omega-3 fatty acids: an untapped resource for improving health r. curtis ellison, md professor of...

Omega-3 Fatty Acids: An Untapped Resource for

Improving Health

R. Curtis Ellison, MDR. Curtis Ellison, MDProfessor of Medicine & Public HealthProfessor of Medicine & Public Health

Director, Institute on Lifestyle & HealthDirector, Institute on Lifestyle & Health

Boston University School of MedicineBoston University School of Medicine

Boston, MA, Boston, MA,

Omega-3 Fatty Acids

* Certain plants contain * Certain plants contain alpha-linolenic acid (ALA)alpha-linolenic acid (ALA)

(plankton, flaxseed, canola oil, soy bean oil)(plankton, flaxseed, canola oil, soy bean oil)

* When fish eat plankton, ALA is changed into* When fish eat plankton, ALA is changed into

“ “fish oils” (fish oils” (EPA and DHAEPA and DHA) )

* Humans get omega-3 from fish or fish oils (EPA,* Humans get omega-3 from fish or fish oils (EPA,

DHA), or from plants, especially canola oil (ALA) DHA), or from plants, especially canola oil (ALA)

Omega-3 Fatty Acids & CHD

Many studies have shown that Many studies have shown that fish consumptionfish consumption decreases coronary heart disease (CHD)decreases coronary heart disease (CHD)

Many studies have shown that taking Many studies have shown that taking fish oilsfish oils decreases CHD, especially sudden deathdecreases CHD, especially sudden death

Limited studies on Limited studies on ALAALA, but ALA has potential , but ALA has potential advantages over fish oilsadvantages over fish oils

Diet & Coronary Heart Disease (CHD)

Before WWII, CHD uncommonBefore WWII, CHD uncommon

In 1950’s-60’s, CHD became an In 1950’s-60’s, CHD became an “epidemic,” killing 2 million/yr in US“epidemic,” killing 2 million/yr in US

Stimulated research on CHD Stimulated research on CHD by by epidemiologistsepidemiologists

Epidemiologists?What Do Epidemiologists Do?

We count bodies!We count bodies!

400 dead bodies in one group 400 dead bodies in one group

200 dead bodies in another group200 dead bodies in another group

What Else Do Epidemiologists Do?

We try to determine what We try to determine what

is causing the difference?is causing the difference?

(Are differences in (Are differences in dietdiet explaining the differences explaining the differences

in deaths between the two groups?)in deaths between the two groups?)

The Seven Countries Study

* Cohorts of healthy men recruited in 7 * Cohorts of healthy men recruited in 7

countriescountries (Greece, Italy, Yugoslavia, Holland, (Greece, Italy, Yugoslavia, Holland, Finland, USA, Japan) Finland, USA, Japan)

** Diet and other lifestyle factors assessed,Diet and other lifestyle factors assessed,

laboratory tests done in early 1960slaboratory tests done in early 1960s

* Subjects followed over > 25 years* Subjects followed over > 25 years

Coronary Heart Disease: Seven Dietary Factors

(Ulbricht and Southgate, Lancet, 1992)

Dietary Promoting Factors?Dietary Promoting Factors?

Saturated fatty acidsSaturated fatty acids * Hypercholesterolemic Fatty Acids* Hypercholesterolemic Fatty Acids (12:0, 14:0, 16:0)(12:0, 14:0, 16:0)

* * Thrombogenic Fatty AcidsThrombogenic Fatty Acids (14:0, 16:0, 18:0)(14:0, 16:0, 18:0)

Lowering Saturated Fat & CVD: Results from 27 Randomized Trials

Total mortality RR = 0.98 Total mortality RR = 0.98 (0.86-1.12)(0.86-1.12)

CV mortality RR = 0.91 CV mortality RR = 0.91 (0.77-1.07)(0.77-1.07)

CV events RR = 0.84 CV events RR = 0.84 (0.72-0.99) (0.72-0.99)

BMJ 2001;322:757-63BMJ 2001;322:757-63

Coronary Heart Disease: Seven Dietary Factors

(Ulbricht and Southgate, Lancet, 1991)

Protective FactorsProtective FactorsPolyunsaturated Fatty Acids, n-6 SeriesPolyunsaturated Fatty Acids, n-6 Series

18:2 – linolenic acid18:2 – linolenic acid

Polyunsaturated Fatty Acids, n-3 SeriesPolyunsaturated Fatty Acids, n-3 Series

18:3 – alpha-linolenic acid18:3 – alpha-linolenic acid

20:5 – eicosapentanoic acid (EPA)20:5 – eicosapentanoic acid (EPA)22:6 – docosahexanoic acid (DHA)22:6 – docosahexanoic acid (DHA)

Monounsaturated Fatty AcidsMonounsaturated Fatty Acids

18:1 – oleic acid 18:1 – oleic acid

Dietary FiberDietary Fiber

AntioxidantsAntioxidants

Seven Countries StudyReview by Professor Serge Renaud

CRETE 9 MED ZUTPHEN USCOHORTS HOLLAND

TOTA L 514 1090 1091 115310 years/10.000 CHD 9 184 420 574

Cholesterol 204 194 232 236(mg/dl)

380 416 252 97 30 18 2 1

Foodstuff Fruit 464 130 82 233(g/day) Meat 35 140 138 273

Fish 18 34 12 3 Edible Fat 95 60 79 33Alcoho l 15 43 3 6

Adapted from A. Keys (1970) and D. Kromhout (1989)

RAILROAD

BreadLegume

Mortality

Fatty Acids from Cholesterol Esters

n

16:0

18:0

18:1 (n-9)

18:2 (n-6)

18:3 (n-3)

Crete

92

11.1 ±0.1

0.7 ±0.0

31.0 ±0.3

41.9 ±0.4

0.9 ±0.1

Zutphen 97 11.9 ±0.1

1.1 ±0.0

21.4 ±0.4

53.1 ±0.7

0.3 ±0.0

Mean ± S.E. ***p<0.001 Adapted from Sandker et al Europ J Clin Nutr 1993

The Lyon Diet Heart StudyProfessor Serge Renaud

•• A clinical trial of post-MI patients comparingA clinical trial of post-MI patients comparing

a Cretan-based “Mediterranean diet” with thea Cretan-based “Mediterranean diet” with the

usual diet advised, a low-fat & cholesterol diet.usual diet advised, a low-fat & cholesterol diet.

•• Used a Canola-oil based margarine to replaceUsed a Canola-oil based margarine to replace

butter; urged use of olive or canola oil instead ofbutter; urged use of olive or canola oil instead of

vegetable oils high in linoleic acid.vegetable oils high in linoleic acid.

The Lyon Diet Heart Study

The Six Dietary Commandments

- - More breadMore bread

- More vegetables and legumes- More vegetables and legumes

- More fish- More fish

- Less meat (beef, lamb, pork), replaced by - Less meat (beef, lamb, pork), replaced by poultrypoultry

- No day without fruit- No day without fruit

- No more butter and cream, replaced by - No more butter and cream, replaced by supplied margarine made from canola oil.supplied margarine made from canola oil.

The Lyon Diet Heart Study

Results

• • Trial stopped early by Monitoring Board Trial stopped early by Monitoring Board because of because of unacceptablyunacceptably higher higher CVD CVD rates in control group (low-fat diet)rates in control group (low-fat diet). .

•• Mediterranean alpha-linolenic acid rich diet in the secondary Mediterranean alpha-linolenic acid rich diet in the secondary prevention of coronary heart disease.prevention of coronary heart disease. De Lorgeril M, Renaud S, De Lorgeril M, Renaud S, Mamelle N, et al. Lancet 1994;343:1454-9.Mamelle N, et al. Lancet 1994;343:1454-9.

• • Cretan Mediterranean diet for prevention of coronary heart disease.Cretan Mediterranean diet for prevention of coronary heart disease. Renaud S, de Lorgeril M, Delaye J, et al. Am J Clin Nutr Renaud S, de Lorgeril M, Delaye J, et al. Am J Clin Nutr 1995;61:1360S-7S.1995;61:1360S-7S.

The Lyon Diet Heart Study CVD Recurrence During 27-mth Follow Up

Control (303)

Exper (302)

RR

p

Cardiac Death (Sudden Death) Acute Myocardial Infarction Total Cardiac Events Non-Cardiac Death Overall Mortality

16 (10)

17

33

4

20

3 (0)

5

8

5

8

0.24

0.27

0.30

<0.02 <0.001 <0.02

Total CV events (including stroke, unstable AP, CHF)

70 14 0.24 <0.0001

The Lyon Diet Heart Study

Intake of Foodstuffs (g/day)

Foodstuffs Control Experimental P Bread 145 167 0.01 Legume 10 20 0.07 Vegetable 288 316 0.07 Fruit 200 241 0.007 Meat 74 47 0.01 Poultry 53 58 0.42 Cheese 35 32 0.25 Butter & Cream 17 3 <0.001 Margarine 5 19 <0.001 Oil 17 16 0.65 Fish 40 47 0.16

The Lyon Diet Heart Study

Plasma Fatty Acids at 8 Weeks

Fatty acids

Control

Experimental

18:0

6.81

0.05

6.49

±

0.05

18:1 (n-9) 19.00 0.20 22.10 ± 0.20 18:1 (trans) 0.23 0.01 0.26 ± 0.01 18:2 (n-6) 29.80 0.40 27.30 ± 0.30 18:3 (n-3) 0.39 0.01 0.65 ± 0.02 20:4 (n-6) 6.80 0.10 6.29 ± 0.09 20:5 (n-3) 0.75

± ± ± ± ± ± ± 0.04 0.92 ± 0.03

Mean ± S.E.

