CORRESPONDENCE: LETTER TO THE EDITOR
Reply
Viola Vaccarino, MD, PhD*,
Thomas Rutledge, PhD,
Vera Bittner, MD, FACC and
C. Noel Bairey Merz, MD, FACC
* Division of Cardiology, Department of Medicine, Emory University School of Medicine, 1256 Briarcliff Road NE, Suite-1 North, Atlanta, Georgia 30306 (Email: viola.vaccarino{at}emory.edu).
We agree with Dr. Manev and colleagues that our study (1) does not rule out the possibility that inflammatory pathways alternative to those pertinent to the common biomarkers C-reactive protein (CRP) and interleukin (IL)-6 may be involved in the link between depression and cardiovascular disease (CVD). Depression is associated with a number of inflammatory markers in addition to CRP and IL-6, including, for example, IL-1 beta and tumor necrosis factor alpha (2). The list may well include 5-lipoxygenase (5-LOX), but unfortunately this has not yet been described, at least in humans. C-reactive protein and IL-6 are the 2 biomarkers most consistently associated with cardiovascular risk and therefore it makes sense to begin with these as we try to disentangle the complex link between depression, inflammation, and CVD. Because they are produced as part of the acute phase response, it is possible that these common biomarkers are not truly biologic markers for depression. On the other hand, inflammatory cytokines have well-characterized effects in the central nervous system that may influence depressive behavior, including effects on neurotransmitter function and stimulation of the hypothalamus-pituitary-adrenal axis (3). These actions suggest that inflammatory processes are central to the pathogenesis of depression similar to many other chronic conditions, such as CVD. It is also possible that inflammation contributes to some, but not all, cases of depression, as suggested by the wide range of inflammatory activity commonly found in samples of depressed individuals. Thus, subsets of individuals at the upper end of cytokine levels could drive most of the association (4).
Dr. Manev and colleagues suggest a central role of an up-regulated leukotriene synthesis pathway in the link between depression and CVD. We agree with this possibility. A number of genetic variations in the arachidonic acid cascade leading to leukotriene synthesis have been linked to the risk of myocardial infarction and increased carotid atherosclerosis (5–7). Unfortunately, no data are yet available regarding the relationship between 5-LOX, or other components of this metabolic pathway, and depression in humans. Until these data become available, this biologic mechanism remains speculative.
We agree with Dr. Manev and colleagues that future studies addressing the interconnections between depression, inflammation, and CVD should include a wider selection of inflammatory markers that may be relevant to both atherosclerosis and depression; 5-LOX should be one of these. At the current stage of knowledge, we believe that no inflammatory biomarker can be credibly considered to be more than just a correlate of depression.
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1. Vaccarino V, Johnson BD, Sheps DS, et al. Depression, inflammation, and incident cardiovascular disease in women with suspected coronary ischemia: the National Heart, Lung, and Blood Institute–sponsored WISE study J Am Coll Cardiol 2007;50:2044-2050.[Abstract/Free Full Text]2. Irwin M. Psychoneuroimmunology of depression: clinical implications Brain Behav Immun 2002;16:1-16.[CrossRef][Web of Science][Medline] 3. Raison CL, Capuron L, Miller AH. Cytokines sing the blues: inflammation and the pathogenesis of depression Trends Immunol 2006;27:24-31.[CrossRef][Web of Science][Medline] 4. Tiemeier H, Hofman A, van Tuijl HR, Kiliaan AJ, Meijer J, Breteler MM. Inflammatory proteins and depression in the elderly Epidemiology 2003;14:103-107.[CrossRef][Web of Science][Medline] 5. Dwyer JH, Allayee H, Dwyer KM, et al. Arachidonate 5-lipoxygenase promoter genotype, dietary arachidonic acid, and atherosclerosis N Engl J Med 2004;350:29-37.[Abstract/Free Full Text] 6. Helgadottir A, Manolescu A, Helgason A, et al. A variant of the gene encoding leukotriene A4 hydrolase confers ethnicity-specific risk of myocardial infarction Nat Genet 2006;38:68-74.[Web of Science][Medline] 7. Helgadottir A, Manolescu A, Thorleifsson G, et al. The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke Nat Genet 2004;36:233-239.[CrossRef][Web of Science][Medline]
Related Article
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Depression, Inflammation, and Cardiovascular Disease: Is 5-Lipoxygenase the Missing Link?
- Hari Manev, Radmila Manev, and Mladen I. Vidovich
J. Am. Coll. Cardiol. 2008 51: 1990-1991.
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