Plasma methylmalonic acid predicts risk of acute myocardial infarction and mortality in patients with coronary heart disease: A prospective 2-cohort study.

BACKGROUND: Elevated plasma methylmalonic acid (MMA) is reported in patients with established coronary heart disease (CHD) and is considered a marker of vitamin B12 deficiency. Moreover, MMA-dependent reactions have been linked to alterations in mitochondrial energy metabolism and oxidative stress, key features in the pathophysiology of cardiovascular diseases (CVDs). OBJECTIVES: We examined whether plasma MMA prospectively predicted the long-term risk of acute myocardial infarction (AMI) and mortality. METHODS AND RESULTS: Using Cox modeling, we estimated hazard ratios (HRs) for endpoints according to per 1-SD increment of log-transformed plasma MMA in two independent populations: the Western Norway Coronary Angiography Cohort (WECAC) (patients evaluated for CHD; n = 4137) and the Norwegian Vitamin Trial (NORVIT) (patients hospitalized with AMI; n = 3525). In WECAC and NORVIT, 12.8% and 18.0% experienced an AMI, whereas 21.8% and 19.9% died, of whom 45.5% and 60.3% from CVD-related causes during follow-up (range 3-11 years), respectively. In WECAC, age- and gender-adjusted HRs (95% confidence interval) were 1.18 (1.09-1.28), 1.25 (1.18-1.33), and 1.28 (1.17-1.40) for future AMI, total mortality, and CVD mortality, respectively. Corresponding risk estimates were 1.19 (1.10-1.28), 1.22 (1.14-1.31), and 1.30 (1.19-1.42) in NORVIT. These estimates were only slightly attenuated after multivariable adjustments. Across both cohorts, the MMA-risk association was stronger in older adults, women, and non-smokers. CONCLUSIONS: Elevated MMA was associated with an increased risk of AMI and mortality in patients with suspected or verified CHD.

Circulating trimethylamine N-oxide levels do not predict 10-year survival in patients with or without coronary heart disease.

BACKGROUND: Trimethylamine N-oxide (TMAO) is an amine oxide generated by gut microbial metabolism. TMAO may contribute to atherothrombosis and systemic inflammation. However, the prognostic value of circulating TMAO for risk stratification is uncertain. METHODS: We assessed prospective relationships of plasma TMAO with long-term risk of all-cause, cardiovascular (CV), and non-CV mortality in the Western Norway Coronary Angiography Cohort (WECAC; 4132 patients with suspected coronary artery disease) and the Hordaland Health Study (HUSK; 6393 community-based subjects). Risk associations were examined using Cox regression analyses. RESULTS: Mean follow-up was 9.8 and 10.5 years in WECAC and HUSK, respectively. Following adjustments for established CV risk factors and indices of renal function in WECAC, the hazard ratios (HRs) (95% confidence intervals [CIs]) per one standard deviation increase in log-transformed plasma TMAO were 1.04 (0.97-1.12), 1.06 (0.95-1.18), and 1.03 (0.93-1.13) for all-cause, CV, and non-CV mortality, respectively. Essentially similar results were obtained in patients with angiographically significant coronary artery disease and patients with reduced left ventricular ejection fraction. Corresponding HRs (95% CIs) in the HUSK cohort were 1.03 (0.96-1.10), 1.01 (0.89-1.13), and 1.03 (0.95-1.12) for all-cause-, CV, and non-CV mortality, respectively. CONCLUSIONS: Circulating TMAO did not predict long-term all-cause, CV, or non-CV mortality in patients with coronary heart disease or in community-based adults. This large study does not support a role of TMAO for patient risk stratification in primary or secondary prevention.

ß-blocker use and risk of all-cause mortality in patients with coronary heart disease: effect modification by serum vitamin A.

