LETTER TO THE EDITOR
Reply
C. J. Wiedermanna,
S. Kiechla,
S. Dunzendorfera,
P. Schratzbergera and
J. Willeita
a Departments of Internal Medicine and Neurology University of Innsbruck Anichstrase 35 A-6020 Innsbruck Austria
Chronic infections have been implicated in the etiology of atherosclerosis, but this presumed association remains controversial (1). Prospective data from the Bruneck study revealed an association between atherosclerosis and endotoxemia, which was particularly evident in smokers and patients with recurrent bacterial infections (2).
In an effort to identify patients with chronic infections or conditions known to be associated with recurrent episodes of exacerbation of infectious disease, we initiated an extensive screening process consisting of two consecutive phases (3). The first step involved obtaining a detailed self-reported medical and medication history, a thorough clinical examination, spirometric measurements, laboratory tests including acute-phase reactants, serologic markers of chronic infection and urinary analysis and a review of Bruneck Hospital’s data bases and medical records provided by general practitioners and dentists. The situation in Bruneck is unique in that the majority of subjects are treated in the local hospital, which offers the only facilities for radiography, computed tomography, lung function testing and microbiologic tests in the survey area. If data were inconclusive or incomplete, individuals were, in a second step, referred for further optional examinations. The diagnosis of common chronic infections was established according to standard diagnostic criteria by an expert committee including medical subspecialists, all of whom had no knowledge of the results of the ultrasound evaluations. Blood samples were drawn after an overnight fast and 12 h abstinence from smoking (4). In patients with an acute infectious disease, samples were drawn after an interval of at least six weeks from the time of the outbreak of the disease. Thus, endotoxemia was not measured during an acute infection or an episode of exacerbation of chronic infection. None of the patients in the study had a fever. The diagnosis of infection was never based on biochemical measurements of C-reactive protein alone.
Commercially available blood collection tubes and heparin used for anticoagulation may be contaminated with endotoxin (5,6). Therefore, in our study, the use of standard tubes for the assessment of endotoxin concentrations in plasma was validated: 1) Aliquots from the blood sampling tubes were filled with endotoxin-free cell culture medium and tested for endotoxin after comparable sample handling. No endotoxin was detected by the commercial test kit used. 2) To further exclude contamination of samples by endotoxin, a sensitive bioassay was used to measure in vitro endothelial cell activation for neutrophil transmigration (7). Aliquots from blood sampling tubes filled with endotoxin-free cell culture medium with and without 10 µg/ml of polymyxin B had no effect on endothelial cell activation for leukocyte transmigration, thus confirming the lack of endotoxin contamination.
Rauchhaus et al. suggest an alternative hypothesis to explain endotoxemia in terms of bacterial translocation across the intestinal wall due to atherosclerotic processes in the mesenteric vasculature. However, because the observed association between endotoxemia at baseline and carotid atherosclerosis at follow-up was particularly pronounced in patients who had no coronary artery disease and in whom there was no ultrasound evidence of carotid and femoral artery atherosclerosis at baseline, it is unlikely that intestinal ischemia with bacterial translocation was present in these patients when endotoxin samples were obtained at baseline. Furthermore, recent data show that elevated levels of antibodies to lipopolysaccharide from Escherichia coli, probably reflecting successful immune responses to intestinal translocation of bacteria, are inversely related to carotid artery atherosclerosis and are not associated with endotoxemia (manuscript submitted). These data indirectly support a role of infections as a source of atherogenic endotoxemia.
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References
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- Kantor RJ, Carson LA, Graham DR, Petersen NJ, Favero MS. Outbreak of pyrogenic reactions at a dialysis center: association with infusion of heparinized saline solution. Am J Med. 1983;74:449–456[CrossRef][Medline]
- Wiedermann CJ, Schratzberger P, Dunzendorfer S, et al. Human and bovine endothelial cell monolayers are differently activated for neutrophil transendothelial migration by human plasma. Ann NY Acad Sci. 1997;832:135–145[Medline]
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