© 1997 American Heart Association, Inc.
Articles |
Chronic Chlamydia pneumoniae Infection Is Associated With a Serum Lipid Profile Known to Be a Risk Factor for Atherosclerosis
From the National Public Health Institute (A.L., A.B., M.L., P.S.), and the Regional Institute of Occupational Health (S.N., J.H.), Oulu, Finland.
Correspondence to Aino Laurila, MD, National Public Health Institute, Department in Oulu, Aapistie 1, PO Box 310, FIN-90101 Oulu, Finland. E-mail aino.laurila{at}ktl.fi
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Abstract |
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Abstract Chlamydia pneumoniae infection has been associated with coronary heart disease. To evaluate the mechanisms of this association, we studied whether chronic C. pneumoniae infection affects serum lipid values similarly to acute infections. Triglyceride, total and HDL cholesterol concentrations, and C. pneumoniae antibodies were measured from paired serum samples of 415 Finnish males taken 3 years apart. Chronic infection, defined as persistent IgG and IgA antibodies, was found in 20%, and the antibodies were negative (IgG<32 and IgA<16 in both samples) in 15% of the cases studied. The serum triglyceride and total cholesterol concentrations were higher in the subjects with a chronic C. pneumoniae infection than in the subjects with no antibodies (1.23 versus 1.03 mmol/L and 6.41 versus 6.31 mmol/L, respectively). The HDL cholesterol concentrations and the ratios of HDL cholesterol to total cholesterol were significantly decreased in the subjects with chronic infection (1.24 versus 1.36 mmol/L, P=.026; and 0.19 versus 0.22, P=.018, respectively). Chronic C. pneumoniae infection seems to be associated with a serum lipid profile considered to increase the risk of atherosclerosis. This finding supports the hypothesis that infections play a role in the pathogenesis of atherosclerosis.
Key Words: antibodies • triglycerides • cholesterol • HDL cholesterol • atherosclerosis
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Introduction |
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Chlamydia pneumoniae infection has recently been associated with acute myocardial infarction and coronary heart disease.1 2 The presence of Chlamydia organisms in atherosclerotic lesions has also been demonstrated by polymerase chain reaction, immunohistochemistry, and electron microscopy in more than half of the patients studied.3 4 However, the causal relationship between C. pneumoniae and atherosclerosis has remained unresolved.
Acute microbial infections are known to affect the lipid metabolism in both experimental animals and humans.5 6 We have shown earlier that profound changes in serum lipids are seen in acute pneumonia caused by C. pneumoniae: triglyceride concentrations are clearly elevated and HDL cholesterol levels decreased compared with the values in patients with pneumonia caused by other bacteria or viruses.7 In our previous cross-sectional study, we also showed a significant association between the presence of C. pneumoniae–specific IgG antibodies, elevated serum triglyceride, and lowered HDL cholesterol concentrations in a male population in Northern Finland.8 To further evaluate the possible association between chronic C. pneumoniae infection and atherosclerosis, we studied the serum lipid values and the persistence of C. pneumoniae antibodies suggestive of chronic infection in 415 males from Northern Finland.
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Methods |
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Study Population
The study population consisted of the men who participated in the reindeer herders' health survey performed in 1985-1989.9 The all-male basic population consisted of men engaged in reindeer herding in Finland in 1985. In 1986, a postal inquiry about social background, work, smoking, disease symptoms, and other factors was sent out to 3720 males, of whom 2705 responded. The study group was then divided into three parts. A medical examination was performed on one group (639 men), a dietary interview was conducted in one group (661 men; the intervention group), and the third group served as control subjects. Blood samples were obtained from all members of the medical examination group and every third member of the intervention group, altogether 883 men. Another inquiry was performed 2 years later, and blood samples were collected from 1053 men according to similar principles in 1989. Of these 1053 men, 415 had also given a blood sample during the earlier study, and 415 paired samples were hence available. The blood samples were taken at 8 to 11 AM after a 12-hour fast. The blood was allowed to clot for 30 minutes, centrifuged, and the serum was frozen at -20°C.
Measurement of Serum Lipids
The total cholesterol, HDL cholesterol,
and triglyceride concentration measurements were performed
in the laboratory of the University Hospital of Oulu by routine
enzymatic methods from 279 samples obtained in 1986 and from all
samples obtained in 1989.
