European Heart Journal Advance Access originally published online on February 7, 2006
European Heart Journal 2006 27(6):757; doi:10.1093/eurheartj/ehi776
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The heart, the brain, and the Kounis syndrome
Medical Sciences, School of Health
Patras Highest Institute of Education
and Technology
7 Aratou Street
Queen Olgas Square
Patras 26221
Greece
E-mail address: ngkounis{at}otenet.gr
Patras Highest Institute of Education and
Technology
Patras
Greece
Patras Highest Institute of Education
and Technology
Patras
Greece
Department of Cardiology
Patras State General Hospital
Patras
Greece
In the elegant editorial1 concerning the recent paper2 published in EHJ, the authors have asked why the two seemingly unrelated conditions, namely depression and left ventricular depression, should be related and what mediators or common pathways could link the two. They have concluded that as far as the brain and the heart are concerned ‘the twain have met’. Although, they have done so, they did not elaborate enough in the mechanisms connecting the two conditions.
Depression and the heart seem to be the two main elements of a magnificent biological pathway. Major depression has often been regarded as a prototype of repeated, chronic, or exaggerated stress, the depressogenic stress, which is not responsive to counter-regulatory forces.3 Depressogenic stress commences with impulses arising from high cortical centres of the brain that are relayed through the limbic system to hypothalamus. Chemical mediators, such as norepinephrine, serotonin, and acetylcholine, are released and activate cells of the paraventricular nucleus of the hypothalamus to produce corticotropin-releasing hormone (CRH), the main coordinator of the depressogenic response. CRH enters the portal venous system of the hypothalamus and activates the corticotrophs of the anterior pituitary gland to produce proopiomelanocortin, which is cleaved to form adrenocorticotropic hormone (ACTH). It also stimulates the locus coeruleous, a dense collection of autonomic cells in the brainstem, to secrete norepinephrine at the sympathetic nerve endings. Activation of the sympathetic system centrally is also transmitted to the adrenal medulla to produce large amounts of epinephrine. ACTH stimulates the adrenal cortex to produce corticosteroids. Depressogenic stress also induces the release of glucagon, growth hormone, and homocysteine. The renin–angiotensin system also participates in the depressogenic stress through the sympathetic innervation of the kidney. All this cascade induces a heightened cardiovascular activity, endothelial injury, myocardial damage, induction of adhesion molecules on the endothelial cells to which recruited inflammatory cells adhere and translocate to the arterial wall.4 An acute phase response, similar to that associated with inflammation, is also engendered, and is characterized by macrophage activation, production of cytokines such as IL-1, IL-6, TNF-
, acute phase proteins, and mast cell activation.4 In contrast, the same cytokines such as IL-1, IL-6, TNF- are released in congestive cardiac failure and play a mediating role in the genesis of depression.2
Kounis syndrome5 is the concurrence of acute coronary syndromes with conditions associated with mast degranulation and is caused via inflammatory mediators released through the mast cell activation. Increasing evidence suggests that emotional or other stress may contribute to myocardial ischaemia and sudden cardiac arrest.6 Mast cell degranulation was induced by immobilization stress in rat cardiac mast cells. This effect was inhibited by pre-treatment with the mast cell stabilizer sodium cromoglycate and was also blocked locally by pre-incubation with antiserum against CRH and was partially inhibited by a CRH type-1 receptor selective antagonist. It has been found that the neuropeptide neurotensin is present in the heart and triggers mast cell degranulation. These findings suggest that acute stress could result in local CRH and neurotensin release, which could contribute to myocardial pathophysiology through direct or indirect cardiac mast cell degranulation.7
It has been suggested that Kounis syndrome might be a nature's own experiment, because mast cell membrane stabilization could abrogate late cardiovascular events. This has already been achieved experimentally.8
References
- Ziegelstein RC, Thombs BD. The brain and the heart: the twain meet. Eur Heart J 2005;26:2607–2608.
[Free Full Text] - van Melle JP, de Jonge P, Ormel J, Crijns HJGM, van Veldhuisen DJ, Honig A, Schene AH, van den Berg MP; for the MINT-IT investigators. Relationship between left ventricular dysfunction and depression following myocardial infarction. Eur Heart J 2005;26:2650–2656.
[Abstract/Free Full Text] - Chrousos GP, Gold PW. The concepts of stress and stress system disorders. Overview of physical and behavioral homeostasis. JAMA 1992;267:1244–1252.[Abstract]
- Black PH, Garbutt LD. Stress, inflammation and cardiovascular disease. J Psychosom Res 2002;52:1–23.[CrossRef][ISI][Medline]
- Kounis NG. Kounis syndrome (allergic angina and allergic myocardial infarction): a natural experiment? Int J Cardiol 2005; in press.
- Jain D, Burg M, Soufer R, Zaret BL. Prognostic implications of mental stress-induced silent left ventricular dysfunction in patients with stable angina pectoris. Am J Cardiol 1995;76:31–35.[CrossRef][ISI][Medline]
- Pang X, Alexacos N, Letourneau R, Seretakis D, Gao W, Boucher W, Cochrane DE, Theoharides TC. A neurotensin receptor antagonist inhibits acute immobilization stress-induced cardiac mast cell degranulation, a corticotrophin-releasing hormone-dependent process. J Pharmacol Exp Ther 1998;287:307–314.
[Abstract/Free Full Text] - Nemmar A, Hoet PHM, Vermylen J, Nemery B, Hoylaerts MF. Pharmacological stabilization of mast cells abrogates late thrombotic events induced by diesel exhaust particles in hamsters. Circulation 2004;110:1670–1677.
[Abstract/Free Full Text]
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