Omega -3 Fatty Acids & Heart Disease · Omega -3 Fatty Acids & Heart Disease: ... Blood lipids Arrhythmias ... (Thick uninflamed cap) Unstable plaques 29.8 32.2 15.1 **

© University of Reading 2007 www.reading.ac.uk

Professor Parveen Yaqoob

OmegaOmega--3 Fatty Acids & 3 Fatty Acids & Heart Disease:Heart Disease:

Just Another Fishy Story?Just Another Fishy Story?

Distribution of some major diseases Distribution of some major diseases

in Greenland Eskimos, 1950in Greenland Eskimos, 1950--19741974

DiseaseDisease No. of cases ExpectedNo. of cases Expected

no. of casesno. of cases

Cancer (all forms)Cancer (all forms) 4646 5353

ApoplexyApoplexy 2525 1515

EpilepsyEpilepsy 1616 88

Peptic ulcerPeptic ulcer 1919 2929

Multiple sclerosisMultiple sclerosis 00 22

PsoriasisPsoriasis 22 4040

Bronchial asthmaBronchial asthma 11 2525

Diabetes mellitusDiabetes mellitus 11 99

Acute myocardial infarctionAcute myocardial infarction 33 4040

The Eskimo DietThe Eskimo DietThe Eskimo Diet

•• Incidence of heart disease is Incidence of heart disease is

7.5% of predicted7.5% of predicted

•• Traditional diet is rich in fatTraditional diet is rich in fat

•• Whale and seal meats are eaten Whale and seal meats are eaten

almost every dayalmost every day

•• High intake of OmegaHigh intake of Omega--3 PUFA 3 PUFA

(> 12% of energy)(> 12% of energy)

Intake of nIntake of n--3 PUFA 3 PUFA

(g/day)(g/day)

Eskimo Adult UKEskimo Adult UK

EPAEPA 4.64.6

DPADPA 2.62.6 < 0.25< 0.25

DHADHA 5.95.9

Bang et al. (1980) American Journal of Clinical Nutrition 33; 26Bang et al. (1980) American Journal of Clinical Nutrition 33; 265757--26612661

Dietary sources of long

chain n-3 PUFA

Dietary sources of long Dietary sources of long

chain nchain n--3 PUFA3 PUFA

Long chain nLong chain n--3 PUFA (EPA, 3 PUFA (EPA,

DPA, DHA) found in:DPA, DHA) found in:

oily fishoily fish (tuna, herring, (tuna, herring,

mackerel, salmon);mackerel, salmon);

fish oilsfish oils (e.g. cod liver oil). (e.g. cod liver oil).

Metabolism of n-6 and n-3 PUFAMetabolism of nMetabolism of n--6 and n6 and n--3 PUFA3 PUFA

Linoleic acid (18:2nLinoleic acid (18:2n--6)6)

GLA (18:3nGLA (18:3n--6)6)

DGLA (20:3nDGLA (20:3n--6)6)

Arachidonic acid (20:4nArachidonic acid (20:4n--6)6)

66--desaturasedesaturase

ElongaseElongase

55--desaturasedesaturase

αααααααα--Linolenic acid (18:3nLinolenic acid (18:3n--3)3)

18:4n18:4n--33

20:4n20:4n--33

EPA (20:5nEPA (20:5n--3)3)

DPA (22:5nDPA (22:5n--3)3) DHA (22:6nDHA (22:6n--3)3)

FOUND IN OILY FISH FOUND IN OILY FISH

& FISH OIL& FISH OIL

UK Recommendation for nUK Recommendation for n--3 PUFA Intakes3 PUFA Intakes

Department of Health, 1994Department of Health, 1994

& Scientific Advisory Committee for Nutrition, 2004:& Scientific Advisory Committee for Nutrition, 2004:

Individuals should consume at least 2 portions of fish Individuals should consume at least 2 portions of fish

per week, one of which should be oily.per week, one of which should be oily.

Current average intakes are 0.3 portions per weekCurrent average intakes are 0.3 portions per week

and 70% of adults eat no oily fish at all.and 70% of adults eat no oily fish at all.

•• NICENICE

Patients should be advised to eat at least two to four Patients should be advised to eat at least two to four portions of oily fish per week.portions of oily fish per week.

If they are not achieving this and have had an MI If they are not achieving this and have had an MI within the past 3 months consider providing at least within the past 3 months consider providing at least 1g daily of omega1g daily of omega--3 acid ethyl esters treatment 3 acid ethyl esters treatment licensed for secondary prevention post MI for up to 4 licensed for secondary prevention post MI for up to 4 years.years.

