Skip to main content
SpringerLink
Log in

Pathogenesis of Atherosclerosis

  • Chapter
  • First Online:
Book cover Essential Cardiology

Abstract

Atherosclerotic vascular disease is a leading cause of death and disability throughout the USA and other industrialized nations and consumes enormous fiscal resources. Atherosclerosis involves the development of a plaque composed of variable amounts of atherogenic lipoproteins, extracellular matrix (collagen, proteoglycans, glycosaminoglycans), calcium, vascular smooth muscle cells, inflammatory and immune cells (chiefly monocyte-derived macrophages, T lymphocytes, mast cells, dendritic cells), and new blood vessels. Atherosclerosis represents a chronic inflammatory response to vascular injury triggered by a variety of risk factors that injure endothelium and promote lipoprotein infiltration, retention, and modification, combined with leukocyte entry, retention, proliferation, and activation. Atherosclerosis predisposes to arterial thrombosis and acute arterial occlusion when plaque disruption leads to activation of the clotting cascade in the vasculature. Ultimately, most lethal and significant occlusive cardiovascular events result from plaque disruption leading to thrombosis. Disruption of plaques is believed to result from inflammation and immune activation in the plaque leading to matrix degradation and inadequate repair. Inflammation plays a crucial role in the initiation, progression, and eventual destabilization of atherosclerotic plaques. Disruption-prone plaques generally contain large necrotic lipid core with adventitial remodeling, plaque cap inflammation, increased neovascularity, and intraplaque hemorrhage.

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 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 299.99
Price excludes VAT (USA)
  • Durable hardcover 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. Atherosclerosis RR. An inflammatory disease. N Engl J Med. 1999;340:115–26.

    Article  Google Scholar 

  2. Skålén K, Gustafsson M, Rydberg EK, Hultén LM, Wiklund O, Innerarity TL, et al. Subendothelial retention of atherogenic lipoproteins in early atherosclerosis. Nature. 2002 Jun 13;417(6890):750–4.

    Article  PubMed  Google Scholar 

  3. Tabas I, Williams KJ, Borén J. Subendothelial lipoprotein retention as the initiating process in atherosclerosis: update and therapeutic implications. Circulation. 2007;116(16):1832–44. Review.

    Article  PubMed  CAS  Google Scholar 

  4. Gustafsson M, Levin M, Skålén K, Perman J, Fridén V, Jirholt P, et al. Retention of low-density lipoprotein in atherosclerotic lesions of the mouse: evidence for a role of lipoprotein lipase. Circ Res. 2007;101(8):777–83. Epub 2007 Aug 30.

    Article  PubMed  CAS  Google Scholar 

  5. McMillian DE. Blood flow and the localization of atherosclerotic plaques. Stroke. 1985;16:582–7.

    Article  Google Scholar 

  6. Nagel T, Resnick N, Atkinson WJ, Dewey Jr CF, Gimbrone Jr MA. Shear stress selectively upregulates intercellular adhesion molecule-1 expression in cultured human vascular endothelial cells. J Clin Invest. 1994;94:885–91.

    Article  PubMed  CAS  Google Scholar 

  7. Resnick N, Collins T, Atkinson W, Bonthron DT, Dewey Jr CF, Gimbrone Jr MA. Platelet-derived growth factor B chain promoter contains a cis-acting fluid shear-stress-responsive element. Proc Natl Acad Sci U S A. 1993;90:4591–5.

    Article  PubMed  CAS  Google Scholar 

  8. Nakashima Y, Raines EW, Plump AS, Breslow JL, Ross R. Upregulation of VCAM-1 and ICAM-1 at atherosclerosis-prone sites on the endothelium in the ApoE-deficient mouse. Arterioscler Thromb Vasc Biol. 1998;18:842–51.

    Article  PubMed  CAS  Google Scholar 

  9. Giachelli CM, Lombardi D, Johnson RJ, Murry CE, Almeida M. Evidence for a role of osteopontin in macrophage infiltration in response to pathological stimuli in vivo. Am J Pathol. 1998;152:353–8.

