From the Department of Thoracic Medicine (P.J.C., D.H.); the University
Department of Medicine (G.Y.H.L., D.G.B.); and the Department of Microbiology
(R.W.), City Hospital, Birmingham, and the School of Mathematics and
Statistics, University of Birmingham (P.D.), United Kingdom.
Correspondence to Dr P.J. Cook, Department of Medicine, Queen Elizabeth Medical Centre, Edgbaston, Birmingham B15, United Kingdom.
Our study was designed to test the association of this organism with HT
in the multiracial inner-city population of north and west Birmingham,
UK, after adjustments for several potential confounding variables.
We subjected the HT patients to echocardiography
with estimation of LVMI. We also measured concentrations of fibrinogen,
fibrin D-dimer, and von Willebrand factor in plasma and
searched for associations of these factors with C.
pneumoniae antibody levels.
Patients in the HT group were recruited from outpatients attending the
hypertension clinic at Birmingham City Hospital. All had had blood
pressures greater than 160/90 on two or more occasions, and were taking
antihypertensive medication. Predisposing conditions (such as
Cushing's and Conn's syndromes, pheochromocytoma, and renal artery
stenosis) had been excluded, where appropriate. Evidence of
end-organ damage (renal failure or proteinuria, hypertensive
retinopathy, or other active
cardiovascular disease) was not required for
recruitment.
Potential control subjects were selected randomly from all admissions
to the Emergency Department with acute, nonpulmonary,
noncardiovascular disorders, provided that there was no
evidence (by the patients' accounts and from the hospital's
records) of coexisting active cardiac, vascular, or
pulmonary disease. Thus, there is no reason to suspect that
they were predisposed to acquire C. pneumoniae
infection.
At recruitment (on admission in the case of control patients), blood
was taken for serology. The HT patients underwent further
investigation, namely EKG, echocardiography, and
determinations of levels of plasma fibrinogen, fibrin D-dimer, and von
Willebrand factor. These investigations, which were ordered by
the responsible physician, were not confined to any part of the study
period or to any discernible subgroup of patients.
LVMI was estimated by echocardiography, using the
formula of Devereux and the Penn conventions of
measurement.12A 12B All echocardiograms were obtained by a
single observer, and the coefficient of variation was <5%. LVH was
defined by LV mass >135 g · m-2 in
males, or >110 g · m-2 in females, as
estimated by echocardiography,12C and
by EKG using the criteria of Sokolow and Lyon (ie, S in
V1+R in V5 or
V6
Demographic characteristics, medical history, smoking habit, drug
therapy, and physical signs were recorded by the admitting medical
staff; ethnic origin and smoking habit were later confirmed by postal
questionnaires. Townsend scores of socioeconomic
deprivation were assigned to those subjects who lived in
the West Midlands conurbation, by linking their post-code sectors to
census enumeration districts. These scores, which include items that
reflect predominantly personal and family income levels, may be
considered to reflect the socioeconomic status of people living within
a particular locality.13 The higher the score
(ie, the more strongly positive), the greater the degree of social
deprivation.
Serological Testing
Sera were tested by one investigator using Maxiscreen
Chlamydia MIF slides (IO International Ltd) and
fluorescein-conjugated anti-human immunoglobulins. Only an
even pattern of elementary body fluorescence was regarded as
positive. In every batch of slides tested, two control serum
preparations known to be positive for this organism and two negative
control samples were each applied to two slides. All sera were screened
at a dilution of 1:8; thereafter, positive sera were tested at
dilutions of 1:8 to 1:1024.
Because HT patients were not acutely ill when bled, we did not expect
to find evidence of acute C. pneumoniae infection, and we
were primarily interested in the frequency of previous infection.
Titers indicating previous infection without recrudescence were
presumed to be IgG 64 to 256, provided that IgM could not be detected.
