Atherosclerosis constitutes the most common medical and surgical problem. This can be mani fested clinically as stroke, coronary artery disease, or peripheral vascular disease. In the present review the microscopic appearance of the normal arterial wall, the definition of atherosclerosis and the five theories of atherogenesis are described. These are: the lipid theory, the hemody namic theory, the fibrin incrustation theory, the nonspecific mesenchymal hypothesis and the response to injury hypothesis. Based on the above theories the sequence of events in athero genesis is analyzed. The classification of the atherosclerotic lesions according to Stary (types I-VI) and their characteristics appear in a table. The epidemiology and the role of the following risk factors are presented in detail: age, sex, lipid abnormalities, cigarette smoking, hyperten sion, diabetes mellitus, physical inactivity, alcohol consumption, obesity, and hemostatic factors. In addition, less common genetically determined associations like homocystinuria, Tangier disease, Hutchinson-Gilford syndrome (progeria), Werner's syndrome, radiation induced ather osclerosis and the implications of Chlamydia pneumoniae on the arterial wall are discussed.
Get full access to this article
View all access options for this article.
References
1.
Johansson B. , Norrving B., Lindgren A.: Increased stroke incidence in Lund-Orup, Sweden, between 1983 to 1985 and 1993 to 1995. Stroke31:481-486, 2000.
2.
LaRosa JC, He J., Vupputuri S.: Effect of statins on risk of coronary disease. A meta-analysis of randomized controlled trials. JAMA282:2340-2346, 1999 .
3.
Criqui MH, Denenberg JO, Langer RD, et al: The epidemiology of peripheral arterial disease: Importance of identifying the population at risk. Vasc Med2:221-226, 1997.
4.
Ham AW: Histology: Arteries and Arterioles, ed. 8. Philadelphia: JB Lippincott, 1979 , pp 592-600.
5.
Woolf N.: Pathology of atherosclerosis. Br Med Bull46:960-985, 1990.
6.
Davies MJ, Woolf N.: Atherosclerosis: What is it and why does it occur? Br Heart J69(suppl 1):3-11, 1993.
7.
Stary HC, Chandler B., Glakov S., et al: A definition of initial, fatty streak, and intermediate lesions of atherosclerosis. Circulation89:2462-2478, 1994.
8.
Stary HC, Chandler B., Dinsmore RE, et al: A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. Atherosclerosis Thromb Vasc Biol15:1512-1531, 1995.
9.
McGill HC Jr: Fatty streaks in the coronary arteries and aorta. Lab Invest18:560-564, 1968.
10.
Smith EB, Slater RS: Relationship between low-density lipoprotein in aortic intima and serum-lipid levels. Lancet26:463-469, 1972.
11.
Yamauchi Y. , Hoff HF: Apolipoprotein B accumulation and development of foam cell lesions in coronary arteries of hypercholesterolemic swine. Lab Invest51:325-332, 1984.
12.
Smith EB: Transport, interactions and retention of plasma proteins in the intima: The barrier function of the internal elastic lamina. Eur Heart J Suppl E:72-81, 1990.
13.
Zhang Y., Cliff WJ, Schoefl GI, et al: Plasma protein insudation as an index of early coronary atherogenesis . Am J Pathol143:496-506, 1993.
14.
Bondjiers G. , Wiklund O., Fager G., et al: Transfer of lipoprotein from plasma to the cell population of the normal and atherosclerotic arterial tissue. Eur Heart J Suppl E:158-163, 1990.
15.
Davies PF, Dewey CF, Bussolari SR, et al: Influence of hemodynamic forces on vascular endothelial function. In vitro studies of shear stress and pinocytosis in bovine aortic cells. J Clin Invest73:1121-1129,1984.
16.
Ku DN, Giddens DP, Zarins CK, et al: Pulsatile flow and atherosclerosis in human carotid bifurcation. Positive correlation between plaque location and low oscillating shear stress . Arteriosclerosis5:293-302, 1985.
17.
Glagov S., Zarins CK, Giddens DP, et al: Hemodynamics and atherosclerosis. Insights and perspectives gained from studies of human arteries. Arch Pathol Lab Med112:1018-1031, 1988.
18.
