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8/14/2019 CVD, Diet and Omega-3 - Anne Minihane
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Diet matters: dietary influence on CVDrisk, with particular reference to
essential fatty acids
Anne M Minihane, BSc, PhD, RNutrHugh Sinclair Human Nutrition Group
University of Reading
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Cardiovascular disease (CVD), definitions, incidence,
pathology
Dietary fat composition
Dietary fat and blood lipids
Essential fatty acid metabolism
Fatty acids/inflammation/CVD
n-3 fatty acids and plaque stability
Genotype, CVD risk and responsiveness to dietary fatty acidchange
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Cardiovascular Disease (CVD)
Coronary Heart Disease (CHD)-angina pectoris-myocardial infarction
-sudden death
Stroke Other vasculardiseases
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Mortality rates in the UK:
CVD remains the major killer!
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Mortality from circulatory diseases GB
(1920-1999) males 15-74y (per 1,000,000)
0
1000
2000
3000
4000
5000
6000
1919 1929 1939 1949 1959 1969 1979 1989 1999
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Diabetes: the epidemic of the 21st century
million
Man may be captain of his fate but is also thevictim of his blood sugar (Oakley, 1962)
150
220
300
0
50
100
150
200
250
300
2000 2010 2025
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Insulin resistance
obesity
age
Sedentary
lifestyle
DIET
Causes and consequences of insulin resistance
Dyslipidaemia-high triglycerides
-low HDL
-high LDL-3
Increased coagulation
hyperglycaemia
hyperinsulinaemia
hypertension
genetics
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Myocardial Infarction
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Development of atherosclerosis
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The Lipid Accumulation Hypothesis
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The Response to Injury Hypothesis
Glass and Witzum, 2001
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Glass and Witzum, 2001
The Response to Injury Hypothesis (contd)
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CHD Pathology
cholesterol
Oxidative Status
Thrombosis &fibrinolysis
Vascular tone& BP
Plaque structure
Inflammation
homocysteine Adipose tissue mass/topography
triglycerides
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Dietary fat quality & quantity arguably the
most important dietary factors influencing
CVD risk 95% as triglycerides
remainder as cholesterol, phospholipids & minor fats
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Long chain n-3 (-3) PUFA
O
O
Eicosapentaenoic acid (EPA, C20:5, n-3)
O
O
Docosahexaenoic acid (DHA, C22:6, n-3)
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Fat composition of common fat sources
0%
10%
20%
30%
40%50%
60%
70%
80%
90%
100%
Dairyfat
Lard
Coconutoil
Palmo
il
CornOil
SafflowerOil
SunflowerOil
RapeseedOil
SoyaOil
OliveOil
Codliveroil
% PUFA
% MUFA
% SFA
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Macronutrient composition of UK diet
16.5 16.6
47.7 48.5
35.8 34.9
13.4 13.2
1.2 1.2
12.1 11.5
5.4 5.3
1.0 1.0
0
10
20
30
40
50
60
%d
ietaryenergy
Protein
CHO
totalfat
SFA
trans-FA
MUFA
PUFAn-6
PUFAn-3
men
women
National Diet & Nutrition Survey 2003
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Essential fatty acid metabolism
C18:2 (n-6) (linoleic acid) C18:3 (n-3) (linolenic acid)
C18:3 (n-6) (-linolenic acid) C18:4 (n-3)
C20:3 (n-6) (dihomo--linolenic acid) C20:4 (n-3)
C20:4 (n-6) (arachadonic acid) C20:5 (n-3) (EPA)
C20:6 (n-3) (DHA
- 6 desaturase
elongase
- 5 desaturase
1.5g/d12g/d
0.5g/d0.2g/d
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Dietary fat & blood lipids
SFA especially C12:0, C14:0, C16:0 LDL-CTrans fatty acids LDLC HDLCCholesterol may LDLC
When replacing SFA in diet
MUFA/n-6 PUFA LDL
High n-6 PUFA may HDLC ?
EPA/DHA triglyceridesmay HDL-C LDL-3
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6 x 1g capsules (50% EPA / DHA) / day or 6g olive
oil/day for 6 weeks with a 12 week washout
Double-blind placebo-controlled cross over study- n=55
Griffin,Minihane et al., 1999
Fish oils & blood lipids in men with dyslipidaemia of diabetes
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-50
-40
-30
-20
-10
0
10
20
TCHDL TAGLD L
LDL-3
Ef fects o f f is h oils on trigly cerides fibra tes
Minihaneet al., 2000a ATVB
%C
hange
****
* p< 0.05 ** p< 0.001
*
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Is EPA or DHA the active component in fish oils?