AIMS: Blockade of ß-adrenoceptors reduces sympathetic nervous system activity and improves survival in patients with heart failure with reduced left ventricular ejection fraction (HFrEF); however, any improvement in longevity among patients with coronary heart disease (CHD) but without HFrEF remains uncertain. Vitamin A has been linked to the activation of tyrosine hydroxylase, the rate-limiting enzyme in the catecholamine synthesis pathway. We investigated if vitamin A status modified the association of ß-blocker use with the risk of all-cause mortality. METHODS AND RESULTS: A total of 4118 patients undergoing elective coronary angiography for suspected stable angina pectoris, of whom the majority had normal left ventricular ejection fraction (LVEF) were studied. Hazard ratios (HRs) of all-cause mortality comparing treatment vs. non-treatment of ß-blockers according to the tertiles of serum vitamin A were explored in Cox proportional hazards regression models. During a median follow-up of 10.3 years, 897 patients (21.8%) died. The overall LVEF was 65% and 283 (6.9%) had anamnestic HF. After multivariable adjustments for traditional risk factors, medical history, and drug therapies of cardiovascular disease, ß-blocker treatment was inversely associated with the risk of all-cause mortality [HR : 0.84; 95% CI (confidence interval), 0.72-0.97]. However, the inverse association was generally stronger among patients in the upper serum vitamin A tertile (HR :0.66; 95% CI, 0.50-0.86; Pinteraction = 0.012), which remained present after excluding patients with LVEF < 40%. CONCLUSION: In patients with suspected CHD, ß-blocker treatment was associated with improved survival primarily among patients with high serum vitamin A levels.

Trimethyllysine predicts all-cause and cardiovascular mortality in community-dwelling adults and patients with coronary heart disease.

Aims: Trimethyllysine (TML) is involved in carnitine synthesis, serves as a precursor of trimethylamine N-oxide (TMAO) and is associated with cardiovascular events in patients with established coronary heart disease (CHD). We prospectively examined circulating TML as a predictor of all-cause and cardiovascular mortality in community-dwelling adults and patients with CHD. Methods and results: By Cox regression modelling, risk associations were examined in 6393 subjects in the community-based Hordaland Health Study (HUSK). A replication study was conducted among 4117 patients with suspected stable angina pectoris in the Western Norway Coronary Angiography Cohort (WECAC). During a mean follow-up of 10.5 years in the HUSK-cohort, 884 (13.8%) subjects died, of whom 287 from cardiovascular causes. After multivariable adjustments for traditional cardiovascular risk factors, the hazard ratio (HR) [95% confidence interval (95% CI)] for all-cause mortality comparing the 4th vs. 1st TML-quartile was 1.66 (1.31-2.10, P < 0.001). Particularly strong associations were observed for cardiovascular mortality [HR (95% CI) 2.04 (1.32-3.15, P = 0.001)]. Corresponding risk-estimates in the WECAC (mean follow-up of 9.8 years) were 1.35 [1.10-1.66, P = 0.004] for all-cause and 1.45 [1.06-1.98, P = 0.02] for cardiovascular mortality. Significant correlations between plasma TML and TMAO were observed in both cohorts (rs ≥ 0.42, P < 0.001); however, additional adjustments for TMAO did not materially influence the risk associations, and no effect modification by TMAO was found. Conclusions: Elevated TML-levels were associated with increased risk of all-cause and cardiovascular mortality both in subjects with and without established CHD.

Transsulfuration metabolites and the association with incident atrial fibrillation - An observational cohort study among Norwegian patients with stable angina pectoris.

BACKGROUND/AIM: Plasma total homocysteine (tHcy) is elevated in patients with persistent vs. paroxysmal atrial fibrillation (AF), and has been related to increased risk of new-onset AF. Homocysteine is degraded to cystathionine (Cysta) and cysteine (Cys). All three metabolites have been linked to potential proarrhythmic traits such as inflammation and atrial fibrosis. We evaluated the prospective association between these metabolites and new-onset AF among patients with suspected stable angina pectoris. METHODS: Information regarding AF was obtained by linking patient data to national health registries. Risk associations were explored by Cox regression and potential improvements in risk reclassification were calculated by the continuous net reclassification index (NRI > 0). RESULTS: At baseline, 3535 patients without any prior history of AF were included. During median follow-up of 7.4 years, 392 patients (10.2%) were registered with incident AF. Higher plasma tHcy and tCys were associated with increased risk of incident AF [age and gender adjusted HRs (95% CI) per 1 log transformed SD 1.23 (1.12-1.35) and 1.23 (1.11-1.38)]; multivariate adjustment yielded similar results. Plasma tHcy and tCys also improved reclassification of patients (NRI > 0 (95% CI)) for tHcy 0.118 (0.02-0.22) and tCys 0.107 (0.002-0.21). No association was seen between plasma Cysta and incident AF. CONCLUSION: Plasma tHcy and tCys, but not Cysta, were associated with, and improved risk classification of, new-onset AF among patients with stable angina pectoris. Our results motivate further studies to explore the relationship between homocysteine metabolism and cardiac arrhythmias.

