Correspondence

Inflammation, Atherosclerosis, and Coronary Artery Disease

N Engl J Med 2005; 353:429-430July 28, 2005

Article

To the Editor:

In his review of inflammation, atherosclerosis, and coronary artery disease, Hansson (April 21 issue)1 focuses on T cells, macrophages, and mast cells as the cellular components of the immune system that play a key role in ischemic heart disease. However, he omits a possible role for neutrophils.

Several lines of evidence support the possibility that these cells are involved in this condition. Early studies showed a strong positive correlation between peripheral-blood neutrophil counts and the risk of acute myocardial infarction2 and documented the presence of activated circulating neutrophils in acute coronary syndromes.3 Furthermore, infiltration by neutrophils of culprit lesions in acute coronary syndromes has been shown.4 Finally, the prognostic value of plasma levels of myeloperoxidase — an enzyme mainly secreted by neutrophils — to identify patients with chest pain who are at risk for cardiac events further reinforces the role of these cells in the pathogenesis that underlies coronary artery disease.5

Jaime García de Tena, M.D., Ph.D.
Hospital Universitario Príncipe de Asturias, 28807 Alcalá de Henares, Spain
jgtena@terra.es

5 References

1. 1

   Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005;352:1685-1695
   Full Text | Web of Science | Medline

2. 2

   Friedman GD, Klatsky AL, Siegelaub AB. The leukocyte count as a predictor of myocardial infarction. N Engl J Med 1974;290:1275-1278
   Full Text | Web of Science | Medline

3. 3

   Mehta J, Dinerman J, Mehta P, et al. Neutrophil function in ischemic heart disease. Circulation 1989;79:549-556
   CrossRef | Web of Science | Medline

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   Naruko T, Ueda M, Haze K, et al. Neutrophil infiltration of culprit lesions in acute coronary syndromes. Circulation 2002;106:2894-2900
   CrossRef | Web of Science | Medline

5. 5

   Brennan M-L, Penn MS, Van Lente F, et al. Prognostic value of myeloperoxidase in patients with chest pain. N Engl J Med 2003;349:1595-1604
   Full Text | Web of Science | Medline

To the Editor:

Hansson's review does not mention aspirin among the therapeutic options for coronary artery disease. Aspirin was found to reduce the risk of a first myocardial infarction by 44 percent.1 Ridker et al.2 found that the beneficial effect of aspirin was directly related to baseline levels of C-reactive protein, with the greatest value among men with the highest baseline concentrations of C-reactive protein. Although the antiplatelet effect of aspirin may be modified by an underlying inflammation, the study by Ridker et al. suggests the possibility that the beneficial effect of aspirin in the prevention of coronary artery disease may be attributed at least in part to its antiinflammatory property.3

Ildikó Kriszbacher, M.Sc.
Miklós Koppán, M.D., Ph.D.
József Bódis, M.D., Ph.D., D.Sc.
Institute of Nursing and Clinical Sciences, H-7621 Pécs, Hungary
bodisj@freemail.hu

3 References

1. 1

   Steering Committee of the Physicians' Health Study Research Group. Final report on the aspirin component of the ongoing Physicians' Health Study. N Engl J Med 1989;321:129-135
   Full Text | Web of Science | Medline

2. 2

   Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997;336:973-979[Erratum, N Engl J Med 1997;337:356.]
   Full Text | Web of Science | Medline

3. 3

   Vane J. The evolution of non-steroidal anti-inflammatory drugs and their mechanisms of action. Drugs 1987;33:Suppl 1:18-27
   CrossRef | Web of Science | Medline

Author/Editor Response

Atherosclerosis is indeed a complex disease. Several cell types are involved in its pathogenesis, and many drugs have been used to treat it or prevent its complications. In my review, I discussed the role of macrophages, T cells, mast cells, and endothelial and smooth-muscle cells in the formation and progression of atherosclerotic lesions. García de Tena suggests that neutrophils may also be important participants in the development of disease. This is an interesting suggestion and has received some support from the clinical and histopathological studies he cites. However, myeloperoxidase, the neutrophil enzyme he proposes as a prognostic marker, is produced not only by neutrophils but also by macrophages present in lesions.1 On balance, the role of neutrophils remains unclear and should be the topic of further investigations.

Kriszbacher et al. point out that aspirin is a valuable therapeutic agent in coronary artery disease. This is certainly true; there is abundant work in the literature supporting the use of aspirin, which is used throughout the world to prevent coronary events. Many years ago, Vane discovered that aspirin inhibits prostaglandin synthesis.2 It is now well established that the formation of thromboxane A₂, which has aggregatory effects on platelets and which is a vasoconstrictive prostaglandin, is inhibited when aspirin acetylates cyclooxygenase.3 In addition, aspirin at a high concentration blocks signaling by nuclear factor-κB and thus inhibits inflammation.4 Whether the low doses of aspirin used for preventing coronary events are sufficient to inhibit inflammation remains controversial. Therefore, although I concur with Kriszbacher et al. that low-dose aspirin should be used in coronary artery disease, I am less convinced that its beneficial effect is due to its antiinflammatory properties. For this reason and because my task was to review mechanisms of disease rather than current therapy, aspirin was not discussed in my article.

Göran K. Hansson, M.D., Ph.D.
Karolinska University Hospital, SE-17176 Stockholm, Sweden
goran.hansson@cmm.ki.se

4 References

1. 1

   Sugiyama S, Okada Y, Sukhova GK, Virmani R, Heinecke JW, Libby P. Macrophage myeloperoxidase regulation by granulocyte macrophage colony-stimulating factor in human atherosclerosis and implications in acute coronary syndromes. Am J Pathol 2001;158:879-891
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   Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature New Biol 1971;231:232-235
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   Funk CD, Funk LB, Kennedy ME, Pong AS, Fitzgerald GA. Human platelet/erythroleukemia cell prostaglandin G/H synthase: cDNA cloning, expression, and gene chromosomal assignment. FASEB J 1991;5:2304-2312
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   Yin MJ, Yamamoto Y, Gaynor RB. The anti-inflammatory agents aspirin and salicylate inhibit the activity of I(kappa)B kinase-beta. Nature 1998;396:77-80
   CrossRef | Web of Science | Medline

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