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(Circulation. 1997;96:404-407.)
© 1997 American Heart Association, Inc.

Articles

Elevated Chlamydia pneumoniae Antibodies, Cardiovascular Events, and Azithromycin in Male Survivors of Myocardial Infarction

Sandeep Gupta, MRCP; Edward W. Leatham, MD; David Carrington, FRCPath; Michael A. Mendall, MD; Juan Carlos Kaski, MD; ; A. John Camm, MD

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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Background The clinical significance of the association between elevated anti–Chlamydia pneumoniae (Cp) antibody titres and coronary heart disease (CHD) is unclear. We explored the relationship between antibodies against Cp and future cardiovascular events in male survivors of myocardial infarction (MI). The effect of azithromycin antibiotic therapy was assessed in a subgroup of post-MI patients.

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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Chronic infections may initiate and perpetuate vascular endothelial damage.¹ Cp, an obligate intracellular pathogen, has been recently implicated in atherogenesis. Epidemiological studies demonstrate a consistent association between elevated Cp antibody titres and MI or chronic CHD,^{2 3 4} but prospective data are sparse.⁵ Whether an elevated antibody titre reflects new, reactivated, or past infection is unclear because laboratory culture of the organism is difficult. Cp elementary bodies and DNA have been demonstrated within atheromatous coronary arteries,^{6 7} but the organism could reside within plaque lesions as an "innocent bystander." Azithromycin is a new-generation macrolide (azalide) antibiotic that is well tolerated by patients,⁸ achieves high tissue concentrations, and has a long half-life.⁹ A short course of the drug is very effective in treating respiratory infection caused by Cp,¹⁰ and a single dose may be sufficient to cure other chlamydial infections.¹¹

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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Study Design
Between February 1995 and September 1995, 220 consecutive male patients attending a post-MI outpatient clinic at St George's Hospital were enrolled. Patients were screened for serum IgG antibodies against Cp by a microimmunofluorescence assay with elementary bodies of Cp strain IOL-207 as test antigen. We excluded patients with chronic bronchitis, those currently taking macrolide antibiotics, and those with MI within the preceding 6 months (to ensure resolution of immune responses caused by infarction). Also excluded were any subjects with serum that cross-reacted with Chlamydia trachomatis or Chlamydia psitticai antigens, as previously described.⁴ Patients were stratified into one of three anti-Cp antibody titre groups: group Cp-ve (n=59), no detectable anti-Cp antibodies (seronegative); group Cp-I (n=74), seropositive at a serum dilution of between 1/8 and 1/32; and group Cp+ve (n=80), seropositive at a serum dilution of 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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Seven patients were excluded because their sera cross-reacted with other chlamydial species; analysis is hence based on the remaining 213 patients. Table 1 shows the baseline clinical characteristics. Anti-Cp titre was persistently elevated (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.

View this table: [in this window] [in a new window]   Table 1. Patient Characteristics and Incidence of Cardiovascular Events at a Mean of 18±4 Months of Follow-up

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.

View this table: [in this window] [in a new window]   Table 2. ORs for CV Events in Seronegative and Seropositive Patient Groups

	Discussion

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This study is the first to assess the relationship between anti-Cp titre and clinical outcome prospectively in a consecutive group of male survivors of MI and to observe a reduction in cardiovascular event rate after antibiotic treatment. The subjects in this study had had an MI as long as 120 months before and are unrepresentative of all MI patients. However, the mean time elapsed since MI was similar in those having further adverse cardiovascular events compared with those who did not (42±29 versus 45±30 months, respectively). Furthermore, adding time since MI into the logistic regression model showed that compared with the Cp-ve group, there was still a fourfold-increased risk for further cardiovascular events in the Cp+ve-NR and Cp+ve-P groups and a relative OR of 0.9 for events in the azithromycin group.

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 processes^{15 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

 

CHD = coronary heart disease Cp = Chlamydia pneumoniae MI = myocardial infarction OR = odds ratio

	Acknowledgments

 
The study was funded by the British Heart Foundation; Dr Sandeep Gupta is supported by a British Heart Foundation Junior Research Fellowship (FS/94075). We thank Pfizer Ltd (Sandwich, Kent, UK) for supplying the azithromycin and placebo tablets and Dr Ike Iheanacho for making critical comments on the manuscript.

Received March 17, 1997; revision received May 23, 1997; accepted May 28, 1997.

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				R. P. Heine, R. B. Ness, and J. M. Roberts Seroprevalence of Antibodies to Chlamydia pneumoniae in Women With Preeclampsia Obstet. Gynecol., February 1, 2003; 101(2): 221 - 226. [Abstract] [Full Text] [PDF]

				J. D. Spence and J. Norris Infection, Inflammation, and Atherosclerosis Stroke, February 1, 2003; 34(2): 333 - 334. [Full Text] [PDF]

				A. Paganini-Hill, E. Lozano, G. Fischberg, M. Perez Barreto, K. Rajamani, S.F. Ameriso, P.N.R. Heseltine, and M. Fisher Infection and Risk of Ischemic Stroke: Differences Among Stroke Subtypes Stroke, February 1, 2003; 34(2): 452 - 457. [Abstract] [Full Text] [PDF]

				M. V. Kalayoglu, P. Libby, and G. I. Byrne Chlamydia pneumoniae as an Emerging Risk Factor in Cardiovascular Disease JAMA, December 4, 2002; 288(21): 2724 - 2731. [Abstract] [Full Text] [PDF]

				J. S. Forrester Prevention of Plaque Rupture: A New Paradigm of Therapy Ann Intern Med, November 19, 2002; 137(10): 823 - 833. [Abstract] [Full Text] [PDF]

				F.-J. Neumann Chlamydia pneumoniae-Atherosclerosis Link: A Sound Concept in Search for Clinical Relevance Circulation, November 5, 2002; 106(19): 2414 - 2416. [Full Text] [PDF]

				D. Sander, K. Winbeck, J. Klingelhofer, T. Etgen, and B. Conrad Reduced Progression of Early Carotid Atherosclerosis After Antibiotic Treatment and Chlamydia pneumoniae Seropositivity Circulation, November 5, 2002; 106(19): 2428 - 2433. [Abstract] [Full Text] [PDF]