From the University of Utah, LDS Hospital, Salt Lake City, Utah.
Correspondence to Joseph B. Muhlestein, MD, Assistant Professor of Medicine, University of Utah, LDS Hospital, 8th Ave & C St, Salt Lake City, UT 84143.
Methods and Results—Thirty New Zealand White rabbits were given
three separate intranasal inoculations of either C
pneumoniae (n=20) or saline (n=10) at 3-week intervals and fed
chow enriched with a small amount (0.25%) of cholesterol.
Immediately after the final inoculation, infected and control rabbits
were randomized and begun on a 7-week course of azithromycin or no
therapy. Three months after the final inoculation, rabbits were
euthanatized and sections of thoracic aortas were blindly evaluated
microscopically for maximal intimal thickness (MIT), percentage of
luminal circumference involved (PLCI), and plaque area index (PAI) of
atherosclerosis. Vascular chlamydial antigen was
assessed by direct immunofluorescence. MIT differed
among treatment groups (P=.009), showing an increase in
infected rabbits (0.55 mm; SE=0.15 mm) compared with
uninfected controls (0.16 mm; SE=0.06 mm) and with infected
rabbits receiving antibiotics (0.20 mm; SE=0.03 mm) (both
P<.025), whereas MIT in infected/treated versus control
rabbits did not differ. PLCI also tended to differ
(P<.1) and PAI differed significantly
(P<.01) among groups with a similar pattern. Chlamydial
antigen was detected in 2 untreated, 3 treated, and 0 control
animals.
Conclusions—Intranasal C pneumoniae infection
accelerates intimal thickening in rabbits given a modestly
cholesterol-enhanced diet. In addition, weekly treatment
with azithromycin after infectious exposure prevents accelerated
intimal thickening. These findings strengthen the etiologic link
between C pneumoniae and atherosclerosis
and should stimulate additional animal and human studies, including
clinical antibiotic trials.
C pneumoniae Strain and Inoculum
Experimental Animals and Study Design
Similarly, 10 control rabbits were intranasally inoculated three times
at 2- to 3-week intervals with 1 mL of normal saline. Thereafter, 5 of
the controls were randomized to the same 7-week course of
azithromycin.
Three months after final intranasal inoculation (at 132 [SE, 6] days
of study), all rabbits were euthanatized. The aortas were removed,
refrigerated, and sent for pathological evaluation.
Pathological Investigations
Immunofluorescence
Statistics
Chlamydial antigen was detected in 2 of 9 infected/untreated, 3 of 10
infected/treated, and 0 of 10 uninfected animals (differences not
significant). Although not statistically significant, rabbits positive
for chlamydial antigen tended to show an increased MIT, regardless of
treatment group (MIT=0.54 mm, antigen positive; MIT=0.30 mm,
antigen negative; P=.2). No association between age or
weight of the rabbits and MIT was found.
Vascular chlamydial antigen was not a useful quantitative marker of
atheromatous effect in our model; it occurred in a
small proportion of both treated and untreated animals and was not
found in uninfected controls. Thus, infection-related
atherosclerosis may occur in the absence of detectable
local vascular antigen, and antibiotic therapy may not immediately
eliminate chlamydial antigen.
Study Strengths and Limitations
The number of animals was adequate for hypothesis testing, but
additional observations will be welcome. The cellular and molecular
mechanisms by which C pneumoniae accelerates
atherosclerosis were not defined. Also, our data are
too limited to exclude a small antiatheromatous effect
of azithromycin apart from its antichlamydial actions. Whether C
pneumoniae can cause atherosclerosis in the
absence of cholesterol feeding was not addressed. The
optimal dose and duration of antibiotic therapy are unknown, and
further dose-ranging studies would be useful. However, the azithromycin
regimen was selected to achieve dose concentrations clinically
effective against chlamydiae and for a duration believed to suppress or
eliminate chronic, persistent, and acute infection. Finally, it must be
remembered that the rabbit model of atherosclerosis is
not identical to that of human disease, and any extrapolations must be
made with caution and confirmed by clinical studies.
Received October 21, 1997;
revision received December 11, 1997;
accepted December 17, 1997.
© 1998 American Heart Association, Inc.
Brief Rapid Communications
Infection With Chlamydia pneumoniae Accelerates the Development of Atherosclerosis and Treatment With Azithromycin Prevents It in a Rabbit Model
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Background—Chlamydia
pneumoniae infection has been associated with
atherosclerosis by serological studies and detection of
bacterial antigen within plaque. We sought to evaluate a possible
causal role in an animal model.
Key Words: atherosclerosis • azithromycin • Chlamydia pneumoniae
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
Atherosclerotic
cardiovascular disease is a major health problem,
causing nearly half of all deaths in the United States. Several
important risk factors for atherosclerosis have been
discovered, but much of the risk remains unexplained. Recently,
infectious agents have been proposed as a possible additional
coronary risk factor. Chlamydia pneumoniae is a
newly discovered third species of chlamydia shown to cause pneumonia,
bronchitis, pharyngitis, and sinusitis.1 C
pneumoniae also has been associated with coronary heart
disease and myocardial infarction in serological
studies.2 3 4 More specifically, C
pneumoniae antigen and elementary bodies have been found in
atheromas from coronary
arteries,5 6 7 carotid
arteries,8 and aorta.9
However, these findings do not establish a causal role. Animal models
would be useful in determining causality and assessing the role of
antibiotic therapy. C pneumoniae causes pneumonitis in the
rabbit,10 and the cholesterol-fed
rabbit is an established model for accelerated
atherosclerosis. Thus, the rabbit may be a suitable
model to study a pathogenetic role of C pneumoniae in
atherosclerosis. Fong et al11
recently reported on a small study of rabbits nasally infected with
C pneumoniae. Two of 11 animals demonstrated early and
intermediate histological lesions of
atherosclerosis. We hypothesized that repeat infections
and the addition of a small supplement of dietary
cholesterol would yield more consistent and
accelerated development of atherosclerotic lesions and that antibiotic
therapy might prevent this process.
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
The objectives of the present study were (1) to determine
whether repeated intranasal C pneumoniae infection of
rabbits fed with chow supplemented with a small amount (0.25%) of
cholesterol would result in significant acceleration of
atherosclerosis compared with saline inoculation and
(2) to assess the efficacy of azithromycin, an antibiotic known to be
effective against C pneumoniae, in preventing accelerated
development of atherosclerosis.
The TWAR American Type Culture Collection strain VR
131012 was used. We harvested viable organisms
from infected cultures of HeLa 229 cells by disrupting infected cells
with glass beads and sonification. Organisms were partially purified by
centrifugation, quantitated, and resuspended in sucrose
phosphate glutamic acid with 10% dimethyl sulfoxide to provide a final
inoculum of 1 to 5x106 inclusion-forming units
per milliliter (method adapted from Mayer et
al13 ).
Thirty female New Zealand White rabbits (2 to 4 months old,
pathogen free) were used. Rabbits were fed standard rabbit chow
fortified with 0.25% cholesterol without antibiotics.
Animal care and processing were performed under strict adherence to the
Institutional Animal Care and Use Committee guidelines. Twenty rabbits
were included in the infection arm of the study. Each was inoculated
with 1 mL (1 to 5x106 inclusion-forming units)
of C pneumoniae suspension via the nasal turbinates with a
plastic catheter under light anesthesia using titrated
intramuscular doses of ketamine. Three separate inoculations
were performed at 
3-week intervals (average, 20±1 [SE] days).
Three days after final inoculation, 10 rabbits were randomized to a
7-week course of azithromycin. For the first week, a daily
intramuscular injection of 30 mg/kg aqueous azithromycin (Pfizer Corp)
was given. For the remaining 6 weeks, twice-weekly intramuscular
injections of 30 mg/kg azithromycin were given.
Aortic specimens were grossly inspected.
Representative cross sections of thoracic and abdominal
aortas were removed from each sample. Adjacent sections were submitted
for either routine histological evaluation or frozen
section staining for direct immunofluorescence.
Histological specimens were fixed in 10% buffered
formalin, paraffin imbedded, and stained with hematoxylin and eosin.
The histological sections were evaluated by an
experienced pathologist blinded to infection/treatment group.
Quantitative evaluation was performed with the use of an Olympus BH-2
microscope equipped with an eyepiece micrometer. The degree
of intimal atheromatous involvement was determined by
use of three prespecified measures: (1) maximal intimal thickness
(MIT), defined as the maximal measurement from the luminal surface to
the internal elastic lamina of the vessel wall; (2) percentage of
luminal circumference involved (PLCI) with atheroma (this
measurement was determined by visual pathological estimate); and (3)
plaque area index (PAI). This was defined as the product of MIT and
PLCI.
Specimens for immunofluorescence were frozen
in optimal cutting temperature medium, cut at 4 µm onto glass
slides, and air dried. After 30 minutes, direct
immunofluorescence was performed with a prediluted
monoclonal antibody (Baxter Scientific). This mouse monoclonal antibody
is directed at a 3000-D lipoprotein common to all Chlamydia
species (ie, trachomatis, psittaci, and
pneumoniae). The antibody has been directly conjugated with
fluorescein isothiocyanate. The genus-specific antibody was
chosen over the species specific (C pneumoniae) because of
its greater sensitivity.14 Slides were washed in
PBS, incubated with the antibody for 30 minutes in a moist chamber at
room temperature, and washed three times in PBS before cover slipping
in aquamount. Slides were examined by use of an Olympus microscope
equipped with epifluorescence and filters configured to detect
fluorescein isothiocyanate. Positive and negative controls
were run with each batch of slides. These consisted of the antigen
controls received with the antibody, which were monkey kidney cells
infected and uninfected with chlamydiae. Elementary bodies of
chlamydiae fluoresce apple green and measure 0.35 to 0.45
µm. Specimens were considered positive if any appropriately sized
fluorescent elementary bodies were detected. The pathologist
was blinded to treatment groups.
MIT, PLCI, and PAI are expressed as mean±SE for the different
treatment groups. MIT was prospectively selected as the primary end
point, with PLCI and PAI as secondary end points. Differences among the
three treatment groups were evaluated by ANOVA, followed by pairwise
Student-Newman-Keuls testing (SPSS version 6.1). (Similar results were
obtained using nonparametric Kruskal-Wallis testing, eg,
P=.032 for MIT.) Immunofluorescence
results are presented as simple proportions.
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
Twenty-nine rabbits survived and could be evaluated, and 1
(in the infection/no treatment group) died under
anesthesia. Fig 1
shows the
results of intimal thickening measurements by infection/treatment
group. Qualitatively, the lesions were uniformly characteristic of
atheromas, with varying proportions of foamy cells, spindle
(smooth muscle) cells, and extracellular matrix. The degree of MIT
varied among the three treatment groups (P=.009 by ANOVA):
MIT was increased in infected rabbits (0.55 mm [SE, 0.15
mm]) compared with uninfected controls (0.16 mm [SE, 0.06
mm]) and with infected rabbits receiving antibiotics (0.20 mm
[SE, 0.03 mm]) (both P<.025 by Student-Newman-Keuls
test), whereas MIT in infected/treated versus control rabbits did not
differ. Response to infection varied among individual animals, with 4
of 10 showing prominent atherogenesis, indicating variability in
success of infection or host response. PLCI tended to differ
(P=.1) and PAI significantly differed (P=.01)
among the three treatment groups: PLCI averaged 50% (SE, 12%) in
infected/untreated animals versus 22% (SE, 8%) in controls and 32%
(SE, 5%) in infected/treated animals. PAI averaged 40% (SE, 15%) in
infected/untreated animals versus 5.0% (SE, 2.4%) in controls and
6.4% (SE, 1.5%) in infected/treated animals (both P<.05
versus infected/untreated animals). There was no difference between
controls given antibiotics versus those given no antibiotics in these
indexes (P=.43) (Fig 1). Photomicrographs of
representative specimens from infected,
infected/treated, and control animals are shown in Fig 2.
View larger version (14K):
[in a new window]
Figure 1. Indexes of aortic atheromatous
involvement by infection and treatment group. Left, maximal intimal
thickness in millimeters. Right, plaque area index, ie, maximal intimal
thickness times plaque luminal circumference involved. I indicates
infected; AB, antibiotic treated; and C, control. Individual data
points (one per animal) are presented with group means and SEs.
Circles represent infected animals, squares represent
controls. Filled symbols represent animals treated with
antibiotic, open symbols those that were not.
View larger version (78K):
[in a new window]
Figure 2. Photomicrographs of representative
aortic sections from animals in the infected/untreated group (A);
control (uninfected/untreated) (B); and infected/treated group (C).
Hematoxylin and eosin–stained section, original magnification
x100.
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
Study Summary
This study confirms and quantifies the capability of intranasal
infection with C pneumoniae to accelerate
atherosclerosis in a rabbit model. Additionally, it
demonstrates the ability of azithromycin to prevent this accelerated
process. These findings are best explained by assigning a causative
role to C pneumoniae in the atherosclerotic process and a
preventive or therapeutic role to azithromycin. The degree of
atherosclerosis acceleration varied among individual
animals, suggesting a variability in the success of establishing
persistent infection or in host response to infection.
This study was larger and more successful than a previous
investigation11 in demonstrating the potential of
chlamydial infection to accelerate atherosclerosis. We
attribute this to the multiple inoculations and to dietary
cholesterol supplementation. Also, the design used
randomization and blinding to ensure objectivity. Importantly, the
study showed that azithromycin can limit the atherogenic effects of
chlamydial infection.
Acknowledgments
This work was supported in part by a grant from the Deseret
Foundation, LDS Hospital, Salt Lake City, Utah.
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
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