•• AHA, USAHA, US

500mg/day EPA+DHA500mg/day EPA+DHA

1.0g/day EPA+DHA1.0g/day EPA+DHA-- diagnosed cardiovascular diagnosed cardiovascular diseasedisease

Other recommendations for nOther recommendations for n--3 PUFA Intakes3 PUFA Intakes

Current UK Intakes of EPA and Current UK Intakes of EPA and

DHADHA

Givens & Gibbs (2006)Givens & Gibbs (2006) 244 mg/d244 mg/d

Euwijk & Vermunt (2007)Euwijk & Vermunt (2007) 246 mg/d246 mg/d

SACN recommendationSACN recommendation 450 mg/d450 mg/d

NICE recommendationNICE recommendation 1000 mg/d1000 mg/d

Fish Consumption & CHD Mortality:Fish Consumption & CHD Mortality:A MetaA Meta--AnalysisAnalysis

11 eligible studies including 222 364 individuals with an averag11 eligible studies including 222 364 individuals with an averagee

of 11.8 y of followof 11.8 y of follow--up.up.

Fish intakeFish intake Pooled RRPooled RR

11--3 times per month3 times per month 0.89 (95% CI 0.79 to 1.01)0.89 (95% CI 0.79 to 1.01)

Once per weekOnce per week 0.85 (95% CI 0.76 to 0.96)0.85 (95% CI 0.76 to 0.96)

22--4 times per week4 times per week 0.77 (95% CI 0.66 to 0.89)0.77 (95% CI 0.66 to 0.89)

5 or more times per week5 or more times per week 0.62 (95% CI 0.46 to 0.82)0.62 (95% CI 0.46 to 0.82)

Conclusion: Each 20 g/d increase in fish intake was related to aConclusion: Each 20 g/d increase in fish intake was related to a

7% lower risk of CHD mortality (P=0.03).7% lower risk of CHD mortality (P=0.03).

He et al., (2004) Circulation 109; 2705He et al., (2004) Circulation 109; 2705--27112711

80080060060040040020020000

8585

9090

9595

100100

Time

Burr et al. (1989) Lancet ii, 757Burr et al. (1989) Lancet ii, 757--761761

Oily fishOily fish

No adviceNo advice

InterventionIntervention-- The DART StudyThe DART Study�� 2033 men aged <70y who2033 men aged <70y who

had suffered an MIhad suffered an MI

�� Advised to eat oily fish orAdvised to eat oily fish or

take fish oil supplementstake fish oil supplements

(3 x 0.5g/d) vs no advice(3 x 0.5g/d) vs no advice

�� CV events and mortalityCV events and mortality

followed for 2yfollowed for 2y

�� 29% reduction in mortality29% reduction in mortality

�� 16% reduction in CV death16% reduction in CV death

% survivors

GISSI Prevenzione Investigators (1999) Lancet 354, 447GISSI Prevenzione Investigators (1999) Lancet 354, 447--455455

Relative risk in fish oil groupRelative risk in fish oil group

InterventionIntervention-- The GISSI StudyThe GISSI Study

�� 11,324 men who had suffered11,324 men who had suffered

MI in the previous 3 monthsMI in the previous 3 months

�� Fish oil vs no treatment Fish oil vs no treatment

(1g n(1g n--3 PUFA/d)3 PUFA/d)

�� FollowFollow--up for 2yup for 2y

Death, nonDeath, non--fatal MI, strokefatal MI, stroke 0.900.90

CV death, nonCV death, non--fatal MI, strokefatal MI, stroke 0.850.85

NN--3 PUFA benefit CVD outcomes:3 PUFA benefit CVD outcomes:

systematic reviewsystematic review

Included 14 RCTs, 25 prospective cohort studies and 7 caseIncluded 14 RCTs, 25 prospective cohort studies and 7 case--

control studies of fish oil supplements or diets high in ncontrol studies of fish oil supplements or diets high in n--3 PUFA3 PUFA

Evidence suggests that increased consumption of nEvidence suggests that increased consumption of n--3 PUFA3 PUFA

reduces the rates of allreduces the rates of all--cause mortality, cardiac and sudden death,cause mortality, cardiac and sudden death,

and possibly stroke.and possibly stroke.

However, aHowever, a--linolenic acid has no effect.linolenic acid has no effect.

