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OBJECTIVE Altered plasma amino acid levels have been implicated as markers of risk for incident type 2 diabetes; however, amino acids are also related to established diabetes risk factors. Therefore, potential for confounding and the impact from competing risks require evaluation. RESEARCH DESIGN AND METHODS We prospectively followed 2,519 individuals with coronary artery disease but without diabetes. Mixed Gaussian modeling identified potential for confounding. Confounding, defined as a change in effect estimate (≥10%), was investigated by comparing amino acid–incident diabetes risk in a Cox model containing age and sex with that in models adjusted for potential confounders (BMI, estimated glomerular filtration rate, HDL cholesterol, triacylglycerol, C-reactive protein), which were further adjusted for plasma glucose, competing risks, and multiple comparisons (false discovery rate = 0.05, Benjamini-Hochberg method). Finally, component-wise likelihood-based boosting analysis including amino acids and confounders was performed and adjusted for competing risks in order to identify an optimal submodel for predicting incident diabetes. RESULTS The mean age of the source population was 61.9 years; 72% were men. During a median follow-up of 10.3 years, 267 incident cases of diabetes were identified. In age- and sex-adjusted models, several amino acids, including the branched-chain amino acids, significantly predicted incident diabetes. Adjustment for confounders, however, attenuated associations. Further adjustment for glucose and multiple comparisons rendered only arginine significant (hazard ratio/1 SD 1.21 [95% CI 1.07–1.37]). The optimal submodel included arginine and asparagine. CONCLUSIONS Adjustment for relevant clinical factors attenuated the amino acid–incident diabetes risk. Although these findings do not preclude the potential pathogenic role of other amino acids, they suggest that plasma arginine is independently associated with incident diabetes. Both arginine and asparagine were identified in an optimal model for predicting new-onset type 2 diabetes.

Higher concentrations of cardiac troponin T are associated with coronary artery disease (CAD) and adverse cardiovascular prognosis. The relation with incident atrial fibrillation (AF) is less explored. We studied this association among 3,568 patients evaluated with coronary angiography for stable angina pectoris without previous history of AF. The prospective association between high-sensitivity cardiac troponin T (hs-cTnT) categories (≤3 ng/L; n = 1,694, 4-9; n = 1,085, 10 to 19; n = 614 and 20 to 30; n = 175) and incident AF and interactions with the extent of CAD were studied by Kaplan-Meier plots and Cox regression. Risk prediction improvements were assessed by receiver operating characteristic area under the curve (ROC-AUC) analyses. During median (25 to 75 percentile) 7.3 (6.3 to 8.6) years of follow-up 412 (11.5%) were diagnosed with AF. In a Cox model adjusted for age, gender, body mass index, hypertension, diabetes mellitus, smoking, estimated glomerular filtration rate, and left ventricular ejection fraction, hazard ratios (HRs) (95% confidence intervals [CIs]) were 1.53 (1.16 to 2.03), 2.03 (1.49 to 2.78), and 2.15 (1.40 to 3.31) when comparing the second, third, and fourth to the first hs-cTnT group, respectively (P for trend

Aims Distinct ceramide lipids have been shown to predict the risk for cardiovascular disease (CVD) events, especially cardiovascular death. As phospholipids have also been linked with CVD risk, we investigated whether the combination of ceramides with phosphatidylcholines (PCs) would be synergistic in the prediction of CVD events in patients with atherosclerotic coronary heart disease in three independent cohort studies. Methods and results Ceramides and PCs were analysed using liquid chromatography–mass spectrometry (LC-MS) in three studies: WECAC (The Western Norway Coronary Angiography Cohort) (N = 3789), LIPID (Long-Term Intervention with Pravastatin in Ischaemic Disease) trial (N = 5991), and KAROLA (Langzeiterfolge der KARdiOLogischen Anschlussheilbehandlung) (N = 1023). A simple risk score, based on the ceramides and PCs showing the best prognostic features, was developed in the WECAC study and validated in the two other cohorts. This score was highly significant in predicting CVD mortality [multiadjusted hazard ratios (HRs; 95% confidence interval) per standard deviation were 1.44 (1.28–1.63) in WECAC, 1.47 (1.34–1.61) in the LIPID trial, and 1.69 (1.31–2.17) in KAROLA]. In addition, a combination of the risk score with high-sensitivity troponin T increased the HRs to 1.63 (1.44–1.85) and 2.04 (1.57–2.64) in WECAC and KAROLA cohorts, respectively. The C-statistics in WECAC for the risk score combined with sex and age was 0.76 for CVD death. The ceramide-phospholipid risk score showed comparable and synergistic predictive performance with previously published CVD risk models for secondary prevention. Conclusion A simple ceramide- and phospholipid-based risk score can efficiently predict residual CVD event risk in patients with coronary artery disease.

ObjectivesOxidised cholesterol metabolites are linked to increased production of the active vitamin A (Vit-A) form and monocyte/macrophage activation, which may be reflected by neopterin, a marker of both interferon-γ–mediated immune activation and coronary artery disease risk. We examined the influence of serum lipid parameters and Vit-A on the risk association between neopterin and incident acute myocardial infarction (AMI).MethodsWe included 4130 patients with suspected stable angina pectoris (SAP), of whom 80% received lipid-lowering treatment with statins. Risk associations between plasma neopterin and AMI are given as HRs per SD increase in log-transformed neopterin.ResultsDuring a median follow-up of 7.5 years, 530 (12.8%) patients experienced an AMI. In age-adjusted and sex-adjusted analysis, plasma neopterin was positively associated with incident AMI (HR (95% CI) per SD: 1.26 (1.17 to 1.35)). However, the estimates were most pronounced in patients with serum low-density lipoprotein cholesterol (LDL-C) or apolipoprotein (apo) B100 below-median (HR (95% CI) per SD: 1.35 (1.24 to 1.48) and 1.42 (1.27 to 1.58), respectively; both pinteraction ≤0.03). We also observed a particularly strong risk association in those with above-median Vit-A (HR (95% CI) per SD: 1.32 (1.21 to 1.44); pinteraction=0.03). The estimates were slightly modified after multivariable adjustment.ConclusionsIn patients with suspected SAP, the majority of whom receiving statin therapy, high plasma neopterin was associated with increased risk of AMI particularly among those with low LDL-C and apoB100 or high Vit-A levels. The particularly strong relationship of plasma neopterin with residual cardiovascular risk in patients with low lipid levels should be further investigated.

In patients with stable angina, the association between high-sensitivity cardiac troponin T (hs-cTnT) and incident acute myocardial infarction (AMI), as well as pathophysiologic mechanisms accounting for an adverse prognosis, remain to be determined. We explored the association between hs-cTnT and future AMI among 3,882 patients evaluated for suspected stable angina pectoris and investigated to which extent hs-cTnT attenuated the relations between traditional coronary heart disease (CHD) risk factors and AMI. Associations between increasing hs-cTnT categories (≤3, 4 to 9, 10 to 19, and 20 to 30 ng/L) and risk of AMI were studied by Cox regression. We investigated whether the associations between traditional CHD risk factors and future AMI were influenced by adjusting for hs-cTnT. Median age was 62 years. During median (25th to 75th percentile) 8 (6.4 to 8.7) years of follow-up, 460 (11.8%) experienced an AMI. There was a strong association between hs-cTnT categories and risk of AMI. The relation was somewhat attenuated, but still present, when adjusting for potential confounders, traditional CHD risk factors, previous peripheral vascular disease, and percutaneous coronary intervention or coronary bypass surgery. Moreover, hs-cTnT slightly attenuated the risk relations between traditional CHD risk factors and incident AMI, but each risk factor remained significantly associated with AMI. In conclusion, among patients with suspected stable angina, hs-cTnT was positively related to incident AMI.

Background Link between inflammation and atrial fibrillation (AF) has been increasingly recognized. Neopterin, a biomarker of cellular immune activation, may be associated with incident AF. Objective To investigate the association between plasma neopterin levels and risk of an inpatient hospital diagnosis of AF, and to evaluate a joint association of neopterin and a nonspecific inflammatory marker C-reactive protein (CRP) in two prospective cohorts. Methods We performed a prospective analysis from a community-based cohort (the Hordaland Health Study (HUSK), n = 6891), and validated the findings in a cohort of patients with suspected stable angina pectoris (the Western Norway Coronary Angiography Cohort (WECAC), n = 2022). Results In both cohorts, higher plasma levels of neopterin were associated with an increased risk of incident AF after adjustment for age, sex, body mass index, current smoking, diabetes, hypertension and renal function. The multivariable-adjusted hazard ratio (HR) (95% CI) per one SD increment of log-transformed neopterin was 1.20 (1.10-1.32) in HUSK and 1.26 (1.09-1.44) in WECAC. Additional adjustment for CRP did not materially affect the risk association for neopterin. The highest risk of AF was found among individuals with both neopterin and CRP levels above the median (HR: 1.54; 95% CI: 1.16-2.05 in HUSK and HR: 1.67; 95% CI: 1.11-2.52 in WECAC). Conclusions Our findings indicate an association of plasma neopterin with risk of an inpatient hospital diagnosis of AF, which remains after adjustment for traditional risk factors as well as for CRP. This study highlights a role of cellular immune activation, in addition to inflammation, in AF pathogenesis.

