J Med. 2018;380:752–62.

    Article  PubMed  PubMed Central  Google Scholar 

  234. Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017;377:1119–31.

    Article  CAS  PubMed  Google Scholar 

  235. Ridker PM. Mortality differences associated with treatment responses in CANTOS and FOURIER: insights and implications. Circulation. 2018;137:1763–6.

    Article  PubMed  Google Scholar 

  236. Tardif J-C, Kouz S, Waters DD, et al. Efficacy and safety of low-dose colchicine after myocardial infarction. N Engl J Med. 2019;381:2497–505.

    Article  CAS  PubMed  Google Scholar 

  237. Jala VR, Haribabu B. Leukotrienes and atherosclerosis: new roles for old mediators. Trends Immunol. 2004;25:315–22.

    Article  CAS  PubMed  Google Scholar 

  238. Ricciotti E, FitzGerald GA. Prostaglandins and inflammation. Arterioscler Thromb Vasc Biol. 2011;31:986–1000.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. Chandrasekharan JA, Sharma-Walia N. Lipoxins: nature’s way to resolve inflammation. J Inflamm Res. 2015;8:181–92.

    PubMed  PubMed Central  Google Scholar 

  240. Prieto P, Cuenca J, Traves PG, Fernandez-Velasco M, Martin-Sanz P, Bosca L. Lipoxin A4 impairment of apoptotic signaling in macrophages: implication of the PI3K/Akt and the ERK/Nrf-2 defense pathways. Cell Death Differ. 2010;17:1179–88.

    Article  CAS  PubMed  Google Scholar 

  241. Tang S, Wan M, Huang W, Stanton RC, Xu Y. Maresins: specialized proresolving lipid mediators and their potential role in inflammatory-related diseases. Mediators Inflamm. 2018;2018:2380319.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  242. Serhan CN, Levy BD. Resolvins in inflammation: emergence of the pro-resolving superfamily of mediators. J Clin Invest. 2018;128:2657–69.

    Article  PubMed  PubMed Central  Google Scholar 

  243. Hansen TV, Vik A, Serhan CN. The protectin family of specialized pro-resolving mediators: potent immunoresolvents enabling innovative approaches to target obesity and diabetes. Front Pharmacol. 2019;9:1582.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  244. Kasikara C, Doran AC, Cai B, Tabas I. The role of non-resolving inflammation in atherosclerosis. J Clin Invest. 2018;128:2713–23.

    Article  PubMed  PubMed Central  Google Scholar 

  245. Bäck M, Yurdagul A, Tabas I, Öörni K, Kovanen PT. Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities. Nat Rev Cardiol. 2019;16:389–406.

    PubMed  PubMed Central  Google Scholar 

  246. Dalli J, Serhan CN. Specific lipid mediator signatures of human phagocytes: microparticles stimulate macrophage efferocytosis and pro-resolving mediators. Blood. 2012;120:e60–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  247. Barrett TJ. Macrophages in atherosclerosis regression. Arterioscler Thromb Vasc Biol. 2020;40:20–33.

    Article  CAS  PubMed  Google Scholar 

  248. Abela GS, Kalavakunta JK, Janoudi A, Leffler D, Dhar G, Salehi N, Cohn J, Shah I, Karve M, Kotaru VPK. Frequency of cholesterol crystals in culprit coronary artery aspirate during acute myocardial infarction and their relation to inflammation and myocardial injury. Am J Cardiol. 2017;120:1699–707.

    Article  CAS  PubMed  Google Scholar 

  249. Ridker PM. Residual inflammatory risk: addressing the obverse side of the atherosclerosis prevention coin. Eur Heart J. 2016;37:1720–2.

    Article  PubMed  Google Scholar 

  250. The Lp-PLA2 Studies Collaboration. Lipoprotein-associated phospholipase A2 and risk of coronary disease, stroke, and mortality: collaborative analysis of 32 prospective studies. Lancet. 2010;375:1536–44.

    Article  PubMed Central  CAS  Google Scholar 

  251. Recchiuti A, Mattoscio D, Isopi E. Roles, actions, and therapeutic potential of specialized pro-resolving lipid mediators for the treatment of inflammation in cystic fibrosis. Front Pharmacol. 2019;10:252.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Cicarrone Center for the Prevention of Cardiovascular Disease, John Hopkins University School of Medicine, Baltimore, MD, USA

    Peter P. Toth

Authors
  1. Peter P. Toth
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Peter P. Toth .

Editor information

Editors and Affiliations

  1. Heart Disease Prevention Program, Division of Cardiology, University of California, Irvine, Irvine, CA, USA

    Nathan D. Wong

  2. Division of Cardiovascular Medicine, University of California, Davis, Sacramento, CA, USA

    Ezra A. Amsterdam

  3. Cicarrone Center for the Prevention of Cardiovascular Disease, John Hopkins University School of Medicine, Baltimore, MD, USA

    Peter P. Toth

Rights and permissions

Reprints and permissions

Copyright information

© 2021 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Toth, P.P. (2021). Inflammation and Atherosclerotic Cardiovascular Disease. In: Wong, N.D., Amsterdam, E.A., Toth, P.P. (eds) ASPC Manual of Preventive Cardiology. Contemporary Cardiology. Springer, Cham. https://doi.org/10.1007/978-3-030-56279-3_14

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-56279-3_14

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-56278-6

  • Online ISBN: 978-3-030-56279-3

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation