***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
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    Input: OBJECTIVES To examine the prospect i ve relation between total homocysteine and major coronary heart disease events . DESIGN A nested case – control study carried out within the British regional heart study , a prospect i ve investigation of cardiovascular disease in men aged 40–59 years at entry .  Serum total homocysteine concentrations  were analysed retrospectively and blindly in baseline sample s from 386 cases who had a myocardial infa rct during 12.8 years of follow up and from 454 controls , frequency matched by age and town .  RESULTS Geometric mean serum total homocysteine  was slightly higher in cases ( 14.2 μmol/l ) than in controls ( 13.5 μmol/l ) , a proportional difference of 5.5 % ( 95 % confidence interval ( CI ) −0.02 % to 10.8 % , p = 0.06 ) . Age adjusted risk of myocardial infa rct ion increased weakly with log total homocysteine concentration ; a 1 SD increase in log total homocysteine ( equivalent to a 47 % increase in total homo cysteine ) was associated with an increase in odds of myocardial infa rct ion of 1.15 ( 95 % CI 1.00 to 1.32 ; p = 0.05 ) . The relation was particularly marked in the top fifth of the total homocysteine distribution ( values > 16.5 μmol/l ) , which had an odds ratio of 1.77 ( 95 % CI 1.28 to 2.42 ) compared with lower levels . Adjustment for other risk factors had little effect on these findings . Total homocysteine concentrations more than 16.5 μmol/l accounted for 13 % of the attributable risk of myocardial infa rct ion in this study population . Serum total homocysteine among control subjects varied between towns and was correlated with town st and ardised mortality ratios for coronary heart disease ( r = 0.43 , p = 0.08 ) . CONCLUSIONS Serum total homocysteine is prospect ively related to increased coronary risk and may also be related to geographical variation in coronary risk within Britain . These results strengthen the case for trials of total homocysteine reduction with folate BACKGROUND A high serum total homocysteine ( tHcy ) concentration is a risk factor for death , but the strength of the relation in patients with type 2 ( non-insulin-dependent ) diabetes mellitus compared with nondiabetic subjects is not known . A cross-sectional study suggested that the association between tHcy and cardiovascular disease is stronger in diabetic than in nondiabetic subjects . We therefore prospect ively investigated the combined effect of hyperhomocysteinemia and type 2 diabetes on mortality . METHODS AND RESULTS Between October 1 , 1989 , and December 31 , 1991 , serum was saved from 2484 men and women , 50 to 75 years of age , who were r and omly selected from the town of Hoorn , The Netherl and s.  Fasting serum tHcy concentration was measured in 171 subjects who died ( cases ; 76 of cardiovascular disease ) and in a stratified r and om sample of 640 survivors ( control subjects ) .  Mortality risks were calculated over 5 years of follow-up by means of logistic regression . The prevalence of hyperhomocysteinemia ( tHcy > 14 micromol/L ) was 25 . 8 % . After adjustment for major cardiovascular risk factors , serum albumin , and HbA(1c ) , the odds ratio ( 95 % CI ) for 5-year mortality was 1.56 ( 1.07 to 2.30 ) for hyperhomocysteinemia and 1.26 ( 1.02 to 1 . 55 ) per 5-micromol/L increment of tHcy . The odds ratio for 5-year mortality for hyperhomocysteinemia was 1.34 ( 0.87 to 2.06 ) in nondiabetic subjects and 2.51 ( 1.07 to 5.91 ) in diabetic subjects ( P=0.08 for interaction ) . CONCLUSIONS Hyperhomocysteinemia is related to 5-year mortality independent of other major risk factors and appears to be a stronger ( 1.9-fold ) risk factor for mortality in type 2 diabetic patients than in nondiabetic subjects The relation of serum total homocysteine and lipoprotein(a ) ( Lp(a ) ) with the incidence of atherosclerotic disease was investigated among 7424 men and women aged 40 - 64 years free of atherosclerotic disease at baseline in 1977 . During the 9-year follow-up , 134 male and 131 female cases with either myocardial infa rct ion or stroke were identified . For each case a control subject was selected belonging to the same sex and 5-year age group .  Serum sample s collected in 1977 were stored at -20 degrees C and analyzed in 1991 . The mean serum homocysteine concentration of male cases and controls was 9.99 mumol/l and 9.82 mumol/l at baseline and that of female cases and controls 9.58 mumol/l and 9.24 mumol/l , respectively . The median serum Lp(a ) concentration of male cases and controls was 73 mg/l and 108 mg/l and that of female cases and controls 113 mg/l and 91 mg/l , respectively . The differences between cases and controls were not statistically significant . There was also no significant association between either homocysteine or Lp(a ) and atherosclerotic disease , myocardial infa rct ion or stroke in logistic regression analyses . The odds ratios varied from 1.00 to 1.26 for homocysteine and from 0.81 to 1.06 for Lp(a ) . The results of this prospect i ve population -based study do not support the hypotheses that serum homocysteine or Lp(a ) are risk factors for atherosclerotic disease . The lack of association between serum homocysteine and atherosclerotic disease may be due to the exceptionally low gene frequency predisposing to homocysteinemia in Finl and Background —Sudden cardiac death ( SCD ) is an important cause of mortality even among apparently healthy population s. However , our ability to identify those at risk for SCD in the general population is poor , and more specific markers are needed . Methods and Results —To compare and contrast the relative importance of  C-reactive protein ( CRP ) , homocysteine , and lipids  as long-term predictors of SCD , we performed a prospect i ve , nested , case-control analysis involving 97 cases of SCD among apparently healthy men enrolled in the Physician ’s Health Study . Of these plasma markers measured , only baseline CRP levels were significantly associated with the risk of SCD over the ensuing 17 years of