Background and aims Apolipoproteins B (apoB) and A1 (apoA1) are major protein constituents of low-density and high-density lipoproteins, respectively, and serum concentrations of these apolipoproteins are associated with risk of atherosclerosis. Vitamin A (VA) has been implicated in lipoprotein metabolism. We evaluated the associations of serum apoB, apoA1 and their ratio (apoBAR) with risk of incident acute myocardial infarction (AMI) and the possible modification by serum VA. Methods Risk associations were assessed by Cox regression, and presented as hazard ratios (HRs) per standard deviation (SD) increment in log-transformed values of the lipid parameters, among 4117 patients with suspected stable angina pectoris, located in Western Norway. Interactions with VA were evaluated by including interaction terms in the models. The multivariate model included age, sex, smoking, hypertension, number of stenotic coronary arteries, left ventricular ejection fraction, C-reactive protein, estimated glomerular filtration rate and statin treatment at discharge. Results Median (25th, 75th percentile) age of the 4117 patients (72% male) was 62 (55, 70) years. ApoB and apoA1 were higher among patients in the upper versus lower tertiles of VA. During a median of 4.6 (3.6, 5.7) years of follow-up, 8.2% of patients experienced an AMI. Overall, we observed no significant associations between lipid parameters and AMI after multivariate adjustment. However, apoB and apoBAR were associated with AMI among patients in the upper tertile of VA (HR per SD 1.35, (95% CI: 1.11–1.65), and 1.42 (1.16–1.74), respectively, p for interactions ≤0.003). Conclusions The associations of apoB and apoBAR with incident AMI were confined to patients with elevated VA.

Aims/hypothesis The tryptophan metabolite kynurenine has potent immune modulatory and vasoactive properties. Experimental data implicate kynurenine in obesity-related morbidities. Epidemiological studies are, however, sparse. We evaluated associations of the plasma and urine kynurenine:tryptophan ratio (KTR) to incident type 2 diabetes. Methods We followed 2519 individuals with coronary artery disease (CAD; 73.1% men) without diabetes at baseline for a median of 7.6 years, during which 173 (6.9%) new incidences of type 2 diabetes were identified. Multivariate Cox regression analyses were applied to investigate the prospective relationships of plasma and urine KTR with new onset type 2 diabetes. Results At inclusion, mean (SD) age was 61.3 (10.4) years, BMI was 25.9 (3.71) kg/m2 and median (interquartile range) HbA1c was 5.6% (5.0%–6.0%) (38 [31–42] mmol/mol). Plasma KTR was not significantly related to type 2 diabetes risk. By contrast, urine KTR showed a strong positive association. Comparing quartile 4 with quartile 1, the HRs (95% CIs) were 2.59 (1.56, 4.30) and 2.35 (1.39, 3.96) in the age- and sex-adjusted and multivariate models, respectively. Conclusions/interpretation Urine KTR is a strong predictor of incident type 2 diabetes in individuals with CAD. Potential clinical implications and possible pathogenic roles of renal kynurenine excretion in type 2 diabetes development should be further elucidated. Electronic supplementary material The online version of this article (doi:10.1007/s00125-017-4329-9) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Background— Serine and glycine interconversion and methylenetetrahydrofolate dehydrogenase 1 (MTHFD1)–mediated 1-carbon transfer are the major sources of methyl groups for 1-carbon metabolism. Recently, plasma glycine and a common polymorphism in MTHFD1 have been associated with risk of acute myocardial infarction (AMI). It is, therefore, of interest to explore if these 2 pathways interact in relation to AMI. Methods and Results— A total of 2571 participants in the WENBIT (Western Norway B Vitamin Intervention Trial) undergoing coronary angiography for stable angina pectoris were studied. Associations of plasma serine and glycine concentrations with risk of AMI across 2 common and functional MTHFD1 polymorphisms ( rs2236225 and rs1076991 ) were explored in Cox regression models. During a median follow-up of 4.7 years, 212 patients (8.2%) experienced an AMI. In age- and sex-adjusted analyses, plasma glycine ( P P =0.52), showed an overall association with AMI. However, interactions of MTHFD1 rs2236225 polymorphism with both plasma serine and glycine were observed ( P interaction =0.03 for both). Low plasma serine and glycine were associated with an increased risk of AMI among patients carrying the rs2236225 minor A allele. Similarly, low plasma glycine showed stronger risk relationship with AMI in the rs1076991 CC genotype carriers but weaker associations in patients carrying the minor T allele ( P interaction =0.02). Conclusions— Our results showed that 2 common and functional polymorphisms in the MTHFD1 gene modulate the risk associations of plasma serine and glycine with AMI. These findings emphasize the possible role of the MTHFD1 in regulating serine and glycine metabolism in relation to atherosclerotic complications. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique Identifier: NCT00354081.

BACKGROUND Metabolites of the kynurenine pathway (mKP) relate to important aspects of heart failure pathophysiology, such as inflammation, energy-homeostasis, apoptosis, and oxidative stress. We aimed to investigate whether mKP predict mortality in patients with heart failure. METHODS The study included 202 patients with heart failure (73.8% with coronary artery disease (CAD)), propensity score matched to 384 controls without heart disease, and 807 controls with CAD (71%). All underwent coronary angiography and ventriculography at baseline. Plasma mKP, pyridoxal 5'phosphate (PLP) and CRP were measured at baseline. Case-control differences were assessed by logistic regression and survival by Cox regression, adjusted for age, gender, smoking, diabetes, ejection fraction, PLP, eGFR and CRP. Effect measures are reported per standard deviation increments. RESULTS Higher plasma levels of kynurenine, 3- hydroxykynurenine (HK), quinolinic acid (QA), the kynurenine-tryptophan-ratio (KTR) and the ratio of HK to xanthurenic acid (HK/XA) were detected in heart failure compared to both control groups. The mortality rate per 1000 person-years was 55.5 in patients with heart failure, 14.6 in controls without heart disease and 22.2 in CAD controls. QA [HR 1.80, p = 0.013], HK [HR 1.77, p = 0.005], HK/XA [HR 1.67, p < 0.001] and KTR [HR 1.55, p = 0.009] were associated with increased mortality in patients with heart failure, while XA [HR 0.68-0.80, p = 0.013-0.037] were associated with lower mortality in all groups. HK and HK/XA had weak associations with increased mortality in CAD-controls. CONCLUSION Elevated plasma levels of mKP and metabolite ratios are associated with increased mortality, independent of CAD, in patients with heart failure.

Purpose We hypothesized that biomarkers and dietary factors related to cardiovascular disease risk were associated with serum retinol and evaluated these potential associations in patients with suspected coronary artery disease (CAD). Methods We used cross-sectional data from 4116 patients hospitalised for suspected CAD. Dietary data were obtained from a subgroup of 1962 patients using a food frequency questionnaire. Potential biomarkers and dietary factors were explored using linear regression modelling adjusted for age and sex. Regression coefficients and corresponding confidence intervals (CI) are given as % change in serum retinol per unit change in the predictors. Analyses were performed in the total population and in strata of serum retinol tertiles. Results In age- and sex-adjusted models, serum creatinine (standardized β: 0.38, 95% CI [0.35, 0.42]), plasma total cysteine (0.26, [0.23, 0.29]), serum uric acid (0.30, [0.26, 0.33]) and plasma neopterin (0.22, [0.18, 0.25]) were positively associated, whereas plasma serine (− 0.15, [− 0.18, − 0.12]) and serum C-reactive protein (− 0.15, [− 0.18, − 0.12]) were inversely associated with serum retinol. When we included the significant biomarkers in a multivariate model, the model explained 33% of the variability (R2 = 0.33) in serum retinol. The results were similar in the lower and upper tertiles of serum retinol. Weak or no associations were observed for dietary factors. Conclusions In patients with suspected CAD, concentrations of creatinine, cysteine and uric acid were positively associated with serum retinol. Future studies should assess whether retinol concentrations are influenced by metabolic alterations in patients at risk of cardiovascular disease.

BACKGROUND Low vitamin B-6 status has been related to increased risk of coronary artery disease (CAD), which is a condition that is associated with inflammation. The most common status marker, plasma pyridoxal 5'-phosphate (PLP), decreases during inflammation; therefore, causal relations are uncertain. OBJECTIVE We evaluated the vitamin B-6 biomarkers PLP, pyridoxal, and pyridoxic acid (PA) and the pyridoxic acid:(pyridoxal + PLP) ratio (PAr), a proposed marker of vitamin B-6 catabolism during activated cellular immunity, as predictors of mortality. DESIGN Associations with risks of long-term all-cause mortality and cardiovascular mortality were evaluated with the use of Cox regression in patients who were undergoing elective coronary angiography for suspected stable angina pectoris (SAP) (n = 4131) and an independent cohort of patients who were hospitalized for acute myocardial infarction (AMI) (n = 3665). RESULTS Plasma PLP (AMI patients only) and PA predicted all-cause mortality in models that were adjusted for established risk predictors, but associations were attenuated or nonsignificant after additional adjustment for inflammatory markers. PAr was correlated with biomarkers of inflammation (Pearson's r ≥ 0.37) and predicted all-cause mortality and cardiovascular mortality after adjustment for established risk predictors. In SAP patients, PAr had greater predictive strength than did current smoking, diabetes, hypertension, apolipoproteins, or C-reactive protein. PAr provided multiadjusted HRs per SD of 1.45 (95% CI: 1.30, 1.63) and 1.31 (95% CI: 1.21, 1.41) in SAP and AMI patients, respectively. In both cohorts, PAr was a particularly strong predictor of all-cause mortality for patients with no previous CAD history (P-interaction ≤ 0.04). CONCLUSION PAr may capture unique aspects of inflammatory activation and thus provide new insights into disease mechanisms that may aid in identifying patients at increased risk of future fatal events.

Background: Methylenetetrahydrofolate dehydrogenase (MTHFD1) catalyzes three sequential reactions that metabolize derivatives of tetrahydrofolate (THF) in folate-dependent one-carbon metabolism. Impaired MTHFD1 flux has been linked to disturbed lipid metabolism and oxidative stress. However, limited information is available on its relation to the development of atherothrombotic cardiovascular disease. Methods and results: We explored the association between a MTHFD1 polymorphism (rs1076991 C > T ) and acute myocardial infarction (AMI), and potential effect modifications by folic acid/B12 and/or vitamin B6 treatment in suspected stable angina pectoris patients (n Z 2381) participating in the randomized Western Norway B Vitamin Intervention Trial (WENBIT). During the median follow-up of 4.9 years 204 participants (8.6%) suffered an AMI. After adjusting for established CVD risk factors, the MTHFD1 polymorphism was significantly associated with AMI (HR: 1.49; 95% CI, 1.23e1.81). A similar association was observed among patients allocated to treatment with vitamin B6 alone (HR: 1.53; 95% CI, 1.01e2.31), and an even stronger relationship was seen in patients treated with both vitamin B6 and folic acid/B12 (HR: 2.35; 95% CI, 1.55 e3.57). However, no risk association between the MTHFD1 polymorphism and AMI was seen in patients treated with placebo (HR: 1.29; 95% CI, 0.86e1.93) or folic acid/B12 (1.17; 95% CI, 0.83e1.65). Conclusion: A common and functional MTHFD1 polymorphism is associated with increased risk of AMI, although the risk seems to be dependent on specific B vitamin treatment. Further studies are warranted to elucidate the possible mechanisms, also in order to explore potential effect modifications by nutritional factors. publishedVersion

Background Although choline metabolism has been associated with atherosclerotic heart disease, less research attention has been paid to the associations of choline and its oxidative metabolite betaine with cardiac arrhythmias. Methods and Results We evaluated associations of plasma concentrations and dietary intakes of choline and betaine with long‐term atrial fibrillation ( AF ) risk in a community‐based cohort, HUSK ([the Hordaland Health Study] n=6949), and validated the findings in 2 patient cohorts: the Western Norway Coronary Angiography Cohort (n=4164) and the NORVIT (Norwegian B‐Vitamin) Trial (n=3733). Information on AF was obtained from the CVDNOR (Cardiovascular Disease in Norway) project. In HUSK , WECAC (Western Norway Coronary Angiography Cohort), and NORVIT , 552, 411, and 663 AF cases were identified during a median follow‐up time of 10.9, 7.3, and, 8.7 years, respectively. Plasma concentrations of choline and betaine were significantly positively associated with later AF risk after multivariable adjustments in HUSK . Such associations were independently replicated in the 2 external prospective patient cohorts. The pooled hazard ratio was 1.13 (95% confidence interval 1.08‐1.19, P P SD increment for log‐transformed choline and betaine, respectively. Moreover, dietary intake of choline was marginally associated with AF risk (pooled hazard ratio 1.29, 95% confidence interval 1.01‐1.66, fifth versus first quintile), whereas no significant association was observed between dietary betaine and AF risk. Conclusions Our findings indicate that plasma concentrations as well as dietary intake of choline, but not betaine, are associated with subsequent risk of AF , suggesting a potential role of choline metabolism in the pathogenesis of AF . Clinical Trial Registration URL: https://www.clinicaltrials.gov.Unique identifier: NCT 00671346.

Systemic fibrinogen and neopterin are related to inflammation. We investigated the prognostic utility and possible interactions of these biomarkers in stable coronary artery disease (SCAD) patients undergoing coronary angiography. We included 3,545 patients with suspected stable angina with a median follow-up of 7.3 and 10.2 years for incident acute myocardial infarction (AMI) and all-cause mortality, respectively. Prospective associations were explored by Cox regression. Potential effect modifications were investigated according to strata of fibrinogen, neopterin or high-sensitivity troponin T (hsTnT) below and above the median, as well as gender and smoking habits. During follow-up, 543 patients experienced an AMI and 769 patients died. In a multivariable model, the hazard ratios (HRs; 95% confidence interval [CI]) per 1 SD increase for fibrinogen in relation to these endpoints were 1.30 (1.20, 1.42; p

Background Plasma total homocysteine (tHcy) has been implicated in the development of cardiovascular disease, but the mechanisms remain unclear. Vitamin A (Vit-A) is involved in homocysteine metabolism and we therefore explored the potential interaction between plasma tHcy and serum Vit-A in relation to incident acute myocardial infarction. Methods Cox proportional hazards models were used to assess the prospective relationships between tHcy and acute myocardial infarction in 2205 patients from Western Norway undergoing elective coronary angiography for suspected stable angina pectoris. Results are reported as hazard ratio per standard deviation increase in log-transformed tHcy. An interaction term for tHcy × Vit-A was added to multivariate models including age, sex, smoking, apolipoprotein B fasting, statin and aspirin prescription and estimated glomerular filtration rate. Results Geometric mean (geometric standard deviation) age of the participants (64.3% men) was 62.3 (1.24) years. Plasma tHcy was higher among participants in the upper versus lower Vit-A tertile. During 7 (2.4) years of follow-up, 15.1% suffered an AMI. A significant association of plasma tHcy with AMI in the total study population was observed. When we stratified the population according to Vit-A tertiles, plasma tHcy was associated with acute myocardial infarction only in the upper Vit-A tertile (hazard ratio per SD: 1.25, 95% confidence interval: 1.04–1.53, pinteraction = 0.03). Conclusions The risk relationship between plasma tHcy and acute myocardial infarction was modified by serum concentrations of Vit-A in patients with suspected stable angina pectoris. This finding may clarify the relationship between tHcy and cardiovascular disease.

Context and Objective Vitamin D status may affect cardiovascular disease (CVD) development and survival. We studied the relationship between concentrations of the circulating biomarker 25-hydroxyvitamin D (25OHD) and all-cause and cardiovascular mortality risk. Design, Setting, Participants, and Main Outcome Measures 25OHD, the sum of 25-hydroxyvitamin D3 and 25-hydroxyvitamin D2, was analyzed in plasma samples from 4114 white patients suspected of having stable angina pectoris and was adjusted for seasonal variation. Hazard ratios (HRs) for all-cause and cardiovascular mortality were estimated by using multivariable Cox models with 25OHD as the main exposure variable, with adjustment for study site, age, sex, smoking, body mass index, estimated glomerular filtration rate, and systolic blood pressure. Results A total of 895 (21.8%) deaths, including 407 (9.9%) from CVD causes, occurred during a mean ± standard deviation follow-up of 11.9 ± 3.0 years. Compared with the first 25OHD quartile, HRs in the second, third, and fourth quartiles were 0.64 [95% confidence interval (CI), 0.54 to 0.77], 0.56 (95% CI, 0.46 to 0.67), and 0.56 (95% CI, 0.46 to 0.67) for all-cause mortality and 0.70 (95% CI, 0.53 to 0.91), 0.60 (95% CI, 0.45 to 0.79), and 0.57 (95% CI, 0.43 to 0.75) for cardiovascular mortality, respectively. Threshold analysis demonstrated increased all-cause and CVD mortality in patients with 25OHD concentrations below ∼42.5 nmol/L. Moreover, analysis suggested increased all-cause mortality at concentrations >100 nmol/L. Conclusion Plasma 25OHD concentrations were inversely associated with cardiovascular mortality and nonlinearly (U-shaped) associated with all-cause mortality.

Aims/hypothesis: A validated mass-spectrometric method was applied to measure Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:0) and Cer(d18:1/24:1) from serum or plasma samples. These ceramides were analysed in a population-based risk factor study (FINRISK 2002, n = 8045), in a cohort of participants undergoing elective coronary angiography for suspected stable angina pectoris (Western Norway Coronary Angiography Cohort [WECAC], n = 3344) and in an intervention trial investigating improved methods of lifestyle modification for individuals at high risk of the metabolic syndrome (Prevent Metabolic Syndrome [PrevMetSyn], n = 371). Diabetes risk score models were developed to estimate the 10 year risk of incident diabetes. Methods: A validated mass-spectrometric method was applied to measure Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:0) and Cer(d18:1/24:1) from serum or plasma samples. These ceramides were analysed in a population-based risk factor study (FINRISK 2002, n = 8045), in a cohort of participants undergoing elective coronary angiography for suspected stable angina pectoris (Western Norway Coronary Angiography Cohort [WECAC], n = 3344) and in an intervention trial investigating improved methods of lifestyle modification for individuals at high risk of the metabolic syndrome (Prevent Metabolic Syndrome [PrevMetSyn], n = 371). Diabetes risk score models were developed to estimate the 10 year risk of incident diabetes. Results: Analysis in FINRISK 2002 showed that the Cer(d18:1/18:0)/Cer(d18:1/16:0) ceramide ratio was predictive of incident diabetes (HR per SD 2.23, 95% CI 2.05, 2.42), and remained significant after adjustment for several risk factors, including BMI, fasting glucose and HbA1c (HR 1.34, 95% CI 1.14, 1.57). The finding was validated in the WECAC study (unadjusted HR 1.81, 95% CI 1.53, 2.14; adjusted HR 1.39, 95% CI 1.16, 1.66). In the intervention trial, the ceramide ratio and diabetes risk scores significantly decreased in individuals who had 5% or more weight loss. Conclusions/interpretation: The Cer(d18:1/18:0)/Cer(d18:1/16:0) ratio is an independent predictive biomarker for incident diabetes, and may be modulated by lifestyle intervention.

