Adipose tissue content of alpha-linolenic acid and the risk of ischemic stroke and ischemic stroke subtypes: A Danish case-cohort study

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Abstract

Background

The plant-derived omega-3 fatty acid alpha-linolenic acid (ALA) may reduce the risk of cardiovascular disease.

Objective

We have investigated associations between the content of ALA in adipose tissue and the risk of ischemic stroke and its subtypes.

Methods

Incident cases of ischemic stroke among participants enrolled into the Danish Diet, Cancer and Health cohort (n = 57,053) were identified by linkage with the Danish National Patient Register. Subsequently, all potential cases were validated and classified into ischemic stroke subtypes. The fatty acid composition of adipose tissue was determined by gas chromatography in cases and in a randomly drawn sub-cohort (n = 3500). Statistical analyses were performed using weighted Cox regression.

Results

During a median of 13.4 years of follow-up, 1735 cases of total ischemic stroke were identified including 297 cases of large artery atherosclerosis, 772 cases of small-vessel occlusion, 99 cases of cardio-embolism, 91 cases with stroke of other etiology and 476 cases with stroke of undetermined etiology. The median content of ALA in adipose tissue within the sub-cohort was 0.84% (95% central range: 0.53–1.19%). Multivariable analyses showed a U-shaped association between adipose tissue content of ALA and the rate of total ischemic stroke, but this association was not statistically significant ( p = 0.172). In analyses of ischemic stroke subtypes, we observed a statistically significant U-shaped association between ALA and the rate of ischemic stroke due to large artery atherosclerosis ( p = 0.017), whereas no appreciable association was observed between ALA and the rate of small-vessel occlusion ( p = 0.427). A positive but statistically non-significant association was observed between ALA and the rate of ischemic stroke due to cardio-embolism ( p = 0.162).

Conclusions

The content of ALA in adipose tissue was statistically non-significantly U-shaped associated with risk of total ischemic stroke. For ischemic stroke subtypes a statistically significant, U-shaped association with large artery atherosclerosis was observed.

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Most cited references 34

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Mediterranean alpha-linolenic acid-rich diet in secondary prevention of coronary heart disease.

M de Lorgeril, S. Renaud, N Mamelle … (1994)

In a prospective, randomised single-blinded secondary prevention trial we compared the effect of a Mediterranean alpha-linolenic acid-rich diet to the usual post-infarct prudent diet. After a first myocardial infarction, patients were randomly assigned to the experimental (n = 302) or control group (n = 303). Patients were seen again 8 weeks after randomisation, and each year for 5 years. The experimental group consumed significantly less lipids, saturated fat, cholesterol, and linoleic acid but more oleic and alpha-linolenic acids confirmed by measurements in plasma. Serum lipids, blood pressure, and body mass index remained similar in the 2 groups. In the experimental group, plasma levels of albumin, vitamin E, and vitamin C were increased, and granulocyte count decreased. After a mean follow up of 27 months, there were 16 cardiac deaths in the control and 3 in the experimental group; 17 non-fatal myocardial infarction in the control and 5 in the experimental groups: a risk ratio for these two main endpoints combined of 0.27 (95% CI 0.12-0.59, p = 0.001) after adjustment for prognostic variables. Overall mortality was 20 in the control, 8 in the experimental group, an adjusted risk ratio of 0.30 (95% CI 0.11-0.82, p = 0.02). An alpha-linolenic acid-rich Mediterranean diet seems to be more efficient than presently used diets in the secondary prevention of coronary events and death.

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Interplay between different polyunsaturated fatty acids and risk of coronary heart disease in men.

