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Chlamydia pneumoniae and Heart Desease

Introduction
The discovery of disease associations of the
Chlamydia strain TW-183 in 1985 led to speculation on
its ability to cause chronic inflammations typical for
other Chlamydia species. Since this agent causes
about 10% of all pneumonias, its association with
chronic obstructive pulmonary disease, asthma and
sarcoidosis was logical. Totally unexpected however,
was the association of this respiratory agent, now
called C. pneumoniae, with acute myocardial infarc-tion
and chronic coronary heart disease.
The alert came in 1988, when paired serum
samples, collected during acute myocardial infarction
episodes, showed a seroconversion against an epitope
of chlamydial lipolysaharide (LPS). This seroconversion
was examined in patients with chronic coronary hearth
disease (CHD), but in both patient groups elevated
antibody titers against C. pneumoniae were found
when compared to healthy matched controls. It was
suggested that chronic CHD patients had a chronic C.
peumoniae infection and acute myocardial infarction
was associated with an acute exacerbation of thisinfection (1). Later on, the rises of titers of antibodies
against chlamydial LPS were sugegested to be due to
relese of the antigen from damaged areas leading to a
subsequent temporal drop in titers when immune
complexes are formed with circulating antibodies (2).
The seroepidemiological association has been
verified in well over hundred studies in many laborato-ries
with different methods of serology. However, anti-bodies
alone, especially of IgG type, seem to be a
marker of atherosclerosis in common and thus have a
poor predictive value for cardiac events, which are
complications of this extremely prevalent disease
condition. Cross-sectional studies and samples col-lected
one to five years before infarction from relatively
young persons give understandably higher risk evalu-ations
(3). IgA antibodies, with their short half-life time,
have generally been better predictors of future cardiac
events than IgG antibodies. Presence of IgA antibodies
can also be a marker of the shift of immune response
from the T helper cells type Th1 to Th2 , which is not
effective against intracellular parasites. One should
always remember that antibodies alone do not show
the site of the infection and how active it is. They should
be combined with inflammation or autoimmunity mark-ers.
The persistent simultaneous presence of anti- C.
pneumoniae IgA antibodies, elevated markers of sys-temic
inflammation like elevated hsCRP, and markers
of autoimmunity like anti- Hsp-60 antibodies, all to-gether
are associated with a highly elevated risk for
cardiac event (4).
Seroepidemiology cannot prove or disprove a
casual association. The next important finding in these
studies was the demonstration of the agent directly in
atheroslerotic lesions, even in some patients without
antibodies. There are now nearly hundred studies, in
which the presence of C. pneumoniae in atheroscle-rotic
plaques has been shown by electron microscopy,
immunohistochemistry, polymerase chain reaction, in
situ hybridization and culture. Only rarely it has been
found in healthy areas of arteries. The results vary
between different laboratories but about half of the
atherosclerotic plaques have been reported to contain
C. pneumoniae elementary bodies, antigens or nucleic
acids. The amount of viable pathogen in this chronic
process seems to be minimal, which explains negative
reports from some laboratories (5). On the contrary,
even claims that all atherosclerotic plaques are in fact
positive if studied carefully enough, have been pre-sented
(6). This finding is unique, since among infec-tious
agents only herpes viruses (citomegalovirus,
HSV-1) have sometimes been found in atherosclerotic
plaques (7).

Mechanisms of association
The question is: what is this pathogen doing in
the plaques? Atherosclerosis is nowadays accepted
as an inflammatory lession (8). Some consider C.
pneumoniae only as an innocent bystander that has
achieved entry into plaques carried within inflamma-tory
cells, which have entered the lesion. Several
studies have reported circulating monocytes contain-ing
C. pneumoniae nucleic acid. Evidence supporting
the active participation of C. pneumoniae in the
atheroslerotic inflammatory process is steadily accu-mulating
(9). C. pneumoniae can multiply in the en-dothelial
and smooth muscle cells of the vessel wall
and this leads to production of adhezins, cytokines,
growth and tissue factors. Macrophages turning to
foam cells are the main cells of atherosclerotic lesions
(Fig. 1). Moreover, C. pneumoniae infected
macrophages start to ingest low-density-lipoprotein
and oxidase it, resulting in formation of foam cells (10).