    PubMed  CAS  Google Scholar 

  10. Dai G, Kaazempur-Mofrad MR, Natarajan S, Zhang Y, Vaughn S, Blackman BR, et al. Distinct endothelial phenotypes evoked by arterial waveforms derived from atherosclerosis-susceptible and -resistant regions of human vasculature. Proc Natl Acad Sci U S A. 2004;101(41):14871–6. Epub 2004 Oct 4.

    Article  PubMed  CAS  Google Scholar 

  11. Parmar KM, Larman HB, Dai G, Zhang Y, Wang ET, Moorthy SN, et al. Integration of flow-dependent endothelial phenotypes by Kruppel-like factor 2. J Clin Invest. 2006;116(1):49–58. Epub 2005 Dec 8.

    Article  PubMed  CAS  Google Scholar 

  12. Cheng C, Tempel D, van Haperen R, van der Baan A, Grosveld F, Daemen MJ, et al. Atherosclerotic lesion size and vulnerability are determined by patterns of fluid shear stress. Circulation. 2006;113(23):2744–53. Epub 2006 Jun 5.

    Article  PubMed  Google Scholar 

  13. Cheng C, Tempel D, van Haperen R, de Boer HC, Segers D, Huisman M, et al. Shear stress-induced changes in atherosclerotic plaque composition are modulated by chemokines. J Clin Invest. 2007;117(3):616–26. Epub 2007 Feb 15.

    Article  PubMed  CAS  Google Scholar 

  14. Jongstra-Bilen J, Haidari M, Zhu SN, Chen M, Guha D, Cybulsky MI. Low-grade chronic inflammation in regions of the normal mouse arterial intima predisposed to atherosclerosis. J Exp Med. 2006;203(9):2073–83. Epub 2006 Aug 7.

    Article  PubMed  CAS  Google Scholar 

  15. Boisvert WA, Santiago R, Curtiss LK, Tekeltaub RA. A leukocyte homologue of the IL-8 receptor CXCR-2 mediates the ­accumulation of macrophages in atherosclerotic lesions of LDL receptor-deficient mice. J Clin Invest. 1998;101:353–63.

    Article  PubMed  CAS  Google Scholar 

  16. Herren B, Raines EW, Ross R. Expression of a disintegrin-like protein in cultured human vascular cells and in vivo. FASEB J. 1997;11:173–80.

    PubMed  CAS  Google Scholar 

  17. Hwang S-J, Ballantyne CM, Sharrett AR, 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. 1997;96:4219–25.

    Article  PubMed  CAS  Google Scholar 

  18. Napoli C, D’Armiento FP, Mancini FP, et al. Fatty streak formation occurs in human fetal aortas and is greatly enhanced by maternal hypercholesterolemia: intimal accumulation of low density lipoprotein and its oxidation precede monocyte recruitment into early atherosclerotic lesions. J Clin Invest. 1997;100:2680–90.

    Article  PubMed  CAS  Google Scholar 

  19. Stary HC, Chandler AB, Glagov S, et al. A definition of initial, fatty streak, and intermediate lesions of atherosclerosis: a report from the Committee on Vascular Lesions of the Council on Atherosclerosis, American Heart Association. Circulation. 1994;89:2462–78.

    Article  PubMed  CAS  Google Scholar 

  20. Kinlay S, Ganz P. Role of endothelial dysfunction in coronary artery disease and implications for therapy. Am J Cardiol. 1997;80:111–61.

    Article  Google Scholar 

  21. Steinberg D. Low density lipoprotein oxidation and its pathobiological significance. J Biol Chem. 1997;272:20963–6.

    Article  PubMed  CAS  Google Scholar 

  22. Khoo JC, Miller E, McLoughlin P, Steinberg D. Enhanced macrophage uptake of low density lipoprotein after self-aggregation. Arteriosclerosis. 1988;8:348–58.

    Article  PubMed  CAS  Google Scholar 

  23. Griendling KK, Alexander RW. Oxidative stress and cardiovascular disease. Circulation. 1997;96:3264–5.

    PubMed  CAS  Google Scholar 

  24. Yla-Herttuala S, Palinski W, Rosenfeld ME, et al. Evidence for the presence of oxidatively modified low density lipoprotein in atherosclerotic lesions of rabbit and man. J Clin Invest. 1989;84:1086–95.

