Infection with Chlamydia pneumoniae accelerates the development of atherosclerosis and treatment with azithromycin prevents it in a rabbit model.

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 (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.

Chlamydia species infect human vascular endothelial cells and induce procoagulant activity.

BACKGROUND: Chlamydia pneumoniae infections have been linked with myocardial infarction, stroke, and the development of atherosclerosis by epidemiologic studies, immunohistochemical studies, and electron microscopic studies. The mechanisms underlying this association are unknown. METHODS: Using cultured human venous endothelial cells, we investigated whether C pneumoniae, C trachomatis (types H and L2/434/BU) could infect these cells. The ability of infected cells to express procoagulant (tissue factor) activity was also measured using clotting and chromogenic substrate assays. Adhesion of platelets to chlamydia-infected cells was also quantitated. RESULTS: We found that C pneumoniae, C trachomatis type H, and C trachomatis L2/434/BU could infect cultured human umbilical vein endothelial cells and stimulate a 4-fold increase in expression of tissue factor, which reached a peak 18 hours postinfection. Tissue factor expression was enhanced even in the presence of tetracycline, suggesting that the chlamydial factor responsible for stimulating synthesis of endothelial cell tissue factor was preformed. Platelet adhesion was significantly enhanced when endothelial cells were infected by chlamydia species. CONCLUSIONS: These in vitro studies suggest possible pathogenic mechanisms that may explain the association of thrombotic events with C pneumoniae infection, including pathologically enhanced production of tissue factor by human endothelial cells and enhanced focal platelet deposition.