Creatinine, total cysteine and uric acid are associated with serum retinol in patients with cardiovascular disease.

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 ß: 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.

Elevated plasma cystathionine is associated with increased risk of mortality among patients with suspected or established coronary heart disease.

BACKGROUND: Elevated circulating cystathionine levels are related to atherosclerotic cardiovascular disease, a leading cause of death globally. OBJECTIVE: We investigated whether plasma cystathionine was associated with mortality in patients with suspected or established coronary heart disease (CHD). METHODS: Data from 2 independent cohorts of patients with suspected stable angina pectoris (SAP) (3033 patients; median 10.7 y follow-up; 648 deaths) or acute myocardial infarction (AMI) (3670 patients; median 7.0 y follow-up; 758 deaths) were included. Hazard ratios with 95% CIs per SD increment of log-transformed cystathionine were calculated using Cox regression modeling. Endpoint data was obtained from a national health registry. RESULTS: Among patients with SAP, there was a positive association between plasma cystathionine and death (age- and sex-adjusted HRs [95% CI] per SD: 1.23 [1.14, 1.32], 1.29 [1.16, 1.44], and 1.17 [1.05, 1.29] for total, cardiovascular, and noncardiovascular mortality, respectively). Corresponding risk estimates were 1.28 (1.19, 1.37) for all-cause, 1.33 (1.22, 1.45) for cardiovascular, and 1.19 (1.06, 1.34) for noncardiovascular death among AMI patients. In both cohorts, estimates were slightly attenuated after multivariate adjustments for established CHD risk factors. Subgroup analyses showed that the relation between cystathionine and all-cause mortality in SAP patients was stronger among nonsmokers and those with lower plasma concentration of pyridoxal-5'-phosphate (P-interaction ≤ 0.01 for both). CONCLUSIONS: Elevated plasma cystathionine is associated with both cardiovascular and noncardiovascular mortality among patients with suspected or established CHD. The joint risk associations of high plasma cystathionine with lifestyle factors and impaired vitamin B-6 status on mortality need further investigation. This trial was registered at clinicaltrials.gov as NCT00354081 and NCT00266487.

Plasma Cystathionine and Risk of Incident Stroke in Patients With Suspected Stable Angina Pectoris.

Background Cystathionine is an intermediate product in the transsulfuration pathway and formed during the B6-dependent conversion of methionine to cysteine. Elevated plasma cystathionine has been related to atherosclerosis, which is a major etiological factor for ischemic stroke. However, the role of cystathionine in stroke development is unknown. Therefore, we prospectively assessed the association of circulating levels of cystathionine with risk of total and ischemic stroke. Methods and Results Two-thousand thirty-six patients (64% men; median age, 62 years) undergoing coronary angiography for suspected stable angina pectoris were included. Stroke cases were identified by linkage to the CVDNOR (Cardiovascular Disease in Norway) project. Hazard ratios with confidence intervals (95% confidence interval) were estimated by using Cox-regression analyses. During 7.3 years of median follow-up, 124 (6.1%) incident strokes were ascertained, which comprised 100 cases of ischemic stroke. There was a positive association of plasma cystathionine with risk of total stroke and ischemic stroke. Comparing the fourth versus the first cystathionine quartiles, age- and sex-adjusted hazard ratios (95% confidence interval) were 2.11 (1.19-3.75) and 2.56 (1.31-4.99) for total and ischemic stroke, respectively. Additional adjustment for major stroke risk factors only slightly attenuated the associations, which tended to be stronger in patients without previous or existing atrial fibrillation at baseline (hazard ratio [95% confidence interval], 2.43 [1.27-4.65] and 2.88 [1.39-5.98] for total and ischemic stroke, respectively). Conclusions In patients with suspected stable angina pectoris, plasma cystathionine was independently related to increased risk of total stroke and, in particular, ischemic stroke. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 00354081.