Rokitansky CV: A Manual of Pathologic Anatomy. London: The Syndenham Society, 1952, pp 265-275.
19.
Duguid JB: Thrombus as a factor in the pathogenesis of coronary atherosclerosis . J Pathol Bacteriol58:207, 1946.
20.
Hand RA, Chandler AB: Atherosclerotic metamorphosis of autologous pulmonary thromboemboli in the rabbit. Am J Pathol40:469-486, 1962.
21.
Badimon L., Chesebro JH, Badimon JJ: Thrombus formation on ruptured atherosclerotic plaques and rethrombosis on evolving thrombi. Circulation86 (suppl III):74-85, 1992.
22.
Berenson GS , Radhakrishnamurthy B., Srinivasan SR, et al: Carbohydrate-protein macromolecules and arterial wall integrity—a role in atherogenesis. Exp Mol Pathol41:267-287, 1984.
23.
Hauss WH: Changes in metabolism of connective tissue associated with aging and arterio- or atherosclerosis. J Atherosclerosis Res6:50, 1962.
24.
Ross R., Glomset JA: The pathogenesis of atherosclerosis (first of two parts). N Engl J Med295:369-377, 1976.
25.
Ross R., Glomset JA: The pathogenesis of atherosclerosis (second of two parts). N Engl J Med295:420-425, 1976.
26.
Ross R.: The pathogenesis of atherosclerosis—an update. N Engl J Med341:488-500, 1986.
27.
Fuster V., Badimon JJ, Badimon L.: Clinical-pathological correlation of coronary disease progression and regression . Circulation86(suppl III):1-11, 1992.
28.
Williams KJ , Tabas I.: The response to injury hypothesis of early atherogenesis. Atherosclerosis Thromb Vasc Biol15:551-561, 1995.
29.
Valente AJ, Rozek MM, Sprague EA, et al: Mechanisms in intimal monocyte-macrophage recruitment. Circulation86 (suppl III) :20-25, 1992.
30.
Gerrity RG: The role of the monocyte in atherogenesis : I. Transition of blood-borne monocytes into foam cells in fatty lesions. Am J Pathol103:181-190, 1981.
31.
Taylor RG, Lewis JC: Endothelial cell proliferation and monocyte adhesion to atherosclerotic lesions of white carneau pigeons. Am J Pathol125:152-160, 1986.
32.
Jurgens G., Hoff HF, Chisolm GM, et al: Modification of human serum low density lipoprotein by oxidation—characterisation and pathophysiological implications. Chem Phys Lipids45:315-336, 1987.
33.
Steinberg D. , Parthasarathy S., Carew TE, et al: Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity . N Engl J Med320:915-924, 1989.
34.
Wolfbauer G. , Glick JM, Minor LK, et al: Development of the smooth muscle foam cell: Uptake of macrophage lipid inclusions. Proc Natl Acad Sci USA83:7760-7764, 1986 .
35.
DiCorleto PE , Bowen-Pope DF: Culture endothelial cells produce a platelet-derived growth factor-like protein . Proc Natl Acad Sci USA80:1919-1923, 1983 .
36.
Raines EW, Ross R.: Smooth muscles cells and the pathogenesis of the lesions of atherosclerosis . Br Heart J69 (suppl) :30-37, 1993.
37.
Barrett TB, Benditt EP: Sis (Platelet-derived growth factor B chain) gene transcript levels are elevated in human atherosclerotic lesions compared to normal artery. Proc Natl Acad Sci USA84:1099-1103, 1987 .
38.
Clowes AW, Clowes MM, Fingerle J., et al: Regulation of smooth muscle cell growth in injured artery. J Cardiovasc Pharmacol14(suppl 6):12-15, 1989.
39.
Campbell GR , Campbell JH: Smooth muscle phenotypic changes in arterial wall homeostasis: Implications for the pathogenesis of atherosclerosis . Exp Mol Pathol42:139-162, 1985.
40.
Gown AM, Tsukada T., Ross R.: Human atherosclerosis. II. Immunocytochemical analysis of the cellular composition of human atherosclerotic lesions. Am J Pathol125:191-207, 1986.
41.
