Omega-3 and Coronary Heart Disease
Biomarkers and Interventions
William S. Harris, PhD
Research Professor of Medicine
Sanford School of Medicine
University of South Dakota
President
OmegaQuant Analytics
Sioux Falls, SD
Senior Scientist
Health Diagnostic Lab, Inc.
Richmond, VA
Summary
Achieving optimal RBC levels of
omega-3 fatty acids can help reduce
risk for cardiovascular disease
Objectives
1. Define 5 fatty acid classes in RBC’s
2. Describe how fatty acid status is assessed
3. Explain how RBC fatty acids relate to
cardiovascular risk
4. Discuss mechanisms of action
5. Review recommended fatty acid intakes
Take Home Messages
1. The RBC membrane contains >20 individual fatty acids of 5
different classes
2. The RBC EPA+DHA content (the Omega-3 Index) is a valid
and stable biomarker of omega-3 fatty acid status
3. For cardiovascular health, an Omega-3 Index >8% is optimal
and an Index < 4% is deficient. Target trans fat levels are <1%.
4. Dietary doses of EPA+DHA reduce risk for CHD via nontraditional pathways by changing membrane physiochemical
properties and improving the eicosanoid profile.
Pharmacologic doses lower triglycerides.
5. Omega-3 EPA+DHA intakes should be 400-500 mg/day for
most adults and twice that for CHD patients.
Objectives
1. Define 5 fatty acid classes in RBC’s
2. Describe how fatty acid status is assessed
3. Explain how RBC fatty acids relate to
cardiovascular risk
4. Discuss mechanisms of action
5. Review recommended fatty acid intakes
Types of Fatty Acids
A fatty acid is a chain of carbon atoms with an acid group
on one end
• Saturated
• Monounsaturated
• Polyunsaturated – Omega-6 and Omega-3 (n-6 or n-3)
• Trans
Omega-6
Polyunsaturated Fatty Acids
Non-Essential Fatty Acids
COOH
COOH
Palmitic acid (PA) C16:0
Saturated Fatty Acid
Linoleic acid (LA) C18:2n-6
ω
COOH
-Linolenic acid (GLA) C18:3n-6
COOH
Arachidonic acid (AA) C20:4n-6
COOH
α
Oleic acid (OA) C18:1n-9
Monounsaturated Fatty Acid
COOH
Elaidic acid (EA)
C18:1n-9 trans; Trans Fatty Acid
Omega-3
Polyunsaturated Fatty Acids
COOH
-Linolenic acid (ALA) C18:3n-3
COOH
Eicosapentaenoic acid, EPA C20:5n-3
COOH
Docosahexaenoic acid, DHA C22:6n-3
Types of Fatty Acids
N-6 Polyunsaturates (PUFAs)
• PUFA have >1 double bond; n-6 and n-3 families.
• Major n-6 PUFAs: linoleic acid (LA, C18:2n-6) and
arachidonic acid (AA, C20:4n-6).
•All n-6 PUFAs can be synthesized from LA, but LA
cannot be made de novo (i.e., essential).
• Linoleic - vegetable oils (corn, safflower, soybean,
etc.) with small amounts in canola, olive and
flaxseed oils. Arachidonic - only in animal products
like meat and eggs (but not in dairy products).
Types of Fatty Acids
N-3 Polyunsaturates
• Major n-3 PUFAs are alpha-linolenic acid (ALA,
C18:3n-3), eicosapentaenoic acid (EPA; C20:5n3), docosapentaenoic acid (DPA; C22:5n-3) and
docosahexaenoic acid (DHA; C22:6n-3)
• All n-3 PUFAs can be synthesized from ALA, but
ALA cannot be made de novo (i.e., essential).
• ALA is in certain plant oils (canola, olive and
flaxseed), whereas EPA and DHA come from
seafoods.
Take Home Message
The RBC membrane contains >20
individual fatty acids of 5
different classes
Objectives
1. Define 5 fatty acid classes in RBC’s
2. Describe how fatty acid status is assessed
3. Explain how RBC fatty acids relate to
cardiovascular risk
4. Discuss mechanisms of action
5. Review recommended fatty acid intakes
Assessing Fatty Acid Status
RBC fatty acids are hydrolyzed from membranes,
derivatized and analyzed by gas chromatography
Assessing Fatty Acid Status
The Omega-3 Index
A measure of the amount of EPA+DHA in red blood cell
membranes expressed as the percent of total fatty acids
There are 64 fatty acids in
this model membrane, 3 of
which are EPA or DHA
3/64 = 4.6%
Omega-3 Index = 4.6%
Harris WS and von Schacky C. Prev Med 2004;39:212-220.
