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Role of Omega3 Fatty Acids in Cardiovascular Disease Prevention Scott Turner, DO, FACC

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Title: Role of Omega3 Fatty Acids in Cardiovascular Disease Prevention Scott Turner, DO, FACC


1
Role of Omega-3 Fatty Acids in Cardiovascular
Disease PreventionScott Turner, DO, FACC
2
Whats Important
  • LDL
  • HDL
  • TG

3
ATP III Changes
  • Focus on Multiple Risk Factors
  • Raises persons with diabetes without CHD, most of
    whom display multiple risk factors, to the risk
    level of CHD risk equivalent.
  • Uses Framingham projections of 10-year absolute
    CHD risk (i.e., the percent probability of having
    a CHD event in 10 years) to identify certain
    patients with multiple (2) risk factors for more
    intensive treatment.
  • Identifies persons with multiple metabolic risk
    factors (metabolic syndrome) as candidates for
    intensified therapeutic lifestyle changes.

4
ATP III Changes
  • Modifications of Lipid and Lipoprotein
    Classification
  • Identifies LDL cholesterol
  • Raises categorical low HDL cholesterol from mg/dL to measure of a depressed HDL.
  • Lowers the triglyceride classification cutpoints
    to give more attention to moderate elevations.

5
ATP III Changes
  • Support for Implementation
  • Recommends a complete lipoprotein profile (total
    cholesterol, LDL cholesterol, HDL cholesterol,
    and triglycerides) as the preferred initial test,
    rather than screening for total cholesterol and
    HDL alone.
  • Encourages use of plant stanols/sterols and
    viscous (soluble) fiber as therapeutic dietary
    options to enhance lowering of LDL cholesterol.
  • Presents strategies for promoting adherence to
    therapeutic lifestyle changes and drug therapies.
  • Recommends treatment beyond LDL lowering for
    persons with triglycerides ³200 mg/dL.

6
ATP III Changes
  • LDL Cholesterol The Primary Target of Therapy
  • Research from experimental animals, laboratory
    investigations, epidemiology, and genetic forms
    of hypercholesterolemia indicate that elevated
    LDL cholesterol is a major cause of CHD.
  • In addition, recent clinical trials robustly show
    that LDL-lowering therapy reduces risk for CHD.
  • For these reasons, ATP III continues to identify
    elevated LDL cholesterol as the primary target of
    cholesterol-lowering therapy.
  • As a result, the primary goals of therapy and the
    cutpoints for initiating treatment are stated in
    terms of LDL.

7
Risk Assessment First Step in Risk Management
8
LDL Cholesterol
  • 100-129 Near optimal/above optimal
  • 130-159 Borderline high
  • 160-189 High
  • ³190 Very high

9
Total Cholesterol
  • 200-239 Borderline high
  • ³240 High
  • HDL Cholesterol
  • ³60 High

10
Major Risk Factors
  • Cigarette smoking
  • Hypertension (BP ³140/90 mmHg or on
    antihypertensive medication)
  • Low HDL cholesterol (
  • Family history of premature CHD (CHD in male
    first degree relative first degree relative
  • Age (men ³45 years women ³55 years)

11
  • Risk Category LDL Goal (mg/dL)
  • CHD and CHD risk equivalents
  • Multiple (2) risk factors
  • Zero to one risk factor
  • Further updates show goal patients.

12
Nutrient Composition of the TLC (therapeutic
Lifstyle Change) Diet
  • Saturated fat Less than 7 of total calories
  • Polyunsaturated fat Up to 10 of total calories
  • Monounsaturated fat Up to 20 of total calories
  • Total fat 25-35 of total calories
  • Carbohydrate 50-60 of total calories
  • Fiber 20-30 g/day
  • Protein Approximately 15 of total calories
  • Cholesterol Less than 200 mg/day
  • Total calories (energy) Balance energy intake
    and expenditure to maintain desirable body
    weight/prevent weight gain

13
Drugs Affecting Lipoprotein Metabolism
  • HMG CoA reductase inhibitors (statins)
  • 18-55 LDL reduction
  • Bile acid Sequestrants
  • 15-30 LDL reduction
  • Nicotinic acid
  • 15-35 HDL increase
  • 20-50 TG reduction
  • Fibric acids
  • 10-20 HDL increase
  • 20-50 TG reduction

