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Chlamydia pneumoniae Seropositivity and Systemic and Renovascular Atherosclerotic Disease
Andre J. A. M. van der Ven, MD, PhD;
Marianne J. Hommels;
Abraham A. Kroon, MD, PhD;
Anton Kessels, MD;
Karin Flobbe, MSc;
Jos van Engelshoven, MD, PhD;
Catrien A. Bruggeman, PhD;
Peter W. de Leeuw, MD, PhD
Arch Intern Med. 2002;162:786-790.
ABSTRACT
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Background Patients with hypertension may be vulnerable to vascular Chlamydia pneumoniae and/or cytomegalovirus (CMV) infection because
of increased expression of adhesion molecules.
Objective To determine whether C pneumoniae or CMV is
associated with the presence of atherosclerotic lesions in hypertensive patients.
Methods Ninety-six angiographic studies on 100 consecutive patients with of
clinical signs or symptoms suggestive of renovascular hypertension were reviewed
for the presence or absence of atherosclerotic lesions at the level of the
renal arteries as well and abdominal aorta. Also, the presence of a hemodynamically
notable renal artery stenosis and antibodies to C pneumoniae (IgG and IgA) and CMV (IgG and IgM) was determined, and all classic
risk factors were recorded.
Results Atherosclerotic lesions were documented in 67 patients (70%), and in
49 patients (51%) such lesions were persent at the level of the renal artery.
In the univariate analysis, significant associations between IgG (odds ratio,
3.8; 95% confidence interval, 1.2-11.7; P = .02)
as well as IgA (odds ratio, 2.6; 95% confidence interval, 1.1-6.7; P = .03) antibodies to C pneumoniae and the
presence of atherosclerosis were found for both the aorta and the renal arteries.
Seroprevalence (IgG) to C pneumoniae in the 23 patients
with a hemodynamically notable renal artery stenosis was 100% and differed
(P = .01) from those without a notable renal artery
stenosis (78%). In the multivariate analysis, IgG seropositivity to C pneumoniae was significantly associated with atherosclerosis
(odds ratio, 6.0; 95% confidence interval, 1.33-27.5; P = .02), and age. There was no association between CMV seropositivity
and atherosclerosis.
Conclusion The presence of antibodies to C pneumoniae
was significantly associated with atherosclerosis and renovascular disease
in hypertensive patients in whom a renal artery stenosis was strongly suspected.
INTRODUCTION
HIGH BLOOD pressure, elevated serum cholesterol level, and smoking are
major risk factors for the development of atherosclerosis. Although still
disputed, an increasing body of evidence suggests that Chlamydia pneumoniae and, to a lesser extent, cytomegalovirus (CMV)
infection may also be involved in the pathogenesis of atherosclerosis.1-3 Some studies indicate
that there is an interaction between these infections and the classical risk
factors for atherosclerosis.4 For instance, C pneumoniae is more common in smokers5-6
and infections in general, and more specific C pneumoniae can induce proatherogenic changes in lipoprotein metabolism.7 The possible interaction between vascular infections
and hypertension in the development of atherosclerotic disease has received
little attention, although hypertension may favor a C pneumoniae or CMV infection. In hypertension, elevated levels of adhesion molecules
have been reported,8 possibly induced by angiotensin.9 These adhesion molecules allow for the recruitment
of monocytes to the vascular tree, supporting neointimal monocyte infiltration,
which is a key step in atheroma formation. The recruitment of infected monocytes
into the plaque, (thereby introducing an infection in the plaque) may significantly
contribute to the process of premature atherosclerosis.
Angiographic studies have only visualized the coronary arteries and
may have been biased toward the selection of patients with unstable plaques.10-14
In our hospital, an intra-arterial digital subtraction renal angiography is
carried out in hypertensive patients in whom a renal artery stenosis is suspected.
During this investigation, a large segment of the aorta below the diaphragma
was visualized as well. Moreover, renal angiography is often carried out in
relatively young patients, in whom symptoms of extensive vascular disease
are mostly absent.
We speculated that in hypertensive patients a C pneumoniae and/or a CMV infection contribute to the development of atherosclerotic
lesions, including those of the renal arteries. After all, renal artery stenoses
are mostly considered only one facet of generalized atherosclerotic disease.15-17 The present study
was designed to determine whether C pneumoniae or
CMV seropositivity is associated with angiographically demonstrated atherosclerotic
lesions in the renal artery and/or the aorta below the diaphragma in hypertensive
patients.
PARTICIPANTS AND METHODS
SUBJECTS
Between October 1998 and October 1999, we investigated 100 consecutive
patients with hypertension of a suspected renovascular origin who attended
the hypertension outpatient clinic of the University Hospital Maastricht,
Maastricht, the Netherlands. The diagnosis of hypertension was made when office
systolic blood pressure was above 140 mm Hg and/or diastolic blood pressure
was above 90 mm Hg on at least 3 different occasions. If on the basis of clinical
or ultrasound data renovascular disease was suspected, patients underwent
digital subtraction angiography. Other major causes of secondary hypertension
were excluded biochemically before the patients underwent angiography of the
renal arteries. The following clinical criteria were used to select patients
for angiography: treatment-resistant hypertension (ie, elevated blood pressure
despite treatment with 2 or more antihypertensive drugs), renal dysfunction
induced by an angiotensin-converting enzyme inhibitor, smoking and diastolic
blood pressure above 110 mm Hg, malignant or accelerated hypertension, and
extrarenal atherosclerosis in 2 or more organ systems. Demographic characteristics
and risk factors such as smoking, diabetes mellitus, and lipid disorders were
recorded. Hypercholesterolemia was defined as a serum total cholesterol level
of above 251 mg/dL (6.5 mmol/L), and combined hyperlipidemia was diagnosed
if triglyceride level was above 195 mg/dL (2.2 mmol/L) as well. At the time
angiography was performed, blood was collected, and 2 mL of serum was obtained
by centrifugation and stored at -80°C until serological analysis.
Written informed consent was obtained from all patients, and the medical ethical
committee of the Maastricht University hospital had approved the study protocol.
SEROLOGICAL TESTS AND RADIOLOGICAL EVALUATION
Serum IgG and IgA antibodies against C pneumoniae were detected using an enzyme-linked immunoabsorbent assay (C pneumoniae IgG and IgA detection kits; Labsystems, Helsinki,
Finland). The presence or absence of IgG and IgA antibodies against C pneumoniae was determined by comparing the absorbance
value of the sample with a cutoff value, as specified by the manufacturer.
Specimens with values greater than the cutoff value (IgG >30 enzyme immunounits
and IgA >8 enzyme immunounits) were positive. This assay shows good agreement
with the microimmunofluorescence method,18-19
which was confirmed in our laboratory. When we tested 83 blood samples from
healthy donors, a sensitivity of 95% and a specificity of 100% were recorded
with the microimmunofluorescence assay as the gold standard. For the qualitative
detection of IgM antibodies against CMV in serum, the ImX CMV assay (Abbott
Laboratories, Abbott Park, Ill) was used, while IgG was measured semiquantitatively
by the AXSym (Abbott Laboratories). Both tests are based on microparticle
enzyme immunoassay technology. Specimens with values above the cutoff value
(IgG >15 antibody units/mL and IgM index value >0.4 g/L) were considered positive.20 All serological studies were performed in a blinded
fashion.
Digital subtraction angiographies were reviewed by 2 independent radiologists
for the presence or absence of atherosclerotic lesions in both renal arteries
and the aorta below the diaphragma. Results were given on the basis of consensus.
If the results of the 2 radiologists did not agree, a third independent radiologist
reevaluated the radiographs and defined the outcome of these cases. The presence
of hemodynamically notable renal artery stenosis was recorded as well if there
was more than a 50% stenosis in 1 or both of the renal arteries and/or an
indication for renal artery angioplasty (venoarterial renin ratio >1.5).
STATISTICAL ANALYSIS
The association of atherosclerotic lesions with C
pneumoniae and CMV antibodies, age, sex, smoking habits, diabetes,
hyperlipidemia, and severity of hypertension was analyzed by univariate regression
and expressed as odds ratios (ORs) with 95% confidence intervals (CIs). With
a multivariate logistic regression model, ORs for the C
pneumoniae and CMV antibodies and their 95% CIs were determined and
adjusted for age, sex, smoking habits, diabetes, hyperlipidemia, and the severity
of hypertension. Patients were divided according to age in quartiles as follows:
quartile 1, 23 to 45 years; quartile 2, 46 to 52 years; quartile 3, 53 to
63 years, and quartile 4, 64 to 78 years. The  2 test or, when
appropriate, Fisher exact test (both 2-sided), was used to test for significance.
A P value of .05 was considered statistically significant.
Statistical analysis was performed with SSPS software (SSPS Inc, Chicago,
Ill) for personal computer.
RESULTS
Because of incomplete angiographic study results, the analyses were
performed on data from 96 of the 100 patients who comprised our study. Demographic
characteristics and the distribution of the classic risk factors for atherosclerosis
in patients with and without angiographically demonstrated atherosclerotic
lesions are presented in Table 1.
Mean age and sex differed between patients with and without atherosclerosis.
Patients with documented atherosclerosis were significantly older (58 years
vs 45 years; P<.001) and more often men (68% vs
41%; P = .02) compared with those without atherosclerosis.
Atherosclerotic lesions at the level of the renal artery were found in 49
patients (mean age, 58 ± 11 years), and in 23 patients (mean age, 61
± 11 years) a hemodynamically notable renal artery stenosis was found.
Fibromuscular dysplasia of the renal artery was documented in 9 patients,
8 of whom had IgG antibodies to C pneumoniae. The
patients with fibromuscular dysplasia of the renal artery were evaluated for
the presence or absence of an atherosclerotic lesion but were excluded from
the evaluation if a hemodynamically notable renal artery stenosis was present.
The presence or absence of an atherosclerotic lesion in patients with fibromuscular
disease can be well assessed, and C pneumoniae, like
the classic risk factors, may also contribute to the development of atherosclerosis.
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Table 1. Characteristics of All Hypertensive Patients With or Without
Documented Atherosclerosis*
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IgG and IgA antibodies to C pneumoniae were
found in 80 (83%) and 64 (67%) of the hypertensive patients, respectively.
All patients with elevated IgA antibodies also had elevated IgG antibodies
to C pneumoniae. Table 2 demonstrates the percentage of patients with elevated C pneumoniae and CMV antibodies in relation to the angiographic
findings. Atherosclerotic lesions were observed in 67 patients (70%), and
in those patients, IgG antibodies to C pneumoniae
were significantly more often demonstrated compared with hypertensive patients
without atherosclerosis (60 [90%] vs 20 [69%]; P
= .02). IgG antibodies to C pneumoniae were also
significantly more present in patients with renal atherosclerotic disease
(44 [90%] vs 20 [69%]; P = .04) or a notable renal
artery stenosis (23 [100%] vs 20 [69%]; P = .003)
compared with those without atherosclerosis. The association between IgA antibodies
and atherosclerosis (49 [73%] vs 15 [52%]; P = .03)
or a notable renal artery stenosis (19 [83%] vs 15 [52]%; P = .04) was also statistically significant. IgG and IgM antibodies
to CMV were found in 41 [43%] and 7 [7%] of patients, respectively, while
seropositivity for CMV (both IgG and IgM) in patients with or without atherosclerosis
did not differ significantly.
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Table 2. Percentage of Subjects With Detectable Antibodies to Chlamydia pneumoniae and/or Cytomegalovirus*
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After excluding the patients with fibromuscular dysplasia, 87 patients
were evaluated for the presence of a hemodynamically notable renal artery
stenosis, which was documented in 23 patients. In these 23 patients, C pneumoniae IgG seropositivity was found more often than
in those in whom no notable renal artery stenosis could be detected (23 [100%]
vs 50 [78%]; P = .001). The difference in seropositivity
for IgA antibodies to C pneumoniae (19 [82%] vs 40
[62%]; P = .07) did not reach statistical significance.
In 11 patients (mean age, 55 years) atherosclerotic lesions were found
only at the level of the renal arteries and not in the aorta. All 11 patients
were C pneumoniae seropositive, and 7 had a hemodynamically
notable renal artery stenosis.
The univariate association of atherosclerosis with age, sex, smoking,
diabetes mellitus, hyperlipidemia, severity of hypertension, and C pneumoniae and CMV antibodies is demonstrated in Table 3. Significant associations were found for age (P = .003) and IgG (P = .02) and IgA (P = .03) antibodies to C pneumoniae.
Smoking (even when analyzed separately for present smoking or a history of
smoking), severity of hypertension, diabetes mellitus, and CMV antibodies
were not associated with the presence of atherosclerosis. The association
between atherosclerosis and hyperlipidemia did not reach significance.
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Table 3. Univariate Associations Between Atherosclerosis and Risk Factors, Chlamydia pneumoniae, and Cytomegalovirus Serology
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In multivariate logistic regression analysis, the OR for C pneumoniae IgG seropositivity and atherosclerosis was 6.04 (95% CI,
1.33-27.5; P = .02). Age was the other variable that
contributed significantly to atherosclerosis: quartile 2 vs 1, OR, 2.89 (95%
CI, 0.71-11.8; P = .1); quartile 3 vs 1, OR, 10.1
(95% CI, 1.71-59.3; P = .01); and quartile 4 vs 1,
OR, 4.94 (95% CI, 0.99-24.6; P = .05). None of the
other variables showed an association with atherosclerosis in this multivariate
regression. When the analysis was performed with IgA antibodies to C pneumoniae (OR, 2.99; 95% CI, 0.93-9.16; P
= .06), only age remained significantly associated with atherosclerosis.
Because the seroprevalence of C pneumoniae
increases with age,19 we analyzed the cumulative
frequency of atherosclerotic lesions in hypertensive patients who were C pneumoniae IgG seropositive or seronegative (Figure 1 and Table 4). A similar graph is obtained when analyzing the cumulative
prevalence of renal atherosclerosis over time; all patients younger than 50
years with renal atherosclerotic disease were C pneumoniae IgG seropositive. The mean age of C pneumoniae
seropositive patients (57 years), however, did not differ from that of the
seronegative patients (59 years).
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The cumulative prevalence of atherosclerosis in the aorta and/or
the renal arteries in hypertensive patients with or without IgG antibodies
against C pneumoniae by different age groups.
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Table 4. Age and the Cumulative Number of Hypertensive Patients With
or Without Atherosclerosis and IgG Antibodies to Chlamydia
pneumoniae
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COMMENT
In this study we demonstrated that IgG antibodies to C pneumoniae are significantly more present in hypertensive patients
with angiographically demonstrated atherosclerotic lesions compared with those
in whom no atherosclerosis could be detected. An association between C pneumoniae and atherosclerosis was found for both the
renal arteries and the abdominal aorta. To our knowledge, the association
between angiographically demonstrated arterial disease and C pneumoniae has been investigated only in coronary heart disease.12-16
Some studies found a significant association with ORs varying between 1.8
and 3.5, while others did not find an association. The endothelial surface
that was investigated in the present study is large compared with the coronary
system, and this factor, as well as there being a different selection of patients,
may have contributed to the strong association. IgA antibodies to C pneumoniae may indicate a persistent, chronic infection; however,
contrary to IgG, these antibodies were only significantly associated with
atherosclerosis in the univariate analysis, but not after adjusting for the
classic risk factors in the multivariate analysis. This may indicate that C pneumoniae contributes more to the initiation of atherosclerotic
lesions than to their progression.
The prevalence of atherosclerosis increases with age, and we found that
the hypertensive patients with atherosclerosis were significantly older than
those without atherosclerosis (59 vs 49 years; P<.001).
In the group of patients with documented atherosclerosis, those seropositive
for C pneumoniae were of similar age to the seronegative
subjects. However, all patients younger than 50 years with atherosclerotic
lesions were C pneumoniae seropositive.
