Vascular Effects of Triglyceride-rich Lipoproteins

Study Overview
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Brief Summary
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Many types of cardiovascular disease begin when the layer of cells lining blood vessels (endothelial cells) start to function abnormally. This causes white blood cells (monocytes) to enter the blood vessel wall and eventually form lesions. Fats from foods we consume are carried in the blood for 3-8 hours after a fatty meal in small particles known as chylomicrons (CM) and chylomicron remnants (CMR). The overall aim of this project is to investigate the idea that n-3 polyunsaturated fatty acids (PUFA) protect against heart disease by modifying the effect of CMR on endothelial cells and monocytes. We hypothesize that n3-PUFA carried in CMR reduce detrimental events which promote blood vessel damage and activate protective mechanisms to improve the function of arteries.

Official Title
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Unravelling the Mechanisms of Vascular Protection by n3-PUFAs to Optimise and Support Their Use as Bioactives by the Food Industry

Conditions
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Postprandial Period, Lipemia, Vasodilation, Vascular Resistance, Nitric Oxide

Intervention / Treatment
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* Dietary Supplement: High-fat meals varying in their fatty acid composition


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy males Non-smokers Aged 35-70 years Fasting TAG concentrations ≥1.2 mmol/L. Exclusion Criteria: Reported history of CVD (myocardial infarction, angina, venous thrombosis, stroke), impaired fasting glucose/uncontrolled type 2 diabetes (or fasting glucose ≥ 6.1 mmol/L), cancer, kidney, liver or bowel disease. Presence of gastrointestinal disorder or use of drug, which is likely to alter gastrointestinal motility or nutrient absorption. History of substance abuse or alcoholism (previous weekly alcohol intake >60 units/men) Current self-reported weekly alcohol intake exceeding 28 units Allergy or intolerance to any component of test meals Unwilling to restrict consumption of any source of fish oil for the length of the study Weight change of >3kg in preceding 2 months Body Mass Index <20 and >35 kg/m2 Fasting blood cholesterol > 7.8 mmol/L Current cigarette smoker. Current use of lipid lowering medication

Ages Eligible for Study
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Minimum Age: 35 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Oleic acid<br>75 g high oleic acid sunflower oil. | Dietary Supplement: High-fat meals varying in their fatty acid composition<br>* 70 g fat incorporated into a muffin and milkshake meal, consumed following fasting baseline measurements<br>* Other names: Purified fish oil;|
| Active Comparator: Linoleic acid<br>75 g high linoleic acid sunflower oil. | Dietary Supplement: High-fat meals varying in their fatty acid composition<br>* 70 g fat incorporated into a muffin and milkshake meal, consumed following fasting baseline measurements<br>* Other names: Purified fish oil;|
| Experimental: Eicosapentaenoic acid and docosahexaenoic acid<br>5 g EPA and DHA derived from fish oil, made up to a total of 75 g with high oleic sunflower oil. | Dietary Supplement: High-fat meals varying in their fatty acid composition<br>* 70 g fat incorporated into a muffin and milkshake meal, consumed following fasting baseline measurements<br>* Other names: Purified fish oil;|
| Experimental: Docosahexaenoic acid<br>5 g DHA derived from algal oil, made up to a total of 75 g with high oleic sunflower oil. | Dietary Supplement: High-fat meals varying in their fatty acid composition<br>* 70 g fat incorporated into a muffin and milkshake meal, consumed following fasting baseline measurements<br>* Other names: Purified fish oil;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Activation of inflammatory/oxidative stress pathways within cultured endothelial cells following treatment with 6 h postprandial chylomicron remnant-rich lipoprotein fraction | The primary outcome of the study is activation of inflammatory/oxidative stress pathways within cultured endothelial cells following incubation with pooled postprandial lipoprotein fractions rich in chylomicron remnants. Due to the nature of this type of research this necessitates more than one primary outcome measure: the primary measures are NF-kappa-beta activation, cytokine production (e.g. interleukin-6) and reactive oxygen species generation in the cultured human endothelial cells. | 6 h post-meal | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incremental area under the plasma concentration versus time curve (iAUC) of triacylglycerol |  | 0, 1, 2, 3, 4, 5 and 6 h post-meal | 
| Incremental area under the plasma concentration versus time curve (iAUC) of glucose |  | 0, 1, 2, 3, 4, 5 and 6 h post-meal | 
| Incremental area under the plasma concentration versus time curve (iAUC) for non-esterified fatty acids |  | 0, 1, 2, 3, 4, 5 and 6 h post-meal | 
| Incremental area under the plasma concentration versus time curve (iAUC) for plasma fatty acid composition (%) |  | 0, 1, 2, 3, 4, 5 and 6 h post-meal | 
| Incremental area under the plasma concentration versus time curve (iAUC) for cholesterol |  | 0, 1, 2, 3, 4, 5 and 6 h post-meal | 
| Incremental area under the unit measure versus time curve for brachial augmentation index |  | 0, 30, 60, 90, 120, 150, 180, 210, 240, 270, 300, 330 and 360 min post-meal | 
| Incremental area under the unit measure versus time curve for systolic blood pressure |  | 0, 30, 60, 90, 120, 150, 180, 210, 240, 270, 300, 330 and 360 min post-meal | 
| Incremental area under the unit measure versus time curve for diastolic blood pressure |  | 0, 30, 60, 90, 120, 150, 180, 210, 240, 270, 300, 330 and 360 min post-meal | 
| Change in digital volume pulse stiffness index |  | 0, 2, 4 and 6 h post-meal | 
| Change in digital volume pulse reflection index |  | 0, 2, 4 and 6 h post-meal | 
| Change in plasma nitrite/nitrate concentrations |  | 0, 2, 4 and 6 h | 
| Change in plasma 8-isoprostane F2alpha concentrations |  | 0, 2, 4 and 6 h post-meal | 
| Activation of inflammatory/oxidative stress pathways within cultured endothelial cells following treatment with 4 h postprandial chylomicron remnant-rich lipoprotein fraction |  | 4 h post-meal | 
| Activation of inflammatory/oxidative stress pathways within cultured endothelial cells following treatment with 5 h postprandial chylomicron remnant-rich lipoprotein fraction |  | 5 h post-meal | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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n-3 PUFA, Endothelial cells, Nitric oxide, Oxidative stress, Blood pressure, Vasodilation, Lipemia, Unsaturated dietary fats