Serological Studies
C. pneumoniae–specific serum IgG and IgA antibodies
were determined by the microimmunofluorescence
method using C. pneumoniae strain Kajaani 6 and C.
trachomatis strain L2 elementary bodies as antigens and
fluorescein isothiocyanate–conjugated anti-human IgG
(Kallestad) and IgA (Sigma) antibodies. The serum samples were
analyzed at fourfold dilutions starting from 1:32 for IgG and
1:16 for IgA in a blinded fashion. The persistence of IgG (
32) and
IgA (16) antibodies in paired serum samples over the 3-year period
was considered a sign of chronic C. pneumoniae infection.
These titres are considered as the positive cutoff points in our
laboratory.10
Statistical Analyses
Analysis of covariance with age as a covariate
was used to test the serum triglyceride, total
cholesterol, and HDL cholesterol concentrations
and the HDL cholesterol:total cholesterol
ratios between the subjects with no antibodies and the subjects with
persistent IgG and IgA antibodies in the two smoking groups. The
statistical analyses were performed with the SPSS and SAS
statistical software.
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Results |
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The study group consisted of 415 males aged between 17 and 80 years (mean 45, SD 12 years). One hundred eleven men were current daily smokers, 15 smoked occasionally, and 63 had quit smoking less than 10 years ago. The 8 men who had quit smoking over 10 years ago were classified as nonsmokers.
The prevalence of positive C. pneumoniae–specific IgG and
IgA antibody titres increased with age, as shown in Table 1
. In 1986, 29% of the youngest age
group were IgG negative, while only 11% of the oldest age group were
negative. The IgG antibody prevalences and geometric mean titres were
generally higher in 1986 than in 1989, whereas the IgA antibody
prevalences and geometric mean titres were lower in 1986 than in 1989.
However, the changes were not statistically significant.
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Persistent C. pneumoniae antibodies (IgG32 and IgA16 in
both samples), suggestive of chronic infection, were present in
20% (83/415) of the men studied, and the antibodies were negative
(IgG<32 and IgA<16 in both samples) in 15% (62/415) of the subjects.
The percentage of men with suspected chronic infection increased with
age, being 0% in men aged under 25 and 28% in those aged 56 to 65
(Table 2). Current smokers more often had
persistent antibodies present than either ex-smokers or nonsmokers,
the percentages being 24%, 19%, and 16%, respectively.
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The geometric mean triglyceride concentration of the whole study group rose somewhat during the follow-up, from 1.0 (range 0.2 to 5.0) mmol/L in 1986 to 1.1 (0.3 to 6.1) mmol/L in 1989, while the mean total cholesterol concentration declined from 6.5 (3.4 to 16.5) mmol/L to 6.4 (3.3 to 10.1) mmol/L. The mean HDL cholesterol also rose from 1.2 (0.5 to 2.8) mmol/L to 1.3 (0.7 to 3.1) mmol/L, respectively. The changes were slightly more pronounced in the subjects with an increase in antibody titres than in the subjects with no change in titres, but the differences were not statistically significant.
In the statistical analysis, cases with no C.
pneumoniae antibodies were compared with cases with chronic
infection. In the nonsmoker group, the geometric mean
triglyceride concentration (interquartile range) was higher
in the subjects with chronic C. pneumoniae infection than in
the subjects with no signs of infection (1.19 [0.88 to 1.65]
mmol/L versus 0.94 [0.66 to 1.26] mmol/L;
P=.045), as shown in Fig 1.
The mean total cholesterol concentration was also higher in
the infection group than in the seronegative group (6.7 [5.7 to
7.4] mmol/L versus 5.9 [5.2 to 6.6] mmol/L;
P=.004), but the mean HDL cholesterol
concentration and the geometric mean ratio of HDL
cholesterol to total cholesterol were lower
(1.29 [1.11 to 1.5] mmol/L versus 1.38 [1.14 to
1.45] mmol/L; P=.3 and 0.19 [0.16 to 0.23]
versus 0.23 [0.19 to 0.27]; P=.009, respectively). In the
smoker group, the differences in the lipid values were similar with the
exception of total cholesterol, which was somewhat lower in
the subjects with chronic infection than in the seronegative subjects.
A statistically significant decrease was found in the HDL
cholesterol levels (mean 1.16 [0.99 to 1.33]
mmol/versus 1.42 [1.19 to 1.52] mmol/L;
P=.001) and the HDL cholesterol:total
cholesterol ratio (geometric mean 0.17 [0.14 to 0.22]
versus 0.21 [0.17 to 0.25]; P=.027).