    Article  PubMed  CAS  Google Scholar 

  25. Han J, Hajjar DP, Febbraio M, Nicholson AC. Native and modified low density lipoproteins increase functional expression of the macrophage class B scavenger receptor, CD36. J Biol Chem. 1997;272:1654–9.

    Article  Google Scholar 

  26. Quinn MT, Parthasarathy S, Fong LG, Steinberg D. Oxidatively modified low density lipoproteins: a potential role in recruitment and retention of monocyte/macrophages during atherogenesis. Proc Natl Acad Sci U S A. 1987;84:2995–8.

    Article  PubMed  CAS  Google Scholar 

  27. Jonasson L, Holm J, Skalli O, Bondjers G, Hansson GK. Regional accumulations of T cells, macrophages, and smooth muscle cells in the human atherosclerotic plaque. Arteriosclerosis. 1986;6:131–8.

    Article  PubMed  CAS  Google Scholar 

  28. Van der Wal AC, Das PK, Bentz van de Berg D, van der Loos CM, Becker AE. Atherosclerotic lesions in humans: in situ immunophenotypic analysis suggesting an immune mediated response. Lab Invest. 1989;61(2):166–70.

    PubMed  Google Scholar 

  29. Hansson GK, Jonasson L, Siefert PS, Stemme S. Immune mechanisms in atherosclerosis. Arteriosclerosis. 1989;9:567–78.

    Article  PubMed  CAS  Google Scholar 

  30. Stemme S, Faber B, Holm J, Wiklund O, Witztum JL, Hansson GK. T lymphocytes from human atherosclerotic plaques recognize oxidized low density lipoprotein. Proc Natl Acad Sci U S A. 1995;92:3893–7.

    Article  PubMed  CAS  Google Scholar 

  31. Qiao J-H, Tripathi J, Mishra NK, et al. Role of macrophage colony-stimulating factor in atherosclerosis: studies of osteopetrotic mice. Am J Pathol. 1997;150:1687–99.

    PubMed  CAS  Google Scholar 

  32. Llodra J, Angeli V, Liu J, Trogan E, Fisher EA, Randolph GJ. Emigration of monocyte-derived cells from atherosclerotic lesions characterizes regressive, but not progressive, plaques. Proc Natl Acad Sci U S A. 2004 Aug 10;101(32):11779–84.

    Article  PubMed  CAS  Google Scholar 

  33. Lord RS, Bobryshev YV. Clustering of dendritic cells in athero-prone areas of the aorta. Atherosclerosis. 1999;146:197–8.

    Article  PubMed  CAS  Google Scholar 

  34. Hollenbaugh D, Mischel-Petty N, Edwards CP, et al. Expression of functional CD40 by vascular endothelial cells. J Exp Med. 1995;182:33–40.

    Article  PubMed  CAS  Google Scholar 

  35. Schonbeck U, Mach F, Sukhova GK, et al. Regulation of matrix metalloproteinase expression in human vascular smooth muscle cells by T lymphocytes: a role for CD40 signaling in plaque rupture? Circ Res. 1997;81:448–54.

    Article  PubMed  CAS  Google Scholar 

  36. Mach F, Schonbeck U, Sukhova GK, Atkinson E, Libby P. Reduction of atherosclerosis in mice by inhibition of CD40 signaling. Nature. 1998;394:200–3.

    Article  PubMed  CAS  Google Scholar 

  37. Waldo SW, Li Y, Buono C, Zhao B, Billings EM, Chang J, et al. Heterogeneity of human macrophages in culture and in ­atherosclerotic plaques. Am J Pathol. 2008;172(4):1112–26. Epub 2008 Mar 5.

    Article  PubMed  Google Scholar 

  38. Hristov M, Weber C. Differential role of monocyte subsets in atherosclerosis. Thromb Haemost. 2011;106(5):757–62.

    Article  PubMed  CAS  Google Scholar 

  39. Tian F, Wang L, Yang M, Aria A, Sharifi BG, Shah PK. Favorable modulation of atherosclerosis and monocyte phenotype by intravenous AAV 8 mediated Apo A-I Milano gene transfer in mice. Circulation. 2010;122:A17407 (abst).

