The Pathogenesis of Atherosclerosis: Myths and Established Facts About Its Relationship to Aging

  • Robert W. Wissler
  • Dragoslava Vesselinovitch


There are three well established approaches to the study of atherogenesis. The first and probably the oldest approach has been that of correlating the development of the atherosclerotic plaque as observed at autopsy with the age of the individual and with selected disease processes such as hypertension, diabetes and hyperlipidemia. This approach has led to many valuable observations including the concept that atherogenesis starts relatively early in life (Figure 2-1) with the accumulation of lipid in the foci which have the potential to progress into raised plaques (1). This approach has also been used to demonstrate that the disease commonly progresses in some populations and not in others (2). The results of these international studies also indicate that raised advanced plaques are frequently present in the third decade in individuals from populations which later demonstrated a high incidence of ischemic cardiovascular, cerebrovascular, and peripheral vascular disease.


Smooth Muscle Cell Atherosclerotic Plaque Arterial Smooth Muscle Cell Human Atherosclerotic Plaque Human Atherosclerotic Lesion 
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  1. 1.
    McGill HC Jr, Geer JC, Strong JP: Natural history of human atherosclerotic lesions. In: Sandler M, Bourne GH (eds):Atherosclerosis and Its Origin. New York, Academic Press, 1963, pp 39–65.Google Scholar
  2. 2.
    McGill HC (ed): The geographic pathology of atherosclerosis. Lab Invest 1968; 18: 463–653.Google Scholar
  3. 3.
    Keys A: Coronary heart disease: The global picture. Atherosclerosis 1975; 22: 149–192.PubMedCrossRefGoogle Scholar
  4. 4.
    Dawber TR: The Framing ham study: The epidemiology of atherosclerotic disease. Cambridge, MA, Harvard Univ Press, 1980.Google Scholar
  5. 5.
    Aravanis C: The classic risk factors for coronary heart disease: Experience in Europe. Prev Med 1983; 12: 16–19.PubMedCrossRefGoogle Scholar
  6. 6.
    Kannel WB: Update on the role of cigarette smoking in coronary artery disease. Am Heart J 1981; 101: 319–328.PubMedCrossRefGoogle Scholar
  7. 7.Hypertension Detection and Follow-up Program Cooperative Group: The Hypertension Detection and Follow-up Program: A Progress Report. Cire Res 1977; 40(Suppl I): 1–106-109.Google Scholar
  8. 8.
    Kromhout D, Bosschieter EB, de Lezenne Coulander C: The inverse relation between fish consumption and 20-year mortality from coronary heart disease. New Engl J Med 1985; 312: 1205–1209.PubMedCrossRefGoogle Scholar
  9. 9.
    Keys A: Atherosclerosis: A problem in newer public health. Mt Sinai J Med 1953; 20: 118–139.Google Scholar
  10. 10.
    Constantinides P: Experimental Atherosclerosis. Amsterdam, Elsevier, 1965.Google Scholar
  11. 11.
    Roberts JC, Strauss R (eds): Comparative Atherosclerosis. New York, Harper and Row, 1965.Google Scholar
  12. 12.
    Wissler RW, Vesselinovitch D: Experimental models of human atherosclerosis. Ann NY Acad Sei 1968; 149: 907–922.Google Scholar
  13. 13.
    Wissler RW, Vesselinovitch D: Differences between human and animal atherosclerosis. In: Schettler G, Weizel A (eds): Atherosclerosis III (Proc 3rd Int Symp), New York, Springer, 1974, pp 319–325.Google Scholar
  14. 14.
    Mahley RW: Dietary fat, cholesterol and accelerated atherosclerosis. In: Paoletti R, Gotto AM Jr (eds): Atherosclerosis Review 5, New York, Raven Press, 1979, pp 1–34.Google Scholar
  15. 15.
    Wissler RW, Vesselinovitch D: Atherosclerosis in non-human primates. In: Brandly CA, Cornelius CE, Simpson CF (eds): Advances in Veterinary Science and Comparative Medicine. New York, Academic Press, 1977; vol 21, pp 351–420.Google Scholar
  16. 16.
