(Circulation. 1997;96:404-407.)
© 1997 American Heart Association, Inc.
Articles |
From the Departments of Cardiological Sciences (S.G., E.W.L., J.C.K., A.J.C.), Virology (D.C.), and Medicine (M.A.M.), St George's Hospital Medical School, London, UK.
Correspondence to Dr Sandeep Gupta, BHF Cardiology Research Fellow, Department of Cardiological Sciences, St George's Hospital Medical School, Cranmer Terrace, Tooting, London SW17 ORE, UK.
| Abstract |
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Methods and Results We screened 220 consecutive male
survivors of MI for anti-Cp antibodies. Of these, 213 patients were
stratified into three groups: group Cp-ve (n=59), no detectable Cp
antibodies; group Cp-I (n=74), intermediate titres of 1/8 to 1/32
dilution; and group Cp+ve (n=80), seropositive at
1/64 dilution.
Patients with persisting seropositivity of
1/64 were randomized to
either oral azithromycin (Cp+ve-A, 500 mg/d for 3 days [n=28] or 500
mg/d for 6 days [n=12]) or placebo (Cp+ve-P, n=20). Cp+ve-NR (n=20)
represented patients not recruited into the antibiotic
trial. The incidence of adverse cardiovascular events
(over a mean follow-up period of 18±4 months) was recorded and
shown to increase with increasing anti-Cp titre: Cp-ve, n=4 (7%);
Cp-I, n=11 (15%); Cp+ve-NR, n=6 (30%); and Cp+ve-P, n=5 (25%).
Cp+ve-NR and Cp+ve-P groups had a fourfold-increased risk for adverse
cardiovascular events compared with the Cp-ve group
(odds ratio [OR], 4.2; 95% confidence interval [CI], 1.2 to 15.5;
P=.03). In contrast, the OR for
cardiovascular events in patients receiving
azithromycin (Cp+ve-A, single or double course) was the same as in the
Cp-ve group (OR, 0.9; 95% CI, 0.2 to 4.6, P=NS). Patients
receiving azithromycin were more likely to experience a decrease in IgG
anti-Cp titres than were those in the placebo group
(P=.02).
Conclusions An increased anti-Cp antibody titre may be a predictor for further adverse cardiovascular events in post-MI patients. Taking a short course of azithromycin may lower this risk, possibly by acting against Cp.
Key Words: Chlamydia pneumoniae antibodies myocardial infarction azithromycin
| Introduction |
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We investigated whether anti-Cp titre is a marker for further adverse cardiovascular events in male survivors of MI and examined the effects of azithromycin therapy in the subgroup of patients with stable elevated anti-Cp titres.
| Methods |
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1/64. Anti-Cp
antibody titres were remeasured after 3 months in the latter group.
Patients with Cp titre (
1 in 64) on both occasions were entered in a
double-blind placebo-controlled study of the effects of azithromycin
therapy (either 500 mg/d for 3 days or two such courses 3 months
apart) on anti-Cp titre and hemostatic and inflammatory markers in
post-MI patients.12 These patients had their anti-Cp titre
and other markers tested at 3 and at 6 months. Adverse cardiovascular events (defined as the first admission to hospital with nonfatal MI; unstable angina requiring either intravenous anti-anginal therapy, coronary angioplasty, or urgent coronary artery bypass surgery; or cardiovascular death) were monitored for 18 months from the original Cp titre determination. The information was obtained from patients' clinic visits, telephone inquiries, case notes, and hospital computerized records.
The study was approved by the local Ethics Committee. All patients gave informed consent.
Statistical Analysis
The frequency of adverse events was assessed in groups Cp-ve,
Cp-I, and Cp+ve. Additionally, Cp+ve patients were further divided into
three subgroups: Cp+ve-NR, patients who did not enter the antibiotic
study; Cp+ve-P, patients who were randomized to receive placebo
medication; and Cp+ve-A, patients who were given either a single or
double course of azithromycin.
The proportion of patients experiencing an adverse event was compared
between group Cp-ve and all other groups by use of the
2 test. The ORs for adverse
cardiovascular events in each Cp+ve group relative to
group Cp-ve were calculated by use of a multiple logistic regression
model before and after adjustment for age, diabetes mellitus,
hypertension, hyperlipidemia, smoking status (current,
ever, or never), and previous coronary artery bypass surgery or
percutaneous transluminal coronary angioplasty
(STATA analysis). A value of P<.05 was considered
significant.
| Results |
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1/64) in 72 of 80 Cp+ve patients (90%). Of these 72
patients, 60 were recruited into the antibiotic trial. Of these 60
patients, 20 received placebo, 28 received a single course of
azithromycin, and 12 received two courses of azithromycin. Of the
remaining 12 patients, 7 were unwilling to enter the trial, and 5 had
other serious medical conditions that prevented their inclusion.