Increased plasma trimethylamine-N-oxide is associated with incident atrial fibrillation.

BACKGROUND: Plasma trimethylamine-N-oxide (TMAO) is associated with cardiovascular disease; however specific relationships with cardiac arrhythmias are unknown. We evaluated the association between plasma TMAO and incident atrial fibrillation (AF). METHODS: Risk associations were explored among 3797 patients with suspected stable angina in the Western Norway Coronary Angiography Cohort (WECAC) and verified in 3143 elderly participants in the community-based Hordaland Health Study (HUSK). Information on endpoints was obtained from nationwide registries. RESULTS: Median follow-up was 7.3 and 10.8 years in the WECAC and HUSK cohorts, respectively, and 412 (10.9%) and 484 (15.4%) subjects were registered with incident AF. The age and gender adjusted HRs were 1.16, 95% CI 1.05-1.28 and 1.10, 95% CI 1.004-1.19 per 1 SD increase in log-transformed plasma TMAO. Adjusting for hypertension, BMI, smoking, diabetes, or intake of total choline, a TMAO precursor, did not materially influence the risk associations. Among patients in WECAC, further extensive adjustment for other AF risk factors yielded similar results. Adding TMAO to traditional AF risk factors (age, gender, hypertension, BMI, smoking and diabetes) yielded a continuous net reclassification improvement of 0.108, 95% CI 0.015-0.202 and 0.139, 95% CI 0.042-0.235. CONCLUSIONS: Plasma TMAO was associated with and improved reclassification of incident AF in two independent Norwegian cohorts with long-term follow-up. The relationship was independent of traditional AF risk factors, as well as of dietary choline intake. Our findings motivate further studies to explore endogenous metabolic factors influencing the relationship between TMAO and cardiovascular disease.

Plasma cystathionine and risk of acute myocardial infarction among patients with coronary heart disease: Results from two independent cohorts.

BACKGROUND: 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). METHODS: 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. RESULTS: 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 H2S production (P < 0.001). CONCLUSIONS: Plasma 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.

Plasma Concentrations and Dietary Intakes of Choline and Betaine in Association With Atrial Fibrillation Risk: Results From 3 Prospective Cohorts With Different Health Profiles.

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<0.001) and 1.16 (95% confidence interval 1.10-1.22, P<0.001) per 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: NCT00671346.

Plasma methionine and risk of acute myocardial infarction: Effect modification by established risk factors.

BACKGROUND AND AIMS: Methionine (Met) is an essential amino acid involved in methylation reactions and lipid metabolism. A Met-deficient diet may cause hepatic lipid accumulation, which is considered an independent risk factor for atherosclerosis. However, the prospective relationship between circulating Met and incident acute myocardial infarction (AMI) is unknown. METHODS: We studied the associations of plasma Met and incident AMI in 4156 patients (77% men; median age 62 years) with stable angina pectoris, among whom the majority received lipid lowering therapy with statins. Risk associations were estimated using Cox-regression analyses. RESULTS: Plasma Met was negatively related to age, serum levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C) and apolipoprotein (apo) B at baseline (all p≤0.05). During a median follow-up of 7.5 years, 534 (12.8%) patients experienced an AMI. There was no overall association between plasma Met and incident AMI; however, plasma Met was inversely associated with risk among patients with high as compared to low levels of serum LDL-C or apo B 100 (multivariate adjusted HRs per SD [95% CI] 0.84 [0.73-0.96] and 0.83[0.73-0.95], respectively; p-interaction ≤0.02). Trends towards an inverse risk relationship were also observed among those younger than 62 years and patients without diabetes or hypertension. CONCLUSIONS: Low plasma Met was associated with increased risk of AMI in patients with high circulating levels of atherogenic lipids, but also in subgroups with presumably lower cardiovascular risk. The determinants of Met status and their relation with residual cardiovascular risk in patients with coronary heart disease should be further investigated.

Fibrinogen and Neopterin Is Associated with Future Myocardial Infarction and Total Mortality in Patients with Stable Coronary Artery Disease.