    Clarkson TB (1986) in this volume.Google Scholar
  17. 17.
    Vesselinovitch D (1986) in this volume.Google Scholar
  18. 18.
    Wissler RW: The emerging cellular pathobiology of atherosclerosis. Artery 1979, 5: 409–423.PubMedGoogle Scholar
  19. 19.
    Wissler RW: The pathobiology of the atherosclerotic plaque in the mid-1980s. In: Malinow MR, Blaton VH (eds): Regression of Atherosclerotic Lesions. New York, Plenum, 1984, pp 5–20.Google Scholar
  20. 20.
    Haust MD, More RH, Movat HZ: The role of the smooth muscle cell in the fibrogenesis of arteriosclerosis. Am J Pathol 1960; 37: 377–389.PubMedGoogle Scholar
  21. 21.
    Geer JC, McGill HC Jr, Strong JP: The fine structure of human atherosclerotic lesions. Am J Pathol 1961; 38: 263–287.PubMedGoogle Scholar
  22. 22.
    Hanig M, Shainoff JR, Lowry AD: Flotational lipoproteins extracted from human atherosclerotic aortas. Science 1956; 124: 176–178.PubMedCrossRefGoogle Scholar
  23. 23.
    Gero S, Gergely J, Jakab L, et al: Comparative immunoelectrophoretic studies on homogenates of aorta, pulmonary arteries and inferior vena cava of atherosclerotic individuals. J Atheroscler Res 1961; 1: 88–91.PubMedCrossRefGoogle Scholar
  24. 24.
    Tracy RE, Merchant EB, Kao V: On the antigenic identity of human serum beta and alpha-2 lipoproteins and their identification in the aortic intima. Circ Res 1961; 9: 472–478.PubMedGoogle Scholar
  25. 25.
    Gero S, Gergely J, Devenyi T, et al: Role of intimal mucoid substances in the pathogenesis of atherosclerosis. I. Complex formation in vitro between mucopolysac-charides from atherosclerotic aortic intimas and plasma B-lipoprotein and fibrinogen. J Atheroscler Res 1961; 1: 67–74.PubMedCrossRefGoogle Scholar
  26. 26.
    Tracy RE, Dzoga K, Wissler RW: Sequestration of serum low-density lipoproteins in the arterial intima by complex formation. Proc Soc Exp Biol Med 1965; 118: 1095–1098.PubMedGoogle Scholar
  27. 27.
    Berenson GS, Radhakrishnamurthy B, Dalferes ER Jr, et al: Carbohydrate macro-molecules and atherosclerosis. Hum Path 1971; 2: 57–79.PubMedCrossRefGoogle Scholar
  28. 28.
    Iverius PH: The interaction between human plasma lipoproteins and connective tissue glycosaminoglycans. J Biol Chem 1972; 247: 2607–2613.PubMedGoogle Scholar
  29. 29.
    Wissler RW: The arterial medial cell, smooth muscle cell or multifunctional mesenchyme? J Atheros Res 1968; 8: 201–213.CrossRefGoogle Scholar
  30. 30.
    Wissler RW: Atherosclerosis—its pathogenesis in perspective In: Homberger F (ed): Comparative pathology of the heart. Basel; Karger, 1974, pp 10–31.Google Scholar
  31. 31.
    Benditt EP, Benditt JM: Evidence for a monoclonal origin of human atherosclerotic plaques. Proc Nat Acad Sei 1973; 70: 1753–1756.CrossRefGoogle Scholar
  32. 32.
    Benditt EP: Implications of the monoclonal character of human atherosclerotic plaques. Am J Pathol 1977; 86: 693–702.PubMedGoogle Scholar
  33. 33.
    Pearson TA, Wang A, Solez K, et al: Clonal characteristics of fibrous plaques and fatty streaks from human aortas. Am J Pathol 1975; 81: 379–387.PubMedGoogle Scholar
  34. 34.
    Thomas WA, Reiner JM, Florentin RA, et al: Arterial smooth muscle cells in atherogenesis: births, deaths and clonal phenomena. In: Schettler G, Goto Y, Hata Y, et al (eds): Atherosclerosis IV. Berlin, Springer, 1977, pp 16–23.Google Scholar
  35. 35.