Titers of IgG
Rheumatoid factor was assayed in patients in whom connective tissue
diseases were suspected on clinical grounds, despite insufficient
evidence to exclude them from the study. C. pneumoniae IgM
antibodies were discounted for serological classification where it was
present, because of its nonspecific IgM
reactivity.14
Analysis of Data
Finally, in the HT patients only, we performed general linear model
ANOVAs of LVMI and concentrations of fibrinogen, fibrin D-dimer, and
von Willebrand factor, stratifying data by all potentially
associated factors. Because the fibrin D-dimer concentration had a very
skewed distribution, we used its logarithmic
(loge) transforms for these analyses, to
stabilize variance.
The remaining 1518 patients (92.8%) were assigned to the control
group. In these patients, the primary indications for admission to the
hospital were abdominal pain in 460, for which causes were established
in 403 cases; chest pain, not suggestive of myocardial ischemia
and for which no cause was found, in 91; malignant disease in 85;
fractures of various bones in 77; urinary obstruction in 64;
complications of diabetes mellitus in 44; and other miscellaneous
medical and surgical diagnoses in 697.
We excluded all patients known or thought likely (by their admitting
physicians) to have connective tissue disease or other autoimmune
disease. After this, there remained in the study 5 HT patients and 133
control subjects in whom we suspected connective tissue diseases on
clinical grounds, and whom we therefore tested for the presence of
rheumatoid factor. Where this test was positive, in 2 HT patients and
24 control subjects, the finding of IgM antibodies was discounted for
the diagnosis of acute C. pneumoniae infection.
Acute infection was diagnosed solely on the basis of IgM titers in 5 HT
patients and 30 control subjects, of whom 5 HT patients and 22 control
subjects would otherwise have been defined by their IgG titers as
previously infected. Two HT patients and 11 control subjects were older
than 60 years, and therefore were within the age group that has been
associated with unsuspected rheumatoid factor
production.19 Of these, 2 HT patients and
1 control subject subsequently took part in the matched
analysis. There were therefore 3 patients in the matched
analysis who might conceivably have been identified wrongly as
having acute infection.
The presence or absence of LVH was ascertained by
echocardiography and EKG in 127 (94.1%) of the HT
patients. Plasma fibrinogen, fibrin D-dimer, and von Willebrand
factor were measured in 118 (87.4%), 115 (85.2%), and 120 (88.9%) of
the HT patients, respectively.
Matching was achieved, on the basis of the criteria stated above,
between 123 HT patients and 123 control subjects
(Table
C. pneumoniae and Hypertension
Regression analysis suggested associations of HT with previous
C. pneumoniae infection (OR, 2 · 5; 95% confidence
interval [CI], 1.3 to 4.7) but not with acute (re)infection (OR, 1.0;
95% CI, 0.4 to 2.6). Among matched HT patients, the distribution of
the three possible serological outcomes—acute (re)infection, previous
infection, and none—differed from that among matched control subjects
with a probability of P<.05, but this difference was
entirely due to levels of previous infection. If we had omitted the 3
matched patients over 60 years of age, not tested for rheumatoid
factor, in whom we detected acute C. pneumoniae infection,
it would not have altered the lack of association between hypertension
and acute (re)infection.
This analysis revealed no evidence of statistical interactions
of ethnic origin, age, sex, or smoking habit with the C.
pneumoniae–HT association. The analysis of unmatched
groups was in agreement with the matched analysis, and it
revealed no evidence of interactions of diabetes mellitus or Townsend
score with the C. pneumoniae–HT association.
C. pneumoniae and LVH in Hypertension
Fibrinogen, Fibrin D-Dimer, and von Willebrand Factor
Levels
There are wide variations in the prevalence and incidence of
hypertension in different parts of the world. Both in the United
Kingdom and United States, it is more common among black people than in
the white population. C. pneu-moniae antibodies have been
associated with Afro-Caribbean origin,22 raising
the possibility that a genetic predisposition to this infection may
contribute to the development of hypertension.