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Discussion |
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We showed in the present study that Finnish men who have had C. pneumoniae–specific IgG and IgA antibodies persistently present for over a 3-year period have elevated triglycerides and total cholesterol and lowered HDL cholesterol levels in their sera, suggesting that chronic C. pneumoniae infection is associated with altered lipid metabolism. Changes in lipid metabolism are well recognized in the pathogenesis of atherosclerosis. Increased triglyceride concentrations, decreased HDL cholesterol, and especially a decreased HDL cholesterol:total cholesterol ratio are known to be important risk factors in this respect. Recently, several chronic infections, in addition to those caused by C. pneumoniae, have also been connected to atherosclerosis. Associations of dental infections, as well as Helicobacter pylori infections, with coronary heart disease in males have been demonstrated.11 12 Apart from the effect of infection on lipid metabolism, the increase in fibrinogen concentrations in subjects with antibodies against C. pneumoniae or H. pylori might be a pathogenetic mechanism of this association.13
The persistence of elevated antibody titres is generally considered a sign of chronic infection.1 14 15 After an acute C. pneumoniae infection, IgG antibody titres rise and usually decrease slowly,16 whereas IgA antibodies tend to disappear rapidly, the half-life of IgA being only 5 to 6 days. In reinfection, the IgA response is often prominent, and elevated IgA titres have been considered a reliable marker of chronic bacterial infection caused by Pseudomonas aeruginosa in cystic fibrosis,14 Helicobacter pylori in gastritis,15 and C. pneumoniae in chronic bronchitis17 18 and coronary heart disease.10 On this basis, the persistence of IgG and especially IgA antibodies-in this study for over a three-year period-could be taken as a marker of chronic C. pneumoniae infection. C. pneumoniae caused a widespread epidemic in northern Finland in 1986. This was reflected as a higher IgG antibody prevalence and higher titres in 1986 than in 1989. Interestingly, the IgA antibody prevalence and titres were higher in 1989 than in 1986, especially in the oldest age groups, suggesting that some men have become chronically infected during the epidemic.
Acute microbial infections have a remarkable effect on lipid
metabolism.5 Infections caused by
Gram-negative bacteria have been shown especially to affect
triglyceride and HDL cholesterol levels. The
phenomenon has been attributed to the action of
lipopolysaccharide (LPS), an endotoxin that is a typical
constituent of a Gram-negative cell wall. LPS is an efficient inducer
of several cytokines, eg, tumor necrosis factor-
(TNF).
Administration of LPS, which mimics infection or TNF in both primates
and Syrian hamsters, causes a decline of HDL cholesterol
levels,19 20 which could be attributed to a decrease in
plasma lecithin:cholesterol acyltransferase
activity.21 22 Furthermore, administration of TNF or
interleukin-1 (IL-1) results in a rapid elevation of serum
triglyceride levels followed by a later rise in
cholesterol levels.23 24 The cytokine-
and LPS-induced alterations in lipid metabolisms can be
considered to be part of the acute-phase response and thus also
beneficial to the host.
C. pneumoniae is a Gram-negative bacterium with LPS as a major constituent of its outer membrane. Even though chlamydial LPS has been shown to have lower endotoxin activity25 than enterobacterial LPS, C. pneumoniae is able to induce the production of TNF and IL-1 in a blood mononuclear cell fraction.26 We have shown earlier that macrophages in atherosclerotic lesions are frequently stained with a monoclonal antibody specific to chlamydial LPS, indicating the presence of LPS inside these cells.4 The persistent presence of C. pneumoniae particles27 28 and their LPS in atherosclerotic lesions may induce continuous low-level production of TNF and IL-1 and thus lead to the kind of altered lipid profile shown to be a risk factor for coronary heart disease.
We have demonstrated earlier that C. pneumoniae–specific IgG antibodies are associated with elevated serum triglyceride and lowered HDL cholesterol concentrations.8 This study confirmed the previous finding, and moreover, it seems that persistent C. pneumoniae antibodies suggesting chronic infection are more strongly associated with an altered lipid profile than merely the presence of antibodies at a certain time point.8 We showed here that persistent C. pneumoniae antibodies suggestive of chronic infection correlate with the kind of altered serum lipid profile considered to increase the risk of atherosclerosis. This observation supports the hypothesis that infections, in this case C. pneumoniae infection, play a role in the pathogenesis of atherosclerosis. However, we cannot exclude the possibility that persons with altered serum lipid profiles have an increased susceptibility to C. pneumoniae infection. The final resolution of the causal relationship between C. pneumoniae infection and altered lipid metabolism could be obtained in intervention trials in which the eradication of infection with antibiotic treatment would lead to the normalization of serum lipid values.
Received March 4, 1997; accepted May 27, 1997.
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