Cholesterol**Systolic blood

pressure*

Low Fruit and vegetable

intake

Tobacco

Inactivity

High BMIDiabetes*

Inflammation*

* Fats & fatty acids

Risk factors for cardiovascular disease: Focus on Dietary Fats R. Uauy 2014

The Lipid Hypothesis

• Dietary fats and fatty acids• Health effect of cis vs trans unsaturated fatty acids• Quality of Dietary fat has a significant effect on CVDs• Conclusions and Recommendations

Seven Countries Study

Total Fat – Ecological Data

Butter 0.546

All dairy products 0.619

Eggs 0.592

Meats 0.561

Sugar and syrup 0.676

Grains, fruits, and vegetables -0.633

*1973 data, all subjects. From Stamler J: Population studies. In Levy R: Nutrition, Lipids, and CHD. New York, Raven, 1979. †All coefficients are significant at the P<0.05 level.

Food Source Correlation Coefficient†

Associations Between the Percent of Calories Derived from Specific Foods and CHD Mortality in the 20 Countries Study*

Age (years) 57 54 52

Weight (kg) 55 63 66 +20%

Serum cholesterol (mg/dL) 181 218 228 +26%

Dietary fat (% of calories) 15 33 38 +253%

Dietary protein (%) 14 17 16

Dietary carbohydrate (%) 63 46 44 -30%

Alcohol (%) 9 4 3 -67%

5-yr CHD mortality rate 1.3 2.2 3.7 +285%(per 1000 persons)

*Data from Kato et al., Am J Epidemiol 97:372, 1973. CHD, coronary heart disease.

Residence

Japan Hawaii California

Men Participating in the Ni-Hon-San Study*

Epidemiologic Studies*

• Populations on diets high in total fat, saturated and trans fats, cholesterol, and sugar have high age-adjusted CHD death rates as well as more obesity, hyperlipidemia, and diabetes

• The converse is also true

*Results from Seven Countries, 18 countries, 20 countries, 40 countries, and Ni-Hon-San Studies

77,878 women in the Nurses Health Study, 1980-2002, Oh et al, AJE 2005

Total Fat and CHD - Cohort Evidence

28.3% 32.6% 35.6% 38.7% 44.0%

Simopoulos AP. Am J Clin Nutr. 1999;70:560-9S.

Hunter-Gatherer

Agricultural

Industrial

Changes in dietary fat sources during Evolution

H   H

|   | C-C-C  C- C-C 

|    | H   H

H H

|    | C-C-C   C-C-C 

H     |    

C-C-C C-C-C

    |     H

Saturated Fatty Acid

Unsaturated Fatty Acid(cis)

Unsaturated Fatty Acid (trans)

Stearic acid 18:0melting point 70 o

C

Elaidic acid t 18:1 n-9melting point 43 o C

Oleic acid c 18:1 n-9melting point 16 o C

Dietary fatty acids There are 3 types of dietary fatty acids

Polyunsaturated fatty acids (two or more double bonds)

Mono-unsaturated fatty acids (one double bond)

Saturated fatty acids (no double bond)

CH3

CH3

CH3

COOH

COOH

COOH

COOH

Docosahexaenoic acid DHA(C22:6 n-3)

Linoleic Acid (18:2 n-6)

COOH

COOH

Oleic acid (C18:1 n-9)

Elaidic acid (C18:1 n-9 trans)

COOH

COOH

Arachidonic acid AA(C20:4 n-6)

- Linolenic acid (C18:3n-3)

COOH

COOH Stearic acid (C18:0 )CH3

n-

Essential Fats

Quality of Fats in Modern Nutrition

• Saturated fats (C12:0, C14:0, C16:0, C18:0)• Trans fatty acids (hydrogenated fats)• Monounsaturated fatty acids (18:1)• Sats/MUFA/PUFA • Cholesterol

• Essential fatty acids w -3 and w -6• Long Chain PUFAs (AA, EPA, DHA)

• Energy Density of diet (fats and carbohydrates)