In a large Finnish study that showed a clear association of high titers
of chlamydial IgG and IgA antibodies with chronic coronary
artery disease and acute myocardial infarction, there was no
correlation with other risk factors for these conditions, including
hypertension.7 However, this lack of correlation
may not be very significant, unless the research is focused on severe
and sustained hypertension, and predisposing conditions (such as
Cushing's and Conn's syndromes, pheochromocytoma, and renal artery
stenosis) are excluded. The authors of the Finnish study did
not specify the criteria for diagnosing hypertension in their report,
and we suggest that our study of chronic severe hypertensive patients
should have a higher probability of detecting such an association.
It is noteworthy that we found substantial levels of acute and previous
infection in control subjects as well as HT patients, reflecting the
high incidence of C. pneumoniae infection in our community.
Nevertheless, the results of our study support an association between
chronic severe essential hypertension and C. pneumoniae
infection. We did not grade the HT patients according to the severity
of their hypertension, but we found no significant differences in
C. pneumoniae antibody levels between patients with and
those without echocardiographic evidence of LVH. We
suggest that several factors may interact to produce this complication
of hypertension.
Strategies to take into account potential confounding variables are
essential in studies of C. pneumoniae antibodies, which have
been associated with Afro-Caribbean origin,22
increasing age,23 male
sex,23 24 and
smoking.23 24 25 In this study, we found no
noteworthy interactions (ie, effect modification) by these factors with
the association between C. pneumoniae and hypertension.
Subjects in the HT and control groups also differed in some other
demographic characteristics whose influences on the risk of C.
pneumoniae infection were unknown (Table
Fibrinogen, fibrin D-dimer, and von Willebrand factor may be
regarded as markers for intravascular thrombogenesis and fibrin
turnover, and for endothelial damage, respectively.
Marked elevation of plasma fibrinogen has been reported in patients
with severe hypertension26 ; and in such patients,
fibrinogen concentration is an independent predictor of blood
pressure.27 28 Infections also lead to increases
in prothrombotic factors,29 30 particularly
fibrinogen,31 fibrin D-dimer (a fragment of
cross-linked fibrin, hence a marker of
thrombosis),32 and anti-cardiolipin antibodies.
However, fibrinogen, fibrin D-dimer, and von Willebrand factor
were not significantly associated with the presence of C.
pneumoniae antibodies in our study.
Serological Testing
IgG titers
IgM is generally considered to signify acute primary
infection.34 54 A threshold titer of
Limitations of this Study
No attempt was made to control for travel history, ethanol consumption,
or diet in this study. Although the last two factors may influence the
probability of systemic hypertension, we do not perceive them to be
important factors in our population of severely hypertensive
patients.
We believe that our strategy for preventing interference by rheumatoid
factor in IgM measurement has allowed us to make a valid interpretation
of the results. However, in the future we would recommend the routine
absorption of sera with anti-human IgG, as advocated by Verkooyen et
al.19
Received February 14, 1997;
first decision March 25, 1997;
accepted August 20, 1997.
© 1998 American Heart Association, Inc.
Scientific Contributions
Chlamydia pneumoniae Antibodies in Severe Essential Hypertension
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
Conclusions
References
Abstract—Several studies have
implied an association between Chlamydia pneumoniae (C.
pneumoniae) and cardiovascular disease. Our
study was designed to determine whether this organism is associated
with severe essential hypertension in a multiracial British population.