Hansson GK, Jonasson L., Seifert PS, et al: Immune mechanisms in atherosclerosis. Arteriosclerosis9:567-578, 1989.
42.
Munro JM, Cotran RS: The pathogenesis of atherosclerosis : Atherogenesis and inflammation . Lab Invest58:249-261, 1988.
43.
Hansson GK, Hellstrand M., Rymo L., et al: Interferon gamma inhibits both proliferation and expression of differentiation—specific alpha-smooth muscle actin in arterial smooth muscle cells. J Exp Med170:1595-1608, 1989 .
44.
Hansson GK, Holm J., Jonasson L.: Detection of activated T lymphocytes in the human atherosclerotic plaque. Am J Pathol135:169-175, 1989.
45.
Bostrom K., Watson KE, Stanford WP, et al: Atherosclerotic calcification: Relation to developmental osteogenesis . Am J Cardiol75:88B-91B, 1995.
46.
Berger CA, Beeuwkes R.: Rupture of coronary vasa vasorum as a trigger of acute myocardial infarction . Am J Cardiol66:41G-43G, 1990.
47.
Falk E., Fernandez-Ortiz A.: Role of thrombosis in atherosclerosis and its complications. Am J Cardiol75:5B-11B, 1995.
48.
Glagov S., Weisenberg E., Zarins CK, et al: Compensatory enlargement of human atherosclerotic coronary arteries . N Engl J Med316:1371-1375, 1987 .
49.
Davies MJ, Thomas A.: Thrombosis and acute coronary-artery lesions in sudden cardiac ischemic death . N Engl J Med310:1137-1140, 1984 .
50.
Falk E.: Unstable angina with fatal outcome: Dynamic coronary thrombosis leading to infarction and/or sudden death. Autopsy evidence of recurrent mural thrombosis with peripheral embolisation culminating in total vascular occlusion. Circulation71:699-708, 1985.
51.
Davies MJ, Thomas A.: Plaque fissuring-the cause of acute myocardial infarction, sudden ischaemic death, and crescendo angina. Br Heart J53:363-373, 1985.
52.
Shah PK, Falk E., Badimon JJ, et al: Human monocyte-derived macrophages induce collagen breakdown in fibrous caps of atherosclerotic plaques. Circulation92:1565-1569, 1995.
53.
Richardson PD, Davies MJ, Born Gvr: Influence of plaque configuration and stress distribution on fissuring of coronary atherosclerotic plaques. Lancet21:941-944, 1989.
Fuster V., Stein B., Ambrose JA, et al: Atherosclerotic plaque rupture and thrombosis. Circulation82 (suppl II) :47-59, 1990.
56.
Falk E.: Coronary thrombosis: Pathogenesis and clinical manifestations. Am J Cardiol68:28B-38B, 1991.
57.
Prins MH, Hirsh J.: A critical review of the relationship between impaired fibrinolysis and myocardial infarction. Am Heart J2:545-551, 1991.
58.
Merlini PA, Bauer KA, Oltrona L., et al: Persistent activation of coagulation mechanism in unstable angina and myocardial infarction. Circulation90:61-68, 1994.
59.
Kannel WB, McGee DL: Diabetes and cardiovascular risk factors: The Framingham study. Circulation59:8-13, 1979.
60.
Fulberg CD, Adams HP, Applegate WB, et al: Effect of lovastatin on early carotid atherosclerosis and cardiovascular events. Circulation90:1679-1687, 1994 .
61.
Sacks FM, Pfeffer MA, Moye LA, et al: The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med335:1001-1009, 1996.
62.
Downs JR, Clearfield M., Weis S., et al: Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels. JAMA279:1615-1622, 1998.
63.
Macmahon S. , Sharpe N., Gamble G., et al: Effects of lowering average or below-average cholesterol levels on the progression of carotid atherosclerosis. Circulation97:1784-1790, 1998.
64.
West of Scotland Coronary Prevention Study Group: Influence of pravastatin and plasma lipids on clinical events in the West of Scotland Coronary Prevention Study (WOSCOPS). Circulation97:1440-1445, 1998 .
65.
Pedersen TR , Olsson AG, Faergeman O., et al: Lipoprotein changes and reduction in the incidence of major coronary heart disease events in the Scandinavian Simvastatin Survival Study. Circulation97:1453-1460, 1998.
