Publications by authors named "Vegard Lysne"

27 Publications

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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.
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http://dx.doi.org/10.1093/jn/nxab367DOI Listing
October 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.
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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.
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http://dx.doi.org/10.3389/fnut.2021.676026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8160433PMC
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.
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http://dx.doi.org/10.3389/fnut.2021.642612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969515PMC
March 2021

Sex differences in transaortic flow rate and association with all-cause mortality in patients with severe aortic stenosis.

Eur Heart J Cardiovasc Imaging 2021 08;22(9):977-982

Department of Cardiology, Royal Brompton Hospital, London, UK.

Aims: It is not known whether transaortic flow rate (FR) in aortic stenosis (AS) differs between men and women, and whether the commonly used cut-off of 200 mL/s is prognostic in females. We aimed to explore sex differences in the determinants of FR, and determine the best sex-specific cut-offs for prediction of all-cause mortality.

Methods And Results: Between 2010 and 2017, a total of 1564 symptomatic patients (mean age 76 ± 13 years, 51% men) with severe AS were prospectively included. Mean follow-up was 35 ± 22 months. The prevalence of cardiovascular disease was significantly higher in men than women (63% vs. 42%, P < 0.001). Men had higher left ventricular mass and lower left ventricular ejection fraction compared to women (both P < 0.001). Men were more likely to undergo an aortic valve intervention (AVI) (54% vs. 45%, P = 0.001), while the death rates were similar (42.0% in men and 40.6% in women, P = 0.580). A total of 779 (49.8%) patients underwent an AVI in which 145 (18.6%) died. In a multivariate Cox regression analysis, each 10 mL/s decrease in FR was associated with a 7% increase in hazard ratio (HR) for all-cause mortality (HR 1.07; 95% CI 1.03-1.11, P < 0.001). The best cut-off value of FR for prediction of all-cause mortality was 179 mL/s in women and 209 mL/s in men.

Conclusion: Transaortic FR was lower in women than men. In the group undergoing AVI, lower FR was associated with increased risk of all-cause mortality, and the optimal cut-off for prediction of all-cause mortality was lower in women than men.
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http://dx.doi.org/10.1093/ehjci/jeab045DOI Listing
August 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.
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http://dx.doi.org/10.1093/eurjpc/zwaa158DOI Listing
March 2021

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

The tricuspid annular plane systolic excursion to systolic pulmonary artery pressure index: Association with all-cause mortality in patients with moderate or severe tricuspid regurgitation.

Int J Cardiol 2020 Oct 5;317:176-180. Epub 2020 Jun 5.

Cardiothoracic Centre, Guy's & St Thomas' NHS Foundation Trust, London, United Kingdom.

Background: In patients with significant tricuspid regurgitation (TR) the conventional markers for the assessment of right ventricular (RV) systolic function may be less accurate. Tricuspid annular plane systolic excursion (TAPSE) indexed to systolic pulmonary artery pressure (SPAP) (TAPSE/SPAP) may be prognostically useful in pulmonary hypertension and left ventricular dysfunction. Our aim was to explore its use in patients with moderate or severe TR.

Methods: A total of 209 patients (72 ± 14 years, 56% women) with moderate (n = 123) or severe (n = 86) TR (primary in 6% and secondary in 94%) were followed up for a median of 80 months (mean 70 ± 33 months). The clinical correlates of TAPSE/SPAP index and association with all-cause mortality were assessed.

Results: The TAPSE/SPAP index was inversely correlated with all-cause mortality with an optimal threshold of 0.49 mm/mmHg. A low index was found in 139 (68%) patients. In a multivariate Cox regression analysis adjusted for age, smoking, coronary artery disease, left ventricular ejection fraction, right atrium area and mitral valve replacement, low TAPSE/SPAP index was associated with significantly higher hazard ratio of all-cause mortality (HR: 2.07; 95% CI 1.32-3.27, p = .002). Age, coronary artery disease, left ventricular ejection fraction and right atrium area were other independent predictors of all-cause mortality.

Conclusion: The TAPSE/SPAP index, reflecting RV systolic function in the longitudinal axis corrected for force generating by the RV is a powerful predictor of all-cause mortality in patients with moderate or severe TR.
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http://dx.doi.org/10.1016/j.ijcard.2020.05.093DOI Listing
October 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.
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http://dx.doi.org/10.1136/bmjopen-2019-035953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7247390PMC
May 2020

Lipid parameters and vitamin A modify cardiovascular risk prediction by plasma neopterin.

Heart 2020 07 12;106(14):1073-1079. Epub 2020 May 12.

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

Objectives: Oxidised cholesterol metabolites are linked to increased production of the active vitamin A (Vit-A) form and monocyte/macrophage activation, which may be reflected by neopterin, a marker of both interferon-γ-mediated immune activation and coronary artery disease risk. We examined the influence of serum lipid parameters and Vit-A on the risk association between neopterin and incident acute myocardial infarction (AMI).

Methods: We included 4130 patients with suspected stable angina pectoris (SAP), of whom 80% received lipid-lowering treatment with statins. Risk associations between plasma neopterin and AMI are given as HRs per SD increase in log-transformed neopterin.

Results: During a median follow-up of 7.5 years, 530 (12.8%) patients experienced an AMI. In age-adjusted and sex-adjusted analysis, plasma neopterin was positively associated with incident AMI (HR (95% CI) per SD: 1.26 (1.17 to 1.35)). However, the estimates were most pronounced in patients with serum low-density lipoprotein cholesterol (LDL-C) or apolipoprotein (apo) B100 below-median (HR (95% CI) per SD: 1.35 (1.24 to 1.48) and 1.42 (1.27 to 1.58), respectively; both p ≤0.03). We also observed a particularly strong risk association in those with above-median Vit-A (HR (95% CI) per SD: 1.32 (1.21 to 1.44); p=0.03). The estimates were slightly modified after multivariable adjustment.

Conclusions: In patients with suspected SAP, the majority of whom receiving statin therapy, high plasma neopterin was associated with increased risk of AMI particularly among those with low LDL-C and apoB100 or high Vit-A levels. The particularly strong relationship of plasma neopterin with residual cardiovascular risk in patients with low lipid levels should be further investigated.
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http://dx.doi.org/10.1136/heartjnl-2019-316165DOI Listing
July 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.
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http://dx.doi.org/10.1016/j.ijcard.2020.05.010DOI Listing
October 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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0226069PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6894826PMC
March 2020

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.
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http://dx.doi.org/10.1016/j.biochi.2019.11.001DOI Listing
June 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.
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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.
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http://dx.doi.org/10.1155/2019/8047627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594300PMC
June 2019

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

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

Am J Clin Nutr 2019 06;109(6):1546-1554

Department of Clinical Science, KG Jebsen Centre for Diabetes Research, University of Bergen, Bergen, Norway.

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.
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http://dx.doi.org/10.1093/ajcn/nqy391DOI Listing
June 2019

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

J Am Heart Assoc 2018 09;7(17):e008824

1 Department of Clinical Science University of Bergen Norway.

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.
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http://dx.doi.org/10.1161/JAHA.118.008824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6201441PMC
September 2018

Plasma choline, homocysteine and vitamin status in healthy adults supplemented with krill oil: a pilot study.

Scand J Clin Lab Invest 2018 Nov - Dec;78(7-8):527-532. Epub 2018 Sep 27.

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

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-, B-, and B 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.
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http://dx.doi.org/10.1080/00365513.2018.1512716DOI Listing
April 2019

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

Atherosclerosis 2018 05 23;272:175-181. Epub 2018 Mar 23.

Department of Clinical Science, University of Bergen, 5021, Bergen, Norway; KG Jebsen Center for Diabetes Research, University of Bergen, 5009, Bergen, Norway; Department of Heart Disease, Haukeland University Hospital, 5021, Bergen, Norway.

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.
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http://dx.doi.org/10.1016/j.atherosclerosis.2018.03.038DOI Listing
May 2018

Expanding the Utilization of Formalin-Fixed, Paraffin-Embedded Archives: Feasibility of miR-Seq for Disease Exploration and Biomarker Development from Biopsies with Clear Cell Renal Cell Carcinoma.

Int J Mol Sci 2018 Mar 10;19(3). Epub 2018 Mar 10.

Department of Clinical Medicine, University of Bergen, 5021 Bergen, Norway.

Novel predictive tools for clear cell renal cell carcinoma (ccRCC) are urgently needed. MicroRNAs (miRNAs) have been increasingly investigated for their predictive value, and formalin-fixed paraffin-embedded biopsy archives may potentially be a valuable source of miRNA sequencing material, as they remain an underused resource. Core biopsies of both cancerous and adjacent normal tissues were obtained from patients ( = 12) undergoing nephrectomy. After small RNA-seq, several analyses were performed, including classifier evaluation, obesity-related inquiries, survival analysis using publicly available datasets, comparisons to the current literature and ingenuity pathway analyses. In a comparison of tumour vs. normal, 182 miRNAs were found with significant differential expression; miR-155 was of particular interest as it classified all ccRCC samples correctly and correlated well with tumour size (² = 0.83); miR-155 also predicted poor survival with hazard ratios of 2.58 and 1.81 in two different TCGA (The Cancer Genome Atlas) datasets in a univariate model. However, in a multivariate Cox regression analysis including age, sex, cancer stage and histological grade, miR-155 was not a statistically significant survival predictor. In conclusion, formalin-fixed paraffin-embedded biopsy tissues are a viable source of miRNA-sequencing material. Our results further support a role for miR-155 as a promising cancer classifier and potentially as a therapeutic target in ccRCC that merits further investigation.
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http://dx.doi.org/10.3390/ijms19030803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5877664PMC
March 2018

