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Elevated plasma concentrations of several one-carbon metabolites are associated with increased CVD risk. Both diet-induced regulation and dietary content of one-carbon metabolites can influence circulating concentrations of these markers. We cross-sectionally analysed 1928 patients with suspected stable angina pectoris (geometric mean age 61), representing elevated CVD risk, to assess associations between dietary macronutrient composition (FFQ) and plasma one-carbon metabolites and related B-vitamin status markers (GC-MS/MS, LC-MS/MS or microbiological assay). Diet-metabolite associations were modelled on the continuous scale, adjusted for age, sex, BMI, smoking, alcohol and total energy intake. Average (geometric mean (95 % prediction interval)) intake was forty-nine (38, 63) energy percent (E%) from carbohydrate, thirty-one (22, 45) E% from fat and seventeen (12, 22) E% from protein. The strongest associations were seen for higher protein intake, i.e. with higher plasma pyridoxal 5'-phosphate (PLP) (% change (95 % CI) 3·1 (2·1, 4·1)), cobalamin (2·9 (2·1, 3·7)), riboflavin (2·4 (1·1, 3·7)) and folate (2·1 (1·2, 3·1)) and lower total homocysteine (tHcy) (-1·4 (-1·9, -0·9)) and methylmalonic acid (MMA) (-1·4 (-2·0, -0·8)). Substitution analyses replacing MUFA or PUFA with SFA demonstrated higher plasma concentrations of riboflavin (5·0 (0·9, 9·3) and 3·3 (1·1, 5·6)), tHcy (2·3 (0·7, 3·8) and 1·3 (0·5, 2·2)) and MMA (2·0 (0·2, 3·9) and 1·7 (0·7, 2·7)) and lower PLP (-2·5 (-5·3, 0·3) and -2·7 (-4·2, -1·2)). In conclusion, a higher protein intake and replacing saturated with MUFA and PUFA were associated with a more favourable metabolic phenotype regarding metabolites associated with CVD risk.

Metabolomics has been utilised in epidemiological studies to investigate biomarkers of nutritional status and metabolism in relation to non-communicable diseases. However, little is known about the effect of prandial status on several biomarker concentrations. Therefore, the aim of this intervention study was to investigate the effect of a standardised breakfast meal followed by food abstinence for 24 h on serum concentrations of amino acids, one-carbon metabolites and B-vitamin biomarkers. Thirty-four healthy subjects (eighteen males and sixteen females) aged 20-30 years were served a breakfast meal (∼500 kcal) after which they consumed only water for 24 h. Blood samples were drawn before and at thirteen standardised timepoints after the meal. Circulating concentrations of most amino acids and metabolites linked to one-carbon metabolism peaked within the first 3 h after the meal. The branched-chain amino acids steadily increased from 6 or 8 hours after the meal, while proline decreased in the same period. Homocysteine and cysteine concentrations immediately decreased after the meal but steadily increased from 3 and 4 hours until 24 h. FMN and riboflavin fluctuated immediately after the meal but increased from 6 h, while folate increased immediately after the meal and remained elevated during the 24 h. Our findings indicate that accurate reporting of time since last meal is crucial when investigating concentrations of certain amino acids and one-carbon metabolites. Our results suggest a need for caution when interpretating studies, which utilise such biomarkers, but do not strictly control for time since the last meal.

Altered hepatic mitochondrial fatty acid β-oxidation and associated tricarboxylic acid (TCA) cycle activity contributes to lifestyle-related diseases, and circulating biomarkers reflecting these changes could have disease prognostic value. This study aimed to determine hepatic and systemic changes in TCA-cycle-related metabolites upon the selective pharmacologic enhancement of mitochondrial fatty acid β-oxidation in the liver, and to elucidate the mechanisms and potential markers of hepatic mitochondrial activity. Male Wistar rats were treated with 3-thia fatty acids (e.g., tetradecylthioacetic acid (TTA)), which target mitochondrial biogenesis, mitochondrial fatty acid β-oxidation, and ketogenesis predominantly in the liver. Hepatic and plasma concentrations of TCA cycle intermediates and anaplerotic substrates (LC-MS/MS), plasma ketones (colorimetric assay), and acylcarnitines (HPLC-MS/MS), along with associated TCA-cycle-related gene expression (qPCR) and enzyme activities, were determined. TTA-induced hepatic fatty acid β-oxidation resulted in an increased ratio of plasma ketone bodies/nonesterified fatty acid (NEFA), lower plasma malonyl-CoA levels, and a higher ratio of plasma acetylcarnitine/palmitoylcarnitine (C2/C16). These changes were associated with decreased hepatic and increased plasma pyruvate concentrations, and increased plasma concentrations of succinate, malate, and 2-hydroxyglutarate. Expression of several genes encoding TCA cycle enzymes and the malate-oxoglutarate carrier ( Slc25a11 ), glutamate dehydrogenase ( Gdh ), and malic enzyme ( Mdh1 and Mdh2 ) were significantly increased. In conclusion, the induction of hepatic mitochondrial fatty acid β-oxidation by 3-thia fatty acids lowered hepatic pyruvate while increasing plasma pyruvate, as well as succinate, malate, and 2-hydroxyglutarate.

Background: Calcium channel blockers (CCBs) are used for the treatment of cardiovascular disease (CVD), including angina pectoris, and hypertension; however, the effect on survival remains uncertain. CCBs impair fibrinolysis and have been linked to elevated plasma homocysteine (Hcy), a CVD risk marker., Objective: We explored the association between CCB use and mortality in a large prospective cohort of patients with suspected stable angina pectoris (SAP), and potential effect modifications by Hcy-lowering B-vitamin treatment (folic acid, B 12 , and/or B 6 ) as 61.8% of the patients participated in a randomized placebo-controlled B-vitamin intervention trial., Methods: Patient baseline continuous characteristics according to CCB treatment were tested by linear regression. Hazard ratios (HRs) for mortality associated with CCB treatment, also according to B-vitamin intervention, were examined using Cox regression analysis. The multivariable model included CVD risk factors, medical histories, and the use of CVD medications., Results: A total of 3991 patients (71.5 % men) were included, of whom 907 were prescribed CCBs at discharge. During 10.3 years of median follow-up, 20.6% died and 8.9% from cardiovascular- and 11.7% from non-cardiovascular causes. Patients treated with CCBs had higher plasma Hcy, fibrinogen levels, and erythrocyte sedimentation rate (all P<0.001). Furthermore, CCB use was positively associated with mortality, also after multivariable adjustments (HRs [95% CIs]: 1.34 [1.15,1.57], 1.35 [1.08,1.70], and 1.33 [1.09,1.64] for total, CVD, and non-CVD death, respectively). Numerically stronger associations were observed among patients not treated with B-vitamins (HR [95% CI]: 1.54 [1.25, 1.88], 1.69 [1.25, 2.30], and 1.41 [1.06, 1.86] for total, CVD deaths, and non-CVD deaths, respectively), whereas no association was seen in patients treated with B-vitamins (HR [95% CI]: 1.15 [0.91, 1.46], 1.09 [0.76, 1.57], and 1.20 [0.88, 1.65])., Conclusions: In patients with suspected SAP, CCB treatment was associated with increased mortality risk primarily among patients not treated with B-vitamins., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Clinical studies on effects of marine-derived omega-3 (n-3) polyunsaturated fatty acids (PUFAs), mainly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and the plant-derived omega-6 (n-6) PUFA linoleic acid (LA) on lipoprotein-lipid components and glucose-insulin homeostasis have shown conflicting results, which may partly be explained by differential responses in females and males. However, we have lacked data on sexual dimorphism in the response of cardiometabolic risk markers following increased consumption of n-3 or n-6 PUFAs., Objective: To explore sex-specific responses after n-3 (EPA + DHA) or n-6 (LA) PUFA supplementation on circulating lipoprotein subfractions, standard lipids, apolipoproteins, fatty acids in red blood cell membranes, and markers of glycemic control/insulin sensitivity among people with abdominal obesity., Methods: This was a randomized double-blind crossover study with two 7-week intervention periods separated by a 9-week washout phase. Females ( n  = 16) were supplemented with 3 g/d of EPA + DHA (fish oil) or 15 g/d of LA (safflower oil), while males ( n  = 23) received a dose of 4 g/d of EPA + DHA or 20 g/d of LA. In fasting blood samples, we measured lipoprotein particle subclasses, standard lipids, apolipoproteins, fatty acid profiles, and markers of glycemic control/insulin sensitivity., Results: The between-sex difference in relative change scores was significant after n-3 for total high-density lipoproteins (females/males: -11%*/-3.3%, p  = 0.036; *: significant within-sex change), high-density lipoprotein particle size (+2.1%*/-0.1%, p  = 0.045), and arachidonic acid (-8.3%*/-12%*, p  = 0.012), and after n-6 for total (+37%*/+2.1%, p  = 0.041) and small very-low-density lipoproteins (+97%*/+14%, p  = 0.021), and lipoprotein (a) (-16%*/+0.1%, p  = 0.028). Circulating markers of glucose-insulin homeostasis differed significantly after n-3 for glucose (females/males: -2.1%/+3.9%*, p  = 0.029), insulin (-31%*/+16%, p  < 0.001), insulin C-peptide (-12%*/+13%*, p  = 0.001), homeostasis model assessment of insulin resistance index 2 (-12%*/+14%*, p  = 0.001) and insulin sensitivity index 2 (+14%*/-12%*, p  = 0.001), and quantitative insulin sensitivity check index (+4.9%*/-3.4%*, p  < 0.001)., Conclusion: We found sex-specific responses after high-dose n-3 (but not n-6) supplementation in circulating markers of glycemic control/insulin sensitivity, which improved in females but worsened in males. This may partly be related to the sex differences we observed in several components of the lipoprotein-lipid profile following the n-3 intervention., Clinical Trial Registration: https://clinicaltrials.gov/, identifier [NCT02647333]., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Laupsa-Borge, Grytten, Bohov, Bjørndal, Strand, Skorve, Nordrehaug, Berge, Rostrup, Mellgren, Dankel and Nygård.)