-40
-35-30
-25
-20
-15-10
-5
0
placebo EPA DHA
% change TG
n=4 weeks, 4.8g EPA/DHA per day
Buckley, Minihane et al., 2004
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Fatty acids, inflammationFatty acids, inflammation
& eicosanoid synthesis& eicosanoid synthesisArachidonic acidArachidonic acid
Leukotrienes (4-series)Leukotrienes (4-series) Prostaglandins, thromboxanes (2-series)Prostaglandins, thromboxanes (2-series)
Lipoxygenase pathwayLipoxygenase pathway Cyclooxygenase pathwayCyclooxygenase pathway
InflammationInflammationCell adhesionCell adhesion
ChemotaxisChemotaxis
InflammationInflammationImmunityImmunity
Blood pressureBlood pressure
PainPain
Blood clottingBlood clotting
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Some pro-inflammatory roles of eicosanoidsSome pro-inflammatory roles of eicosanoids
synthesised from arachidionic acidsynthesised from arachidionic acid
PGE2PGE2Induces feverInduces fever
Increases vascular permeabilityIncreases vascular permeabilityIncreases vasodilationIncreases vasodilation
Causes painCauses pain
Enhances pain caused by other agentsEnhances pain caused by other agents
Induces COX-2Induces COX-2
Increases production of IL-6Increases production of IL-6
LTB4LTB4Increases vascular permeabilityIncreases vascular permeability
Enhances local blood flowEnhances local blood flowChemotactic agent for leukocytesChemotactic agent for leukocytes
Induces release of lysosomalInduces release of lysosomal
enzymesenzymes
Induces release of reactiveInduces release of reactive
oxygen speciesoxygen species
Increases production of TNF, IL-1Increases production of TNF, IL-1and IL-6and IL-6
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Eicosanoid synthesisEicosanoid synthesis
Arachidonic acidArachidonic acid
Eicosapentaenoic acidEicosapentaenoic acid
Leukotrienes (4-series)Leukotrienes (4-series)
Leukotrienes (5-series)Leukotrienes (5-series)Prostaglandins, thromboxanes (2-series)Prostaglandins, thromboxanes (2-series)
Prostaglandins, thromboxanes (3-series)Prostaglandins, thromboxanes (3-series)
Lipoxygenase pathwayLipoxygenase pathway Cyclooxygenase pathwayCyclooxygenase pathway
InflammationInflammationCell adhesionCell adhesion
ChemotaxisChemotaxis
InflammationInflammationImmunityImmunity
Blood pressureBlood pressure
PainPain
Blood clottingBlood clotting
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ARACHIDONIC ACIDARACHIDONIC ACID
2-Series PG2-Series PG 4-Series LT4-Series LT
Inflammation andInflammation and
dysregulated immunitydysregulated immunity
EPAEPA
3-Series PG3-Series PG 5-Series LT5-Series LT
Less inflammationLess inflammation
and improved immunityand improved immunity
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ArachidonicArachidonic acidacid EPAEPAEPA
00
1010
2020
3030
%o
fTotalfattyacidsin
%ofTotalfattyacidsin
%ofTotalfattyaci
dsin
mousemacropha
ges
mousemacropha
ges
Low fatLow fat
Coconut oilCoconut oil
Olive oilOlive oil
Safflower oilSafflower oil
Fish oilFish oil
Dietary means of decreasing theDietary means of decreasing theAA:EPA ratio of membranes (1) fish oil feedingAA:EPA ratio of membranes (1) fish oil feeding
Wallace et al., (2000) Immunol. & Cell Biol., 78; 40-48Wallace et al., (2000) Immunol. & Cell Biol., 78; 40-48
Di t m n f d in thDietary means of decreasing the
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-2.5
-2.0
-1.5
-1.0
-0.5
0.0
0.5
1.0
placebo
medium EPA/DHA
high EPA/DHA
medium ALNA
high ALNA
*ALNAC18:3
AA C20:4
DTA C22:4
%p
lateletphospholipidfattyacid
**
**
Dietary means of decreasing theDietary means of decreasing theAA:EPA ratio of membranes (2) ALNA feedingAA:EPA ratio of membranes (2) ALNA feeding
Finnegan, Minihane et al., AJCN 2003
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-1.0
-0.5
0.0
0.5
1.0
1.5
placebo
medium EPA/DHA
high EPA/DHA
medium ALNA
high ALNA
%p
lateletphospholipidFAacid
*
*
**
*
*
EPA
C20:5
DPA
C22:5 DHA
C22:6
Dietary means of decreasing theDietary means of decreasing theAA:EPA ratio of membranes (2) ALNA feedingAA:EPA ratio of membranes (2) ALNA feeding
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Essential fatty acid metabolism
C18:2 (n-6) (linoleic acid) C18:3 (n-3) (linolenic acid)
C18:3 (n-6) (-linolenic acid) C18:4 (n-3)
C20:3 (n-6) (dihomo--linolenic acid) C20:4 (n-3)
C20:4 (n-6) (arachadonic acid) C20:5 (n-3) (EPA)
C20:6 (n-3) (DHA
- 6 desaturase
elongase
- 5 desaturase
1.5g/d12g/d
0.5g/d0.2g/d
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Plaque stability and acute events
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Fish oil supplementation & plaque stabilityThies, Calderet al., Lancet 2003
n=162
patients awaiting carotid endarterectomy
placebo vs sunflower oil vs fish oil (6g, 1.4g EPA+DHA/d)
7-189d, median 42d
Principal outcomes
- EPA/DHA plaque lipids