Antibodies to C. pneumoniae were measured by
microimmunofluorescence in 123 patients with
chronic severe hypertension and 123 control subjects, matched for
ethnic origin, age, sex, and smoking habit, admitted to the same
hospital with various noncardiovascular,
nonpulmonary disorders. Previous infection was defined by IgG
64 to 256, provided that there was no detectable IgM. Multiple
regression analyses of matched and unmatched data were used to
investigate the influences of antibody levels and potential confounding
factors (ethnic origin, age, sex, smoking habit, diabetes mellitus, and
social deprivation) on hypertension. A portion of the
hypertensive patients underwent echocardiography,
estimation of left ventricular mass index, and measurements
of fibrinogen, D-dimer, and von Willebrand factor
concentrations. Thirty-five percent of hypertensive patients and 17.9%
of matched control subjects had antibody titers consistent with
previous C. pneumoniae infection. The hypertensive
patients differed significantly from their matched control subjects in
their level of previous infection, with an odds ratio of 2.5 (95%
confidence interval, 1.3 to 4.7). There were no significant differences
in antibody levels between patients with left ventricular
hypertrophy and those without it. Fibrinogen, D-dimer, and
von Willebrand factor concentrations were not significantly
associated with antibody levels. These data support an association of
C. pneumoniae with severe essential hypertension. They
provide no evidence of a predisposition to develop left
ventricular hypertrophy in hypertensive
patients with C. pneumoniae infection or of associations
with hypercoagulability or endothelial dysfunction.
Key Words: hypertension, essential • cardiovascular diseases • infection
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
Conclusions
References
Chlamydia pneumoniae was first described
in 1986.1 Serological studies indicate that it is one of
the most prevalent infectious agents worldwide,2 3 4 5 with a
wide range of clinical manifestations, including exacerbations of
chronic obstructive pulmonary disease and chronic
asthma.6 Several groups have demonstrated serological
associations with coronary artery disease,7 8 9 10
strokes and transient cerebral ischemia,11 and
asymptomatic carotid
atherosclerosis.12
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
Conclusions
References
Study Subjects and Investigations
Approval for this project was obtained from the Hospital
Ethical Committee at the City Hospital, Birmingham. Subjects were
patients admitted to this hospital via the Emergency Department, all of
whom gave informed consent to participation. All patients were
initially considered to be eligible: recruitment was prospective and
continued at a steady rate, so that those who were eventually included
in the HT and control groups were admitted consecutively throughout a
24-month period (March 1993 through March 1995). Exclusion criteria
were known or suspected immunodeficiency, hypergammaglobulinemia,
connective tissue disease, and other autoimmune disease. 
35 mm).12D
Two to five milliliters of serum was obtained by
centrifugation within 6 hours of
venipuncture and stored at –20°C until analysis.
Each blood sample was labeled only with a serial number; thus, the
investigator was blind to all patient data at the time of testing, and
remained so until statistical analysis of the results. 512 or IgM 8 were considered to indicate acute
infection or reinfection just before entry into the study. Clearly,
acute infections should have no bearing on long-standing hypertension,
but because they could mask serological evidence of previous infection,
patients with such titers were considered separately from previously
infected and noninfected patients in the analysis of
results.
After recruitment was complete, we used a computer program to
match each of the HT patients with one of the much larger number of
potential control subjects for broad ethnic origin (Caucasian,
Afro-Caribbean, or Asian), age (±10 years), sex, and smoking habit
(current or previous versus never). We predicted (from our previous
research and that of other published studies) that the prevalence of
IgG anti–C. pneumoniae antibodies at titers of 64 would
be approximately 15% to 20% in the population under
study.3 15 16 With the nominal 
or type I
error level (two-tailed) set at .05, and the ß or type II error level
set at .20 (giving a power of 80%), and after we applied the
z statistic for dichotomous variables, we estimated that
72 to 162 patients would be required in each of the matched groups to
detect a difference of 15% to 20% in the frequencies of such
titers.17 A conditional logistic regression
method for matched data, implemented in the EGRET statistical
package,18 was used to explore possible
associations of C. pneumoniae antibody levels and the
matched variables with hypertension. We attempted to confirm the
results of this analysis by applying a logistic regression
modeling method, also from the EGRET package, to the unmatched HT and
control groups, exploring the influences of ethnic origin, age, sex,
and smoking habit on any association of C. pneumoniae
antibody levels with hypertension. The latter method was also used to
investigate possible influences of other characteristics for which
matching was not achieved, ie, diabetes mellitus and Townsend score, on
this association. Hence we derived an odds ratio (OR) expressing the
association of previous C. pneumoniae infection with the
presence or absence of hypertension, adjusted for potential confounding
factors.