66.
Castelli WP, Garrison RJ, Wilson PW, et al: Incidence of coronary heart disease and lipoprotein cholesterol levels. JAMA256:2835-2838, 1986 .
67.
Bostom AG, Gagnon DR, Cupples A., et al: A prospective investigation of elevated lipoprotein (a) detected by electrophoresis and cardiovascular disease in women. Circulation90:1688-1695, 1994.
68.
Hammond EC, Horn D.: Smoking and death rates— report on forty-four months of follow-up of 187,783 men. CA Cancer J Clin38:28-58, 1988.
69.
Willett WC, Green A., Stampfer MJ, et al: Relative and absolute excess risks of coronary heart disease among women who smoke cigarettes. N Engl J Med317:1303-1309, 1987.
70.
Criqui MH, Wallace RB, Heiss G., et al: Cigarette smoking and plasma high-density lipoprotein cholesterol : The Lipid Research Clinics Program Prevalence Study. Circulation62:IV70-76, 1980.
71.
Meade TW, Imeson J., Stirling Y.: Effects of changes in smoking and other characteristics on clotting factors and the risk of ischaemic heart disease. Lancet31:986-988, 1987.
72.
Kannel WB, Dawber TR, McGee DL: Perspectives on systolic hypertension. The Framingham study. Circulation61:1179-1182, 1980 .
73.
Stamler J., Stamler R., Neaton JD: Blood pressure, systolic and diastolic, and cardiovascular risks. US population data. Arch Intern Med153:598-615, 1993.
74.
Reunanen A. : Mortality in type 2 diabetes. Ann Clin Res15 (suppl 37):26-28, 1983.
75.
Fuller JH, Shipley MJ, Rose G., et al: Mortality from coronary heart disease and stroke in relation to degree of glycaemia: The Whitehall study. Br Med J (Clin Res Ed)24:867-870, 1983.
76.
Leon AS, Connett J., Jacobs DR Jr, et al: Leisure-time physical activity levels and risk of coronary heart disease and death. The Multiple Risk Factor Intervention Trial. JAMA258:2388-2395, 1987 .
77.
Berlin JA, Colditz GA: A meta-analysis of physical activity in the prevention of coronary heart disease . Am J Epidemiol132:612-628, 1990.
78.
Sacco RL, Benjamin EG, Broderick JP, et al: Risk factors (AHA conference proceedings). Stroke28:1507-1517, 1997.
79.
Fraser GE, Upsdell M.: Alcohol and other discriminants between cases of sudden death and myocardial infarction. Am J Epidemiol114:462-476, 1981.
80.
Gordon T., Kannel WB: Drinking habits and cardiovascular disease: The Framingham Study. Am Heart J105:667-673, 1983.
81.
Moore RD, Pearson TA: Moderate alcohol consumption and coronary artery disease. A review. Medicine (Baltimore) 65:242-267, 1986.
82.
Stampfer MJ , Colditz GA, Willett WC, et al: A prospective study of moderate alcohol drinking and risk of diabetes in women. Am J Epidemiol128:549-558, 1988.
83.
Criqui MH, Cowan LD, Tyroler HA, et al: Lipoproteins as mediators for the effects of alcohol consumption and cigarette smoking on cardiovascular mortality: Results from the Lipid Research Clinics Follow-up Study. Am J Epidemiol126:629-637, 1987.
84.
Gaziano JM, Buring JE, Breslow JL, et al: Moderate alcohol intake, increased levels of high-density lipoprotein and its subfractions, and decreased risk of myocardial infarction. N Engl J Med329:1829-1834, 1993 .
85.
Mann GV: The influence of obesity on health (second of two parts). N Engl J Med291:226-232, 1974.
86.
Hubert HB: The importance of obesity in the development of coronary risk factors and disease: The epidemiologic evidence. Annu Rev Public Health7:493-502, 1986.
87.
Harlan WR, Landis JR, Flegal KM, et al: Secular trends in body mass in the United States, 1960-1980 . Am J Epidemiol128:1065-1074, 1988 .
88.
