®

Omega-3 Index for

Heart Health

Prof. Dr. C. von Schacky, FAHA, FESC

Preventive Cardiology

Medizinische Klinik und Poliklinik I

Ludwig Maximilians-Universität München

Clemens.vonSchacky@med.uni-muenchen.de

and Omegametrix, Martinsried

c.vonschacky@omegametrix.eu

Newcastle, 07 November 2013

Rischio & Prevenzione, NEJM 2013;368:1800-8

Meta-Analysis Omega-3 Fatty Acids and Cardiovascular Events

Kotwal et al Circ Cardiovasc Qual Outcome 2012;5:808-18

Meta-Analysis Omega-3 Fatty Acids and Cardiovascular Events

Kotwal et al Circ Cardiovasc Qual Outcome 2012;5:808-18

Meta-Analysis Omega-3 Fatty Acids in Atrial Fibrillation

Mozaffarian et al, JACC 2013, in press

Brouwer et al, Eur Heart J 2009;30:820-26

Meta-Analysis Omega-3 Fatty Acids and ICD-Actions

GISSI-HF, Lancet 2008,372:1231

Total mortality + hospitalizations

AHA Secondary Prevention Guidelines

“omega-3 fatty acids from fish or fish oil capsules (1 g/d) for cardiovascular disease risk

reduction.” Smith et al Circulation 2011;124

ESC Cardiovascular Prevention Guidelines

“Fish at least twice a week, one of which to be oily fish.”

Perk et al, Eur Heart J 2012;33:1635

ESC Treatment after myocardial infarction

Not specifically mentioned Steg et al, Eur Heart J 2012;33:2569

ESC Atrial Fibrillation Guidelines

Not mentioned Camm et al Eur Heart J 2010;31:2369

AHA/ESC Ventricular Arrhythmia Guidelines

“omega-3 may be considered for patients with ventr. arrhythmias and underlying CHD”

Outdated, but B IIb Zipes DP et al. Eur Heart J 2006, 27:2099

ESC Heart Failure

„An n-3 PUFA preparation may be considered“

IIb B McMurray et al, Eur Heart J 2012;33:1787

My fellow cardiologists:

Omega-3‘s not effective

Euro Market 15% of US

Hu F et al, JAMA 2002, 287:1815

Limited Plausibility of nutritional surveys…

Archer et al PlosONE 2013;8:76632

Siscovick D et al, Am J Clin Nutr 2000; 71:208S

Better: standardized procedure

A B C D E

…one sample in 5 Labs…

HS-Omega-3 Index®

measured in Erythrocytes

% Eicosapentaenoic + Docosahexaenoic Acid

Standardized and validated Method

in Europe only with Omegametrix®

®

1. Harris WS and von Schacky C. The Omega-3 Index: A New Risk Factor for Death from CHD? Preventive Medicine 2004;39:212-20

2. Harris WS, et al. Omega-3 Fatty Acid Levels in Transplanted Human Hearts: Effect of Supplementation and Comparison with Erythrocytes. Circulation

2004;110;1645-9

3. Sands SA, et al. The impact of age, body mass index, and fish intake on the EPA and DHA content of human erythrocytes. Lipids 2005;40:343-7

4. Harris WS, et al. Effects of Omega-3 Fatty Acids on Heart Rate in Cardiac Transplant Recipients. Am J Cardiol 2006;98:1393-5

5. von Schacky C. Omega-3 Fettsäuren in der Kardiologie – neueste Entwicklungen. Münch Med Wochenschr 2007;149:97-101

6. Harris WS. Omega-3 Fatty Acids and Cardiovascular Disease. A case for the Omega-3 Index as a New Risk Factor. Pharmacol Res 2007;55:217-23

7. Harris WS, et al. Stearidonic Acid Supplementation Increases Red Blood Cell and Heart Omega 3 Index in Dogs. Lipids 2007;42:325-333

8. Harris WS, et al. Tissue n-3 and n-6 fatty acids and risk for coronary heart disease events. Atherosclerosis 2007;193:1-10

9. von Schacky C, Harris WS. Cardiovascular Risk and the Omega-3 Index. J Cardiovasc Med 2007;8 (suppl 1):S46-9

10. Harris WS, et al. Blood Omega-3 and Trans Fatty Acids in Middle-Aged Acute Coronary Syndrome Patients. Am J Cardiol 2007;99:154-8

11. Harris WS, et al. Comparison of the effects of fish and fish oil capsules on the n-3 fatty acid content of blood cells and plasma phospholipids. Am J Clin Nutr

2007;86:1621-25.

12. Aarsetoey H, et al. Low levels of cellular omega-3 increases the risk of ventricular fibrillation during the acute ischaemic phase of a myocardial infarction.

Resuscitation 2008;78:258-64

13. Hwang I, et al. n-3 Polyunsaturated Fatty Acids and Atopy in Korean Preschoolers. Lipid 2007;42,345-349

14. Harris WS, von Schacky C N-3 Fatty Acids, Acute Coronary Syndrome, and Sudden Death. Curr Cardiovasc Risk Rpt 2008;2:161-6

15. Lee E, et al. n-3 Polyunsaturated fatty acids and trans fatty acids in patients with the metabolic syndrome: a case-control study in Korea. Br J Nutr. 2008;100:609-

14

16. von Schacky C. Omega-3 fatty acids pro-arrhythmic, anti-arrhythmic or both ? Curr Op Nutr Metab Care 2008;11:94-99

17. Amin AA, et al. Acute Coronary Syndrome Patients With Depression Have Low Blood Cell Membrane Omega-3 Fatty Acid Levels. Psychosom Med. 2008;70:856-

62.