Dariush Mozaffarian, Alberto Ascherio, Frank Hu … (2005)

Consumption of polyunsaturated fatty acids (PUFAs) may reduce coronary heart disease (CHD) risk, but n-6 PUFAs may compete with n-3 PUFA metabolism and attenuate benefits. Additionally, seafood-based, long-chain n-3 PUFAs may modify the effects of plant-based, intermediate-chain n-3 PUFAs. However, the interactions of these PUFAs in relation to CHD risk are not well established. Among 45,722 men free of known cardiovascular disease in 1986, usual dietary intake was assessed at baseline and every 4 years by using validated food-frequency questionnaires. CHD incidence was prospectively ascertained. Over 14 years of follow-up, participants experienced 218 sudden deaths, 1521 nonfatal myocardial infarctions (MIs), and 2306 total CHD events (combined sudden death, other CHD deaths, and nonfatal MI). In multivariate-adjusted analyses, both long-chain and intermediate-chain n-3 PUFA intakes were associated with lower CHD risk, without modification by n-6 PUFA intake. For example, men with > or = median long-chain n-3 PUFA intake (> or =250 mg/d) had a reduced risk of sudden death whether n-6 PUFA intake was below ( or =11.2 g/d; HR=0.60; 95% CI=0.39 to 0.93) the median compared with men with a or = median intake of intermediate-chain n-3 PUFAs (> or =1080 mg/d) was associated with a reduced total CHD risk whether n-6 PUFA intake was lower (HR=0.88; 95% CI=0.78 to 0.99) or higher (HR=0.89; 95% CI=0.79 to 0.99) compared with a < median intake of both. Intermediate-chain n-3 PUFAs were particularly associated with CHD risk when long-chain n-3 PUFA intake was very low (<100 mg/d); among these men, each 1 g/d of intermediate-chain n-3 PUFA intake was associated with an approximately 50% lower risk of nonfatal MI (HR=0.42; 95% CI=0.23 to 0.75) and total CHD (HR=0.53; 95% CI=0.34 to 0.83). n-3 PUFAs from both seafood and plant sources may reduce CHD risk, with little apparent influence from background n-6 PUFA intake. Plant-based n-3 PUFAs may particularly reduce CHD risk when seafood-based n-3 PUFA intake is low, which has implications for populations with low consumption or availability of fatty fish.

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Consumption of (n-3) fatty acids is related to plasma biomarkers of inflammation and endothelial activation in women.

Esther López-García, Matthias B. Schulze, JoAnn Manson … (2004)

We evaluated the hypothesis that intake of (n-3) fatty acids is inversely associated with biomarkers of inflammation and endothelial activation. We conducted a cross-sectional study of 727 women from the Nurses' Health Study I cohort, aged 43-69 y, apparently healthy at time of a blood draw in 1990. Dietary intake was assessed by a validated FFQ in 1986 and 1990. C-reactive protein (CRP) levels were 29% lower among those in the highest quintile of total (n-3) fatty acids, compared with the lowest quintile; interleukin-6 (IL-6) levels were 23% lower, E-selectin levels 10% lower, soluble intracellular adhesion molecule (sICAM-1) levels 7% lower, and soluble vascular adhesion molecule (sVCAM-1) levels 8% lower. The intake of alpha-linolenic acid was inversely related to plasma concentrations of CRP (beta = -0.55, P = 0.02), Il-6 (beta = -0.36, P = 0.01), and E-selectin (beta = -0.24, P = 0.008) after controlling for age, BMI, physical activity, smoking status, alcohol consumption, and intake of linoleic acid (n-6) and saturated fat. Long-chain (n-3) fatty acids (eicosapentaenoic and docosahexaenoic) were inversely related to sICAM-1 (beta = -0.11, P = 0.03) and sVCAM-1 (beta = -0.17, P = 0.003). Total (n-3) fatty acids had an inverse relation with CRP (beta = -0.44, P = 0.007), IL-6 (beta = -0.26, P = 0.009), E-selectin (beta = -0.17, P = 0.004), sICAM-1 (beta = -0.07, P = 0.02), and sVCAM-1 (beta = -0.10, P = 0.004). These associations were not modified by intake of vitamin E, dietary fiber, trans fatty acids, or by the use of postmenopausal hormone therapy. In conclusion, this study suggests that dietary (n-3) fatty acids are associated with levels of these biomarkers reflecting lower levels of inflammation and endothelial activation, which might explain in part the effect of these fatty acids in preventing cardiovascular disease.