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., (© 2023 The Association for the Publication of the Journal of Internal Medicine.)

Aims: The association of dairy products with cardiovascular disease and mortality risk remains heavily debated. We aimed to investigate the association between intake of total dairy and dairy products and the risk of acute myocardial infarction (AMI), stroke, and cardiovascular and all-cause mortality., Methods and Results: We included 1929 patients (80% men, mean age 62 years) with stable angina pectoris from the Western Norway B-vitamin Intervention Trial. Dietary data were obtained via a 169-item food frequency questionnaire. Risk associations were estimated using Cox proportional hazard regression models adjusted for relevant covariates. Non-linear associations were explored visually. The mean (±SD) dairy intake in the study population was 169 ± 108 g/1000 kcal. Median follow-up times were 5.2, 7.8, and 14.1 years for stroke, AMI, and mortality, respectively. Higher intake of total dairy and milk were positively associated with stroke risk [HR (95% CI): 1.14 (1.02, 1.27) and 1.13 (1.02, 1.27), cardiovascular mortality 1.06 (1.00, 1.12) and 1.07 (1.01, 1.13)] and all-cause mortality [1.07 (1.03, 1.11) and 1.06 (1.03, 1.10)] per 50 g/1000 kcal. Higher cheese intake was inversely associated with AMI risk [0.92 (0.83, 1.02)] per 10 g/1000 kcal. Butter was associated with increased AMI risk [1.10 (0.97, 1.24)] and all-cause mortality [1.10 (1.00, 1.20) per 5 g/1000 kcal., Conclusion: Higher dairy and milk consumption were associated with increased risk of mortality and stroke. Cheese was associated with decreased, and butter with increased, risk of AMI. Dairy is a heterogenous food group with divergent health effects and dairy products should therefore be investigated individually., Competing Interests: Conflict of interest: The authors have no conflicts of interest to declare., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Physical activity (PA) influences sympathetic stimulation, platelet activation as well as vascular function, and has been associated with improved health outcomes in patients with coronary heart disease. β-blocker therapy reduces sympathetic activity and improves platelet and endothelial function. We investigated if β-blocker treatment modifies the association of self-reported PA with the risk of all-cause mortality., Methods: A total of 2284 patients undergoing elective coronary angiography for suspected stable angina pectoris (SAP) were studied. Using Cox modeling, we examined associations between PA (categorized as 'sedentary/inactive', 'low', 'moderate', and 'high') and all-cause mortality according to β-blocker therapy., Results: During a median follow-up of 10.3 years, 390 patients (17.1%) died. Higher PA was generally associated with a more favorable cardiovascular risk profile. Compared to the patients who were sedentary or inactive, the age and sex adjusted HRs (95% CI) for all-cause mortality were 0.89 (0.66-1.20), 0.73 (0.57-0.95) and 0.72 (0.55-0.95) in the low, moderate and high PA group, respectively. However, and notably, these risk estimates were 0.85 (0.60-1.20), 0.65 (0.47-0.89) and 0.58 (0.41-0.81) in β-blocker treated subjects vs. 1.00 (0.57-1.78), 0.96 (0.61-1.52) and 1.20 (0.74-1.95) in non-treated groups ( P interaction  = 0.018). The results were essentially similar in the multivariable adjusted models., Conclusions: In patients with suspected SAP, increased PA was associated with reduced mortality risk primarily in patients treated with β-blockers., Competing Interests: None declared., (© 2022 The Authors.)

Background: Acylcarnitines are essential for mitochondrial fatty acid oxidation. Earlier studies suggest that impaired energy metabolism may be implicated in the pathogenesis of microvascular angina. We explored metabolites from the carnitine pathway as predictors of cardiovascular disease (CVD) - and all-cause mortality among patients with non-obstructive coronary artery disease (NOCAD)., Methods: A total of 1046 patients with suspected stable coronary syndrome underwent coronary angiography during 2000-2004, with findings of NOCAD. Serum levels of 8 selected carnitine metabolites were analyzed through liquid chromatography tandem mass spectrometry. Associations with CVD- and all-cause mortality were assessed by multivariable Cox regression models., Results: Median age at inclusion was 57 years. 51.5% were men. During median (25th- 75th percentiles), 14.1 (13.2-15.4) years of follow-up, 5.7% of the participants died from CVD and the incidence of all-cause mortality was 17.3%. Serum acetyl, octanoyl- and palmitoylcarnitine predicted CVD mortality with multivariable HR and 95% CI (per SD increment log transformed) of 1.36 (1.01-1.83), 1.49 (1.15-1.93) and 2.07 (1.49-2.85), p ≤ 0.04, respectively. Higher serum acetyl- and palmitoylcarnitines were also associated with increased risk of all-cause mortality (HR (95% CI): 1.27 (1.01-1.50), and 1.51 (1.26-1.81), p ≤ 0.007. Baseline levels of the precursors trimethyllysine and ƴ-butyrobetaine, carnitine or the odd chained propionylcarnitine and (iso)valerylcarnitine were not associated with adverse outcomes., Conclusion: Elevated serum even-chained acylcarnitines predicted adverse long-term prognosis in NOCAD. The strongest risk estimates were observed for palmitoylcarnitine, which predicted both CVD- and all-cause mortality after extensive multivariable adjustments. Underlying pathomechanisms should be further elucidated., Competing Interests: The authors declare that there is no conflict of interest associated with this manuscript., (© 2022 The Authors.)

