The risk factors for atherogenesis are well known - they include hypertension, obesity, hypercholesterolemia and smoking. The pathological appearances of the lesions at all stages of their development are also established. However, the picture is incomplete. The mechanism leading to the earliest arterial change - damage to the endothelium - is still unknown. Recently, attention has turned to the possible role of an intracellular bacterium, Chlamydia pneumoniae.

C. pneumoniae is responsible for about 10% of community-acquired pneumonia; however, most of the population has been exposed to the organism, but with only slight or no symptoms. In 1988 a Finnish epidemiological study first demonstrated an association between serological evidence of prior C. pneumoniae infection and the occurrence of coronary heart disease. Since then, subsequent studies have led to the conclusion that the presence of antibodies to C. pneumoniae is associated with a 2-fold increased relative risk for heart disease.

The presence of C. pneumoniae in atherosclerotic lesions has been demonstrated in 59% of affected arteries, compared with 3.1% in control arterial tissue, and the organism has been cultured from up to 16% of carotid atherosclerotic plaques. Moreover, the presence of C. pneumoniae in smooth muscle cells in the arterial intima is associated with cellular damage - vacuolization, loss of myofilaments, and lipid accumulation.

In spite of these reports, a causative role for C. pneumoniae in atherogenesis is not yet proven. It may be that the organism is merely an innocent bystander. Other infectious candidates have been nominated. Helicobacter pylori, a common cause of gastritis and peptic ulcer, is one. Another is human cytomegalovirus (HCMV), which is capable, in experimental studies, of inducing the migration of infected smooth muscle cells to the intima.¹ Doubtless other contenders will emerge. At all events, the role of an infectious agent - viral or bacterial - is becoming quite acceptable, even attractive.

Further support for this view comes from a recently reported study.² The serum level of acute phase C-reactive protein (CRP) is an established marker for systemic inflammation. Elevated levels have been shown to be associated with an increased risk of myocardial infarction, ischemic stroke, peripheral arterial disease, and coronary heart disease mortality. Overweight and obesity are also known risk factors for these conditions. The study examined whether overweight and obese people have elevated CRP levels, indicative of low-grade inflammation.

Over 16,000 men and women from the US Third National Health and Nutrition Examination Survey provided body weight, height, waist and hip measurements, and serum samples for CRP determinations. Body mass index (BMI) was calculated as weight in kilograms divided by the square of the height in meters. Serum cotinine levels were used to determine cigarette-smoking status, and a latex fixation test for rheumatoid factor was done in subjects over 60. Other possibly confounding factors were established by questionnaire.

For the purpose of analysis, the subjects were categorized into those with undetectable CRP (<0.22mg/dL), those with elevated CRP (>0.22 mg/d/L) and those with values indicative of inflammation (>1.0 mg/dL). Overweight was defined as BMI 25-29.9 kg/m2, and obesity as BMI >30 kg/m2.

Elevated CRP levels were present in 21.8% of men and 33.1% of women. The prevalence of raised CRP levels rose with increasing BMI: after adjusting for confounding factors such as smoking, obese men were 2.13 times and obese women 6.23 times more likely to have elevated CRP levels than normal-weight subjects. In women, clinically raised CRP levels (>1.0 mg/dL) were 4.76 times commoner in obese than in normal-weight women.

The authors of the study conclude that the results demonstrate a state of low-grade systemic inflammation in overweight and obese persons. Similar findings have been reported before in elderly people, but were somewhat suspect because of the prevalence of rheumatoid arthritis, diabetes and cardiovascular diseases in such persons. The present study controlled for such factors, and also extended the association to younger adults (17 to 39 years).

Adipose tissue is known to express the proinflammatory cytokine interleukin 6 (IL-6), which, amongst other activities, stimulates the production of acute-phase protein by the liver. Unfortunately, IL-6 could not be measured in the study just summarized - it's determination might have provided an additional dot in the picture being drawn of the relationship between infection and atherosclerosis. However, it must be noted that a direct association between CRP levels and coronary heart disease has not yet been established.

The fact that such direct links remain to be established has not deterred some investigators from conducting clinical trials of macrolide antibiotics in the secondary prevention of myocardial infarction. The success of statin drugs (HMGCoA-reductase inhibitors) in reducing cardiovascular mortality has been related to concomitant reductions in CRP levels, rather than their effect on cholesterol levels; indeed, the statins have been shown to have anti-inflammatory effects in vitro. It seems possible, therefore, that in the near future we shall have rational medications that will attack the basic mechanism of atherogenesis. In the meantime, however, there should be no let-up in the vigorous attention paid to other major risk factors, such as hypertension, smoking, diabetes etc.