14
Framingham Risk Assessment
  • Age
  • Total Cholesterol
  • Smoking
  • HDL
  • SBP
  • (10 year risk )

15
Back to Omega 3
16
The Cardioprotective Effects of Omega-3 Fatty
Acids
  • Essential FA metabolism
  • Evidence for benefit
  • Mechanism of action
  • RBC omega-3 FA a new CHD risk factor?
  • Recommended intake

17
Essential Fatty Acid Families
?-3 family
?-6 family
C183 ?-3
  • ?-Linolenic
  • Flaxseed Oil
  • Canola Oil
  • Soybean Oil

C182 ?-6
Linoleic
  • Corn Oil
  • Safflower Oil
  • Sunflower Oil

H3C
COOH
H3C
C205 ?-3
Eicosapentaenoic (EPA)
COOH
C204 ?-6
Arachidonic
H3C
COOH
C226 ?-3
Docosahexaenoic (DHA)
Less thrombotic and inflammatory metabolites
More thrombotic and inflammatory metabolites
  • Oily Fish
  • Fish Oil Capsules

18
Problems with the n6n3 Ratio
  • Fails to distinguish between short- and
    long-chain essential fatty acids
  • Effectively presumes physiological equivalence
    within class
  • Infinite number of absolute intakes give the same
    ratio
  • Similar problem with the now-abandoned P/S ratio
  • Suggests that equal benefit can be obtained from
    reducing n-6 intake as from increasing n-3 intake
  • Low n-6 intake associated with increased CHD risk
  • CHD cases have lower EPA/DHA in blood but same
    (or lower) AA as controls
  • Lower LA intakes do not reduce tissue AA content
  • Tissue AA content is best lowered by increasing
    EPA/DHA intake

Gebauer S et al. In Akoh CC et al. Healthful
Lipids. Champaign, IL AOCS Press, 2005221-248.
19
Japan EPA Lipid Intervention Study (JELIS)
19
Control
Cumulative Incidence of Major Coronary Events ()
EPA
Hazard ratio 0.81 (0.690.95)p 0.011
0
1
2
3
4
5
Years
18,645 Japanese (70 women, mean age 61 years)
randomized to statin alone or statin EPA (1.8
g/d) and followed for 5 years
Yokoyama M. Presented at American Heart
Association Scientific Sessions, Dallas, Texas,
14 November 2005.
20
Relative Risk of Sudden Cardiac Death and Blood
Omega-3 Levels Physicians' Health Study
90reductionin risk
p for trend 0.001
Relative Risk
1
2
3
4
Blood Omega-3 FA () by Quartile
Albert CM et al. N Engl J Med 20023461113-1118.
21
GISSI-Prevenzione Time Course of Clinical Events
11,300 post-MI patients were given usual care
with or without 850 mg EPADHA for 3.5 years
n-3 PUFA Control
Total mortality reduced by 28 (p0.027)
Probability
0.59 (0.360.97)p0.037
0.72 (0.540.96)p0.027
Days
Sudden deathreduced by 47 (p0.0136)
n-3 PUFA Control
Probability
0.47 (0.220.99)p0.048
0.53 (0.320.88)p0.0136
Days
Marchioli R et al. Circulation 20021051897-1903.
22
GISSI-Prevenzione Effects of 850 mg/d of EPADHA
on Serum Lipids
Total Cholesterol
LDL Cholesterol
mg/dL
mg/dL
HDL Cholesterol
Triglycerides
mg/dL
mg/dL
1
2
3
4
5
6
1
2
3
4
5
6
Months
Months
Marchioli R et al. Circulation 20021051897-1903.
23
The Cochrane Omega-3 Meta-Analysis
  • Hooper et al. analyzed fish advice/supplementation
    trials and 4 cohort studies and concluded that
    there was no strong evidence for a reduced risk
    for death with increased consumption of omega-3
    fatty acids
  • There are a number of reasons for these
    conclusions
  • Inclusion of a large (and poor-quality) fish
    advice study that reported adverse effects of
    fish oils in patients with stable angina without
    this study, the conclusions change
  • Failure to consider biomarker studies which have
    been strongly supportive of CHD benefit
  • Failure to include cohort studies that tracked
    fish intake
  • The Hooper analysis, although controversial and
    not considered authoritative, points to the
    needed for further research on the cardiovascular
    effects of omega-3 FA