Objective: Limiting SFA intake may minimise the risk of CHD. However, such reduction often leads to increased intake of carbohydrates. We aimed to evaluate associations and the interplay of carbohydrate and SFA intake on CHD risk., Design: Prospective cohort study., Setting: We followed participants in the Hordaland Health Study, Norway from 1997-1999 through 2009. Information on carbohydrate and SFA intake was obtained from a FFQ and analysed as continuous and categorical (quartiles) variables. Multivariable Cox regression estimated hazard ratios (HR) and 95 % CI. Theoretical substitution analyses modelled the substitution of carbohydrates with other nutrients. CHD was defined as fatal or non-fatal CHD (ICD9 codes 410-414 and ICD10 codes I20-I25)., Participants: 2995 men and women, aged 46-49 years., Results: Adjusting for age, sex, energy intake, physical activity and smoking, SFA was associated with lower risk (HRQ4 v. Q1 0·44, 95 % CI 0·26, 0·76, Ptrend = 0·002). For carbohydrates, the opposite pattern was observed (HRQ4 v. Q1 2·10, 95 % CI 1·22, 3·63, Ptrend = 0·003). SFA from cheese was associated with lower CHD risk (HRQ4 v. Q1 0·44, 95 % CI 0·24, 0·83, Ptrend = 0·006), while there were no associations between SFA from other food items and CHD. A 5 E% substitution of carbohydrates with total fat, but not SFA, was associated with lower CHD risk (HR 0·75, 95 % CI 0·62, 0·90)., Conclusions: Higher intake of predominantly high glycaemic carbohydrates and lower intake of SFA, specifically lower intake from cheese, were associated with higher CHD risk. Substituting carbohydrates with total fat, but not SFA, was associated with significantly lower risk of CHD.

Aims: Blockade of β-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 β-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 β-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, β-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, β-blocker treatment was associated with improved survival primarily among patients with high serum vitamin A levels., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Troponin-based algorithms are made to identify myocardial infarctions (MIs) but adding either standard acute coronary syndrome (ACS) risk criteria or a clinical risk score may identify more patients eligible for early discharge and patients in need of urgent revascularization., Methods and Results: Post-hoc analysis of the WESTCOR study including 932 patients (mean 63 years, 61% male) with suspected NSTE-ACS. Serum samples were collected at 0, 3, and 8-12 h and high-sensitivity cTnT (Roche Diagnostics) and cTnI (Abbott Diagnostics) were analysed. The primary endpoint was MI, all-cause mortality, and unplanned revascularizations within 30 days. Secondary endpoint was non-ST-elevation myocardial infarction (NSTEMI) during index hospitalization. Two combinations were compared: troponin-based algorithms (ESC 0/3 h and the High-STEACS algorithm) and either ACS risk criteria recommended in the ESC guidelines, or one of eleven clinical risk scores, HEART, mHEART, CARE, GRACE, T-MACS, sT-MACS, TIMI, EDACS, sEDACS, Goldman, and Geleijnse-Sanchis. The prevalence of primary events was 21%. Patients ruled out for NSTEMI and regarded low risk of ACS according to ESC guidelines had 3.8-4.9% risk of an event, primarily unplanned revascularizations. Using HEART score instead of ACS risk criteria reduced the number of events to 2.2-2.7%, with maintained efficacy. The secondary endpoint was met by 13%. The troponin-based algorithms without evaluation of ACS risk missed three-index NSTEMIs with a negative predictive value (NPV) of 99.5% and 99.6%., Conclusion: Combining ESC 0/3 h or the High-STEACS algorithm with standardized clinical risk scores instead of ACS risk criteria halved the prevalence of rule-out patients in need of revascularization, with maintained efficacy., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background & Aims: Marine-derived omega-3 (n-3) polyunsaturated fatty acids (PUFAs), mainly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), lower circulating levels of triacylglycerols (TAGs), and the plant-derived omega-6 (n-6) PUFA linoleic acid (LA) may reduce cholesterol levels. Clinical studies on effects of these dietary or supplemental PUFAs on other blood fat fractions are few and have shown conflicting results. This study aimed to determine effects of high-dose supplemental n-3 (EPA + DHA) and n-6 (LA) PUFAs from high-quality oils on circulating lipoprotein subfractions and standard lipids (primary outcomes), as well as apolipoproteins, fatty acids, and glycemic control (secondary outcomes), in females and males with abdominal obesity., Methods: This was a randomized double-blind crossover study with two 7-wk intervention periods separated by a 9-wk washout phase. Females (n = 16) were supplemented with 3 g/d of EPA + DHA (TAG fish oil) or 15 g/d of LA (safflower oil), while males (n = 23) received a dose of 4 g/d of EPA + DHA or 20 g/d of LA. In fasting blood samples, we investigated lipoprotein particle subclasses by nuclear magnetic resonance spectroscopy, as well as standard lipids, apolipoproteins, fatty acid profiles, and glucose and insulin. Data were analyzed by linear mixed-effects modeling with 'subjects' as the random factor., Results: The difference between interventions in relative change scores was among the lipoprotein subfractions significant for total very-low-density lipoproteins (VLDLs) (n-3 vs. n-6: -38%∗ vs. +16%, p < 0.001; ∗: significant within-treatment change score), large VLDLs (-58%∗ vs. -0.91%, p < 0.001), small VLDLs (-57%∗ vs. +41%∗, p < 0.001), total low-density lipoproteins (LDLs) (+5.8%∗ vs. -4.3%∗, p = 0.002), large LDLs (+23%∗ vs. -2.1%, p = 0.004), total high-density lipoproteins (HDLs) (-6.0%∗ vs. +3.7%, p < 0.001), large HDLs (+11%∗ vs. -5.3%, p = 0.001), medium HDLs (-24%∗ vs. +6.2%, p = 0.030), and small HDLs (-9.9%∗ vs. +9.6%∗, p = 0.002), and among standard lipids for TAGs (-16%∗ vs. -2.6%, p = 0.014), non-esterified fatty acids (-19%∗ vs. +5.5%, p = 0.033), and total cholesterol (-0.28% vs. -4.4%∗, p = 0.042). A differential response in relative change scores was also found for apolipoprotein (apo)B (+0.40% vs. -6.0%∗, p = 0.008), apoA-II (-6.0%∗ vs. +1.5%, p = 0.001), apoC-II (-11%∗ vs. -1.7%, p = 0.025), and apoE (+3.3% vs. -3.8%, p = 0.028)., Conclusions: High-dose supplementation of high-quality oils with n-3 (EPA + DHA) or n-6 (LA) PUFAs was followed by reductions in primarily TAG- or cholesterol-related markers, respectively. The responses after both interventions point to changes in the lipoprotein-lipid-apolipoprotein profile that have been associated with reduced cardiometabolic risk, also among people with TAG or LDL-C levels within the normal range., Registration: Registered under ClinicalTrials.gov Identifier: NCT02647333., Clinical Trial Registration: Registered at https://clinicaltrials.gov/ct2/show/NCT02647333., Competing Interests: Conflict of interest All the authors declare to have no conflicts of interest., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background Cardiac troponin (cTn) permits early rule-out/rule-in of patients admitted with possible non-ST-segment-elevation myocardial infarction. In this study, we developed an admission and a 0/1 hour rule-out/rule-in algorithm for a troponin assay with measurable results in >99% of healthy individuals. We then compared its diagnostic and long-term prognostic properties with other protocols. Methods and Results Blood samples were collected at 0, 1, 3, and 8 to 12 hours from patients admitted with possible non-ST-segment-elevation myocardial infarction. cTnT (Roche Diagnostics), cTnI (Abbott) (Abbott Diagnostics), and cTnI (sgx) (Singulex Clarity System) were measured in 971 admission and 465 1-hour samples. An admission and a 0/1 hour rule-out/rule-in algorithm were developed for the cTnI (sgx) assay and its diagnostic properties were compared with cTnT ESC (European Society of Cardiology), cTnI (Abbott)ESC , and 2 earlier cTnI (sgx) algorithms. The prognostic composite end point was all-cause mortality and future nonfatal myocardial infarction during a median follow-up of 723 days. non-ST-segment-elevation myocardial infarction prevalence was 13%. The novel cTnI (sgx) algorithms showed similar performance regardless of time from symptom onset, and area under the curve was significantly better than comparators. The cTnI (sgx)0/1 hour algorithm classified 92% of patients to rule-in or rule-out compared with ≤78% of comparators. Patients allocated to rule-out by the prior published 0/1 hour algorithms had significantly fewer long-term events compared with the rule-in and observation groups. The novel cTnI (sgx)0/1 hour algorithm used a higher troponin baseline concentration for rule-out and did not allow for prognostication. Conclusions Increasingly sensitive troponin assays may improve identification of non-ST-segment-elevation myocardial infarction but could rule-out patients with subclinical chronic myocardial injury. Separate protocols for diagnosis and risk prediction seem appropriate.

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 (R 2  = 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.

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., Competing Interests: Declaration of competing interest No conflict of interest reported by any of the authors., (Copyright © 2019 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)

Objective: The role of vitamin K in the regulation of vascular calcification is established. However, the association of dietary vitamins K1 and K2 with risk of coronary heart disease (CHD) is inconclusive., Design: Prospective cohort study., Setting: We followed participants in the community-based Hordaland Health Study from 1997 - 1999 through 2009 to evaluate associations between intake of vitamin K and incident (new onset) CHD. Baseline diet was assessed by a past-year food frequency questionnaire. Energy-adjusted residuals of vitamin K1 and vitamin K2 intakes were categorised into quartiles., Participants: 2987 Norwegian men and women, age 46-49 years., Methods: Information on incident CHD events was obtained from the nationwide Cardiovascular Disease in Norway (CVDNOR) Project. Multivariable Cox regression estimated HRs and 95% CIs with test for linear trends across quartiles. Analyses were adjusted for age, sex, total energy intake, physical activity, smoking and education. A third model further adjusted K1 intake for energy-adjusted fibre and folate, while K2 intake was adjusted for energy-adjusted saturated fatty acids and calcium., Results: During a median follow-up time of 11 years, we documented 112 incident CHD cases. In the adjusted analyses, there was no association between intake of vitamin K1 and CHD (HR Q4vsQ1 = 0.92 (95% CI 0.54 to 1.57), p for trend 0.64), while there was a lower risk of CHD associated with higher intake of energy-adjusted vitamin K2 (HR Q4vsQ1 = 0.52 (0.29 to 0.94), p for trend 0.03). Further adjustment for potential dietary confounders did not materially change the association for K1, while the association for K2 was slightly attenuated (HR Q4vsQ1 = 0.58 (0.28 to 1.19))., Conclusions: A higher intake of vitamin K2 was associated with lower risk of CHD, while there was no association between intake of vitamin K1 and CHD., Trial Registration Number: NCT03013725., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives. The main aim of the Aiming toWards Evidence baSed inTerpretation of Cardiac biOmarkers in patients pResenting with chest pain (WESTCOR-study) (Clinical Trials number NCT02620202) is to improve diagnostic pathways for patients presenting to the Emergency department (ED) with acute chest pain. Design. The WESTCOR-study is a two center, cross-sectional and prospective observational study recruiting unselected patients presenting to the ED with suspected non-ST elevation acute coronary syndrome (NSTE-ACS). Patient inclusion started September 2015 and we plan to include 2250 patients, finishing in 2019. The final diagnosis will be adjudicated by two independent cardiologists based on all available information including serial high sensitivity cardiac troponin measurements, coronary angiography, coronary CT angiography and echocardiography. The study includes one derivation cohort ( N  = 985) that will be used to develop rule out/rule in algorithms for NSTEMI and NSTE-ACS (if possible) using novel troponin assays, and to validate established NSTEMI algorithms, with and without clinical scoring systems. The study further includes one subcohort ( n  = 500) where all patients are examined with coronary CT angiography independent of biomarker status, aiming to assess the associations between biomarkers and the extent and severity of coronary atherosclerosis. Finally, an external validation cohort ( N  = 750) will be included at Stavanger University Hospital. Prospective studies will be based on the merged cohorts. Conclusion. The WESTCOR study will provide new diagnostic algorithms for early inclusion and exclusion of NSTE-ACS and insights in the associations between cardiovascular biomarkers, CT-angiographic findings and short and long-term clinical outcomes.

A fatty acid analogue, 2-(tridec-12-yn-1-ylthio)acetic acid (1-triple TTA), was previously shown to have hypolipidemic effects in rats by targeting mitochondrial activity predominantly in liver. This study aimed to determine if 1-triple TTA could influence carbohydrate metabolism. Male Wistar rats were treated for three weeks with oral supplementation of 100 mg/kg body weight 1-triple TTA. Blood glucose and insulin levels, and liver carbohydrate metabolism gene expression and enzyme activities were determined. In addition, human myotubes and Huh7 liver cells were treated with 1-triple TTA, and glucose and fatty acid oxidation were determined. The level of plasma insulin was significantly reduced in 1-triple TTA-treated rats, resulting in a 32% reduction in the insulin/glucose ratio. The hepatic glucose and glycogen levels were lowered by 22% and 49%, respectively, compared to control. This was accompanied by lower hepatic gene expression of phosphenolpyruvate carboxykinase, the rate-limiting enzyme in gluconeogenesis, and Hnf4A, a regulator of gluconeogenesis. Gene expression of pyruvate kinase, catalysing the final step of glycolysis, was also reduced by 1-triple TTA. In addition, pyruvate dehydrogenase activity was reduced, accompanied by 10-15-fold increased gene expression of its regulator pyruvate dehydrogenase kinase 4 compared to control, suggesting reduced entry of pyruvate into the TCA cycle. Indeed, the NADPH-generating enzyme malic enzyme 1 (ME1) catalysing production of pyruvate from malate, was increased 13-fold at the gene expression level. Despite the decreased glycogen level, genes involved in glycogen synthesis were not affected in livers of 1-triple TTA treated rats. In contrast, the pentose phosphate pathway seemed to be increased as the hepatic gene expression of glucose-6-phosphate dehydrogenase (G6PD) was higher in 1-triple TTA treated rats compared to controls. In human Huh7 liver cells, but not in myotubes, 1-triple-TTA reduced glucose oxidation and induced fatty acid oxidation, in line with previous observations of increased hepatic mitochondrial palmitoyl-CoA oxidation in rats. Importantly, this work recognizes the liver as an important organ in glucose homeostasis. The mitochondrially targeted fatty acid analogue 1-triple TTA seemed to lower hepatic glucose and glycogen levels by inhibition of gluconeogenesis. This was also linked to a reduction in glucose oxidation accompanied by reduced PHD activity and stimulation of ME1 and G6PD, favouring a shift from glucose- to fatty acid oxidation. The reduced plasma insulin/glucose ratio indicate that 1-triple TTA may improve glucose tolerance in rats., Competing Interests: The authors have declared that no competing interests exist.

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., (© 2019 by the American Diabetes Association.)

Purpose: Fish is a source of various nutrients beneficial for bone health, but few studies have investigated the association between bone mineral density (BMD) and fish consumption. Thus, the aim was to investigate the relationship between total fish intake and BMD and between both lean and fatty fish intake and BMD., Method: These cross-sectional analyses include 4656 participants in the Hordaland Health Study, a community-based study conducted in 1997-1999. The study includes two birth cohorts of men and women from Hordaland county (Norway) born in 1950-1951 and 1925-1927. BMD was measured by dual-energy X-ray absorptiometry and dietary intake was obtained from a semi-quantitative food-frequency questionnaire., Results: The average total fish intake was 33 ± 18 g/1000 kcal and was primarily lean fish. Older women had significantly lower BMD than older men and middle-aged men and women. In older women, total and lean fish intake (50 g/1000 kcal) was significantly and positively associated with BMD also after multivariate adjustments (β-coefficient 0.018, p = 0.017 and 0.026, p = 0.021)., Conclusion: A high intake of fish, in particular lean fish, was positively associated with BMD in older women. No association between intake of fatty fish and BMD was found in either of the age and sex groups.

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., (Copyright © American Society for Nutrition 2019.)

Plasma concentrations of metabolites along the choline oxidation and tryptophan degradation pathways have been linked to lifestyle diseases and dietary habits. This study aimed to investigate how krill oil, a source of ω-3 polyunsaturated fatty acids (PUFAs) with a high phosphatidylcholine content, affected these parameters. The pilot study was conducted as a 28 days intervention in 17 healthy volunteers (18-36 years), who received a supplement of 4.5 g krill oil per day, providing 833 mg ω-3 PUFAs, and 1750 mg phosphatidylcholine. Krill oil supplementation increased fasting plasma choline (+28.4%, p < .001), betaine (+26.6%, p < .001), dimethylglycine (+33.7%, p < .001) and sarcosine (+16.8%, p < .001), whereas no statistically significant changes were seen for plasma glycine, serine, methionine, total homocysteine, cysteine, cystathionine, methionine sulfoxide, folate, cobalamin, B 2 -, B 3 -, and B 6 vitamers, tryptophan, kynurenines, nicotinamide, vitamin A and vitamin E. In summary, krill oil supplementation influenced choline metabolite levels, but not plasma metabolites of the tryptophan-kynurenine-nicotinamide pathways and vitamins. These observations should be confirmed in a placebo-controlled trial, including an ω-3 PUFA supplement without phospholipids to explore the potential additive effects of the different active ingredients.

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, p interaction  = 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.

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.

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 H 2 S 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., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

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., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: Obesity is associated with increased inflammation and insulin resistance. In conditions with chronic immune activation, low plasma vitamin B6-levels are described, as well as an increased kynurenine:tryptophan-ratio (KTR). We investigated circulating tryptophan, kynurenine and its metabolites, neopterin, B-vitamins, CRP, and HbA1c in individuals with obesity before and after bariatric surgery., Methods: This longitudinal study included 37 patients with severe obesity, scheduled for bariatric surgery. Blood samples were taken at inclusion and at three months and one year postoperatively., Results: We observed significant positive correlations between HbA1c and both 3-hydroxy-kynurenine and 3-hydroxyanthranilic acid at inclusion. After surgery, fasting glucose, HbA1C and triglycerides decreased, whereas HDL-cholesterol increased. Tryptophan, kynurenine and its metabolites, except for anthranilic acid, decreased during weight loss. The KTR and CRP decreased while vitamin B6 increased during the year following operation, indicating reduced inflammation (all p<0.05)., Conclusions: In patients with obesity subjected to bariatric surgery, levels of 3-hydroxykynurenine and 3-hydroxyanthranilic acid seemed to be positively correlated to impaired glucose tolerance. One year following surgery, plasma levels of the kynurenine metabolites were substantially decreased, along with a metabolic improvement. The relation of circulating kynurenine pathway metabolites with biomarkers of metabolic impairment in patients with obesity needs further evaluation.

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., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: An elevated circulating cystathionine concentration, which arises in part from insufficiencies of vitamin B-6, B-12, or folate, has been shown to be associated with cardiovascular disease (CVD) risk. Hydrogen sulfide (H 2 S) is a gasotransmitter involved in vasodilation, neuromodulation, and inflammation. Most endogenously produced H 2 S is formed by pyridoxal phosphate (PLP)-dependent enzymes by noncanonical reactions of the transsulfuration pathway that yield H 2 S concurrently form lanthionine and homolanthionine. Thus, plasma lanthionine and homolanthionine concentrations can provide relative information about H 2 S production in vivo. Objective: To determine the metabolic consequences of an elevated plasma cystathionine concentration in adults with stable angina pectoris (SAP), we conducted both targeted and untargeted metabolomic analyses. Methods: We conducted NMR and LC-mass spectrometry (MS) metabolomic analyses on a subset of 80 plasma samples from the Western Norway Coronary Angiography Cohort and selected, based on plasma cystathionine concentrations, a group with high cystathionine concentrations [1.32 ± 0.60 μmol/L (mean ± SD); n = 40] and a group with low cystathionine concentrations [0.137 ± 0.011 μmol/L (mean ± SD); n = 40]. Targeted and untargeted metabolomic analyses were performed and assessed with the use of Student's t tests corrected for multiple testing. Overall differences between the cystathionine groups were assessed by untargeted NMR and LC-MS metabolomic methods and evaluated by partial least squares discriminant analysis (PLS-DA) with significant discriminating metabolites identified with 99% confidence. Results: Subjects with high cystathionine concentrations had 75% higher plasma lanthionine concentrations (0.12 ± 0.044 μmol/L) than subjects with low cystathionine concentrations [0.032 ± 0.013 μmol/L ( P < 0.001)]. Although plasma homolanthionine concentrations were notably higher than lanthionine concentrations, they were not different between the groups ( P = 0.47). PLS-DA results showed that a high plasma cystathionine concentration in SAP was associated with higher glucose, branched-chain amino acids, and phenylalanine concentrations, lower kidney function, and lower glutathione and plasma PLP concentrations due to greater catabolism. The high-cystathionine group had a greater proportion of subjects in the postprandial state. Conclusion: These data suggest that metabolic perturbations consistent with higher CVD risk exist in SAP patients with elevated plasma cystathionine concentrations., Competing Interests: Author disclosures: BND, MAR, VL, FT, ID, ASE, TJG, ØM, PMU, OKN, and JFG, no conflicts of interest., (© 2017 American Society for Nutrition.)

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/m 2 and median (interquartile range) HbA 1c 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.

Background: Functional (metabolic) markers of B-vitamin status, including plasma total homocysteine (tHcy) for folate and plasma methylmalonic acid (MMA) for vitamin B-12, suffer from moderate sensitivity and poor specificity. Ratios of metabolites belonging to the same pathway may have better performance characteristics. Objective: We evaluated the ratios of tHcy to total cysteine (tCys; Hcy:Cys), tHcy to creatinine (Hcy:Cre), and tHcy to tCys to creatinine (Hcy:Cys:Cre) as functional markers of B-vitamin status represented by a summary score composed of folate, cobalamin, betaine, pyridoxal 5'-phosphate (PLP), and riboflavin concentrations measured in plasma. Methods: Cross-sectional data were obtained from a cohort of patients with stable angina pectoris (2994 men and 1167 women) aged 21-88 y. The relative contribution of the B-vitamin score, age, sex, smoking, body mass index, and markers of renal function and inflammation to the variance of the functional B-vitamin markers was calculated by using multiple linear regression. Results: Compared with tHcy alone, Hcy:Cys, Hcy:Cre, and Hcy:Cys:Cre all showed improved sensitivity and specificity for detecting plasma B-vitamin status. Improvements in overall performance ranged from 4-fold for Hcy:Cys to ∼8-fold for Hcy:Cys:Cre and were particularly strong in subjects with the common 5,10-methylenetetrahydrofolate reductase (MTHFR) 677CC genotype. Conclusions: Ratios of tHcy to tCys and/or creatinine showed a severalfold improvement over tHcy alone as functional markers of B-vitamin status in Norwegian coronary angiography screenees. The biological rationale for these ratios is discussed in terms of known properties of enzymes involved in the catabolism of homocysteine and synthesis of creatine and creatinine., Competing Interests: 2: Author disclosures: A Ulvik, S Hustad, A McCann, Ø Midttun, O Nygård, and PM Ueland, no conflicts of interest., (© 2017 American Society for Nutrition.)

Objectives: To study the importance of weight change with regard to mortality in older people., Design: Prospective cohort study., Participants: The cohort includes participants in the Hordaland Health Study, Norway, 1997-99 (N=2935, age 71-74 years) who had previously participated in a survey in 1992-93., Measurements: Participants with weight measured at both surveys were followed for mortality through 2012. Cox proportional hazards models were used to calculate risk of death according to changes in weight. Hazard ratios (HR) with 95% confidence intervals (CIs) for people with stable weight (± <5% weight change) were compared to people who lost (≥5%) or gained (≥5%) weight. Cox regression with penalized spline was used to evaluate the association between weight change (in kg) and mortality. Analyses were adjusted for age, sex, physical activity, smoking, diabetes, hypertension, and previous myocardial infarction or stroke. Participants with cancer were excluded., Results: Compared to those with stable weight, participants who lost ≥5% weight had an increased mortality risk (HR 1.59 [95% CI: 1.35-1.89]) while the group with weight gain ≥5% did not (HR 1.07 [95% CI 0.90-1.28]). Penalized spline identified those who lost more than about three kg or gained more than about 12 kg as having increased risk of death., Conclusion: Even a minor weight loss of ≥5% or >3 kg were significantly associated with increased risk of mortality. Thus, weight should be routinely measured in older adults., Competing Interests: The authors declare that they have no conflict of interest. Prof. Dierkes has nothing to disclose. Prof. Vollset has nothing to disclose. Prof. Nygård has nothing to disclose. Prof. Tell has nothing to disclose. Ph.d Vinknes has nothing to disclose. MD, Ph.d Sulo has nothing to disclose. BS.c Reinhard Seifert has nothing to disclose. MS.c Teresa Risan Haugsgjerd has nothing to disclose.

Objective: Preeclampsia is a complex heterogeneous disease commonly defined by new-onset hypertension and proteinuria in pregnancy. Women experiencing preeclampsia have increased risk for cardiovascular diseases (CVD) later in life. Preeclampsia and CVD share risk factors and pathophysiologic mechanisms, including dysregulated inflammation and raised blood pressure. Despite commonalities, little is known about the contribution of shared genes (pleiotropy) to these diseases. This study aimed to investigate whether genetic risk factors for hypertension or inflammation are pleiotropic by also being associated with preeclampsia., Methods: We genotyped 122 single nucleotide polymorphisms (SNPs) in women with preeclampsia (n = 1006) and nonpreeclamptic controls (n = 816) from the Norwegian HUNT Study. SNPs were chosen on the basis of previously reported associations with either nongestational hypertension or inflammation in genome-wide association studies. The SNPs were tested for association with preeclampsia in a multiple logistic regression model., Results: The minor (G) allele of the intronic SNP rs17367504 in the gene methylenetetrahydrofolate reductase (MTHFR) was associated with a protective effect on preeclampsia (odds ratio 0.65, 95% confidence interval 0.53-0.80) in the Norwegian cohort. This association did not replicate in an Australian preeclampsia case-control cohort (P = 0.68, odds ratio 1.05, 95% confidence interval 0.83-1.32, minor allele frequency = 0.15)., Conclusion: MTHFR is important for regulating transmethylation processes and is involved in regulation of folate metabolism. The G allele of rs17367504 has previously been shown to protect against nongestational hypertension. Our study suggests a novel association between this allele and reduced risk for preeclampsia. This is the first study associating the minor (G) allele of a SNP within the MTHFR gene with a protective effect on preeclampsia, and in doing so identifying a possible pleiotropic protective effect on preeclampsia and hypertension.

Background: Different aspects of dietary pattern, including macronutrient and food profiles, may affect visceral fat mass and metabolic syndrome., Objective: We hypothesized that consuming energy primarily from carbohydrate or fat in diets with similar food profiles would differentially affect the ability to reverse visceral adiposity and metabolic syndrome., Design: Forty-six men (aged 30-50 y) with body mass index (in kg/m 2 ) >29 and waist circumference >98 cm were randomly assigned to a very high-fat, low-carbohydrate (VHFLC; 73% of energy fat and 10% of energy carbohydrate) or low-fat, high-carbohydrate (LFHC; 30% of energy fat and 53% of energy carbohydrate) diet for 12 wk. The diets were equal in energy (8750 kJ/d), protein (17% of energy), and food profile, emphasizing low-processed, lower-glycemic foods. Fat mass was quantified with computed tomography imaging., Results: Recorded intake of carbohydrate and total and saturated fat in the LFHC and VHFLC groups were 51% and 11% of energy, 29% and 71% of energy, and 12% and 34% of energy, respectively, with no difference in protein and polyunsaturated fatty acids. Mean energy intake decreased by 22% and 14% in the LFHC and VHFLC groups. The diets similarly reduced waist circumference (11-13 cm), abdominal subcutaneous fat mass (1650-1850 cm 3 ), visceral fat mass (1350-1650 cm 3 ), and total body weight (11-12 kg). Both groups improved dyslipidemia, with reduced circulating triglycerides, but showed differential responses in total and low-density lipoprotein cholesterol (decreased in LFHC group only), and high-density lipoprotein cholesterol (increased in VHFLC group only). The groups showed similar reductions in insulin, insulin C-peptide, glycated hemoglobin, and homeostasis model assessment of insulin resistance. Notably, improvements in circulating metabolic markers in the VHFLC group mainly were observed first after 8 wk, in contrast to more acute and gradual effects in the LFHC group., Conclusions: Consuming energy primarily as carbohydrate or fat for 3 mo did not differentially influence visceral fat and metabolic syndrome in a low-processed, lower-glycemic dietary context. Our data do not support the idea that dietary fat per se promotes ectopic adiposity and cardiometabolic syndrome in humans. This study was registered at clinicaltrials.gov as NCT01750021., (© 2017 American Society for Nutrition.)

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 (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., (© 2016 American Heart Association, Inc.)

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 = 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, 1.23-1.81). A similar association was observed among patients allocated to treatment with vitamin B6 alone (HR: 1.53; 95% CI, 1.01-2.31), and an even stronger relationship was seen in patients treated with both vitamin B6 and folic acid/B12 (HR: 2.35; 95% CI, 1.55-3.57). However, no risk association between the MTHFD1 polymorphism and AMI was seen in patients treated with placebo (HR: 1.29; 95% CI, 0.86-1.93) or folic acid/B12 (1.17; 95% CI, 0.83-1.65)., 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., (Copyright © 2015 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. All rights reserved.)

Background: Glycine is an amino acid involved in antioxidative reactions, purine synthesis, and collagen formation. Several studies demonstrate inverse associations of glycine with obesity, hypertension, and diabetes mellitus. Recently, glycine-dependent reactions have also been linked to lipid metabolism and cholesterol transport. However, little evidence is available on the association between glycine and coronary heart disease. Therefore, we assessed the association between plasma glycine and acute myocardial infarction (AMI)., Methods and Results: A total of 4109 participants undergoing coronary angiography for suspected stable angina pectoris were studied. Cox regression was used to estimate the association between plasma glycine and AMI, obtained via linkage to the CVDNOR project. During a median follow-up of 7.4 years, 616 patients (15.0%) experienced an AMI. Plasma glycine was higher in women than in men and was associated with a more favorable baseline lipid profile and lower prevalence of obesity, hypertension, and diabetes mellitus (all P<0.001). After multivariate adjustment for traditional coronary heart disease risk factors, plasma glycine was inversely associated with risk of AMI (hazard ratio per SD: 0.89; 95% CI, 0.82-0.98; P=0.017). The inverse association was generally stronger in those with apolipoprotein B, low-density lipoprotein cholesterol, or apolipoprotein A-1 above the median (all Pinteraction≤0.037)., Conclusions: Plasma glycine was inversely associated with risk of AMI in patients with suspected stable angina pectoris. The associations were stronger in patients with apolipoprotein B, low-density lipoprotein cholesterol, or apolipoprotein A-1 levels above the median. These results motivate further studies to elucidate the relationship between glycine and lipid metabolism, in particular in relation to cholesterol transport and atherosclerosis., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00354081., (© 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Unlabelled: In the large community-based Hordaland Health Study, low plasma dimethylglycine was associated with low bone mineral density in both middle-aged and elderly subjects and to an increased risk of subsequent hip fracture among the elderly. These associations seemed to be particularly strong among subjects exposed to nicotine., Introduction: Dimethylglycine (DMG) is a product of the choline oxidation pathway and formed from betaine during the folate-independent remethylation of homocysteine (Hcy) to methionine. Elevated plasma DMG levels are associated with atherosclerotic cardiovascular disease and inflammation, which in turn are related to osteoporosis. High plasma total Hcy and low plasma choline are associated with low bone mineral density (BMD) and hip fractures, but the role of plasma DMG in bone health is unknown., Methods: We studied the associations of plasma DMG with BMD among 5315 participants (46-49 and 71-74 years old) and with hip fracture among 3310 participants (71-74 years old) enrolled in the Hordaland Health Study., Results: In age and sex-adjusted logistic regression models, subjects in the lowest versus highest DMG tertile were more likely to have low BMD (odds ratio [OR] 1.68, 95% confidence interval [CI] 1.43-1.99). The association was stronger in participants exposed compared to those unexposed to nicotine (OR 2.31, 95% CI 1.73-3.07 and OR 1.43, 95% CI 1.16-1.75, respectively, p interaction = 0.008). In the older cohort, Cox regression analyses adjusted for sex showed that low plasma DMG was associated with an increased risk of hip fracture (hazard ratio [HR] 1.70, 95% CI 1.28-2.26). A trend toward an even higher risk was found among women exposed to nicotine (HR 3.41, 95% CI 1.40-8.28)., Conclusion: Low plasma DMG was associated with low BMD and increased risk of hip fractures. A potential effect modification by nicotine exposure merits particular attention.

Background: Amount and type of dietary protein have been shown to influence blood lipids. The present study aimed to evaluate the effects of a water-soluble fraction of chicken protein (CP) on plasma and hepatic lipid metabolism in normolipidemic rats., Methods: Male Wistar rats were fed either a control diet with 20 % w/w casein as the protein source, or an experimental diet where casein was replaced with CP at 6, 14, or 20 % w/w for 4 weeks., Results: Rats fed CP had markedly reduced levels of triacylglycerols (TAG) and cholesterol in both plasma and liver, accompanied by stimulated hepatic mitochondrial fatty acid oxidation and carnitine palmitoyltransferase 2 activity in the 20 % CP group compared to the control group. In addition, reduced activities and gene expression of hepatic enzymes involved in lipogenesis were observed. The gene expression of sterol regulatory element-binding transcription factor 1 was reduced in the 20 % CP-fed rats, whereas gene expression of peroxisome proliferator-activated receptor alpha was increased. Moreover, 6, 14, and 20 % CP-fed rats had significantly increased free carnitine and acylcarnitine plasma levels compared to control rats. The plasma methionine/glycine and lysine/arginine ratios were reduced in 20 % CP-treated rats. The mRNA level of ATP-binding cassette 4 was increased in the 20 % CP group, accompanied by the increased level of plasma bile acids., Conclusions: The present data suggest that the hypotriglyceridemic property of a water-soluble fraction of CP is primarily due to effects on TAG synthesis and mitochondrial fatty acid oxidation. The cholesterol-lowering effect by CP may be linked to increased bile acid formation.

Background: There is little recent evidence on the impact of comorbidities and access to revascularisation procedures on educational inequalities in mortality after acute myocardial infarction (AMI). The aim of the study was to investigate educational inequalities in mortality among all patients hospitalised for an incident AMI during 2001-2009 in Norway., Methods: Data were obtained through the Cardiovascular Disease in Norway (CVDNOR) project. Incident AMI was defined as an AMI-hospitalisation without any AMI-events in the previous 7 years. Education was categorised as basic, upper secondary or tertiary (college/university). Cox regression was used to assess educational differences in 28-day and 29-365-day mortality after an incident AMI in terms of hazard ratios and relative index of inequality (RII). RII can be interpreted as the ratio in mortality between the 0 th and the 100th percentile of the education distribution., Results: 111 993 incident AMIs were included (39.4% women). Among patients aged 35-69, RIIs (95% CI) adjusted for age, sex and year were 1.86 (1.59-2.18) and 2.10 (1.69-2.59) for 28-day and 29-365-day mortality respectively. Among patients aged 70-94 the corresponding RIIs were 1.12 (1.06-1.30) and 1.28 (1.19-1.38). Educational inequalities in mortality were attenuated after adjustment for comorbidities and revascularisation, but were still significant. Educational inequalities did not decrease during 2001-2009., Conclusion: Educational inequalities in both 28-day and 29-365 day mortality were strong and persistent during 2001-2009. Further research is needed to investigate if these disparities are driven by inequalities in the severity of the AMI or by inequitable access to treatment and rehabilitation., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: Increasing differences in cardiovascular disease (CVD) mortality across levels of education have been reported in Norway. The aim of the study was to investigate educational inequalities in acute myocardial infarction (AMI) incidence and whether such inequalities have changed during the past decade using a nationwide longitudinal study design., Methods: Data on 141 332 incident (first) AMIs in Norway during 2001-2009 were obtained through the Cardiovascular Disease in Norway (CVDNOR) project. Educational inequalities in AMI incidence were assessed in terms of age-standardised incidence rates stratified on educational level, incidence rate ratios (IRR), relative index of inequality (RII) and slope index of inequality (SII). All calculations were conducted in four gender and age strata: Men and women aged 35-69 and 70-94 years., Results: AMI Incidence rates decreased during 2001-2009 for all educational levels except in women aged 35-69 among whom only those with basic education had a significant decrease. In all gender and age groups; those with the highest educational level had the lowest rates. The strongest relative difference was found among women aged 35-69, with IRR (95% CI) for basic versus tertiary education 3.04 (2.85-3.24)) and RII (95% CI) equal to 4.36 (4.03-4.71). The relative differences did not change during 2001-2009 in any of the four gender and age groups, but absolute inequalities measured as SII decreased among the oldest men and women., Conclusions: There are substantial educational inequalities in AMI incidence in Norway, especially for women aged 35-69. Relative inequalities did not change from 2001 to 2009.

A combination of high folate with low vitamin B12 plasma status has been associated with cognitive impairment in a population exposed to mandatory folic acid fortification. The objective of the present study was to examine the interactions between plasma concentrations of folate and vitamin B12 markers in relation to cognitive performance in Norwegian elderly who were unexposed to mandatory or voluntary folic acid fortification. Cognitive performance was assessed by six cognitive tests in 2203 individuals aged 72-74 years. A combined score was calculated using principal component analysis. The associations of folate concentrations, vitamin B12 markers (total vitamin B12, holotranscobalamin (holoTC) and methylmalonic acid (MMA)) and their interactions in relation to cognitive performance were evaluated by quantile regression and least-squares regression, adjusted for sex, education, apo-ɛ4 genotype, history of CVD/hypertension and creatinine. Cross-sectional analyses revealed an interaction (P= 0·009) between plasma concentrations of folate and vitamin B12 in relation to cognitive performance. Plasma vitamin B12 concentrations in the lowest quartile ( < 274 pmol/l) combined with plasma folate concentrations in the highest quartile (>18·5 nmol/l) were associated with a reduced risk of cognitive impairment compared with plasma concentrations in the middle quartiles of both vitamins (OR 0·22, 95 % CI 0·05, 0·92). The interaction between folate and holoTC or MMA in relation to cognitive performance was not significant. In conclusion, this large study population unexposed to mandatory folic acid fortification showed that plasma folate, but not plasma vitamin B12, was associated with cognitive performance. Among the elderly participants with vitamin B12 concentrations in the lower range, the association between plasma folate and cognitive performance was strongest.