18. Block RC, et al. EPA and DHA in blood cell membranes from acute coronary syndrome patients and controls. Atherosclerosis 2008;197:821

19. Block RC, et al. Omega-6 and trans fatty acids in blood cell membranes: a risk factor for acute coronary syndromes? Am Heart J. 2008;156:1117-23

20. Block RC, et al. Determinants of blood cell omega-3 fatty acid content. The Open Biomarkers J 2008;1:1-6

21. Cohen BE, et al. Red blood cell EPA and DHA concentrations are positively associated with Socioeconomic status in patients with established coronary artery

disease: Data from the Heart and Soul Study. J Nutrition 2008;138:1135-40

22. Farzaneh-Far R, et al. Inverse association of erythrocyte n-3 fatty acid levels with inflammatory biomarkers in stable coronary artery disease: The Heart and Soul

Study. Atherosclerosis 2009;205:538-43

23. Larson MK, et al. Effects of Omega-3 Acid Ethyl Esters and Aspirin, Alone and in Combination, on Platelet Function in Healthy Subjects. J Thromb Haemost

2008;100:634-41.

24. Harris WS, et al. Stearidonic Acid-Enriched Soybean Oil Increased the Omega-3 Index, an Emerging Cardiovascular Risk Marker. Lipids 2008;43:805-811.

25. von Schacky C. Use of red cell fatty acid profiles as biomarkers in cardiac disease Biomark Med 2009;3:25-32

Publications based on Omega-3 Index

26. Ali S, et al. Association between omega-3 fatty acids and depressive symptoms among patients with established coronary artery disease: Data from the Heart and

Soul Study. Psychother Psychosom. 2009;78:125-127.

27. Shearer GC, et al. Red Blood Cell Fatty Acid Patterns and Acute Coronary Syndrome. PLoS ONE 2009;4: e5444. doi:10.1371/journal.pone.0005444

28. Aarsetoey H, et al. (n-3) fatty acid content of red blood cells does not predict risk of future cardiovascular events following an acute coronary syndrome. J Nutr

2009;139:1–7.

29. Park Y, et al. Erythrocyte fatty acid profiles can predict acute non-fatal myocardial infarction. Br J Nutr. 2009;102:1355-6

30. von Schacky C. Cardiovascular disease prevention and treatment. Prostaglandins Leukot Essent Fatty Acids 2009;81:193-8

31. Park Y, et al. Low level of n-3 polyunsaturated fatty acids in erythrocytes is a risk factor for both acute ischemic and hemorrhagic stroke in Koreans. Nutr Res.

2009;29:825-30

32. Duda MK, et al. Fish oil but not flaxseed oil decreases inflammation and prevents pressure-overload induced cardiac dysfunction. Cardiovasc Res 2009;81:319

33. Harris WS, Thomas RM Biological variability of blood omega-3 biomarkers. Clin Biochem 2009;Sep, e-pub, 2010;43:338-40

34. An WS, et al. Comparison of fatty acid contents of erythrocyte membrane in hemodialysis and peritoneal dialysis patients. J Ren Nutr. 2009;19:267-74.

35. Harris WS The Omega-3 Index: From Biomarker to Risk Marker to Risk Factor. Curr Athero Rep 2009;11:411-7

36. Park Y, et al. Correlation of erythrocyte fatty acid composition and dietary intakes with markers of atherosclerosis in patients with myocardial infarction. Nutr Res.

2009;29:391-6.

37. Carney et al Omega-3 Augmentation of Sertaline in Treatment of Depression in Patients with Coronary Heart Disease JAMA 2009;302:1651-3

38. Shearer GC et al Myocardial infarction does not affect fatty acid profiles in rats. Prostaglandins Leukot Essent Fatty Acids2009; 81:411-6

39. Farzneh-Far et al, Association of marine omega-3 fatty acid levels with telomeric aging in patients with coronary heart disease JAMA 2010;303:250-7

40. von Schacky C Omega-3 fatty acids vs. cardiac disease: the contribution of the omega-3 index. Cell Mol Biol 2010;56:90-98

41. von Schacky C. Omega-3 Index and Sudden Cardiac Death. Nutritives 2010;2:375-8

42. Köhler A, et al. Effects of a convenience drink fortified with n-3 fatty acids on the n-3 index. Br J Nutr 2010; 104:729-36

43. Billman GE, et al. Effects of dietary omega-3 fatty acids on ventricular function in dogs with healed myocardial infarctions: in vivo and in vitro studies. Am J Physiol

Heart Circ Physiol. 2010;298:H1219-28

44. Ebbesson SO, et al. Heart rate is associated with red blood cell fatty acid concentration: the Genetics of Coronary Artery Disease in Alaska Natives (GOCADAN)

study.Am Heart J. 2010;159:1020-5.

