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

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Total Fat Ecological Data
Seven Countries Study
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Associations Between the Percent of Calories
Derived from Specific Foods and CHD Mortality in
the 20 Countries Study
Food Source Correlation Coefficient
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 Plt0.05 level.
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Men Participating in the Ni-Hon-San Study
Residence
Japan Hawaii California
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 97372,
1973. CHD, coronary heart disease.
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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
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Total Fat and CHD - Cohort Evidence
28.3 32.6 35.6 38.7
44.0
77,878 women in the Nurses Health Study,
1980-2002, Oh et al, AJE 2005
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Changes in dietary fat sources during Evolution
Industrial
Agricultural
Hunter-Gatherer

• Simopoulos AP. Am J Clin Nutr. 199970560-9S.

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H   H
 
C-C-C C- C-C
 
H   H
Saturated Fatty Acid
Stearic acid 180 melting point 70 o C
H   H
 
C-C-C C-C-C
Unsaturated Fatty Acid(cis)
Oleic acid c 181 n-9 melting point 16 o C
H    
   
C-C-C C-C-C
   
    H
Unsaturated Fatty Acid (trans)
Elaidic acid t 181 n-9 melting point 43 o C
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Dietary fatty acids
There are 3 types of dietary fatty acids
Saturated fatty acids (no double bond)
COOH
CH3
Mono-unsaturated fatty acids (one double bond)
CH3
COOH
Polyunsaturated fatty acids (two or more double
bonds)
COOH
CH3
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w-
COOH
Stearic acid (C180 )
CH3
n-
COOH
COOH
Elaidic acid (C181 n-9 trans)
Oleic acid (C181 n-9)
Essential Fats
COOH
COOH
a - Linolenic acid (C183n-3)
Linoleic Acid (182 n-6)
COOH
COOH
Docosahexaenoic acid DHA(C226 n-3)
Arachidonic acid AA(C204 n-6)
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Quality of Fats in Modern Nutrition

• Saturated fats (C120, C140, C160, C180)
• Trans fatty acids (hydrogenated fats)
• Monounsaturated fatty acids (181)
• 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)

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n - 6 / n - 3 LCPUFA ratio modulates inflammation
and thrombosis
Linoleate
Arachidonic
Eicosapentaenoic
Linolenate
n-3 PUFA
n-6 PUFA
Membrane Phospholipids
Arachidonic ac / Eicosapentaenoic ac
Leukotrienes
Thromboxanes
Prostacyclins
Prostaglandin
Inflammation
Thrombosis
Bronchoconstriction
Inmune response
Bronchoconstriction
Chemotaxis
Vascular reactivity
Citokines
Inflammation
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Fatty acids total
n-3 PUFA

n-6 PUFA
Monounsaturated
Saturated
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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

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WHO TRS 916 Report strength of evidence on
nutritional factors and risk of developing CVD
Evidence Decreased risk No
relationship Increased risk Convincing Regular
physical activity Vitamin E Myristic and
palmitic acids Linoleic acid
182n-6 Supplements 140 160 Fish and
fish oils Trans fatty acids (EPA
DHA) High sodium intake
Vegetables fruits (including
Overweight berries) High
alcohol intake Potassium
Low to moderate alcohol intake Probable
a-Linolenic acid 183 n-3 Stearic acid
Dietary cholesterol Oleic acid 181
n-9 180 Unfiltered boiled coffee
Fibre Nuts (unsalted) Plant
sterols/stanols Folate Possible
Flavonoids Fats rich in lauric acid
Soy products Impaired fetal
nutrition Beta-carotene supplement
TRS 916 WHO 2003
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WHO TRS 916 Report risk of developing CVD
Evidence Decreased risk No
relationship Increased risk Convincing Regular
physical activity Myristic and palmitic acids
Linoleic acid 182n-6 Vitamin E 140
160 Fish and fish oils (EPA DHA)
Supplements Trans fatty acids Vegetables
fruits High sodium intake
(berries) Overweight
Potassium Low to moderate High
alcohol intake alcohol intake Probable
a-Linolenic acid 183 n-3 Stearic acid
Dietary cholesterol Oleic acid 181
n-9 180 Unfiltered boiled coffee Fibre
Nuts (unsalted) Plant sterols/stanols
Folate Possible Flavonoids
Fats rich in lauric acid Soy
products Restricted fetal growth
Beta-carotene supplement
TRS 916 WHO 2003
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Population dietary changes explain much of the
reduction in heart disease mortality in Finland.
Observed and Predicted Declines in Coronary
Mortality in Eastern Finland, Men
Decline in mortality
0
-10
-20
Observed Predicted Cholesterol Blood
pressure Smoking
-30
-40
-50
-60
72
92
76
80
84
88
74
78
82
86
90
Vartiainen, Puska et al BMJ 1995
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UK White Paper 04 Dept Health
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Causal relationship web
Physical
Age
Activity
Diabetes
DIET
Fat Salt
-
HDL
LDL
CHD
Chol
BMI
Diastolic BP
Smoking
A B marks a postulated influence from A
to B
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Diet effects on LDL receptor activity
High saturated or trans fat diets
Healthy fats
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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

