Risk factors for cardiovascular disease:
Focus on Dietary Fats
R. Uauy 2014
Systolic blood
pressure*
Cholesterol**
Inactivity
Low Fruit and
vegetable
intake
High BMI
Diabetes*
Inflammation*
Tobacco
* Fats & 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
Total Fat – Ecological Data
Seven Countries Study
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 P<0.05 level.
Men Participating in the Ni-Hon-San Study*
Residence
Age (years)
Japan
57
Hawaii
54
California
52
Weight (kg)
55
63
66
+20%
Serum cholesterol (mg/dL) 181
218
228
+26%
Dietary fat (% of calories)
15
33
38
Dietary protein (%)
14
17
16
Dietary carbohydrate (%)
63
46
44
-30%
9
4
3
-67%
1.3
2.2
3.7
+285%
Alcohol (%)
5-yr CHD mortality rate
(per 1000 persons)
+253%
*Data from Kato et al., Am J Epidemiol 97:372, 1973. CHD, coronary heart disease.
Epidemiologic Studies*
• Populations on diets high in total fat, saturated and
trans fats, cholesterol, and sugar have high ageadjusted 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
Total Fat and CHD - Cohort Evidence
1.30
1.20
1.10
RR 1.00
0.90
0.80
0.70
I
II
28.3%
32.6%
III
35.6%
IV
38.7%
V
44.0%
Quintiles of Total Fat Consumption
77,878 women in the Nurses Health Study, 1980-2002, Oh et al, AJE 2005
Changes in dietary fat sources during Evolution
Industrial
Hunter-Gatherer
Agricultural
Simopoulos AP. Am J Clin Nutr. 1999;70:560-9S.
Saturated Fatty Acid
Stearic acid 18:0
melting point 70 o C
Unsaturated Fatty Acid
(cis) Oleic acid c 18:1 on-9
melting point 16 C
H
|
C-C-C
|
H
H
|
C- C-C
|
H
H
|
C-C-C
H
|
C-C-C
H
Unsaturated Fatty Acid
(trans)
Elaidic acid t 18:1 n-9
melting point 43 o C
|
C-C-C
C-C-C
|
H
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
wn-
COOH
CH3
Stearic acid (C18:0 )
COOH
COOH
Elaidic acid (C18:1 n-9 trans)
Oleic acid (C18:1 n-9)
Essential Fats
COOH
Linoleic Acid (18:2 n-6)
COOH
a - Linolenic acid (C18:3n-3)
COOH
COOH
Arachidonic acid AA(C20:4 n-6)
Docosahexaenoic acid DHA(C22:6 n-3)
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)
n - 6 / n - 3 LCPUFA ratio modulates inflammation and thrombosis
Linoleate
Arachidonic
Eicosapentaenoic
n-6 PUFA
Linolenate
n-3 PUFA
Membrane
Phospholipids
Arachidonic ac /
Eicosapentaenoic ac
Prostaglandin
Inflammation
Citokines
Prostacyclins
Inmune response
Vascular reactivity
Thromboxanes
Thrombosis
Bronchoconstriction
Leukotrienes
Bronchoconstriction
Chemotaxis
Inflammation
Fatty acids % total
n-3 PUFA
n-6 PUFA
Monounsaturated
Saturated
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
WHO TRS 916 Report : strength of evidence on
nutritional factors and risk of developing CVD
Evidence
Decreased risk
Convincing Regular physical activity
Linoleic acid 18:2n-6
Fish and fish oils
(EPA &DHA)
No relationship
Vitamin E
Supplements
α-Linolenic acid 18:3 n-3
Oleic acid 18:1 n-9
Myristic and palmitic acids
14:0 16:0
Trans fatty acids
High sodium intake
Overweight
High alcohol intake
Vegetables & fruits (including
berries)
Potassium
Low to moderate alcohol intake
Probable
Increased risk
Stearic acid
18:0
Dietary cholesterol
Unfiltered boiled coffee
Fibre
Nuts (unsalted)
Plant sterols/stanols
Possible
Folate
Flavonoids
Soy products
Fats rich in lauric acid
Impaired fetal nutrition
Beta-carotene supplement
TRS 916 WHO 2003
WHO TRS 916 Report : risk of developing CVD
Evidence
Convincing
Decreased risk
No relationship
Regular physical activity
Linoleic acid 18:2n-6
Fish and fish oils (EPA &DHA)
Myristic and palmitic acids
Vitamin E
Supplements
Vegetables & fruits
(berries)
Potassium
Low to moderate
alcohol intake
Probable
α-Linolenic acid 18:3 n-3
Oleic acid 18:1 n-9
Increased risk
14:0 16:0
Trans fatty acids
High sodium intake
Overweight
High alcohol intake
Stearic acid
18:0
Dietary cholesterol
Unfiltered boiled coffee
Fibre
Nuts (unsalted)
Plant sterols/stanols
Possible
Folate
Flavonoids
Soy products
Fats rich in lauric acid
Restricted fetal growth
Beta-carotene supplement
TRS 916 WHO 2003
Observed and Predicted Declines in Coronary
Mortality in Eastern Finland, Men
Population dietary changes
0
explain much of the reduction in
heart disease mortality in
Finland.
-10
Observed
Predicted
Cholesterol
Blood pressure
Smoking
% Decline in mortality
-20
-30
-40
-50
-60
Vartiainen, Puska et al BMJ 1995
72
74
76
78
80
82
84
86
88
90
92
UK White Paper
04 Dept Health
Causal relationship web
Age
Physical
Activity
Diabetes
DIET
Fat & Salt
HDL- LDL
Chol
BMI
Smoking
A
B marks a postulated influence from A to B
Diastolic
BP
CHD
Diet effects on LDL receptor activity
Saturated or Trans
fatty acids
Healthy fats
High saturated
or trans fat diets
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
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 P<0.05 level.
