Update in Dyslipidemias
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This document discusses the evaluation and management of dyslipidemias. It begins by defining different types of lipids and their functions. It then evaluates cardiovascular risk scores and current lifestyle modification guidelines. The document reviews the 2013 AHA/ACC guidelines for dyslipidemia management and evaluates pharmacologic treatment options, including statins, ezetimibe, fibrates, niacin, and omega-3 fatty acids. It concludes by outlining recommendations for when to initiate statin therapy or add additional pharmacologic treatment based on a patient's lipid panel and risk factors.
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Update in Dyslipidemias
- 1. Kristopher Maday, MS, PA-C, CNSC University of Alabama at Birmingham Pegasus Emergency Group
- 2. • Review the different types of lipids that are important for clinical practice • Discuss the cardiovascular risk scores • Describe current lifestyle modification recommendations in the treatment of hyperlipidemia • Evaluate the 2013 AHA/ACC guidelines for dyslipidemia management • Appraise the pharmacologic treatment options for dyslipidemias
- 3. • Carbon and hydrogen containing compounds that are insoluble in water, but are soluble in organic solvents • Functions – Sources of energy – Formation of cell membrane – Constitute bile acids • Derived from both dietary sources and internal body processes
- 5. • Sterols – Cholesterol • Neutral Fats – Triglycerides – Free Fatty Acids • Conjugated Lipids – Phospholipids – Lipoproteins
- 6. • Necessary for the formation of cell membranes, bile salts, adrenocorticosteroids, estrogens, and androgens • 75% is bound to LDL • Levels can fluctuate as much as 8% during one day and 15% from day to day
- 7. • Travel through bloodstream combined with albumin • Blood levels are never high unless stimulated to release fat – Same stimulus will also elevate triglycerides • Utilized for energy in muscle tissue
- 8. • Combination of 3 FFA and 1 glycerol molecule • Main form of lipid storage • Used in the body to provide energy: – Directly as a energy source – Indirectly for gluconeogenesis • Transported by VLDL and LDL
- 9. • 3 main types – Lecithins • Involved in pulmonary gas exchange – Cephalins • Major constituent of thromboplastin – Sphingomyelins • Involved with formation of myelin sheath in CNS • Important for the formation of cell membrane and transportation of fatty acids through the intestinal mucosa into lymph • Lecithin:Sphingomyelin ratio – Fetal lung maturation
- 10. • Main function is to transport cholesterol and triglycerides • Grouped by density – Chylomicrons • Primarily triglycerides – Very-Low Density Lipoprotein (VLDL) • Mainly triglycerides – Low Density Lipoprotein (LDL) • Primarily cholesterol – High Density Lipoprotein (HDL) • Mainly protein with small amount of cholesterol
- 11. • Predominant carrier of blood triglycerides • High concentrations cause alterations of appearance of serum (ie. hazy, turbid) • Associated with increased risk of CAD
- 12. • Very cholesterol rich • High association with CAD • ***Main focus of pharmacotherapy*** • Friedewald Formula – LDL = TC – (HDL + (triglycerides/5))
- 14. Lipoprotein Size Density Major Apolipoprotein Origins Comments Chylomicron Largest Least ApoB-48 Intestines Primarily triglycerides Very Low- Density Lipoprotein (VLDL) ApoB-100 Liver and Intestines Primarily triglycerides Intermediate- density Lipoprotein (IDL) ApoB-100 Chylomicrons and VLDL Transitional forms Low-density Lipoprotein (LDL) ApoB-100 End-product of VLDL Major carrier of cholesterol High-density Lipoproteins (HDL) Smallest Most ApoA-1 Intestines and liver Removes cholesterol
- 15. • 6 different phenotypes of lipoproteins • Each phenotype has correlated with genetically determined abnormalities as well as a variety of acquired conditions • Useful in diagnosing and treating specific hyperlipoproteinemias
- 19. • Majority of hypercholesterolemia patients are diagnosed by laboratory abnormalities • Extremely elevated LDL and triglycerides – Eruptive xanthomas • Red-yellow papules – Tendinous xanthomas – Lipemia retinalis • Cream-colored blood vessels in fundus
- 25. • Diet – Decrease: • Total fat to 25-30% of calories – Saturated fat < 7% of calories • Total cholesterol < 200 mg/dl • Physical Activity – 150 minutes a week • Weight loss – > 10% for overweight patients
- 28. • Clinical Atherosclerotic Cardiovascular Disease (ASCVD) – Acute Coronary Syndrome – Myocardial Infarction – Stable or Unstable Angina – Revascularization Procedures – Cerebrovascular Disease – Peripheral Arterial Disease • LDL ≥ 190 mg/dL • Type I or II Diabetes AND age 40-75 • 10-year ASCVD risk ≥ 7.5% AND age 40-75
- 29. • Calculates a patient’s 10 year risk for a major cardiovascular event – Framingham Score • Age, Gender, Total cholesterol, HDL, SBP, Smoking – Reynolds Score • Age, Smoking, SBP, Total Cholesterol, CRP, Family History – PROCAM Score • Age, Gender, DM, Smoking, Family History, SBP, BMI, Antihypertensive therapy
- 31. LDL receptor– mediated hepatic uptake of LDL and VLDL remnants Serum VLDL remnants Serum LDL-C Cholesterol synthesis LDL receptor (B–E receptor) synthesis Intracellular Cholesterol Apo B Apo E Apo B Systemic CirculationHepatocyte Reduce hepatic cholesterol synthesis, lowering intracellular cholesterol, which stimulates upregulation of LDL receptor and increases the uptake of non-HDL particles from the systemic circulation. LDL Serum IDL VLDLR VLDL
- 32. Endpoints +20 –35–30–250 –5 –10–15–20 Relative Risk Reduction (%) –40–45–50 Major coronary events Coronary deaths Cardiovascular deaths Noncardiovascular events Total mortality Strokes Intermittent claudication Angina
- 33. • Common side effects - Headache – Myalgia – Fatigue - GI intolerance – Flu-like symptoms • Increase in liver enzymes – Occurs in 0.5 to 2.5% of cases in dose-dependent manner – Serious liver problems are exceedingly rare – Manage by reducing statin dose or discontinue until levels return to normal • Myopathy – Occurs in 0.2 to 0.4% of patients – Rare cases of rhabdomyolysis – Reduce by • Cautiously using statins in patients with impaired renal function • Using the lowest effective dose • Cautiously combining statins with fibrates • Avoiding drug interactions • Careful monitoring of symptoms – Presence of muscle toxicity requires the discontinuation of the statin
- 36. Liver Circulation HDL Serum VLDL results in reduced lipolysis to LDL Serum LDL VLDL Decreases hepatic production of VLDL and ApoB VLDL secretion Apo B Hepatocyte Systemic Circulation Mobilization of FFA TG synthesis VLDL LD L
- 37. • Products available (daily dose) • Immediate-release, 2–4 g/d • Extended-release (Niaspan®), 1–2 g/d • OTC products, sustained-release, 2 g/d • Best agent to raise HDL-C • Adverse effects • Flushing, itching, headache (immediate-release, Niaspan®) • Hepatotoxicity, GI (sustained-release) • Activation of peptic ulcer • Hyperglycemia and reduced insulin sensitivity • Contraindications • Active liver disease or unexplained LFT elevations • Peptic ulcer disease
- 38. Net Effect: LDL-C Gall Bladder LDL Receptors VLDL and LDL removal Cholesterol 7- hydroxylase Conversion of cholesterol to BA BA Secretion Liver BA Excretion Terminal Ileum Bile Acid Enterohepatic Recirculation Reabsorption of bile acids
- 39. • Products available: • Cholestyramine (Questran), 4–16 g/d • Colestipol (Colestid), 5–20 g/d • Colesevelam (WelChol) 625 mg tablets, 6–7 tablets/d • Reduce coronary events (LRC-CPPT) • Adverse effects • GI intolerance: constipation, bloating, abdominal pain, flatulence • Lack systemic toxicity • Drug interactions (colestipol and cholestyramine) • Bind other negatively charged drugs • Impede the absorption of drugs and/or fat-soluble vitamins • Must give other drugs 1 hour before or 4–6 hours after
- 41. • Products available: • Fenofibrate 48-160mg • Fenofibric acid 35-105mg • Gemfibrozil 600mg • Adverse effects • GI side effects • Myositis • Abnormal liver function • Contraindications • Hepatic or renal dysfunction • Pre-existing gall bladder disease
- 43. • Lipid effect – Reduced hepatic VLDL production • EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) in fish oils are more effective than alpha-linolenic acid in vegetable sources • Doses >7g/day – decreased TG 25% and increased TC 2% in normal patients; – 28% and 7%, respectively, in HTG patients • Omacor (85% omega-3 fatty acid ethyl esters) at 4g/day = 27-45% TG reduction • Side Effects: fishy aftertaste
- 45. • Encourage lifestyle modifications • Start statin pharmacotherapy if: – (+) ASCVD – LDL > 190 mg/dL – 40-75yo AND: • DM type I or II or • > 7.5% 10-year CV risk • Tailor additional pharmacotherapy based on lipid panel
Editor's Notes
- IN the intestinal cell, FFA combine with glycerol to form triglycerides. Triglycerides and cholesterol are assembled intracellularly into chylomicrons in order to be able to move into the systemic circulation. Then the are broken down into their parts for metabolism. Liver synthesizes VLDL from unused glucose and FFA, which contain a core of triglycerides and cholesterol. VLDL is the hydrolized by LPL into IDL, which is devoid of triglycerides. IDL is then converted to LDL via hepatic lipase
- HDL Metabolism and Reverse Cholesterol Transport Cholesterol that is synthesized or deposited in peripheral tissues is returned to the liver in a process referred to as reverse cholesterol transport in which high-density lipoprotein (HDL) plays a central role. HDL may be secreted by the liver or intestine in the form of nascent particles consisting of phospholipid and apolipoprotein A-I (apoA-I). Nascent HDL interacts with peripheral cells, such as macrophages, to facilitate the removal of excess free cholesterol (FC), a process facilitated by the ATP-binding cassette protein 1 (ABC1) gene. FC is generated in part by the hydrolysis of intracellular cholesteryl ester (CE) stores. HDL is then converted into mature CE–rich HDL as a result of the plasma cholesterol-esterifying enzyme lecithin:cholesterol acyltransferase (LCAT), which is activated by apoA-I. CE may be removed by several different pathways, including selective uptake by the liver, ie, the removal of lipid without the uptake of HDL proteins (shown in this slide). Selective uptake appears to be mediated by the scavenger receptor class-B, type I (SR-BI), which is expressed in the liver and has been shown to be a receptor for HDL. CE derived from HDL contributes to the hepatic–cholesterol pool used for bile acid synthesis. Cholesterol is eventually excreted from the body either as bile acid or as free cholesterol in the bile.
- Pathogenesis of atherosclerosis 1. Chronic endothelial cell injury by hyperlipidemia, hypertension, toxins in cigarette smoke, elevated levels of homocysteine, and hemodynamic forces (e.g., turbulent blood flow) leads to endothelial cell dysfunction. 2. Endothelial cells regulate vasodilation and constriction, promote hemostasis, and otherwise prevent thrombosis. Endothelial dysfunction promotes thrombosis and increased permeability as well as allows monocytes and lymphocytes to adhere to the surface and migrate into the intima. 3. Low-density lipoproteins (LDL) can move into and out of the intima; however, the presence of macrophages (derived from blood monocytes) results in production of enzymes that oxidize LDL. Oxidized LDL is engulfed by macrophages through scavenger receptors. 4. Finally, smooth muscle cells migrate into the intima: The smooth muscle cells convert from a contractile role in the media to a secretory role in the intima, where they produce extracellular matrix. Smooth muscle cells secrete extracellular matrix components (e.g., collagen) that contribute to the development of plaque. Smooth muscle cells, like macrophages, are capable of engulfing oxidized LDL.