follow-up ( P for trend=0.001 ) . The increase in risk associated with CRP levels was primarily seen among men in the highest quartile , who were at a 2.78-fold increased risk of SCD ( 95 % CI 1.35 to 5.72 ) compared with men in the lowest quartile . These results were not significantly altered in analyses that ( in addition to the matching variables of age and smoking status ) controlled for lipid parameters , homocysteine , and multiple cardiac risk factors ( relative risk for highest versus lowest quartile 2.65 , 95 % CI 0.79 to 8.83;P for trend=0.03 ) . In contrast to the positive relationship observed for CRP , neither homocysteine nor lipid levels were significantly associated with risk of SCD . Conclusions —These prospect i ve data suggest that  CRP levels may be useful in identifying apparently healthy men who are at an increased long-term risk of SCD BACKGROUND Since inflammation is believed to have a role in the pathogenesis of cardiovascular events , measurement of markers of inflammation has been proposed as a method to improve the prediction of the risk of these events . METHODS We conducted a prospect i ve , nested case-control study among 28,263 apparently healthy postmenopausal women over a mean follow-up period of three years to assess the risk of cardiovascular events associated with base-line levels of markers of inflammation . The markers included high-sensitivity C-reactive protein ( hs-CRP ) , serum amyloid A , interleukin-6 , and soluble intercellular adhesion molecule type 1 ( sICAM-1 ) . We also studied homocysteine and a variety of lipid and lipoprotein measurements .  Cardiovascular events were defined as death from coronary heart disease , nonfatal myocardial infa rct ion or stroke , or the need for coronary-revascularization procedures . RESULTS Of the 12 markers measured , hs-CRP was the strongest univariate predictor of the risk of cardiovascular events ; the relative risk of events for women in the highest as compared with the lowest quartile for this marker was 4.4 ( 95 percent confidence interval , 2.2 to 8.9 ) . Other markers significantly associated with the risk of cardiovascular events were serum amyloid A ( relative risk for the highest as compared with the lowest quartile , 3.0 ) , sICAM-1 ( 2.6 ) , interleukin-6 ( 2.2 ) , homocysteine ( 2.0 ) , total cholesterol ( 2.4 ) , LDL cholesterol ( 2.4 ) , apolipoprotein B-100 ( 3.4 ) , HDL cholesterol ( 0.3 ) , and the ratio of total cholesterol to HDL cholesterol ( 3.4 ) . Prediction models that incorporated markers of inflammation in addition to lipids were significantly better at predicting risk than models based on lipid levels alone ( P<0.001 ) . The levels of hs-CRP and serum amyloid A were significant predictors of risk even in the subgroup of women with LDL cholesterol levels below 130 mg per deciliter ( 3.4 mmol per liter ) , the target for primary prevention established by the National Cholesterol Education Program . In multivariate analyses , the only plasma markers that independently predicted risk were hs-CRP ( relative risk for the highest as compared with the lowest quartile , 1.5 ; 95 percent confidence interval , 1.1 to 2.1 ) and the ratio of total cholesterol to HDL cholesterol ( relative risk , 1.4 ; 95 percent confidence interval , 1.1 to 1.9 ) . CONCLUSIONS The addition of the measurement of C-reactive protein to screening based on lipid levels may provide an improved method of identifying persons at risk for cardiovascular events CONTEXT Individuals with elevated levels of homocysteine tend to have higher prevalence of cardiovascular disease . However , prospect i ve studies of homocysteine are inconsistent and data among women are limited . OBJECTIVE To determine whether elevated homocysteine levels in healthy postmenopausal women predict risk of developing cardiovascular disease . DESIGN Prospect i ve , nested case-control study with a mean 3-year follow-up . SETTING The Women 's Health Study , an ongoing US primary prevention trial initiated in 1993 . PARTICIPANTS From a total cohort of 28,263 postmenopausal women with no history of cardiovascular disease or cancer at baseline , 122 women who subsequently experienced cardiovascular events were defined as cases , and 244 age- and smoking status-matched women who remained free of disease during follow-up were defined as controls . MAIN OUTCOME MEASURES Incidence of death due to cardiovascular disease , nonfatal myocardial infa rct ion ( MI ) , stroke , percutaneous transluminal coronary angioplasty , or coronary artery bypass graft by baseline homocysteine level . RESULTS Of the 122 cases , there were 85 events of MI or stroke and 37 coronary revascularizations . Case subjects had significantly higher baseline homocysteine levels than controls ( 14.1 vs 12.4 micromol/L ; P = .02 ) . Subjects with homocysteine levels in the highest quartile had a 2-fold increase in risk of any cardiovascular event ( relative risk [ RR ] , 2.0 ; 95 % confidence interval [ CI ] , 1.1 - 3.8 ) . This effect was largely due to an excess of cases with high levels of homocysteine ; the RR for those with homocysteine levels at or higher than the 95th percentile ( 20.7 micromol/L ) was 2.6 ( 95 % CI , 1.1 - 5.7 ) . Risk estimates were independent of traditional risk factors and were greatest for the end points of MI and stroke ( RR for those with baseline homocysteine levels in the top quartile , 2.2 ; 95 % CI , 1.1 - 4.6 ) . Self-reported multivitamin supplement use at study entry was associated with significantly reduced levels of homocysteine ( P<.001 ) . However , the association between increasing quartile of homocysteine level and risk of MI or stroke remained significant in analyses controlling for baseline multivitamin supplement use ( P = .003 for trend ) , and subgroup analyses limited to women who were ( P = .02 for trend ) or were not ( P = .04 for trend ) taking multivitamin supplements . CONCLUSIONS Among healthy postmenopausal US women , 
    Output:
    
Each increase of 5 micromol/L in homocysteine level increases the risk of CHD events by approximately 20 % , independently of traditional CHD risk factors