The Lyon Diet Heart Study

Cardiac Death and Non-fatal MI(46 months follow up)

Cretan diet 0.28 Cretan diet 0.28 (95 % C.I. 0.15-0.53)(95 % C.I. 0.15-0.53)

18:3 (n-3)*18:3 (n-3)* 00..20 20 (95 % C.I. 0.05-0.84)(95 % C.I. 0.05-0.84)

* 18:3(n-3) plasma levels at 2 months, adjusted for age,* 18:3(n-3) plasma levels at 2 months, adjusted for age,

sex, smoking, cholesterol, BP, other risk fasex, smoking, cholesterol, BP, other risk factorsctors

ALA and CHDStudies Showing Protective Effects

Proc Soc ExpProc Soc Exp BiolBiol Med 1992;200:177-82.Med 1992;200:177-82. Prospective study in 6,250 men Prospective study in 6,250 men (death (death ))

BMJ 1996;313:84-90. Prospective study in health BMJ 1996;313:84-90. Prospective study in health professionals professionals (non-fatal MI (non-fatal MI ))

Am J Clin Nutr 1999;69:890. Prospective studyAm J Clin Nutr 1999;69:890. Prospective study in 70,000 nurses in 70,000 nurses (cardiac death (cardiac death ))

Dietary Linolenic Acid and Coronary Heart Disease

The NHLBI Family Heart StudyThe NHLBI Family Heart Study

Luc Djoussé, James S. PankowLuc Djoussé, James S. Pankow

John H. Eckfeldt, Aaron R. FolsomJohn H. Eckfeldt, Aaron R. Folsom

Paul N. Hopkins, Michael A. ProvincePaul N. Hopkins, Michael A. Province

Yuling Hong, R. Curtis EllisonYuling Hong, R. Curtis Ellison

Odds Ratio of CHD by Linolenic Acid Intake (Men)

0.1

0.4

0.7

1

1.3

Q1 Q2 Q3 Q4 Q5

Odds Ratio of CHD by Linolenic Acid Intake (Women)

0.1

0.4

0.7

1

1.3

Q1 Q2 Q3 Q4 Q5

Odds Ratio of CHD by Fish Intake

0

0.2

0.4

0.6

0.8

1

1.2

0/wk 1/wk 2+/wk

Clinical Trials Showing that N-3 Fatty Acids Prevent CHD

Intervention trialsIntervention trials demonstrate the inverse demonstrate the inverse association between n-3 fatty acids and CHD association between n-3 fatty acids and CHD without changes in serum cholesterolwithout changes in serum cholesterol

Risk RatioRisk Ratio

N N-3 Cardiac Death Non fatal MIN N-3 Cardiac Death Non fatal MI

DART 2,000 Fish DART 2,000 Fish 0.70 0.70 1.001.00

GISSI 11,000 Fish oil GISSI 11,000 Fish oil 0.80 0.80 0.960.96

Lyon 600 Canola oil Lyon 600 Canola oil 0.24 0.24 0.270.27

India 1,000 Mustard oil 0.33India 1,000 Mustard oil 0.33 0.470.47

Advantages of Canola Oil Over Fish Oils for Preventing CHD

* Many people do not like to eat fish* Many people do not like to eat fish

* The usual fried fish consumed in US has very* The usual fried fish consumed in US has very

low levels of fish oil (and who likes mackerel?)low levels of fish oil (and who likes mackerel?)

* Increasing concerns about organic chemical* Increasing concerns about organic chemical

contamination of fish and fish oilcontamination of fish and fish oil

* Data are beginning to show better protection * Data are beginning to show better protection

against CHD from ALA rather than fish oilsagainst CHD from ALA rather than fish oils

Time to Change to a Mediterranean-type Diet

with Canola Oil?

Yes!Yes!

Mediterranean-type Diet

* A diet that is preferable to the very low-fat * A diet that is preferable to the very low-fat diets of the American Heart Associationdiets of the American Heart Association

* Preferable to the very low-carbohydrate * Preferable to the very low-carbohydrate diets (Atkins, South Beach, etc.)diets (Atkins, South Beach, etc.)

* Canola Oil and canola oil-based margarine * Canola Oil and canola oil-based margarine belong on the Med-Diet (belong on the Med-Diet (avoid trans fatsavoid trans fats!)!)

Is the “Mediterranean-type Diet” Acceptable in North America?

• Our Institute developed such a dietOur Institute developed such a diet• Used olive oil and canola oil-based Used olive oil and canola oil-based

margarinemargarine• Tested in people in Boston on a strict Tested in people in Boston on a strict

low-fat diet following heart surgerylow-fat diet following heart surgery• Tested among African-Americans with Tested among African-Americans with

heart disease in South Carolina heart disease in South Carolina

Testing a Med-Diet in South CarolinaComments from 27 African-American Subjects

“ “ I was very pleasantly surprised howI was very pleasantly surprised how

delicious the meal was.”delicious the meal was.”

“ “ It contained more fats and oils that my It contained more fats and oils that my

current diet, so the meal was a treat!”current diet, so the meal was a treat!”

“ “ This diet is something I can live with.”This diet is something I can live with.”

Summary

* Diet affects the risk of CHD and death* Diet affects the risk of CHD and death

* The “Mediterranean-type diet” seems to* The “Mediterranean-type diet” seems to

be the healthiest option be the healthiest option

* Canola oil & canola oil-based margarine:* Canola oil & canola oil-based margarine:

key components of this “Healthy Diet”key components of this “Healthy Diet”