- 1% reduction in cholesterol = 3% reduction in mortality
- Plant stanols/sterols – block absorption of chlesterol in intestine -
- Prospective Cardiovascular Munster Study
- Statins: mechanism of action As inhibitors of hepatic HMG-CoA reductase, the enzyme catalyzing the rate-limiting step in hepatic cholesterol synthesis, statins decrease synthesis of cholesterol by the liver, which results in two important effects: the up-regulation of LDL receptors by hepatocytes and consequent increased removal of apolipoprotein (apo) E– and B–containing lipoproteins from the circulation, and a reduction in the synthesis and secretion of lipoproteins from the liver. The net effect of statin therapy is to lower plasma concentrations of cholesterol-carrying lipoproteins, the most prominent of which is LDL. Importantly, however, statins also increase the removal and reduce the secretion of remnant particles, i.e., very low density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL). This means that in patients who have an elevation of both LDL-C and triglycerides (indicating increased levels of triglyceride-rich VLDL and IDL remnants as well as LDL), a statin is one of the therapies of choice because of its ability to effectively lower LDL-C and non–high-density lipoprotein cholesterol (non-HDL-C) levels.
- CHD risk reduction with statin therapy Practically every clinical manifestation of atherosclerosis has been shown to be reduced by statin therapy, including fatal and nonfatal myocardial infarction, sudden CHD death, episodes of unstable angina, revascularization procedures including percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass grafting (CABG), stroke, symptoms of peripheral arterial disease, and total mortality. Importantly, statin therapy has not been associated with an increase in noncardiovascular events. These data demonstrate that statins improve the quality of life (by reducing nonfatal events) and also lengthen life (by reducing total mortality). References: LaRosa JC, He J, Vupputuri S. Effect of statins on risk of coronary disease: a meta-analysis of randomized controlled trials. JAMA 1999;282:2340-2346. Crouse JR III, Byington RP, Hoen HM, Furberg CD. Reductase inhibitor monotherapy and stroke prevention. Arch Intern Med 1997;157:1305-1310. Pedersen TR, Kjekshus J, Pyorala K, Olsson AG, Cook TJ, Musliner TA, Tobert JA, Haghfelt T. Effect of simvastatin on ischemic signs and symptoms in the Scandinavian Simvastatin Survival Study (4S). Am J Cardiol 1998;81:333-335.
- Statin adverse events Statins are very safe. 95% of patients can tolerate them; 5% cannot. Common side effects include headache, upset stomach, fatigue, flu-like symptoms, and myalgia (without changes in creatine kinase [CK]). One or both liver transaminases may be elevated to >3 times the upper limit of normal on two consecutive occasions in 0.5% (with starting doses) to as high as 2.5% (with high doses) of patients in a dose-dependent manner. Whether statin-induced elevations in liver enzymes constitute true hepatotoxicity has not been determined. Cases of serious liver dysfunction or failure are exceedingly rare and not clearly related to statin therapy. Enzymes will frequently return to normal by reducing doses or even with continuation of therapy. If an elevation persists, discontinuation of therapy for a short period until levels return to normal is advised. Statin therapy may then be reinitiated. Myopathy defined as muscle symptoms (muscle weakness, aches, or soreness) plus CK >10 times the upper limit of normal is seen in 2–4 patients per 1000. In 77,000 patient-years of use in the landmark clinical trials, 8 cases of myopathy were reported. Very rare cases of rhabdomyolysis, myoglobinuria, acute renal necrosis, and death have been reported. The incidence of myopathy appears related to the systemic blood concentration of the statin. Myopathy is most likely to occur with higher doses, in patients with renal impairment, when a statin is combined with a fibrate, when a drug interfering with the metabolism of the statin is given concurrently (e.g., macrolide antibiotics, certain antifungal medications, gemfibrozil, cyclosporine), and in elderly women. All patients started on statins should be instructed to report immediately muscle symptoms or brown urine and to have CK measured. If myopathy is present or strongly suspected, the statin should be discontinued immediately.