Wang et al., (2006) Am J Clin Nutr 84; 5Wang et al., (2006) Am J Clin Nutr 84; 5--1717

Risks and benefits of omegaRisks and benefits of omega--3 fats:3 fats:

systematic reviewsystematic review

Included 48 RCTs and 41 cohort studies (short and long chain)Included 48 RCTs and 41 cohort studies (short and long chain)

““Results inconsistentResults inconsistent””

No strong evidence of reduced risk of total mortality orNo strong evidence of reduced risk of total mortality or

cardiovascular eventscardiovascular events

This systematic review includes the angina study by Burr et al.,This systematic review includes the angina study by Burr et al.,

which has been much criticisedwhich has been much criticised

Hooper et al., (2006) Br Med J 332; 752Hooper et al., (2006) Br Med J 332; 752--760760

Rauch et al., (2010) OMEGA, a randomized, placeboRauch et al., (2010) OMEGA, a randomized, placebo--controlled trial to test the effect of highly purifiedcontrolled trial to test the effect of highly purified

omegaomega--3 fatty acids on top of modern guideline3 fatty acids on top of modern guideline--adjusted therapy after myocardial infarction. Circulation 122, 2adjusted therapy after myocardial infarction. Circulation 122, 2152152--21592159

Results of the OMEGA studyResults of the OMEGA study�� 3851 patients 33851 patients 3--14 days after MI14 days after MI

undergoing standard therapyundergoing standard therapy

(including coronary angiography(including coronary angiography

& other intervention)& other intervention)

�� 1 g/d omega1 g/d omega--3 ethyl esters 3 ethyl esters

(460 mg EPA, 380mg DHA) or (460 mg EPA, 380mg DHA) or

1g olive oil (placebo).1g olive oil (placebo).

�� FollowFollow--up for 1 yrup for 1 yr-- all primaryall primary

and secondary eventsand secondary events

No effect on sudden cardiac death.No effect on sudden cardiac death.

No effect on total mortality.No effect on total mortality.

No effect on nonNo effect on non--fatal events.fatal events.

•• Low overall numbers of events.Low overall numbers of events.

•• Beneficial effects of nBeneficial effects of n--3 PUFA 3 PUFA

overestimated? Power based on 45% risk overestimated? Power based on 45% risk

reduction in absence of CV therapy. reduction in absence of CV therapy.

•• A 30% effect would require ~20,000 A 30% effect would require ~20,000

patients.patients.

•• High levels of fish consumption.High levels of fish consumption.

The OMEGA StudyThe OMEGA Study

Kromhout et al., (2010) nKromhout et al., (2010) n--3 Fatty acids and Cardiovascular Events after Myocardial Infarct3 Fatty acids and Cardiovascular Events after Myocardial Infarction. New Engl J Med 363, 21.ion. New Engl J Med 363, 21.

ResultsResults

�� 4837 MI patients, 604837 MI patients, 60--80y, 80y,

receiving antihypertensive, antireceiving antihypertensive, anti--

thrombotic and lipid modifyingthrombotic and lipid modifying

therapy.therapy.

�� 40 months intervention with40 months intervention with

margarine: EPA+DHA (400mg/d),margarine: EPA+DHA (400mg/d),

ALA (2g/d), EPA+DHA+ALA orALA (2g/d), EPA+DHA+ALA or

placebo.placebo.

�� Primary endpoint: rate of majorPrimary endpoint: rate of major

CV events (fatal, nonCV events (fatal, non--fatal,fatal,

CV intervention).CV intervention).

•• 671 CV events (13.9%).671 CV events (13.9%).

•• No effect of any treatment.No effect of any treatment.

•• Low dose.Low dose.

Kromhout study 2010Kromhout study 2010

Possible mechanisms for effectsPossible mechanisms for effects

of nof n--3 PUFA in CHD3 PUFA in CHD

Blood clottingBlood clotting

Blood pressureBlood pressure

Blood lipidsBlood lipids

ArrhythmiasArrhythmias

InflammationInflammation

Eicosanoid synthesisEicosanoid synthesis

Arachidonic acidArachidonic acid

Eicosapentaenoic acidEicosapentaenoic acid

Leukotrienes (4Leukotrienes (4--series)series)

Leukotrienes (5Leukotrienes (5--series)series)Prostaglandins, thromboxanes (2Prostaglandins, thromboxanes (2--series)series)

Prostaglandins, thromboxanes (3Prostaglandins, thromboxanes (3--series)series)

Lipoxygenase pathwayLipoxygenase pathway Cyclooxygenase pathwayCyclooxygenase pathway


Cell adhesionCell adhesion

ChemotaxisChemotaxis


ImmunityImmunity


PainPain


Bleeding time in Greenland EskimosBleeding time in Greenland Eskimos

Bleeding time (min)Bleeding time (min)

EskimosEskimos 8.05 8.05 ±± 2.562.56

DanesDanes 4.76 4.76 ±± 1.391.39

Significant difference (P<0.01; Wilcoxon signed ranks test)Significant difference (P<0.01; Wilcoxon signed ranks test)

Data are mean Data are mean ±± SD for 21 Eskimos and 21 sexSD for 21 Eskimos and 21 sex-- and ageand age--matched Danes.matched Danes.

Dyerberg & Bang (1979) Lancet 433Dyerberg & Bang (1979) Lancet 433--435435

Thorngren & Gustafson (1981) Lancet ii, 1190Thorngren & Gustafson (1981) Lancet ii, 1190--11931193

ResultResult

Oily Fish & Bleeding TimeOily Fish & Bleeding Time

�� 10 healthy young men10 healthy young men

(students at Lund University)(students at Lund University)

�� Increased intake of mackerelIncreased intake of mackerel

& salmon for 11 weeks,& salmon for 11 weeks,

providing 2providing 2--3 g/d EPA3 g/d EPA

�� Bleeding time & plateletBleeding time & platelet

aggregation assessedaggregation assessed

Fish diet prolonged bleeding timeFish diet prolonged bleeding time

by 42% and decreased plateletby 42% and decreased platelet

aggregabilityaggregability

MetaMeta--analysis of trials of fish oilanalysis of trials of fish oil

& blood pressure& blood pressure

36 controlled trials reviewed incl. 22 double blind36 controlled trials reviewed incl. 22 double blind

Fish oil:Fish oil:

-- decreased systolic BP by 2.1 mm Hg decreased systolic BP by 2.1 mm Hg

(95% CI 1.0, 3.2; P < 0.01)(95% CI 1.0, 3.2; P < 0.01)

-- decreased diastolic BP by 1.6 mm Hg decreased diastolic BP by 1.6 mm Hg

(95% CI 1.0, 2.2; P < 0.01)(95% CI 1.0, 2.2; P < 0.01)

Effects greater in older subjectsEffects greater in older subjects

Effects greater in hypertensive subjectsEffects greater in hypertensive subjects

Conclusion Conclusion ““increased intake of fish oil may lower BP, increased intake of fish oil may lower BP,

especially in older and hypertensive subjectsespecially in older and hypertensive subjects””

Geleijnse et al. (2002) J. Hypertens. 20, 1493Geleijnse et al. (2002) J. Hypertens. 20, 1493--14991499








Blood lipids in Greenland EskimosBlood lipids in Greenland Eskimos

EskimosEskimos DanesDanes

CholesterolCholesterol 2.33 2.33 ±± 0.350.35 2.73 2.73 ±± 0.490.49

(g/L)(g/L)

TriglyceridesTriglycerides 0.57 0.57 ±± 0.4280.428 1.29 1.29 ±± 0.620.62

(g/L)(g/L)

Significant difference (P<0.001)Significant difference (P<0.001)

Data are mean Data are mean ±± SD for 61 male Eskimos and sexSD for 61 male Eskimos and sex-- and ageand age--matched Danes.matched Danes.

Dyerberg & Bang (1971) Lancet 1143Dyerberg & Bang (1971) Lancet 1143--11451145

-50

-40

-30

-20

-10

0

10

20

TC

TAG

Fish oil lowers blood Fish oil lowers blood triglycerides,triglycerides,

but not blood cholesterolbut not blood cholesterol

% change

**

LeighLeigh--Firbank L, et al. British Journal of Nutrition 2002;87:435Firbank L, et al. British Journal of Nutrition 2002;87:435--445. 445.

Minihane AM, et al. Arteriosclerosis Thrombosis and Vascular BioMinihane AM, et al. Arteriosclerosis Thrombosis and Vascular Biology 2000;20:1990logy 2000;20:1990--7. 7.