Linoleate Arachidonic

Membrane Phospholipids

Arachidonic ac /Eicosapentaenoic ac

n-3 PUFA

Prostaglandin

Inflammation ThrombosisBronchoconstriction

Bronchoconstriction Chemotaxis Inflammation

n - 6 / n - 3 LCPUFA ratio modulates inflammation and thrombosis

Inmune responseVascular reactivity

n-6 PUFA

Eicosapentaenoic Linolenate

Leukotrienes

Citokines

Thromboxanes Prostacyclins

Saturated

Monounsaturated

n-6 PUFA

Fatty acids % totaln-3 PUFA

Diet and Fats Influence Risk of Coronary Heart Disease• Effects on Lipoprotein and Cholesterol metabolism receptor

systems, gene expression and regulation (LDL, HDL, Lp(a), TG) : TRANS FATS, SATS, PUFAs n-3 and n-6,

• Prostanoids:(Eicosanoids and Docosanoids) related functions Inflammation/cytokines depend on: PUFAs n-3 & n-6,

• Blood pressure. SODIUM POTASSIUM & PUFAs n-3 & n-6,

• Thrombosis and thrombolytic mechanisms PUFAs n-3 & n-6

• Oxidative stress and re-perfusion injury PUFAs n-3 & n-6

• Endothelial function & adhesion molecules PUFAs n-3 & n-6

• Cardiac Rhythm (arrhythmias) PUFAs n-3

• Insulin Sensitivity PUFAs n-3 & n-6; Trans

Evidence Decreased risk No relationship Increased risk

Convincing Regular physical activity Vitamin E Myristic and palmitic acidsMyristic and palmitic acids Linoleic acid 18:2n-6Linoleic acid 18:2n-6 Supplements 14:0 16:014:0 16:0 Fish and fish oils Fish and fish oils Trans fatty acidsTrans fatty acids (EPA &DHA(EPA &DHA) High sodium intake Vegetables & fruits (including Overweight berries) High alcohol intake

Potassium Low to moderate alcohol intake

Probable α-Linolenic acidα-Linolenic acid 18:3 n-3 18:3 n-3 Stearic acidStearic acid Dietary cholesterolDietary cholesterol Oleic acid 18:1 n-9Oleic acid 18:1 n-9 18:018:0 Unfiltered boiled coffee Fibre Nuts (unsalted)

Plant sterols/stanolsPlant sterols/stanols Folate

Possible Flavonoids Fats rich in lauric acidFats rich in lauric acid Soy products Impaired fetal nutrition

Beta-carotene supplement

WHO TRS 916 Report : strength of evidence on nutritional factors and risk of developing CVD

TRS 916 WHO 2003

Evidence Decreased risk No relationship Increased risk

Convincing Regular physical activityRegular physical activity Myristic and palmitic acids Linoleic acid 18:2n-6 Vitamin EVitamin E 14:0 16:0 Fish and fish oils (EPA &DHA) SupplementsSupplements Trans fatty acids

Vegetables & fruits Vegetables & fruits High sodium intakeHigh sodium intake (berries) (berries) OverweightOverweight PotassiumPotassium Low to moderate Low to moderate High alcohol intakeHigh alcohol intake alcohol intakealcohol intake

Probable α-Linolenic acid 18:3 n-3 Stearic acid Dietary cholesterol

Oleic acid 18:1 n-9 18:0 Unfiltered boiled coffeeUnfiltered boiled coffee FibreFibre Nuts (unsaltedNuts (unsalted) Plant sterols/stanols

FolateFolatePossible FlavonoidsFlavonoids Fats rich in lauric acid

Soy productsSoy products Restricted fetal growthRestricted fetal growth

Beta-carotene supplementBeta-carotene supplement

WHO TRS 916 Report : risk of developing CVD

TRS 916 WHO 2003

Population dietary changes Population dietary changes explain much of the explain much of the reduction in heart disease reduction in heart disease mortality in Finland.mortality in Finland.

Vartiainen, Puska et al BMJ 1995

ObservedPredictedCholesterolBlood pressureSmoking

Observed and Predicted Declines in Coronary Observed and Predicted Declines in Coronary Mortality in Eastern Finland, MenMortality in Eastern Finland, Men

72 9276 80 84 8874 78 82 86 90

0

-10

-20

-30

-40

-50

-60

% Decline in mortality

UK White Paper 04 Dept Health

Causal relationship web

A B marks a postulated influence from A to B

Age

CHD

DiastolicBP

HDL-Chol

Diabetes

BMI

Fat & SaltDIET

Physical Activity

Smoking

LDL

Healthy fats High saturated or trans fat diets

Diet effects on LDL receptor activity

Saturated or Trans

fatty acids

The Lipid Hypothesis

• Dietary fats and fatty acids

• Health effect of cis vs trans unsaturated fatty acids

• Quality of Dietary fat has a significant effect on CVDs

• Conclusions and Recommendations

Butter 0.546

All dairy products 0.619

Eggs 0.592

Meats 0.561

Sugar and syrup 0.676

Grains, fruits, and vegetables -0.633

*1973 data, all subjects. From Stamler J: Population studies. In Levy R: Nutrition, Lipids, and CHD. New York, Raven, 1979. †All coefficients are significant at the P<0.05 level.

Food Source Correlation Coefficient†

Associations Between the Percent of Calories Derived from Specific Foods and CHD Mortality in the 20 Countries Study*

Seven Countries Study

Total Fat – Ecological Data

Age (years) 57 54 52

Weight (kg) 55 63 66 +20%

Serum cholesterol (mg/dL) 181 218 228 +26%

Dietary fat (% of calories) 15 33 38 +253%

Dietary protein (%) 14 17 16

Dietary carbohydrate (%) 63 46 44 -30%

Alcohol (%) 9 4 3 -67%

5-yr CHD mortality rate 1.3 2.2 3.7 +285%(per 1000 persons)

*Data from Kato et al., Am J Epidemiol 97:372, 1973. CHD, coronary heart disease.

Residence

Japan Hawaii California

Men Participating in the Ni-Hon-San Study*

Epidemiologic Studies*

• Populations on diets high in total fat, saturated and trans fats, cholesterol, and sugar have high age-adjusted CHD death rates as well as more obesity, hyperlipidemia, and diabetes

• The converse is also true

*Results from Seven Countries, 18 countries, 20 countries, 40 countries, and Ni-Hon-San Studies

77,878 women in the Nurses Health Study, 1980-2002, Oh et al, AJE 2005

Total Fat and CHD - Cohort Evidence

28.3% 32.6% 35.6% 38.7% 44.0%

Oomen CM, et al. Lancet 2001; 357: 746-51

TFA 2.4%

Reduction in the Consumption of Trans Fatty Acids and the Risk of CHD in The Netherlands-Zutphen

CHD 23%

Health benefits of polyunsaturated fatty acids

Dietary Intervention Studies

Significant benefit in CHD risk reduction and mortality in primary and secondary prevention noted with:

• Decreasing saturated fat and increasing polyunsaturated fat (Finnish Mental Hospital, LA-VA, and Oslo Diet Heart Studies)• Increasing fish or fish oil intake (DART, GISSI)• Increasing alpha linolenic acid intake (Lyon Diet Heart Study)

Dietary Counseling can work, but it must be intensive and sustainedCirculation 59:1,1979; Acta Med Scand 466:1,1966; Circulation 40:1,1969;Lancet 2:757,1989, Lancet 343:1454,1994; Lancet 354:447,1999.

Source: Keys et al. Metabolism, 1965

MUFA

PUFA

SAFA

change in fat intake (en%)

chan

ge

in T

C (

mg

/dL

)

TC=1.2(2S'-P)S'=C12+C14+C16

Dietary fatty acids and blood cholesterol

LDL-chol HDL-chol

-0.05

-0.04

-0.03

-0.02

-0.01

0

0.01

mm

ol/

L c

han

ge

per

% e

ner

gy

monounsaturated FAspolyunsaturated FAscarbohydratestrans FAs

TC/HDL-chol ratio

Source: Mensink et al Am J Clin Nutr 2003

-0.04

-0.03

-0.02

-0.01

0

0.01

0.02

chan

ges

per

en

%

Effect on lipoproteins of replacing saturated fat with specific fatty acids or carbohydrates

In summary, our results provide evidence that high intake of trans-fat increases the risk of CHD in women, the effects are stronger among younger women.

Our findings also support a benefit of polyunsaturated fat intake, at least up to approximately 7 percent of energy, in preventing CHD, particularly among women who are younger or overweight.

