CVD, Diet and Omega-3 - Anne Minihane

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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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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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

Documents

CVD, Diet and Omega-3 - Anne Minihane