- Nicotinic acid: mechanism of action The last of our LDL-C–lowering drugs is nicotinic acid, or niacin. Niacin appears to exert its effects by inhibiting lipoprotein synthesis and decreasing the production of VLDL particles by the liver. It inhibits the peripheral mobilization of free fatty acids, thus reducing hepatic synthesis of triglycerides and the secretion of VLDL. It also reduces apo B. The net result is a reduction in VLDL particles secreted by the liver and thus less substrate to make LDL particles. It increases the production of apo A-I and thereby HDL through mechanisms that are not clear.
- Clinical features of nicotinic acid Three niacin products are available: an over-the-counter immediate-release formulation, an extended-release prescription formulation (Niaspan), and several over-the-counter sustained-release preparations. The LDL-C–lowering and HDL-C–raising efficacy of the sustained-release products is modest compared with the immediate-release products. Niaspan at its maximum daily dose of 2 g/d reduces LDL-C by about 15%. These products also differ importantly in the side effects they can produce (see below). Immediate-release niacin has been shown to reduce fatal and nonfatal myocardial infarction in the Coronary Drug Project, a 6-year, placebo-controlled, randomized clinical trial. Nine years later (15 years after initiating niacin therapy), total mortality in niacin-treated patients was found to be significantly lower. Additionally, niacin has been used in combination with a bile acid resin in several angiographic trials showing a slowed progression of atherosclerosis. Niacin is the best agent available for raising HDL-C and, in patients with mixed hyperlipidemia, shifts cholesterol from small LDL particles to larger ones, thus converting patients from the atherogenic pattern B to a less-atherogenic pattern A. Its primary limitation is side effects. Immediate-release niacin and Niaspan cause flushing, itching, and headache, which limit the number of people who are willing or able to tolerate therapy on a long-term basis. Niaspan is recommended to be dosed at bedtime to limit this side effect. Additionally, aspirin should be taken 30 minutes before the first daily dose of niacin to limit these symptoms. Patients should also take their niacin dose with food to limit the flushing side effect. Daily doses of 2 g or more of sustained-release niacin can cause hepatotoxicity, which is manifest in its mildest form as asymptomatic increases in liver transaminases and in its severest form as malaise, lethargy, anorexia, and other symptoms of hepatitis. Because of this risk, daily doses of these products should not exceed 2 g, and close monitoring of liver function (i.e., at baseline, every 6–12 weeks for the first year, and approximately every 6 months thereafter) should accompany use of these products. Most authorities recommend that the immediate-release or extended-release dosage forms be given preference to sustained-release products to avoid this risk. Other side effects include activation of peptic ulcer, hyperglycemia, and gout. Niacin reduces insulin sensitivity and often worsens hyperglycemia in persons with type 2 diabetes. References: Coronary Drug Project Research Group. Clofibrate and niacin in coronary heart disease. JAMA 1975;231:360-381. Canner PL, Berge KG, Wenger NK, Stamler J, Friedman L, Prineas RJ, Friedewald W, for the Coronary Drug Project Research Group. Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol 1986;8:1245-1255.
- Bile acid resins: mechanism of action Bile acid resins bind bile acids in the intestine, which reduces the enterohepatic recirculation of bile acids. This promotes the upregulation of 7- hydroxylase and the conversion of more cholesterol in the hepatocyte into bile acids. This decreases the cholesterol content in the hepatocyte, which enhances LDL-receptor expression, which in turn increases the removal of LDL and VLDL remnant particles from the circulation. The liver also increases its synthesis of cholesterol, which partially negates the LDL-C–lowering efficacy of the bile acid resin. In some persons, especially in patients who have an elevated triglyceride level, resins increase hepatic VLDL production and thereby raise serum triglyceride levels.