Some of these reactions can be induced with purified
Chlamydia components, like lipopolisaharid (LPS) and
Chlamydia Hsp-60. In chronic Chlamydia infection,
Chlamydia Hsp-60 is produced in large amounts and it
is found in plaques alongside human Hsp60. The
continuous presence of Chlamydia Hsp60 may even-tually
lead to autoimmune reaction against human
Hsp60 due to cross-reactive epitopes shared by these
highly conserved proteins (9).
Atherosclerosis is a multifactorial disease. There
are many risk factors which may be implicated in the
pathogenesis. Several risk factors may be associated
with chronic C. pneumoniae infection or may be partly
its reflection (Table 1). Since the majority of individuals
are exposed to C. pneumoniae infection during their
Fig. 1: Electron micrograph of Chlamydia pneumoniae in
a foam cell in the coronary artery atheroma (A) and in an
interstitial macrophage of the lung from a mouse inocu-lated
intranasally with C. pneumoniae (B). Note the typical
pear-shaped morphology of the elementary body of C.
pneumoniae (arrows); 9,300x magnification (10).lifetime, dose, route of infection and genetic factors
from both, the host and the pathogen may determine
the final outcome. The frequent persistence of C.
pneumoniae in the lungs of even apparently healthy
persons, provides a continuous source of infectious
monocytes leaking into circulation (11,12). Chronic
infection leads to elevated cytokine production, which
may lead to fatigue and depression, which are also risk
factors for atherosclerosis (Fig. 2). Physical activity
improves immune defense mechanisms and protects
against cardiac events. Chronic C. pneumoniae infec-tion
is associated with lipid profile typical for CHD
(elevated triglyceride and cholesterol concentrations
and lowered high-density-lipoprotein). Markers of in-flammation
found in atherosclerosis, like CRP, can be
due to chronic C. pneumoniae infection (Fig. 3). Im-mune
defense mechanisms of smokers are hampered.
Some reports have evaluated the association of the
presence of chronic C. pneumoniae with obesity and
elevated blood pressure and C. pneumoniae also
seems to be a factor in the metabolic syndrome.
Pathogenetic mechanisms through which C.
pneumoniae could affect the development of athero-sclerosis
(7) are presented on Fig. 4.
Animal models are important in the studying of
aterosclerosis and fortunately several models are avail-able
for C. pneumoniae. When rabbits are inoculated
intranasally with C. pneumoniae, those on normal diet
develop atherosclerotic lesions, and in rabbits on a diet
enriched with cholesterol, the development of lesions
is enhanced. This effect is prevented by macrolides if
given early in the development of the disease. Myco-plasma
pneumoniae given intranasally to rabbits pro-duces
a generalised infection, but it does not lead to
focal lesion in arteries (14). In mouse experiments (15),
both normal and gene-knock-out mice have been used.
Cholesterol should usually be added in the diet of mice.
The development of the atherosclerotic lesions is
accelerated by repeated intranasal inoculations of C.
pneumoniae. Interestingly, C. trachomatis (strain
mouse pneumonitis) produces similar systemic infec-tion
in mice and can be detected in the aorta after
Fig. 2: Endothelial Dysfunction in Atherosclerosis. The
earliest changes that precede the formation of lesions of
atherosclerosis take place in the endothelium. These
changes include increased endothelial permeability to
lipoproteins and other plasma constituents, which is me-diated
by nitric oxide, prostacyclin, platelet-derived growth
factor, angiotensin II, and endothelin; up-regulation of
leukocyte adhesion molecules, including L-selectin,
integrins, and platelet-endothelial-cell adhesion molecule
1, and the up-regulation of endothelial adhesion mol-ecules,
which include E-selectin, P-selectin, intercellular
adhesion molecule 1, and vascular-cell adhesion mol-ecule
1; and migration of leukocytes into the artery wall,
which is mediated by oxidized low-density lipoprotein,
monocyte chemotactic protein 1, interleukin-8, platelet-derived
growth factor, macrophage colony-stimulating
factor, and osteopontin (13).