Assessing Fatty Acid Status
Low Biological Variability & Long-Term Marker
10%
9%
Plasma
EPA+DHA
Percent of total FAs
Plasma
8%
7%
6%
5%
4%
Total Coefficients of
Variability (CVs)
3%
2%
1%
0%
12%
RBC EPA+DHA
Percent of total FAs
10%
RBC
20 healthy volunteers
tested weekly for 6
weeks
8%
6%
4%
2%
EPA+DHA in…
• RBC = 4.1%
• Whole Blood = 6.7%
• Plasma = 16%
• Plasma PL = 15%
0%
Week 0 Week 1 Week 2 Week 3 Week 4 Week 5 Week 6
Harris and Thomas. Clin Biochem 2010;43:338–340
Take Home Message
The RBC EPA+DHA content (the
Omega-3 Index) is a valid and stable
biomarker of omega-3 fatty acid status
Objectives
1. Define 5 fatty acid classes in RBC’s
2. Describe how fatty acid status is assessed
3. Explain how RBC fatty acids relate to
cardiovascular risk
4. Discuss mechanisms of action
5. Review recommended fatty acid intakes
RBC Fatty Acids and CVD Risk
Strong evidence
• Omega-3 Index: Low levels = High risk
Intermediate evidence
• Trans fats: High levels = High risk
• Linoleic acid (n-6): Low levels = High risk
Little evidence
• Saturated
• Monounsaturated
• Plant n-3 (α-linolenic acid)
RBC Fatty Acids and CVD Risk
Selecting Omega-3 Index Targets
Greatest Protection
10%
GISSI-P:~9–10%
CHS: 8.8%
8%
DART:~8–9%
SCIMO: 8.3%
Least Protection
PHS: 3.9%
6%
4%
SCIMO: 3.4%
Seattle: 3.3%
8.1%
5 epi studies:~8%
PHS: 7.3%
Seattle: 6.5%
2%
Harris WS and von Schacky. Prev Med 2004;39:212-220.
RBC Fatty Acids and CVD Risk
Omega-3 Index Risk Zones
USA/EU
Undesirable
Undesirable
Japan
Intermediate
4%
Desirable
8%
Percent of EPA+DHA in RBC
Risk for cardiac death in the US is
45x higher than in Japan
Harris WS and von Schacky. Prev Med 2004;39:212-220.
Itomura, in vivo 2008;22:131-136.
He et al. Circ 2004;109:2705-2711
Iso et al. Circ 2006;113:195-202
The Omega-3 EPA+DHA
Index Worldwide
14%
Korea
12%
Korea
10%
Japan
Japan
Alaska
Alaska
8%
Spain
Norway
Norway
Spain
6%
Healthy subjects
Ill subjects
Germany
Germany
4%
USA
2%
0%
0
5
10
15
20
25
Marchioli and Harris, unpublished
RBC Fatty Acids and CVD Risk
Omega-3 Index and Acute Coronary Syndromes
(768 case-control pairs)
p=0.03
p for trend < 0.0001
p<0.001
p=0.017
Multivariable logistic regression model including: age; race; gender; history of
diabetes mellitus, hypertension, hyperlipidemia and/or myocardial infarction; a
family history of coronary artery disease; and LDL-C, HDL-C, and triglycerides.
Block RC, et al. Atherosclerosis 2008;197 :821-828.
RBC Fatty Acids and CVD Risk
The Omega-3 Index and Cellular Aging
RBC Fatty Acids and CVD Risk
Blood Omega-3 is Inversely Associated with
the Rate of Telomere Attrition
P<0.001 for trend
Adapted from Farzanah-Far, et al. JAMA 2010;303:250-257
RBC Fatty Acids and CVD Risk
Omega-3 Index and Time to Death in 982 CHD Patients
< 4.6%
≥4.6%
1.2 yrs
It took 1.2 years longer for 20% of the
population to die in the higher vs. the
lower omega-3 group
≥4.6%
< 4.6%
Pottala et al. Circ CV Outcomes & Qual 2010;3 406-412
RBC Fatty Acids and CVD Risk
Why is the Omega-3 Index Target 8%?
• The average Omega-3 Index estimated from 11
studies was 8.1%
• An Omega-3 Index of >8% was associated with
reduced probability for acute coronary syndrome
compared to an Index of <4%
• The Omega-3 Index associated with the slowest
rate of cellular aging was 8.7%
• The average Index in Japan (where CHD is rare)
is 9-10%
Clinical Evidence – Cross Sectional
Primary Cardiac Arrest and the Omega-3 Index
Seattle PCA Study
Odds Ratio
90%
reduction
in risk
*p<0.05
vs Q1
3.3%
4.3%
5.0%
6.5%
Midrange RBC EPA+DHA by Quartile
Adapted from Siscovick DS et al. JAMA 1995;274:1363-1367.