- morphology (Type 4- fibrous, Type 5- thin)- macrophage content of plaque
EPA/DHA t t f l
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EPA/DHA content of plaques
Thies, Calder et al., Lancet 2003
g/100g total fatty acids in phospholipids
Placebo Sunflower oil Fish oil
EPA 0.6(0.4) 0.6(0.5) 1.1 (0.6)*
DHA 3.3(1.2) 2.9(1.0) 3.6(1.2)*
Mean(SD) * P
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Plaque morphologyThies, Calderet al., Lancet 2003
60
30
61
32
72
15
0
10
20
30
4050
60
70
80
placebo sunflower
oil
fish oil
AHA- Type 4
AHA- Type 5
% of plaques
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Monocyte infiltrationThies, Calderet al., Lancet 2003
13
84
19
81
38
62
0
10
20
30
4050
60
70
80
90
placebo sunflower
oil
fish oil
Moderate
Heavy
%
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GENOTYPE, CVD RISK AND
RESPONSIVENESS TO DIETARY FATCHANGE
Potential of genetic screening for the earlyidentification of disease risk and the
personalisation of therapeutic advice
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Nature 409 15 Feb 2001
www.nature.com/genomics/human/
The Human Genome Project
Science 16 Feb 2001
www.sciencemag.org/genome2001/
Celera
~ 35,000 genes
15-20,000 involved in CHD
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Genetic Variation
99.8% genetic information homogenous
0.2% variable- insertions or deletions (e.g. Familial Hypercholesterolaemia)
- repeat sequences (e.g. Huntington disease CAG repeats)
- single nucleotide polymorphisms (SNPs) (mostmultifactorial diseases- over 200,000 functional SNPs
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Genotype
Risk of CHD
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1role:- lipoprotein metabolism- mediator of oxidative status
Apolipoprotein E
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Polymorphic protein
3 common alleles
-E2 Cys 112, Cys 158
-E3 Cys 112, Arg 158
-E4 Arg 112, Cys 158
0
10
20
30
40
50
60
apoE2 apoE3 apoE4
12-15%
55-60%
25-27%
%freque
ncy
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apoE genotype and CHD
Meta-analysisWilson PWF et al.,
1996
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apoE genotype & AD incidence
1
4
16
0
24
6
8
10
1214
16
18
20
no E4 allele 1 E4 allele 2 E4 alleleIncide
nceofAlzheimers
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apoE genotype CHD/atherosclerosis
apoE genotype:
cholesterol clearance
apoE genotype:
antioxidant
status
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apoE genotype & CHD risk in part attributable to
circulating cholesterol levels
4.02
4.29
4.51
2.28
2.69
2.90
2
3
4
5
TC LDLC
E2+
E3/E3
E4+
EARS 11 study, 415 controls, Dallongeville, 1999
(mmo
l/l)
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NCEP diet Sarkkinen et al 1998
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-1
-0.8
-0.6
-0.4
-0.2
0
0.2
TC LDLC HDLC TG
E3E3
E3E4
E4E4
-0.2
-0.1
0
0.1
0.2
0.3
0.4
0.5
0.6
TC LDLC HDLC TG
The impact of apoE genotype
on cholesterol levels/CHD risk
depends on the total fat and
cholesterol content of the
background diet
NCEP diet
NCEP diet+ cholesterol
Sarkkinen et al., 1998
Cha ng e ( m
mo l/l)
Cha ng e ( mm
o l /l)
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-50
-40
-30
-20
-10
0
10
20
-30
-25
-20
-15
-10
-5
0TCHD L TAGLDL
LD L-3 TAG TAGNEFAAU C IAUCAU C
Eff ect of Fish O il on Fas ting andPos tprandial Lipids
AUC = area under the Postprandial TG Curve
IAUC = Incremental area under the PP TG curve
Minihaneet al., 2000a ATVB
%
Change
****
**
* p< 0.05 ** p< 0.001
*
**
Minihane et al 2000
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% change LDL-C by apoE genotype
0
5
10
15
20
25
1 2 3
apoE subgroup
%
changeLDL-C
Fat composition
and apoE genotype-
cholesterol-CHD
associations
E2 E3 E4
Minihane et al., 2000
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More widespread genetic testing-ethics
Refinement of family history Diagnosis of risk prior to development of disease Early intervention-delay or prevent pathology
Personalised health advice Stress-benefit: effective treatment needed Should testing be compulsory? Who has access to information?
Could genetic testing result in discrimination? Currently Human Genetic Commission has set up a5y amnesty
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Summary points
CVD remains the greatest cause of morbidity and mortality
in the UK Inflammatory processes are central to the pathophysiology
of the disease
Diet and in particular dietary fat has a large impact on
atherosclerosis/thrombosis Fish oil fatty acids are cardioprotective by an array of
molecular mechanisms
An individuals genotype is an important predictor ofdisease risk and response to dietary change. However, the
potential of genetic screening as a public health measureremains to be established