Skip Navigation

Cardiovascular Research 2002 56(2):178-180; doi:10.1016/S0008-6363(02)00652-1
© 2002 by European Society of Cardiology
This Article
Right arrow Extract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by van der Wal, A. C
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by van der Wal, A. C
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Copyright © 2002, European Society of Cardiology

Chlamydia pneumoniae inside the atherosclerotic plaque—does it affect plaque inflammation and plaque progression?

Allard C van der Wal*

Department of Cardiovascular Pathology, Academic Medical Centre, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands

* Tel.: +31-20-566-5633; fax: +31-20-691-4738. a.c.vanderwal{at}amc.uva.nl

Received 27 August 2002; accepted 28 August 2002

See article by Ezzahiri et al. [5] (pages 269–276) in this issue.


   1. Introduction
Top
 1. Introduction
2. Chlamydia pneumoniae...
 3. Chlamydia pneumoniae...
 References
 
Exposure to Chlamydia pneumoniae (Cp) is very common among the human population world-wide. Circa 50% of adults bear antibodies to Cp and re-infections occur frequently: most people have 2–3 infections in a lifetime [1]. In Cardiovascular Medicine, interest for such a common opportunistic agent was initiated by insights in seroepidemiologic associations between Cp infection and the risk of atherosclerotic vascular disease, myocardial infarction and stroke [2]. Atherosclerosis has recently been classified as a chronic inflammatory disease [3], so potentially the disease could indeed be initiated or modulated by infectious agents. Still, despite numerous clinical and pathological observations that suggest a link between Cp infection and atherosclerosis (Table 1), the underlying pathophysiological mechanisms are far from elucidated. Is Cp infection capable of initiating atherosclerosis or has it only a contributory role superimposed on effects of classical risk factors? Does systemic Cp infection affect plaque growth/thrombosis through circulating proinflammatory molecules (cytokines, acute phase proteins) or is Cp itself pathologically active inside the atherosclerotic plaque? And, is this of clinical relevance at all? An unsolved issue derived from these questions is whether or not Cp, invading the plaque in parasitized mononuclear cells, could influence the inflammatory response inside atherosclerotic lesions. An item of clinical importance also, since plaque inflammation increases the risk of plaque disruption, and hence thrombotic occlusion of the vessel [4].


View this table:
[in this window]
[in a new window]

  		Table 1 Areas of research implicating evidence for a role of Chlamydia in atherosclerotic vascular disease

 
In this issue of Cardiovascular Research, Ezzahiri et al. [5] provide interesting insights in this matter by describing increased T-cell infiltration and increased plaque maturation in Cp-infected hypercholesterolemic mice.


   2. Chlamydia pneumoniae infection and plaque inflammation
Top
 1. Introduction
 2. Chlamydia pneumoniae...
3. Chlamydia pneumoniae...
 References
 
The authors investigated atherosclerotic plaque inflammation in hypercholesterolemic (fat fed Apo E3 Leiden) mice exposed to Cp infection, which was visualised by quantifying the numbers of infiltrated CD4 immunopositive T-lymphocytes in lesions. Mice were infected twice, plaque composition was evaluated at different time intervals up to 9 months post infection and compared with mock-infected Apo E3 Leiden mice at each time point. Infection resulted in a significant increase in T-cell infiltration (0.29 cells/µm2 in mock infected mice vs. 2.63 cells/µm2 in Cp-infected mice) only in the early stages of infection, whereas at later stages (after 6 months) no substantial effect on the influx of T cells was noticed. In addition Cp was detected immunocytochemically in the subendothelial areas of about 30% of investigated plaques. Do these findings indicate that Cp infection initiates plaque inflammation? Not likely, since both in animals and in humans adequate serum levels of atherogenic lipids are required to produce something like a fatty streak or an atherosclerotic plaque with a lipid core. Lesions that are basically inflammatory in nature [3], also in the absence of Cp. And moreover, in normocholesterolemic mice Cp infection leads to inflammatory changes in blood vessels but no evidence of atherosclerotic plaque formation can be found [6]. Still, an aggravating effect on plaque inflammation, which is concluded from this study, should be considered of equal importance. The current belief is that plaque progression is an episodic rather than a continuous process. Multiple infections (2–3 in a life time) therefore, could implicate several episodes of increased T-cell infiltration and associated remodelling of the plaque composition (see below). A feature of Cp is their persistence in tissues; the bacterial antigens remain accessible to immune competent cells and are capable of sustaining inflammation for at least 4 weeks [7]. The inflammatory response in some but not all human plaques bears immune memory for Chlamydia antigens. T-cell lines raised from symptomatic carotid artery plaques in our laboratory showed antigenic specificity for Chlamydial antigens in circa 50% of plaques (all derived from different patients) [8]. This indicates that plaques in a subpopulation of patients are at least suitable for Cp-mediated inflammation. The point of view that Cp infection (among other inflammatory triggers) indeed may contribute to plaque inflammation is supported by several recently published observations. Increased numbers of activated plaque T cells [9], circulating Cp-positive T cells [10] and Cp-containing plaque tissue [11] have all been detected in blood and symptomatic plaques of patients with ischemic coronary syndromes.


