Nonfasting plasma total homocysteine level and mortality in middle-aged and elderly men and women in Jerusalem.

BACKGROUND: Elevated plasma total homocysteine level has been associated with cardiovascular disease in many studies, mostly in Europe and North America. Data on persons from other areas and on associations with overall mortality are sparse. OBJECTIVE: To determine the relation of plasma homocysteine level to all-cause and cause-specific mortality. DESIGN: Prospective observational study with 9- to 11-year follow-up. SETTING: A free-living, multiethnic Jewish population in western Jerusalem, Israel. PARTICIPANTS: 1788 residents of Jerusalem (808 men and 980 women) who were at least 50 years of age and were examined between 1985 and 1987 as part of the Kiryat Yovel Community Health Study. MEASUREMENTS: Nonfasting plasma homocysteine level was determined in frozen stored samples. Deaths during follow-up were identified by linkage with the national population registry. RESULTS: Plasma homocysteine levels exceeded 14 micromol/L in 28% of men and 20% of women. During the study period, 405 deaths occurred. In multivariate Cox models that controlled for possible confounders, a nonmonotonic increase in mortality hazard ratios was associated with ascending quintile of homocysteine level: 1.0, 1.4, 1.3, 1.5, and 2.0 (P < 0.001 for trend). The relation was similar for cardiovascular and noncardiovascular causes of death (excluding cancer). The association was weaker when deaths that occurred during the first 5 years of follow-up were excluded; corresponding hazard ratios for ascending quintile of homocysteine level were 1.0, 1.0, 1.2, 1.1, and 1.6 (P = 0.063 for trend). Age- and sex-adjusted percentages of deaths "attributable" to elevated plasma homocysteine level (> or = 14 micromol/L) were 12.5% (95% CI, 6.7% to 18.8%) for all deaths, 16.0% (CI, 7.2% to 25.6%) for deaths during the first 5 years of follow-up, and 8.3% (CI, 1.5% to 16.1%) for later deaths. CONCLUSIONS: A mildly to moderately elevated nonfasting plasma homocysteine level is a substantial risk marker for death from all causes. The association seems to be stronger during the first 5 years of follow-up.     

Nonfasting plasma total homocysteine levels and stroke incidence in elderly persons: the Framingham Study.

BACKGROUND: Total homocysteine levels are associated with arteriosclerotic outcomes. OBJECTIVE: To determine whether total homocysteine levels predict incident stroke in elderly persons. DESIGN: Prospective population-based cohort study with 9.9 years of follow-up. SETTING: Framingham, Massachusetts. PATIENTS: 1947 Framingham Study participants (1158 women and 789 men; mean age +/- SD, 70 +/- 7 years). MEASUREMENTS: Baseline total homocysteine levels and 9.9-year stroke incidence. RESULTS: The quartiles of nonfasting total homocysteine levels were as follows: quartile 1, 4.13 to 9.25 micromol/L; quartile 2, 9.26 to 11.43 micromol/L; quartile 3, 11.44 to 14.23 micromol/L; quartile 4, 14.24 to 219.84 micromol/L. During follow-up, 165 incident strokes occurred. In proportional hazards models adjusted for age, sex, systolic blood pressure, diabetes, smoking, and history of atrial fibrillation and coronary heart disease, relative risk (RR) estimates comparing quartile 1 with the other three quartiles were as follows: quartile 2 compared with quartile 1--RR, 1.32 (95% CI, 0.81 to 2.14); quartile 3 compared with quartile 1--RR, 1.44 (CI, 0.89 to 2.34); quartile 4 compared with quartile 1--RR, 1.82 (CI, 1.14 to 2.91). The linear trend across the quartiles was significant (P < 0.001). CONCLUSION: Nonfasting total homocysteine levels are an independent risk factor for incident stroke in elderly persons.     