Enhanced tryptophan degradation via the kynurenine pathway has been related to several pathological conditions. However, little is known about the effect of diet on individual metabolites of this pathway. We investigated cross-sectional associations between reported intake of fish and omega-3 (n-3) long-chain PUFA (LC-PUFA) and plasma metabolites related to the kynurenine pathway. Participants were 2324 individuals with coronary artery disease from the Western Norway B Vitamin Intervention Trial. Fish and n-3 LC-PUFA intakes were assessed using a food frequency questionnaire. Plasma concentrations of tryptophan, kynurenine, kynurenic acid, anthranilic acid, 3-hydroxykynurenine, xanthurenic acid, 3-hydroxyanthranilic acid, neopterin, and kynurenine-to-tryptophan ratio (KTR) were analyzed. Associations were investigated using partial Spearman’s rank correlations and multiple linear regressions. Median age at inclusion was 62 years (80 % males), and 84 % had stable angina pectoris. Intake of fatty fish and n-3 LC-PUFA was inversely associated with plasma 3-hydroxykynurenine. Consumption of total fish, lean fish, and n-3 LC-PUFA was inversely associated with plasma neopterin. Intake of total fish, fatty fish, and n-3 LC-PUFA was inversely associated with KTR. All these correlations were weak (ρ between −0.12 and −0.06, P

Background: The kynurenine pathway, the main metabolic route of tryptophan degradation, has been related to inflammatory responses. Some of its metabolites, referred to as kynurenines, have been associated with prevalence of coronary heart disease (CHD) in cross-sectional studies. This prospective study aims to investigate whether increased concentrations of kynurenines are associated with risk of acute coronary events, defined as unstable angina pectoris, acute myocardial infarction, and/or sudden death in community-dwelling elderly.Methods: The baseline examinations included 2819 individuals aged 71-74 years recruited into the Hordaland Health Study. Participants with known CHD at baseline were excluded from analyses. Baseline plasma concentrations of tryptophan, kynurenine, kynurenic acid, anthranilic acid, 3-hydroxykynurenine, xanthurenic acid, and 3-hydroxyanthranilic acid were measured by LC-MS/MS. During a median follow-up period of 10.8 years, with linkage to acute coronary event endpoints through the CVDNOR project, hazard ratios (HRs) for acute coronary events (n = 376) were estimated using Cox proportional hazard analyses.Results: After adjustment for established cardiovascular risk factors, HRs (95% CI) comparing the 4th vs 1st quartile were 1.86 (1.19-2.92) for kynurenine and 1.72 (1.19-2.49) for 3-hydroxykynurenine. Tryptophan, kynurenic acid, anthranilic acid, xanthurenic acid and 3-hydroxyanthranilic acid were not associated with acute coronary events.Conclusions: Kynurenine and 3-hydroxykynurenine were associated with increased risk of acute coronary events in community-dwelling elderly without a known history of CHD. These results suggest the involvement of the kynurenine pathway in the early development of CHD, and their potential usefulness to estimate CHD risk. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

Background Data from recent meta-analyses question an association between dietary intake of saturated fatty acids (SFAs) and risk of cardiovascular disease (CVD). Moreover, the prognostic effect of dietary SFA in patients with established CVD treated with modern conventional medication has not been extensively studied. Objective We investigated the associations between self-reported dietary SFA intake and risk of subsequent coronary events and mortality in patients with coronary artery disease (CAD). Methods This study included patients who participated in the Western Norway B-Vitamin Intervention Trial and completed a 169-item semiquantitative food-frequency questionnaire after coronary angiography. Quartiles of estimated daily intakes of SFA were related to risk of a primary composite endpoint of coronary events (unstable angina pectoris, nonfatal acute myocardial infarction, and coronary death) and separate secondary endpoints (total acute myocardial infarction, fatal coronary events, and all-cause death) with use of Cox-regression analyses. Results This study included 2412 patients (81% men, mean age: 61.7 y). After a median follow-up of 4.8 y, a total of 292 (12%) patients experienced at least one major coronary event during follow-up. High intake of SFAs was associated with a number of risk factors at baseline. However, there were no significant associations between SFA intake and risk of coronary events [age- and sex-adjusted HR (95% CI) was 0.85 (0.61, 1.18) for the upper vs. lower SFA quartile] or any secondary endpoint. Estimates were not appreciably changed after multivariate adjustments. Conclusions There was no association between dietary intake of SFAs and incident coronary events or mortality in patients with established CAD.

Cystathionine is a thio-ether and a metabolite formed from homocysteine during transsulfuration. Elevated plasma cystathionine levels are reported in patients with cardiovascular disease; however prospective relationships with acute myocardial infarction (AMI) are unknown. We investigated associations between plasma cystathionine and AMI among patients with suspected and/or verified coronary heart disease (CHD).Subjects from two independent cohort studies, the Western Norway Coronary Angiography Cohort (WECAC) (3033 patients with stable angina pectoris; 263 events within 4.8 years of median follow-up) and the Norwegian Vitamin Trial (NORVIT) (3670 patients with AMI; 683 events within 3.2 years of median follow-up) were included.In both cohorts, plasma cystathionine was associated with several traditional CHD risk factors (P 0.001). Comparing the cystathionine quartile 4 to 1, age and gender adjusted hazard ratios (95% confidence intervals) for AMI were 2.08 (1.43-3.03) and 1.41 (1.12-1.76) in WECAC and NORVIT, respectively. Additional adjustment for traditional risk factors slightly attenuated the risk estimates, which were generally stronger in both cohorts among non-smokers, patients with higher age, and lower BMI or PLP status (P-interaction ≤ 0.04). Risk associations also tended to be stronger in patients not treated with B-vitamins. Additionally, in a subset of 80 WECAC patients, plasma cystathionine associated strongly negatively with glutathione, an important antioxidant and positively with lanthionine, a marker of HPlasma cystathionine is associated with increased risk of AMI among patients with either suspected or verified coronary heart disease, and is possibly related to altered redox homeostasis.

Background Excess levels of serum acylcarnitines, which are intermediate products in metabolism, have been observed in metabolic diseases such as type 2 diabetes mellitus. However, it is not known whether acylcarnitines may prospectively predict risk of cardiovascular death or acute myocardial infarction in patients with stable angina pectoris. Methods and Results This study included 4164 patients (median age, 62 years; 72% men). Baseline serum acetyl‐, octanoyl‐, palmitoyl‐, propionyl‐, and (iso)valerylcarnitine were measured using liquid chromatography/tandem mass spectrometry. Hazard ratios ( HR s) and 95% CI s for quartile 4 versus quartile 1 are reported. The multivariable model included age, sex, body mass index, fasting status, current smoking, diabetes mellitus, apolipoprotein A1, apolipoprotein B, creatinine, left ventricular ejection fraction, extent of coronary artery disease, study center, and intervention with folic acid or vitamin B6. During median 10.2 years of follow‐up, 10.0% of the patients died of cardiovascular disease and 12.8% suffered a fatal or nonfatal acute myocardial infarction. Higher levels of the even‐chained acetyl‐, octanoyl‐, and palmitoyl‐carnitines were significantly associated with elevated risk of cardiovascular death, also after multivariable adjustments ( HR [95% CI ]: 1.52 [1.12, 2.06]; P =0.007; 1.73 [1.23, 2.44]; P =0.002; and 1.61 [1.18, 2.21]; P =0.003, respectively), whereas their associations with acute myocardial infarction were less consistent. Conclusions Among patients with suspected stable angina pectoris, elevated serum even‐chained acylcarnitines were associated with increased risk of cardiovascular death and, to a lesser degree with acute myocardial infarction, independent of traditional risk factors. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 00354081.