Fig. 3: Unstable Fibrous Plaques in Atherosclerosis. Rup-ture
of the fibrous cap or ulceration of the fibrous plaque
can rapidly lead to thrombosis and usually occurs at sites
of thinning of the fibrous cap that covers the advanced
lesion. Thinning of the fibrous cap is apparently due to the
continuing influx and activation of macrophages, which
release metalloproteinases and other proteolytic enzymes
at these sites. These enzymes cause degradation of the
matrix, which can lead to hemorrhage from the vasa
vasorum or from the lumen of the artery and can result in
thrombus formation and occlusion of the artery (13).intranasal inoculation. However, it does not persist
there and does not cause the development of athero-sclerosis.
Pigs are also infected and apes are chroni-cally
infected with C. pneumoniae, but studies on
possible atherosclerosis induced in them are lacking.
Final evidence can be found after intervention and
vaccination trials. Original small studies were
encourageing and several large-scale placebo-control-led
intervention studies were started even before any-one
knew of treatment for chronic Chlamydia infection.
The results of these large trials, typically in advanced
atherosclerosis in order to prevent secondary myocar-dial
infarctions, have been disappointing (16). Even
prolonged one or two year monotherapy was not
effective (17, 18). There can be several reasons for this
failure. Perhaps when trying to prevent secondary
events the disease has proceeded further, so that it
cannot be treated with antibiotic therapy. Moreover, in
animal experiments monotherapy has not eradicated
chronic C. pneumoniae infection (19). C. pneumoniae
infection of human monocytes has been resistant to
antibiotics (20) as shown in a chronic infection cell
culture model (21). In intervention trials, no similar fall
in specific antibodies after successful eradication of
helicobacter has been reported. Azitromycin treat-ment
alone for C. pneumoniae in mice was not suc-cessful
but in combination with rifampicin, it was
effective in erdicating agent from chronically infected
mice (22). The problem of the treatment of chronic C.
pneumoniae infection should be solved in cell cultures
and animal experiments before new human interven-tion
trials are started. Until then, we can continue using
CHD drugs that have demonstrated anti-C. pneumoniae
activity- aspirin(23) and statins (24) inhibiting cytokine
expression and bacterial development in human en-dothelial
cells.

References
1. Saikku P, Leinonen M, Mattila K, Ekman MR, Nieminen
MS, Mäkelä PH, Huttunen JK, Valtonen V. Serological evi-dence
of an association of a novel Chlamydia, TWAR,
with chronic coronary heart disease and acute myocar-dial
infarction. Lancet. 1988;2(8618):983-6. doi:10.1016/
S0140-6736(88)90741-6 PMID: 2903406
2. Leinonen M, Linnanmäki E, Mattila K, Nieminen MS,
Valtonen V, Leirisalo-Repo M, Saikku P. Circulating im-mune
complexes containing chlamydial lipopolysaccha-ride
in acute myocardial infarction. Microb Pathog.
1990;9(1):67-73. doi:10.1016/0882-4010(90)90042-O
PMID:2077346
3. Arcari CM, Gaydos CA, Nieto FJ, Krauss M, Nelson KE.
Association between Chlamydia pneumoniae and acute
myocardial infarction in young men in the United States
military: the importance of timing of exposure measure-ment.
Clin Infect Dis. 2005;40(8):1123-30. doi:10.1086/
428730 PMID:15791511
4. Huittinen T, Leinonen M, Tenkanen L, Virkkunen H,
Mänttäri M, Palosuo T, Manninen V, Saikku P. Synergistic

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