Results
Top
Abstract
Introduction
Methods
Results
Discussion
Conclusions
References
Study Subjects and Samples
Twenty-seven potential HT patients and 312 potential control
subjects were excluded from this study by the criteria stated above,
and 53 potential control subjects refused to participate. One thousand
six hundred fifty-three subjects were recruited. One hundred
thirty-five (8.2%) were in the HT group. 
). The following examination of C.
pneumoniae antibody levels in hypertension relates only to the
matched analysis.
View this table:
[in a new window]
Table 1. Demographic Characteristics of HT and Control Groups (Matched)
Of the matched HT patients, 43 (35.0%) had serological evidence
of previous infection, 9 (7.3%) acute (re)infection, and 71 (57.7%)
no infection. Of the matched control subjects, 22 (17.9%) had evidence
of previous infection, 11 (8.9%) acute (re)infection, and 90 (73.2%)
none.
Among 127 of the HT patients, EKG and
echocardiography showed LVH in 92 and were normal
in 35. Mean LVMI measurements were 173.5 and 124.1 g ·
m-2, respectively. Serological results indicated
previous infection, acute (re)infection, and no infection in 34.8%,
5.4%, and 59.8% of patients with LVH, and 31.4%, 2.9%, and 65.7%
of those with no LVH. By 
2 analysis,
there was no significant variation between the two categories in their
distributions of previous infection, acute (re)infection, and no
infection.
In HT patients with serological evidence of previous infection,
acute (re)infection, and no infection (after adjustment by regression
analysis for variations in ethnic origin, age, sex, and smoking
habit), mean plasma concentrations of fibrinogen were 10.9 (95% CI,
9.4 to 12.6), 10.9 (8.8 to 12.9), and 11.5 (10.0 to 12.9)
µmol/L; of fibrin D-dimer, 273 (184 to 405), 253 (150 to 424), and
228 (156 to 333) ng/dL; and of von Willebrand factor, 120 (110
to 131), 120 (101 to 140), and 125 (115 to 135) IU/dL, respectively.
There were thus no significant differences in these variables
between HT patients with previous infection, acute (re)infection, and
no infection.
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
Conclusions
References
C. pneumoniae and Hypertension
Hypertension exemplifies probably better than any other disorder
the complexity of polygenic disease. In 95% of cases (so-called
"essential hypertension"), no single cause can be identified;
although factors such as consumption of alcohol and caffeine, salt
intake, smoking, obesity, and physical inactivity may clearly
contribute to increasing blood pressure. The notion that infections may
predispose to hypertension is not new. For example, such a role has
been proposed for Helicobacter pylori: of 33 patients in one
urban general practice with unequivocal H. pylori gastritis,
42% had sustained hypertension compared with 12% of dyspeptic
patients without H. pylori.20 Schreiber et
al (1992) reported that intravenous injections of either
live or heat-killed group B ß-hemolytic streptococci in newborn lambs
caused significant dose-dependent increases in systemic vascular
resistance and mean systemic arterial pressure and that
these effects were partly blocked by leukotriene D4
receptor antagonists, suggesting that
leukotrienes might mediate hypertension in this
infection.21 This is one of several immunologic
changes that might be relevant to the infectious origin of essential
hypertension. Furthermore, chronic chlamydial infections have a marked
propensity to cause fibrosis (as seen, for example, in the cicatricial
scarring of the cornea that characterizes trachoma and in fibrosis of
the Fallopian tubes in pelvic inflammatory disease due to C.
trachomatis). It is therefore reasonable to speculate that
C. pneumoniae within vascular endothelial
cells might, by a similar process, lead to an increase in vascular
resistance. 
