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. Methods and Results-Thirty New Zealand White rabbits were given three separate intranasal inoculations of either C pneumoniae (nϭ20) or saline (nϭ10) 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) 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.2-4 More specifically, C pneumoniae antigen and elementary bodies have been found in atheromas from coronary arteries, 5-7 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 al 11 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. MethodsThe 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. C pneumoniae Strain and InoculumThe TWAR American Type Culture Collection strain VR 1310 12 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 Received October 21, 1997; revision received December 11, 1997; accepted December 17, 1997. From the University of Utah, LDS Hospi...

Background-Chlamydia pneumoniae commonly causes respiratory infection, is vasotropic, causes atherosclerosis in animal models, and has been found in human atheromas. Whether it plays a causal role in clinical coronary artery disease (CAD) and is amenable to antibiotic therapy is uncertain. Methods and Results-CAD patients (nϭ302) who had a seropositive reaction to C pneumoniae (IgG titers Ն1:16) were randomized to receive placebo or azithromycin, 500 mg/d for 3 days, then 500 mg/wk for 3 months. Circulating markers of inflammation (C-reactive protein [CRP], interleukin [IL]-1, IL-6, and tumor necrosis factor [TNF]-␣), C pneumoniae antibody titers, and cardiovascular events were assessed at 3 and 6 months. Treatment groups were balanced, with age averaging 64 (SDϭ10) years; 89% of the patients were male. Azithromycin reduced a global rank sum score of the 4 inflammatory markers at 6 (but not 3) months (Pϭ0.011) as well as the mean global rank sum change score: 531 (SDϭ201) for active drug and 587 (SDϭ190) for placebo (Pϭ0.027). Specifically, change-score ranks were significantly lower for CRP (Pϭ0.011) and IL-6 (Pϭ0.043). Antibody titers were unchanged, and number of clinical cardiovascular events at 6 months did not differ by therapy (9 for active drug, 7 for placebo). Azithromycin decreased infections requiring antibiotics (1 versus 12 at 3 months, Pϭ0.002) but caused more mild, primarily gastrointestinal, adverse effects (36 versus 17, Pϭ0.003). Conclusions-In CAD patients positive for C pneumoniae antibodies, global tests of 4 markers of inflammation improved at 6 months with azithromycin. However, unlike another smaller study, no differences in antibody titers and clinical events were observed. Longer-term and larger studies of antichlamydial therapy are indicated. (Circulation. 1999;99:1540-1547.)

Background-Chlamydia pneumoniae is associated with coronary artery disease (CAD), although its causal role is uncertain. A small preliminary study reported a Ͼ50% reduction in ischemic events by azithromycin, an antibiotic effective against C pneumoniae, in seropositive CAD patients. We tested this prospectively in a larger, randomized, double-blind study. Methods and Results-CAD patients (nϭ302) seropositive to C pneumoniae (IgG titers Ն1:16) were randomized to placebo or azithromycin 500 mg/d for 3 days and then 500 mg/wk for 3 months. The primary clinical end point included cardiovascular death, resuscitated cardiac arrest, nonfatal myocardial infarction (MI), stroke, unstable angina, and unplanned coronary revascularization at 2 years. Treatment groups were balanced, and azithromycin was generally well tolerated. During the trial, 47 first primary events occurred (cardiovascular death, 9; resuscitated cardiac arrest, 1; MI, 11; stroke, 3; unstable angina, 4; and unplanned coronary revascularization, 19), with 22 events in the azithromycin group and 25 in the placebo group. There was no significant difference in the 1 primary end point between the 2 groups (hazard ratio for azithromycin, 0.89; 95% CI, 0.51 to 1.61; Pϭ0.74). Events included 9 versus 7 occurring within 6 months and 13 versus 18 between 6 and 24 months in the azithromycin and placebo groups, respectively. Conclusions-This study suggests that antibiotic therapy with azithromycin is not associated with marked early reductions (Ն50%) in ischemic events as suggested by an initial published report. However, a clinically worthwhile benefit (ie, 20% to 30%) is still possible, although it may be delayed. Larger (several thousand patient), longer-term (Ն3 to 5 years) antibiotic studies are therefore indicated. (Circulation. 2000;102:1755-1760.)