Azithromycin, Chlamydia pneumoniae, and Intimal Thickening
To the Editor:
In the February 24, 1998, issue of Circulation, Muhlestein et al1 reported on cholesterol-fed rabbits that had repeated nasal inoculations of Chlamydia pneumoniae and whose thoracic aortas showed intimal thickness 3 months later. The authors concluded that weekly treatment with azithromycin for 7 weeks after infectious exposure prevents accelerated intimal thickening.
We appreciate the importance of the study and see the implications of its results; however, the conclusion in its present form raises some comments. First, we would be interested in the data on whether and to what extent neointima had been seen at the intermediate time points of weeks 3 and 10. The question remains whether azithromycin treatment really prevents intimal thickening because of its antichlamydial effect. It is important to note that it is uncertain precisely when neointima formation in response to the C pneumoniae pathogen starts. After endothelial denudation, neointima is usually seen after 10 to 14 days. Other possibilities related to the authors’ conclusions could be (1) that this antibiotic (similar to the macrolide rapamycin) simply has induced lesional regression or (2) even has acted via both preventive and regressive mechanisms. Furthermore, one would like to see the specific effects of C pneumoniae (and possibly those of azithromycin) in the absence of cholesterol feeding.
Second, we would like to comment on the conclusion drawn from the lesional morphology of the aortic section determined as representative of the infected/treated animal group. The original photomicrograph of Figure 2C shows a circumscript, excentric intimal lesion with a dense texture, whereas adjacent parts of the vascular wall were free of intimal disease. This lesion contrasted significantly with the large concentric lesion, with its loose texture, found in infected/untreated animals (Figure 2A). If it is true that apoptosis is the key mechanism that determines intimal cell density2 and mediates intimal lesion regression, as has been suggested recently,3 one would expect to find a homogeneously reduced, concentric intimal lesion or even to find no lesion. In addition, the presence of a padlike intimal lesion with a smooth surface, as illustrated in Figure 2C, points to a newly developed lesion (after a phase of complete regression). Irregular luminal borders and cellular structural defects due to persistent apoptosis (5% to 10%) and low cellularity have been identified as findings typical for late regression events in balloon-injured carotid arteries.4 On the basis of these morphological findings, one may conclude that the lesion illustrated in Figure 2C evidences the pertinacity of the arteriosclerotic disease once having been initiated rather than indicates the prevention of an accelerated intimal thickening.
- Copyright © 1998 by American Heart Association
Muhlestein JB, Anderson JL, Hammond EH, Zhao L, Trehan S, Schwobe EP, Carlquist JF. Infection with Chlamydia pneumoniae accelerates the development of atherosclerosis and treatment with azithromycin prevents it in a rabbit model. Circulation. 1998;97:633–636.
Bauriedel G, Schluckebier S, Hutter R, Welsch U, Kandolf R, Lüderitz B, Prescott MF. Apoptosis in restenosis versus stable angina atherosclerosis: implications for the pathogenesis of restenosis. Arterioscler Thromb Vasc Biol. 1998;18:1132–1139.
Hutter R, Bauriedel G, Schmidt T, Schmücking I, Welsch U, Lüderitz B. Long-term course of arterial injury: evidence for plaque regression and apoptosis. Eur Heart J. 1997;18:368. Abstract.
We appreciate the interesting and insightful comments of Bauriedel, Hutter, and Lüderitz. We provide the following response. First, regarding whether and to what extent neointima appears at the intermediate time points at weeks 3 and 10, all rabbits in this first pilot study were euthanized at the same time at the completion of the 3-month follow-up, so no intermediate analysis was possible. In future larger studies, pathological evaluation of neointimal formation at multiple time points during the course of the study should be performed to determine details of the time course of pathophysiological events that occur after chlamydial infection.
Second, regarding azithromycin’s mechanism of action, we agree that we cannot determine from this study the exact mechanism whereby azithromycin exerted its actions. Whether intimal proliferation is affected through its antibacterial effect or by some other mechanism will require further study.
Third, regarding the effect of cholesterol in the diet, this article evaluated chlamydia infection occurring on top of a low-dose-cholesterol–supplemented diet; other studiesR1 R2 have documented similar, although less marked, effects on intimal thickening in rabbits receiving standard noncholesterol-enriched chow.
Fourth, regarding the interpretation of pathological findings, Bauriedel et al allege, on the basis of their work, that if apoptosis is important, the morphological appearance of the plaque in Figure 2C suggests newly developed disease. We do not know whether the sequence of morphology they describe in restenosis is applicable to this model/diet/animal. The number of animals and sections that we reviewed precludes our making general statements about the morphology in this study. That is why we chose to make semiquantitative measurements instead. We concur that additional studies are indicated.
Fong IW, Chiu B, Vira E, Fong MW, Jang D, Mahony J. Rabbit model for Chlamydia pneumoniae infection. J Clin Microbiol. 1997;35:48–52.
Laitinen K, Laurila A, Pyhala L, Leinonen M, Saikku P. Chlamydia pneumoniae infection induces inflammatory changes in the aortas of rabbits. Infect Immun. 1997;65:4382–4385.