   3. Chlamydia pneumoniae infection and plaque progression
Top
 1. Introduction
 2. Chlamydia pneumoniae...
 3. Chlamydia pneumoniae...
References
 
In human atherosclerosis, the progression and maturation of lesions can be graded histomorphologically according to the American Heart Classification of lesions. Ezzahiri et al. [5] extrapolated this classification to the situation in mice and systematically graded lesion morphology, in order to compare plaque progression in mock-infected and Cp-infected mice at different time intervals post infection (p.i.). Cp-infected mice showed a significant shift towards more lesions with a lipid core (type IV) at 6 months p.i. and more lesions with a fibrous cap (type V) at 9 months p.i. when compared with mock-infected mice. This suggests that infection indeed has accelerated the process of plaque maturation towards a more complex morphology. Although still speculative, but supported by lots of experimental work on plaque cells previously published [3,12], the secretory products of activated immune cell could be held responsible for this effect. Unfortunately, the authors did not further explore whether T cells expressed activation antigens such as CD40 ligand or interleukin 2 receptors, of pivotal importance since only activated T cells modulate the plaque morphology through a burst of cytokine production.

Finally, the extent of plaque formation was evaluated by means of planimetric quantification of lesional areas in the aortic arch of all mice, but no effects of Cp infection on lesion number and size of plaques could be detected. This seems to be a controversial point, since some investigators also did not notice any significant differences in lesion size between infected and control animals, whereas others reported accelerated plaque growth after infection with Cp (see discussion of Ezzahiri et al. [5] for references). The authors assume that, apart from differences in infection protocols and time intervals of data analysis, also species specific features could provide an explanation for such divergent results. This might indeed be valid, but at the same time raises the question how these data relate to the situation in human atherosclerosis, particularly when plaque growth comes into the discussion. Mice and men share many pathogenetic mechanisms of plaque formation, such as inflammation, lipid accumulation, SMC hyperplasia, and a fibrotic response, but the lesions in both species look morphologically different. And notably, disrupted and thrombosed plaques are extremely rare in aortas of hyperlipidemic mice, and were not found in the present study with CP-infected mice.

Nonetheless, despite these limitations, the present work provides another step forward in the intriguing possibility that a widespread opportunistic pathogen, Cp, will be capable of maintaining or accelerating plaque inflammation, in combination with hypercholesterolemia (Table 2).


View this table:
[in this window]
[in a new window]

  		Table 2 Areas of research implicating evidence for a role of chlamydia infection in atherosclerotic plaque inflammation

 


   References
Top
 1. Introduction
 2. Chlamydia pneumoniae...
 3. Chlamydia pneumoniae...
 References
 

  1. Ngeh J., Gupta S. Chlamydia pneumoniae and atherosclerosis—what we know and what we don’t. Clin Microbiol Infect (2002) 8:2–13.[CrossRef][Web of Science][Medline]
  2. Saikku P., Leinonen M., Matilla K., et al. Serological evidence of an association of a novel Chlamydia, TWAR, with chronic coronary heart disease and acute myocardial infarction. Lancet (1988) 2:983–986.[Web of Science][Medline]
  3. Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med (1999) 340:1269–1276.[Free Full Text]
  4. Van der Wal A.C., Becker A.E. Plaque rupture—pathologic basis of plaque stability and instability. Cardiovasc Res (1999) 41:334–344.[Free Full Text]
  5. Ezzahiri R., Nelissen-Vrancken H.J.M.G., Kurvers H.A.J.M., Stassen F.R.M., Vliegen I., Grauls G.E.L.M., van Pul M.M.L., Kitselaar P.J.E.H.M., Bruggeman C.A. Chlamydophila pneumoniae (Chlamydia pneumoniae) accelerates formation of complex lesions in Apo E3-Leiden mice. Cardiovasc Res (2002) 56:269–276.[Abstract/Free Full Text]
  6. Blessing E., Lin T.M., Campbell L.A., et al. Chlamydia pneumoniae induces inflammatory changes in the heart and aorta of normocholesterolemic C57BL/6J mice. Infect Immun (2000) 68:4765–4768.[Abstract/Free Full Text]
  7. King L.E., Stratton C.W., Mitchell W.M. Chlamydia pneumoniae in chronic skin wounds: a focused review. J Invest Dermatol Proc (2001) 6:233–237.[CrossRef]
  8. De Boer O.J., van der Wal A.C., Houtkamp M.A., et al. Unstable atherosclerotic plaques contain T-cells that respond to Chlamydia pneumoniae. Cardiovasc Res (2000) 48:402–408.[Abstract/Free Full Text]
  9. Van der Wal A.C., Piek J.J., de Boer O.J., et al. Recent activation of the plaque immune response in coronary lesions underlying acute coronary syndromes. Heart (1998) 80:14–18.[Abstract/Free Full Text]
  10. Kaul R., Uphoff J., Yadlapalli S., Wenman W.M. Detection of Chlamydia pneumoniae DNA in CD3+ lymphocytes from healthy blood donors and patients with coronary artery disease. Circulation (2000) 102:2341–2346.[Abstract/Free Full Text]
  11. Muhlestein J.B., Hammond E.H., Carlquist J.F., et al. Increased incidence of chlamydia species within the coronary arteries of patient with symptomatic atherosclerotic versus other forms of cardiovascular disease. J Am Coll Cardiol (1996) 27:1555–1561.[Abstract]
  12. Libby P. Current concepts of the pathogenesis of acute coronary syndromes. Circulation (2001) 104:365–372.[Free Full Text]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Cardiovasc ResHome page
M. D. de Kruif, E. C.M. van Gorp, T. T. Keller, J. M. Ossewaarde, and H. ten Cate
Chlamydia pneumoniae infections in mouse models: relevance for atherosclerosis research
Cardiovasc Res, February 1, 2005; 65(2): 317 - 327.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Extract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by van der Wal, A. C
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by van der Wal, A. C
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?