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

J Clin Endocrinol Metab 2018 03;103(3):1033-1041

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

Context: Carnitine and its metabolites are centrally involved in fatty acid metabolism. Although elevated circulating concentrations have been observed in obesity and insulin resistance, prospective studies examining whether these metabolites are associated with incident type 2 diabetes mellitus (T2D) are sparse.

Objective: We performed a comprehensive evaluation of metabolites along the carnitine pathway relative to incident T2D.

Design: A total of 2519 patients (73.1% men) with coronary artery disease, but without T2D, were followed for median 7.7 years until the end of 2009, during which 173 (6.9%) new cases of T2D were identified. Serum levels of free carnitine, its precursors trimethyllysine (TML) and γ-butyrobetaine, and the esters acetyl-, propionyl-, (iso)valeryl-, octanoyl-, and palmitoylcarnitine were measured by liquid chromatography/tandem mass spectrometry. Risk associations were explored by logistic regression and reported per (log-transformed) standard deviation increment.

Results: Median age at inclusion was 62 years and median body mass index (BMI) 26.0 kg/m2. In models adjusted for age, sex, fasting status, BMI, estimated glomerular filtration rate, glycated hemoglobin A1c, triglyceride and high-density lipoprotein cholesterol levels, and study center, serum levels of TML and palmitoylcarnitine associated positively [odds ratio (95% confidence interval), 1.22 (1.04 to 1.43) and 1.24 (1.04 to 1.49), respectively], whereas γ-butyrobetaine associated negatively [odds ratio (95% confidence interval) 0.81 (0.66 to 0.98)] with T2D risk.

Conclusion: Serum levels of TML, γ-butyrobetaine, and the long-chained palmitoylcarnitine predict long-term risk of T2D independently of traditional risk factors, possibly reflecting dysfunctional fatty acid metabolism in patients susceptible to T2D development.
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http://dx.doi.org/10.1210/jc.2017-02139DOI Listing
March 2018

Corrigendum: Biomarkers and Algorithms for the Diagnosis of Vitamin B Deficiency.

Front Mol Biosci 2017 8;4:53. Epub 2017 Aug 8.

Laboratory of Clinical Biochemistry and Metabolism, Department for Pediatrics, Medical Center, University of FreiburgFreiburg, Germany.

[This corrects the article on p. 27 in vol. 3, PMID: 27446930.].
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http://dx.doi.org/10.3389/fmolb.2017.00053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5550675PMC
August 2017

Metabolomic Evaluation of the Consequences of Plasma Cystathionine Elevation in Adults with Stable Angina Pectoris.

J Nutr 2017 09 9;147(9):1658-1668. Epub 2017 Aug 9.

Departments of Food Science and Human Nutrition and

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 (HS) is a gasotransmitter involved in vasodilation, neuromodulation, and inflammation. Most endogenously produced HS is formed by pyridoxal phosphate (PLP)-dependent enzymes by noncanonical reactions of the transsulfuration pathway that yield HS concurrently form lanthionine and homolanthionine. Thus, plasma lanthionine and homolanthionine concentrations can provide relative information about HS production in vivo. 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. 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); = 40] and a group with low cystathionine concentrations [0.137 ± 0.011 μmol/L (mean ± SD); = 40]. Targeted and untargeted metabolomic analyses were performed and assessed with the use of Student's 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. 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 ( < 0.001)]. Although plasma homolanthionine concentrations were notably higher than lanthionine concentrations, they were not different between the groups ( = 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. These data suggest that metabolic perturbations consistent with higher CVD risk exist in SAP patients with elevated plasma cystathionine concentrations.
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http://dx.doi.org/10.3945/jn.117.254029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5572496PMC
September 2017

Biomarkers and Algorithms for the Diagnosis of Vitamin B12 Deficiency.

Front Mol Biosci 2016 27;3:27. Epub 2016 Jun 27.

Laboratory of Clinical Biochemistry and Metabolism, Department for Pediatrics, Medical Center, University of Freiburg Freiburg, Germany.

Vitamin B12 (cobalamin, Cbl, B12) is an indispensable water-soluble micronutrient that serves as a coenzyme for cytosolic methionine synthase (MS) and mitochondrial methylmalonyl-CoA mutase (MCM). Deficiency of Cbl, whether nutritional or due to inborn errors of Cbl metabolism, inactivate MS and MCM leading to the accumulation of homocysteine (Hcy) and methylmalonic acid (MMA), respectively. In conjunction with total B12 and its bioactive protein-bound form, holo-transcobalamin (holo-TC), Hcy, and MMA are the preferred serum biomarkers utilized to determine B12 status. Clinically, vitamin B12 deficiency leads to neurological deterioration and megaloblastic anemia, and, if left untreated, to death. Subclinical vitamin B12 deficiency (usually defined as a total serum B12 of <200 pmol/L) presents asymptomatically or with rather subtle generic symptoms that oftentimes are mistakenly ascribed to unrelated disorders. Numerous studies have now established that serum vitamin B12 has limited diagnostic value as a stand-alone marker. Low serum levels of vitamin B12 not always represent deficiency, and likewise, severe functional deficiency of the micronutrient has been documented in the presence of normal and even high levels of serum vitamin B12. This review discusses the usefulness and limitations of current biomarkers of B12 status in newborn screening, infant and adult diagnostics, the algorithms utilized to diagnose B12 deficiency and unusual findings of vitamin B12 status in various human disorders.
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http://dx.doi.org/10.3389/fmolb.2016.00027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4921487PMC
July 2016

Peroxisome Proliferator-Activated Receptor Activation is Associated with Altered Plasma One-Carbon Metabolites and B-Vitamin Status in Rats.

Nutrients 2016 Jan 5;8(1). Epub 2016 Jan 5.

Department of Clinical Science, University of Bergen, 5020 Bergen, Norway.

Plasma concentrations of metabolites along the choline oxidation pathway have been linked to increased risk of major lifestyle diseases, and peroxisome proliferator-activated receptors (PPARs) have been suggested to be involved in the regulation of key enzymes along this pathway. In this study, we investigated the effect of PPAR activation on circulating and urinary one-carbon metabolites as well as markers of B-vitamin status. Male Wistar rats (n = 20) received for 50 weeks either a high-fat control diet or a high-fat diet with tetradecylthioacetic acid (TTA), a modified fatty acid and pan-PPAR agonist with high affinity towards PPARα. Hepatic gene expression of PPARα, PPARβ/δ and the enzymes involved in the choline oxidation pathway were analyzed and concentrations of metabolites were analyzed in plasma and urine. TTA treatment altered most biomarkers, and the largest effect sizes were observed for plasma concentrations of dimethylglycine, nicotinamide, methylnicotinamide, methylmalonic acid and pyridoxal, which were all higher in the TTA group (all p < 0.01). Hepatic Pparα mRNA was increased after TTA treatment, but genes of the choline oxidation pathway were not affected. Long-term TTA treatment was associated with pronounced alterations on the plasma and urinary concentrations of metabolites related to one-carbon metabolism and B-vitamin status in rats.
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http://dx.doi.org/10.3390/nu8010026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728640PMC
January 2016

A Protein Extract from Chicken Reduces Plasma Homocysteine in Rats.

Nutrients 2015 Jun 4;7(6):4498-511. Epub 2015 Jun 4.

Department of Clinical Science, University of Bergen, 5020 Bergen, Norway.

The present study aimed to evaluate effects of a water-soluble protein fraction of chicken (CP), with a low methionine/glycine ratio, on plasma homocysteine and metabolites related to homocysteine metabolism. Male Wistar rats were fed either a control diet with 20% w/w casein as the protein source, or an experimental diet where 6, 14 or 20% w/w of the casein was replaced with the same amount of CP for four weeks. Rats fed CP had reduced plasma total homocysteine level and markedly increased levels of the choline pathway metabolites betaine, dimethylglycine, sarcosine, glycine and serine, as well as the transsulfuration pathway metabolites cystathionine and cysteine. Hepatic mRNA level of enzymes involved in homocysteine remethylation, methionine synthase and betaine-homocysteine S-methyltransferase, were unchanged, whereas cystathionine gamma-lyase of the transsulfuration pathway was increased in the CP treated rats. Plasma concentrations of vitamin B2, folate, cobalamin, and the B-6 catabolite pyridoxic acid were increased in the 20% CP-treated rats. In conclusion, the CP diet was associated with lower plasma homocysteine concentration and higher levels of serine, choline oxidation and transsulfuration metabolites compared to a casein diet. The status of related B-vitamins was also affected by CP.
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http://dx.doi.org/10.3390/nu7064498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4488798PMC
June 2015
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