Am J Epidemiol 2005;161:672–679

Nurses’ Health Study: changes in risk of coronary heart disease associated with iso-energetic diet substitutions

Source: Hu et al, JAMA, 2002

Decreased Risk Increased Risk

Zock et al Am J Clin Nutr, 1995

% of energy as trans fatty acids (C18:1 trans)0 2 4 6 8 10 12

-0.2

0

0.2

0.4

Ch

an

ge in

(m

mol/

L)

HDL

LDLZock

Mensink

Judd

Nestel

Judd

Lichtenstein

Adverse effects of trans FAs on blood cholesterol

44

Fatty acid (1%

energy exchange)

Total

cholesterol

LDL

cholesterol

HDL

cholesterol

Total:HDL

cholesterol

Lauric acid (12:0) +0.069 +0.052 +0.027 -0.037

Myristic acid (14:0) +0.059 +0.048 +0.018 -0.003

Palmitic acid (16:0 +0.041 +0.039 +0.010 +0.005

Stearic acid (18:0) -0.010 -0.004 +0.002 -0.013

Elaidic acid (18:1 trans) +0.031 +0.040 0.000 +0.022

Oleic acid (18:1 cis) -0.006 -0.009 +0.008 -0.026

Linoleic acid) (18:2n-6) -0.021 -0.019 +0.006 -0.032

Changes in serum lipids (mmol/L by replacing 1% E individual fatty ac for carbohydrate based on meta-analysis [EFSA J (2004) 81, 1-49]

0

0.5

1

1.5

2

Top 1/5(14.8%)

Bottom 1/5(5.7%)

Saturated Fat Intake Quintiles (% of calories)

Ascherio et al BMJ 1996

0

0.5

1

1.5

Top 1/5 Bottom 1/5

Alpha Linolenic Fatty Acid Intake Quintiles (% of calories)

a 1% increase in calories from linolenic acid (2-3 grams/day).

Relative risk was after adjusting for dietary fiber intake.

0.41

1.72

ORs for Risk of Nonfatal Acute MI by tercile of Linolenic & Trans FA content of Adipose Tissue in

Costa Rica

A Baylin et al Circulation 107:1586-91 2003

Adipose Tissuetrans fatty acidsAdipose Tissue n-3

alpha-linolenic acids

Odds Ratio

A reduction in total blood cholesterol level by each percent leads to a reduction of :

Data from a meta analysis including 10 prospective cohort studies, 3 large international trial and 28 intervention studies

Small reduction in blood cholesterol significant reduction in CHD

Age (years) Risk CHD 35-44 -5.4% 45-54 -3.9% 55-64 -2.7% 65-74 -2.0%

Law et al, British Medical Journal 1994

“…increasing consensus that it is the quality rather than the quantity of fat that counts….”

Limiting calories is more important to health than cutting fats

USA 2005 dietary recommendations:

Fat quality versus quantity

D. Mozaffarian JAMA, 2006 Vol 296: 1885-97

D. Mozaffarian JAMA, 2006 Vol 296: 1885-97

Overview of beneficial effects of PUFA• Omega 6 (Linoleic acid)

– Blood lipids: clearly protective

• Omega 3 (Linolenic acid)– Blood lipids: probably similar to linoleic acid– Other risk factors: mostly inconsistent

• Omega 3 (EPA/DHA)– Blood lipids: in high dose lowers TG, but LDL up

– Other risk factors: blood pressure ? reduced thrombosis and likely improved endothelial relaxation, lowers inflammation and risk of fatal cardiac arrhythmias

Design: a follow-up study of 11 pooled American and European cohort studies including 344,696 persons; outcome CHD over a 4–10 yr FU, 5249 coronary events and 2155 coronary deaths occurred Results:

For a 5%lower energy intake from SFAs and a concomitant higher energy intake from PUFAs risk of coronary events HR: 0.87 (95% CI: 0.77-0.97); HR for coronary deaths 0.74 (0.61-0.89).

For a 5% lower energy intake from SFAs and a concomitant higher energy intake from CHO there was a significant association with coronary events (HR 1.07; (CI: 1.01- 1.14); for coronary deaths 0.96 (0.82- 1.13).

