Dietary choline is related to increased risk of acute myocardial infarction in patients with stable angina pectoris.

High plasma choline has been associated with the metabolic syndrome and risk of chronic diseases, including cardiovascular disease. However, dietary choline is not correlated with choline plasma concentrations, and there are few studies and contradictory evidence regarding dietary choline and cardiovascular events. In addition, a recommended dietary allowance for choline has not been established and remains a point of contention. This study assessed the association between dietary choline, including choline forms, and risk of incident acute myocardial infarction (AMI) in patients with suspected stable angina pectoris (SAP). In total 1981 patients (80% men, median age 62) from the Western Norway B Vitamin Intervention Trial were included in this analysis. Information on dietary choline was obtained using a 169-item food frequency questionnaire. The Cardiovascular Disease in Norway project provided data on AMI. Risk associations were estimated using Cox-regression analysis using energy-adjusted choline intake. Median (25th, 75th percentile) total energy-adjusted choline intake was 288 (255, 326) mg/d. During a median (25th, 75th percentile) follow-up of 7.5 (6.3, 8.8) years, 312 (15.7%) patients experienced at least one AMI. Increased intakes of energy-adjusted choline (HR [95% CI] per 50 mg increase 1.11 [1.03, 1.20]), phosphatidylcholine (HR per 50 mg increase 1.24 [1.08, 1.42]) and sphingomyelin (HR per 5 mg increase 1.16 [1.02, 1.31]) were associated with higher AMI risk. In conclusion, higher dietary intakes of total choline, phosphatidylcholine and sphingomyelin were associated with increased risk of AMI in patients with SAP. Future studies are necessary to explore underlying mechanisms for this observation.

Plasma Amino Acids and Incident Type 2 Diabetes in Patients With Coronary Artery Disease.

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.

Plasma Homoarginine Concentrations According to Use of Hormonal Contraception.

Estrogen is a potent vasodilator through activation of endothelial nitric oxide synthase (eNOS). Arginine and its homologue homoarginine are substrates for NOS, while asymmetric dimethylarginine (ADMA) is a NOS inhibitor. Healthy, never-pregnant women aged 18 to 40 years (n = 158) were categorized according to use of hormonal contraception into non-users (n = 76), users of estrogen contraceptives (EC-users, n = 58) and users of progestins-only contraceptives (PC-users, n = 24). Plasma homoarginine, arginine, ADMA and SDMA concentrations were assayed using a LC-MS/MS method. Compared to non-users, EC users had higher plasma homoarginine (median (interquartile range) 1.63 (1.24, 2.04) vs. 2.39 (2.05, 2.85) µmol/L, p < 0.001), lower arginine (80.8 (72.4, 94.3) vs. 72.1 (62.9, 85.1) µmol/L, p = 0.008) and ADMA (0.52 (0.46, 0.59) vs. 0.48 (0.42, 0.54) µmol/L, p = 0.003) concentrations. The lowest median plasma homoarginine concentration (1.34 (0.92, 1.75) µmol) was seen in PC-users. No differences were seen in SDMA concentrations according to use of hormonal contraception. In healthy, never-pregnant women aged 18 to 40 years, use of estrogen containing contraception was associated with significantly higher plasma concentrations of homoarginine and lower plasma concentrations of arginine and ADMA as compared to non-users, while the lowest plasma homoarginine concentrations were seen in progestin-only users. Whether the observed changes in relation to use of hormonal contraception have an impact on cardiovascular status, should be evaluated in an intervention study.

Usefulness of Higher Levels of Cardiac Troponin T in Patients With Stable Angina Pectoris to Predict Risk of Acute Myocardial Infarction.

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.

Plasma 25-Hydroxyvitamin D and Mortality in Patients With Suspected Stable Angina Pectoris.

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.

Relations between lipoprotein(a) concentrations, LPA genetic variants, and the risk of mortality in patients with established coronary heart disease: a molecular and genetic association study.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: 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.

Association between Body Mass Index, Asymmetric Dimethylarginine and Risk of Cardiovascular Events and Mortality in Norwegian Patients with Suspected Stable Angina Pectoris.

BACKGROUND: Asymmetric 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. METHODS: Multivariable 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. RESULTS: A 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. CONCLUSION: Plasma ADMA levels were associated with risk of AMI and cardiovascular death among patients with low BMI only.

Glycated hemoglobin and long-term prognosis in patients with suspected stable angina pectoris without diabetes mellitus: a prospective cohort study.

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 (<5.0, 5.0-5.6 (reference), 5.7-6.4), and followed for median 4.9 years. The primary end-point was major coronary events (including non-fatal and fatal acute myocardial infarctions, and sudden cardiac death). Secondary end-points were death from cardiovascular disease (CVD) and all-cause mortality. Hazard ratios (HRs) (95% confidence intervals [CIs]) were obtained by Cox regression. RESULTS: Median age at inclusion was 62 years, 73% were males, median HbA1c was 5.6% and random plasma-glucose 5.4 mmol/L. After multivariate adjustment, HbA1c levels within the pre-diabetic range were not associated with risk of major coronary events, HR (95% CI): 1.13 (0.79-1.62); P=0.49, death from CVD or all-cause mortality HR (95% CI): 0.95 (0.55-1.66) and 1.04 (0.70-1.53), respectively; P≥0.85. Similarly, there was no significant association between HbA1c values within the lowest category and risk of study outcomes, (P≥0.18). CONCLUSION: In non-diabetic patients with suspected SAP, there was no overall association between HbA1c levels and prognosis, questioning an independent role of glycemia in the pathogenesis of atherosclerotic complications in these patients.

Dietary intake of saturated fat is not associated with risk of coronary events or mortality in patients with established coronary artery disease.

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.

Associations of plasma kynurenines with risk of acute myocardial infarction in patients with stable angina pectoris.

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 (Pint≤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.

Association of body mass index with risk of acute myocardial infarction and mortality in Norwegian male and female patients with suspected stable angina pectoris: a prospective cohort study.

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 (<18.5 kg/m2) patients were excluded from the study. RESULTS: Of 4131 patients with complete data, 72% were males and 75% were diagnosed with significant CAD. The mean (standard deviation (SD)) age in the total population was 62 (10) years. Mean (SD) BMI was 26.8 (3.9) kg/m2, 34% was normal weight, 48% overweight and 19% obese. During follow up, a total of 337 (8.2%) experienced an AMI and 302 (7.3%) patients died, of whom 165 (4.0%) died from cardiovascular causes. We observed a significant interaction between BMI groups and gender with regards to risk of AMI (p = 0.011) and CV death (p = 0.031), but not to risk of all-cause mortality; obese men had a multivariate adjusted increased risk of AMI (HR 1.80 (1.28, 2.52)) and CV death (HR 1.60 (1.00, 2.55)) compared to normal weight men. By contrast, overweight women had a decreased risk of AMI (HR 0.56 (0.33, 0.98)) compared to normal weight women. The risk of all-cause mortality did not differ between BMI categories. CONCLUSION: Compared with normal weight subjects, obese men had an increased risk of AMI and CV death, while overweight women had a decreased risk of AMI. These findings may potentially explain some of the result variation in previous studies reporting on the obesity paradox.

Fish oil and the pan-PPAR agonist tetradecylthioacetic acid affect the amino acid and carnitine metabolism in rats.

Peroxisome proliferator-activated receptors (PPARs) are important in the regulation of lipid and glucose metabolism. Recent studies have shown that PPARα-activation by WY 14,643 regulates the metabolism of amino acids. We investigated the effect of PPAR activation on plasma amino acid levels using two PPARα activators with different ligand binding properties, tetradecylthioacetic acid (TTA) and fish oil, where the pan-PPAR agonist TTA is a more potent ligand than omega-3 polyunsaturated fatty acids. In addition, plasma L-carnitine esters were investigated to reflect cellular fatty acid catabolism. Male Wistar rats (Rattus norvegicus) were fed a high-fat (25% w/w) diet including TTA (0.375%, w/w), fish oil (10%, w/w) or a combination of both. The rats were fed for 50 weeks, and although TTA and fish oil had hypotriglyceridemic effects in these animals, only TTA lowered the body weight gain compared to high fat control animals. Distinct dietary effects of fish oil and TTA were observed on plasma amino acid composition. Administration of TTA led to increased plasma levels of the majority of amino acids, except arginine and lysine, which were reduced. Fish oil however, increased plasma levels of only a few amino acids, and the combination showed an intermediate or TTA-dominated effect. On the other hand, TTA and fish oil additively reduced plasma levels of the L-carnitine precursor γ-butyrobetaine, as well as the carnitine esters acetylcarnitine, propionylcarnitine, valeryl/isovalerylcarnitine, and octanoylcarnitine. These data suggest that while both fish oil and TTA affect lipid metabolism, strong PPARα activation is required to obtain effects on amino acid plasma levels. TTA and fish oil may influence amino acid metabolism through different metabolic mechanisms.

Urinary excretion of kynurenine and tryptophan, cardiovascular events, and mortality after elective coronary angiography.

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.

Plasma dimethylglycine and risk of incident acute myocardial infarction in patients with stable angina pectoris.

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<0.001) when comparing plasma dimethylglycine quartile 4 to 1 in a Cox regression model adjusted for age, sex, and fasting status. Adjusting for traditional coronary artery disease risk factors only slightly modified the estimates, which were particularly strong among nonsmokers and among patients with serum triglyceride or apolipoprotein B100 levels ≤ median (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.