Total Fat – Ecological Data
Seven Countries Study
Men Participating in the Ni-Hon-San Study*
Residence
Age (years)
Japan
57
Hawaii
54
California
52
Weight (kg)
55
63
66
+20%
Serum cholesterol (mg/dL) 181
218
228
+26%
Dietary fat (% of calories)
15
33
38
Dietary protein (%)
14
17
16
Dietary carbohydrate (%)
63
46
44
-30%
9
4
3
-67%
1.3
2.2
3.7
+285%
Alcohol (%)
5-yr CHD mortality rate
(per 1000 persons)
+253%
*Data from Kato et al., Am J Epidemiol 97:372, 1973. CHD, coronary heart disease.
Epidemiologic Studies*
• Populations on diets high in total fat, saturated and
trans fats, cholesterol, and sugar have high ageadjusted 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
Total Fat and CHD - Cohort Evidence
1.30
1.20
1.10
RR 1.00
0.90
0.80
0.70
I
II
28.3%
32.6%
III
35.6%
IV
38.7%
V
44.0%
Quintiles of Total Fat Consumption
77,878 women in the Nurses Health Study, 1980-2002, Oh et al, AJE 2005
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
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
sustained
Circulation 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.
change in TC (mg/dL)
Dietary fatty acids and blood cholesterol
TC=1.2(2S'-P)
S'=C12+C14+C16
SAFA
MUFA
PUFA
change in fat intake (en%)
Source: Keys et al. Metabolism, 1965
Effect on lipoproteins of replacing saturated
fat with specific fatty acids or carbohydrates
LDL-chol
HDL-chol
0.02
TC/HDL-chol ratio
0.01
0
0
changes per en%
mmol/ L change per % energy
0.01
-0.01
-0.02
-0.03
-0.04
-0.05
monounsaturated FAs
polyunsaturated FAs
carbohydrates
trans FAs
-0.01
-0.02
-0.03
-0.04
Source: Mensink et al Am J Clin Nutr 2003
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
Adverse effects of trans FAs on blood cholesterol
0.4
Nestel
Mensink
Judd
Lichtenstein
Change in (mmol/L)
0.2
LDL
Zock
Judd
0
HDL
-0.2
0
2
4
6
8
10
12
% of energy as trans fatty acids (C18:1 trans)
Zock et al Am J Clin Nutr, 1995
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
LDL
HDL
Total:HDL
cholesterol cholesterol cholesterol 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
44
+0.006
-0.032
Relative risk was after adjusting for dietary fiber intake.
2
1.72
Saturated Fat Intake
1.5
Quintiles (% of calories)
Alpha Linolenic Fatty Acid
Intake Quintiles (% of calories)
1.5
1
1
0.5
0.41
0.5
0
0
Top 1/5
(14.8%)
Ascherio et al BMJ 1996
Bottom 1/5
(5.7%)
Top 1/5
Bottom 1/5
a 1% increase in calories from
linolenic acid (2-3 grams/day).
ORs for Risk of Nonfatal Acute MI by tercile of Linolenic &
Trans FA content of Adipose Tissue in Costa Rica
Odds
Ratio
Adipose Tissue n-3
alpha-linolenic acids
Adipose Tissue
trans fatty acids
A Baylin et al Circulation 107:1586-91 2003
Small reduction in blood cholesterol
 significant reduction in CHD
A reduction in total blood cholesterol level by
each percent leads to a reduction of :
Age (years)
35-44
45-54
55-64
65-74
Risk CHD
-5.4%
-3.9%
-2.7%
-2.0%
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
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
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
0.87 (0.77-0.97)
coronary deaths
0.74 (0.61-0.89)
Jakobsen et al Am J Clin Nutr 89:1–8 2009
coronary
events
coronary
events
1.07 (1.01-1.14)
Jakobsen et al Am J Clin Nutr 89:1–8
coronary
deaths
coronary
deaths
0.96 (0.82-1.13)
2009;.
Coronary Heart Disease
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
Stroke
0.81 (0.62-1.05)P = 0.11
Total CVDs
1.0 (0.89-1.11)P = 0.95
Am J Clin Nutr 2010;91: 1764–8.
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.
Pooled Analysis of 11 Major Cohort Studies
Change in CHD Risk for Each 5% Energy
-20
SFA → PUFA
SFA → Carb
-10
0
10
20
*
*
SFA → MUFA
Total of 344,696 individuals with 5,249 CHD events. *p<0.05
Jakobsen et al, AJCN 2009
Saturated Fat vs. CHO Quality
Change in CHD Risk for Each 5% Energy
-20
-10
0
10
20
30
40
SFA → Low GI CHO
SFA → Med GI CHO
*
SFA → High GI CHO
Risk of CHD among 53,644 adults followed for 12 years. *p<0.05
Jakobsen et al, AJCN 2010
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,
1972–2000 (25–59-year-old)
%
Year
Saturated Fat from Milk and Fat on Bread gr/day
50
40
30
20
North Karelia
Kuopio province
10
Southwest Finland
Helsinki area
0
1972
1977
1982
Year
1987
1992
Butter & Margarine Consumption Finland 1979–01
Age-adjusted Mortality Rates of CHD in North Karelia and
the all of Finland in males aged 35–64 years 1969 to 2002.
700
start of the North Karelia Project
600
Mortality per
100 000
population
extension of the Project nationally
500
North Karelia
400
300
- 82 %
All Finland
200
- 75%
100
69
6th ICPC, Iguassy Falls 21.-25.5. 2005 (3.)
72
75
78
81
84
87
90
93
Year
96
99 2002