    Google Scholar 

  40. Feig JE, Rong JX, Shamir R, Sanson M, Vengrenyuk Y, Liu J, et al. HDL promotes rapid atherosclerosis regression in mice and alters inflammatory properties of plaque monocyte-derived cells. Proc Natl Acad Sci U S A. 2011 Apr 26;108(17):7166–71.

    Article  PubMed  CAS  Google Scholar 

  41. 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  PubMed  CAS  Google Scholar 

  42. Ait-Oufella H, Pouresmail V, Simon T, Blanc-Brude O, Kinugawa K, Merval R, et al. Defective mer receptor tyrosine kinase signaling in bone marrow cells promotes apoptotic cell accumulation and accelerates atherosclerosis. Arterioscler Thromb Vasc Biol. 2008;28:1429–31.

    Article  PubMed  CAS  Google Scholar 

  43. 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. Arterioscler Thromb Vasc Biol. 2008 Aug;28(8):1421–8.

    Article  PubMed  CAS  Google Scholar 

  44. Feng B, Zhang D, Kuriakose G, Devlin CM, Kockx M, Tabas I, et al. Heterozygosity confers resistance to lesional necrosis and macrophage apoptosis in murine atherosclerosis. Proc Natl Acad Sci U S A. 2003;100(18):10423–8. Epub 2003 Aug 15.

    Article  PubMed  CAS  Google Scholar 

  45. 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 that form early in disease. Nature. 2010;464(7293):1357–61.

    Article  PubMed  CAS  Google Scholar 

  46. 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(7):e11765.

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  48. Gibbons GH, Pratt RE, Dzau VJ. Vascular smooth muscle cell hypertrophy vs. hyperplasia: autocrine transforming growth factor-beta 1 expression determines growth response to angiotensin II. J Clin Invest. 1992;90:456–61.

    Article  PubMed  CAS  Google Scholar 

  49. Lacy F, O’Connor DT, Schmid-Schonbein GW. Plasma hydrogen peroxide production in hypertensive and normotensive subjects as genetic risk of hypertension. J Hypertens. 1998;16:291–303.

    Article  PubMed  CAS  Google Scholar 

  50. Nehler MR, Taylor Jr LM, Porter JM. Homocysteinemia as a risk factor for atherosclerosis: a review. Cardiovasc Surg. 1997;6:559–67.

    Article  Google Scholar 

  51. Nygard O, Nordrehaug JE, Refsum H, Ueland PM, Farstad M, Vollset SE. Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med. 1997;337:230–6.

    Article  PubMed  CAS  Google Scholar 

  52. Omenn GS, Beresford SSA, Motulsky AG. Preventing coronary heart disease: B vitamins and homocysteine. Circulation. 1998;97:421–4.

    Article  PubMed  CAS  Google Scholar 

  53. Debreceni B, Debreceni L. Why do homocysteine-lowering B vitamin and antioxidant E vitamin supplementations appear to be ineffective in the prevention of cardiovascular diseases? Cardiovasc Ther. 2011;30(4):227–33. doi:10.1111/j.1755-5922.2011.00266.x.

    Article  PubMed  Google Scholar 

  54. Hendrix MG, Salimans MM, van Boven CP, Bruggeman CA. High prevalence of latently present cytomegalovirus in arterial walls of patients suffering from grade III atherosclerosis. Am J Pathol. 1990;136:23–8.

    PubMed  CAS  Google Scholar 

  55. Jackson LA, Campbell LA, Schmidt RA, et al. Specificity of detection of Chlamydia pneumoniae in cardiovascular atheroma: evaluation of the innocent bystander hypothesis. Am J Pathol. 1997;150:1785–90.

    PubMed  CAS  Google Scholar 

  56. Melnick JL, Adam E, Debakey ME. Cytomegalovirus and atherosclerosis. Eur Heart J. 1993;14(suppl K):30–8.

    PubMed  Google Scholar 

  57. Nicholson AC, Hajjar DP. Herpesviruses in atherosclerosis and thrombosis: etiologic agents or ubiquitous bystanders? Arteriocler Thromb Vasc Biol. 1998;18:339–48.