Background: \ud \ud Lipoprotein(a) concentrations in plasma are associated with cardiovascular risk in the general population. Whether lipoprotein(a) concentrations or LPA genetic variants predict long-term mortality in patients with established coronary heart disease remains less clear.\ud \ud Methods: \ud \ud We obtained data from 3313 patients with established coronary heart disease in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. We tested associations of tertiles of lipoprotein(a) concentration in plasma and two LPA single-nucleotide polymorphisms ([SNPs] rs10455872 and rs3798220) with all-cause mortality and cardiovascular mortality by Cox regression analysis and with severity of disease by generalised linear modelling, with and without adjustment for age, sex, diabetes diagnosis, systolic blood pressure, BMI, smoking status, estimated glomerular filtration rate, LDL-cholesterol concentration, and use of lipid-lowering therapy. Results for plasma lipoprotein(a) concentrations were validated in five independent studies involving 10 195 patients with established coronary heart disease. Results for genetic associations were replicated through large-scale collaborative analysis in the GENIUS-CHD consortium, comprising 106 353 patients with established coronary heart disease and 19 332 deaths in 22 studies or cohorts.\ud \ud Findings: \ud \ud The median follow-up was 9·9 years. Increased severity of coronary heart disease was associated with lipoprotein(a) concentrations in plasma in the highest tertile (adjusted hazard radio [HR] 1·44, 95% CI 1·14–1·83) and the presence of either LPA SNP (1·88, 1·40–2·53). No associations were found in LURIC with all-cause mortality (highest tertile of lipoprotein(a) concentration in plasma 0·95, 0·81–1·11 and either LPA SNP 1·10, 0·92–1·31) or cardiovascular mortality (0·99, 0·81–1·2 and 1·13, 0·90–1·40, respectively) or in the validation studies.\ud \ud Interpretation: \ud \ud In patients with prevalent coronary heart disease, lipoprotein(a) concentrations and genetic variants showed no associations with mortality. We conclude that these variables are not useful risk factors to measure to predict progression to death after coronary heart disease is established.\ud \ud Funding: \ud \ud Seventh Framework Programme for Research and Technical Development (AtheroRemo and RiskyCAD), INTERREG IV Oberrhein Programme, Deutsche Nierenstiftung, Else-Kroener Fresenius Foundation, Deutsche Stiftung für Herzforschung, Deutsche Forschungsgemeinschaft, Saarland University, German Federal Ministry of Education and Research, Willy Robert Pitzer Foundation, and Waldburg-Zeil Clinics Isny.

Background Plasma total homocysteine ( tH cy) is related to plasma neopterin, an indicator of interferon‐γ‐mediated immune activation, and both biomarkers positively predict cardiovascular risk. We examined whether the association between tH cy and subsequent risk of acute myocardial infarction ( AMI ) was modified by systemic concentrations of neopterin and C‐reactive protein among patients with coronary heart disease. Methods and Results By Cox modeling, we explored the association between tH cy and risk of AMI in 4164 patients with suspected stable angina pectoris. Subgroup analyses were performed according to median levels of neopterin and C‐reactive protein. A replication study was performed among 3749 patients with AMI at baseline. Median follow‐up was 7.3 and 8.3 years among patients with stable angina pectoris and AMI , respectively. tH cy and neopterin correlated in both cohorts ( r s =0.34 and r s =0.30 among stable angina pectoris and AMI patients, respectively, both P tH cy predicted AMI in both cohorts, independent of B‐vitamin treatment. However, significant risk associations were confined to patients with plasma neopterin above the median (hazard ratios [95% confidence interval] per 1‐ SD increment of log‐transformed tH cy 1.38 [1.26–1.50] and 1.18 [1.10–1.26] among stable angina pectoris and AMI patients, respectively) ( P int tH cy and neopterin improved model discrimination and reclassification. tH cy and C‐reactive protein were weakly related, and no effect modification was found by C‐reactive protein. Conclusions Among patients with coronary heart disease, tH cy predicted risk of AMI only in subjects with concomitantly elevated plasma neopterin. Our results motivate further research on the relationship between homocysteine metabolism, cellular immune activation, and atherothrombosis.

Plasma choline has been associated with cardiovascular disease and nonalcoholic steatohepatitis.We sought to study relations of plasma choline and its metabolite betaine to long-term risk of acute myocardial infarction (AMI) and all-cause mortality according to smoking status, in patients undergoing coronary angiography for stable angina pectoris.Samples were obtained before angiography from 2568 patients who were subsequently randomized in the Western Norway B-Vitamin Intervention Trial (WENBIT). Hazard ratios (HR) were calculated using multivariate Cox-regression and p-values were reported for trends over quartiles.Plasma concentrations of choline, but not betaine, were lower in smokers, and choline was positively associated with C-reactive protein and troponin T in nonsmokers, but not in smokers (p for interaction0.03). During a follow up of 4.8 ± 1.4 (mean ± SD) years, 8.3% suffered from AMI and 6.1% died. In the total population, choline was not associated with AMI or all-cause mortality. However, comparing the highest vs. the lowest quartiles, plasma choline was associated with increased risk of AMI in nonsmokers (HR 2.63, 95% CI 1.56 to 5.51; p for trend = 0.013) and no risk in smokers (p for interaction 0.001). Plasma choline significantly improved discrimination and reclassification when added to established cardiovascular risk factors. Plasma betaine was not associated with either endpoint.In patients with stable angina pectoris, elevated plasma choline is associated with elevated troponin levels and increased risk of AMI in nonsmokers. These results motivate further research into the relation between choline metabolism, smoking, and atherothrombosis.

Immune system activation is involved in atherosclerosis. Neopterin production and tryptophan catabolism through the kynurenine pathway, measured by the kynurenine-tryptophan ratio (KTR), are induced by interferon gamma, thus both are considered markers of cell mediated immune activation. This study prospectively investigated their predictive value on acute coronary events among Norwegian community-dwelling older adults without previous coronary heart disease.1112 men and 1631 women, 71-74 years old were examined during 1997-99 as part of the Hordaland Health Study. They were followed until an acute coronary event (defined as unstable angina, non-fatal or fatal acute myocardial infarction or sudden death) or December 31, 2006. Kaplan-Meier hazard curves were constructed for quartiles of plasma neopterin and KTR. Cox proportional hazards models adjusted for sex, body mass index, smoking, hypertension, renal function and cholesterol were used to examine the relation between neopterin and KTR quartiles and the study endpoint.Median (interquartile range) values were 8.6 (7.2-10.4) nmol/L for neopterin and 25.8 (25.3-31.1) nmol/μmol for KTR. During the follow up, 265 participants had at least one acute coronary event. Increased baseline levels of plasma neopterin and KTR were associated with continuous increased risk of developing the study endpoint (P-values for trend0.001 and 0.019, respectively). Adjusted hazard ratios comparing the fourth quartile to the first were 1.65 (95% CI; 1.11-2.47; P=0.013) for neopterin and 1.57 (95% CI 1.03-2.39; P=0.036) for KTR.Plasma neopterin and KTR levels predict acute coronary events in older adults without previous coronary heart disease.

Aims Kynurenine is a potent endothelium-derived vasodilator. Its synthesis from tryptophan is stimulated by interferon γ and may represent an important compensatory pathway for the regulation of vascular function in inflammatory conditions. We assessed associations of urine kynurenine to tryptophan ratio (KTR) levels to incident major coronary events (MCEs), acute myocardial infarction (AMI), and ischaemic stroke and mortality in patients with suspected stable coronary artery disease (CAD). Methods and results A total of 3224 patients (mean age 62 years, 69% men) underwent urine and blood sampling prior to elective coronary angiography and were subsequently followed up for median 55 months. A total of 8.4% experienced an MCE, 7.8% suffered an AMI, and 7.6% died. In age- and gender-adjusted analyses, the hazard ratios [HRs; 95% confidence intervals (CI)] of MCE, AMI, and all-cause mortality were 1.43 (1.29–1.59), 1.44 (1.29–1.59), and 1.38 (1.23–1.54) per standard deviation increment of the (log-transformed) urinary KTR, respectively. These estimates were only minimally attenuated after adjustment for potential confounders. The addition of the urine KTR to a model of conventional risk factors significantly improved goodness of fit, discrimination, and risk classification for these clinical endpoints. No association was seen between the urine KTR and the risk of incident ischaemic stroke. Conclusion A novel urinary inflammation marker, KTR, is strongly associated with adverse prognosis in patients with suspected stable CAD. Underlying pathomechanisms should be further elucidated.

Aims The aim was to study the prognostic value of plasma ceramides (Cer) as cardiovascular death (CV death) markers in three independent coronary artery disease (CAD) cohorts. Methods and results Corogene study is a prospective Finnish cohort including stable CAD patients (n = 160). Multiple lipid biomarkers and C-reactive protein were measured in addition to plasma Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:0), and Cer(d18:1/24:1). Subsequently, the association between high-risk ceramides and CV mortality was investigated in the prospective Special Program University Medicine - Inflammation in Acute Coronary Syndromes (SPUM-ACS) cohort (n = 1637), conducted in four Swiss university hospitals. Finally, the results were validated in Bergen Coronary Angiography Cohort (BECAC), a prospective Norwegian cohort study of stable CAD patients. Ceramides, especially when used in ratios, were significantly associated with CV death in all studies, independent of other lipid markers and C-reactive protein. Adjusted odds ratios per standard deviation for the Cer(d18:1/16:0)/Cer(d18:1/24:0) ratio were 4.49 (95% CI, 2.24-8.98), 1.64 (1.29-2.08), and 1.77 (1.41-2.23) in the Corogene, SPUM-ACS, and BECAC studies, respectively. The Cer(d18:1/16:0)/Cer(d18:1/24:0) ratio improved the predictive value of the GRACE score (net reclassification improvement, NRI = 0.17 and ΔAUC = 0.09) in ACS and the predictive value of the Marschner score in stable CAD (NRI = 0.15 and ΔAUC = 0.02). Conclusions Distinct plasma ceramide ratios are significant predictors of CV death both in patients with stable CAD and ACS, over and above currently used lipid markers. This may improve the identification of high-risk patients in need of more aggressive therapeutic interventions.