    Thomas WA, Janakidevi K, Florentin RA, et al: The reversibility of the human atherosclerotic plaque. In: Hauss WH, Wissler RW, Lehmann R (eds): International Symposium: State of Prevention and Therapy in Human Arteriosclerosis and in Animal Models. Opladen, Westdeutscher Verlag, 1978, pp 73–80.Google Scholar
  36. 36.
    Campbell GR, Chamley-Campbell JH; Smooth muscle phenotypic modulation: Role in atherogenesis. Med Hypoth 1981; 7: 729–735.CrossRefGoogle Scholar
  37. 37.
    Chamley-Campbell J, Campbell GR, Ross R; The smooth muscle cell in culture. Physiol Rev 1979; 59:1–61.PubMedGoogle Scholar
  38. 38.
    Kao VCY, Wissler RW, Dzoga K: The influence of hyperlipemic serum on the growth of medial smooth muscle cells of rhesus monkey aorta in vitro. Circulation 38(Suppl VI): 12.Google Scholar
  39. 39.
    Fischer-Dzoga K, Fraser R, Wissler RW: Stimulation of proliferation in stationary primary cultures of monkey and rabbit aortic smooth muscle cells. I. Effects of lipoprotein fractions of hyperlipemic serum and lymph. Exp Mol Pathol 1976; 24: 346–359.PubMedCrossRefGoogle Scholar
  40. 40.
    Fischer-Dzoga K, Wissler RW: Stimulation of proliferation in stationary primary cultures of monkey aortic smooth muscle cells. II. Effect of varying concentrations of hyperlipemic serum and low density lipoproteins of varying dietary fat origins. Atherosclerosis 1976; 24: 515–525.PubMedCrossRefGoogle Scholar
  41. 41.
    Wissler RW: Interactions of low-density lipoproteins from hypercholesterolemic serum with arterial wall cells and their extracellular products in atherogenesis and regression. In: Scanu A, Wissler RW, Getz GS (eds): The Biochemistry of Atherosclerosis. New York, Marcel Dekker Inc, 1978, pp 345–368.Google Scholar
  42. 42.
    Yoshida Y, Fischer-Dzoga K, Wissler RW: Effects of normolipidemic high-density lipoproteins on proliferation of monkey aortic smooth muscle cells induced by hyperlipidemic low-density lipoproteins. Exp Mol Pathol 1984; 41: 258–266.PubMedCrossRefGoogle Scholar
  43. 43.
    Miller NE: Prevention of coronary heart disease: The role of high density lipoproteins. Postgrad Med J 1980; 56: 575–578.PubMedCrossRefGoogle Scholar
  44. 44.
    Chen RM, Getz GS, Fischer-Dzoga K, et al: The role of hyperlipidemic serum on the proliferation and necrosis of aortic medial cells in vitro. Exp Mol Pathol 1977; 26: 359–374.PubMedCrossRefGoogle Scholar
  45. 45.
    Bates SR: Accumulation and loss of cholesterol esters in monkey arterial smooth muscle cells exposed to normal and hyperlipemic serum lipoproteins. Atherosclerosis 1979; 32: 165–176.PubMedCrossRefGoogle Scholar
  46. 46.
    Elates SR: Effect of HDL on the interaction of hyperlipemic LDL with monkey smooth muscle cells. Artery 1980; 7: 303–315.Google Scholar
  47. 47.
    Wissler RW, Fischer-Dzoga K, Bates SR, et al: Arterial smooth muscle cells in tissue culture. In: Schwartz CJ, Werthessen NT, Wolf S (eds): Structure and Function of the Circulation. New York, Plenum Press, 1981, vol III, pp 427–474.Google Scholar
  48. 48.
    Scanu AM, Edelstein C, Vitello L, et al: The serum high density lipoproteins of Macacus rhesus. I. Isolation, composition, and properties. J Biol Chem 1973; 248: 7648–7652.PubMedGoogle Scholar
  49. 49.
    Fless GM, Wissler RW, Scanu AM: Study of abnormal plasma low density lipoprotein in rhesus monkeys with diet-induced hyperlipidemia. Biochemistry 1976; 15: 5799–5805.PubMedCrossRefGoogle Scholar
  50. 50.
    Rudel LL, Pitts LLII, Nelson CA: Characterization of plasma low density lipoproteins of nonhuman primates fed dietary cholesterol. J Lipid Res 1977; 18: 211–222.PubMedGoogle Scholar
  51. 51.
    Fless GM, Kirchhausen T, Fischer-Dzoga K, et al: Relationship between the properties of the apo B containing low-density lipoproteins (LDL) of normolipidemic rhesus monkeys and their mitogenic action on arterial smooth muscle cells grown in vitro. In: Gotto AM Jr, Smith LC, Allen B (eds): Atherosclerosis V. New York, Springer-Verlag, 1980, pp 607–615.Google Scholar
  52. 52.
    Fless GM, Kirchhausen T, Fischer-Dzoga K, et al: Serum low-density lipoproteins with mitogenic effect on cultured aortic smooth muscle cells. Atherosclerosis 1982; 41: 171–183.PubMedCrossRefGoogle Scholar
  53. 53.
    Mahley RW: Atherogenic hyperlipoproteinemia: The cellular and molecular biology of plasma lipoproteins altered by dietary fat and cholesterol. Med Clin North Am 1982; 66: 375–402.PubMedGoogle Scholar
  54. 54.
    Mahley RW: Development of accelerated atherosclerosis: Concepts derived from cell biology and animal model studies. Arch Path Lab Med 1983; 107: 393–399.PubMedGoogle Scholar
  55. 55.
    Assmann G: Lipid Metabolism and Atherosclerosis. Stuttgart, Schattauer Verlag, 1982.Google Scholar
  56. 56.
    Schonfeld G: Disorders in lipid transport—update 1983. Prog Cardiovasc Dis 1983; 26: 89–108.PubMedCrossRefGoogle Scholar
  57. 57.
    Assmann G, Schmitz G, Menzel HJ, et al: Apolipoprotein E polymorphism and hyperlipidemia. Clin Chem 1984; 30: 641–643.PubMedGoogle Scholar
  58. 58.
    Sirtori CR, Franceschini G: Familial disorders of plasma apolipoproteins. Klin Wochenschr 1985; 63: 481–489.PubMedCrossRefGoogle Scholar
  59. 59.
    Ross R, Glomsett JA: Atherosclerosis and the arterial smooth muscle cells. Science 1973; 180: 1332–1339.PubMedCrossRefGoogle Scholar
  60. 60.
    Bulkley BH, Roberts WC: The heart in systemic lupus erythematosus and the changes induced in it by corticosteroid therapy: A study of 36 necropsy patients. Am J Med 1975; 58: 243–264.PubMedCrossRefGoogle Scholar
  61. 61.
    Wissler RW, Vesselinovitch D, Davis HR, et al: A new way to look at atherosclerotic involvement of the artery wall and the functional effects. Ann NY Acad Sei 1985; 454: 9–22.CrossRefGoogle Scholar
  62. 62.
    Wissler RW: Principles of the pathogenesis of atherosclerosis. In: Braunwald E (ed): Heart Disease: A Textbook of Cardiovascular Medicine ed 2. Philadelphia, WB Saunders Co, 1984, pp 1183–1204.Google Scholar
  63. 63.
    Ross R, Glomset JA: The pathogenesis of atherosclerosis. New Engl J Med 1976; 295: 420–425.PubMedCrossRefGoogle Scholar
  64. 64.
    Frederickson DS, Goldstein JL, Brown MS: The familial hyperlipoproteinemias. In: Stanbury JB, Wyngaarden JB, Frederickson DS (eds): The Metabolic Basis of Inherited Diseases. New York, McGraw-Hill, 1978, pp 604–605.Google Scholar
  65. 65.
    Roberts WC: The status of the coronary arteries in fatal ischemic heart disease. Cardiovasc Clin 1975; 7(2): 1–24.PubMedGoogle Scholar
  66. 66.
    Seftel HC, Baker SG, Sandler MP, et al: A host of hypercholesterolaemic homozygotes in South Africa. Brit Med J 1980; 281: 633–636.PubMedCrossRefGoogle Scholar
  67. 67.