    Article  CAS  Google Scholar 

  58. Shah PK. Plaque disruption and coronary thrombosis: new insight into pathogenesis and prevention. Clin Cardiol. 1997;20(II):38–44.

    Google Scholar 

  59. Muhlestein JB, Anderson JL, Hammond EH, Zhao L, Trehan S, Schwobe EP, et al. Infection with Chlamydia pneumoniae accelerates the development of atherosclerosis and treatment with azithromycin prevents it in a rabbit model. Circulation. 1998;97:633–6.

    Article  PubMed  CAS  Google Scholar 

  60. Gurfinkel E, Bozovich G, Daroca A, Beck E, Mautner B. Randomized trial of Roxithromycin in non-Q-wave coronary syndromes: ROXIS Pilot Study. ROXIS Study Group [see comments]. Lancet. 1997;350:404–7.

    Article  PubMed  CAS  Google Scholar 

  61. Gupta S, Leatham EW, Carrington D, Mendall MA, Kaski JC, Camm AJ. Elevated Chlamydia pneumoniae antibodies, cardiovascular events, and azithromycin in male survivors of myocardial infarction. Circulation. 1997;96:404–7.

    Article  PubMed  CAS  Google Scholar 

  62. Cercek B, Shah PK, Noc M, Zahger D, Zeymer U, Matetzky S, et al. AZACS investigators: effect of short-term treatment with azithromycin on recurrent ischemic events in patients with acute coronary syndrome in the Azithromycin in Acute Coronary Syndrome (AZACS) trial: a randomised controlled trial. Lancet. 2003 Mar 8;361(9360):809–13.

    Article  PubMed  CAS  Google Scholar 

  63. O’Connor CM, Dunne MW, Pfeffer MA, Muhlestein JB, Yao L, Gupta S, et al. Investigators in the WIZARD study: azithromycin for the secondary prevention of coronary heart disease events: the WIZARD study: a randomized controlled trial. JAMA. 2003;290(11):1459–66.

    Article  PubMed  Google Scholar 

  64. Cannon CP, Braunwald E, McCabe CH, Grayston JT, Muhlestein B, Giugliano RP, et al. Pravastatin or atorvastatin evaluation and infection therapy-thrombolysis in myocardial infarction 22 investigators: antibiotic treatment of Chlamydia pneumoniae after acute coronary syndrome. N Engl J Med. 2005;352(16):1646–54.

    Article  PubMed  CAS  Google Scholar 

  65. Grayston JT, Kronmal RA, Jackson LA, Parisi AF, Muhlestein JB, Cohen JD, et al. ACES investigators: azithromycin for the secondary prevention of coronary events. N Engl J Med. 2005;352(16):1637–45.

    Article  PubMed  CAS  Google Scholar 

  66. Koren O, Spor A, Felin J, Fåk F, Stombaugh J, Tremaroli V, et al. Human oral, gut, and plaque microbiota in patients with atherosclerosis. Proc Natl Acad Sci U S A. 2011;108(1):4592–8.

    Article  PubMed  CAS  Google Scholar 

  67. Wang Z et al. Gut flora metabolism of phosphatidylcholine promotes cardio-vascular disease. Nature. 2011;472:57.

    Article  PubMed  CAS  Google Scholar 

  68. Xu XH 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  PubMed  CAS  Google Scholar 

  69. Michelsen KS et al. TLR signaling: an emerging bridge from innate immunity to atherogenesis. J Immunol. 2004;173:5901–7.

    PubMed  CAS  Google Scholar 

  70. Michelsen KS. Lack of Toll-like receptor 4 or myeloid differentiation factor 88 reduces atherosclerosis and alters plaque phenotype in mice deficient in apolipoprotein E. Proc Natl Acad Sci U S A. 2004;101:10679–84.

    Article  PubMed  CAS  Google Scholar 

  71. Bjorkbacka H et al. Reduced atherosclerosis in MyD88-null mice links elevated serum cholesterol levels to activation of innate immunity signaling pathways. Nat Med. 2004;10:416–21.