BackgroundAsymmetric dimethylarginine (ADMA) is associated with increased risk of atherosclerotic cardiovascular disease and mortality through inhibition of nitrogen oxide (NO) synthesis. As positive correlations between serum concentrations of NO and body mass index (BMI) have been observed, we aimed to explore whether the potential associations between plasma ADMA levels and the risk of acute myocardial infarction (AMI) and mortality were modified by BMI.MethodsMultivariable Cox proportional hazard models were used to estimate the hazard ratios (HR) for AMI, cardiovascular death and all-cause mortality according to baseline plasma ADMA levels in 4122 patients with suspected stable angina pectoris. Analyses were subsequently repeated in patients with BMI below (low BMI) or above (high BMI) median.ResultsA total of 2982 patients (72%) were men. Median (range) age, plasma ADMA level and BMI were 62 (21-88) years, 0.54 (0.10-1.25) μmol/L and 26.3 (18.5-54.3) kg/m2, respectively. During a mean (standard deviation) follow-up time of 4.7 (1.4) years, 337 (8%) patients suffered from an AMI, 300 (7%) died, whereof 165 (55%) due to cardiovascular disease. Each 0.1 μmol/L increment in plasma ADMA level was associated with an increased risk of AMI (HR (95% CI) 1.21 (1.08, 1.35) and cardiovascular death 1.30 (1.13, 1.49) in participants with low BMI only. Interactions were significant for AMI (p = 0.04) and CV death (p = 0.03). BMI did not modify the association between plasma ADMA levels and all-cause mortality.ConclusionPlasma ADMA levels were associated with risk of AMI and cardiovascular death among patients with low BMI only.

Objectives Primary hyperparathyroidism (PHPT) has been associated with low-grade inflammation and elevated risk of cardiovascular disease (CVD). In inflammatory conditions, interferon-γ (IFN-γ) activity is enhanced and a decreased circulating concentration of vitamin B6 is often observed. Such changes in IFN-γ activity or vitamin B6 levels have been associated with increased incidence of CVD. The aim of the study was to investigate systemic markers of IFN-γ-mediated immune activation, such as neopterin, the kynurenine-to-tryptophan ratio (KTR) and kynurenine pathway metabolites, as well as B6 vitamers in patients with PHPT. Design/subjects A total of 57 patients with PHPT and a control group of 20 healthy blood donors were included in this study. PHPT patients who responded positively to parathyroidectomy were followed for 6 months. Forty-three patients participated in the longitudinal study in which blood samples were taken at inclusion and 1, 3 and 6 months after surgery. Results Plasma concentrations of the B6 vitamers pyridoxal 5′-phosphate (PLP) (P = 0.007) and pyridoxal (P = 0.013) were significantly lower in the patient group compared to healthy control subjects. An increase in the KTR indicated that the kynurenine pathway of tryptophan metabolism was altered in PHPT patients (P = 0.015). During the initial 6 months after surgery, levels of PLP (P

OBJECTIVE: To estimate the association of maternal plasma concentrations of tryptophan and six kynurenine pathway metabolites with the risk of preeclampsia. METHODS: The study was based on a subsample of 2,936 pregnant women who delivered singleton neonates in the Norwegian Mother and Child Cohort Study in 2002–2003. Maternal blood plasma was obtained at approximately gestational week 18 and was measured for tryptophan, kynurenine, kynurenic acid, anthranilic acid, 3-hydroxykynurenine, xanthurenic acid, and 3-hydroxyanthranilic acid. RESULTS: Of the 2,936 pregnant women included in this study, 116 (4.0%, 95% confidence interval [CI] 3.2–4.7) had preeclampsia subsequently diagnosed. The prevalence of preeclampsia was significantly higher among women with plasma kynurenic acid concentrations greater than the 95th percentile than among those with concentrations in the 25th–75th percentile (11.0% compared with 3.3%, P

Background: A negative association between systemic markers of inflammation and plasma vitamin B-6 has been observed in population-based and patient cohorts; however, vitamin B-6 (pyridoxine) treatment has mostly failed to improve inflammatory indexes. Objective: We aimed to assess the effect of pyridoxine treatment on B-6 vitamer and inflammatory marker relations. Design: We measured pyridoxal 5#-phosphate (PLP), pyridoxal, 4-pyridoxic acid (PA), C-reactive protein (CRP), neopterin, and the kynurenine-to-tryptophan ratio (KTR) in plasma and the white blood cell count (WBC). A partial Spearman’s correlation was used to assess associations of B-6 vitamers with inflammatory markers before and after daily treatment with 40 mg pyridoxine hydrochloride. Generalized additive and segmented regression analysis were used for nonlinear relations. Results: A 9‐60-fold increase in B-6 vitamer concentrations over baseline values was observed after 28 d of treatment with pyridoxine. PLP was negatively associated with all 4 inflammatory markers at baseline and, predominantly, with CRP and KTR at day 28. The catabolite PA was positively associated with neopterin and KTR before and after treatment. The dose-response relation between CRP and B-6 vitamers at day 28 was nonlinear, with an increased steepness of slope at CRP .7 mg/L. Finally, changes in B-6 vitamer concentrations were correlated with changes in inflammatory marker concentrations over a time span of 4 wk. Conclusions: The associations between plasma vitamin B-6 and inflammatory markers were preserved or even increased after pyridoxine treatment. The results suggest that the acute phase and activated cellular immunity are associated with increased cellular uptake and catabolism of vitamin B-6, respectively. Am J Clin Nutr doi: 10. 3945/ajcn.111.029751.

Objective— Interferon γ (IFN-γ) is centrally involved in atherosclerosis-related inflammation, but its activity cannot be reliably assessed by systemic measurements. In activated macrophages, IFN-γ stimulates production of neopterin and conversion of tryptophan to kynurenine. We evaluated the relationships of plasma neopterin and plasma kyunernine:tryptophan ratio (KTR) to long-term prognosis in patients with stable angina pectoris and angiographically verified significant coronary artery disease. Methods and Results— Samples were obtained from 2380 patients with a mean age of 63.7 years; 77.3% were men. During a median follow-up of 56 months, 10.8% of patients experienced a major coronary event (MCE), and 9.5% died. For MCE, each SD increment of neopterin and KTR (logarithmically transformed) was associated with multivariable adjusted hazard ratios and 95% CIs of 1.28 (1.10 to 1.48) and 1.28 (1.12 to 1.48), respectively. The corresponding hazard ratios (95% CIs) for all-cause mortality were 1.40 (1.21 to 1.62) (neopterin) and 1.23 (1.06 to 1.43) (KTR). Conclusion— In patients with stable angina pectoris, systemic markers of IFN-γ activity, plasma neopterin, and plasma KTR provide similar risk estimates for MCE and mortality. Our results support experimental data linking IFN-γ to acute atherosclerotic complications.

Objectives Osteoprotegerin (OPG) is a member of the tumor necrosis factor superfamily with pleiotropic effects on bone metabolism, endocrine function and the immune system. Circulating OPG levels are elevated in cardiovascular disease (CVD). We assessed serum OPG as predictor of long-term prognosis in patients with suspected stable angina pectoris (SAP) undergoing elective coronary angiography. Methods Samples were obtained from 1025 patients (median [25th, 75th percentile] age 62 [54, 70] years, 71.9% men). At inclusion, 43.2% of patients had single or double vessel disease, whereas 34.3% had triple vessel disease. Results During a median follow-up of 73 months, 11.0% of patients died, 5.9% died from CVD and 10.0% experienced an acute myocardial infarction (MI). In univariable analyses, strong associations were observed between OPG concentrations and all-cause mortality, CVD mortality and the incidence of MI (fatal or nonfatal). However, adjustment for conventional risk factors attenuated the risk estimates which were no longer significant, except for the subgroup with levels above the 90th percentile. For decile 10 versus deciles 1–9 of serum OPG, the following multivariable hazard ratios (95% confidence intervals) were observed: All-cause mortality: 1.94 (1.18, 3.18), p = 0.01; CVD mortality: 2.29 (1.16, 4.49), p = 0.02; and MI: 1.76 (1.02, 3.06), p = 0.04. Conclusion In patients with SAP, elevated serum OPG is associated with increased risk of all-cause mortality, CVD mortality and MI, but independent effects are mainly confined to levels above the 90th percentile.