45. Pottala JV, et al.Blood Eicosapentaenoic and Docosahexaenoic Acids Predict All-Cause Mortality in Patients With Stable Coronary Heart Disease: The Heart and

Soul Study. Circ Cardiovasc Qual Outcomes. 2010;3:406-12

46. von Schacky C. Omega-3 Index and cardiovascular disease prevention: principle and rationale. Lipid Technology 2010;22:151-4

47. Arnold C, et al. Arachidonic acid-metabolizing cytochrome P-450 enzymes are targets of omega-3 fatty acids. J Biol Chem 2010; 285:32720-33

48. Carney RM, et al Effect of Omega-3 Fatty Acids on Heart Rate Variability in Depressed Patients With Coronary Heart Disease. Psychosom Med 2010;72:748-54

49. Lemke SL, et al. Dietary intake of stearidonic acid-enriched soybean oil increases the omega-3 index: randomized, double-blind clinical study of efficacy and

safety. Am J Clin Nutr. 2010; 92:766-75

50. Harris WS. The Omega-3 Index: Clinical Utility for Therapeutic Intervention. Curr Cardiol Rep 2010;12:503-8

Publications based on Omega-3 Index

51. von Schacky C. Schwangerschaft, kindliche Entwicklung, Omega-3-Fettsäuren und HS-Omega-3 Index. J Frauengesundheit 2010;3:10-21 52. Neubronner J, et al. Enhanced increase of omega-3 index in response to long-term n-3 fatty acid supplementation from triacylglycerides versus ethyl

esters. Eur J Clin Nutr. 2011;65:247-54 53. Kim M et al. Erythrocyte α-linolenic acid is associated with the risk for mild dementia in Korean elderly. Nutr Res 2010;30:756-761 54. Baghai TC, et al. Major depressive disorder is associated with cardiovascular risk factors and low Omega-3 index. J Clin Psy 2011;72:1242-7 55. Skulas-Ray AC, et al. Dose-response effects of omega-3 fatty acids on triglycerides, inflammation, and endothelial function in healthy persons with

moderate hypertriglyceridemia. Am J Clin Nutr 2011;93:243- 52 56. Park Y, et al. Association between 24-hour ambulatory blood pressure and erythrocyte n-3 polyunsaturated fatty acids in Korean subjects with

hypertension. Nutr Res 2010;30:807-14 57. Yang R, et al. Pre-feeding with omega-3 fatty acids suppresses inflammation following hemorrhagic shock. J Parenter Enteral Nutr. 2010;34:496-502. 58. Chen J, et al. Omega-3 fatty acids prevent pressure overload-induced cardiac fibrosis through activation of cGMP/PKG signaling in cardiac fibroblasts.

Circulation 2011;123:584-93 59. Aarsetoey H, et al. Low Levels of the Omega-3 Index are Associated with Sudden Cardiac Arrest and Remain Stable in Survivors in the Subacute Phase.

Lipids. 2011;46:151-61 60. Moyers B, et al. Relation of Whole Blood n-3 Fatty Acid Levels to Exercise Parameters in Patients With Stable Coronary Artery Disease (from the Heart and

Soul Study). Am J Cardiol. 2011;107:1149-54 61. Harris WS, Klurfeld DM. Twentieth-century trends in essential fatty acid intakes and the predicted omega-3 index: evidence versus estimates. Am J Clin

Nutr. 2011;93:907-8 62. Sala-Vila A, et al. Determinants of the omega-3 index in a Mediterranean population at increased risk for CHD. Br J Nutr. 2011;106:425-31 63. Billman GE, Harris WS. Effect of Dietary Omega-3 Fatty Acids on the Heart Rate and the Heart Rate Variability Response to Myocardial Ischemia or

Submaximal Exercise. Am J Physiol Heart Circ Physiol. 2011;300:H2288-99 64. An WS, et al. Association of adiponectin and leptin with serum lipids and erythrocyte omega-3 and omega-6 fatty acids in dialysis patients. Clin Nephrol.

2011;75:195-203. 65. Salisbury AC et al. Predictors of omega-3 index in patients with acute myocardial infarction. Mayo Clin Proc. 2011;86:626-32 66. Son YK, et al. Association Between Vascular Calcification Scores on Plain Radiographs and Fatty Acid Contents of Erythrocyte Membrane in Hemodialysis

Patients. J Ren Nutr. 2012;22:58-66 67. Park Y, Kim M. Serum 25-hydroxyvitamin D concentrations are associated with erythrocyte levels of n-3 PUFA but not risk of CVD. Br J Nutr.

2011;106:1529-34 68. von Schacky C. The Omega-3 Index as a Risk Factor for Cardiovascular Diseases. Prostaglandins and Other Lipid Mediators. 2011;96:94–8 69. Park Y, et al. N-3 polyunsaturated fatty acid consumption produces neurobiological effects associated with prevention of depression in rats after the forced

swimming test. J Nutr Biochem 2012;23:924-928 70. Schuchardt JP, et al. Moderate doses of EPA and DHA from re-esterified triacylglycerols but not from ethyl-esters lower fasting serum triacylglycerols in

statin-treated dyslipidemic subjects: Results from a six month randomized controlled trial. Prostaglandins Leukot Essent Fatty Acids 2011;85:381-6 71. Ladesich JB, et al. Membrane levels of omega-3 docosahexaenoic acid is associated with obstructive sleep apnea. J Clin Sleep Med 2011;7:391-6 72. Maki KC, et al. Effects of prescription omega-3-acid ethyl esters, coadministered with atorvastatin, on circulating levels of lipoprotein particles,

apolipoprotein CIII, and lipoprotein-associated phospholipase A2 mass in men and women with mixed dyslipidemia. J Clin Lipidol. 2011;5:483-92 73. Salisbury AC, et al. Relation Between Red Blood Cell Omega-3 Fatty Acid Index and Bleeding During Acute Myocardial Infarction. Am J Cardiol.

2012;109:13-8 74. Dewell A, et al. Dose-Dependent Effects of Plant and Marine Omega-3 Fatty Acids on Inflammatory Markers in Insulin Resistant Adults. A Randomized

Controlled Trial. J Nutrition 2011;141:2166-71 75. Harris WS. Stearidonic Acid-Enhanced Soybean Oil: A Plant-Based Source of (n-3) Fatty Acids for Foods. J Nutr 2012;142:600S-4S

Publications based on Omega-3 Index

76. Harris WS. Stearidonic Acid as a ‘Pro-Eicosapentaenoic Acid’. Curr Opin Lipidol 2012;23:30-4, 77. Shearer GC, et al. Fish oil: How does it reduce plasma triglycerides? Biochim Biophys Acta 2012;1821:843-51 78. Krul ES, et al. Effects of duration of treatment and dosage of eicosapentaenoic acid and stearidonic acid on red blood cell eicosapentaenoic acid content.

Prostaglandins Leukot Essent Fatty Acids 2012;86:51-9, e-pub 2011 Nov 5 79. An WS, et al. Effect of omega-3 fatty acids on the modification of erythrocyte membrane fatty acid content including oleic acid in peritoneal dialysis patients.

Prostaglandins Leukot Essent Fatty Acids. 2012;86:29-34, e-pub 2011 Nov 7 80. Billman GE, et al. Dietary Omega-3 Fatty Acids and Susceptibility to Ventricular Fibrillation: Lack of Protection and A Proarrhythmic Effect. Circ Arrhythm

Electrophysiol. 2012 Feb 14. [Epub ahead of print] 81. Hussey EK, Portelli S, Fossler MJ, Gao F, Harris WS, Blum RA, Lates CD, Gould E, Abu-Baker O, Johnson S, Reddy KK. Relative bioavailability of an Emulsion

Formulation for Omega-3-Acid Ethyl Esters Compared to theCommercially Available Formulation : A Randomized, Parallel-Group, Single-Dose Study Followed by Repeat dosing in healthy volunteers. Clin Pharm Drug Develop 2012;1:14-2

82. Tan ZS, et al. Red Blood Cell Omega-3 Fatty Acid Levels and Markers of Accelerated Brain Aging. Neurology 2012;78:658-64 . 83. Pottala JV, et al. Red Blood Cell Fatty Acids are Associated with Depression in a Case-Control Study of Adolescents. Prostaglandins Leukot Essent Fatty Acids

2012;86:161-5 e-pub 2012 Mar 28 84. Kim YJ, et al. Omega-3 index and smoking in patients with acute ST-elevation myocardial infarction taking statins: a case-control study in Korea. Lipids Health Dis.

2012;11:43 85. Moon HJ, et al. Positive correlation between erythrocyte levels of n-3 polyunsaturated fatty acids and bone mass in postmenopausal Korean women with

osteoporosis. Ann Nutr Metab 2012;60:146-53 86. von Schacky C. Omega-3 fatty acids: anti-arrhythmic, pro-arrhythmic, or both? Frontiers in Cardiac Electrophysiology, 2012;3: 98 87. Block RC, et al. The Effects of EPA+DHA and Aspirin on Inflammatory Cytokines and Angiogenesis Factors. World J Cardiovasc Dis. 2012;2:14-19. 88. Park YS, et al. Erythrocyte n-3 polyunsaturated fatty acid and seafood intake decrease the risk of depression: case-control study in Korea. Ann Nutr Metab

2012;61:25-31 89. Harris WS, et al. Changes in Erythrocyte Membrane Trans and Marine Fatty Acids between 1999 and 2006 in Older Americans. J Nutr. 2012;142:1297-303 90. Voruganti VS, et al. Variants in CPT1A, FADS1, and FADS2 are associated with higher levels of estimated plasma and erythrocyte delta-5 desatureases in Alaskan

Eskimos. Front Genet 2012;3:86. 91. Harris WS, et al. Clinical correlates and heritability of erythrocyte eicosapentaenoic and docosahexaenoic acid content in the Framingham Heart Study.

Atherosclerosis. 2012;225:425-31 92. Johnston DT, et al. Red blood cell omega-3 fatty acid levels and neurocognitive performance in deployed U.S. Servicemembers. Nutr Neurosci. 2013;16:30-8 93. Keenan AH, et al. Basal omega-3 fatty acid status affects fatty acid and oxylipin responses to high-dose n3-HUFA in healthy volunteers. J Lipid Res. 2012;53:1662-

9 94. Pottala JV, et al. Correcting the Effects of -20 °C Storage and Aliquot Size on Erythrocyte Fatty Acid Content in the Women's Health Initiative. Lipids. 2012;47:835-

46 95. Shearer GC, et al. Effects of prescription niacin and omega-3 fatty acids on lipids and vascular function in metabolic syndrome: a randomized controlled trial. J

Lipid Res. 2012;53:2429-35] 96. Schmidt S, et al. Transcriptome-based identification of antioxidative gene expression after fish oil supplementation in normo- and dyslipidemic men. Nutr Metab

(Lond). 2012 23;9:45 97. Skulas-Ray AC, et al. Effects of Marine-Derived Omega-3 Fatty Acids on Systemic Hemodynamics at Rest and During Stress: a Dose-Response Study. Ann Behav

Med. 2012;44:301-8 98. An WS, et al . Omega-3 fatty acid supplementation increases 1,25-dihydroxyvitamin D and fetuin-A levels in dialysis patients. Nutr Res. 2012;32:495-502 99. von Schacky C. Die Bedeutung des Omega-3 Index für den Sportler. Vitalstoffe 2012;2:47-51 100. Schmidt S, et al. Different gene expression profiles in normo- and dyslipidemic men after fish oil supplementation: results from a randomized controlled trial. Lipids

Health Dis. 2012 Aug 29;11:105

Publications based on Omega-3 Index

101. Harris WS, et al. Red blood cell fatty acid levels improve GRACE score prediction of 2-yr mortality in patients with myocardial infarction.Int J Cardiol. 2012 Oct 5. pii: S0167-5273(12)01182-5. doi: 10.1016/j.ijcard.2012.09.076.