    Article  PubMed  Google Scholar 

  72. Barger AC, Beeuwkes R, Iainey LL, Silverman KJ. Hypothesis: Vasa vasorum and neovascularization of human coronary arteries. N Engl J Med. 1984;310:175–7.

    Article  PubMed  CAS  Google Scholar 

  73. O’Brien ER, Garvin MR, Dev R, Stewart DK, Hiniohara T, Simpson JB, et al. Angiogenesis in human atherosclerotic plaques. Am J Pathol. 1994;145:883–94.

    PubMed  Google Scholar 

  74. Virmani R, Kolodgie FD, Burke AP, Finn AV, Gold HK, Tulenko TN, et al. Atherosclerotic plaque progression and vulnerability to rupture: angiogenesis as a source of intraplaque hemorrhage. Arterioscler Thromb Vasc Biol. 2005;10:2054–61.

    Article  Google Scholar 

  75. Bot I, de Jager SC, Zernecke A, Lindstedt KA, van Berkel TJ, Weber C, et al. Perivascular mast cells promote atherogenesis and induce plaque destabilization in apolipoprotein E–deficient mice. Circulation. 2007;115:2516–25.

    Article  PubMed  CAS  Google Scholar 

  76. Bot I, de Jager SC, Bot M, van Heiningen SH, de Groot P, Veldhuizen RW, et al. The neuropeptide substance P mediates adventitial mast cell activation and induces intraplaque hemorrhage in advanced atherosclerosis. Circ Res. 2010;106:89–92.

    Article  PubMed  CAS  Google Scholar 

  77. Sharifi BG, Zeng Z, Wang L, Song L, Chen H, Qin M, et al. Pleiotrophin induces transdifferentiation of monocytes into functional endothelial cells. Arterioscler Thromb Vasc Biol. 2006 Jun;26(6):1273–80.

    Article  PubMed  CAS  Google Scholar 

  78. Moulton KS, Heller E, Konerding MA, Flynn E, Palinski W, Folkman J. Angiogenesis inhibitor endostatin or TNP-470 reduces intimal neovascularization and plaque growth in apolipoprotein E deficient mice. Circulation. 1999;99:1726–32.

    Article  PubMed  CAS  Google Scholar 

  79. Falk E, Shah PK, Fuster V. Pathogenesis of plaque distribution. In: Fuster V, Ross R, Topol EJ, editors. Atherosclerosis and coronary artery disease, vol. 2. Philadelphia: Lippincott-Raven; 1996. p. 492–510.

    Google Scholar 

  80. Shah PK. Role of inflammation and metalloproteinases in plaque disruption and thrombosis. Vasc Med. 1998;3:199–206.

    PubMed  CAS  Google Scholar 

  81. Shah PK. Plaque disruption and thrombosis. Potential role of inflammation and infection. Cardiol Clin. 1999;17:271–81.

    Article  PubMed  CAS  Google Scholar 

  82. Xu XP, Meisel SR, Ong JM, Kaul S, Cercek B, Rajavashisth TB, et al. Oxidized low-density lipoprotein regulates matrix metalloproteinase-9 and its tissue inhibitor in human monocyte-derived macrophages. Circulation. 1999;99:993–8.

    Article  PubMed  CAS  Google Scholar 

  83. Rajavashisth TB, Xu XP, Jovinge S, Meisel S, Xu XO, Chai NN, et al. Membrane type 1 matrix metalloproteinase expression in human atherosclerosis plaques: evidence for activation by proinflammatory mediators. Circulation. 1999;99:3103–9.

    Article  PubMed  CAS  Google Scholar 

  84. Geng Y-J, Libby P. Evidence for apoptosis in advanced human atheroma: colocalization with interleukin-1 beta-converting enzyme. Am J Pathol. 1995;147:251–66.

    PubMed  CAS  Google Scholar 

  85. Wallner K, Li C, Shah PK, Wu KJ, Schwartz S, Sharifi BG. The EGF-L domain of tenascin-C is pro-apoptotic for cultured smooth muscle cells. Arterioscler Thromb Vasc Biol. 2004;24:1416–21.

