What is the Data on Fish Oil for There are no conflicts of interest - PowerPoint PPT Presentation

4/19/2013 What is the Data on Fish Oil for • There are no conflicts of interest Peripheral Artery Disease? Marlene Grenon, MD …In fact, I am allergic to fish and seafood… Assistant Professor of Surgery, UCSF UCSF VASCULAR SURGERY SYMPOSIUM SAN FRANCISCO, CA APRIL 2013 Goals Nutritional Patterns • Nutritional patterns have changed considerably in • Review the biological effects of n-3 PUFA on the last century vasculature – Industrial revolution ~60s – Increase in corn oil • Summarize the evidence for the use of n-3 PUFA • Grenon et al., Vasc Med (2012) • Polyunsaturated fatty acids (PUFAs) ratios altered in cardiovascular disease (n-6:n-3) – Hunter-Gatherers: 2:1 • Determine if n-3 PUFA could improve treatment – American Diet: 15:1 of patients with PAD • Cordain et al. Eur J Clin Nutr (2002) • Kris-Etherton et al. Am J Clin Nutr (2000) 1

4/19/2013 A Healthy Diet… 2002 AHA Recommendations: American Heart Association Fish and fish oil • Balance calorie intake and physical activity to achieve or Patient Population Recommendation maintain a healthy body weight • Diet rich in vegetables and fruits Patients without documented Eat a variety of (preferably fatty) fish at least twice a week . Include oils and foods rich in • Whole-grain, high-fiber foods coronary heart disease (CHD) alpha-linolenic acid (flaxseed, canola and • Minimize intake of beverages and foods with added sugars soybean oils; flaxseed and walnuts). • Choose and prepare foods with little or no salt Consume about 1 g of EPA+DHA per day, Patients with documented CHD • Alcohol in moderation preferably from fatty fish. EPA+DHA in • When you eat food that is prepared outside of the home, capsule form could be considered in consultation with the physician. follow the AHA diet and lifestyle recommendations. 2 to 4 grams of EPA+DHA per day provided Patients who need to lower • Limit intake of saturated fat to <7% of energy, trans fat to <1% triglycerides as capsules under a physician’s care. of energy and cholesterol to <300 mg/day • Consume fish, especially oily fish, at least twice a week Fish 101. www.americanheart.org Rich in n-3 PUFA Lichtenstein et al. Circulation 2006; 114:82-96. Essential Fatty Acid Families What are fatty acids? ω -6 family ω -3 family • Fatty Acids H 3 C H 3 C COOH COOH – Carboxylic acid with a long unbranched chain which is either C18:3 ω -3 α -Linolenic C18:2 ω -6 Linoleic • Flaxseed Oil saturated or unsaturated • Corn Oil • Canola Oil • Unsaturated • Safflower Oil • Soybean Oil • Sunflower Oil – Double-bond in the fatty acid chain H 3 C COOH – When double-bonds are formed, hydrogen is eliminated H 3 C C20:5 ω -3 Eicosapentaenoic COOH (EPA) – Confers different biological properties C20:4 ω -6 Arachidonic H 3 C • Poultry COOH • Meats C22:6 ω -3 Docosahexaenoic (DHA) Carbonyl carbon Methyl carbon More thrombotic Less thrombotic • Oily Fish and inflammatory and inflammatory • Fish Oil Capsules metabolites metabolites With permission from Harris WS 2

4/19/2013 Where are they found? Postulated Effects of n-3 PUFA • Reduction of serum triglycerides • Incorporation in the phospholipids of cell membranes, replacing AA with potentially less pro-thrombotic and vasoconstrictive derivatives • Direct effects on endothelial activation – reduction in production of cytokines (IL-1 and TNF in LPS-stimulated nomocytes) – reduction in production of PDGF-A and –B protein and mRNA – reduction of tissue factor by monocytes – increased bioavailability of endothelial nitric oxide – downregulation of gene expression of MCP-1 – reduced expression of endothelial adhesion molecules (VCAM-1, E-Selectin, and to less extent ICAM-1) – reduction in VCAM-1 mRNA by Norther blot – reduction in NF-kB system of transcription factors (this controls the coordinated expression of adhesion molecules and of leukocyte-specific chemoattractants upon cytokine stimulation) • Reduced monocyte cell adhesion to cytokine-activated endothelium Grenon et al, Vasc Med 2012 Massaro et al. Cellular and Molecular Biology 56, N°1, 59-82, 2010 Vascular Laboratory- UCSF Monocyte Adhesion • Non-activated • n-3 MEASUREMENTS: • n-6 Confluent Confluent • vehicle alone -Adhesion assays • Activated (TNF) ECs ECs -Gene Expression • n-3 + TNF • n-6 + TNF • TNF alone • Non-activated • n-3 • n-6 Confluent Confluent MEASUREMENTS: • vehicle alone • Activated (TNF) -Adhesion assays ECs ECs • n-3 + TNF • n-6 + TNF • TNF alone Grenon et al, J Surg Res 2012 3