Hooper L et al. BMJ 2001322757-763.
24
Omega-3 FA Infusion Prevents Ventricular
Tachyarrhythmias in Dogs
Billman GE et al. Proc Natl Acad Sci U S A
1994914427-4430.
25
EPA Increases Resistance to Electrical Pacing in
Individual Rat Myocardiocytes
Leaf A et al. Circulation 20031072646-2652.
26
Omega-3 FA and Risk for VT/VF in Patients with
ICDs
  • NO BENEFIT
  • 200 patients with ICD and a recent history of
    sustained VT or VF
  • 1.3 g/d EPADHA vs. placebo
  • 2-year follow-up
  • Endpoint time to first ICD therapy for
    arrhythmia
  • 60 with class III/IV HF
  • None taking anti-arrhythmic drugs
  • BENEFIT
  • 402 with ICD implanted for cardiac arrest or
    sustained VT/VF
  • 2.6 g/d EPADHA vs. placebo
  • 1-year follow-up
  • Endpoint time to first ICD therapy or death
  • 15 with class III/IV HF
  • 35 taking anti-arrhythmic drugs

Raitt MH et al. JAMA 20052932884-2891. Leaf A
et al. Circulation 20051122762-2768.
27
Time to ICD Therapy for VT/VF or Death from Any
Cause
All randomized patients (n402multivariate RR
0.67 p0.02)
Cumulative Proportion of Time to First Event
Months
All patients who were compliant for at least 11
months (n236 multivariate RR 0.52 p0.006)
Months
Leaf A et al. Circulation 20051122762-2768.
28
Omega-3 FA and Risk for VT/VF in Patients with
ICDs Time to First Episode of ICD Therapy
All Patients
Patients with Ventricular Tachycardia
without VT or VF
Log-rank p .19
Log-rank p .007
720
540
360
180
0
720
540
360
180
0
720
540
360
180
0
720
540
360
180
0
Days
Days
No. at RiskPlaceboFish Oil
100100
6556
5747
4835
3119
6964
4326
3722
3014
188
Raitt MH et al. JAMA 20052932884-2891.
29
Omega-3 FA and Risk for VT/VF in Patients with
ICDs
  • Omega-3 FA appear to protect against the
    development of VF secondary to an acute ischemic
    event. This is not the same as an ICD discharge
    for VT/VF
  • In clinical trials, omega-3 FA benefited patients
    who had a recent MI but relatively good LV
    function. In this study, patients did not have a
    recent MI, but had significantly reduced LV
    function and a history of sustained VT/VF
  • In the failed study, the development of VT/VF was
    based not on ischemia but on myocardial
    scarbased re-entry
  • Na-channel blockade may be protective in
    ischemia-based VF but permissive in patients with
    premature ventricular contractions

Raitt MH et al. JAMA 20052932884-2891.
30
Omega-3 FA for Prevention of Atrial Fibrillation
post CABG
  • 160 patients awaiting CABG
  • Randomized to usual care or 2 capsules, each
    containing 866 mg EPADHA ethyl esters (12)
  • Supplementation began at least 5 days prior to
    surgery and continued through hospitalization
  • Endpoint was atrial fibrillation detected by ECG
    during hospitalization AF 5 min or requiring
    intervention for angina or hemodynamic compromise
  • Secondary endpoint was length of stay post CABG

Calo L et al. J Am Coll Cardiol 2005451723-1728.
31
Omega-3 FA and Atrial Fibrillation post CABG
Calo L et al. J Am Coll Cardiol 2005451723-1728.
32
Exploring the Mechanism of Action of Low Omega-3
FA Intake in CHD Patients
  • History of CHD with EF
  • Randomized, double-blind, placebo-controlled
    crossover
  • Assigned to EPADHA (810 mg/d) or placebo
  • 4 months on each treatment
  • Assessed effects on lipids, inflammatory markers,
    blood pressure, cardiac function, arterial
    compliance, and heart rate variability

OKeefe JH Jr et al. Am J Cardiol
2006971127-1130.
33
Effect of EPADHA (810 mg/d ? 4 mo) on Heart Rate
in 18 CHD Patients
74 vs 69 bpm, pPlacebo
bpm
Omega-3
Supine
Standing
Sitting at rest
0
10
20
30
40
50
60
70
Minutes
OKeefe JH Jr et al. Am J Cardiol
2006971127-1130.
34
Heart Rate and Risk for Sudden Cardiac Death
Framingham Heart Study
Men
p5.9
4.7
  • Quintiles
  • 65
  • 6673
  • 7479
  • 8087
  • 88

