Publications by authors named "Ottar Nygård"

183 Publications

Assessment of Dietary Choline Intake, Contributing Food Items and Associations with One-carbon and Lipid Metabolites in Middle-aged and Elderly Adults: The Hordaland Health Study.

J Nutr 2021 Oct 13. Epub 2021 Oct 13.

Centre for Nutrition, Department of Clinical Science, University of Bergen, Bergen, Norway.

Background: Choline is an essential nutrient for humans and is involved in various physiological functions. Through its metabolite betaine, it is closely connected to the one-carbon metabolism and the fat-soluble choline form phosphatidylcholine is essential for very-low-density-lipoprotein synthesis and secretion in the liver connecting choline to the lipid metabolism. Dietary recommendations for choline are not available in the Nordic countries primarily due to data scarcity.

Objective: The aim of this study was to investigate the dietary intake of total choline and individual choline forms, dietary sources, and the association of total choline intake with circulating one-carbon metabolites and lipids.

Methods: We included 5746 participants in the Hordaland Health Study (HUSK), a survey including community-dwelling adults born in 1925-1927 (mean age 72 years, 55% women) and 1950-1951 (mean age 48 years, 57% women). Dietary data was obtained using a 169-item food frequency questionnaire and choline content was calculated using the USDA Database for Choline Content of Common Foods, release 2. Metabolites of the one-carbon and lipid metabolism were measured in a non-fasting blood sample obtained at baseline and association with total choline intake were assessed using polynomial splines.

Results: The geometric mean (95% prediction interval) energy-adjusted total choline intake was 260 (170, 389) mg/d with phosphatidylcholine being the main form (44%). The major food items providing dietary choline were eggs, low-fat milk, potatoes, and leafy vegetables. Dietary total choline was inversely associated with circulating concentrations of total homocysteine, glycine and serine and positively associated with choline, methionine, cystathionine, cysteine, trimethyllysine, trimethylamine-N-oxide and dimethylglycine. A weak association was observed between choline intake and serum lipids.

Conclusion: Phosphatidylcholine was the most consumed choline form in community-dwelling adults in Norway. Our findings suggest that choline intake is associated with the concentration of most metabolites involved in the one-carbon and lipid metabolism.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jn/nxab367DOI Listing
October 2021

Hepatic Energy Metabolism Underlying Differential Lipidomic Responses to High-Carbohydrate and High-Fat Diets in Male Wistar Rats.

J Nutr 2021 Sep;151(9):2610-2621

Department of Clinical Science, University of Bergen, Bergen, Norway.

Background: Low-carbohydrate diets are suggested to exert metabolic benefits by reducing circulating triacylglycerol (TG) concentrations, possibly by enhancing mitochondrial activity.

Objective: We aimed to elucidate mechanisms by which dietary carbohydrate and fat differentially affect hepatic and circulating TG, and how these mechanisms relate to fatty acid composition.

Methods: Six-week-old, ∼300 g male Wistar rats were fed a high-carbohydrate, low-fat [HC; 61.3% of energy (E%) carbohydrate] or a low-carbohydrate, high-fat (HF; 63.5 E% fat) diet for 4 wk. Parameters of lipid metabolism and mitochondrial function were measured in plasma and liver, with fatty acid composition (GC), high-energy phosphates (HPLC), carnitine metabolites (HPLC-MS/MS), and hepatic gene expression (qPCR) as main outcomes.

Results: In HC-fed rats, plasma TG was double and hepatic TG 27% of that in HF-fed rats. The proportion of oleic acid (18:1n-9) was 60% higher after HF vs. HC feeding while the proportion of palmitoleic acid (16:1n-7) and vaccenic acid (18:1n-7), and estimated activities of stearoyl-CoA desaturase, SCD-16 (16:1n-7/16:0), and de novo lipogenesis (16:0/18:2n-6) were 1.5-7.5-fold in HC vs. HF-fed rats. Accordingly, hepatic expression of fatty acid synthase (Fasn) and acetyl-CoA carboxylase (Acaca/Acc) was strongly upregulated after HC feeding, accompanied with 8-fold higher FAS activity and doubled ACC activity. There were no differences in expression of liver-specific biomarkers of mitochondrial biogenesis and activity (Cytc, Tfam, Cpt1, Cpt2, Ucp2, Hmgcs2); concentrations of ATP, AMP, and energy charge; plasma carnitine/acylcarnitine metabolites; or peroxisomal fatty acid oxidation.

Conclusions: In male Wistar rats, dietary carbohydrate was converted into specific fatty acids via hepatic lipogenesis, contributing to higher plasma TG and total fatty acids compared with high-fat feeding. In contrast, the high-fat, low-carbohydrate feeding increased hepatic fatty acid content, without affecting hepatic mitochondrial fatty acid oxidation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jn/nxab178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8417924PMC
September 2021

Primary cardiovascular risk prediction by LDL-cholesterol in Caucasian middle-aged and older adults: a joint analysis of three cohorts.

Eur J Prev Cardiol 2021 Jun 1. Epub 2021 Jun 1.

Zora Biosciences Oy, Tietotie 2C, 02150 Espoo, Finland.

Aims: Low-density lipoprotein cholesterol (LDL-C) is an established causal driver of atherosclerotic cardiovascular disease (ASCVD), but its performance and age-dependency as a biomarker for incident events and mortality arising from ASCVD is less clear. The aim was to determine the value of LDL-C as a susceptibility/risk biomarker for incident coronary heart disease (CHD), ASCVD, and stroke events and deaths, for the age groups <50 and ≥50 years.