GISSI GISSI PrevenzionePrevenzione Investigators (1999) Lancet 354, 447Investigators (1999) Lancet 354, 447--455455

Relative risk in fish oil groupRelative risk in fish oil group

InterventionIntervention-- The GISSI StudyThe GISSI Study

�� 11,372 men who had suffered11,372 men who had suffered

MI in the previous 3 monthsMI in the previous 3 months

�� Fish oil Fish oil vsvs placebo placebo

(1g n(1g n--3 PUFA/d)3 PUFA/d)

�� FollowFollow--up for 2yup for 2y

Death, nonDeath, non--fatal MI, strokefatal MI, stroke 0.850.85

CV death, nonCV death, non--fatal MI, strokefatal MI, stroke 0.800.80

All fatal eventsAll fatal events 0.800.80

CV deathCV death 0.700.70

Sudden deathSudden death 0.550.55








•• 162 patients undergoing carotid endarterectomy162 patients undergoing carotid endarterectomy

•• Placebo vs sunflower oil vs fish oilPlacebo vs sunflower oil vs fish oil

•• 6 g oil/d (0.86g EPA + 0.5g DHA per d)6 g oil/d (0.86g EPA + 0.5g DHA per d)

•• Duration 7Duration 7--190 days190 days

Carotid plaque studyCarotid plaque study

Thies, Garry, Yaqoob, Rerkasem, Shearman, Gallagher, Calder, GriThies, Garry, Yaqoob, Rerkasem, Shearman, Gallagher, Calder, Grimblemble

Lancet (2003) 361, 477Lancet (2003) 361, 477--485485

nn--3 fatty acids in carotid plaque lipids3 fatty acids in carotid plaque lipids

PlaceboPlacebo SOSO Fish oilFish oil

EPA in PLEPA in PL 0.60.6 0.60.6 1.1**1.1**

DHA in PLDHA in PL 3.33.3 2.92.9 3.6*3.6*

Significant linear correlation between length of fish Significant linear correlation between length of fish

oil supplementation and %EPA in plaqueoil supplementation and %EPA in plaque


Lancet (2003) 361, 477Lancet (2003) 361, 477--485485

Plaque stability : AHA classificationPlaque stability : AHA classification


Stable plaquesStable plaques 59.659.6 60.760.7 71.771.7****

(Thick uninflamed cap)(Thick uninflamed cap)

Unstable plaquesUnstable plaques 29.829.8 32.232.2 15.115.1****

(Thin, inflamed cap)(Thin, inflamed cap)

There was a positive relationship between plaque stability There was a positive relationship between plaque stability

and omegaand omega--3 content of the plaque i.e. more stable plaques 3 content of the plaque i.e. more stable plaques

contained more EPA and DHA than unstable plaquescontained more EPA and DHA than unstable plaques


Lancet (2003) 361, 477Lancet (2003) 361, 477--485485

Macrophage infiltration into plaqueMacrophage infiltration into plaque


Macrophage stainingMacrophage staining

NoneNone 2.62.6 00 00

ModerateModerate 13.213.2 19.419.4 38.138.1****

HeavyHeavy 84.284.2 80.680.6 61.961.9****

There was a negative relationship between macrophage There was a negative relationship between macrophage

staining and omegastaining and omega--3 content of the plaque i.e. plaques 3 content of the plaque i.e. plaques

with more macrophages contained less EPA and DHA with more macrophages contained less EPA and DHA


Lancet (2003) 361, 477Lancet (2003) 361, 477--485485

Estimated doses required for specificEstimated doses required for specific

effects on CVD risk factorseffects on CVD risk factors

↓↓ thrombosis (>2g/d)thrombosis (>2g/d)

Improves plaque Improves plaque

stability (~1.5g/d)stability (~1.5g/d) ↓↓ blood pressureblood pressure

(>2(>2--3g/d)3g/d)

inflammation/endothelial function/vascular inflammation/endothelial function/vascular

tone > 2g/dtone > 2g/d+ve effects on blood lipids +ve effects on blood lipids

(>2g/d)(>2g/d)

SummarySummary

•• Consumption of fish is associated with a lower risk of mortalitConsumption of fish is associated with a lower risk of mortalityy

•• Fish oil supplementation has been shown to decrease mortalityFish oil supplementation has been shown to decrease mortality

in some secondary prevention trials of cardiovascular diseasein some secondary prevention trials of cardiovascular disease

•• OmegaOmega--3 fatty acids could protect against heart disease through3 fatty acids could protect against heart disease through

effects on blood lipids, blood clotting, arrhythmias & inflameffects on blood lipids, blood clotting, arrhythmias & inflammationmation

•• Fish oil supplementation has been shown to improve plaqueFish oil supplementation has been shown to improve plaque

stability in carotid endarterectomy patientsstability in carotid endarterectomy patients

Omega -3 Fatty Acids & Heart Disease · Omega -3 Fatty Acids & Heart Disease: ... Blood lipids Arrhythmias ... (Thick uninflamed cap) Unstable plaques 29.8 32.2 15.1 **

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