Atherosclerosis is an inflammatory disease. Because high plasma concentrations of cholesterol, in particular those of low-density lipoprotein (LDL) cholesterol, are one of the principal risk factors for atherosclerosis,1 the process of atherogenesis has been considered by many to consist largely of the accumulation of lipids within the artery wall; however, it is much more than that. Despite changes in lifestyle and the use of new pharmacologic approaches to lower plasma cholesterol concentrations,2,3 cardiovascular disease continues to be the principal cause of death in the United States, Europe, and much of Asia.4,5 In fact, the lesions of atherosclerosis represent . . .

https://www.nejm.org/doi/pdf/10.1056/NEJM199901143400207

Atherosclerosis — An Inflammatory Disease

Atherosclerosis is an Inflammatory Disease

This report is the continuation of two earlier reports that defined human arterial intima and precursors of advanced atherosclerotic lesions in humans. This report describes the characteristic components and pathogenic mechanisms of the various advanced atherosclerotic lesions. These, with the earlier definitions of precursor lesions, led to the histological classification of human atherosclerotic lesions found in the second part of this report. The Committee on Vascular Lesions also attempted to correlate the appearance of lesions noted in clinical imaging studies with histological lesion types and corresponding clinical syndromes. In the histological classification, lesions are designated by Roman numerals, which indicate the usual sequence of lesions progression. The initial (type I) lesion contains enough atherogenic lipoprotein to elicit an increase in macrophages and formation of scattered macrophage foam cells. As in subsequent lesion types, the changes are more marked in locations of arteries with adaptive intimal thickening. (Adaptive thickenings, which are present at constant locations in everyone from birth, do not obstruct the lumen and represent adaptations to local mechanical forces). Type II lesions consist primarily of layers of macrophage foam cells and lipid-laden smooth muscle cells and include lesions grossly designated as fatty streaks. Type III is the intermediate stage between type II and type IV (atheroma, a lesion that is potentially symptom-producing). In addition to the lipid-laden cells of type II, type III lesions contain scattered collections of extracellular lipid droplets and particles that disrupt the coherence of some intimal smooth muscle cells. This extracellular lipid is the immediate precursor of the larger, confluent, and more disruptive core of extracellular lipid that characterizes type IV lesions. Beginning around the fourth decade of life, lesions that usually have a lipid core may also contain thick layers of fibrous connective tissue (type V lesion) and/or fissure, hematoma, and thrombus (type VI lesion). Some type V lesions are largely calcified (type Vb), and some consist mainly of fibrous connective tissue and little or no accumulated lipid or calcium (type Vc).

A Definition of Advanced Types of Atherosclerotic Lesions and a Histological Classification of Atherosclerosis A Report From the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association

Serological evidence of an association of a novel Chlamydia, TWAR, with chronic coronary heart disease and acute myocardial infarction.

Inflammation, obesity, stress and coronary heart disease: is interleukin-6 the link?

Chlamydia pneumoniae is a human respiratory pathogen that causes acute respiratory disease and approximately 10% of community-acquired pneumonia. The infections are geographically widespread. Antibody prevalence studies have shown that virtually everyone is infected with the C. pneumoniae organisms at some time and that reinfection is common. In addition to respiratory disease, seroepidemiologic studies have shown an association of this organism with coronary artery disease. C. pneumoniae was detected in coronary artery atheromas by immunocytochemistry (15/36) and by polymerase chain reaction (PCR) (13/30) in 20 of 36 autopsy cases from Johannesburg, South Africa. Sequence analysis of the C. pneumoniae rRNA genes amplified by PCR confirmed that the amplified gene products were C. pneumoniae. Electron microscopy revealed typical pear-shaped C. pneumoniae elementary bodies in 6 of 21 atheromatous plaques. These findings support the seroepidemiologic studies and offer further evidence that C. pneumoniae may be involved in the atherosclerotic process.

Demonstration of Chlamydia pneumoniae in Atherosclerotic Lesions of Coronary Arteries

There is serological evidence that a recently described new strain of Chlamydia, namely Chlamydia pneumoniae TWAR, is associated with coronary artery disease. This study describes the detection of TWAR organisms in the coronary arterial fatty streaks and atheromatous plaques in 7 autopsy cases. TWAR-like organisms were observed ultrastructurally in the lipid-rich core area of fibrolipid plaques and in intimal smooth-muscle cells. In 5 cases, immunoperoxidase staining showed positive reactions to Chlamydia genus- and C. pneumoniae species-specific monoclonal antibodies.