MUFA intake was not associated with CHD. Jakobsen et al Am J Clin Nutr 89:1–8 2009

coronary events coronary deaths

Jakobsen et al Am J Clin Nutr 89:1–8 2009

0.87 (0.77-0.97) 0.74 (0.61-0.89)

coronary events coronary deaths

Jakobsen et al Am J Clin Nutr 89:1–8 2009;.

coronary events coronary deaths

1.07 (1.01-1.14) 0.96 (0.82-1.13)

Coronary Heart Disease

Stroke

Total CVDs

Risk ratios and 95% CIs for fully adjusted random-effects models examining associations between saturated fat intake in relation to coronary heart disease & stroke

Am J Clin Nutr doi: 10.3945/ajcn.2009.27725

1.07 (0.96, 1.19)P = 0.22

1.0 (0.89-1.11)P = 0.95

0.81 (0.62-1.05)P = 0.11

We aimed to investigate the risk of myocardial infarction (MI) associated with a higher energy intake from carbohydrates and a concomitant lower energy intake from SFAs. Carbohydrates with different glycemic index (GI) values were also investigated.

Design: Our prospective cohort study included 53,644 women and men free of MI at baseline.

Conclusion: This study suggests that replacing SFAs with carbohydrates with low-GI values is associated with a lower risk of MI, whereas replacing SFAs with carbohydrates with high-GI values is associated with a higher risk of MI.

Am J Clin Nutr 2010;91: 1764–8.

Pooled Analysis of 11 Major Cohort Studies

Jakobsen et al, AJCN 2009

Total of 344,696 individuals with 5,249 CHD events. *p<0.05

SFA → PUFA

SFA → Carb

SFA → MUFA

*

*

Saturated Fat vs. CHO Quality

Jakobsen et al, AJCN 2010

Risk of CHD among 53,644 adults followed for 12 years. *p<0.05

SFA → Low GI CHO

SFA → Med GI CHO

SFA → High GI CHO*

A More Complete Diet-Heart Paradigm

Key messages for Health Professionals• Strong Convincing Evidence that a diet low in saturate and trans

fats, and high polyunsaturated fats lowers cholesterol and reduces risk of CVD

• Diet can reduce LDL - cholesterol up to 30 %

• Simple dietary changes can make a significant difference to the CVD risk

• Changes in Diet and Physical activity are

the cornerstone of primary prevention of CVDs

Recommendations on PUFA and trans

• General international agreement on absolute levels.- Total PUFA: 4-15 en% (8-10 en% most common)- Linoleic acid n-6 : up to 14 en% (8 en% most common)- Linolenic acid n-3: 0.2 to 1.0 en%- EPA+DHA : 200-500 mg/day

• Trans fatty acids: as low as possible, lower than 1-2 % • Some give recommendations for omega-6:omega-3 ratio,

others do not. Most often not to exceed ~ 5:1• In many societies the intake of Omega 3 is lower and that

of trans is higher than recommended

%

Type of Fat Consumed on Bread in North Karelia, Type of Fat Consumed on Bread in North Karelia, 19721972––2000 2000 (25(25––59-year-old)59-year-old)

Year

Saturated Fat from Milk and Fat on Bread Saturated Fat from Milk and Fat on Bread gr/day

0

10

20

30

40

50

1972 1977 1982 1987 1992Year

North Karelia

Kuopio province

Southwest Finland

Helsinki area

Butter & Margarine Consumption Finland 1979Butter & Margarine Consumption Finland 1979––01 01

Age-adjusted Mortality Rates of CHD in North Karelia and Age-adjusted Mortality Rates of CHD in North Karelia and the all of Finland in males aged 35the all of Finland in males aged 35––64 years 1969 to 2002.64 years 1969 to 2002.

Mortality per Mortality per 100 000 100 000 populationpopulation

Year

100

200

300

400

500

600

700

69 72 75 78 81 84 87 90 93 96 99 2002

North KareliaNorth Karelia

All FinlandAll Finland

start of the North Karelia Projectstart of the North Karelia Project

- 82 %- 82 %

- 75%- 75%

extension of the Project nationally

6th ICPC, Iguassy Falls 21.-25.5. 2005 (3.)6th ICPC, Iguassy Falls 21.-25.5. 2005 (3.)