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At 6 months, in the patients participating in the antibiotic trial,
anti-Cp titre fell to
1/16 in 43% of patients (17 of 40) receiving
azithromycin compared with only 10% patients (2 of 20) taking placebo
(P=.02). The ORs for adverse cardiovascular
events are shown for all groups in Table 2
. The frequency of adverse events
increased with rising anti-Cp titre, which persisted after correction
for confounding variables. Because there were no significant
differences in cardiovascular risk factors or events
between the Cp+ve-NR and Cp+ve-P groups, results of the two groups were
combined in the calculation of the ORs. The rate of further
cardiovascular events in the Cp+ve-A group was similar
to that in the Cp-ve group (8% versus 7%; OR, 0.9; P=NS).
Compared with patients in the combined placebo/nonrandomized group, the
azithromycin-treated group had a fivefold reduction in
cardiovascular events, with an OR of 0.2 (95%
confidence interval, 0.05 to 0.8; P=.03). There was no
difference between the patients receiving either single or double
azithromycin course in the proportion having a decrease in anti-Cp
titre or the cardiovascular event rate.
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| Discussion |
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It is not clear whether elevated anti-Cp antibody titre
represents active or past infection. Ninety percent of post-MI
patients had stable elevated IgG titres when rechecked at 3 months,
consistent with persistent antigenic stimulation resulting from
chronic active infection. In a matched group of male control subjects
without CHD, we found that only 11% had persistently elevated IgG
anti-Cp titres (
1/64) when the tests were rechecked 3 months
later.13 Theoretically, increased anti-Cp titre might
result from cross-reactions with other antigens, eg, to other
microorganisms or to heat shock protein 65 (which is implicated in the
atherogenesis14 ). This is unlikely in our study, however,
because titres were specific for Cp and only 7 of 220 subjects (3%)
exhibited antibody cross-reactivity with C.
trachomatis and C. psitticai.
Furthermore, elevated antibody titres fell after treatment with
azithromycin, which has high activity against Cp. The association
between further cardiovascular events and anti-Cp titre
may result from confounding by conventional risk factors. Contrary to
this possibility, however, is the fact that anti-Cp titre remained an
independent risk factor for future cardiovascular
events after controlling for confounding clinical variables, such
as smoking and diabetes mellitus. The vast majority of patients
(>95%) in each of the Cp titre groups were taking regular aspirin, so
this could not account for the improved clinical outcome in the
azithromycin-treated group. Furthermore, all 29 patients with
recorded cardiovascular events were on regular
aspirin.
Possible explanations for the association between elevated anti-Cp antibody titres and risk of adverse cardiovascular events include direct involvement of Cp in atherogenesis. Chronic infection of macrophages may contribute to inflammatory processes15 16 or trigger a procoagulant state through tissue factor expression.12 17 The bacterial lipopolysaccharide cell wall itself may contribute to direct endothelial cell damage. Kuo et al6 showed that the chances of identifying Cp within atherosclerotic lesions was inversely related to serum antibody, suggesting that hypersensitivity to Cp may play a role in atherogenesis, analogous to the involvement of C. trachomatis in the pathogenesis of trachoma.18 However, the study findings by Kuo et al were based on a small number of autopsy coronary atheroma specimens, and the antibody titres from hemolysed sera were difficult to evaluate. Furthermore, when similar diagnostic techniques were used in a more recent study, results demonstrated Cp organisms within coronary atherectomy specimens of patients with angina and found no such inverse relationship between the likelihood of detecting the organism and the height of the Cp-specific antibody titre.19 It is hence reasonable to propose that azithromycin may have been acting against Cp within the coronary arteries of our post-MI patients with elevated antibody titres. This may account for the observed reduction in adverse cardiovascular events in the treated group.
Whatever the relationship between anti-Cp titre and cardiovascular outcome, the reduction in event rate after treatment with azithromycin is intriguing, particularly because the benefit was not restricted to subjects who had a decrease in titres. Azithromycin, by eradicating or suppressing infection, may have helped to "stabilize" active plaque lesions, in part by dampening inflammation and hypercoagulation.12 Azithromycin may have acted against other infections, eg, Helicobacter pylori, which has been linked to prevalent CHD and cardiovascular risk factors.15 Alternatively, the results seen could be secondary to an effect unrelated to the antimicrobial action of azithromycin. The inclusion of an arm in our antibiotic trial in which Cp-ve subjects (presumed free of infection) were treated may have helped to clarify whether the effect of the antibody resulted from direct action against Cp or through other mechanisms. We cannot dismiss the possibility that additional antibiotic treatment for intercurrent infections was taken by patients, but such usage would probably be low and similar for all subgroups. Finally, given that anti-Cp antibody titres are also associated with atherosclerotic disease other than CHD,20 future studies are needed to ascertain whether the graded risks with anti-Cp antibody titre apply to those CHD patients yet to suffer from MI or to other high-risk groups (such as those with atheromatous peripheral vascular or cerebrovascular disease).
In conclusion, these findings may have important implications for the secondary prevention of CHD, especially given the safety of azithromycin and the fact that the beneficial effects are observed after only a short course of treatment. Larger antibiotic eradication trials, now being designed, are needed to confirm these findings.
| Selected Abbreviations and Acronyms |
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| Acknowledgments |
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Received March 17, 1997; revision received May 23, 1997; accepted May 28, 1997.
| References |
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