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C HAPTER 5 / Atherosclerosis, Inflammation, and Acute Coronary Syndrome 121
statement about using inflammatory markers in clinical and pub- That folic acid and vitamins B 6 and B 12 participate in Hcy me-
lic health practice 174 after systematically reviewing the evidence of tabolism provides a ready target for intervention; several studies
association between inflammatory markers (mainly CRP) and have demonstrated dose-dependent reductions in Hcy after sup-
CHD and stroke. CRP levels show a consistent dose-dependent plementation of folic acid, vitamin B 6 , and vitamin B 12 . 182,183
and independent association with cardiovascular risk, and it can Measurement of Hcy is inexpensive and reliable. 184,185 Because
be measured reliably and relatively cheaply. 175 These preliminary dietary intervention and supplementation could alter CVD risk
studies suggest that hsCRP may be able to predict response to as- by lowering plasma Hcy, it makes Hcy an attractive biomarker.
pirin and lipid-lowering therapy, although more data are required The AHA has not yet defined hyperhomocystinemia (high plasma
to confirm if interventions can be reliably targeted to and guided homocysteine levels) as a major risk factor for CVD and does not
by hsCRP levels. However, limitations in the use of this biomarker yet recommend widespread use of folic acid and B vitamin sup-
exist, namely its lack of specificity and the uncertainty surround- plements to reduce the risk of heart disease and stroke.
ing its etiological roles. 176
Interleukin 6
Homocysteine IL-6 is a pleiotropic cytokine produced by several cell types and is
Homocysteine (Hcy) is a sulfur-containing amino acid that is a central mediator of the acute-phase response. It regulates hu-
closely related to the essential amino acid methionine and to cys- moral and cellular responses and plays a central role in inflamma-
teine. Hcy is formed during the metabolism of methionine in the tion and tissue injury. 186 The effects of IL-6 are mediated through
methionine cycle and is metabolized through two pathways: the interaction of IL-6 with its receptor complex, IL-6R. IL-6 is
remethylation or transsulfuration. The remethylation of homo- the primary determinant of CRP release from the liver and is pro-
cysteine is performed by the enzyme methionine synthase, which duced in response to several factors, including IL-1, interferon- ,
requires vitamin B 12 and methyltetrahydrofolate. In the liver and and TNF. 187 This cytokine is the only known biomarker that can
kidneys, an alternative pathway for the remethylation of homo- induce the synthesis of all acute phase proteins. In addition to its
cysteine exists, but most tissues are entirely dependent on the for- role in inflammatory processes, experimental evidence suggests
mer mechanism of homocysteine recycling. The remaining ho- that IL-6 possesses procoagulant activity. 188 IL-6 is synthesized in
mocysteine is converted in the transsulfuration pathway to the endothelial and smooth muscle cells from normal and
cysteine in two reactions requiring vitamin B 6 . Cysteine is a pre- aneurysmal arteries. 189,190 Large quantities of IL-6 have been
cursor to glutathione, the major cellular reduction/oxidation identified in human atherosclerotic plaques. 191 Approximately
(redox) buffer, which in turn regulates various aspects of cellular one third of circulating IL-6 is synthesized from adipose tissue,
function. The transsulfuration pathway also directs Hcy to degra- which suggests that IL-6 and obesity may be interrelated 192,193 ;
dation and its ultimate removal as sulfate through the kidneys. this is particularly relevant given that obesity is a risk factor for
Hcy exists in several forms; the combined measurement is CVD. Some cytokines have been demonstrated to inhibit insulin
termed total homocysteine (tHcy). Plasma tHcy increases signaling, 194 induce hypertriglyceridemia, 195 and cause endothe-
throughout life, being low in childhood and increasing during pu- lial activation. 196 Epidemiological studies suggest that chronic in-
berty, with the relative increase being greater in males. It is at this flammatory states are associated with insulin resistance and en-
time that population differences start to emerge. On menopause, dothelial dysfunction. 197
the gender-related differences in tHcy diminish, but concentra- Whereas the epidemiological evidence demonstrating an asso-
tions remain lower in women than in men. The higher tHcy con- ciation between IL-6 and CVD independent of CRP is mixed and
centrations seen in the elderly may be caused by many factors such limited, it remains suggestive. After adjustment for CRP and
as malabsorption, insufficient dietary supply, reduced metabolic other cardiovascular risk factors, men segregated in the highest
activity, reduced kidney function, and other physiological age-re- quartile of baseline IL-6 levels from the PHS cohort exhibited
lated changes. In addition, many drugs affect tHcy levels either by greater than twice the risk of first myocardial infarction than did
reducing the absorption of cofactors or by increasing their catab- those in the lowest quartile. 198 Complimentary results were ob-
olism. Certain diseases also influence homocysteine metabolism. served in women with CVD participating in the Women’s Health
A role for homocysteine levels in the risk of CVD was first sug- and Ageing Study. Similarly, after adjustment for CRP and other
gested by detection of an association between hyperhomocystine- cardiovascular risk factors, women found in the highest tertile of
mia and premature vascular disease in individuals with inherited the cohort’s IL-6 levels displayed a three-fold increased risk of
homocystinuria. 156,177 Subsequent studies exploring the potential death compared with members of the lowest tertile. 199 In con-
of modest changes in plasma Hcy levels correlating with risk of trast, the associated risk of mortality and IL-6 and CRP in the eld-
CVD yielded mixed results. 178,179 Results have not been consistent erly was found to be similar for those with and without CVD, al-
but seem to support a continuous positive relationship with risk, though their effects were not assayed independently. 200 In a
in addition to a potential threshold effect. A preliminary meta- population-based cross-sectional study, ECG abnormalities were
analysis indicates a positive association with CVD risk in which found to be associated independently with elevated IL-6. 201 This
every 5 mmol/L increase in Hcy increased the risk of incident biomarker appears to be predictive of future heart disease 200 and
coronary disease by 60% in men and 80% in women. 178 However, is elevated in patients with unstable angina. 202 Patients displaying
this report was not corroborated in a subsequent study. 179 Several persistent IL-6 elevation tend to experience a worse in-hospital
hypotheses may prove to account for the association of Hcy with outcome after admission with unstable angina. 203,204
risk of CVD. They include the ability of Hcy to stimulate the en- IL-6 is a systemic biomarker not specific to CVD, which
dothelium directly, thereby increasing proliferation of smooth means routine cardiovascular risk evaluation cannot be based on
muscle cells 180 and the tendency toward thrombosis. 178 The corre- isolated consideration of IL-6 levels. Taken with the lack of a spe-
lation of Hcy with renal dysfunction, smoking, fibrinogen levels, cific treatment for elevated IL-6 levels, more data are required be-
and plasma CRP levels suggests the potential for confounding. 181 fore the clinical use of this promising biomarker.