    Goldstein JL, Brown MS: The low-density lipoprotein pathway and its relation to atherosclerosis. Ann Rev Biochem 1977; 46: 897–930.PubMedCrossRefGoogle Scholar
  68. 68.
    DeDuve C: The participation of lysosomes in the transformation of smooth muscle cells to foamy cells in the aorta of cholesterol-fed rabbits. Acta Cardiol 1974; 20(suppl): 9–25.PubMedGoogle Scholar
  69. 69.
    Steinberg D: Lipoproteins and atherosclerosis: A look back and a look ahead. Arteriosclerosis 1983; 3: 283–301.PubMedCrossRefGoogle Scholar
  70. 70.
    Goldstein JL, Ho YK, Basu SK, et al: A binding site on macrophages that mediates the uptake and degradation of acetylated low-density lipoproteins producing massive cholesterol deposition. Proc Nat Acad Sei 1979; 76: 333–337.CrossRefGoogle Scholar
  71. 71.
    Brown MS, Goldstein JL: Lipoprotein metabolism in the macrophage: implications for cholesterol deposition in atherosclerosis. Annual Rev Biochem 1983; 52: 223–261.CrossRefGoogle Scholar
  72. 72.
    Wissler RW, Vesselinovitch D: Atherosclerosis—relationship to coronary blood flow. Am J Cardiol 1983; 52: 2A-7A.PubMedCrossRefGoogle Scholar
  73. 73.
    Wissler RW, Vesselinovitch D: Experimental models of human atherosclerosis. Ann NY Acad Sei 1968; 149: 907–922.Google Scholar
  74. 74.
    Schaffner T, Einer VM, Bauer M, et al: Acid lipase: a histochemical and biochemical study using tri ton X100-naththyl palmitate micelles. J Histochem Cytochem 1978; 26: 696–712.PubMedCrossRefGoogle Scholar
  75. 75.
    Schaffner T, Taylor K, Bartucci EJ, et al: Arterial foam cells exhibit distinctive immunomorphologic and histochemical features of macrophages. Am J Pathol 1980; 100: 57–80.PubMedGoogle Scholar
  76. 76.
    Davis HR, Vesselinovitch D, Wissler RW: Reticuloendothelial system response to hyperlipidemia in rhesus and cynomolgus monkeys. J Leukocyte Biol 1984; 36: 63–80.PubMedGoogle Scholar
  77. 77.
    Davis HR, Wissler RW: Apoprotein B quantification in rhesus and cynomolgus monkey atherosclerotic lesions. Atherosclerosis 1984; 50: 241–252.PubMedCrossRefGoogle Scholar
  78. 78.
    Davis HR, Vesselinovitch D, Wissler RW: Histochemical detection and quantification of macrophages in rhesus and cynomolgus monkey atherosclerotic lesions. J Histochem Cytochem 1984; 32: 1319–1327.PubMedCrossRefGoogle Scholar
  79. 79.
    Daoud AS, Jarmolych J, Augustyn JM, et al: Regression of advanced atherosclerosis in swine. Arch Pathol Lab Med 1976; 100: 372–379.PubMedGoogle Scholar
  80. 80.
    Weber G, Fabbrini P, Resi L, et al: Regression of arteriosclerotic lesions in rhesus monkey aortas after regression diet: Scanning and transmission electron microscope observations of the endothelium. Atherosclerosis 1977; 26: 535–547.PubMedCrossRefGoogle Scholar
  81. 81.
    Daoud AS, Jarmolych J, Augustyn JM, et al: Sequential morphologic studies of regression of advanced atherosclerosis. Arch Pathol Lab Med 1981; 105: 233–239.PubMedGoogle Scholar
  82. 82.
    Watanabe Y: Serial inbreeding of rabbits with hereditary hyperlipidemia (WHHL-rabbit). Incidence and development of atherosclerosis and xanthoma. Atherosclerosis 1980; 36: 261–268.PubMedCrossRefGoogle Scholar

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© Springler-Verlag New York Inc. 1987

Authors and Affiliations

  • Robert W. Wissler
  • Dragoslava Vesselinovitch

There are no affiliations available

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