Detection of Chlamydia pneumoniae in coronary arterial fatty streaks and atheromatous plaques.

An association of Chlamydia pneumoniae with atherosclerosis of coronary and carotid arteries and aorta has been found by seroepidemiology and by demonstration of the organism in atheromata. Age-matched control tissue from persons without atherosclerosis was usually not available. We studied autopsy tissue from young persons, many with no atherosclerosis, to determine whether C. pneumoniae is present in atheroma in young persons with early atherosclerosis and to compare the findings in age- and sex-matched persons without atherosclerosis. A left anterior descending coronary artery sample, formalin-fixed, from 49 subjects, 15-34 years of age, from the multicenter study called Pathobiological Determinants of Atherosclerosis in Youth (PDAY), was examined by immunocytochemistry and the polymerase chain reaction (PCR) for the presence of C. pneumoniae and by PCR for cytomegalovirus. A hematoxylin/eosin-stained section was used to determine disease present in the studied sample. Seven of the artery samples were found to have atheromatous plaque, 11 had intimal thickening, and 31 had no lesions. Eight of the samples were positive for C. pneumoniae by immunocytochemistry (n = 7) and/or PCR (n = 3). Six of the 7 (86%) atheroma, 2 of the 11 (18%) with intimal thickening, and none of the 31 normal-appearing coronary samples were positive. Four were positive by PCR for cytomegalovirus, 2 from diseased arteries and 2 from normal arteries. Examination of the adjacent left coronary artery sample with a fat stain found abnormalities in 25 of the patients, but 19 still showed no evidence of atherosclerosis as a result of either examination. Thus, C. pneumoniae is found in coronary lesions in young adults with atherosclerosis but is not found in normal-appearing coronary arteries of both persons with and without other evidence of atherosclerosis.

https://www.pnas.org/content/pnas/92/15/6911.full.pdf

Chlamydia pneumoniae (TWAR) in coronary arteries of young adults (15-34 years old)

Recent evidence has shown the presence of Chlamydia pneumoniae antigens and nucleic acid in coronary artery atheromas from autopsy patients in South Africa. In this study, the immunocytochemical technique was used to demonstrate C pneumoniae antigens in atheromas of the aorta in autopsy patients from retrospective aortic atherosclerosis studies at the University of Washington. The patients were 34 to 58 years old. Immunoperoxidase staining using Chlamydia-specific monoclonal antibodies showed one of four fatty streaks and six of 17 fibrous plaques were positive for C pneumoniae antigens; four control aortic tissues were negative. Two of the positive plaques were from the same patient. Double-label immunocytochemical staining using Chlamydia- and tissue type-specific monoclonal antibodies demonstrated the antigens in the cytoplasm of macrophages and smooth muscle cells in the atheromatous lesion. This study suggested a wider involvement of C pneumoniae organisms in atherosclerotic lesions of the arterial system than has previously been documented.

Detection of Chlamydia pneumoniae in aortic lesions of atherosclerosis by immunocytochemical stain.

Chlamydia pneumoniae has been postulated to cause systemic disease by infection of monocytes/macrophages and spread via the blood or lymphatics. To investigate how C. pneumoniae disseminates, the ability of the organism to infect murine macrophages in vivo and whether infection can be transferred via macrophages were determined. C. pneumoniae was detected by direct plating, isolation, and polymerase chain reaction in alveolar macrophages from intranasally inoculated mice and peritoneal macrophages from intraperitoneally inoculated mice. C. pneumoniae were also detected in peripheral blood mononuclear cells, but not plasma, of intranasally and intraperitoneally inoculated mice. When alveolar or peritoneal macrophages were adoptively transferred by intraperitoneal injection from infected to uninfected mice, C. pneumoniae DNA was detected by polymerase chain reaction in lung, thymus, spleen, and/or abdominal lymph nodes. These results demonstrate the ability of C. pneumoniae to infect macrophages in vivo and to disseminate systemically via infected macrophages by hematogenous and lymphatic routes.

C. C. Kuo

Papers

Demonstration of Chlamydia pneumoniae in Atherosclerotic Lesions of Coronary Arteries

Detection of Chlamydia pneumoniae in coronary arterial fatty streaks and atheromatous plaques.

Chlamydia pneumoniae (TWAR) in coronary arteries of young adults (15-34 years old)

Detection of Chlamydia pneumoniae in aortic lesions of atherosclerosis by immunocytochemical stain.

Evidence of Systemic Dissemination of Chlamydia pneumoniae via Macrophages in the Mouse