BACKGROUND Several compounds in the choline oxidation pathway are associated with insulin resistance and prevalent diabetes; however, prospective data are scarce. We explored the relationships between systemic and urinary choline-related metabolites and incident type 2 diabetes in an observational prospective study among Norwegian patients. METHODS We explored risk associations by logistic regression among 3621 nondiabetic individuals with suspected stable angina pectoris, of whom 3242 provided urine samples. Reclassification of patients was investigated according to continuous net reclassification improvement (NRI >0). RESULTS After median (25th to 75th percentile) follow-up of 7.5 (6.4–8.7) years, 233 patients (6.4%) were registered with incident type 2 diabetes. In models adjusted for age, sex, and fasting status, plasma betaine was inversely related to new-onset disease [odds ratio (OR) per 1 SD, 0.72; 95% CI, 0.62–0.83; P < 0.00001], whereas positive associations were observed for urine betaine (1.25; 1.09–1.43; P = 0.001), dimethylglycine (1.22; 1.06–1.40; P = 0.007), and sarcosine (1.30; 1.13–1.49; P < 0.001). The associations were maintained in a multivariable model adjusting for body mass index, hemoglobin A1c, urine albumin-to-creatinine ratio, estimated glomerular filtration rate, C-reactive protein, HDL cholesterol, and medications. Plasma betaine and urine sarcosine, the indices most strongly related to incident type 2 diabetes, improved reclassification [NRI >0 (95% CI) 0.33 (0.19–0.47) and 0.16 (0.01–0.31), respectively] and showed good within-person reproducibility. CONCLUSIONS Systemic and urinary concentrations of several choline metabolites were associated with risk of incident type 2 diabetes, and relevant biomarkers may improve risk prediction.

The long-chain polyunsaturated fatty acids are considered to be of major health importance, and recent studies indicate that their endogenous metabolism is influenced by B-vitamin status and smoking habits. We investigated the associations of circulating B-vitamins and smoking habits with serum polyunsaturated fatty acids among 1,366 patients who underwent coronary angiography due to suspected coronary heart disease at Haukeland University Hospital, Norway. Of these, 52% provided information on dietary habits by a food frequency questionnaire. Associations were assessed using partial correlation (Spearman's rho). In the total population, the concentrations of most circulating B-vitamins were positively associated with serum n-3 polyunsaturated fatty acids, but negatively with serum n-6 polyunsaturated fatty acids. However, the associations between B-vitamins and polyunsaturated fatty acids tended to be weaker in smokers. This could not be solely explained by differences in dietary intake. Furthermore, plasma cotinine, a marker of recent nicotine exposure, showed a negative relationship with serum n-3 polyunsaturated fatty acids, but a positive relationship with serum n-6 polyunsaturated fatty acids. In conclusion, circulating B-vitamins are, in contrast to plasma cotinine, generally positively associated with serum n-3 polyunsaturated fatty acids and negatively with serum n-6 polyunsaturated fatty acids in patients with suspected coronary heart disease. Further studies should investigate whether B-vitamin status and smoking habits may modify the clinical effects of polyunsaturated fatty acid intake.

Objective— Enhanced tryptophan degradation, induced by the proinflammatory cytokine interferon-γ, has been related to cardiovascular disease progression and insulin resistance. We assessed downstream tryptophan metabolites of the kynurenine pathway as predictors of acute myocardial infarction in patients with suspected stable angina pectoris. Furthermore, we evaluated potential effect modifications according to diagnoses of pre-diabetes mellitus or diabetes mellitus. Approach and Results— Blood samples were obtained from 4122 patients (median age, 62 years; 72% men) who underwent elective coronary angiography. During median follow-up of 56 months, 8.3% had acute myocardial infarction. Comparing the highest quartile to the lowest, for the total cohort, multivariable adjusted hazard ratios (95% confidence intervals) were 1.68 (1.21–2.34), 1.81 (1.33–2.48), 1.68 (1.21–2.32), and 1.48 (1.10–1.99) for kynurenic acid, hydroxykynurenine, anthranilic acid, and hydroxyanthranilic acid, respectively. The kynurenines correlated with phenotypes of the metabolic syndrome, and risk associations were generally stronger in subgroups classified with pre-diabetes mellitus or diabetes mellitus at inclusion ( P int ≤0.05). Evaluated in the total population, hydroxykynurenine and anthranilic acid provided statistically significant net reclassification improvements (0.21 [0.08–0.35] and 0.21 [0.07–0.35], respectively). Conclusions— In patients with suspected stable angina pectoris, elevated levels of plasma kynurenines predicted increased risk of acute myocardial infarction, and risk estimates were generally stronger in subgroups with evidence of impaired glucose homeostasis. Future studies should aim to clarify roles of the kynurenine pathway in atherosclerosis and glucose metabolism.

Background: Inflammation is important in the pathogenesis of atherosclerosis. Polymorphisms of Fc receptors for IgG (FcγR) are associated with modifying effects of several infectious and autoimmune diseases. We have assessed the relationship between polymorphisms in three different FcγR genes and coronary artery disease (CAD). Methods and results: We genotyped for the FcγRIIA-R/H131, the FcγRIIIB-Na1/Na2, and the FcγRIIIA-F/V158 polymorphisms in 882 patients undergoing diagnostic coronary angiography. Significant CAD was defined as ≥50% lumen diameter stenosis in at least one coronary artery. In the analysis, no association was found between the FcγRIIA and FcγRIIIB genotypes and CAD, whereas the FcγRIIIA genotype was strongly related. Compared to those being heterozygous, or homozygous for the F allele, patients homozygous for the V allele had significantly reduced risk: OR, 0.53; (CI, 0.32–0.90). Additional adjustment for classical risk factors and sedimentation rate did not affect the results. The V/V genotype was also inversely related to the extent of CAD defined as no CAD, single, double or triple vessel disease ( P trend=0.002). Conclusions: Our data provide evidence for an association between FcγRIIIA allelic variants and coronary atherosclerosis. Genetic variation in this IgG-receptor may influence the clearance of antibodies by monocyte-derived macrophages involved in the pathogenesis of CAD.

Objective: Associations of glycated hemoglobin A1c (HbA1c) levels to incident coronary and cardiovascular events among non-diabetic patients with coronary artery disease are unclear. We investigated relations of HbA1c to long-term prognosis in such patients. Methods: A prospective cohort of 2519 patients undergoing elective coronary angiography for suspected stable angina pectoris (SAP) was divided into pre-defined categories according to HbA1c (%) levels (

Background A number of previous studies have suggested that overweight or obese patients with coronary artery disease (CAD) may have lower morbidity and mortality than their leaner counterparts. Few studies have addressed possible gender differences, and the results are conflicting. We examined the association between body mass index (BMI) and risk of acute myocardial infarction (AMI), cardiovascular (CV) death and all-cause mortality in men and women with suspected stable angina pectoris. Method The cohort included 4164 patients with suspected stable angina undergoing elective coronary angiography between 2000 and 2004. Events were registered until the end of 2006. Hazard ratios (HR) (95% confidence intervals) were estimated using Cox regression by comparing normal weight (18.5-24.9 kg/m2) with overweight (25–29.9 kg/m2) and obese (≥30 kg/m2) patients. Underweight (

Background: Plasma concentrations of PL 5#-phosphate (PLP), which is the active coenzyme form of vitamin B-6, are reduced during inflammation. The underlying mechanisms may include altered tissue distribution or increased catabolism via pyridoxal (PL) to pyridoxic acid (PA). Recently, we showed that catabolic enzyme activity could be assessed by substrate product ratios measured in plasma. Objective: We evaluated the ratios PA:PL, PA:PLP, and PA:(PL + PLP) as possible markers of vitamin B-6 catabolism. Design: Cross-sectional and longitudinal data were derived from the Western Norway B-Vitamin Intervention Trial. We analyzed associations of ratios with inflammatory markers and other clinical variables by using multiple linear regression and partial correlation. In addition, intraclass correlation coefficients (ICCs) were used to assess the ability of plasma indexes to differentiate between subjects. Results: PA:(PL + PLP) had the highest ICC of all vitamin B-6 metabolites and ratios tested. In regression models, the inflammatory markers C-reactive protein, white blood cell count, neopterin, and kynurenine:tryptophan collectively accounted for 28% of the total and . 90% of the explained variation in PA:(PL + PLP). For individual B-6 metabolites, corresponding numbers were 19‐25% and 20‐44%, respectively, with vitamin supplement intake, smoking, and kidney function (estimated glomerular filtration rate) as additional predictors. In an analysis of receiver operating characteristics, PA:(PL + PLP) discriminated high inflammatory concentrations with an area under the curve (95% CI) of 0.85 (0.81, 0.89). Conclusions: Broad-specificity enzymes upregulated to reduce oxidative and aldehyde stress could explain increased catabolism of vitamin B-6 during inflammation. The ratio PA:(PL + PLP) may provide novel insights into pathologic processes and potentially predict risk of future disease. Am J Clin Nutr 2014;100:250‐5.