). Using unmatched data,
we found no interactions of diabetes mellitus or Townsend score with
the association between C. pneumoniae and hypertension,
although we believe that larger studies would be required to draw firm
conclusions about these factors.
Various techniques are available to detect C.
pneumoniae antibodies.33 The best and most
widely used is the MIF assay,34 which is
time-consuming and subject to some operator variation but is sensitive
and species-specific and reliably detects IgG, IgM, and
IgA.35 The kit that we used has been used in
several studies,3 36 37 and has a
performance similar to other MIF assays. 
256 may persist for many months38
and have generally been accepted (in a single serum specimen) as
evidence of previous infection,39 provided that
there is no rise in IgM antibodies. Titers 512 are generally regarded
as indicating acute infection or reinfection. Many authors have used
these serological criteria,15 40 41 42 43 44 45 46 47 48 49 50 and a large
study combining serology with an examination of pharyngeal swabs by
polymerase chain reaction has provided evidence in support of
them.51 We chose to reject IgG titers <64 to
minimize the probability of false-positive
results.52 53 16 has
been proposed, with titers of 8 indicating "probable acute
infection,"42 but we found no difference in the
proportions of patients with IgM antibodies at these two titers in a
large pilot study, and therefore saw no merit in drawing a distinction
between such low levels of antibody production provided that
only an even distribution of definite elementary body
fluorescence was accepted as positive. It has been
suggested55 that rheumatoid factor may make the
measurement of IgM antibodies unreliable,14
particularly in elderly patients.19 We therefore
excluded from this study all patients known or thought likely to have
connective tissue disease or other autoimmune disease, and measured
rheumatoid factor in a further 138 cases in which such diseases were
considered less probable, discounting IgM antibodies in the 26 cases in
which it was present. As demonstrated above, ignoring IgM titers
from the remaining matched patients over 60 years of age (3 patients)
would not have significantly altered the relationships of HT to acute
and chronic C. pneumoniae infections.
In the HT group, the presence or absence of LVH was ascertained in
94.1% of patients. There appears to be no association of C.
pneumoniae infection with the development of LVH. Plasma
fibrinogen, fibrin D-dimer, and von Willebrand factor levels
were measured in fewer than 90% of the HT patients; in future studies,
it will be important to measure these levels in larger numbers of
patients, both with and without serological evidence of C.
pneumoniae infection.
Conclusions
Top
Abstract
Introduction
Methods
Results
Discussion
Conclusions
References
These data support the associations of chronic severe hypertension
with previous C. pneumoniae infection. We believe that more
research to elucidate the mechanism(s) of this association is
warranted.
Selected Abbreviations and Acronyms
EKG
=
electrocardiography
HT
=
chronic severe essential hypertension (study group)
HT patients
=
patients enrolled in chronic severe essential hypertension study group
LV
=
left ventricle
LVH
=
left ventricular hypertrophy
LVMI
=
left ventricular mass index
MIF
=
microimmunofluorescence
Acknowledgments
We thank IO International Ltd., London, for their generous
support of this project. PJC is supported by the Peel Medical
Research Trust, the British Heart Foundation and the Stroke
Association. At the City Hospital, Birmingham, we wish to acknowledge
the advice of Richard Matthews (Virology Laboratory) and Hilary Joyce
(Immunology). We thank Dr Andrew Blann for assistance with plasma
fibrinogen and von Willebrand factor measurements. At the
University of London, the advice and support of Dr John Treharne
(Senior Lecturer in Virology) and Prof Sorab Darougar (Emeritus
Professor of Public Health Ophthalmology) are also gratefully
acknowledged. We also thank the referees of an earlier draft of this
paper for their helpful comments and suggestions.
References
Top
Abstract
Introduction
Methods
Results
Discussion
Conclusions
References
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