The PoolingProject Research Group: Relationship of blood pressure, serum cholesterol, smoking habit, relative weight and ECG abnormalities to incidence of major coronary events: Final report of the pooling project . Chronic Dis31:201-306, 1978.
89.
Noppa H., Bengtsson C., Wedel H., et al: Obesity in relation to morbidity and mortality from cardiovascular disease. Am J Epidemiol111:682-692, 1980.
90.
Tuomilehto J., Salonen JT, Marti B., et al: Body weight and risk of myocardial infarction and death in the adult population of eastern Finland. Br Med J (Clin Res Ed)295:623-627, 1987.
91.
Meade TW, Mellows S., Brozovic M., et al: Haemostatic function and ischaemic heart disease: Principal results of the Northwick Park Heart Study. Lancet8506:533-537, 1986.
92.
Rainer C., Kawanishi DT, Chandraratna PA, et al: Changes in blood rheology in patients with stable angina pectoris as a result of coronary artery disease. Circulation76:15-20, 1987.
93.
Yarnell JW, Baker IA, Sweetnam PM, et al: Fibrinogen, viscosity, and white blood cell count are major risk factors for ischemic heart disease. The Caerphilly and Speedwell collaborative heart disease studies. Circulation83:836-844, 1991.
94.
Yang XC, Jing TY, Resnick LM, et al: Relation of hemostatic risk factors to other risk factors for coronary heart disease and to sex hormones in men. Arteriosclerosis Thromb13:467-471, 1993.
95.
Green D., Ruth KJ, Folsom AR, et al: Hemostatic factors in the Coronary Artery Risk Development in Young Adults (CARDIA) Study. Arteriosclerosis Thromb14:686-693, 1994.
96.
Ernst E., Resch KL: Fibrinogen as a cardiovascular risk factor: A meta-analysis and review of the literature. Ann Intern Med118:956-963, 1993.
97.
Trip MD, Cats VM, van Capelle FJ, et al: Platelet hyperreactivity and prognosis in survivors of myocardial infarction. N Engl J Med322:1549-1554, 1990.
98.
Thaulow E., Erikssen J., Sandvik L., et al: Blood platelet count and function are related to total and cardiovascular death in apparently healthy men. Circulation84:613-617, 1991.
99.
Gaull GE: Homocystinuria, vitamin B6, and folate: Metabolic interrelationships and clinical significance. J Pediatr81:1014-1018, 1972.
100.
Boers GH, Smals AG, Trijbels FJ, et al: Heterozygosity for homocystinuria in premature peripheral and cerebral occlusive arterial disease. N Engl J Med313:709-715, 1985.
101.
Schaefer EJ , Zech LA, Schwartz DE, et al: Coronary heart disease prevalence and other clinical features in familial high-density lipoprotein deficiency (Tangier disease). Ann Intern Med93:261-266, 1980.
102.
DeBusk FLThe Hutchinson-Gilford progeria syndrome. Report of 4 cases and review of the literature. J Pediatr80:697-724, 1972.
103.
Salk D.: Werner's syndrome: A review of recent research with an analysis of connective tissue metabolism, growth control of cultured cells, and chromosomal aberrations . Hum Genet62:1-5, 1982.
104.
Levinson SA , Close MB, Ehrenfeld WK, et al: Carotid artery occlusive disease following external cervical irradiation. Arch Surg107:395-397, 1973.
105.
Campbell LA , O'Brien ER, Cappuccio AL, et al: Detection of Chlamydia pneumoniae TWAR in human coronary atherectomy tissues. J Infect Dis172:585-588, 1995.
106.
Grayston JT , Kuo CC, Coulson AS, et al: Chlamydia pneumoniae (TWAR) in atherosclerosis of the carotid artery. Circulation92:3397-3400, 1995.
107.
Juvonen J. , Juvonen T., Laurila A., et al: Demonstration of Chlamydia pneumoniae in the walls of abdominal aortic aneurysms. J Vasc Surg25:499-505, 1997.
108.
Kuo CC, Coulson AS, Campbell LA, et al: Detection of Chlamydia pneumoniae in atherosclerotic plaques in the walls of arteries of lower extremities from patients undergoing bypass operation for arterial obstruction. J Vasc Surg26:29-31, 1997.