102. von Schacky C. Omega-3 Fettsäuren – HS-Omega-3 Index und Gesundheit von Herz und Hirn. Vitalstoffe 2012;2/4:28-36 103. von Schacky C. Meta-Analysing randomised controlled trials with omega-3 fatty acids in cardiovascular disease. Evidence based medicine, ebmed-2012-100960, 104. Harris WS. Are n-3 fatty acids still cardioprotective? Curr Opin Clin Nutr Metab Care. 2013;16:141-9 105. Oh JS, et al. Comparison of erythrocyte membrane Fatty Acid contents in renal transplant recipients and dialysis patients. Transplant Proc. 2012;44:2932-5. 106. Harris WS, et al. Erythrocyte omega-3 fatty acids increase and linoleic acid decreases with age: Observations from 160,000 patients. Prostaglandins Leukot Essent

Fatty Acids. 2013;88:257-63 107. Oelrich B, et al. Effect of fish oil supplementation on serum triglycerides, LDL cholesterol and LDL subfractions in hypertriglyceridemic adults. Nutr Metab Cardiovasc

Dis. 2013;23:350-7 108. Schuchardt JP, Hahn A. Bioavailability of long-chain omega-3 fatty acids. Prostaglandins Leukot Essent Fatty Acids 2013;89:1-8 109. Schuchardt JP, et al. Comparison of free serum oxylipin concentrations in hyper- vs. normolipidemic men. Prostaglandins Leukot Essent Fatty Acids. 2013;89:19-29 110. Metkus T, et al. Omega-3 fatty acid therapy reduces triglycerides and interleukin-6 in hypertriglyeridemic HIV patients. HIV Med. 2013;14:530-9 111. Grenon SM, et al. Association between n-3 polyunsaturated fatty acid content of red blood cells and inflammatory biomarkers in patients with peripheral artery

disease. J Vasc Surg. 2013;8:176-84 112. Park Y, et al. Effect of n-3 polyunsaturated fatty acid supplementation in patients with rheumatoid arthritis: a 16-week randomized, double-blind, placebo-controlled,

parallel-design multicenter study in Korea. J Nutr Biochem 2013; 24:1367–1372 113. Kim TH, et al. Differences in omega-3 and fatty acid profiles between patients with endometriosis and those with a functional ovarian cyst. J Obstet Gynaecol.

2013;33:597-600 114. Lemke SL, . Consumption of stearidonic Acid-rich oil in foods increases red blood cell eicosapentaenoic Acid. J Acad Nutr Diet. 2013;113:1044-56 115. Udani JK, Ritz BW. High potency fish oil supplement improves omega-3 fatty acid status in healthy adults: an open-label study using a web-based, virtual platform.

Nutr J. 2013;12:112. [Epub ahead of print] 116. Lee AL, Park Y. The association between n-3 polyunsaturated fatty acid levels in erythrocytes and the risk of rheumatoid arthritis in Korean women. Ann Nutr Metab

2013;63:88-95 117. Grenon SM, et al. n-3 Polyunsaturated fatty acids supplementation in peripheral artery disease: the OMEGA-PAD trial. Vasc Med. 2013 Sep 19. [Epub ahead of print] 118. Ammann EM, et al. Omega-3 fatty acids and domain-specific cognitive aging: Secondary analyses of data from WHISCA. Neurology. 2013 Sep 25. [Epub ahead of

print] 119. Harris WS, et al. The Comparative Effects Of An Acute Dose Of Fish Oil On Omega-3 Fatty Acid Levels in Red Blood Cells Versus Plasma: Implications for Clinical

Utility. J Clin Lipidol 2013;7:433-440 120. Baek D, Park Y. Association between erythrocyte n-3 polyunsaturated fatty acids and biomarkers of inflammation and oxidative stress in patients with and without

depression. Prostaglandins Leukot Essent Fatty Acids. E-pub 2013 Sep 21 121. Harris WS. Assessing Fatty Acid Biostatus: Red Blood Cells or Plasma? Lipid Technol 2013 (in press). 122. Jo S, et al. Erythrocyte n-3 Polyunsaturated Fatty Acids and the Risk of Type 2 Diabetes in Koreans: A Case-control Study. Ann Nutr Metab 2013 (in press).

Publications based on Omega-3 Index

Chapters in Books / Buchkapitel von Schacky C. Prevention of cardiovascular disease – what can we learn from epidemiology? In Omega-3 Fatty Acids and Cardiovascular Diseases; von Schacky C, ed., Uni-Med Verlag, Bremen, London, Boston, 2010, p 22-25 Harris WS, von Schacky C. The omega-3 index in clinical research and medicine. In Omega-3 Fatty Acids and Cardiovascular Diseases; von Schacky C, ed., Uni-Med Verlag, Bremen, London, Boston, 2010, p 72-80 von Schacky C. Mechanisms of action of omega-3 fatty acids. Effects on cardiac rhythm. In Omega-3 Fatty Acids and Cardiovascular Diseases; von Schacky, C, ed., Uni- Med Verlag, Bremen, London, Boston, 2010, p 32-35 von Schacky C. Large clinical trials in patients with coronary artery disease or equivalent risk. In Omega-3 Fatty Acids and Cardiovascular Diseases; von Schacky, C, ed., Uni-Med Verlag, Bremen, London, Boston, 2010, p 44-50 von Schacky C. Prävention kardiovaskulärer Erkrankungen – was lehrt uns die Epidemiologie? In Omega-3 Fettsäuren und kardiovaskuläre Erkrankungen; von Schacky C, ed., Uni-Med Verlag, Bremen, London, Boston, 2012, p 12-25 von Schacky C. Wirkmechanismen von Omega-3 Fettsäuren und Interventionsstudien mit < 200 Teilnehmern. In Omega-3 Fettsäuren und kardiovaskuläre Erkrankungen; von Schacky C, ed., Uni-Med Verlag, Bremen, London, Boston, 2012, p 26-49 von Schacky C. Große Klinische Interventionsstudien bei Patienten mit kardialen Erkrankungen. In Omega-3 Fettsäuren und kardiovaskuläre Erkrankungen; von Schacky C, ed., Uni-Med Verlag, Bremen, London, Boston, 2012, p 50-67 von Schacky C. HS-Omega-3 Index in Forschung und Klinik. In Omega-3 Fettsäuren und kardiovaskuläre Erkrankungen; von Schacky C, ed., Uni-Med Verlag, Bremen, London, Boston, 2012, p 82-97 von Schacky C. Andere Wirkungen von Omega-3 Fettsäuren. In Omega-3 Fettsäuren und kardiovaskuläre Erkrankungen; von Schacky C, ed., Uni-Med Verlag, Bremen, London, Boston, 2012, p 98-101 von Schacky C. Optimal Omega-3 Levels for different age groups In Omega-6/3 Fatty acids – Functions, Sustainability Strategies, and Perspectives; De Meester F, Watson RR, Zidadi S, ed., Humana Press, Nutrition and Health Series (Bendich A ed.), 2013, p 53-64 Harris WS, von Schacky C, Park Y. Standardizing Methods for Assessing Omega-3 Fatty Acid Biostatus. In The Omega-3 Fatty Acid Deficiency Syndrome; McNamara RK ed., Nova Science Publishers 2013 von Schacky C. Convenience Drinks Fortified with n-3 Fatty Acids: A Systematic Review. In Nutrition and Health (Series Editor: Adrianne Bendich), Handbook of Food Fortification – From Concepts to Public Health Applications Volume 2, Preedy VR, Srirajaskanthan R, Patel VB, eds., Humana Press, 2013, p 95-103

Publications based on Omega-3 Index

Biological and analytial Variability of EPA+DHA in various Compartments

Harris WS, Thomas R Clin Biochem 2009;43:338-40

0%

2%

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8%

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12%

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CV analytical CV biological

RBC

Whole blood

Whole plasma

Plasma PL

*

* *

* p<0.03 vs RBC

Correlation Heart / Erythrocytes

Harris WS et al Circulation 2004;110:1645

HS-Omega-3 Index

In the experimental animal also true for

Kidneys

Brain cortex

Liver

Lung

Pancreas

Arnold et al, JBC, 2010; 285:32720-33

Marchioli and Harris, unpublished

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Japan

Korea

USA

Germany

Norway

Spain

*http://circ.ahajournals.org/content/123/4/e18

CHD Death Rates* and the Omega-3 Index

Unadjusted Kaplan Meier Survival Curve

Number at Risk

Logrank p=0.02

3,6 % whole blood EPA+DHA equivalent to

4,6 % Omega-3 Index

Potalla et al, Circ Cardiovasc Qual Outcomes 2010;3:406-12

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Baseline Creatinine

History of congestive heart failure

History of Revascularization

In-Hospital Revascularization

Current Smoker

History of diabetes

White

Male

Age (10 years)

Economic burden: Moderate vs. None

Economic burden: High vs. None

Economic burden: High vs. Moderate

Omega-3 index <4%

Hazard Ratio (HR)

0.25 0.50 1 2 4 8

Baseline Creatinine

History of congestive heart failure

History of Revascularization

In-Hospital Revascularization

Current Smoker

History of diabetes

White

Male

Age (10 years)

Economic burden: Moderate vs. None

Economic burden: High vs. None

Economic burden: High vs. Moderate

Omega-3 index <4%

1.2 (1.1, 1.4)

2.4 (1.4, 4.2)

1.4 (0.9, 2.3)

0.7 (0.4, 1.1)

1.2 (0.7, 2.0)

1.0 (0.6, 1.7)

0.3 (0.2, 0.6)

1.2 (0.8, 2.0)

1.8 (1.4, 2.2)

1.3 (0.7, 2.3)

1.8 (1.1, 3.2)

1.4 (0.8, 2.5)

2.0 (1.2, 3.3)

Variable HR (95% CI)

Mohammad Abuannadi et al, Poster, AHA QCOR Meeting, May 19-21, 2010

Predictors 1-Year Mortality after myocardial infarction - TRIUMPH • 1424 Pat., 27% (387) omega-3 index <4%.