An atherosclerotic lesion of at least 1 of the renal arteries was found
in 49 patients, 23 of whom were diagnosed as having a hemodynamically notable
renal artery stenosis. The association between C pneumoniae serology and a notable renal artery stenosis was significant. We found
that a negative C pneumoniae serology excluded the
presence of a notable stenosis; IgG antibodies to C pneumoniae had a negative predictive value of 100%. The positive predictive value
was 30%, and it seems that IgG antibodies to C pneumoniae have no great influence on the pretest probability of renal vascular
hypertension. By using strict clinical criteria to perform renal angiography,
renal vascular hypertension was detected in 23 (24%) of our patients. However,
our study was carried out in a selected group of hypertensive patients who
were referred to a hypertension outpatient clinic of a university hospital;
the predictive value of C pneumoniae serology as
a diagnostic tool may be less in an unselected group of hypertensive patients.
Renal arterial atherosclerotic disease is often considered as only one
facet of generalized atherosclerosis or of the aorta in particular. However,
in 11 of the 49 patients with documented atherosclerotic lesions of at least
1 of the renal arteries, no atherosclerosis was detected at the level of the
aorta. All 11 patients were C pneumoniae IgG seropositive.
Although these numbers are small, these data suggest that C pneumoniae may be a risk factor for the development of atherosclerotic
lesions limited to the renal artery in this highly selected group of patients.
Chlamydia pneumoniae infection of the renal
artery may have hemodynamic consequences with worsening of hypertension, stimulation
of atherogenesis, and possibly an increased susceptibility for vascular reinfections.
This viscious circle may lead to serious vascular disease. Our study did not
address the question whether C pneumoniae is associated
with hypertension. Unfortunately, previous studies addressing this question
showed conflicting results. In a large Finnish study21
focused on chronic coronary heart disease and acute myocardial infarction,
no association was found between high titers of IgG and IgA antibodies to C pneumoniae and hypertension, while another study specially
designed for this purpose found more seropositivity in patients with severe
essential hypertension compared with healthy controls.22
The authors of the latter study suggest that C pneumoniae infection of blood vessels induces fibrosis, which may be a causal
factor for hypertension. Our study indicates that a substantial number of
hypertensive patients have C pneumoniae–associated
generalized atherosclerosis, which may contribute to high blood pressure by
reducing vascular compliance.
Similar to C pneumoniae, CMV can infect endothelial
cells and blood mononuclear cells. In addition, after primo-infection, latency
and reactivations occur, and the CMV seroprevalence increases with age. However,
the association between CMV and atherosclerosis is weaker, and CMV can be
detected in atherosclerotic and normal blood vessels,23
while C pneumoniae is mostly detected in atherosclerotic
vessels.24-26
In the present study, no association between CMV and atherosclerosis was found.
The process of atherosclerosis is multifactorial. The other risk factor in
our study included age. Unlike previous studies, smoking was not found to
be a significant risk factor, possibly due to the small number of patients
included. This may also explain why hyperlipidemia did not reach significance
as a risk factor. In the multivariate analysis, only IgG antibodies to C pneumoniae and age remained significant independent confounding
factors.
In conclusion, the presence of antibodies to C pneumoniae was significantly associated with atherosclerosis, renovascular disease,
and a hemodynamically notable renal artery stenosis in hypertensive patients
in whom a renal artery stenosis was strongly suspected. Possibly, C pneumoniae contributes to the development of atherosclerosis in a
direct way as well as an indirect way via deterioration of blood pressure.
AUTHOR INFORMATION
Accepted for publication July 31, 2001.
We wish to thank Ger Grauls for technical assistance.
Corresponding author: Andre J. A. M. van der Ven, MD, PhD, Department
of Medical Microbiology, Academic Hospital Maastricht, PO Box 5800, 6202 AZ
Maastricht, the Netherlands (e-mail: avve{at}lmib.azm.nl).
From the Cardiovascular Research Institute, Maastricht University,
Maastricht, the Netherlands, and the Departments of Medical Microbiology (Drs
van der Ven and Bruggeman), Internal Medicine (Ms Hommels and Drs Kroon and
de Leeuw), Clinical Epidemiology and Medical Technology Assessment (Dr Kessels),
and Radiology (Ms Flobbe and Dr Engelshoven), Academic Hospital Maastricht,
Maastricht.
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