Serum sex hormone and plasma homocysteine levels in middle-aged and elderly men

OBJECTIVE: To investigate whether circulating levels of testosterone (total, bioavailable), estradiol (total, bioavailable), and DHEA sulfate (DHEAS) are associated with fasting plasma homocysteine (tHcy) levels in middle-aged and elderly men. DESIGN: A population-based sample of 400 independently living men between 40 and 80 years of age in a cross-sectional study. METHODS: Total testosterone, sex hormone binding globulin (SHBG), and total estradiol were measured by RIA methods and bioavailable testosterone and estradiol were calculated. DHEAS was measured using an immunometric technique. Fasting homocysteine was measured by fluorescence polarization immunoassay. Anthropometric characteristics were also measured and two standardized questionnaires completed, including life-style factors and diet. Linear regression analysis adjusted for age, body mass index (BMI), creatinine clearance, and mean visceral fat was used to assess the association of endogenous sex hormones and fasting plasma homocysteine levels. RESULTS: After adjustment for age, BMI, creatinine clearance, and mean visceral fat no statistically significant association was observed between testosterone (total, bioavailable), DHEAS, and estradiol (total, bioavailable)levels with natural log tHcy (beta = -2 x 10(-3); 95% confidence intervals (CI) -9 x 10(-3); 5 x 10(-3)), (beta = -4 x 10(-3); 95% CI -18 x 10(-3); 9 x 10(-3)), (beta = 3 x 10(-3); 95% CI -6 x 10(-3); 12 x 10(-3)), (beta = -9.3 x 10(-5); 95% CI -1 x 10(-3); 1 x 10(-3)), and (beta = 0.00; 95% CI -3 x 10(-3); 2 x 10(-3)) respectively. Additional adjustment for smoking, alcohol intake, daily physical activity, diabetes mellitus, and hypertension did not change these findings. CONCLUSION: The results of our study do not support a direct role for circulating sex hormone levels in the regulation of fasting plasma tHcy concentrations in middle-aged and elderly men.     

Relation of plasma total homocysteine to cardiovascular mortality in a French population

Although there is considerable epidemiologic evidence for a relation between plasma homocysteine (HCY) and cardiovascular (CV) disease, the role of HCY as a causal CV risk factor remains controversial, mainly because of the intercorrelation between HCY and other CV risk factors. The goal of the present nested case-control prospective study is to determine the multiadjusted relation between HCY and CV mortality in a large and low CV risk population after a mean follow-up of 14 years. In 1980 and 1981, plasma was saved from 5,000 patients who underwent a systematic health checkup, including clinical and biologic examinations. In 1999, HCY concentration was measured in 110 subjects who died of CV disease (cases) and in 154 randomly matched survivors (control subjects). Statistical analysis was adjusted for CV risk factors. Based on Cox analyses, 3 factors emerged as independent predictors of CV mortality: C-reactive protein, systolic blood pressure, and HCY. The adjusted hazard ratio for CV mortality was 1.22 (95% confidence interval 1.04 to 1.41) per 1 SD (3.9 micromol/L) increment of HCY. Thus, HCY is an independent risk predictor for CV mortality. Because of extensive adjustment procedures, the present study provides additional epidemiologic evidence for a causal relation between HCY and CV disease.     

Monocyte cytokine production, systemic inflammation and cardiovascular disease in very elderly men and women: the Framingham Heart Study.

In very elderly participants of the Framingham Heart Study (mean age 79 years, 276 men and 462 women), interleukin-6 correlated with C-reactive protein (CRP) levels. Interleukin-6, tumour necrosis factor alpha and interleukin-1 production, and CRP were not associated with prevalent cardiovascular disease, and nonsteroidal anti-inflammatory drug use did not influence cytokine or CRP levels. Further studies are warranted to examine the prognostic implications of CRP and related cytokines for CVD in the elderly.     

Circulating adiponectin levels and mortality in elderly men with and without cardiovascular disease and heart failure

BACKGROUND: High adiponectin levels have been associated with reduced cardiovascular risk but have been shown to predict mortality in those at high risk for vascular disease. We examined the relationship between adiponectin levels and mortality in older men with and without diagnosed cardiovascular disease (CVD) and heart failure. METHODS: Prospective study of 4046 men aged 60 to 79 years drawn from general practices in 24 British towns and followed up for a mean of 6 years, during which 734 deaths occurred. The men were divided into the following groups according to the presence of physician-diagnosed CVD and heart failure: (1) those with no CVD or heart failure; (2) those with CVD but without heart failure; and (3) those with heart failure (with or without CVD). RESULTS: After adjustment for a wide range of baseline characteristics, adiponectin levels were positively associated with significantly increased all-cause and CVD mortality in men with no diagnosed CVD or heart failure (top third vs bottom third adjusted relative risk, 1.55 [95% confidence interval (CI), 1.19-2.02; P = .002 for trend] vs 1.53 [95% CI, 1.03-2.27; P = .02 for trend]), as well as in men with diagnosed heart failure ([adjusted relative risk, 2.37 [95% CI, 0.64-8.79; P = .04 for trend] vs 3.43 [95% CI, 0.54-21.70; P = .008 for trend]). No association was seen in those with diagnosed CVD without heart failure. Adjustment for weight loss and renal function made minor differences to these relationships. CONCLUSIONS: In older men, high adiponectin levels are associated with increased all-cause and CVD mortality in those with heart failure and those free of CVD. Such observations suggest that adiponectin levels may reflect a balance of both protective and harmful factors.     