3.1
Biennial Age-adjusted Rate per 1000
2.5
1.8
1.5
1.5
1.1
0.6
Women
0.2
1
2
3
4
5
Quintile of Heart Rate
Kannel WB et al. Am Heart J 1985109876-885.
35
Omega-3 FA and Plaque Stability Plaque
Characteristics
Control
Omega-3
Omega-6
  • Patients awaiting carotid endarterectomy (n188)
    were randomized to control, fish oil (omega-3),
    or sunflower oil (omega-6) supplementation for
    median 34, 46, and 43 days preprocedure
  • Plaques in omega-3 patients appeared to be more
    stable

p
Percent
IV
V
VI
ThinCap
AHA Type
Theis F et al. Lancet 2003361477-485.
36
Omega-3 FA and Plaque Stability Macrophage
Staining Intensity
Control
Omega-3
Omega-6
  • Plaque burden of macrophages (CD68) and T cells
    (CD3) was examined by immuno-histochemistry
  • There was less macrophage staining in the omega-3
    group, but equivalent T-cell staining

p
Percent
Low
Mid
High
Macrophage Staining Intensity
Theis F et al. Lancet 2003361477-485.
37
Omega-3 Acid Ethyl Esters
90 Omega-3
DHA 375 mg
Other Omega-3 60 mg
EPA465 mg
Omega-6 80 mg
Omega-7 and -9 80 mg
Other FA 10 mg
38
LOVAZATM for Triglyceride Lowering
  • The effects of 4 g of Lovaza per day were
    assessed in two randomized, placebo-controlled,
    double-blind, parallel-group studies
  • 84 adult patients (42 on Lovaza, 42 on placebo)
    with very high triglyceride levels
  • Patients whose baseline triglyceride levels were
    between 500 and 2000 mg/dL were enrolled in these
    two studies of 6 and 16 weeks duration

Harris WS et al. J Cardiovasc Risk
19974385-391. Pownall HJ et al.
Atherosclerosis 1999143285-297.
39
Omega-3 Ethyl Esters and Lipid Levels in Patients
with Triglycerides 500 mg/dL
Non-HDL-C27
TG816
HDL-C22
Chol296
VLDL-C175
LDL-C89
Baseline(mg/dL)
P45.0
PP0.0015
PP0.0002
P0.0059
9.1
6.7
0.0
-0.9
-1.7
-3.6
-4.8
-9.7
-13.8
-42.0
-45.0
Placebo
Omega-3 Acid Ethyl Esters (4 g/day)
Pooled analysis Harris WS et al. J Cardiovasc
Risk 19974385-391. Pownall HJ et al.
Atherosclerosis 1999143285-297.
40
Potential Triglyceride-Lowering Mechanisms of
Omega-3 FA
NEFA
Hormone-Sensitive Lipase
Glucose Uptake

Adipose TG
FA Uptake
Cell membrane
Acetyl-CoA carboxylase FA synthase

Acyl-CoA synthase
?-oxidation
Acyl-CoA
FA
Acetyl CoA
MitochondriaCPT-I, -II Acyl-CoAdehydrogenase
Lipogenesis


?-oxidation
DAG
TG
VLDL
DGAT

PA
Glycerol-3-P
Lyso PA
PAP



Apo B-100
Phospholipids
Peroxisome Acyl-CoA oxidase (rodents only?)