Block RC et al, Atherosclerosis 2008;197:821

HS-Omega-3 Index and ACS

Plasma-PL Omega-3 and subsequent Atrial Fibrillation

Wu et al, Circulation 2012;125:1084

Plasma-PL Omega-3 and subsequent Congestive Heart Failure

Mozaffarian et al, Ann Int Med 2011;155:160

Plasma-PL Omega-3 and survival with Congestive Heart Failure

Masson et al Am Heart J 2013;165:208

Framingham Score

Fatty acid spectrum

Fatty acid spectrum + FRS

Chance

Sh

ea

rer

et

al,

Plo

sO

ne,

20

09

Park Y, 2009, Br J Nutr July 2009

Shea

rer

et

al, P

LO

Sone 2

009;4

:e544

4

Reclassification:

Improvement of individual Risk assessment

on statins

Increasing the Omega-3 Index –

Some Effects on Surrogate Parameters

Heart rate q (Harris et al Am J Cardiol 2006; 98:1393-5)

Heart rate variability p (Carney et al Psychosom Med 2010;72:748)

Platelet function q (Larsson et al, Thromb Haemost 2008;100:

634;Harris et al, Lipids 2008;43:805)

Inflammatory biomarkers q (Duda et al Cardiovasc Res 2009;81:319

Dewell et al J Nutrition 2011;141:2166

Blocket al World J Cardiovasc Dis2012;2:14

Triglycerides q (Skulas-Ray Am J Clin Nutr 2011;93:243,

Schuchardt et al PLEFA 2011;85:381

Shearer et al J Lipid Res. 2012;53:2429)

Small dense LDL q (Maki et al J Clin Lipidol 2011;5:483)

Large bouyant LDL p (Maki et al J Clin Lipidol 2011;5:483)

2418121 6

6

4

2

SCIMO – Erythrocyte phospholipid fatty acids

3 mo 3.3 g / day, 21 mo 1.65 g / day EPA+DHA

von Schacky et al. Ann Int Med 1999, 130:554

EPA

DHA

EPA+DHA=3.4 % EPA+DHA=8.3 %

Coronary Lesions changed

Placebo EPA+DHA

(n=48) (n=55)

n (%) n (%)

moderate progression (+2) 5 (10.4) 4 (7.1)

mild progression (+1) 36 (75.0) 35 (63.6)

mild regression (-1) 7 (14.6) 14 (25.5)

moderate Regression (-2) 0 (0.0) 2 (3.6)

p=0.041* * Wilcoxon rank sum test, comparison between groups

SCIMO - Primary endpoint

von Schacky et al, Ann Int Med 1999; 130:554

AHA, USPSTF Criteria for new Biomarkers as Risk Factors

1. Method

2. Independent

3. Reclassification

4. Therapetic Consequence

Hlatky et al, Circulation 2009;119:2408

Helfand et al, USPTFS Ann Int Med 2009;151:496

von Schacky C, Lipid Tech 2010;22:151

HS-Omega-3 Index

+

+

+

(+)

Missing:

Large intervention trial with clinical endpoints

A low Omega-3 Index is associated with increased risk for

- all cause mortality

- fatal myocardial infarction

- non-fatal myocardial infarction (acute coronary syndrome)

- sudden cardiac death / ventricular arrhythmias

- atrial fibrillation (plasma phospholipids)

- (development of) and death from congestive heat failure

Surrogate and intermediate Parameters in keeping.

A low Omega-3 Index is a cardiovascular risk factor

with incremental information to conventional risk factors.

But large trial results so far neutral. How can this be?

What have levels to do with intake?

Ebbeson et al, Am J Cardiol 2010, 159:120-5

Intake vs. Levels

… reported consumption of omega-3 fatty acids

explained <16% of total variation of omega-3 fatty acids

in the red cell membrane.

In multivariate models, consumption of EPA + DHA was

the strongest predictor of the omega-3 index, but explained

only 12% of its variability (p<0.001).

Sala-Vila et al, Br J Nutr 2011;106:425-31

Intake Levels

…major components due to heritability (24%), EPA + DHA

intake (25%), and fish oil supplementation (15%).

Harris et al, Atherosclerosis 2012; 225:425-31

Bioavailability

Definition: fraction of an administered dose

that reaches the systemic circulation

Schuchardt & Hahn PLEFA 2013;e-pub May 12

High Fat Meal

Low Fat Meal

Bioavailability of EPA+DHA Ethyl-Ester (Omacor®, Lovaza®, Zodin®)

