Updates Linking Evidence and Experience
Chlamydia pneumoniae and Atherosclerosis
Allan Shor, MMed; James I. Phillips, PhD
Atherosclerosis is a major cause of stroke, coronary heart disease,
peripheral vascular disease, and aortic aneurysm. Because of the prevalence
and importance of these diseases, atherosclerotic lesions within arteries
have been extensively studied.1, 2
While many risk factors have been identified,1, 2
the mechanism by which the lesions are formed remains unknown. The most popular
concept is that the endothelium lining the lumen of the artery becomes damaged.
This damage alters the properties of the endothelium and leads to a cascade
of events culminating in fibrosis, necrosis, lipid accumulation, and eventually
calcification. There have been several candidates forwarded as putative initiators
of endothelial injury including microorganisms.1
Recent studies have shown an association between an obligate intracellular
bacterium, Chlamydia pneumoniae, and atherosclerosis.3, 4
Chlamydia pneumoniae was first described by
Grayston et al5 in 1986. Seroepidemiological
studies have concluded that the majority of the population has been exposed
to the organism.6 While C pneumoniae appears to cause 10% of community-acquired pneumonia,
infection is typically mild or asymptomatic.7
The association of the organism with heart disease was first demonstrated,
serologically, in a Finnish population.8 This
association has been shown in subsequent studies.9, 10
A meta-analysis of seroepidemiological studies demonstrated that overall,
having antibodies to C pneumoniae conferred a 2-fold
relative risk for heart disease.11 The strength
of the serological association and heart disease varies from study to study
and some of the variation may be due to methods.12
The association of C pneumoniae and atherosclerotic
lesions itself was first shown in 1992 in a South African population.13 This association has been established in several
countries, in a wide range of arteries, using a variety of techniques, such
as polymerase chain reaction (PCR), immunocytochemistry, immunofluorescence,
in situ hybridization, enzyme immunoassay, and electron microscopy.14, 15 Using these methods, on average, C pneumoniae is detected in 59% of atheromatous arteries
and in only 3.1% of control arterial tissue.14
Although PCR has been the most common method used, it does not appear to give
the most consistent results16 and has been
associated with detection rates in atherosclerotic lesions from 0%17 to 100%.18 The standardization
of the PCR technique has been called for.12, 19
Chlamydia pneumoniae has been cultured from
atherosclerotic arteries, attesting to the viability of the organism in the
lesion,20-22 with
some laboratories reporting a 16% recovery rate for atherosclerotic lesions.23 Reverse transcriptase PCR has also indicated that
the organisms are viable in atherosclerotic plaques of the carotid artery.24
There is much speculation as to the role C pneumoniae may play in initiating or contributing to atherosclerosis.15, 25 A MEDLINE search of the terms C pneumoniae and atherosclerosis
from 1991 to August 1999 produced 155 references, of which only 70 (45%) present
original data and the remaining 85 (55%) offer an opinion, present a hypothesis,
or review the subject. Opinion varies from the organism being an innocent
bystander to a causative agent.7, 14
However strong the association, causality cannot simply be implied.
Criteria that determine whether an association is causal have been examined
for C pneumoniae and atherosclerosis and many of
the criteria are fulfilled.4 To test the hypothesis
of causality, clinical trials using antibiotics to eradicate C pneumoniae have been initiated.26
The reported findings from these early trials27-30
suggest antibiotics may confer some benefit; however, the trials were small
and the results by no means conclusive. It has been suggested that the benefits
might be ascribed to the anti-inflammatory properties of the antibiotics used
rather than their antichlamydial properties.12
Larger antibiotic trials are in progress but not complete.26
Animal studies indicate that C pneumoniae can accelerate
the development of atherosclerosis and antibiotic administration can prevent
it.31
Another line of investigation is to examine the pathology of the lesion
with respect to the presence of C pneumoniae. Such
investigations have shown the organism to be present in the earliest stages
of the lesion, adding weight to the argument that it plays an initiating role
rather than being a secondary invader.4 To
date, most of the studies that demonstrate C pneumoniae in atherosclerotic lesions have largely dealt with the question of
presence of the organism. Some of the techniques used such as PCR do not allow
visualization of C pneumoniae, and information about
which cell types are affected by the organism come from in situ hybridization,
immunocytochemistry, and electron microscopy. Apart from 1 report of weak
positive staining using immunocytochemistry,32 C pneumoniae has not been demonstrated in human arterial
endothelium in vivo. In atherosclerotic arteries, however, it has been reported
in smooth muscle cells and macrophages of the intima. The intima of the artery
is the innermost layer and includes the endothelium, underlying connective
tissue, and smooth muscle on the luminal side of the internal elastic lamina.