Methods And Results: The performance of LDL-C was evaluated in three cohorts, FINRISK 2002 (n = 7709), HUSK (n = 5431), and ESTHER (n = 4559), by Cox proportional hazards models, C-statistics, and net reclassification index calculations. Additionally, the hazard ratios (HRs) for the three cohorts were pooled by meta-analysis. The most consistent association was observed for CHD [95% confidence interval (CI) for HRs per standard deviation ranging from 0.99 to 1.37], whereas the results were more modest for ASCVD (0.96-1.18) due to lack of association with stroke (0.77-1.24). The association and discriminatory value of LDL-C with all endpoints in FINRISK 2002 and HUSK were attenuated in subjects 50 years and older [HRs (95% CI) obtained from meta-analysis 1.11 (1.04-1.18) for CHD, 1.15 (1.02-1.29) for CHD death, 1.02 (0.98-1.06) for ASCVD, 1.12 (1.02-1.23) for ASCVD death, and 0.97 (0.89-1.05) for stroke].

Conclusion: In middle-aged and older adults, associations between LDL-C and all the studied cardiovascular endpoints were relatively weak, while LDL-C showed stronger association with rare events of pre-mature CHD or ASCVD death among middle-aged adults. The predictive performance of LDL-C also depends on the studied cardiovascular endpoint.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/eurjpc/zwab075DOI Listing
June 2021

Food Sources Contributing to Intake of Choline and Individual Choline Forms in a Norwegian Cohort of Patients With Stable Angina Pectoris.

Front Nutr 2021 14;8:676026. Epub 2021 May 14.

Centre for Nutrition, Department of Clinical Science, University of Bergen, Bergen, Norway.

Choline is an essential nutrient involved in a wide range of physiological functions. It occurs in water- and lipid-soluble forms in the body and diet. Foods with a known high choline content are eggs, beef, chicken, milk, fish, and selected plant foods. An adequate intake has been set in the US and Europe, however, not yet in the Nordic countries. A higher intake of lipid-soluble choline forms has been associated with increased risk of acute myocardial infarction, highlighting the need for knowledge about food sources of the individual choline forms. In general, little is known about the habitual intake and food sources of choline, and individual choline forms. Investigate foods contributing to the intake of total choline and individual choline forms. The study population consisted of 1,929 patients with stable angina pectoris from the Western Norway B Vitamin Intervention Trial. Dietary intake data was obtained through a 169-item food frequency questionnaire. Intake of total choline and individual choline forms was quantified using the USDA database, release 2. The geometric mean (95% prediction interval) total choline intake was 287 (182, 437) mg/d. Phosphatidylcholine accounted for 42.5% of total choline intake, followed by free choline (25.8%) and glycerophosphocholine (21.2%). Phosphocholine and sphingomyelin contributed 4.2 and 4.5%, respectively. The main dietary choline sources were eggs, milk, fresh vegetables, lean fish, and bread. In general, animal food sources were the most important contributors to choline intake. This study is, to the best of our knowledge, the first to assess the intake of all choline forms and their dietary sources in a European population. Most choline was consumed in the form of phosphatidylcholine and animal food sources contributed most to choline intake. There is a need for accurate estimates of the dietary intake of this essential nutrient to issue appropriate dietary recommendations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fnut.2021.676026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8160433PMC
May 2021

Changes in lipoprotein particle subclasses, standard lipids, and apolipoproteins after supplementation with n-3 or n-6 PUFAs in abdominal obesity: A randomized double-blind crossover study.

Clin Nutr 2021 05 3;40(5):2556-2575. Epub 2021 Apr 3.

Department of Heart Disease, Haukeland University Hospital, 5021 Bergen, Norway; Mohn Nutrition Research Laboratory, Department of Clinical Science, University of Bergen, 5020 Bergen, Norway. Electronic address:

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clnu.2021.03.040DOI Listing
May 2021

The Association of Meat Intake With All-Cause Mortality and Acute Myocardial Infarction Is Age-Dependent in Patients With Stable Angina Pectoris.

Front Nutr 2021 4;8:642612. Epub 2021 Mar 4.

Department of Clinical Science, Centre for Nutrition, University of Bergen, Bergen, Norway.

Red and processed meat intake have been associated with increased risk of morbidity and mortality, and a restricted intake is encouraged in patients with cardiovascular disease. However, evidence on the association between total meat intake and clinical outcomes in this patient group is lacking. To investigate the association between total meat intake and risk of all-cause mortality, acute myocardial infarction, cancer, and gastrointestinal cancer in patients with stable angina pectoris. We also investigated whether age modified these associations. This prospective cohort study consisted of 1,929 patients (80% male, mean age 62 years) with stable angina pectoris from the Western Norway B-Vitamin Intervention Trial. Dietary assessment was performed by the administration of a semi-quantitative food frequency questionnaire. Cox proportional hazards models were used to investigate the association between a relative increase in total meat intake and the outcomes of interest. The association per 50 g/1,000 kcal higher intake of total meat with morbidity and mortality were generally inconclusive but indicated an increased risk of acute myocardial infarction [HR: 1.26 (95% CI: 0.98, 1.61)] and gastrointestinal cancer [1.23 (0.70, 2.16)]. However, we observed a clear effect modification by age, where total meat intake was associated with an increased risk of mortality and acute myocardial infarction among younger individuals, but an attenuation, and even reversal of the risk association with increasing age. Our findings support the current dietary guidelines emphasizing a restricted meat intake in cardiovascular disease patients but highlights the need for further research on the association between meat intake and health outcomes in elderly populations. Future studies should investigate different types of meat separately in other CVD-cohorts, in different age-groups, as well as in the general population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fnut.2021.642612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969515PMC
March 2021

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

Eur J Prev Cardiol 2021 Mar 8. Epub 2021 Mar 8.

Mohn Nutrition Research Laboratory, Department of Clinical Sciences, University of Bergen, N-5021 Bergen, Norway.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/eurjpc/zwaa158DOI Listing
March 2021

Clinical risk scores identify more patients at risk for cardiovascular events within 30 days as compared to standard ACS risk criteria: the WESTCOR study.

Eur Heart J Acute Cardiovasc Care 2021 May;10(3):287-301

Department of Clinical Medicine, University of Bergen, Bergen, Norway.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ehjacc/zuaa016DOI Listing
May 2021

Plasma 3-hydroxyisobutyrate (3-HIB) and methylmalonic acid (MMA) are markers of hepatic mitochondrial fatty acid oxidation in male Wistar rats.

Biochim Biophys Acta Mol Cell Biol Lipids 2021 04 14;1866(4):158887. Epub 2021 Jan 14.

Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Heart Disease, Haukeland University Hospital, Bergen, Norway. Electronic address:

Objective: Discovery of specific markers that reflect altered hepatic fatty acid oxidation could help to detect an individual's risk of fatty liver, type 2 diabetes and cardiovascular disease at an early stage. Lipid and protein metabolism are intimately linked, but our understanding of this crosstalk remains limited.

Methods: In male Wistar rats, we used synthetic fatty acid analogues (3-thia fatty acids) as a tool to induce hepatic fatty acid oxidation and mitochondrial biogenesis, to gain new insight into the link between fatty acid oxidation, amino acid metabolism and TCA cycle-related intermediate metabolites in liver and plasma.

Results: Rats treated with 3-thia fatty acids had 3-fold higher hepatic, but not adipose and skeletal muscle, expression of the thioesterase 3-hydroxyisobutyryl-CoA hydrolase (Hibch), which controls the formation of 3-hydroxyisobutyrate (3-HIB) in the valine degradation pathway. Consequently, 3-thia fatty acid-stimulated hepatic fatty acid oxidation and ketogenesis was accompanied by decreased plasma 3-HIB and increased methylmalonic acid (MMA) concentrations further downstream in BCAA catabolism. The higher plasma MMA corresponded to higher MMA-CoA hydrolase activity and hepatic expression of GTP-specific succinyl-CoA synthase (Suclg2) and succinate dehydrogenase (Sdhb), and lower MMA-CoA mutase activity. Plasma 3-HIB correlated positively to plasma and hepatic concentrations of TAG, plasma total fatty acids, plasma NEFA and insulin/glucose ratio, while the reverse correlations were seen for MMA.

Conclusion: Our study provides new insight into TCA cycle-related metabolic changes associated with altered hepatic fatty acid flux, and identifies 3-HIB and MMA as novel circulating markers reflective of mitochondrial β-oxidation in male Wistar rats.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbalip.2021.158887DOI Listing
April 2021

Role of the Neutral Amino Acid Transporter SLC7A10 in Adipocyte Lipid Storage, Obesity, and Insulin Resistance.

Diabetes 2021 03 6;70(3):680-695. Epub 2021 Jan 6.

Mohn Nutrition Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, Norway

Elucidation of mechanisms that govern lipid storage, oxidative stress, and insulin resistance may lead to improved therapeutic options for type 2 diabetes and other obesity-related diseases. Here, we find that adipose expression of the small neutral amino acid transporter SLC7A10, also known as alanine-serine-cysteine transporter-1 (ASC-1), shows strong inverse correlates with visceral adiposity, insulin resistance, and adipocyte hypertrophy across multiple cohorts. Concordantly, loss of Slc7a10 function in zebrafish in vivo accelerates diet-induced body weight gain and adipocyte enlargement. Mechanistically, SLC7A10 inhibition in human and murine adipocytes decreases adipocyte serine uptake and total glutathione levels and promotes reactive oxygen species (ROS) generation. Conversely, SLC7A10 overexpression decreases ROS generation and increases mitochondrial respiratory capacity. RNA sequencing revealed consistent changes in gene expression between human adipocytes and zebrafish visceral adipose tissue following loss of SLC7A10, e.g., upregulation of (lipid storage) and downregulation of (lipid oxidation). Interestingly, ROS scavenger reduced lipid accumulation and attenuated the lipid-storing effect of SLC7A10 inhibition. These data uncover adipocyte SLC7A10 as a novel important regulator of adipocyte resilience to nutrient and oxidative stress, in part by enhancing glutathione levels and mitochondrial respiration, conducive to decreased ROS generation, lipid accumulation, adipocyte hypertrophy, insulin resistance, and type 2 diabetes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/db20-0096DOI Listing
March 2021

Cardiac Troponin Assays With Improved Analytical Quality: A Trade-Off Between Enhanced Diagnostic Performance and Reduced Long-Term Prognostic Value.

J Am Heart Assoc 2020 12 26;9(23):e017465. Epub 2020 Nov 26.

Department of Heart Disease Haukeland University Hospital Bergen Norway.

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 Diagnostics), and cTnI (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 assay and its diagnostic properties were compared with cTnT (European Society of Cardiology), cTnI, and 2 earlier cTnI 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 algorithms showed similar performance regardless of time from symptom onset, and area under the curve was significantly better than comparators. The cTnI 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 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/JAHA.120.017465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763786PMC
December 2020

Intake of carbohydrates and SFA and risk of CHD in middle-age adults: the Hordaland Health Study (HUSK).

Public Health Nutr 2020 Sep 10:1-15. Epub 2020 Sep 10.

Department of Global Public Health and Primary Care, University of Bergen, Årstadveien 17, 5009Bergen, Norway.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1017/S1368980020003043DOI Listing
September 2020

Association of dietary vitamin K and risk of coronary heart disease in middle-age adults: the Hordaland Health Study Cohort.

BMJ Open 2020 05 21;10(5):e035953. Epub 2020 May 21.

Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway.

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 = 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 = 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 = 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bmjopen-2019-035953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7247390PMC
May 2020

Systemic Cardiac Troponin T Associated With Incident Atrial Fibrillation Among Patients With Suspected Stable Angina Pectoris.

Am J Cardiol 2020 07 12;127:30-35. Epub 2020 Apr 12.

Department of Heart Disease, Haukeland University Hospital, Bergen, Norway; Department of Clinical Science, University of Bergen, Bergen, Norway.

Higher concentrations of cardiac troponin T are associated with coronary artery disease (CAD) and adverse cardiovascular prognosis. The relation with incident atrial fibrillation (AF) is less explored. We studied this association among 3,568 patients evaluated with coronary angiography for stable angina pectoris without previous history of AF. The prospective association between high-sensitivity cardiac troponin T (hs-cTnT) categories (≤3 ng/L; n = 1,694, 4-9; n = 1,085, 10 to 19; n = 614 and 20 to 30; n = 175) and incident AF and interactions with the extent of CAD were studied by Kaplan-Meier plots and Cox regression. Risk prediction improvements were assessed by receiver operating characteristic area under the curve (ROC-AUC) analyses. During median (25 to 75 percentile) 7.3 (6.3 to 8.6) years of follow-up 412 (11.5%) were diagnosed with AF. In a Cox model adjusted for age, gender, body mass index, hypertension, diabetes mellitus, smoking, estimated glomerular filtration rate, and left ventricular ejection fraction, hazard ratios (HRs) (95% confidence intervals [CIs]) were 1.53 (1.16 to 2.03), 2.03 (1.49 to 2.78), and 2.15 (1.40 to 3.31) when comparing the second, third, and fourth to the first hs-cTnT group, respectively (P for trend <0.000001). The strongest association between hs-cTnT levels and incident AF was found among patients without obstructive CAD (P = 0.024) and adding hs-cTnT to established AF risk factors improved risk classification slightly (ΔROC 0.006, p = 0.044). In conclusion, in patients with suspected stable angina higher levels of hs-cTnT predicted increased risk of incident AF. This was most pronounced in patients without obstructive CAD suggesting an association not mediated by coronary disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.amjcard.2020.03.036DOI Listing
July 2020

Hepatic steatosis induced in C57BL/6 mice by a non-ß oxidizable fatty acid analogue is associated with reduced plasma kynurenine metabolites and a modified hepatic NAD/NADH ratio.

Lipids Health Dis 2020 May 14;19(1):94. Epub 2020 May 14.

Department of Clinical Science, University of Bergen, Bergen, Norway.

Background: Non-alcoholic fatty liver disease is often associated with obesity, insulin resistance, dyslipidemia, and the metabolic syndrome in addition to mitochondrial dysfunction and nicotinamide adenine dinucleotide (NAD) deficiency. The aim of this study was to investigate how inhibition of mitochondrial fatty acid oxidation using the compound tetradecylthiopropionic acid (TTP) would affect hepatic triacylglycerol level and plasma levels of kynurenine (Kyn) metabolites and nicotinamide.

Methods: 12 C57BL/6 mice were fed a control diet, or an intervention diet supplemented with 0.9% (w/w) tetradecylthiopropionic acid for 14 days. Blood and liver samples were collected, enzyme activities and gene expression were analyzed in liver, in addition to fatty acid composition. Metabolites in the tryptophan/kynurenine pathway and total antioxidant status were measured in plasma.

Results: Dietary treatment with tetradecylthiopropionic acid for 2 weeks induced fatty liver accompanied by decreased mitochondrial fatty acid oxidation. The liver content of the oxidized form of NAD was increased, as well as the ratio of NAD/NADH, and these changes were associated by increased hepatic mRNA levels of NAD synthetase and nicotinamide mononucleotide adenyltransferase-3. The downstream metabolites of kynurenine were reduced in plasma whereas the plasma nicotinamide content was increased. Some effects on inflammation and oxidative stress was observed in the liver, while the plasma antioxidant capacity was increased. This was accompanied by a reduced plasma ratio of kynurenine/tryptophan. In addition, a significant decrease in the inflammation-related arachidonic fatty acid in liver was observed.

Conclusion: Fatty liver induced by short-time treatment with tetradecylthiopropionic acid decreased the levels of kynurenine metabolites but increased the plasma levels of NAD and nicotinamide. These changes are most likely not associated with increased inflammation and oxidative stress. Most probably the increase of NAD and nicotinamide are generated through the Preiss Handler pathway and/or salvage pathway and not through the de novo pathway. The take home message is that non-alcoholic fatty liver disease is associated with the metabolic syndrome in addition to mitochondrial dysfunction and nicotinamide adenine dinucleotide (NAD) deficiency. Inducing fatty liver in mice by inhibition of fatty acid oxidation resulted in a concomitant change in kynurenine metabolites increasing the plasma levels of nicotinamides and the hepatic NAD/NADH ratio, probably without affecting the de novo pathway of kynurenines.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12944-020-01271-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7227213PMC
May 2020

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

Int J Cardiol 2020 Oct 8;317:75-80. Epub 2020 May 8.

