High Lipoprotein(a) May Explain One-Quarter of Clinical Familial Hypercholesterolemia Diagnoses in Danish Lipid Clinics.

CONTEXT: Cholesterol carried in lipoprotein(a) adds to measured low-density lipoprotein cholesterol (LDL-C) and may therefore drive some diagnoses of clinical familial hypercholesterolemia (FH). OBJECTIVE: We investigated plasma lipoprotein(a) in individuals referred to Danish lipid clinics and evaluated the effect of plasma lipoprotein(a) on a diagnosis of FH. METHODS: Individuals referred to 15 Danish lipid clinics who were suspected of having FH according to nationwide referral criteria were recruited between September 1, 2020 and November 30, 2021. All individuals were classified according to the Dutch Lipid Clinical Network criteria for FH before and after LDL-C was adjusted for 30% cholesterol content in lipoprotein(a). We calculated the fraction of individuals fulfilling a clinical diagnosis of FH partly due to elevated lipoprotein(a). RESULTS: We included a total of 1166 individuals for analysis, of whom 206 fulfilled a clinical diagnosis of FH. Median lipoprotein(a) was 15 mg/dL (29 nmol/L) in those referred and 28% had lipoprotein(a) greater than or equal to 50 mg/dL (105 nmol/L), while 2% had levels greater than or equal to 180 mg/dL (389 nmol/L). We found that in 27% (55/206) of those fulfilling a clinical diagnosis of FH, this was partly due to high lipoprotein(a). CONCLUSION: Elevated lipoprotein(a) was common in individuals referred to Danish lipid clinics and in one-quarter of individuals who fulfilled a clinical diagnosis of FH, this was partly due to elevated lipoprotein(a). These findings support the notion that the LPA gene should be considered an important causative gene in patients with clinical FH and further support the importance of measuring lipoprotein(a) when diagnosing FH as well as for stratification of cardiovascular risk.

Omega-3 Blood Levels and Stroke Risk: A Pooled and Harmonized Analysis of 183 291 Participants From 29 Prospective Studies.

BACKGROUND: The effect of marine omega-3 PUFAs on risk of stroke remains unclear. METHODS: We investigated the associations between circulating and tissue omega-3 PUFA levels and incident stroke (total, ischemic, and hemorrhagic) in 29 international prospective cohorts. Each site conducted a de novo individual-level analysis using a prespecified analytical protocol with defined exposures, covariates, analytical methods, and outcomes; the harmonized data from the studies were then centrally pooled. Multivariable-adjusted HRs and 95% CIs across omega-3 PUFA quintiles were computed for each stroke outcome. RESULTS: Among 183 291 study participants, there were 10 561 total strokes, 8220 ischemic strokes, and 1142 hemorrhagic strokes recorded over a median of 14.3 years follow-up. For eicosapentaenoic acid, comparing quintile 5 (Q5, highest) with quintile 1 (Q1, lowest), total stroke incidence was 17% lower (HR, 0.83 [CI, 0.76-0.91]; P<0.0001), and ischemic stroke was 18% lower (HR, 0.82 [CI, 0.74-0.91]; P<0.0001). For docosahexaenoic acid, comparing Q5 with Q1, there was a 12% lower incidence of total stroke (HR, 0.88 [CI, 0.81-0.96]; P=0.0001) and a 14% lower incidence of ischemic stroke (HR, 0.86 [CI, 0.78-0.95]; P=0.0001). Neither eicosapentaenoic acid nor docosahexaenoic acid was associated with a risk for hemorrhagic stroke. These associations were not modified by either baseline history of AF or prevalent CVD. CONCLUSIONS: Higher omega-3 PUFA levels are associated with lower risks of total and ischemic stroke but have no association with hemorrhagic stroke.

Intake of marine n-3 polyunsaturated fatty acids and risk of hemorrhagic stroke and its subtypes: a Danish follow-up study.

BACKGROUND: A diet rich in marine n-3 polyunsaturated fatty acids (PUFAs) may lower the risk of coronary heart disease and ischemic stroke. However, the association between intake of marine n-3 PUFAs and risk of hemorrhagic stroke has only been sparsely explored. We aimed to investigate the associations between intake of the major marine n-3 PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and their sum in relation to incident hemorrhagic stroke and its subtypes intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH). METHODS: We analyzed data from the Danish Diet, Cancer and Health Cohort, which was established between 1993 and 1997. Information on dietary intake of marine n-3 PUFAs was obtained through a validated food frequency questionnaire. Potential hemorrhagic stroke cases were identified by linkage to the Danish National Patient Register and subsequently validated. Hazard ratios obtained by Cox proportional hazard regression were used as measures of association. RESULTS: A total of 394 subjects among 55,519 individuals developed hemorrhagic stroke during a median follow-up period of 13.5 years. In multivariable analyses including adjustment for established risk factors, we observed weak and statistically non-significant indications of inverse associations between intake of EPA, DHA, and EPA + DHA and the rate of incident hemorrhagic stroke. In analyses of hemorrhagic stroke subtypes, we found indications of lower rates of ICH among participants in the highest quartile of EPA, DHA, and EPA + DHA compared with those in the lowest quartile, and indications of lower rates of SAH in the highest quartile of EPA intake compared to the lowest quartile but the findings were statistically non-significant. CONCLUSIONS: Indications of inverse statistically non-significant associations were found between EPA, DHA, and EPA + DHA and hemorrhagic stroke.

Possible explanations for the common clinical familial hypercholesterolemia phenotypes in the Faroe Islands.

BACKGROUND: The prevalence of clinical familial hypercholesterolemia (FH) is very high in the Faroe Islands, but the possible causes are unknown. OBJECTIVES: We aimed to describe potential genetic causes of FH in the Faroe Islands and to investigate whether levels of lipoprotein(a) and measures of dietary habits were associated with clinical FH in the Faroe Islands. METHODS: In this case-control study, we identified potential clinical FH cases aged 18-75 years registered within a nationwide clinical laboratory database in the Faroe Islands and invited them for diagnostic evaluation according to clinical FH scoring systems. Controls were identified in the background population. Lipoprotein(a) was measured in plasma, while the fatty acid composition was determined in adipose tissue. The habitual diet of the participants was assessed using a food frequency questionnaire. Genetic testing for FH and polygenic variants was performed in a selection of clinical FH cases. RESULTS: A total of 121 clinical FH cases and 123 age- and sex-matched controls were recruited. We found a very low frequency of monogenic FH (2.5%), but a high level of polygenic FH (63%) in those genetically tested (67%). High levels of plasma lipoprotein(a) were associated with high odds of clinical FH. Clinical FH cases had a lower intake of saturated fatty acids (SFAs) measured by a high fat-score and a lower content of SFAs in adipose tissue compared with controls. CONCLUSION: The high prevalence of FH in the Faroe Islands may be due to polygenic causes of hypercholesterolemia and to a lesser extent other genetic factors and elevated plasma lipoprotein(a) levels.

Adipose tissue n-3/n-6 fatty acids ratios versus n-3 fatty acids fractions as predictors of myocardial infarction.

BACKGROUND: Tissue levels of n-3 polyunsaturated fatty acids (PUFAs) have been inversely related with risk of myocardial infarction (MI). Whether ratios of n-3 to n-6 PUFAs, reflecting both dietary intake of n-3 PUFAs and competing n-6 PUFAs, are better predictors of future MI than n-3 PUFA fractions is unclear. We aimed at investigating whether such ratios in adipose tissue better predict MI than n-3 PUFA fractions. METHODS: Subcutaneous adipose tissue biopsies were obtained in a random sample (n = 3,500) of the Diet, Cancer and Health cohort (n = 57,053). Adipose tissue content of eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), docosahexaenoic acid (DHA), alpha-linolenic acid (ALA), arachidonic acid (AA) and linoleic acid was determined using gas chromatography. Fractions of selected n-3 PUFAs and n-3/n-6 PUFA ratios were correlated to the 15-year occurrence of MI in a case-cohort design. RESULTS: A total of 2,406 participants experienced an MI during follow-up. Adipose tissue total marine n-3 PUFAs, EPA+DHA, EPA, EPA/AA, DHA/AA and (EPA + DPA + DHA)/AA were all inversely associated with risk of incident MI. Evaluating the predictive power (Harrel's C-index) of the selected metrics, fractions of marine n-3 PUFAs and ratios of EPA/AA, DHA/AA, (EPA + DHA)/AA and (EPA + DPA + DHA)/AA all refined risk prediction over age and sex alone. At multivariable analyses, however, the above ratios were the only metrics providing additional risk prediction. Differences in ratios were related to differences in food intake. CONCLUSIONS: Both adipose tissue n-3 PUFAs fractions and ratios of n-3 PUFAs/AA were associated with a lower occurrence of MI, but ratios provided superior risk prediction. Dietary strategies affecting n-3/n-6 PUFA ratios should be further investigated for prediction of MI with dietary interventions at the population level and in intervention studies.

Genetic testing increases the likelihood of a diagnosis of familial hypercholesterolaemia among people referred to lipid clinics: Danish national study.

BACKGROUND AND AIMS: It is unclear to what extent genetic testing improves the ability to diagnose familial hypercholesterolaemia (FH). We investigated the percentage with FH among individuals referred to Danish lipid clinics, and evaluated the impact of genetic testing for a diagnosis of FH. METHODS: From September 2020 through November 2021, all patients referred for possible FH to one of the 15 Danish lipid clinics were invited for study participation and >97% (n = 1488) accepted. The Dutch Lipid Clinical Network criteria were used to diagnose clinical FH. The decision of genetic testing for FH was based on local practice. RESULTS: A total of 1243 individuals were referred, of whom 25.9% were diagnosed with genetic and/or clinical FH. In individuals genetically tested (n = 705), 21.7% had probable or definite clinical FH before testing, a percentage that increased to 36.9% after genetic testing. In individuals with unlikely and possible FH before genetic testing, 24.4% and 19.0%, respectively, had a causative pathogenic variant. CONCLUSIONS: In a Danish nationwide study, genetic testing increased a diagnosis of FH from 22% to 37% in patients referred with hypercholesterolaemia suspected of having FH. Importantly, approximately 20% with unlikely or possible FH, who without genetic testing would not have been considered having FH (and family screening would not have been undertaken), had a pathogenic FH variant. We therefore recommend a more widespread use of genetic testing for evaluation of a possible FH diagnosis and potential cascade screening.

Equivalent Impact of Elevated Lipoprotein(a) and Familial Hypercholesterolemia in Patients With Atherosclerotic Cardiovascular Disease.

BACKGROUND: Genetically elevated plasma lipoprotein(a) and familial hypercholesterolemia each result in premature atherosclerotic cardiovascular disease (ASCVD); however, a direct comparison in the same population is needed of these 2 genetic traits on the risk of ASCVD. OBJECTIVES: We determined the level of plasma lipoprotein(a) that is equivalent to low-density lipoprotein (LDL) cholesterol in clinically and genetically diagnosed familial hypercholesterolemia on risk of myocardial infarction and ASCVD. METHODS: We examined the CGPS (Copenhagen General Population Study) with determination of lipoprotein(a) and familial hypercholesterolemia in 69,644 individuals followed for 42 years, during which time, 4,166 developed myocardial infarction and 11,464, ASCVD. RESULTS: For risk of myocardial infarction, the plasma lipoprotein(a) level equivalent to LDL cholesterol in clinical familial hypercholesterolemia was 67 mg/dL (142 nmol/L) for MEDPED (Make Early Diagnosis to Prevent Early Death), 110 mg/dL (236 nmol/L) for Simon Broome, 256 mg/dL (554 nmol/L) for possible DLCN (Dutch Lipid Clinic Network), and 402 mg/dL (873 nmol/L) for probable+definite DLCN, whereas it was 180 mg/dL (389 nmol/L) for genetic familial hypercholesterolemia. Corresponding values for ASCVD were 130 mg/dL (280 nmol/L), 150 mg/dL (323 nmol/L), 227 mg/dL (491 nmol/L), 391 mg/dL (849 nmol/L), and 175 mg/dL (378 nmol/L), respectively. Individuals with both elevated lipoprotein(a) and either familial hypercholesterolemia or a family history of premature myocardial infarction had a higher risk of myocardial infarction and ASCVD compared with individuals with only 1 of these genetic traits, with the highest HRs being for lipoprotein(a) upper 20% vs lower 50% of 14.0 (95% CI: 9.15-21.3) for myocardial infarction and 5.05 (95% CI: 3.41-7.48) for ASCVD. CONCLUSIONS: Lipoprotein(a) levels equivalent to LDL cholesterol in clinical and genetic familial hypercholesterolemia were 67 to 402 mg/dL and 180 mg/dL, respectively, for myocardial infarction and 130 to 391 mg/dL and 175 mg/dL, respectively, for ASCVD.

Familial hypercholesterolaemia: a study protocol for identification and investigation of potential causes and markers of subclinical coronary artery disease in the Faroe Islands.

INTRODUCTION: Familial hypercholesterolaemia (FH) is the most common monogenic autosomal dominant genetic disorder and is associated with a high risk of premature atherosclerotic cardiovascular disease. The prevalence of FH has been reported to be particularly high in certain founder populations. The population of the Faroe Islands is a founder population, but the prevalence of FH has never been investigated here. We aim to assess the prevalence of FH and to describe the genetic and clinical characteristics and potential causes of FH in the Faroe Islands. Furthermore, we aim to investigate whether indicators of subclinical coronary artery disease are associated with FH. METHODS AND ANALYSIS: The prevalence of FH will be estimated based on an electronic nationwide laboratory database that includes all measurements of plasma lipid levels in the Faroe Islands since 2006. Subsequently, we will identify and invite subjects aged between 18 and 75 years registered with a plasma low-density lipoprotein cholesterol above 6.7 mmol/L for diagnostic evaluation. Eligible FH cases will be matched to controls on age and sex. We aim to include 120 FH cases and 120 controls.Detailed information will be collected using questionnaires and interviews, and a physical examination will be undertaken. An adipose tissue biopsy and blood samples for genetic testing, detailed lipid analyses and samples for storage in a biobank for future research will be collected. Furthermore, FH cases and controls will be invited to have a transthoracic echocardiography and a cardiac CT performed. ETHICS AND DISSEMINATION: The project has been approved by the Ethical Committee and the Data Protection Agency of the Faroe Islands. The project is expected to provide important information, which will be published in international peer-reviewed journals.

Are fatty acids associated with disease activity and biomarkers in patients with psoriatic arthritis? Data from a multicenter clinical trial.

The pathogenesis of psoriatic arthritis (PsA) involves inflammation and bone and soft tissue turnover. Dietary fatty acids have previously been associated with pro-inflammatory effects induced by saturated fatty acids (SFA) and anti-inflammatory effects achieved by at least some polyunsaturated fatty acids (PUFA). The aim of the study was to investigate the correlations between the content of fatty acids in granulocytes and clinical and biochemical markers of PsA. A total of 140 patients with PsA were included. Skin and joint disease activity were assessed. Fatty acid composition in granulocytes was determined by gas chromatography. Competitive enzyme-linked immunosorbent assays were used to assess bone and soft tissue turnover. The content of SFA, n-6 PUFA or n-3 PUFA in granulocytes was not associated with disease activity. Marine n-3 PUFA was significantly positively correlated with collagen degradation. In contrast, n-6 PUFA was significantly positively correlated with collagen formation and negatively correlated with collagen degradation. However, the correlations were all weak. No association was found between the content of fatty acids in granulocytes and disease activity in this population of patients with PsA. The correlation between fatty acids and biomarkers of bone and soft tissue turnover needs further investigation.

Omega-3 fatty acids in adipose tissue and risk of atrial fibrillation.

BACKGROUND: The aim of the present study was to examine the relation between adipose tissue content of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and the risk of incident atrial fibrillation (AF). METHODS: In this case-cohort study based on data from the Danish Diet, Cancer and Health cohort, a total of 5255 incident cases of AF was identified during 16.9 years of follow-up. Adipose tissue biopsies collected at baseline from all cases and from a randomly drawn subcohort of 3440 participants were determined by gas chromatography. Data were analysed using weighted Cox regression. RESULTS: Data were available for 4741 incident cases of AF (2920 men and 1821 women). Participants in the highest vs. the lowest quintile of EPA experienced a 45% lower risk of AF (men HR 0.55 (95% CI 0.41-0.69); women HR 0.55 (0.41-0.72)). For DHA, no clear association was found in men, whereas in women, participants in the highest quintile of DHA in adipose tissue had a 30% lower risk of incident AF (HR 0.70 (0.54-0.91)) compared to participants in the lowest quintile. CONCLUSIONS: A monotonous inverse association was found for the content of EPA in adipose tissue and risk of AF in both men and women. The content of DHA was inversely associated with the risk of AF in women, whereas no clear association was found for men.

One year of omega 3 polyunsaturated fatty acid supplementation does not reduce circulating prothrombotic microvesicles in elderly subjects after suffering a myocardial infarction.

BACKGROUND & AIMS: Circulating microvesicles (cMV) are both effectors and biomarkers of cardiovascular disease (CVD), and the effects of omega 3 polyunsaturated fatty acids (n3 PUFA) in MV shedding are not yet well known. Therefore, we aimed to investigate the effects of long-term n3 PUFA supplementation on cMV release from cells of the vascular compartment in elderly subjects at very high risk of CVD. METHODS: We included 156 elderly patients 2-8 weeks after suffering an acute myocardial infarction from the OMEMI cohort. Subjects were randomly allocated to receive 930 mg EPA + 660 mg DHA (n3 PUFA intervention) or corn oil (56% linoleic acid, 32% oleic acid, 10% palmitic acid) used as placebo daily for two years. At inclusion and after one-year follow-up, prothrombotic [annexin V (AV)+] cMV derived from blood and vascular cells were phenotyped by flow cytometry. RESULTS: No differences were observed in the levels of cMV between the randomized groups at inclusion in the study. After one-year follow-up, total AV+, platelet-derived CD61+/AV+, and endothelial-derived CD31+/AV+ and CD31+/CD42b-/AV+ cMV increased significantly in both groups. In the n3 PUFA supplemented group, platelet-derived CD62P+/AV+, CD42b+/AV+ and CD31+/CD42b+/AV+; leukocyte-derived CD62L+/AV+, CD45+/AV+, and CD11b+/AV+, as well as endothelial derived CD146+/AV+, CD62E+/AV+, and CD309+/AV+ cMV also increased significantly. No significant differences were however, observed in the changes of cMV levels between groups. CONCLUSION: In elderly Norwegians who have suffered a recent acute myocardial infarction and treated as per guidelines, long-term supplementation with 1.8 g/day n3 PUFA does not modulate prothrombotic MV release from blood and vascular cells. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01841944.

Intake of marine n-3 polyunsaturated fatty acids and the risk of rheumatoid arthritis: protocol for a cohort study using data from the Danish Diet, Cancer and Health cohort and Danish health registers.

INTRODUCTION: Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory joint disease with multifactorial aetiology. Smoking is a well-established lifestyle risk factor, but diet may also have an impact on the risk of RA. Intake of the major marine n-3 polyunsaturated fatty acids in particular eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been hypothesised to lower the risk of RA due to their anti-inflammatory effects, although based on limited knowledge. Therefore, we aim to investigate the associations between dietary intake of EPA and DHA and the risk of incident RA. METHODS AND ANALYSIS: A cohort study. The follow-up design will be based on data from the Danish Diet, Cancer and Health cohort, which was established between 1993 and 1997. The participants will be followed through record linkage using nationwide registers including the Danish Civil Registration System, the Danish National Patient Registry and the Danish National Prescription Registry using the unique Civil Personal Registration number. Time-to-event analyses will be conducted with RA as the outcome of interest. The participants will be followed from inclusion until date of RA diagnosis, death, emigration or end of follow-up. HRs with 95% CIs obtained using Cox proportional hazard regression models, with age as underlying time scale and adjustment for established and potential risk factors, will be used as measures of association. ETHICS AND DISSEMINATION: The study has been approved by the Data Protection Committee of Northern Jutland, Denmark (2019-87) and the North Denmark Region Committee on Health Research Ethics (N-20190031). Study results will be disseminated through peer-reviewed journals and presentations at international conferences.

Serum Levels of Dihomo-Gamma (γ)-Linolenic Acid (DGLA) Are Inversely Associated with Linoleic Acid and Total Death in Elderly Patients with a Recent Myocardial Infarction.

Dihomo-gamma-linolenic acid (DGLA) is an n-6 polyunsaturated fatty acid (PUFA) derived from linoleic acid (LA). The LA:DGLA ratio reflects conversion from LA to DGLA. Low levels of DGLA in serum have been related to poor outcome in myocardial infarction (MI) patients. Aims: To assess the association of DGLA and LA:DGLA with total death as a primary aim and incident cardiovascular events as a secondary objective. Methods: Baseline samples from 1002 patients, aged 70 to 82 years, included 2-8 weeks after an MI and followed for 2 years, were used. Major adverse clinical events (MACE) consisted of nonfatal MI, unscheduled coronary revascularization, stroke, hospitalization for heart failure or all-cause death. Cox regression analysis was used to relate serum n-6 PUFA phospholipid levels (%wt) to the risk of MACE, adjusting for the following: (1) age, sex and body mass index (BMI); (2) adding baseline cod liver oil supplementation; (3) adding prevalent hypertension, chronic kidney disease and diabetes mellitus. Results: Median DGLA level in serum phospholipids was 2.89 (Q1-Q3 2.43-3.38) %wt. DGLA was inversely related to LA and LA:DGLA ratio. There were 208 incident cases of MACE and 55 deaths. In the multivariable analysis, the hazard ratio (HR) for the total death in the three higher quartiles (Q2-4) of DGLA as compared to Q1 was 0.54 (0.31-0.95), with p = 0.03 (Model-1), 0.50 (0.28-0.91), with p = 0.02 (Model-2), and 0.47 (0.26-0.84), with p = 0.012 (Model-3), and non-significant for MACE. Risk of MACE (Model 3) approached borderline significance for LA:DGLA in Q2-4 vs. Q1 [HR 1.42 (1.00-2.04), p = 0.052]. Conclusions: Low levels of DGLA were related to a high LA:DGLA ratio and risk of total death in elderly patients with recent MI.

Marine n-3 Polyunsaturated Fatty Acids and Bone Mineral Density in Kidney Transplant Recipients: A Randomized, Placebo-Controlled Trial.

Kidney transplant recipients are at high risk of progressive bone loss and low-energy fractures in the years following transplantation. Marine n-3 polyunsaturated fatty acids (n-3 PUFA) supplementation may have beneficial effects on bone strength. The Omega-3 fatty acids in Renal Transplantation (ORENTRA) trial was an investigator initiated, randomized, placebo-controlled trial investigating the effects of marine n-3 PUFA supplementation after kidney transplantation. Effects of supplementation on bone mineral density (BMD) and calcium metabolism were pre-defined secondary endpoints. Adult kidney transplant recipients (n = 132) were randomized to 2.6 g marine n-3 PUFA supplement or olive oil (control) from 8 to 52 weeks post-transplant. Dual energy X-ray absorptiometry was performed to assess changes in bone mineral density of hip, spine, and forearm, as well as trabecular bone score (TBS) of the lumbar spine. Student's t test was used to assess between-group differences. There were no differences in ΔBMD between the two groups (intervention vs. control) at lumbar spine (-0.020 ± 0.08 vs. -0.007 ± 0.07 g/cm², p = 0.34), total hip (0.001 ± 0.03 vs. -0.005 ± 0.04, p = 0.38), or other skeletal sites in the intention-to-treat analyses. There was no difference in the change in TBS score (0.001 ± 0.096 vs. 0.009 ± 0.102, p = 0.62). Finally, no effect on biochemical parameters of mineral metabolism was seen. Results were similar when analyzed per protocol. In conclusion, we found no significant effect of 44 weeks of supplementation with 2.6 g of marine n-3 PUFA on BMD in kidney transplant recipients.

Effect of n-3 PUFA on extracellular matrix protein turnover in patients with psoriatic arthritis: a randomized, double-blind, placebo-controlled trial.

Psoriatic arthritis (PsA) is a chronic inflammatory disease characterized by involvement of skin, axial and peripheral skeleton. An altered balance between extracellular matrix (ECM) formation and breakdown is a key event in PsA, and changes in ECM protein metabolites may provide insight to tissue changes. Dietary fish oils (n-3 PUFA) might affect the inflammation driven tissue turnover. The aim was to evaluate ECM metabolites in patients with PsA compared to healthy individuals and investigate the effects of n-3 PUFA. The 24-week randomized, double-blind, placebo-controlled trial of PUFA included 142 patients with PsA. Fifty-seven healthy individuals were included for comparison. This study is a sub-study investigating biomarkers of tissue remodelling as secondary outcomes. Serum samples at baseline and 24 weeks and healthy individuals were obtained, while a panel of ECM metabolites reflecting bone and soft tissue turnover were measured by ELISAs: PRO-C1, PRO-C3, PRO-C4, C1M, C3M, C4M, CTX-I and Osteocalcin (OC). C1M, PRO-C3, PRO-C4 and C4M was found to be elevated in PsA patients compared to the healthy individuals (from 56 to 792%, all p < 0.0001), where no differences were found for OC, CTX-I, PRO-C1 and C3M. PRO-C3 was increased by 7% in patients receiving n-3 PUFA after 24 weeks compared to baseline levels (p = 0.002). None of the other biomarkers was changed with n-3 PUFA treatment. This indicates that tissue turnover is increased in PsA patients compared to healthy individuals, while n-3 PUFA treatment for 24 weeks did not have an effect on tissue turnover. Trial registration NCT01818804. Registered 27 March 2013-Completed 18 February 2016. https://clinicaltrials.gov/ct2/show/NCT01818804?term=NCT01818804&rank=1.

Linoleic acid in adipose tissue and the risk of myocardial infarction: a case-cohort study.

PURPOSE: We investigated risk of myocardial infarction (MI) associated with the content of linoleic acid (LA) in adipose tissue, a biomarker of long-term dietary intake of LA and a marker of endogenous LA exposure. METHODS: Between 1993 and 1997, 57,053 middle-aged subjects were included in the Danish Diet, Cancer and Health cohort. We performed a case-cohort study that included a random sample of the full cohort (n = 3167) and all incident MI cases appearing during 16 years of follow-up (n = 2819). Information on incident MI cases was obtained by linkage with Danish nationwide registries. Adipose tissue biopsies were taken from the buttocks of the participants, and their fatty acid composition was determined using gas chromatography. HRs (hazard ratios) with 95% confidence intervals (CIs) were used to describe the associations between content of LA in adipose tissue and the risk of MI. HRs were calculated using weighted Cox proportional hazards regression with robust variance. RESULTS: After adjustment for established risk factors of MI, adipose tissue content of LA was not associated with the risk of MI in men and women combined (quintiles 5 versus 1, HR, 1.03 (95% CI, 0.85-1.25), P-trend = 0.970) or in men and women separately (quintiles 5 versus 1, HR, 1.05 (95% CI, 0.83-1.33), P-trend = 0.871 and quintiles 5 versus 1, HR, 0.99 (95% CI 0.72-1.37), P-trend = 0.928, respectively). Investigating the association between LA and MI with a shorter, 5- or 10-year duration of follow-up provided similar results. CONCLUSION: Content of LA in adipose tissue was not associated with the risk of MI.

Substitutions between potatoes and other vegetables and risk of ischemic stroke.

PURPOSE: Intake of vegetables has been associated with a lower risk of ischemic stroke in observational studies controlling for total energy intake. However, adjustment for energy intake introduces a substitution aspect, which affects the interpretation of the results. We investigated replacement of potatoes with other vegetables, substitutions between vegetable subgroups, and risk of ischemic stroke and ischemic stroke subtypes. METHODS: The Danish Diet, Cancer and Health cohort included 57,053 participants aged 50-64 years at recruitment in 1993-1997. Diet was assessed from a validated 192-item semi-quantitative food frequency questionnaire. We calculated hazard ratios (HR) with 95% confidence intervals (CI) for the incidence of ischemic stroke using Cox proportional hazard regression. RESULTS: During 13.5 years of follow-up, 1879 cases of ischemic stroke were identified including 319 cases of large-artery atherosclerosis and 844 cases of small-vessel occlusion. The adjusted HR for total ischemic stroke associated with food substitutions of equal amounts (500 g/week) was 0.86 (95% CI 0.76, 0.97) for replacement of potatoes with fruiting vegetables and 0.92 (95% CI 0.84, 1.02) for replacement of potatoes with other root vegetables. The HR for replacing potatoes with the sum of other vegetables was 0.95 (95% CI 0.90, 1.00). Substitution of cabbage for either potatoes, fruiting vegetables or other root vegetables was associated with a statistically non-significant higher risk of ischemic stroke. The patterns of associations were similar for ischemic stroke subtypes and for equivalent substitutions using isocaloric amounts. CONCLUSION: Replacing potatoes with fruiting vegetables was associated with a lower risk of ischemic stroke.

Effects of n-3 Fatty Acid Supplements in Elderly Patients After Myocardial Infarction: A Randomized, Controlled Trial.

BACKGROUND: High intake of marine n-3 polyunsaturated fatty acids (PUFA) has been associated with reduced risk of cardiovascular events; however, this has not been confirmed in patients with a recent acute myocardial infarction (AMI). Elderly patients are at particularly increased cardiovascular risk after myocardial infarction, but few trials address this group specifically. Omega-3 fatty acids hold the potential to reduce cardiovascular events with limited adverse effects in this vulnerable group. The hypothesis was that daily addition of 1.8g n-3 PUFA to standard of care secondary prophylaxis in elderly patients who have survived an AMI would reduce the risk of subsequent cardiovascular events during 2 years follow-up. METHODS: The OMEMI trial (Omega-3 Fatty acids in Elderly with Myocardial Infarction) is an investigator-initiated, multicenter, randomized clinical trial adding 1.8 g n-3 PUFA (930 mg eicosapentaenoic acid and 660 mg docosohexaenoic acid) versus placebo (corn oil) daily to standard of care in patients aged 70 to 82 years with recent (2-8 weeks) AMI. The primary endpoint was a composite of nonfatal AMI, unscheduled revascularization, stroke, all-cause death, heart failure hospitalization after 2 years. The secondary outcome was new atrial fibrillation. The safety outcome was major bleeding. Serum fatty acids were measured as biomarkers of adherence. RESULTS: In total, 1027 patients were randomized. Follow-up data were available for 1014 patients who were included in the intention-to-treat analysis. Mean±SD age was 75±3.6 years, 294 (29%) were female, and mean triglycerides were 111.4±61.9 mg/dL. The primary endpoint occurred in 108 (21.4%) patients on n-3 PUFA versus 102 (20.0%) on placebo (hazard ratio, 1.08 [95% CI, 0.82-1.41]; P=0.60). The secondary endpoint occurred in 28 (7.2%) patients on n-3 PUFA versus 15 (4.0%) on placebo (1.84 [0.98-3.45]; P=0.06). Median changes in eicosapentaenoic acid and docosahexaenoic acid were +87% and +16% for n-3 PUFA versus -13% and -8% for placebo. Major bleeding occurred in 54 (10.7%) and 56 (11.0%) in the n-3 PUFA and placebo groups, respectively (P=0.87). Similar results were found in per-protocol analysis (n=893). CONCLUSIONS: We could not detect reduction in clinical events in our elderly patients with recent AMI who were treated with 1.8 g n-3 PUFAs daily for 2 years. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01841944.

Plasma Trans Fatty Acid Levels, Cardiovascular Risk Factors and Lifestyle: Results from the Akershus Cardiac Examination 1950 Study.

Intake of industrially produced trans fatty acids (iTFAs) has previously been associated with dyslipidemia, insulin resistance, hypertension and inflammation, as well as increased cardiovascular (CV) morbidity and mortality. iTFA intake declined in Norway after the introduction of legislative bans against iTFA consumption. However, the relationship between the current iTFA intake and CV health is unclear. The aim of the present study was to investigate the association between current iTFA intake, reflected by plasma iTFA levels, and established CV risk factors. We also examined the associations between plasma ruminant TFA levels and CV risk factors. In this cross-sectional study, we included 3706 participants from a Norwegian general population, born in 1950 and residing in Akershus County, Norway. The statistical method was multivariable linear regression. Plasma iTFA levels were inversely associated with serum triglycerides (p < 0.001), fasting plasma glucose (p < 0.001), body mass index (p < 0.001), systolic and diastolic blood pressure (p = 0.001 and p = 0.03) and C-reactive protein (p = 0.001). Furthermore, high plasma iTFA levels were associated with higher education and less smoking and alcohol consumption. We found that plasma ruminant trans fatty acids (rTFA) levels were favorably associated with CV risk factors. Furthermore, plasma iTFA levels were inversely associated with CV risk factors. However, our results might have been driven by lifestyle factors. Overall, our findings suggest that the current low intake of iTFAs in Norway does not constitute a threat to CV health.