Lower bone mineral density (BMD) in smokers may be attributable to lower body weight or fat mass, rather than to a direct effect of smoking. We analyzed the effects of smoking exposure, assessed by plasma cotinine, and body fat on BMD and the risk of subsequent hip fracture. In the community-based Hordaland Health Study (HUSK), 3003 participants 46–49 years and 2091 subjects 71–74 years were included. Cotinine was measured in plasma and information on health behaviors was obtained from self-administered questionnaires. BMD and total body soft tissue composition were measured by dual X-ray absorptiometry. Information on hip fracture was obtained from computerized records containing discharge diagnoses for hospitalizations between baseline examinations 1997–2000 through December 31st, 2009. In the whole cohort, moderate and heavy smokers had stronger positive associations between fat mass and BMD compared to never smokers (differences in regression coefficient (95% CI) per % change in fat mass = 1.38 (0.24, 2.52) and 1.29 (0.17, 2.4), respectively). In moderate and heavy smokers there was a nonlinear association between BMD and fat mass with a stronger positive association at low compared to high levels of fat mass (Davies segmented test, p

A beneficial effect of a high n-3 long-chain polyunsaturated fatty acid (LCPUFA) intake has been observed in heart failure patients, who are frequently insulin resistant. We investigated the potential influence of impaired glucose metabolism on the relation between dietary intake of n-3 LCPUFAs and risk of acute myocardial infarction (AMI) in patients with coronary artery disease. This prospective cohort study was based on the Western Norway B-Vitamin Intervention Trial and included 2,378 patients with coronary artery disease with available baseline glycosylated hemoglobin (HbA1c) and dietary data. Patients were sub-grouped as having no diabetes (HbA1c

Objective— Dimethylglycine is linked to lipid metabolism, and increased plasma levels may be associated with adverse prognosis in patients with coronary artery disease. We evaluated the relationship between plasma dimethylglycine and risk of incident acute myocardial infarction in a large prospective cohort of patients with stable angina pectoris, of whom approximately two thirds were participants in a B-vitamin intervention trial. Model discrimination and reclassification when adding plasma dimethylglycine to established risk factors were obtained. We also explored temporal changes and the test–retest reliability of plasma dimethylglycine. Approach and Results— Four thousand one hundred fifty patients (72% men; median age 62 years) were included. Plasma dimethylglycine was associated with several traditional coronary artery disease risk factors. During a median follow-up of 4.6 years, 343 (8.3%) patients experienced an acute myocardial infarction. The hazard ratio (95% confidence interval) for acute myocardial infarction was 1.95 (1.42–2.68; P P for interaction=0.004, 0.004, and 0.03, respectively). Plasma dimethylglycine improved discrimination and reclassification and had high test–retest reliability. Conclusions— Plasma dimethylglycine is independently related to incident acute myocardial infarction and enhances risk prediction in patients with stable angina pectoris. Our results motivate further studies on the relationship between 1-carbon metabolism and atherothrombosis. A potential interplay with lipid and energy metabolism merits particular attention.

It is unclear whether reduced plasma pyridoxal 5'-phosphate (PLP) during inflammation reflects an altered distribution or increased requirement of vitamin B-6 that may impair overall vitamin B-6 status in tissues. In plasma from 3035 patients undergoing coronary angiography for suspected coronary heart disease, we investigated if plasma concentrations of any metabolites in the kynurenine pathway, which depend on PLP as cofactor, may serve as metabolic marker(s) of vitamin B-6 status. We also examined the association of vitamin B-6 status with serum or plasma concentrations of several inflammatory markers. Among the kynurenines, only 3-hydroxykynurenine (HK) was inversely related to PLP and showed a positive relation to 4 investigated inflammatory markers. A segmented relationship was observed between PLP and HK, with a steep slope at PLP concentrations18.4 nmol/L, corresponding to the 5th percentile, and an almost zero slope at higher PLP concentrations. Low PLP and the steep PLP-HK slope were essentially confined to participants with 1 or more inflammatory markers in the upper tertile. Oral supplementation with pyridoxine hydrochloride (40 mg/d) for 1 mo increased plasma PLP 8-fold, reduced the geometric mean (95% CI) of HK from 29.5 to 20.2 nmol/L (P0.001), and abolished the steep segment of the PLP-HK curve. The steep inverse relationship of plasma PLP with HK at low plasma PLP and the lowering of HK by pyridoxine suggest plasma HK as a metabolic marker of vitamin B-6 status. Thus, low plasma PLP during inflammation may reflect impaired cellular vitamin B-6 status, as indicated by the concurrent increase in plasma HK.

Background: Consumption of fish and n‐3 (omega-3) long-chain polyunsaturated fatty acids (LCPUFAs) has been associated with reduced risk of coronary artery disease (CAD) mortality. Objective: The aim was to examine the relation between dietary intake of n‐3 LCPUFAs or fish and risk of future coronary events or mortality in patients with well-characterized CAD. Design: This was a substudy of 2412 participants in the Western Norway B Vitamin Intervention Trial with a median follow-up time of 57 mo. Patients aged .18 y diagnosed with CAD (81% men) completed a food-frequency questionnaire at baseline, from which daily intakes of eicosapentaenoic, docosapentaenoic, and docosahexaenoic acids as well as fish were estimated on the basis of diet and intakes of supplements including fish and cod liver oils. The main endpoint was a composite of coronary events, including coronary death, nonfatal acute myocardial infarction, and unstable angina pectoris. Results: The mean (6SD) intakes of n‐3 LCPUFAs in quartiles 1‐4 were 0.58 6 0.29, 0.83 6 0.30, 1.36 6 0.44, and 2.64 6 1.18 g/d, respectively. We found no dose-response relation between quartiles of n‐3 LCPUFAs (based on intake as percentage of total energy) or fish and coronary events or separate endpoints. A post hoc additive proportional hazards model showed a slightly increased risk of coronary events at an intake of n‐3 LCPUFAs ,’ 0.30 g/d. Conclusion: Among Norwegian patients with CAD consuming relatively high amounts of n‐3 LCPUFAs and fish, there were no significant trends toward a reduced risk of coronary events or mortality with increasing intakes. This trial was registered at clinicaltrials.gov as NCT00354081. Am J Clin Nutr doi: 10.3945/ajcn. 2010.29175.

Context Observational studies have reported associations between circulating total homocysteine concentration and risk of cardiovascular disease. Oral administration of folic acid and vitamin B(12) can lower plasma total homocysteine levels. Objective To assess the effect of treatment with folic acid and vitamin B(12) and the effect of treatment with vitamin B(6) as secondary prevention in patients with coronary artery disease or aortic valve stenosis. Design, setting, and participants Randomized, double-blind controlled trial conducted in the 2 university hospitals in western Norway in 1999-2006. A total of 3096 adult participants undergoing coronary angiography (20.5% female; mean age, 61.7 years) were randomized. At baseline, 59.3% had double- or triple-vessel disease, 83.7% had stable angina pectoris, and 14.9% had acute coronary syndromes. Interventions Using a 2 x 2 factorial design, participants were randomly assigned to 1 of 4 groups receiving daily oral treatment with folic acid, 0.8 mg, plus vitamin B(12), 0.4 mg, plus vitamin B(6), 40 mg (n = 772); folic acid plus vitamin B(12) (n = 772); vitamin B(6) alone (n = 772); or placebo (n = 780). Main outcome measures The primary end point was a composite of all-cause death, nonfatal acute myocardial infarction, acute hospitalization for unstable angina pectoris, and nonfatal thromboembolic stroke. Results Mean plasma total homocysteine concentration was reduced by 30% after 1 year of treatment in the groups receiving folic acid and vitamin B(12). The trial was terminated early because of concern among participants due to preliminary results from a contemporaneous Norwegian trial suggesting adverse effects from the intervention. During a median 38 months of follow-up, the primary end point was experienced by a total of 422 participants (13.7%): 219 participants (14.2%) receiving folic acid/vitamin B(12) vs 203 (13.1%) not receiving such treatment (hazard ratio, 1.09; 95% confidence interval, 0.90-1.32; P = .36) and 200 participants (13.0%) receiving vitamin B(6) vs 222 (14.3%) not receiving vitamin B(6) (hazard ratio, 0.90; 95% confidence interval, 0.74-1.09; P = .28). Conclusions This trial did not find an effect of treatment with folic acid/vitamin B(12) or vitamin B(6) on total mortality or cardiovascular events. Our findings do not support the use of B vitamins as secondary prevention in patients with coronary artery disease. Trial registration clinicaltrials.gov Identifier: NCT00354081.

Background Loop diuretics are widely used in patients with heart and renal failure, as well as to treat hypertension and peripheral edema. However, there are no randomized, controlled trials (RCT) evaluating their long term safety, and several observational reports have indicated adverse effects. We sought to evaluate the impact of loop diuretics on long term survival in patients with suspected coronary artery disease, but without clinical heart failure, reduced left ventricular ejection fraction or impaired renal function. Method and Findings From 3101 patients undergoing coronary angiography for suspected stable angina pectoris, subjects taking loop diuretics (n=109) were matched with controls (n=198) in an attempted 1:2 ratio, using propensity scores based on 59 baseline variables. During median follow-up of 10.1 years, 37.6% in the loop diuretics group and 23.7% in the control group died (log-rank p-value 0.005). Treatment with loop diuretics was associated with a hazard ratio (95% confidence interval) of 1.82 (1.20, 2.76), and the number needed to harm was 7.2 (4.1, 30.3). Inclusion of all 3101 patients using propensity score weighting and adjustment for numerous covariates provided similar estimates. The main limitation is the potential of confounding from unmeasured patient characteristics. Conclusions The use of loop diuretics in patients with suspected coronary artery disease, but without systolic heart failure or renal impairment, is associated with increased risk of all-cause mortality. Considering the lack of randomized controlled trials to evaluate long term safety of loop diuretics, our data suggest caution when prescribing these drugs to patients without a clear indication. publishedVersion