    Article  PubMed  CAS  Google Scholar 

  86. Sato K, Niessner A, Kopecky SL, Frye RL, Goronzy JJ, Weyand CM. Trail expressing T cells induce apoptosis of vascular smooth muscle cells in atherosclerotic plaque. J Exp Med. 2006;203(1):239–50.

    Article  PubMed  CAS  Google Scholar 

  87. Pryschep S, Sato K, Goronzy JJ, Weyand CM. T cell recognition and killing of vascular smooth muscle cells in acute coronary syndromes. Circ Res. 2006;98(9):1168–76.

    Article  Google Scholar 

  88. Moreno PR, Bernardi VH, López-Cuéllar J, Murcia AM, Palacios IF, Gold HK, et al. Macrophages, smooth muscle cells, and tissue factor in unstable angina. Implications for cell-mediated thrombogenicity in acute coronary syndromes. Circulation. 1996;94:3090–7.

    Article  PubMed  CAS  Google Scholar 

  89. Burke AP, Farb A, Malcom GT, Liang Y, Smialek J, Virmani R. Effect of risk factors on the mechanism of acute thrombosis and sudden coronary death in women. Circulation. 1998;97(21):2110–6.

    Article  PubMed  CAS  Google Scholar 

  90. 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  PubMed  CAS  Google Scholar 

  91. Haverkate F, Thompson SG, Pyke SD, Gallimore JR, Pepys MB. Production of C-reactive protein and risk of coronary events in stable and unstable angina: European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. Lancet. 1997;349:462–6.

    Article  PubMed  CAS  Google Scholar 

  92. Berk BC, Weintraub WS, Alexander RW. Elevation of C-reactive protein in ‘active’ coronary artery disease. Am J Cardiol. 1990;65:168–72.

    Article  PubMed  CAS  Google Scholar 

  93. Levenson J, Giral P, Razavian M, Gariepy J, Simon A. Fibrinogen and silent atherosclerosis in subjects with cardiovascular risk factors. Arterioscler Thromb Vasc Biol. 1995;15:1263–8.

    Article  PubMed  CAS  Google Scholar 

Recommended Reading

  • Bot I, de Jager SC, Zernecke A, Lindstedt KA, van Berkel TJ, Weber C, et al. Perivascular mast cells promote atherogenesis and induce plaque destabilization in apolipoprotein E–deficient mice. Circulation. 2007;115:2516–25.

    Article  PubMed  CAS  Google Scholar 

  • 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 that form early in disease. Nature. 2010;464(7293):1357–61.

    Article  PubMed  CAS  Google Scholar 

  • 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  PubMed  CAS  Google Scholar 

  • Tabas I, Williams KJ, Borén J. Subendothelial lipoprotein retention as the initiating process in atherosclerosis: update and therapeutic implications. Circulation. 2007;116(16):1832–44. Review.

    Article  PubMed  CAS  Google Scholar 

  • Virmani R, Kolodgie FD, Burke AP, Finn AV, Gold HK, Tulenko TN, et al. Atherosclerotic plaque progression and vulnerability to rupture: angiogenesis as a source of intraplaque hemorrhage. Arterioscler Thromb Vasc Biol. 2005;25(10):2054–61.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Cardiology, Cedars Sinai Heart Institute, Suite 5531, 8700 Beverly Blvd, Los Angeles, 90048, CA, USA

    Prediman K. Shah MD

Authors
  1. Prediman K. Shah MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Prediman K. Shah MD .

Editor information

Editors and Affiliations

  1. The Mount Sinai School of Medicine, The James J. Peters VA Medical Center, Department of Medicine, West Kingsbridge Rd 130, Bronx, 10468, New York, USA

    Clive Rosendorff

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer Science+Business Media New York

About this chapter

Cite this chapter

Shah, P.K. (2013). Pathogenesis of Atherosclerosis. In: Rosendorff, C. (eds) Essential Cardiology. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-6705-2_21

Download citation

  • DOI: https://doi.org/10.1007/978-1-4614-6705-2_21

  • Published:

  • Publisher Name: Springer, New York, NY

  • Print ISBN: 978-1-4614-6704-5

  • Online ISBN: 978-1-4614-6705-2

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation