Intake of marine and plant-derived n-3 fatty acids and development of atherosclerotic cardiovascular disease in the Danish Diet, Cancer and Health cohort.

PURPOSE: The objective of this study was to investigate the association between intake of seafood and plant-derived n-3 polyunsaturated fatty acids (PUFA) and development of total atherosclerotic cardiovascular disease (ASCVD) and acute major ischemic events. METHODS: A total of 53,909 men and women were enrolled between 1993 and 1997 into the Danish Diet, Cancer and Health cohort and followed through nationwide Danish registries for development of total ASCVD defined as a first registration of myocardial infarction, peripheral artery disease, or ischemic stroke due to large artery atherosclerosis or small-vessel occlusion. At recruitment, the intake of the major marine n-3 PUFA, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and the plant-derived n-3 PUFA, alpha-linolenic acid (ALA), was assessed using a validated food frequency questionnaire. Statistical analyses were conducted using sex-stratified multivariable Cox proportional hazard regression models. RESULTS: During a median of 13.5 years of follow-up, 3958 participants developed ASCVD including 3270 patients with an acute major ischemic event. In multivariable analyses including adjustment for established risk factors, we found no associations for intake of ALA, but indications of inverse associations between intake of EPA, DHA and EPA + DHA and the rate of total ASCVD and acute major ischemic events. CONCLUSIONS: A high intake of marine n-3 PUFA was associated with a lower risk of total ASCVD and acute major ischemic events, whereas no association could be demonstrated for the plant-derived ALA.

Plant n-3 PUFA intake may lower the risk of atherosclerotic cardiovascular disease only among subjects with a low intake of marine n-3 PUFAs.

The role of the major plant-derived n-3 PUFA, alpha-linolenic acid (ALA), on the risk of atherosclerotic cardiovascular (ASCVD) remains unclear, but most studies have reported no association. However, the association between intake of ALA and the risk of ASCVD may depend on the intake of marine n-3 PUFAs. We investigated this hypothesis among more than 53,909 middle-aged, Danish men and women followed for a median of 13.4 years. We found a statistically significant inverse association between ALA intake modelled as a restricted cubic spline and the rate of ASCVD in subjects with a low intake of marine n-3 PUFAs, while no association was observed among subjects with a higher intake of marine n-3 PUFAs. Our findings suggest that the intake of ALA may be associated with a lower risk of total ASCVD, but only among subjects with a low intake of marine n-3 PUFAs.

Intake of dairy products and associations with major atherosclerotic cardiovascular diseases: a systematic review and meta-analysis of cohort studies.

Specific types of dairy products may be differentially associated with atherosclerotic cardiovascular disease (CVD). We conducted a systematic review and meta-analysis of cohort studies to summarize findings on the associations between total dairy product intake and intake of dairy product subgroups and the risk of major atherosclerotic CVDs in the general adult population. Our protocol was registered in PROSPERO (CRD42019125455). PubMed and Embase were systematically searched through 15 August 2019. For high versus low intake and dose-response meta-analysis, random-effects modelling was used to calculate summary risk ratios (RR). There were 13 cohort studies included for coronary heart disease (CHD), 7 for ischemic stroke and none for peripheral artery disease. High-fat milk was positively associated with CHD (RR 1.08 (95% confidence interval 1.00-1.16) per 200 g higher intake/day) and cheese was inversely associated with CHD (RR 0.96 (95% confidence interval 0.93-0.98) per 20 g higher intake/day). Heterogeneity, however, was observed in high versus low meta-analyses. Milk was inversely associated with ischemic stroke in high versus low meta-analysis only. In conclusion, this systematic review indicates a positive association of high-fat milk and an inverse association of cheese with CHD risk. The findings should be interpreted in the context of the observed heterogeneity.

Intake of marine n-3 polyunsaturated fatty acids and the risk of incident peripheral artery disease.

BACKGROUND: A high intake of marine n-3 polyunsaturated fatty acids (PUFAs) may lower the risk of coronary heart disease and ischemic stroke. The association between intake of marine n-3 PUFAs and development of peripheral artery disease (PAD), however, remains unexplored. We hypothesised that intake of marine n-3 PUFAs, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and the sum of EPA + DHA was associated with a lower risk of incident PAD. METHODS: We used data from the Danish Diet, Cancer and Health cohort and investigated the associations between intake of EPA, DHA and EPA + DHA and development of PAD. Information on intake of n-3 PUFAs was obtained through a validated food frequency questionnaire. Potential PAD cases were identified through linkage to the Danish National Patient Register and subsequently, all cases were validated. RESULTS: Data were available from 55,248 participants and during a median of 13.6 years of follow-up, 950 cases of PAD were identified. Multivariate Cox regression analyses with adjustments for established risk factors showed no statistically significant associations between intake of EPA (p = 0.255), DHA (p = 0.071) or EPA + DHA (p = 0.168) and the rate of incident PAD. CONCLUSIONS: We did not confirm our hypothesis that intake of EPA, DHA or EPA + DHA was associated with a lower risk of incident PAD.

Marine and plant-based n-3 PUFA and atherosclerotic cardiovascular disease.

n-3 PUFA may exert favourable effects on several processes that may inhibit the atherosclerotic process. However, the role of n-3 PUFA in lowering the risk of atherosclerotic CVD (ASCVD) has been fiercely debated. In the present paper, we summarise the main findings from previous follow-up studies of intake and studies using adipose tissue as an objective biomarker to investigate exposure to n-3 PUFA in relation to ASCVD risk and discuss some perspectives for further research. The majority of previous studies investigating intake of marine- and plant-based n-3 PUFA have focused on CHD while other ASCVD such as ischaemic stroke and peripheral artery disease have been less studied. However, recent data from Danish Diet, Cancer and Health cohort suggest that marine n-3 PUFA may be inversely associated with risk of myocardial infarction, ischaemic stroke and peripheral arterial disease caused by atherosclerosis. The effect of the plant-derived n-3 PUFA α-linolenic acid on ASCVD is less clear and several gaps in the literature remain to be explored.

Marine n-3 Polyunsaturated Fatty Acids and the Risk of Ischemic Stroke.

Background and Purpose- We hypothesized that total marine n-3 polyunsaturated fatty acids (PUFA), in particular eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in the diet and in adipose tissue (biomarkers of long-term intake and endogenous exposure) were inversely associated with the risk of ischemic stroke and its subtypes. Methods- The Diet, Cancer and Health cohort consisted of 57 053 participants aged 50 to 65 years at enrolment. All participants filled in a food frequency questionnaire and had an adipose tissue biopsy taken at baseline. Information on ischemic stroke during follow-up was obtained from The Danish National Patient Register, and all cases were validated. Cases and a random sample of 3203 subjects from the whole cohort had their fatty acid composition of adipose tissue determined by gas chromatography. Results- During 13.5 years of follow-up 1879 participants developed an ischemic stroke. Adipose tissue content of EPA was inversely associated with total ischemic stroke (hazard ratio [HR], 0.74; 95% CI, 0.62-0.88) when comparing the highest with the lowest quartile. Also, lower rates of large artery atherosclerosis were seen with higher intakes of total marine n-3 PUFA (HR, 0.69; 95% CI, 0.50-0.95), EPA (HR, 0.66; 95% CI, 0.48-0.91) and DHA (HR, 0.72; 95% CI, 0.53-0.99), and higher adipose tissue content of EPA (HR, 0.52; 95% CI, 0.36-0.76). Higher rates of cardioembolism were seen with higher intakes of total marine n-3 PUFA (HR, 2.50; 95% CI, 1.38-4.53) and DHA (HR, 2.12; 95% CI, 1.21-3.69) as well as with higher adipose tissue content of total marine n-3 PUFA (HR, 2.63; 95% CI, 1.33-5.19) and DHA (HR, 2.00; 95% CI, 1.04-3.84). The EPA content in adipose tissue was inversely associated with small-vessel occlusion (HR, 0.69; 95% CI, 0.55-0.88). Conclusions- EPA was associated with lower risks of most types of ischemic stroke, apart from cardioembolism, while inconsistent findings were observed for total marine n-3 PUFA and DHA.

Substitution of Fish for Red Meat or Poultry and Risk of Ischemic Stroke.

We investigated the risk of ischemic stroke and its subtypes when red meat or poultry was substituted with fish. A total of 57,053 participants aged 50⁻65 years at baseline were included in the Danish Diet, Cancer and Health study. All participants filled in a food-frequency questionnaire at recruitment. Potential ischemic stroke cases were identified by linkage to the Danish National Patient Register, and all cases were validated and subclassified. Substitutions were investigated as 150 g/week of fish for 150 g/week of red meat or of poultry using multivariable Cox proportional hazard regression models. During 13.5 years of follow-up, 1879 participants developed an ischemic stroke. Replacing red meat or poultry with fish was not associated with the rate of total ischemic stroke, but there was a statistically significant lower rate of large artery atherosclerosis when fish replaced processed (hazard ratio (HR): 0.78; 95% confidence interval (CI): 0.67; 0.90) and unprocessed (HR: 0.87; 95% CI: 0.75; 0.99) red meat. A statistically significant higher rate of cardioembolism was found when poultry was replaced by total fish (HR: 1.42; 95% CI: 1.04; 1.93). When fatty fish replaced unprocessed red meat, a statistically significant lower rate of small-vessel occlusion was found (HR: 0.88; 95% CI: 0.77; 0.99). In conclusion, replacing red meat with fish was not associated with risk of total ischemic stroke but was associated with a lower risk of subtypes of ischemic stroke.

Dietary Intake of α-Linolenic Acid Is Not Appreciably Associated with Risk of Ischemic Stroke among Middle-Aged Danish Men and Women.

Background: Intake of the plant-derived omega-3 (n-3) fatty acid α-linolenic acid (ALA) may reduce the risk of ischemic stroke. Objective: We have investigated the associations between dietary intake of ALA and the risk of ischemic stroke and ischemic stroke subtypes. Methods: This was a follow-up study. A total of 57,053 participants aged 50-64 y were enrolled into the Danish Diet, Cancer and Health cohort between 1993 and 1997. Intake of ALA was assessed by a validated semiquantitative food frequency questionnaire. Potential incident cases of ischemic stroke were identified in the Danish National Patient Register, validated, and classified into subtypes based on assumed etiology. Statistical analyses were performed via Cox proportional hazard regression with adjustment for established ischemic stroke risk factors. Results: A total of 1859 ischemic stroke cases were identified during a median of 13.5 y of follow-up. In multivariable analyses using restricted cubic splines adjusting for traditional risk factors for ischemic stroke, we observed no clear associations between dietary intake of ALA and the risk of total ischemic stroke or any of its subtypes including ischemic stroke due to large artery atherosclerosis, ischemic stroke due to small-vessel occlusion, and ischemic stroke due to cardio-embolism. Conclusion: Dietary intake of ALA was neither consistently nor appreciably associated with the risk of ischemic stroke or ischemic stroke subtypes among middle-aged Danish men and women. This study was registered at clinicaltrials.gov as NCT03258983.

Substitution of Linoleic Acid for Other Macronutrients and the Risk of Ischemic Stroke.

BACKGROUND AND PURPOSE: Ischemic stroke is a major health problem worldwide, but the influence of dietary factors on stroke risk is not well known. This study aimed to investigate the risk of ischemic stroke and its subtypes with a higher intake from linoleic acid and a concomitant lower intake from saturated fatty acids, monounsaturated fatty acids, or glycemic carbohydrates. METHODS: In the Danish prospective Diet, Cancer, and Health Study of 57 053 participants aged 50 to 64 years at baseline, information on diet was collected using a validated semiquantitative food frequency questionnaire. Information on ischemic stroke was obtained from the Danish National Patient Register, and cases were all validated and subclassified according to the TOAST (Trial of ORG 10172 in Acute Stroke Treatment) classification. Substitution of linoleic acid for saturated fatty acid, monounsaturated fatty acid, or glycemic carbohydrates was investigated in relation to the risk of ischemic stroke and subtypes. Cox proportional hazards regression was used to estimate the associations with ischemic stroke adjusting for appropriate confounders. RESULTS: During 13.5 years of follow-up 1879 participants developed ischemic stroke. A slightly lower risk of ischemic stroke was found with a 5% higher intake of linoleic acid and a concomitant lower intake of saturated fatty acid (hazard ratio, 0.98; 95% confidence interval, 0.83-1.16), monounsaturated fatty acid (hazard ratio, 0.80; 95% confidence interval, 0.63-1.02), and glycemic carbohydrates (hazard ratio, 0.92; 95% confidence interval, 0.78-1.09), although not statistically significant. Similar patterns of association were found for large-artery atherosclerosis and small-vessel occlusions. CONCLUSIONS: This study suggests that replacing saturated fatty acid, glycemic carbohydrate, or monounsaturated fatty acid with linoleic acid may be associated with a lower risk of ischemic stroke.