31
Associations Between the Percent of Calories
Derived from Specific Foods and CHD Mortality in
the 20 Countries Study
Food Source Correlation Coefficient
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 Plt0.05 level.
32
Total Fat Ecological Data
Seven Countries Study
33
Men Participating in the Ni-Hon-San Study
Residence
Japan Hawaii California
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 97372,
1973. CHD, coronary heart disease.
34
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
35
Total Fat and CHD - Cohort Evidence
28.3 32.6 35.6 38.7
44.0
77,878 women in the Nurses Health Study,
1980-2002, Oh et al, AJE 2005
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Reduction in the Consumption of Trans Fatty Acids
and the Risk of CHD in The Netherlands-Zutphen
?TFA 2.4
? CHD 23
Oomen CM, et al. Lancet 2001 357 746-51
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Health benefits of polyunsaturated fatty acids
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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 sustained

Circulation 591,1979 Acta Med Scand 4661,1966
Circulation 401,1969 Lancet 2757,1989, Lancet
3431454,1994 Lancet 354447,1999.
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Dietary fatty acids and blood cholesterol
?TC1.2(2?S'-?P) S'C12C14C16
change in TC (mg/dL)
change in fat intake (en)
Source Keys et al. Metabolism, 1965
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Effect on lipoproteins of replacing saturated fat
with specific fatty acids or carbohydrates
LDL-chol
HDL-chol
TC/HDL-chol ratio
Source Mensink et al Am J Clin Nutr 2003
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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 2005161672679
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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
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Adverse effects of trans FAs on blood cholesterol
of energy as trans fatty acids (C181 trans)
Zock et al Am J Clin Nutr, 1995
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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
Fatty acid (1 energy exchange) Total cholesterol LDL cholesterol HDL cholesterol TotalHDL cholesterol
Lauric acid (120) 0.069 0.052 0.027 -0.037
Myristic acid (140) 0.059 0.048 0.018 -0.003
Palmitic acid (160 0.041 0.039 0.010 0.005
Stearic acid (180) -0.010 -0.004 0.002 -0.013
Elaidic acid (181 trans) 0.031 0.040 0.000 0.022
Oleic acid (181 cis) -0.006 -0.009 0.008 -0.026
Linoleic acid) (182n-6) -0.021 -0.019 0.006 -0.032
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Relative risk was after adjusting for dietary
fiber intake.
Saturated Fat Intake Quintiles ( of calories)
Alpha Linolenic Fatty Acid Intake Quintiles ( of
calories)
1.72
0.41
a 1 increase in calories from linolenic acid
(2-3 grams/day).
Ascherio et al BMJ 1996
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ORs for Risk of Nonfatal Acute MI by tercile of
Linolenic Trans FA content of Adipose Tissue in
Costa Rica
Odds Ratio
Adipose Tissue trans fatty acids
Adipose Tissue n-3 alpha-linolenic acids
A Baylin et al Circulation 1071586-91 2003
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Small reduction in blood cholesterol ?
significant reduction in CHD
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
Law et al, British Medical Journal 1994
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Fat quality versus quantity
USA 2005 dietary recommendations
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
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D. Mozaffarian JAMA, 2006 Vol 296 1885-97
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D. Mozaffarian JAMA, 2006 Vol 296 1885-97
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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

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Design a follow-up study of 11 pooled American
and European cohort studies including 344,696
persons outcome CHD over a 410 yr FU, 5249
coronary events and 2155 coronary deaths occurred
Results For a 5lower 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 8918 2009
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coronary events
coronary deaths
0.87 (0.77-0.97)
0.74 (0.61-0.89)
Jakobsen et al Am J Clin Nutr 8918 2009
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coronary events
coronary deaths
coronary events
coronary deaths
1.07 (1.01-1.14)
0.96 (0.82-1.13)
Jakobsen et al Am J Clin Nutr 8918 2009.
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Coronary Heart Disease
Am J Clin Nutr doi 10.3945/ajcn.2009.27725
Risk ratios and 95 CIs for fully adjusted
random-effects models examining associations
between saturated fat intake in relation to
coronary heart disease stroke
1.07 (0.96, 1.19)P 0.22
Stroke
0.81 (0.62-1.05)P 0.11
Total CVDs
1.0 (0.89-1.11)P 0.95
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Am J Clin Nutr 201091 17648.
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.
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Pooled Analysis of 11 Major Cohort Studies
SFA ? PUFA SFA ? Carb SFA ? MUFA


Total of 344,696 individuals with 5,249 CHD
events. plt0.05
Jakobsen et al, AJCN 2009
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Saturated Fat vs. CHO Quality
SFA ? Low GI CHO SFA ? Med GI CHO SFA ? High GI
CHO

Risk of CHD among 53,644 adults followed for 12
years. plt0.05
Jakobsen et al, AJCN 2010
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A More Complete Diet-Heart Paradigm
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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

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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- EPADHA 200-500 mg/day
• Trans fatty acids as low as possible, lower
  than 1-2
• Some give recommendations for omega-6omega-3
  ratio, others do not. Most often not to exceed
  51
• In many societies the intake of Omega 3 is lower
  and that of trans is higher than recommended

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Type of Fat Consumed on Bread in North Karelia,
19722000 (2559-year-old)

Year
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Saturated Fat from Milk and Fat on Bread gr/day
Year
65
Butter Margarine Consumption Finland 197901
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Age-adjusted Mortality Rates of CHD in North
Karelia and the all of Finland in males aged
3564 years 1969 to 2002.
700
start of the North Karelia Project
600
extension of the Project nationally
Mortality per 100 000 population
500
North Karelia
400
300
- 82
All Finland
200
- 75
100
Year
6th ICPC, Iguassy Falls 21.-25.5. 2005 (3.)