Omega-3 and Coronary Heart Disease Biomarkers and Interventions

Transcription

1 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

2 Summary Achieving optimal RBC levels of omega-3 fatty acids can help reduce risk for cardiovascular disease

3 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

4 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 mg/day for most adults and twice that for CHD patients.

5 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

6 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 Omega-3 Polyunsaturated Fatty Acids Linoleic acid (LA) C18:2n-6 COOH COOH Palmitic acid (PA) C16:0 Saturated Fatty Acid COOH -Linolenic acid (ALA) C18:3n-3 COOH -Linolenic acid (GLA) C18:3n-6 ω Oleic acid (OA) C18:1n-9 Monounsaturated Fatty Acid COOH α COOH Eicosapentaenoic acid, EPA C20:5n-3 Arachidonic acid (AA) C20:4n-6 COOH COOH Elaidic acid (EA) C18:1n-9 trans; Trans Fatty Acid COOH Docosahexaenoic acid, DHA C22:6n-3

7 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).

8 Types of Fatty Acids N-3 Polyunsaturates Major n-3 PUFAs are alpha-linolenic acid (ALA, C18:3n-3), eicosapentaenoic acid (EPA; C20:5n- 3), 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.

9 Take Home Message The RBC membrane contains >20 individual fatty acids of 5 different classes

10 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

11 Assessing Fatty Acid Status RBC fatty acids are hydrolyzed from membranes, derivatized and analyzed by gas chromatography

12 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 Harris WS and von Schacky C. Prev Med 2004;39: 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%

13 Assessing Fatty Acid Status Low Biological Variability & Long-Term Marker Plasma Percent of total FAs 10% 9% 8% 7% 6% 5% 4% 3% 2% 1% 0% Plasma EPA+DHA 20 healthy volunteers tested weekly for 6 weeks Total Coefficients of Variability (CVs) RBC Percent of total FAs 12% 10% 8% 6% 4% 2% RBC EPA+DHA 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:

14 Take Home Message The RBC EPA+DHA content (the Omega-3 Index) is a valid and stable biomarker of omega-3 fatty acid status

15 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

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17 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)

18 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% Least Protection 6% SCIMO: 8.3% 5 epi studies:~8% 8.1% PHS: 3.9% 4% PHS: 7.3% SCIMO: 3.4% Seattle: 6.5% Seattle: 3.3% 2% Harris WS and von Schacky. Prev Med 2004;39:

19 RBC Fatty Acids and CVD Risk Omega-3 Index Risk Zones USA/EU Japan Undesirable Intermediate Desirable 4% 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: Itomura, in vivo 2008;22: He et al. Circ 2004;109: Iso et al. Circ 2006;113:

20 14% The Omega-3 Index Worldwide EPA+DHA 12% Korea Korea 10% Japan Japan 8% 6% Germany Germany Spain Norway Spain Norway Alaska Alaska Healthy subjects Ill subjects 4% USA 2% 0% Marchioli and Harris, unpublished

21 RBC Fatty Acids and CVD Risk Omega-3 Index and Acute Coronary Syndromes (768 case-control pairs) p=0.03 p for trend < 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 :

22 RBC Fatty Acids and CVD Risk The Omega-3 Index and Cellular Aging

23 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:

24 RBC Fatty Acids and CVD Risk Omega-3 Index and Time to Death in 982 CHD Patients < 4.6% 4.6% It took 1.2 years longer for 20% of the population to die in the higher vs. the lower omega-3 group 1.2 yrs 4.6% < 4.6% Pottala et al. Circ CV Outcomes & Qual 2010;

25 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%

26 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:

27 Clinical Evidence Prospective Sudden Cardiac Death and the Omega-3 Index Physicians' Health Study Relative Risk 90% reduction in risk p for trend = % 4.8% 5.6% 6.9% Mean Blood Omega-3 FA (%) by Quartile Albert CM et al. N Engl J Med 2002:346:

28 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 (%) A B C D Visual Memory Executive Function Abstract Thinking Lower Index = The MRI Smaller finding Volume of Lower lower Index = Poorer brain Function p=0.005 p=0.026 p=0.025 p=0.001 Age, sex, education, time interval volume [in those with an Omega-3 A with apoe4 and homocysteine B with physical activity and BMI B with diabetes, sbp, smoking, A-fib, prevalent CVD and total cholesterol p=0.005 p=0.026 p=0.038 p=0.002 Index <4.4%] represents a change p=0.008 p=0.024 p=0.046 p=0.002 equivalent to approximately 2 years of structural brain aging. p=0.011 p=0.079 p=0.108 p=0.001 n=1575; age=67 Tan Z, et al. Neurology 2012

29 Executive Functioning and Cognitive Flexibility by Quartile of the HS-Omega-3 Index in Army Members Deployed in Iraq Standardized Test Scores Executive Function Score Cognitive Flexibility Score P<0.01 for trend Omega-3 Quartile Johnston et al. Nutr Neurosci 2012 (in press) N=78, mean age 31 yrs

30 Take Home Message For cardiovascular (and possibly neurocognitive) health, an Omega-3 Index >8% is optimal and an Index < 4% is deficient.

31 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

32 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:

33 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.

34 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

35 AHA Scientific Statement on Omega-3s Population Patients without documented CHD Patients with documented CHD Patients needing TG lowering Recommendation Eat a variety of fish (preferably oily) at least twice a week*, include oils and foods rich in ALA 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 Kris-Etherton, Harris, & Appel. Circulation, 2002;106: *Equal to about mg EPA+DHA/day

36 AHA Recommendations for Women Population Women with high blood cholesterol or triglycerides; for primary or secondary prevention Recommendation Consumption of omega- 3 fatty acids in the form of fish or capsules (e.g., EPA 1800 mg/d) Mosca et al. Circulation 2011;123:

37 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

38 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 mg/day for most adults and twice that for CHD patients.