4/19/2013 Gene Expression: Adhesion Molecules Gene Expression: Inflammation Grenon et al, J Surg Res 2012 Grenon et al, J Surg Res 2012 Inflammation and Resolution of Old tale or the new tale… inflammation inflammation • New tale • Old tale • – Resolution is an active process rubor – Resolution of inflammation is • tumor a passive process • calor • dolor – Lipid mediators are actively – No active participation of lipid mediators in resolution involved in the resolution by process switching their phenotype – Mediators: – Mediators: • Decrease cytokines • Resolvins • Decrease PGs • Protectins • Decrease oxygen species • Lipoxins • Aspirin-triggered lipoxins • Maresins Stables and Gilroy, Prog Lip Res 2011 Fredman and Serhan, Biochem J 2011 4

4/19/2013 Effects of resolution mediators on Chemical Mediators cell function Fredman and Serhan, Biochem J 2011 Fredman and Serhan, Biochem J 2011 • n-3 PUFA are tightly related to inflammation and resolution of inflammation • Patients with PAD may have a deficit in the resolution of inflammation 5

4/19/2013 Goals Potential EPA and DHA Effects • Reduced atherosclerosis • Review the biological effects of n-3 PUFA on • Antiarrythmic effects vasculature • Improvement in autonomic function • Decreased platelet aggregation • Vasodilation • Summarize the evidence for the use of n-3 PUFA • Decreased blood pressure in cardiovascular disease • Anti-inflammatory • Improvement in endothelial function • Plaque stabilization • Determine if n-3 PUFA could improve treatment • Reduced free fatty acids and triglycerides • Up-regulation of adiponectin synthesis of patients with PAD • Reduced collagen deposition Massaro et al. Cell & Mol Biol 2010 Diet and Reinfarction trial (DART) DART: Reduction in mortality • The subjects advised to eat fatty fish experienced a 29% • First large randomized controlled trial reduction in 2-year all-cause mortality compared to • Dietary intervention with fish in the secondary those not so advised. prevention of MI. – Reduction in fat intake with an increase in the ratio of PUFAs to saturated fat – Increase in the fatty fish intake – Increase in cereal fibre intake • 2033 men who had recovered from MI Burr et al, Lancet 1989 Burr et al, Lancet 1989 6

4/19/2013 Gissi Trial Gissi Trial • Omega-3 FAs reduced the • Randomized study primary end point by 15% (p=0.023). • 11 323 patients with recent MI (< 3 months) • Mortality was significantly • Treated and followed for 3.5 years lower after 3 months of – Omega-3 FAs (1gm/day; EPA/DHA 1:2) (n=2836) treatment • Sudden death was – Vitamin E (300mg/day) (n=2830) significantly decreased – Omega-3 + Vitamin E (n=2830) starting at 4 months – Controls (n=2828) • Decrease in cardiovascular, • Primary endpoint: composite of death, nonfatal MI cardiac and coronary deaths were observed after 6-8 and stroke months of treatment. • Analysis: intention-to-treat analysis. Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Gissi Prevenzione Investigators, Lancet 1999 Prevenzione Investigators, Lancet 1999 Japan EPA Lipid Intervention Study JELIS trial: Reduction in MCE (JELIS- 2007) • Prospective, randomized open-label, blinded endpoint evaluation All Patients Primary Prevention Secondary Prevention All population Primary prevention Secondary prevention • 18,645 patients with total cholesterol of 6.5mmol/L or greater • Randomized to: – 1800mg of EPA daily with statin (n=9326) – statin only (n=9319) • 5 year follow-up, intention-to-treat analysis • Primary endpoints: MCE Yokoyama et al. (JELIS), Lancet 2007 Yokoyama et al. (JELIS), Lancet 2007 7

4/19/2013 JELIS trial, PAD subgroup The OMEGA trial • First randomized study on the effects of highly purified omega-3 acid ethyl ester in addition to current guideline therapy 3-14 days after MI • 1gm/day for 1 year • Double-blinded, multicenter trial • N=3,851 • Primary endpoint: SCD • Secondary endpoints: total mortality and non-fatal events Rauch et al, Circulation 2010, 122:2152-2159 Ishikawa, Circ J 2010 The OMEGA trial The OMEGA trial -Very Underpowered (20%) -Dose far too low -Fish consumption increased significantly Rauch et al, Circulation 2010, 122:2152-2159 Eckel RH, Circulation 2010 8

4/19/2013 Meta-analysis – Cardiovascular Effects Fish oil on Endothelial function (FMD) (JAMA 2012) Rizos et al, JAMA 2012 Xin et al, PLUS ONE 2012 Goals • Review the biological effects of n-3 PUFA on Since the pathogenesis of coronary vasculature heart disease and peripheral arterial disease (PAD) is closely related, • Summarize the evidence for the use of n-3 PUFA could n-3 PUFA also be effective in in cardiovascular disease the treatment and prevention of PAD? • Determine if n-3 PUFA could improve treatment of patients with PAD 9