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BACKGROUND Decreased circulating 25-hydroxy-vitamin D (25-OH-vitamin D) concentrations have been associated with mortality rates, but it is unclear whether this association is causal. We performed a Mendelian randomization study and analyzed whether 3 common single-nucleotide polymorphisms (SNPs) associated with 25-OH-vitamin D concentrations are causal for mortality rates. METHODS Genotypes of SNPs in the group-specific component gene (GC, rs2282679), 7-dehydrocholesterol reductase gene (DHCR7, rs12785878), and cytochrome P450 IIR-1 gene (CYP2R1, rs10741657) were determined in a prospective cohort study of 3316 male and female participants [mean age 62.6 (10.6) years] scheduled for coronary angiography between 1997 and 2000. 25-OH-vitamin D concentrations were determined by RIA. The main outcome measures were all-cause deaths, cardiovascular deaths, and noncardiovascular deaths. RESULTS In a linear regression model adjusting for month of blood sampling, age, and sex, vitamin D concentrations were predicted by GC genotype (P < 0.001), CYP2R1 genotype (P = 0.068), and DHCR7 genotype (P < 0.001), with a coefficient of determination (r2) of 0.175. During a median follow-up time of 9.9 years, 955 persons (30.0%) died, including 619 deaths from cardiovascular causes. In a multivariate Cox regression adjusted for classical risk factors, GC, CYP2R1, and DHCR7 genotypes were not associated with all-cause mortality, cardiovascular mortality, or noncardiovascular mortality. CONCLUSIONS Genetic variants associated with 25-OH-vitamin D concentrations do not predict mortality. This suggests that low 25-OH-vitamin D concentrations are associated with, but unlikely to be causal for, higher mortality rates.

Background: Asymmetrical dimethylarginine (ADMA) is increased in conditions associated with increased risk of atherosclerosis. We investigated the use of ADMA to predict total and cardiovascular mortality in patients scheduled for coronary angiography.Methods: In 2543 persons with and 695 without coronary artery disease (CAD) identified by angiography we measured ADMA and recorded total and cardiovascular mortality during a median follow-up of 5.45 years.Results: ADMA was correlated positively to age, female sex, diabetes mellitus, former and current smoking, and C-reactive protein and inversely to HDL cholesterol and triglycerides. ADMA was not associated with body mass index, hypertension, LDL cholesterol, or the presence or absence of angiographic CAD. Glomerular filtration rate and homocysteine were the strongest predictors of ADMA. At the 2nd, 3rd and 4th quartile of ADMA, hazard ratios for all-cause mortality adjusted for age, sex, and cardiovascular risk factors were 1.12 [95% confidence interval (CI) 0.83–1.52], 1.35 (95% CI 1.01–1.81), and 1.87 (95% CI 1.43–2.44), respectively, compared with the 1st quartile. Hazard ratios for cardiovascular death were 1.13 (95% CI 0.78–1.63), 1.42 (95% CI 1.00–2.02), and 1.81 (95% CI 1.31–2.51). ADMA in the highest quartile remained predictive of mortality after accounting for medication at baseline. The predictive value of ADMA was similar to that in the entire cohort in persons with CAD, stable or unstable, but was not statistically significant in persons without angiographic CAD.Conclusions: ADMA concentration predicts all-cause and cardiovascular mortality in individuals with CAD independently of established and emerging cardiovascular risk factors.

Background: Neopterin is produced upon activation of the cell-mediated immune response, and may be a novel risk marker for adverse outcomes resulting from coronary artery disease. Methods: We measured neopterin in 1801 study participants with and 511 without angiographic coronary artery disease. Rates of death were determined after a median follow-up of 8.0 years. Results: Estimated glomerular filtration rate and N-terminal pro-B–type natriuretic peptide (NT-proBNP) were the strongest predictors of neopterin. Neopterin was positively related to age and inversely related to LDL cholesterol, HDL cholesterol, and triglycerides. Use of lipid-lowering drugs lowered neopterin. Sex, body mass index, diabetes mellitus, hypertension, smoking status, Friesinger coronary score, and clinical instability at presentation were not associated with neopterin. Unlike C-reactive protein, neopterin was not increased in unstable angina pectoris, non–ST–elevation myocardial infarction, or ST-elevation myocardial infarction. In the third and fourth quartiles of neopterin, unadjusted hazard ratios for death from any cause were 1.94 (95% CI 1.44–2.61) and 3.32 (95% CI 2.53–4.30) compared to individuals in the first quartile, whereas hazard ratios for death from cardiovascular causes were 2.14 (95% CI 1.44–3.18) and 3.84 (95% CI 2.67–5.52), respectively. Neopterin remained predictive of total and cardiovascular mortality after adjusting for sex, age, body mass index, type 2 diabetes, hypertension, smoking status, LDL cholesterol, HDL cholesterol, triglycerides, estimated glomerular filtration rate, NT-proBNP, and clinical status at presentation, but NT-proBNP substantially weakened this association. Conclusions: Neopterin is an independent predictor of all-cause and cardiovascular mortality in individuals with or without stable coronary artery disease.