Haukeland University Hospital, Dept of Heart Disease, Bergen, Norway; University of Bergen, Dept of Clinical Science, Bergen, Norway.

Background/aim: Plasma total homocysteine (tHcy) is elevated in patients with persistent vs. paroxysmal atrial fibrillation (AF), and has been related to increased risk of new-onset AF. Homocysteine is degraded to cystathionine (Cysta) and cysteine (Cys). All three metabolites have been linked to potential proarrhythmic traits such as inflammation and atrial fibrosis. We evaluated the prospective association between these metabolites and new-onset AF among patients with suspected stable angina pectoris.

Methods: Information regarding AF was obtained by linking patient data to national health registries. Risk associations were explored by Cox regression and potential improvements in risk reclassification were calculated by the continuous net reclassification index (NRI > 0).

Results: At baseline, 3535 patients without any prior history of AF were included. During median follow-up of 7.4 years, 392 patients (10.2%) were registered with incident AF. Higher plasma tHcy and tCys were associated with increased risk of incident AF [age and gender adjusted HRs (95% CI) per 1 log transformed SD 1.23 (1.12-1.35) and 1.23 (1.11-1.38)]; multivariate adjustment yielded similar results. Plasma tHcy and tCys also improved reclassification of patients (NRI > 0 (95% CI)) for tHcy 0.118 (0.02-0.22) and tCys 0.107 (0.002-0.21). No association was seen between plasma Cysta and incident AF.

Conclusion: Plasma tHcy and tCys, but not Cysta, were associated with, and improved risk classification of, new-onset AF among patients with stable angina pectoris. Our results motivate further studies to explore the relationship between homocysteine metabolism and cardiac arrhythmias.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijcard.2020.05.010DOI Listing
October 2020

Plasma kynurenines and prognosis in patients with heart failure.

PLoS One 2020 10;15(1):e0227365. Epub 2020 Jan 10.

Department of Clinical Science, University of Bergen, Bergen, Norway.

Background: Metabolites of the kynurenine pathway (mKP) relate to important aspects of heart failure pathophysiology, such as inflammation, energy-homeostasis, apoptosis, and oxidative stress. We aimed to investigate whether mKP predict mortality in patients with heart failure.

Methods: The study included 202 patients with heart failure (73.8% with coronary artery disease (CAD)), propensity score matched to 384 controls without heart disease, and 807 controls with CAD (71%). All underwent coronary angiography and ventriculography at baseline. Plasma mKP, pyridoxal 5'phosphate (PLP) and CRP were measured at baseline. Case-control differences were assessed by logistic regression and survival by Cox regression, adjusted for age, gender, smoking, diabetes, ejection fraction, PLP, eGFR and CRP. Effect measures are reported per standard deviation increments.

Results: Higher plasma levels of kynurenine, 3- hydroxykynurenine (HK), quinolinic acid (QA), the kynurenine-tryptophan-ratio (KTR) and the ratio of HK to xanthurenic acid (HK/XA) were detected in heart failure compared to both control groups. The mortality rate per 1000 person-years was 55.5 in patients with heart failure, 14.6 in controls without heart disease and 22.2 in CAD controls. QA [HR 1.80, p = 0.013], HK [HR 1.77, p = 0.005], HK/XA [HR 1.67, p < 0.001] and KTR [HR 1.55, p = 0.009] were associated with increased mortality in patients with heart failure, while XA [HR 0.68-0.80, p = 0.013-0.037] were associated with lower mortality in all groups. HK and HK/XA had weak associations with increased mortality in CAD-controls.

Conclusion: Elevated plasma levels of mKP and metabolite ratios are associated with increased mortality, independent of CAD, in patients with heart failure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0227365PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953806PMC
April 2020

Short-term treatment with a peroxisome proliferator-activated receptor α agonist influences plasma one-carbon metabolites and B-vitamin status in rats.

PLoS One 2019 5;14(12):e0226069. Epub 2019 Dec 5.

Department of Clinical Science, University of Bergen, Bergen, Norway.

Introduction: Peroxisome proliferator-activated receptors (PPARs) have been suggested to be involved in the regulation of one-carbon metabolism. Previously we have reported effects on plasma concentrations of metabolites along these pathways as well as markers of B-vitamin status in rats following treatment with a pan-PPAR agonist. Here we aimed to investigate the effect on these metabolites after specific activation of the PPARα and PPARγ subtypes.

Methods: For a period of 12 days, Male Wistar rats (n = 20) were randomly allocated to receive treatment with the PPARα agonist WY-14.643 (n = 6), the PPARγ agonist rosiglitazone (n = 6) or placebo (n = 8). The animals were sacrificed under fasting conditions, and plasma concentration of metabolites were determined. Group differences were assessed by one-way ANOVA, and planned comparisons were performed for both active treatment groups towards the control group.

Results: Treatment with a PPARα agonist was associated with increased plasma concentrations of most biomarkers, with the most pronounced differences observed for betaine, dimethylglycine, glycine, nicotinamide, methylnicotinamide, pyridoxal and methylmalonic acid. Lower levels were observed for flavin mononucleotide. Fewer associations were observed after treatment with a PPARγ agonist, and the most notable was increased plasma serine.

Conclusion: Treatment with a PPARα agonist influenced plasma concentration of one-carbon metabolites and markers of B-vitamin status. This confirms previous findings, suggesting specific involvement of PPARα in the regulation of these metabolic pathways as well as the status of closely related B-vitamins.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0226069PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6894826PMC
March 2020

The Associations Between Cognitive Prognosis and Kynurenines Are Modified by the Apolipoprotein ε4 Allele Variant in Patients With Dementia.

Int J Tryptophan Res 2019 15;12:1178646919885637. Epub 2019 Nov 15.

Department of Clinical Science, University of Bergen, Bergen, Norway.

Background: The apolipoprotein E ε4 gene variant (APOEε4) confers considerable risk for dementia and affects neuroinflammation, brain metabolism, and synaptic function. The kynurenine pathway (KP) gives rise to neuroactive metabolites, which have inflammatory, redox, and excitotoxic effects in the brain.

Aim: To assess whether the presence of at least one APOEε4 allele modifies the association between kynurenines and the cognitive prognosis.

Methods: A total of 152 patients with sera for metabolite measurements and APOE genotype were included from the Dementia of Western Norway. The participants had mild Alzheimer disease and Lewy body dementia. Apolipoprotein E ε4 gene variant allele status was classified as one or more ε4 versus any other. Mini-Mental State Examination (MMSE) was measured at baseline and for 5 consecutive years. Mann-Whitney tests and linear mixed-effects models were used for statistical analysis.

Results: There were no significant differences in serum concentrations of tryptophan and kynurenine according to the presence or absence of APOEε4. High serum concentrations of kynurenic acid, quinolinic acid, and picolinic acid, and a higher kynurenine-to-tryptophan ratio, were all associated with more cognitive decline in patients without APOEε4 compared to those with the APOEε4 allele (-value of the interactions < .05).

Conclusions: Kynurenic acid, quinolinic acid, picolinic acid, and the kynurenine-to-tryptophan ratio were associated with a significant increase in cognitive decline when the APOEε4 variant was absent, whereas there was a relatively less decline when the APOEε4 variant was present.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1178646919885637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6859685PMC
November 2019

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

Biochimie 2020 Jun 7;173:68-75. Epub 2019 Nov 7.

Centre for Nutrition, Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Heart Disease, Haukeland University Hospital, Bergen, Norway.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biochi.2019.11.001DOI Listing
June 2020

Increased fatty acid oxidation and mitochondrial proliferation in liver are associated with increased plasma kynurenine metabolites and nicotinamide levels in normolipidemic and carnitine-depleted rats.

Biochim Biophys Acta Mol Cell Biol Lipids 2020 02 30;1865(2):158543. Epub 2019 Oct 30.

Department of Clinical Science, University of Bergen, 5020 Bergen, Norway; Department of Heart Disease, Haukeland University Hospital, 5021 Bergen, Norway. Electronic address:

Dysregulation of the tryptophan (Trp)-NAD pathway has been related to several pathological conditions, and the metabolites in this pathway are known to influence mitochondrial respiration and redox status. The aim of this project was to investigate if stimulation of beta-oxidation and mitochondrial proliferation by the mitochondrial-targeted compound 2-(tridec-12-yn-1-ylthio)acetic acid (1-triple TTA) would influence metabolites of the Trp-Kyn-NAD pathway. We wished to investigate how carnitine depletion by meldonium-treatment influenced these metabolites. After dietary treatment of male Wistar rats with 1-triple TTA for three weeks, increased hepatic mitochondrial- and peroxisomal fatty acid oxidation resulted. The plasma content of total carnitines decreased compared to control animals, whereas hepatic genes involved in CoA biosynthesis were upregulated by 1-triple TTA treatment. The plasma Trp level and individual metabolites in the kynurenine pathway were increased by 1-triple TTA, associated with decreased hepatic gene expression of indoleamine2,3-dioxygenase. 1-triple TTA treatment increased conversion of Trp to nicotinamide (Nam) as the plasma content of quinolinic acid, Nam and N1-methylnicotinamide (mNam) increased, accompanied with suppression of hepatic gene expression of α-amino-α-carboxymuconate-ε-semialdehyde decarboxylase. A positive correlation between mitochondrial fatty acid oxidation and Trp-derivatives was found. Almost identical results were obtained by 1-triple TTA in the presence of meldonium, which alone exerted minor effects. Moreover, the plasma Kyn:Trp ratio (KTR) correlated negatively to mitochondrial function. Whether increased flux through the Trp-NAD pathway increased redox status and lowered inflammation locally and systemically should be considered.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbalip.2019.158543DOI Listing
February 2020

Components of the choline oxidation pathway modify the association between the apolipoprotein ε4 gene variant and cognitive decline in patients with dementia.

Brain Res 2020 01 22;1726:146519. Epub 2019 Oct 22.

Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Internal Medicine, Haraldsplass Deaconess Hospital, Bergen, Norway. Electronic address:

Background: Metabolites involved in one-carbon metabolism (OCM) may predict cognitive prognosis in dementia. The link between OCM, apolipoprotein E (APOE), and DNA methylation creates a biologically plausible mechanism of interaction.

Aim: To assess OCM metabolites as predictors of 5-year cognitive prognosis in patients with mild dementia, and in subgroups defined by the APOEε4 allele variant.

Methods: We followed one-hundred and fifty-two patients with mild dementia (86 with Alzheimer's disease, 66 with Lewy body dementia, including 90 with at least one APOEε4 allele) for 5 years with annual Mini-Mental State Examinations (MMSE). Total homocysteine, methionine, choline, betaine, dimethylglycine, sarcosine, folate, cobalamin and pyridoxal 5'-phoshate were measured in serum at baseline. We used linear mixed models to assess metabolite-MMSE associations, including 3-way interactions between metabolites, time, and APOEε4. False-discovery rate adjusted p-values (Q-values) are reported.

Results: Metabolite concentrations were not different in patients with dementia according to the presence of APOEε4. Overall, serum concentration of total homocysteine was inversely associated with MMSE performance, while betaine was positively associated with MMSE (Q < 0.05), but neither was associated with MMSE decline. Serum concentrations of betaine, dimethylglycine and sarcosine, however, were associated with slower MMSE decline in patients with APOEε4, but with faster MMSE decline in patients without the allele (all 3-way interactions: Q < 0.05).

Conclusion: Components of the choline oxidation pathway are associated with a better cognitive prognosis in APOEε4 carriers and a worse cognitive prognosis in non-carriers. Further research investigating targeted metabolic interventions according to APOE allele status is warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.brainres.2019.146519DOI Listing
January 2020

Tryptophan catabolites as metabolic markers of vitamin B-6 status evaluated in cohorts of healthy adults and cardiovascular patients.

Am J Clin Nutr 2020 01;111(1):178-186

Department of Clinical Science, University of Bergen, Bergen, Norway.

Background: Vitamin B-6 status is routinely measured as pyridoxal 5'-phosphate (PLP) in plasma. Low concentrations of PLP are associated with rheumatic, cardiovascular, and neoplastic diseases. We have previously shown that vitamin B-6 status affects the kynurenine (Kyn) pathway of tryptophan (Trp) catabolism.

Objective: This study aimed to comprehensively evaluate the use of Kyns as potential markers of functional vitamin B-6 status across 2 large cohorts.

Methods: We measured circulating concentrations of the first 6 metabolites in the Trp catabolic pathway by LC-MS-MS in the community-based Hordaland Health Study (HUSK; n = 7017) and cardiovascular patient-based Western Norway Coronary Angiography Cohort (WECAC; n = 4161). Cross-sectional and longitudinal associations of plasma PLP with Kyns were estimated using linear and nonlinear regression-based methods.

Results: 3'-Hydroxykynurenine (HK), a substrate, and all 4 products formed directly by the PLP-dependent enzymes kynurenine transaminase and kynureninase contributed to the explanation of circulating PLP in multivariable-adjusted regression models. The construct HK:(kynurenic acid + xanthurenic acid + 3'-hydroxyanthranilic acid + anthranilic acid), termed HK ratio (HKr), was related to plasma PLP with standardized regression coefficients (95% CIs) of -0.47 (-0.49, -0.45) and -0.46 (-0.49, -0.43) in HUSK and WECAC, respectively. Across strata of cohort and sex, HKr was 1.3- to 2.7-fold more sensitive, but also 1.7- to 2.9-fold more specific to changes in PLP than a previously proposed marker, HK:xanthurenic acid. Notably, the association was strongest at PLP concentrations < ∼20 nmol/L, a recognized threshold for vitamin B-6 deficiency. Finally, PLP and HKr demonstrated highly sex-specific and corroborating associations with age.

Conclusions: The results demonstrate that by combining 5 metabolites in the Kyn pathway into a simple index, HKr, a sensitive and specific indicator of intracellular vitamin B-6 status is obtained. The data also underscore the merit of evaluating alterations in Kyn metabolism when investigating vitamin B-6 and health.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ajcn/nqz228DOI Listing
January 2020

A mitochondria-targeted fatty acid analogue influences hepatic glucose metabolism and reduces the plasma insulin/glucose ratio in male Wistar rats.

PLoS One 2019 24;14(9):e0222558. Epub 2019 Sep 24.

Department of Clinical Science, University of Bergen, Bergen, Norway.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0222558PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759202PMC
March 2020

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

Eur J Nutr 2020 Sep 9;59(6):2383-2393. Epub 2019 Sep 9.

Centre for Nutrition, Department of Clinical Science, University of Bergen, Haukelandsbakken, 5009, Bergen, Norway.

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 = 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00394-019-02086-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413901PMC
September 2020

Short-Term Activation of Peroxisome Proliferator-Activated Receptors and Induces Tissue-Specific Effects on Lipid Metabolism and Fatty Acid Composition in Male Wistar Rats.

PPAR Res 2019 12;2019:8047627. Epub 2019 Jun 12.

Department of Clinical Science, University of Bergen, Bergen, Norway.

Dietary fatty acids (FAs) affect certain metabolic routes, including pathways controlled by the peroxisome proliferator-activated receptors (PPARs), but tissue-specific effects are not well-defined. Thus, the aim was to compare the metabolic response in hepatic, adipose, and cardiac tissues after treatment with specific PPAR agonists. Male Wistar rats were randomized into three groups: a control group receiving placebo (n=8); a PPAR agonist group receiving WY-14,643 (n=6); and a PPAR agonist group receiving rosiglitazone (n=6) for 12 days. All animals received a low-fat standard chow diet and were given a daily dose of placebo or agonist orally. Lipids and FA methyl esters were measured in plasma, liver, and heart and gene expression was measured in liver and adipose tissue, while enzyme activities were measured in liver. Treatment with the PPAR agonist was associated with higher liver mass relative to body weight (liver index), lower plasma, and hepatic total cholesterol, as well as lower plasma carnitine and acylcarnitines, compared with control. In heart, PPAR activation leads to overall lower levels of free FAs and specific changes in certain FAs, compared with control. Furthermore, -oxidation in liver and the enzymatic activities of well-known PPAR targeted genes were higher following PPAR administration. Overall, rats treated with the PPAR agonist had higher hepatic saturated FAs (SFAs) and monounsaturated FAs (MUFAs) and lower n-6 and n-3 PUFAs, compared to control. Treatment with the PPAR agonist was associated with a lower liver index, lower plasma triglycerides (TAG) and phospholipids, and higher hepatic phospholipids, compared with control. PPAR target genes were increased specifically in adipose tissue. Moreover, lower total cardiac FAs and SFA and higher cardiac n-6 PUFA were also associated with PPAR activation. Altogether, there were characteristic effects of PPAR activation in liver and heart, as well as in plasma. PPAR effects were not only confined to adipose tissue, but specific effects were also seen in liver, heart, and plasma. In conclusion, short-term treatment with PPAR agonists induced tissue-specific effects on FA composition in liver and heart. Moreover, both PPAR and PPAR activation lowered plasma TAG and phospholipids, most likely through effects on liver and adipose tissue, respectively. In future studies we aim to reveal whether similar patterns can be found through diet-induced activation of specific pathways.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2019/8047627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594300PMC
June 2019

Aiming toWards Evidence baSed inTerpretation of Cardiac biOmarkers in patients pResenting with chest pain-the WESTCOR study: study design.

Scand Cardiovasc J 2019 Oct 1;53(5):280-285. Epub 2019 Jul 1.

Department of Clinical Science, University of Bergen , Bergen , Norway.

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. 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 ( = 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 ( = 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 ( = 750) will be included at Stavanger University Hospital. Prospective studies will be based on the merged cohorts. 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/14017431.2019.1634280DOI Listing
October 2019

Development and validation of a ceramide- and phospholipid-based cardiovascular risk estimation score for coronary artery disease patients.

Eur Heart J 2020 01;41(3):371-380

Zora Biosciences Oy, Tietotie 2C, 02150 Espoo, Finland.

Aims: Distinct ceramide lipids have been shown to predict the risk for cardiovascular disease (CVD) events, especially cardiovascular death. As phospholipids have also been linked with CVD risk, we investigated whether the combination of ceramides with phosphatidylcholines (PCs) would be synergistic in the prediction of CVD events in patients with atherosclerotic coronary heart disease in three independent cohort studies.

Methods And Results: Ceramides and PCs were analysed using liquid chromatography-mass spectrometry (LC-MS) in three studies: WECAC (The Western Norway Coronary Angiography Cohort) (N = 3789), LIPID (Long-Term Intervention with Pravastatin in Ischaemic Disease) trial (N = 5991), and KAROLA (Langzeiterfolge der KARdiOLogischen Anschlussheilbehandlung) (N = 1023). A simple risk score, based on the ceramides and PCs showing the best prognostic features, was developed in the WECAC study and validated in the two other cohorts. This score was highly significant in predicting CVD mortality [multiadjusted hazard ratios (HRs; 95% confidence interval) per standard deviation were 1.44 (1.28-1.63) in WECAC, 1.47 (1.34-1.61) in the LIPID trial, and 1.69 (1.31-2.17) in KAROLA]. In addition, a combination of the risk score with high-sensitivity troponin T increased the HRs to 1.63 (1.44-1.85) and 2.04 (1.57-2.64) in WECAC and KAROLA cohorts, respectively. The C-statistics in WECAC for the risk score combined with sex and age was 0.76 for CVD death. The ceramide-phospholipid risk score showed comparable and synergistic predictive performance with previously published CVD risk models for secondary prevention.

Conclusion: A simple ceramide- and phospholipid-based risk score can efficiently predict residual CVD event risk in patients with coronary artery disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/eurheartj/ehz387DOI Listing
January 2020

Using metabolic profiling and gene expression analyses to explore molecular effects of replacing saturated fat with polyunsaturated fat-a randomized controlled dietary intervention study.

Am J Clin Nutr 2019 05;109(5):1239-1250

Department of Nutrition, Institute for Basic Medical Sciences, University of Oslo, Blindern, Oslo, Norway.

Background: Replacing dietary saturated fatty acids (SFAs) with polyunsaturated fatty acids (PUFA) reduces the plasma low-density lipoprotein (LDL) cholesterol and subsequently the risk of cardiovascular disease. However, beyond changes in LDL cholesterol, we lack a complete understanding of the physiologic alterations that occur when improving dietary fat quality.

Objectives: The aim of this study was to gain knowledge of metabolic alterations paralleling improvements in the fat quality of the diet.

Methods: We recently conducted an 8-wk, double-blind, randomized controlled trial replacing SFAs with PUFAs in healthy subjects with moderate hypercholesterolemia (n = 99). In the present substudy, we performed comprehensive metabolic profiling with multiple platforms (both nuclear magnetic resonance- and mass spectrometry-based technology) (n = 99), and analyzed peripheral blood mononuclear cell gene expression (n = 95) by quantitative real-time polymerase chain reaction.

Results: A large number of lipoprotein subclasses, myristoylcarnitine and palmitoylcarnitine, and kynurenine were reduced when SFAs were replaced with PUFAs. In contrast, bile acids, proprotein convertase subtilisin/kexin type 9, acetate, and acetoacetate were increased by the intervention. Some amino acids were also altered by the intervention. The mRNA levels of LXRA and LDLR were increased, in addition to several liver X receptor α target genes and genes involved in inflammation, whereas the mRNA levels of UCP2 and PPARD were decreased in peripheral blood mononuclear cells after replacing SFAs with PUFAs. Partial least squares-discriminant analysis showed that the 30 most important variables that contributed to class separation spanned all classes of biomarkers, and was in accordance with the univariate analysis.

Conclusions: Applying metabolomics in randomized controlled dietary intervention trials has the potential to extend our knowledge of the biological and molecular effects of dietary fat quality. This study was registered at clinicaltrials.gov as NCT01679496.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ajcn/nqy356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6499508PMC
May 2019
-->