Chronic kidney disease and risk of incident myocardial infarction and all-cause and cardiovascular disease mortality in middle-aged men and women from the general population.

AIMS: Chronic kidney disease (CKD) was found to be an independent risk factor for all-cause mortality as well as adverse cardiovascular disease (CVD) events in high-risk populations. Findings from population-based studies are scarce and inconsistent. We investigated the gender-specific association of CKD with all-cause mortality, cardiovascular mortality, and incident myocardial infarction (MI) in a population-based cohort. METHODS AND RESULTS: The study was based on 3860 men and 3674 women (aged 45-74 years) who participated in one of the three MONICA Augsburg surveys between 1984 and 1995. CKD was defined by an estimated glomerular filtration rate between 15 and 59 mL/min/1.73 m(2). Hazard ratios (HRs) were estimated from Cox proportional hazard models. In this study, 890 total deaths, 400 CVD deaths, and 321 incident MIs occurred in men up to 31 December 2002; the corresponding numbers in women were 442, 187, and 102. In multivariable analyses, the HR for women with CKD compared to women with preserved renal function was significant for incident MI [HR 1.67; 95% confidence interval (CI) 1.07-2.61] and CVD mortality (HR 1.60; 95% CI 1.17-2.18). In men, CKD was also significantly associated with incident MI (HR 1.51; 95% CI 1.09-2.10) and CVD mortality (HR 1.48; 95% CI 1.15-1.92) after adjustment for common CVD risk factors. In contrast, men and women with CKD had no significant increased risk of all-cause mortality. CONCLUSION: CKD was strongly associated with an increased risk of incident MI and CVD mortality independent from common cardiovascular risk factors in men and women from the general population.     

Low physical activity as a predictor for total and cardiovascular disease mortality in middle-aged men and women in Finland.

AIMS: To investigate separately for men and women whether moderate or high leisure time physical activity, occupational physical activity, and commuting activity are associated with a reduced cardiovascular disease (CVD) and all-cause mortality, independent of CVD risk factors and other forms of physical activity. METHODS AND RESULTS: Prospective follow-up of 15,853 men and 16,824 women aged 30-59 years living in eastern and south-western Finland (median follow-up time 20 years). CVD and all-cause mortality were lower (9-21%) in men and women (2-17%) who were moderately or highly physically active during leisure time. Moderate and high levels of occupational physical activity decreased CVD and all-cause mortality by 21-27% in both sexes. Women spending daily 15 min or more in walking or cycling to and from work had a reduced CVD and all-cause mortality before adjustment for occupational and leisure time physical activity. Commuting activity was not associated with CVD or all-cause mortality in men. CONCLUSION: Moderate and high levels of leisure time and occupational physical activity are associated with a reduced CVD and all-cause mortality among both sexes. Promoting already moderate levels of leisure time and occupational physical activity are essential to prevent premature CVD and all-cause mortality.     

Serum folate and cardiovascular disease mortality among US men and women

BACKGROUND: Folate has been linked to cardiovascular disease (CVD) through its role in homocysteine metabolism. OBJECTIVE: To assess the relationship between serum folate and CVD mortality. DESIGN: In this prospective study, serum folate concentrations were measured on a subset of adults during the Second National Health and Nutrition Examination Survey (1976-1980) and vital status ascertained after 12 to 16 years. SETTING AND PATIENTS: A national probability sample consisting of 689 adults who were 30 to 75 years of age and did not have a history of CVD at baseline. MAIN OUTCOME MEASURE: Vital status was determined by searching national databases that contained information about US decedents. RESULTS: The associations between serum folate and CVD and all-cause mortality differed by diabetes status (P =.04 and P =.03, respectively). Participants without diabetes in the lowest compared with the highest serum folate tertile had more than twice the risk of CVD mortality after adjustment for age and sex (relative risk [RR], 2.64; 95% confidence interval [CI], 1.15-6.09). This increased risk for participants in the lowest tertile was attenuated after adjustment for CVD risk factors (RR, 2.28; 95% CI, 0.96-5.40). Serum folate tertiles were not significantly associated with total mortality, although the age- and sex-adjusted risk was increased for participants in the lowest compared with highest tertile (RR, 1.74; 95% CI, 0.96-3.15). Risk estimates for participants with diabetes were unstable because of the small sample size (n = 52). CONCLUSION: These data suggest that low serum folate concentrations are associated with an increased risk of CVD mortality among adults who do not have diabetes. Arch Intern Med. 2000;160:3258-3262.     

The relation of plasma total homocysteine levels to prevalent cardiovascular disease in older patients with ischemic stroke

The objectives of this study were to describe the distribution of serum levels of total homocysteine (HCys) in a sample of older patients consecutively admitted following acute ischemic cerebral stroke, as compared with healthy controls, and to test for possible relationships of HCys levels to some of the prevalent cardiovascular diseases in these stroke patients. One hundred and thirty-seven stroke patients and 132 healthy controls (age > or =60) participated in this study. HCys levels were determined by HPLC method with fluorescence detection. Correlates of HCys levels and clinical data were examined. The results showed that stroke patients (mean age 74.6+/-9.2) had higher HCys levels as compared with controls (13.8 and 9.8 respectively, p<0.001). Advanced age, male gender, absence of diabetes and a positive history of previous myocardial infarction were the factors associated with HCys levels higher than 10 mmol/L (Odds ratio 2.72, 2.54, 3.12, 3.55, respectively). We conclude that hyperhomocysteinemia is prevalent in older patients with acute ischemic stroke. Few factors associated with increased risk for hyperhomocysteinemia in these stroke patients were identified. The study supports earlier observations regarding elevated HCys levels in stroke patients and increased prevalence of associated cardiovascular disease.     

Relationship between plasma lipids and all-cause mortality in nondemented elderly

OBJECTIVES: To investigate the relationship between plasma lipids and risk of death from all causes in nondemented elderly. DESIGN: Prospective cohort study. SETTING: Community-based sample of Medicare recipients, aged 65 years and older, residing in northern Manhattan. PARTICIPANTS: Two thousand two hundred seventy-seven nondemented elderly, aged 65 to 98; 672 (29.5%) white/non-Hispanic, 699 (30.7%) black/non-Hispanic, 876 (38.5%) Hispanic, and 30 (1.3%) other. MEASUREMENTS: Anthropometric measures: fasting plasma total cholesterol, triglyceride, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and non-HDL-C, body mass index, and apolipoprotein E (APOE) genotype. clinical measures: neuropsychological, neurological, medical, and functional assessments; medical history of diabetes mellitus, heart disease, hypertension, stroke, and treatment with lipid-lowering drugs. Vital status measure: National Death Index date of death. Survival methods were used to examine the relationship between plasma lipids and subsequent mortality in younger and older nondemented elderly, adjusting for potential confounders. RESULTS: Nondemented elderly with levels of total cholesterol, non-HDL-C, and LDL-C in the lowest quartile were approximately twice as likely to die as those in the highest quartile (rate ratio (RR)=1.8, 95% confidence interval (CI)=1.3-2.4). These results did not vary when analyses were adjusted for body mass index, APOE genotype, diabetes mellitus, heart disease, hypertension, stroke, diagnosis of cancer, current smoking status, or demographic variables. The association between lipid levels and risk of death was attenuated when subjects with less than 1 year of follow-up were excluded (RR=1.4, 95% CI=1.0-2.1). The relationship between total cholesterol, non-HDL-C, HDL-C, and triglycerides and risk of death did not differ for older (>or=75) and younger participants (>75), whereas the relationship between LDL-C and risk of death was stronger in younger than older participants (RR=2.4, 95% CI=1.2-4.9 vs RR=1.6, 95% CI=1.02-2.6, respectively). Overall, women had higher mean lipid levels than men and lower mortality risk, but the risk of death was comparable for men and women with comparable low lipid levels. CONCLUSION: Low cholesterol level is a robust predictor of mortality in the nondemented elderly and may be a surrogate of frailty or subclinical disease. More research is needed to understand these associations.     