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Author and article information

Contributors

Christian Sørensen Bork:

ORCID: http://orcid.org/0000-0001-5233-2902

Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: Writing – original draftRole: Writing – review & editing

Stine Krogh Venø: Role: SupervisionRole: Writing – review & editing

Søren Lundbye-Christensen: Role: MethodologyRole: SupervisionRole: Writing – review & editing

Marianne Uhre Jakobsen:

ORCID: http://orcid.org/0000-0001-6518-4136

Role: MethodologyRole: SupervisionRole: Writing – review & editing

Anne Tjønneland: Role: ConceptualizationRole: Data curationRole: Writing – review & editing

Philip C. Calder: Role: SupervisionRole: Writing – review & editing

Kim Overvad: Role: ConceptualizationRole: Data curationRole: MethodologyRole: SupervisionRole: Writing – review & editing

Erik Berg Schmidt: Role: ConceptualizationRole: MethodologyRole: ResourcesRole: SupervisionRole: Writing – review & editing

Juan J. Loor: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Electronic): 1932-6203

Publication date (Electronic): 11 June 2018

Publication date Collection: 2018

Volume: 13

Issue: 6

Electronic Location Identifier: e0198927

Affiliations

[1 ] Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark

[2 ] Human Development & Health Academic Unit, Faculty of Medicine, University of Southampton, MP887 Southampton General Hospital, Southampton, United Kingdom

[3 ] Department of Clinical Medicine, Aalborg University, Aalborg, Denmark

[4 ] Unit of Clinical Biostatistics, Aalborg University Hospital, Aalborg, Denmark

[5 ] Atrial Fibrillation Study Group, Aalborg University Hospital, Aalborg, Denmark

[6 ] National Food Institute, Technical University of Denmark, Kgs. Lyngby, Denmark

[7 ] Danish Cancer Society Research Center, Copenhagen, Denmark

[8 ] National Institute for Health Research Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust and University of Southampton, Southampton, United Kingdom

[9 ] Department of Public Health, Section for Epidemiology, Aarhus University, Aarhus, Denmark

University of Illinois, UNITED STATES

Author notes

Competing Interests: The authors have declared that no competing interests exist.

* E-mail: c.bork@ 123456rn.dk

Author information

Christian Sørensen Bork http://orcid.org/0000-0001-5233-2902

Marianne Uhre Jakobsen http://orcid.org/0000-0001-6518-4136

Article

Publisher ID: PONE-D-18-06077

DOI: 10.1371/journal.pone.0198927

PMC ID: 5995395

PubMed ID: 29889889

SO-VID: e40222f7-eb0d-4640-b497-e30224b7c259

License:

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 25 February 2018

Date accepted : 29 May 2018

Page count

Figures: 1, Tables: 2, Pages: 13

Funding

Funded by: funder-id http://dx.doi.org/10.13039/100007405, Hjerteforeningen;

Award ID: 17-R115-A7415-22060

Award Recipient :

ORCID: http://orcid.org/0000-0001-5233-2902

Christian Sørensen Bork

This work was supported by The Danish Heart Foundation, grant number 17-R115-A7415-22060 ( https://hjerteforeningen.dk/forskning/). The grant was given to CSB. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Custom metadata

Data Availability Data are available from the Diet, Cancer and Health Institutional Data Access ( https://www.cancer.dk/research/diet-genes-environment/dgedch/). To access data, an application must be approved by the Scientific Board. Furthermore, as data contain potentially identifying or sensitive information, access to data has to be registered and approved by The Danish Data Protection Agency ( https://www.datatilsynet.dk/english/the-danish-data-protection-agency) and/or a Health Research Ethics Committee ( http://www.nvk.dk/english).”

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Adipose tissue content of alpha-linolenic acid and the risk of ischemic stroke and ischemic stroke subtypes: A Danish case-cohort study

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PLOS: COVID-19 pandemic

Most cited references 34

Mediterranean alpha-linolenic acid-rich diet in secondary prevention of coronary heart disease.

Interplay between different polyunsaturated fatty acids and risk of coronary heart disease in men.

Consumption of (n-3) fatty acids is related to plasma biomarkers of inflammation and endothelial activation in women.

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