Background: Lipoprotein-associated phospholipase A2 (LpPLA2), also denoted as platelet-activating factor acetylhydrolase, is a lipoprotein-bound enzyme involved in inflammation and atherosclerosis. In this cohort study we investigated LpPLA2 activity to predict cardiac mortality in patients scheduled for coronary angiography. Methods: LpPLA2 activity was determined in 2513 patients with and in 719 patients without angiographically confirmed coronary artery disease (CAD). Results: During the median observation period of 5.5 years, 501 patients died. In patients with tertiles of LpPLA2 activity of 420–509 U/L or ≥510 U/L, unadjusted hazard ratios (HRs) for cardiac death were 1.7 (95% CI 1.3–2.4; P = 0.001), and 1.9 (95% CI 1.4–2.5; P Conclusions: LpPLA2 activity predicts risk for 5-year cardiac mortality independently from established risk factors and indicates risk for cardiac death in patients with low and medium-high hsCRP concentrations. Therefore, LpPLA2 activity may provide information for the identification and management of patients at risk beyond established risk stratification strategies.

Background: Measurement of N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) measurement can be used to predict mortality in patients with acute coronary syndromes. Information on the value of NT-pro-BNP in clinically stable persons scheduled for angiography is limited.Methods: We used Cox proportional hazards regression to examine the effect of NT-pro-BNP on total and cardiovascular mortality in 1135 with and 506 individuals without stable coronary artery disease (CAD).Results: NT-pro-BNP was associated with New York Heart Association functional class, left ventricular (LV) systolic function, and LV end-diastolic pressure. NT-pro-BNP was positively related to age, female sex, hypertension, and former and current smoking and negatively related to body mass index and glomerular filtration rate. During a median follow-up of 5.45 years, NT-pro-BNP concentrations of 100–399, 400-1999, or ≥2000 ng/L resulted in unadjusted hazard ratios (95% CI) for all-cause death of 3.2 (1.8–5.6), 6.63 (3.8–11.6), and 16.5 (9.2–29.8), respectively, compared with concentrations Conclusions: NT-pro-BNP is predictive of all-cause and cardiovascular mortality in individuals with or without stable angiographic CAD independently of other cardiovascular risk factors, coronary atherosclerosis, and cardiac function.

Cytochrome P450 epoxygenases metabolize arachidonic acid to epoxyeicosatrienoic acids (EETs), which possess various biological properties with a role in coronary vascular function. Therefore, the cytochrome P450, family 2, subfamily J, polypeptide 2 ( CYP2J2 ) gene, which encodes CYP2J2, the predominant epoxygenase isoform involved in EET formation in the human heart, has been considered a candidate gene for coronary artery disease (CAD) (1). A frequent G-to-T polymorphism at position −50 leads to a 50% reduction in CYP2J2 promoter activity (2)(3). In a cohort of 544 patients, this polymorphism was independently associated with an increased risk of CAD (3). We investigated whether the −50G>T polymorphism is associated with angiographic CAD, myocardial infarction (MI), or mortality in the Ludwigshafen Risk and Cardiovascular Health (LURIC) cohort, which included white patients hospitalized for coronary angiography between June 1997 and May 2001. The study was approved by the ethics review committee at the Landesarztekammer Rheinland-Pfalz (Mainz, Germany). …

Apolipoprotein A-II (apoA-II)1 was recently shown by Birjmohun and coworkers to be inversely associated with future risk for coronary artery disease in 912 cases and 1635 controls (1). This finding is important, because prior data have suggested that apoA-II has poor antiatherogenic properties and may even be proatherogenic. We now confirm and extend the antiatherogenic association of apoA-II to cardiac and total mortality on the basis of data collectd after 8 years of follow-up in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study, which is investigating patients who underwent elective coronary angiography (2). Complete clinical and biochemical data from 3261 participants in the LURIC study are available. For these study participants, 752 deaths were recorded, and causes of death were obtained from official death certificates. Death from cardiac causes was recorded in 431 cases. Patients with …