C-reactive protein and risk of cardiovascular disease in men and women from the Framingham Heart Study

BACKGROUND: Determination of C-reactive protein (CRP) level has been suggested to improve cardiovascular disease (CVD) risk assessment. This study examines the utility of CRP levels to assess CVD risk in a community setting. METHODS: We performed a prospective observational cohort study on a community population sample. A total of 1949 men and 2497 women without CVD from the Framingham Heart Study underwent CVD risk factor assessment. Initial CVD events during 8 years of follow-up were recorded. RESULTS: There were 283 major CVD and 160 major coronary heart disease incident events. Age-, sex-, and multivariable-adjusted analyses generally used CRP level categories of less than 1, 1 to 3, and greater than 3 mg/L. In age- and sex-adjusted models, the traditional risk factors and elevated CRP levels indicated increased risk. The age- and sex-adjusted relative risk (RR) and 95% confidence interval (CI) of CRP level greater than 3 mg/L for major CVD was elevated (RR, 1.60; 95% CI, 1.19-2.14), with evidence of attenuation (RR, 1.22; 95% CI, 0.90-1.66) in multivariable models. The C statistic, a measure of the discriminatory capability of the prediction models, was 0.74 for prediction of major CVD with age and CRP level. In multivariable models that included traditional risk factors, the C statistic was 0.78, a value that was unchanged with the addition of CRP to the multivariable model. Similar relations were noted for major coronary heart disease events. CONCLUSION: Elevated CRP level provided no further prognostic information beyond traditional office risk factor assessment to predict future major CVD and major coronary heart disease in this population sample.     

Body mass index and total and cardiovascular mortality in men with a history of cardiovascular disease

BACKGROUND: Previous studies designed to identify an association between body mass index (BMI) (calculated as weight in kilograms divided by the square of height in meters) and cardiovascular or total mortality in populations with known atherosclerotic disease have shown conflicting results. In this study, we used the Physicians' Health Study enrollment cohort to examine the risk of total and cardiovascular mortality among men reporting a history of myocardial infarction or stroke, excluding those who reported a history of cancer. METHODS: Cause-specific death was ascertained for 5010 men during a mean follow-up of 5.0 years. End points were classified as total deaths and deaths due to cardiovascular causes. Four BMI categories (<22.0, 22.0-24.9 [referent], 25.0-27.9, and > or =28.0) were created a priori. We used proportional hazards models to calculate age and multivariate-adjusted relative risks (RRs) for each BMI category for each end point. RESULTS: Compared with men with a BMI of 22.0 to 24.9, men with a BMI of 28.0 or greater had an age-adjusted RR of 1.11 (95% confidence interval [CI], 0.91-1.36), a multivariate RR of 1.04 (95% CI, 0.84-1.28) in a model that did not include biological mediators of obesity, and a multivariate RR of 1.06 (95% CI, 0.78-1.44) in a model that included these mediators. The RRs for cardiovascular mortality were similar, at 1.07 (95% CI, 0.85-1.35), 1.01 (95% CI, 0.79-1.29), and 1.01 (95% CI, 0.71-1.43), respectively. A BMI of less than 22.0 was associated with a small increased risk of total mortality and cardiovascular mortality. CONCLUSION: These findings indicate that elevated BMI may not be strongly associated with total or cardiovascular mortality among men with previously manifested coronary artery disease.     

Plasma total homocysteine levels in postmenopausal women with unstable coronary artery disease

An elevated plasma total homocysteine (tHcy) level is considered a risk factor for coronary artery disease (CAD), but the relationship between plasma tHcy and well-defined CAD in women is still unclear. Plasma tHcy concentrations and the covariates serum folate, vitamin B12, and creatinine were analysed in 157 angiographically examined postmenopausal women with unstable CAD and in 101 healthy controls. At coronary angiography, 16% had normal vessels and 84% had coronary atherosclerosis. Mean plasma tHcy concentration (micromol/l, 95% confidence interval) did not differ in patients compared to controls (13.1 (12.3-13.8) vs. 12.5 (11.6-13.5)) or in patients with or without coronary atherosclerosis (13.3 (12.4-14.1) vs. 12.0 (10.8-13.2)). A trend to an increasing plasma tHcy with increasing degree of coronary atherosclerosis was attenuated after adjustment for age and the previous mentioned covariates. Odds ratio for the risk of coronary artery disease and coronary atherosclerosis in hyperhomocysteinemic patients (> or =90th percentile in controls) was approximately 3. However, the confidence interval included unity in half of the groups and the significance was therefore difficult to judge. Receiver operating characteristics showed age to be the only variable with a significant discriminatory ability regarding the presence of coronary atherosclerosis (area 0.77). Mild hyperhomocysteinemia seems not to be related to the risk of unstable CAD in postmenopausal women. The trend towards higher plasma tHcy with increasing degree of coronary atherosclerosis may be a marker of the disease. In future studies adjustment for age and the other three covariates should be considered.