This intimal layer has been referred to as the battleground of the atherosclerotic
process.33 Using in situ hybridization, heavy
staining for C pneumoniae has been reported in the
intimal layer of an atherosclerotic coronary artery.20
Immunoperoxidase double-labeling techniques have localized chlamydial antigens
to both smooth muscle cells and infiltrating macrophages.32, 34-36
Transmission electron microscopy has identified structures with the morphologic
features of C pneumoniae in smooth muscle cells and
macrophages of the intima of atherosclerotic arteries that are positive for C pneumoniae by PCR or immunocytochemical techniques.3, 4, 13, 37-39
While only 1 study to date has examined the pathology of the atherosclerotic
lesion with respect to the presence of C pneumoniae,38 previous studies have noted that the presence of
the organism in smooth muscle cells is associated with cellular damage.3, 4, 13, 37, 39
The damage takes the form of vacuolation of the smooth muscle cells (Figure 1 and Figure 2) with a concomitant loss of intracellular myofilaments
and an accumulation of intracellular lipid. We also have noted that fragmented
smooth muscle cells are often associated with C pneumoniae and these fragments, with their accompanying organisms, are engulfed
by macrophages (Figure 2). The presence
of C pneumoniae in macrophages in association with
fragmented extracellular matrix adjacent to apoptotic and necrotic cells of
the intima has recently been reported elsewhere.37
It has been suggested that macrophages carry C pneumoniae from the lungs to arteries.25, 34, 40
An alternative mechanism to account for the presence of the organism in macrophages
may be through engulfing damaged, infected, smooth muscle cells.38
In summary, the presence of C pneumoniae in
many atherosclerotic lesions can no longer be disputed.14
The organisms have been demonstrated to be viable20-24
and present in early lesions.4, 13
They have been identified in the smooth muscle cells of the intima and are
associated with pathological changes.4, 37-39
Determining the exact nature of the association between C pneumoniae and atherosclerosis is extremely important. If C pneumoniae is found to be causal or to significantly contribute to
the lesion, some of the world's major diseases become amenable to new regimens
for treatment or prevention. Chlamydia pneumoniae
fulfills many of the criteria for causality.4
Attempts to test the causality hypothesis have revolved around antibiotic
intervention. So far studies in animal and human subjects have not been conclusive.27-31, 41
Larger trials are needed and the lesion itself needs to be examined to determine
the effects of antibiotic treatment.42 Future
researchers should be cognizant of the fact that the lesion is not sterile.
If C pneumoniae plays a role in atherosclerosis,
the underlying pathological process needs to be elucidated.
Author/Article Information
Author Affiliations: National Centre for Occupational
Health (Drs Shor and Phillips) and South African Institute for Medical Research,
School of Pathology, University of the Witwatersrand, (Dr Shor) Johannesburg,
South Africa.
Corresponding Author and Reprints: Allan
Shor, MMed, National Centre for Occupational Health, PO Box 4788, Johannesburg
2000, South Africa (e-mail: AShor@ncoh.pwv.gov.za).
Edited by Margaret A. Winker, MD, Deputy
Editor, JAMA.
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