Clinical Evidence – Prospective
Sudden Cardiac Death and the Omega-3 Index
Physicians' Health Study
Relative Risk
90%
reduction
in risk
p for trend = 0.001
3.6%
4.8%
5.6%
6.9%
Mean Blood Omega-3 FA (%) by Quartile
Albert CM et al. N Engl J Med 2002:346:1113-1118.
The Omega-3 Index, Brain Volume and
Cognitive Function in Framingham
Quartile 1 vs 2-4 (<4.4% vs above)
Model
Covariates
Total Cerebral Brain
Volume (%)
Visual Memory
Lower Index =
Smaller Volume
Executive
Function
Abstract Thinking
“The MRI finding of lower brain
A
volume [in those with an Omega-3
B
Index <4.4%] represents a change
C
equivalent to approximately 2 years of
D
structural brain aging.”
Lower Index = Poorer Function
Age, sex, education,
time interval
p=0.005
p=0.026
p=0.025
p=0.001
A with apoE4 and
homocysteine
p=0.005
p=0.026
p=0.038
p=0.002
B with physical
activity and BMI
p=0.008
p=0.024
p=0.046
p=0.002
B with diabetes, sBP,
smoking, A-fib,
prevalent CVD and
total cholesterol
p=0.011
p=0.079
p=0.108
p=0.001
n=1575; age=67
Tan Z, et al. Neurology 2012
Executive Functioning and Cognitive Flexibility by
Quartile of the HS-Omega-3 Index in Army Members
Deployed in Iraq
Executive Function Score
Standardized Test Scores
120
P<0.01 for trend
Cognitive Flexibility Score
100
80
60
40
20
0
1
2
3
4
Omega-3 Quartile
Johnston et al. Nutr Neurosci 2012 (in press)
N=78, mean age 31 yrs
Take Home Message
For cardiovascular (and possibly
neurocognitive) health, an Omega-3
Index >8% is optimal and an Index <
4% is deficient.
Objectives
1. Define 5 fatty acid classes in RBC’s
2. Describe how fatty acid status is assessed
3. Explain how RBC fatty acids relate to
cardiovascular risk
4. Discuss mechanisms of action
5. Review recommended fatty acid intakes
Effects of Omega-3*…
• Reduced heart rate
• Reduced inflammation
• Improved vascular function
• Reduced susceptibility to cardiac arrhythmias
* Primarily from nutritionally-achievable intakes: 500-1,000 mg/d
Mediated by….
• Altered cell membrane
physiochemical properties
• Shifts in eicosanoid production
• Altered gene expression
Mozaffarian and Wu. JACC 2011; 58:2047–67
Take Home Message
Dietary doses of EPA+DHA reduce
risk for CHD via non-traditional
pathways by changing membrane
physiochemical properties and
improving the eicosanoid profile.
Pharmacologic doses lower
triglycerides.
Objectives
1. Define 5 fatty acid classes in RBC’s
2. Describe how fatty acid status is assessed
3. Explain how RBC fatty acids relate to
cardiovascular risk
4. Discuss mechanisms of action
5. Review recommended fatty acid intakes
AHA Scientific Statement on Omega-3s
Population
Patients without
documented CHD
Recommendation
Patients with
documented CHD
Consume ~1 gm of EPA+DHA per
day, preferably from fish,
supplements could be used in
consultation with a physician
2 – 4 gm of EPA+DHA per day
provided as capsule under a
physician’s care
Patients needing TG
lowering
Kris-Etherton, Harris, & Appel.
Circulation, 2002;106:2747-57.
Eat a variety of fish (preferably
oily) at least twice a week*,
include oils and foods rich in ALA
*Equal to about 400-500 mg EPA+DHA/day
AHA Recommendations for Women
Population
Women with high blood
cholesterol or
triglycerides; for
primary or secondary
prevention
Mosca et al. Circulation 2011;123:1243-6.
Recommendation
Consumption of omega3 fatty acids in the form
of fish or capsules (e.g.,
EPA 1800 mg/d)
Our tests of 16
leading pill brands
found that all
contained roughly as
much omega-3s as
their labels claimed,
and none were
contaminated or
spoiled. So choose
them based mainly
on price
Take Home Messages
1. The RBC membrane contains >20 individual fatty acids of 5
different classes
2. The RBC EPA+DHA content (the Omega-3 Index) is a valid
and stable biomarker of omega-3 fatty acid status
3. For cardiovascular health, an Omega-3 Index >8% is optimal
and an Index < 4% is deficient. Target trans fat levels are <1%.
4. Dietary doses of EPA+DHA reduce risk for CHD via nontraditional pathways by changing membrane physiochemical
properties and improving the eicosanoid profile.
Pharmacologic doses lower triglycerides.
5. Omega-3 EPA+DHA intakes should be 400-500 mg/day for
most adults and twice that for CHD patients.