Factor 13

Davidson et al J Clin Lipidol. 2012;6:573-84

EE

EE

EE

EE

EE

EE

TG

TG

Kotwal et al Circ Cardiovasc Qual Outcome 2012;5:808-18

The Risk & Prevention, N Engl J Med 2013;368:1800-8

EE

Fish

TG

ca. 0.9 g / day

0.9 g / day

0.9 g / day

0.9 g / day

0.9 g / day

0.4 g / day

1.6 g / day

1.8 g / day

2.4 g / day

1.8 g / day

1.8 g EPA / day

0.6 g / day

*

* * *

* = breakfast

*

#

# = at night

+

+ = three times a day

Meta-Analysis Omega-3 Fatty Acids and Cardiovascular Events

TG

Risk&Prevention (2013) EE 0.9 g / day 0.97 (0.88, 1.08) 733/6239 745/6266

Factor 14

Factor 21

Omacor

Lovaza

Ethyl-Ester in Ethyl-Ester in Ethyl-Ester

Hussey et al Clin Pharm Drug Develop 2012;1:14

GSK comparing bioavailabilities of Ethyl-Ester preparations

in fasting volunteers, plasma phospholipids

Triglycerides: Matrix effects

Haug et al, Eur J Lipid Sci Technol 2011;113:137

0

2

4

6

8

10

12

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 R1

mean before 4.37 + 0.51, after 8 Weeks 6.80 + 1.45 %

in Intervention group, p<0.0001, paired t-test

But inter-individually factor 13

HS-Omega-3 Index

Effect of 0.5 g EPA+DHA / day

Köhler et al, Br J Nutr 2010, 104:729-36

…translates into variability of metabolite response…

Nording NL PlosONE 2013;8:e76575

Chemical Forms of long-chain omega-3‘s

Schuchardt & Hahn PLEFA 2013;e-pub May 12

Krill

rTAG

EE

AUC EPA+DHA Krill 80.03+34.71, rTAG 59.78+36.75, EE 47.53+38.42, n.s.

Single dose, double blind cross-over, 12 healthy volunteers

1680 mg EPA+DHA as Krill, rTAG, EE, plasma phospholipid fatty acids

Schuchardt et al Lipids Health Dis 2011;10:145

umol/l Fish oil Krill Oil no supplementation

Plasma EPA +45.2+29.65 +44.5+35.21 -6.6+28.58

Plasma DHA +23.4+16.55 +19.4+23.75 -6.1+21.25

Ulven et al, Lipids 2011;46:37-46

Effects of 864 mg EPA+DHA in Fish Oil

vs 543 mg EPA+DHA in Krill Oil vs control

113 volunteers, normal or slightly elevated blood lipids, 7 weeks

Authors conclusion: „Krill oil and fish oil thus represent comparable

dietary sources of n-3 PUFAs, even if the EPA DHA dose in the

krill oil was 62.8% of that in the fish oil.“

Uptake of EPA+DHA depending on chemical Form

Humans, two weeks, plasma phospholipid fatty acids

Dyerberg et al, Prostaglandins Leukot Essent Fatty Acids 2010;83:137

Issues in Study Design

Conventional Design of Intervention

studies with omega-3‘s:

- omega-3‘s with breakfast, a low-fat meal

poor bioavailability

- recruitment of participants irrespective

of baseline omega-3 status

- treatment with fixed dose of omega-3‘s

HS-Omega-3 Index

5000 randomly selected measurements in Europe

0

5

10

15

20

25

1 146 291 436 581 726 871 1016 1161 1306 1451 1596 1741 1886 2031 2176 2321 2466 2611 2756 2901 3046 3191 3336 3481 3626 3771 3916 4061 4206 4351 4496 4641 4786 4931

Measurements

HS

-Om

eg

a-3

In

de

x

Omega-3 Index in 5000 Individuals in Europe

Mean (+Standard deviation): 7.15 (+2.19%) %.

range: 1.89 to 20.74% (statistically normal distribution)

Individuals in target range (8 – 11%): 1210 (24.4%)

below: 3515 (70%), above: 275 (5.5%)

von Schacky, Handbook of Food Fortification, 2013, in press

Conventional Design of Intervention

studies with omega-3‘s:

- omega-3‘s with breakfast, a low-fat meal

poor bioavailability

- recruitment of participants irrespective

of baseline omega-3 status

- treatment with fixed dose of omega-3‘s

0

2

4

6

8

10

12

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 R1

mean before 4.37 + 0.51, after 8 Weeks 6.80 + 1.45 %

in Intervention group, p<0.0001, paired t-test

But inter-individually factor 13

HS-Omega-3 Index

Effect of 0.5 g EPA+DHA / day

Köhler et al, Br J Nutr 2010, 104:729-36

0

2

4

6

8

10

12

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25

Omega-3 Index

no supplementation 1 g /day EPA+DHA-EE

von Schacky, Curr Op Nutr Metab 2008; 11:94

Summary

A low Omega-3 Index is associated with increased risk for

- all cause mortality

- fatal myocardial infarction

- non-fatal myocardial infarction (acute coronary syndrome)

- sudden cardiac death / ventricular arrhythmias

- atrial fibrillation (plasma phospholipids)

- (development of) and death from congestive heat failure

- a low Omega-3 Index is a cardiovascular risk factor

Except for congestive heart failure, this could not be demonstrated in large RCT‘s

Guidelines lukewarm

Two major problems overlooked in conventional trial design:

- Bioavailability: depends on meal and its fat content, emulsion, individual variation,

genes, distribution volume, asf, chemical form PL>rTAG>TAG>FFA>EE

- Study design: recruitment irrespective of baseline omega-3 levels

treatment with fixed dose, i.e. irrespective of bioavailability issues

- rather: recruit participants with low levels, treat to target range (8 – 11%)

- new generation of large intervention trials in cardiovascular diseases needed

Currently: Omega-3‘s poorly used in Europe, costs lives.

However, omega-3‘s as safe and tolerable as placebo…

®

Omega-3 Index for

Heart & Brain Health

Prof. Dr. C. von Schacky, FAHA, FESC

Preventive Cardiology

Medizinische Klinik und Poliklinik I

Ludwig Maximilians-Universität München

Clemens.vonSchacky@med.uni-muenchen.de

and Omegametrix, Martinsried

c.vonschacky@omegametrix.eu

Newcastle, 07 November 2013