Secondary prevention of atherosclerosis through chlamydia pneumoniae eradication (SPACE Trial): a randomised clinical trial in patients with peripheral arterial disease.

BACKGROUND: Sero-epidemiological and experimental studies suggest that Chlamydia pneumoniae infections play an important role in the development of atherosclerosis. Clinical trials have shown contradictory results regarding the efficacy of antibiotics to prevent atherosclerosis-related complications in patients with coronary artery disease. Our aim was to study the effect of a short course of azithromycin on the incidence of cardiovascular events and peripheral vascular function in patients with stable peripheral arterial disease (PAD). PATIENTS AND METHODS: Five hundred and nine PAD-patients were randomised to receive either a 3-day course of azithromycin (500 mg daily) or placebo, with 2 years of follow-up. C. pneumoniae serology was determined at baseline. Clinical endpoints were death, coronary events (myocardial infarction, unstable angina, and/or coronary revascularization procedures), cerebral events (stroke, TIA, and/or carotid endarterectomy) and peripheral arterial complications (increased PAD-symptoms with decreased ankle-brachial index (ABPI, 0.1-point decrease after 12 months), and/or peripheral revascularization procedures). RESULTS: Five hundred and nine patients (160 women) with an atherosclerotic risk factor profile were randomised, 257 patients to azithromycin and 252 to placebo. Four hundred and forty nine patients (88%) had intermittent claudication and 60 (12%) had critical limb ischemia. By 24-month follow up, 182 patients (36%) developed 252 complications (45 deaths, 34 coronary events, 34 cerebral events and 139 peripheral arterial complications). C. pneumoniae IgA-titres were associated with the development of cardiovascular events. Nevertheless, the number of complications (131 in the azithromycin group vs. 121 in the placebo group) and the number of patients that developed complications (98 (38%) in the azithromycin vs. 84 (33%) in the placebo group) was comparable in both treatment groups. Life table analysis showed no effect of azithromycin on survival or ABPI. CONCLUSION: A short-term course of azithromycin offers no benefits for survival or ankle pressure in PAD-patients.

Chlamydia pneumoniae infection induces an unstable atherosclerotic plaque phenotype in LDL-receptor, ApoE double knockout mice.

OBJECTIVES: To study whether Chlamydia pneumoniae (Cpn) infection affects atherosclerotic plaque morphology in atherogenic (LDLr/ApoE(-/-)) mice. METHODS: In mice sacrificed 20 or 40 weeks after Cpn infection aortic arch sections were analysed for lesion and fibrous cap area and the presence of matrix metalloproteinases (MMP)-2 and -9. RESULTS: All infected mice seroconverted, demonstrated Cpn DNA in their aortas on PCR and developed atherosclerotic plaques. Infection was not associated with changes in lesion area or type, but was associated with reduced the fibrous cap area and increased MMP-2 and -9 immunoreactivity. CONCLUSION: These findings suggest that Cpn infection may predispose to plaque instability.

Screening for asymptomatic internal carotid artery stenosis and aneurysm of the abdominal aorta: comparing the yield between patients with manifest atherosclerosis and patients with risk factors for atherosclerosis only.

OBJECTIVE: The purpose of this study was to investigate whether screening for internal carotid artery stenosis (ICAS) and aneurysm of the abdominal aorta (AAA) is indicated in patients with either manifest atherosclerotic disease or with only risk factors for atherosclerosis. STUDY DESIGN: Data were obtained for 2274 patients enrolled in the SMART study, an ongoing single-center, prospective cohort study of patients referred to our vascular center with manifest atherosclerotic disease (peripheral atherosclerotic disease [PAD]; transient ischemic attack [TIA], stroke, or ICAS; AAA; angina pectoris; or myocardial infarction [MI]) or with only risk factors for atherosclerosis (diabetes mellitus, hypertension, hyperlipidemia). The presence of ICAS or AAA was determined with duplex scanning and ultrasonography. RESULTS: The prevalence of ICAS 70% or greater is low in patients with risk factors for atherosclerosis only (1.8%-2.3%), intermediate in patients with angina pectoris or MI (3.1%), and highest in patients with PAD (12.5%) or AAA (8.8%). The prevalence of AAA 3 cm or larger is low in patients with risk factors for atherosclerosis only (0.4-1.6%), intermediate in patients with angina pectoris or MI (2.6%), and highest in patients with PAD (6.5%) or TIA, stroke, or ICAS (6.5%). The prevalence of AAA larger than 5 cm is low in all of the considered patient groups. The yield of screening can be optimized through selection on the basis of simple patient characteristics. In patients with PAD, selecting those with advanced age (>54 years) increased the prevalence of ICAS to 21.8%. Selecting patients with lower diastolic blood pressure (<83 mm Hg) increased the prevalence of ICAS to 17.9%. In patients with both advanced age and lower diastolic blood pressure, the prevalence of ICAS increased to 34.7%. Selecting patients with advanced age increased the prevalence of AAA 3 cm or larger to 9.6%. In patients with TIA, stroke, or ICAS, selecting those with advanced age increased the prevalence of AAA 3 cm or larger to 8.2%. Selecting patients with taller stature (>169 cm) increased the prevalence of AAA 3 cm or larger to 9.3%. In patients with advanced age and taller stature, the prevalence of AAA 3 cm or larger increased to 13.1%. CONCLUSIONS: Screening for ICAS should be limited to patients referred with PAD or AAA, especially those with advanced age or with low diastolic blood pressure. Screening for AAA should be limited to patients referred with PAD or with TIA, stroke, or ICAS, particularly those with advanced age or tall stature. In patients referred with angina pectoris or MI and those referred with only risk factors for atherosclerosis, screening cannot be endorsed.

Chlamydophila pneumoniae (Chlamydia pneumoniae) accelerates the formation of complex atherosclerotic lesions in Apo E3-Leiden mice.

OBJECTIVE: Atherosclerosis is an inflammatory process and is characterised by the presence of T-lymphocytes in the lesions. To study the role of Chlamydophila pneumoniae (C. pneumoniae) in this process and the effect of infection on T-cell influx, we infected Apo E3-Leiden mice with C. pneumoniae and investigated the effect on lesion development and T-cell influx in atherosclerotic lesions at different time points post infection (pi). METHODS: Nine week old mice, fed an atherogenic diet, were either mock-infected or infected with C. pneumoniae and sacrificed at 1, 6 and 9 months pi. Longitudinal sections of the aortic arches of the mice were stained with hematoxylin-eosin for atherosclerotic lesion type and lesion area analysis, or with rabbit-anti-CD3(+) to detect the presence of T-cells in the atherosclerotic lesions. T-cell influx was expressed as number of T-lymphocytes/lesion area. RESULTS: At 1 month pi, type 1, 2 and 3 lesions were present. At other time points pi, more complex lesion types 4, 5a and 5b were also present. Although infection did not influence the total lesion number or area, we observed an effect of C. pneumoniae infection on lesion type. Infection resulted in a significant shift in lesion formation from type 3 to type 4 (P=0.022) at 6 months pi, and from type 4 to type 5a (P=0.002) at 9 months pi. T-cells were observed at every time point pi. At 1 month pi, a significant increase in T-cell influx in the C. pneumoniae-infected atherosclerotic lesions was observed (P=0.0005). CONCLUSION: This study shows that C. pneumoniae infection enhances the inflammatory process by increasing T-lymphocytes in the plaque and accelerates the formation of complex lesions.