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Interleukin-6 (IL-6) is a variably glycosylated, secreted 22-27 kDa glycoprotein with a helical structure. It is a pro-inflammatory cytokine that is present at low levels in the plasma of normal individuals, but which shows substantial increases in response to a number of pathological conditions including cancer and acute coronary syndromes. It is a primary mediator of the acute phase response, with levels greatly increased after surgery.
IL-6 is an independent predictor of mortality, cardiovascular events and development of type 2 diabetes in healthy individuals and of mortality in those with coronary heart disease. Among apparently healthy men, individuals with IL-6 values in the highest quartile (IL-6 > 2.28 pg/mL) were 2.3 times more likely to suffer a myocardial infarction than individuals in the lowest quartile (IL-6 < 1.04 pg/mL; Circulation 2000;101:1767-1772).
Assays for human IL-6 are widely available. However, routine measurement of IL-6 is not currently recommended for assessment of risk in any population.
Levels of IL-6 can be reduced by weight reduction and by 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (statins). Angiotensin receptor blockers, oral antihyperglycaemic agents and cyclo-oxygenase-2 inhibitors have also been shown to reduce IL-6 levels.
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Interleukin-6 (IL-6) is a pro-inflammatory cytokine and a major mediator of the acute phase response. It has a range of humoral and cellular immune effects that play a central role in host defence, tissue injury and inflammation. It may also have procoagulant properties.
IL-6 is released by a range of tissues, such as muscle, in response to stimulation by the monocyte-derived cytokines interleukin-1 (IL-1) and tumour necrosis factor. It is expressed by macrophage foam cells and smooth muscle cells in fatty streaks and in the 'cap' and 'shoulder' regions of atheromatous plaques. By reflecting the intensity of plaque inflammation, plasma levels of IL-6 may be an indicator of the vulnerability of plaque rupture. In this way, IL-6 may play a direct role in the progression of atherosclerosis.
IL-6 may also have indirect effects on the progression of cardiovascular disease. It is the primary driver for hepatic synthesis of C-reactive protein (CRP), the well-validated independent risk marker for atherosclerotic disease. Despite of the close relationship between IL-6 and CRP, several studies have found that the value of IL-6 as a predictor of cardiovascular events is independent of CRP.
Adipose tissue is a potent source of IL-6, which may play a role in the association between obesity and cardiovascular disease. IL-6 is also an independent risk marker for type 2 diabetes.
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Elevated levels of IL-6 have been widely associated with cardiovascular and metabolic disease. Outcomes for which IL-6 is an independent predictor include:
myocardial infarction in healthy men (Circulation 2000;101:1767-72)
vascular events in healthy postmenopausal women (JAMA 2002;288:980-7)
mortality and cardiovascular events in the healthy elderly (Am J Med 1999;106:506-512; Circulation 2003;108:2317-22)
mortality in patients with unstable coronary artery disease (JAMA 2001;286:2107-13)
left ventricular remodelling after reperfused myocardial infarction (Clin Cardiol 2004;27:417-20)
development of type 2 diabetes in healthy women (JAMA 2001;286:327-34)
Interleukin-6 has also been identified as an independent marker of cardiovascular and metabolic disease including:
stable angina vs. acute coronary syndrome (Cardiovasc Res 1998;40:389-95)
coronary heart disease/previous myocardial infarction (Clin Chem 1999;45:1967-73; Scand J Clin Lab Invest 2002;62:59-68; Atherosclerosis 2003;171:359-67)
increased insulin resistance (J Am Geriatr Soc 2004;52:399-404)
diabetes (diabetologia 2004;47:1029-37)
In addition to the independent relationships listed above, associations have also been identified between increased levels of IL-6 and:
cardiovascular and cerebrovascular events in healthy postmenopausal women (N Engl J Med 2000;342:836-43)
carotid atherosclerosis in healthy individuals and haemodialysis patients (Kidney Int 2002;61:1143-52; Stroke 2004;35:1619-24)
peripheral vascular disease (J Surg Res 2003;111:215-21; Diabet Med 2004;21:336-41)
complicated or poor outcome after acute coronary syndrome (Circulation 1999;99:2079-84; Ital Heart J 2002;3:28-33; Semin Thromb Hemost 2004;30:347-50)
increased obesity, in particular visceral obesity (Circulation 2002;105:804-9; Mech Ageing Dev 2003;124:495-502; Diabetes Care 2004;27:47-52)
complications of diabetes (nephropathy, macular oedema; Nephron 2000;85:81-5; Jpn J Ophthalmol 2002;46:78-83)
hypertension (Hypertension 2001;38:399-403; Hypertens Res 2002;25:475-80)
IL-6 levels have shown correlations with intima-media thickness and with the extent of coronary atherosclerosis lesions (Arterioscler Thromb Vasc Biol 1999;19:2355-63; Res Commun Mol Pathol Pharmacol 2001;109:241-8)
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Sensitive and specific commercial IL-6 assays are available for use with serum, plasma and urine. In healthy individuals, plasma IL-6 levels are usually 1 pg/mL. IL-6 plays a central role in inflammation, tissue injury and defence against infection. Its levels are increased in a number of pathological conditions, and by strenuous exercise. Elevated IL-6 levels are thus not specific for cardiovascular or metabolic disease.
Interleukin-6 has a shorter half-life (4 hours) than other markers of inflammation, such as CRP and serum amyloid A (19 hours). IL-6 levels also show diurnal variation. These features may limit the clinical utility of IL-6 as an inflammatory risk marker. The use of indwelling intravenous catheters for repeated assay of plasma IL-6 levels should be undertaken with caution (Psychoneuroendocrinology 2002;27:921-31).
A numeric relationship between IL-6 level and generalised cardiovascular risk or mortality has not been established. However, a study of apparently healthy men found those with IL-6 values in the highest quartile (IL-6 > 2.28 pg/mL) were 2.3 times more likely to suffer a myocardial infarction than those in the lowest quartile (IL-6 < 1.04 pg/mL; Circulation 2000;101:1767-1772).
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Measurement of IL-6 is not currently recommended in routine risk assessments. However, IL-6 is an independent risk marker of mortality, cardiovascular events and type 2 diabetes in healthy individuals, as well as mortality in those with coronary heart disease. The value of IL-6 as an independent predictor of cardiovascular events is retained even in low-risk subgroups, such as non-smoking men.
These data suggest that routine screening for IL-6 might be beneficial in identifying individuals at increased risk of diabetes and atherosclerotic events, particularly in those not identified using traditional risk factors. However, as levels of IL-6 and CRP are linked, and as CRP is generally the stronger predictor of cardiovascular events than IL-6, of the two, CRP is maybe the more useful inflammatory risk marker.
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Interleukin-6 (IL-6) levels can be reduced by dietary and lifestyle changes, and by a range of pharmacotherapies. In obese individuals, weight loss leads to significant reductions in plasma IL-6 levels (Circulation 2002;105:804-9; Arterioscler Thromb Vasc Biol 2003;23:1042-7; Eur J Endocrinol 2003;148:535-42; JAMA 2003;167:1799-804; Obes Res 2003;11:1048-54). Adoption of a very low calorie diet and dietary supplementation with alpha-linolenic acid are also associated with reductions in IL-6 levels (J Endocrinol Metab 2000;85:3338-42; Atherosclerosis 2003;167:237-42).
Statins have been shown to reduce IL-6 levels in patients with familial and non-familial hypercholesterolaemia, and in individuals with obesity (Int J Cardiol 2001;77:247-53; Arterioscler Thromb Vasc Biol 2002;22:1194-9; Clin Chem 2002;48:877-83; Atherosclerosis 2003;169:283-91; Horm Metab Res 2003;35:479-85). These studies all used simvastatin or atorvastatin. However, atorvastatin did not reduce IL-6 levels in patients in the MIRACL trial, all of whom sustained a recent acute coronary syndrome (Circulation 2003;108:1560-6).
Patients recovering from an acute coronary syndrome have shown a reduction in IL-6 levels in response to cyclo-oxygenase-2 inhibition (rofecoxib; Chest 2004;125:1610-5). In addition, the angiotensin receptor blocker irbesartan, has been shown to reduce IL-6 levels in patients with CAD, who have undergone angioplasty (J Am Coll Cardiol 2004;44:362-8). In poorly controlled diabetics, improvements in glycaemic control also appear to reduce plasma IL-6 levels (Diabet Med 2003;20:930-4).
http://atvb.ahajournals.org/cgi/content ... /6/1231%20