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<0.001). In elderly women and men, heavy smokers had an increased risk of hip fracture compared to never smokers (hazard ratio = 3.31, 95% CI: 2.05, 5.35; p<0.001). In heavy smokers there was a tendency of a lower risk of hip fracture with higher percentage of fat mass. The deleterious effect of smoking on bone health is stronger in lean smokers than in smokers with high fat mass.

Choline, obtained from diet and formed by biosynthesis, is the immediate precursor of betaine. Animal studies suggest an impact of choline on bone metabolism. We examined the associations of plasma choline and betaine with bone mineral density (BMD), the risk of hip fractures, and possible effect-modification by nicotine exposure. The Hordaland Health Study (1998 to 2000) included 7074 women and men (ages 46 to 49 or 71 to 74 years). In 5315, BMD was measured. The oldest (n = 3311) were followed for hip fractures through 2009. Risk associations were studied by logistic and Cox regression by comparing the lowest and middle tertiles with the highest, as well as trends across tertiles of plasma choline and betaine. In analyses adjusted for sex and age, participants in the lowest (odds ratio [OR] = 2.00, 95% confidence interval [CI] 1.69-2.37) and middle (OR = 1.39, CI 1.17-1.66) tertiles of plasma choline had an increased risk of low BMD (lowest quintile) (p trend < 0.001). Separate analyses for sex and age groups revealed the strongest relations in elderly women (lowest tertile: OR = 2.84, CI 1.95-4.14; middle tertile: OR = 1.80, CI 1.22-2.67, p trend < 0.001), and highest OR among those in the lowest tertile who were exposed to nicotine (OR = 4.56, CI 1.87-11.11). Low plasma choline was also associated with an increased risk of hip fracture in elderly women and men (lowest tertile: hazard ratio [HR] = 1.45, CI 1.08-1.94; middle tertile: HR = 1.13, CI 0.83-1.54, p trend = 0.012). In elderly women, the HR for hip fracture was 1.90 (CI 1.32-2.73) and 1.36 (CI 0.92-1.99) (p trend < 0.001) for lowest and middle tertiles of choline, and the highest HR was found among women in the lowest tertile exposed to nicotine (HR = 2.68, CI 1.16-6.19). Plasma betaine was not related to BMD or hip fracture. Low plasma choline was associated with low BMD in both sexes and increased the risk of hip fracture in elderly women. These results should motivate further studies on choline, nicotine exposure, and bone metabolism., (© 2014 American Society for Bone and Mineral Research.)

Tetradecylthioacetic acid (TTA) is a hypolipidemic antioxidant with immunomodulating properties involving activation of peroxisome proliferator-activated receptors (PPARs) and proliferation of mitochondria. This study aimed to penetrate the effect of TTA on the development of atherosclerotic lesions in apolipoprotein (apo)-E(-/-) mice fed a high-fat diet containing 0.3% TTA for 12 weeks. These mice displayed a significantly less atherosclerotic development vs control. Plasma cholesterol was increased by TTA administration and triacylglycerol (TAG) levels in plasma and liver were decreased by TTA supplementation, the latter, probably due to increased mitochondrial fatty acid oxidation and reduced lipogenesis. TTA administration also changed the fatty acid composition in the heart, and the amount of arachidonic acid (ARA) and eicosapentaenoic acid (EPA) was reduced and increased, respectively. The heart mRNA expression of inducible nitric oxidase (NOS)-2 was decreased in TTA-treated mice, whereas the mRNA level of catalase was increased. Finally, reduced plasma levels of inflammatory mediators as IL-1α, IL-6, IL-17, TNF-α and IFN-γ were detected in TTA-treated mice. These data show that TTA reduces atherosclerosis in apoE(-/-) mice and modulates risk factors related to atherosclerotic disorders. TTA probably acts at both systemic and vascular levels in a manner independent of changes in plasma cholesterol, and triggers TAG catabolism through improved mitochondrial function.

The popularity of high-protein diets for weight reduction is immense. However, the potential benefits from altering the source of dietary protein rather than the amount is scarcely investigated. In the present study, we examined the effects of fish protein supplement on glucose and lipid metabolism in overweight adults. A total of thirty-four overweight adults were randomised to 8 weeks' supplementation with fish protein or placebo tablets (controls). The intake of fish protein supplement was 3 g/d for the first 4 weeks and 6 g/d for the last 4 weeks. In this study, 8 weeks of fish protein supplementation resulted in lower values of fasting glucose (P< 0·05), 2 h postprandial glucose (P< 0·05) and glucose-area under the curve (AUC) (five measurements over 2 h, P< 0·05) after fish protein supplementation compared to controls. Glucose-AUC was decreased after 8 weeks with fish protein supplement compared to baseline (P< 0·05), concomitant with increased 30 min and decreased 90 min and 2 h insulin C-peptide level (P< 0·05), and reduced LDL-cholesterol (P< 0·05). Body muscle % was increased (P< 0·05) and body fat % was reduced (P< 0·05) after 4 weeks' supplementation. Physical activity and energy and macronutrients intake did not change during the course of the study. In conclusion, short-term daily supplementation with a low dose of fish protein may have beneficial effects on blood levels of glucose and LDL-cholesterol as well as glucose tolerance and body composition in overweight adults. The long-term effects of fish protein supplementation is of interest in the context of using more fish as a protein source in the diet, and the effects of inclusion of fish in the diet of individuals with low glucose tolerance should be evaluated.

Objectives: The aim was to rank coronary heart disease (CHD) risk factors according to their importance in predicting CHD morbidity and mortality using a scale-independent statistical approach., Design: We studied 15 515 community-dwelling adults in a population-based cohort established during 1992-93 in Western Norway. Participants were 40-42 and 65-67 years old at baseline and were followed through 2006. Endpoints were non-fatal/fatal acute myocardial infarction (AMI) and CHD death. Each factor was rank transformed and scaled to the range 0-5 before estimation of Cox models. Hazard ratios (HR) may thus be interpreted as HR per quintile increment for each factor, and the magnitude of the HR was used to rank the risk factors according to strength., Results: Total cholesterol and triglycerides were important risk factors for both CHD death and non-fatal/fatal AMI only in the middle-aged group. Risk factors were generally stronger in the middle-aged, except total homocysteine which was significantly associated with CHD death in the oldest group only. The only significant difference between men and women was found for single living which was an important risk factor for non-fatal/fatal AMI in middle-aged women but not in middle-aged men., Conclusions: We have demonstrated a simple method for direct and scale-independent comparison of the strength of both categorical and continuous risk factors. The importance of individual risk factors differed substantially between the two age groups.

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 < 0.001) and anthranilic acid (P < 0.001) increased significantly, whereas neopterin decreased (P = 0.018)., Conclusions: The results of this study demonstrate altered levels of vitamin B6 and the KTR in PHPT patients, both of which may reflect cellular immune activation. These abnormalities should be considered in relation to the increased risk of CVD previously observed in patients with PHPT., (© 2012 The Association for the Publication of the Journal of Internal Medicine.)