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 < 0.001) and 1.22 (1.13, 1.31; p < 0.001), respectively. For neopterin, the HRs (95% CI) were 1.31 (1.23, 1.40; p < 0.001) and 1.24 (1.15, 1.34; p < 0.001), respectively. No significant interaction between fibrinogen and neopterin was observed. The prognostic utility of neopterin for incident AMI was improved in patients with an hsTnT above the median, for total mortality in non-smokers, and for both total mortality and AMI in females. In conclusion, both fibrinogen and neopterin were associated with future AMI and total mortality, but had low discriminatory impact. No interaction was observed between these two biomarkers. The prognostic utility of neopterin was improved in patients with hsTnT levels above the median, and in females and non-smokers.

Serum Carnitine Metabolites and Incident Type 2 Diabetes Mellitus in Patients With Suspected Stable Angina Pectoris.

Context: Carnitine and its metabolites are centrally involved in fatty acid metabolism. Although elevated circulating concentrations have been observed in obesity and insulin resistance, prospective studies examining whether these metabolites are associated with incident type 2 diabetes mellitus (T2D) are sparse. Objective: We performed a comprehensive evaluation of metabolites along the carnitine pathway relative to incident T2D. Design: A total of 2519 patients (73.1% men) with coronary artery disease, but without T2D, were followed for median 7.7 years until the end of 2009, during which 173 (6.9%) new cases of T2D were identified. Serum levels of free carnitine, its precursors trimethyllysine (TML) and γ-butyrobetaine, and the esters acetyl-, propionyl-, (iso)valeryl-, octanoyl-, and palmitoylcarnitine were measured by liquid chromatography/tandem mass spectrometry. Risk associations were explored by logistic regression and reported per (log-transformed) standard deviation increment. Results: Median age at inclusion was 62 years and median body mass index (BMI) 26.0 kg/m2. In models adjusted for age, sex, fasting status, BMI, estimated glomerular filtration rate, glycated hemoglobin A1c, triglyceride and high-density lipoprotein cholesterol levels, and study center, serum levels of TML and palmitoylcarnitine associated positively [odds ratio (95% confidence interval), 1.22 (1.04 to 1.43) and 1.24 (1.04 to 1.49), respectively], whereas γ-butyrobetaine associated negatively [odds ratio (95% confidence interval) 0.81 (0.66 to 0.98)] with T2D risk. Conclusion: Serum levels of TML, γ-butyrobetaine, and the long-chained palmitoylcarnitine predict long-term risk of T2D independently of traditional risk factors, possibly reflecting dysfunctional fatty acid metabolism in patients susceptible to T2D development.

Neopterin as an Effect Modifier of the Cardiovascular Risk Predicted by Total Homocysteine: A Prospective 2-Cohort Study.

BACKGROUND: Plasma total homocysteine (tHcy) 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 tHcy 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 tHcy 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. tHcy and neopterin correlated in both cohorts (rs=0.34 and rs=0.30 among stable angina pectoris and AMI patients, respectively, both P<0.001). tHcy 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 tHcy 1.38 [1.26-1.50] and 1.18 [1.10-1.26] among stable angina pectoris and AMI patients, respectively) (Pint<0.005 in both cohorts). Further, adding information on the interaction between tHcy and neopterin improved model discrimination and reclassification. tHcy and C-reactive protein were weakly related, and no effect modification was found by C-reactive protein. CONCLUSIONS: Among patients with coronary heart disease, tHcy 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.

Cardiovascular disease risk associated with serum apolipoprotein B is modified by serum vitamin A.

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.

The kynurenine:tryptophan ratio as a predictor of incident type 2 diabetes mellitus in individuals with coronary artery disease.

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.

Serum Acylcarnitines and Risk of Cardiovascular Death and Acute Myocardial Infarction in Patients With Stable Angina Pectoris.

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 (HRs) and 95% CIs 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: NCT00354081.

Methylenetetrahydrofolate Dehydrogenase 1 Polymorphisms Modify the Associations of Plasma Glycine and Serine With Risk of Acute Myocardial Infarction in Patients With Stable Angina Pectoris in WENBIT (Western Norway B Vitamin Intervention Trial).

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<0.01), but not serine (P=0.52), showed an overall association with AMI. However, interactions of MTHFD1 rs2236225 polymorphism with both plasma serine and glycine were observed (Pinteraction=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 (Pinteraction=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.

Prospective Associations of Systemic and Urinary Choline Metabolites with Incident Type 2 Diabetes.

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.