Degradation
Harris WS and Bulchandani D. Curr Opin Lipidol
2006 17387-393.
41
Should blood omega-3 fatty acid levels be
considered as a potential risk factor for sudden
cardiac death?
If so, what would high- and low-risk levels be?
42
Risk for Primary Cardiac Arrest and Red Blood
Cell EPADHA Level
90reductionin risk
pOdds Ratio
3.3
4.3
5.0
6.5
Mean RBC EPADHA by Quartile
Adapted from Siscovick DS et al. JAMA
19952741363-1367.
43
Omega-3 Index
A measure of the amount of EPADHA 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 et al. Prev Med 200439212-220.
44
Relationship Between Reported Intake of Tuna and
Other Non-fried Fish and the Omega-3 Index (n163)
Omega-3 Index ()
13/mon(42)
1/wk(18)
12/wk(15)
2/wk(12)
Frequency of Intake ( of Population)
Sands SA et al. Lipids 200540343-347.
45
Correlation of Myocardial and Red Blood Cell
EPADHA Levels (n20)
R 0.82 pHeart EPA DHA ()
0
5
15
10
RBC EPA DHA ()
Harris WS et al. Circulation 20041101645-1649.
46
Omega-3 Index Study Estimates
Greatest Protection
GISSI-P910
10
CHS 8.8
8
DART89
SCIMO 8.3
8.1
6
5 epi studies8
Least Protection
4
PHS 7.3
PHS 3.9
SCIMO 3.4
Seattle 6.5
Seattle 3.3
2
Harris WS et al. Prev Med 200439212-220.
47
Proposed Omega-3 Index Risk Zones Relative Risk
for Death from CHD
Undesirable
Intermediate
Desirable
10
8
4
0
Percent of EPA DHA in RBC
Harris WS et al. Prev Med 200439212-220.
48
Distribution of Omega-3 Index in 163 Adults Not
Taking Omega-3 Supplements
9 of sample
Omega-3 Index ()
47 of sample
44 of sample
Sands SA et al. Lipids 200540343-347.
49
The Omega-3 Index How Does It Compare with
Traditional CHD Risk Factors?Physicians Health
Study
Relative Risk for Sudden Cardiac Death by Risk
Factor
P for trend
0.98
0.37
0.56
.017
0.87
0.06
RR SCD
CRP
Hcy
TC
LDL
HDL
TG
TC/HDL
?-3FA
Albert CM et al. Circulation 20021052595-2599.
Albert CM et al. N Engl J Med
20023461113-1118.
50
Omega-3 Index Does It Fulfill Criteria for a
Risk Factor?
  • Consistent epidemiological findings
  • Between populations yes
  • Within populations yes
  • Prospective intervention studies yes
  • Independent from other risk factors at present
  • Biological plausibility omega-3 FA in cardiac
    membranes reduce susceptibility to fatal
    arrhythmias
  • Strength of association high (90 risk
    reduction)
  • Adds significant prognostic value unknown

51
Omega-3 Index A Modifiable Risk Factor
  • Omega-3 Index is responsive to changes in omega-3
    FA intake (fish or capsules)
  • Correcting the Omega-3 Index is
  • Safe Highest AHA recommended intake for CHD
    prevention (1 g/d) is 1/3 of amount the FDA
    regards as safe for inclusion in the food supply
  • Easy Eat more oily fish or take 13 fish oil
    capsules per day
  • Affordable Standard drug store capsules can
    provide about 1 g/d for as little as 7

52
AHA Recommendations for Omega-3 FA Intake
Kris-Etherton PM et al. Circulation
20021062747-2757.
53
Omega-3 FA Content of Wild vs. Farmed Fish
Atlantic Salmon
Rainbow Trout

EPA DHA Sum

g FA/100 g Serving


n 46
n 10
n 37
n 10
Farmed
Wild
Farmed
Wild
pRaw, skinless fillets analyzed fat content
varied from 1.316 g/100 g flesh in both farmed
and wild Atlantic salmon
Blanchet C et al. Lipids 200540529-531.
54
Ways to Get 1 g/d EPADHA
  • Fish
  • 23 oz salmon, sardines, mackerel per day
  • Dietary Supplements
  • Low Potency 300 mg EPADHA/g(Typical drug store
    capsules 3 g/d)
  • Mid Potency 500700 mg EPADHA/g(Mail-order,
    online, etc 2 g/d
  • Drugs
  • High Potency 850 mg EPADHA/g(Omega-3 acid
    ethyl esters 1 g/d)
  • Cod Liver Oil
  • 1 tsp (RDA for vitamin D 2? RDA for vitamin A)

55
Omega-3 and CHD Summary
  • EPA and DHA have cardioprotective properties
    effects of ALA are unclear
  • Mechanisms of action
  • TG lowering via a combination of inhibited
    hepatic TG synthesis/secretion and enhanced
    VLDL-TG clearance
  • Reduced risk for sudden cardiac death via an
    increased resistance to ischemia-induced
    ventricular arrhythmias
  • The Omega-3 Index (RBC EPADHA) has the potential
    to be a new risk factor for CHD death
  • AHA-recommended intakes range from 2 (preferably
    oily fish) meals/wk (1 prevention), to 1 g/d
    (2 prevention), to 24 g/d (triglyceride
    lowering)
  • Omega-3 FA may be obtained from oily fish, cod
    liver oil, dietary supplements, and a
    pharmaceutical preparation
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