Page 787 - Cardiac Nursing

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C HAPTER 32 / Coronary Heart Disease Risk Factors 763
women using placebo, women using estrogen plus progestin had evaluate the association between homocysteine and various mani-
a 29% increase in the risk of CHD, a 26% increase in the risk of festations of cardiovascular disease, including CHD, stroke, and
breast cancer, a 41% increase in the risk of stroke, a doubling of peripheral vascular disease. The majority of studies show a positive
risk of pulmonary embolus, a 37% decrease in the risk of colorec- association between homocysteine levels and these condi-
tal cancer, and a 44% decrease in the risk of hip fracture. Al- tions. 143,146 Homocysteine levels are higher in women and men
though many of these findings were in the expected direction, the with angiographically confirmed obstruction of one or more ma-
increase in the risk of CHD and stroke was unexpected. The study jor coronary arteries than in those with normal coronaries. 147,148
investigators concluded that HRT should not be used for the pri- In the Framingham Heart Study, high plasma homocysteine con-
mary prevention of coronary disease. Like the estrogen plus prog- centrations and low concentrations of folate were associated with
esterone arm of the study, the estrogen only arm was stopped pre- increased risk of extracranial carotid artery stenosis. 149 In Athero-
maturely after an average follow up of 6.8 years. 136 The results of sclerosis Risk in Communities Study, the relative risk for carotid
this trial demonstrated that estrogen therapy significantly in- artery intimal–medial wall thickening among participants in
creased the risk for stroke, reduced the risk for hip and other frac- the highest versus the lowest quintiles of plasma homocysteine
tures, and had no effect on CHD or overall mortality. was 3.2. 150
Further evidence against a cardiovascular benefit of HRT In a 2-year prospective study, HRT was associated with an
comes from the ERA trial. 137 In this randomized, controlled trial, 11% decrease in homocysteine. The decrease was 17% in women
neither unopposed estrogen nor estrogen plus progestin altered with high homocysteine levels, whereas levels in women with low
the progression of angiographically verified coronary disease com- homocysteine did not change. 151 Increasing homocysteine after
pared to placebo after a mean of 3.2 0.6 years. A similar trial menopause may partially explain the increase in CHD risk associ-
showed no effect of HRT on progression of carotid atherosclero- ated with aging. Postmenopausal women have an excessive in-
sis. 138 More recently, results from the Women’s International crease in homocysteine after a methionine load compared with
Study of Long Oestrogen after Menopause trial, a multicenter, premenopausal women, and folic acid supplementation decreases
randomized, placebo controlled, double blind trial in the United this increase in homocysteine after methionine loading. 152
Kingdom, Australia, and New Zealand, found that hormone re- Despite evidence from observational studies that homocys-
placement therapy increased CVD and thromboembolic risk teine is associated with an increased risk for cardiovascular disease,
when started many years after menopause. 139 there is currently no evidence that lowering homocysteine levels
Thus, although trial data support a protective effect of HRT decreases coronary morbidity and mortality. Several studies have
against fracture, and possibly colorectal cancer, concerns about failed to show a relationship between reduction in homocysteine
breast cancer risk have been confirmed, and hopes that HRT levels and reduced CVD events or risks. The Vitamin Interven-
would protect against cardiovascular disease and dementia have tion for Stroke Prevention, a randomized controlled trial which
been reversed. The American College of Obstetricians and Gyne- included subjects with previous nondisabling cerebrovascular in-
cologists now recommends that HRT use should be limited to farct, did not show any effect on vascular outcomes in the 2 years
short-term therapy for vasomotor symptoms. 140 of study follow up despite moderate reduction in mean homocys-
teine levels. 153 Similarly, results from the Norwegian Vitamin trial,
which evaluated the efficacy of lowering homocysteine levels with
B vitamins in individuals with previous MI, did not find any effect
FOLATE AND HOMOCYSTEINE upon lowering risk of recurrent cardiovascular disease despite a
27% reduction in homocysteine levels. 154 The Heart Outcomes
Homocysteine is an amino acid that is an intermediate byprod- Prevention Evaluation-2 trial, another randomized controlled trial
uct of methionine metabolism. Homocysteine levels are higher in that examined reduction in homocysteine levels using folic acid
postmenopausal than in premenopausal women, lower in women and B vitamins, failed to show a reduction in risk of major cardio-
than in men, positively correlated with age, and negatively corre- vascular events in patients with vascular disease. 155 However, the
lated with serum/plasma levels of folic acid, vitamin B6, and vi- debate regarding homocysteine continues; it has been suggested
tamin B12. 141–144 Homocysteine levels of 5 to 15 mol/L are that longer trials are needed, as are trials focusing on those with
considered normal, and elevations of 16 to 30, 31 to 100, and higher homocysteine levels as well as achievement of greater re-
greater than 100 mol/L are considered moderate, intermediate, ductions in homocysteine levels. 156,157 Therefore, because con-
or severe, respectively. Methylenetetrahydrofolate is an enzyme clusive evidence for intervention does not yet exist, at this time,
that contributes to the remethylation of homocysteine to methion- population-wide screening of homocysteine is considered inap-
ine. This reaction requires folate as the substrate, and levels of dietary propriate. 143,146,158,159
and blood folate are strong determinants of homocysteine levels. 145
Normally present in only small amounts ( 10 mol/L), homocys-
teine is highly toxic to the vascular endothelium. Homocysteine is
associated with endothelial dysfunction, arterial intimal–medial ANTIOXIDANTS
thickening, wall stiffening, and a procoagulant activity. 146 People
with homocysteinuria, a rare autosomal recessive condition in which Epidemiologic findings that antioxidants decrease CHD risk are
homocysteine levels are severely elevated, are at extremely high risk supported by evidence that oxidized LDL is present in atheroscle-
for premature atherosclerosis. rotic lesions. 160,161 The accumulation of lipids in the arterial in-
Even mild elevations in homocysteine appear to be associated tima is the hallmark of early atherosclerotic lesions, and oxidation
with increased CHD risk, and there is no specific threshold for the of LDL enhances its accumulation in the arterial wall lesions. In-
association between homocysteine and CHD risk. Numerous ob- terest in the effects of antioxidants and CHD risk has centered on
servation cohort and case-control studies have been conducted to vitamins E and C and -carotene. 160,162 Although observational