- Clinical features of BARs The Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT) compared cholestyramine to placebo in 3806 hypercholesterolemic men for 7.4 years and reported a 10% reduction in LDL-C and a 19% reduction in nonfatal myocardial infarction and CHD death. Beneficial effects have also been reported in other trials that used bile acid resins in combination with other lipid-modifying drugs. Bile acid resins are not absorbed from the GI tract and thus lack systemic toxicity. However, the GI side effects are numerous and dose limiting. These include constipation, bloating, abdominal pain, nausea, and flatulence. Patients can rarely tolerate more than 2–4 packets of the older bile acid resins, colestipol and cholestyramine (10–20 g/d and 8–16 g/d, respectively). Colesevelam is administered as 6–7 625-mg tablets daily. It is much easier to administer and has improved GI tolerance. Bile acid resins can decrease the absorption of other drugs administered concurrently, including fat-soluble vitamins, and so it is recommended that other drugs be taken an hour before or 4 hours after the bile acid resin. Colesevelam also has not been found to reduce the absorption of coadministered drugs in studies to date. References: Lipid Research Clinics Program: The Lipid Research Clinics Coronary Primary Prevention Trial results. I. Reduction in incidence of coronary heart disease. JAMA 1984;251:351-364. Lipid Research Clinics Program: The Lipid Research Clinics Coronary Primary Prevention Trial results. II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering. JAMA 1984;251:365-374.
- Fibric acid derivatives The final group of triglyceride-lowering drugs that may be useful in reaching non-HDL-C goals is the fibrates. The mechanism of action of fibrates is very complex and not entirely understood. Their principal effect appears to be mediated through nuclear transcription factor peroxisome proliferator-activated receptor (PPAR-) in liver, adipose, and other tissues. Their agonist effect on these receptors down-regulates the apo C-III gene and up-regulates genes for apo A-I, fatty acid transport protein, fatty acid oxidation, and possibly lipoprotein lipase. The effects on lipoprotein lipase and apo C-III (which inhibits lipoprotein lipase) enhance the catabolism of triglyceride-rich lipoproteins, whereas increased fatty acid oxidation reduces formation of VLDL triglycerides. Increased synthesis of apo A-I tends to raise HDL-C levels. The prominent effect of the fibrates is to reduce elevated triglyceride by 25–50% and secondarily to raise HDL-C by 15–25%. Fibrates are generally well tolerated in most patients. GI complaints are the most common side effects. All drugs in this class appear to increase the lithogenicity of bile and increase the likelihood of cholesterol gallstones. Additionally, the fibrates are highly bound to serum albumin and may displace warfarin, increasing its anticoagulant effects. Since fibrates are excreted primarily by the kidneys, caution should be observed in patients with renal failure. Myopathy has been observed particularly when combined with a statin. More comment will be given to this issue in slide 30. References: Frick MH, Elo O, Haapa K, Heinonen OP, Heinsalmi P, Helo P, Huttunen JK, Kaitaniemi P, Koskinen P, Manninen V, Mäenpää H, Mälkönen M, Mänttäri M, Norola S, Pasternack A, Pikkarainen J, Romo M, Sjöblom T, Nikkilä EA. Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med 1987;317:1237-1245. Frick MH, Syvänne M, Nieminen MS, Kauma H, Majahalme S, Virtanen V, Kesäniemi YA, Pasternack A, Taskinen M-R, for the Lopid Coronary Angiography Trial (LOCAT) Study Group. Prevention of the angiographic progression of coronary and vein-graft atherosclerosis by gemfibrozil after coronary bypass surgery in men with low levels of HDL cholesterol. Circulation 1997;96:2137-2143. Ericsson C-G, Hamsten A, Nilsson J, Grip L, Svane B, de Faire U. Angiographic assessment of effects of bezafibrate on progression of coronary artery disease in young male postinfarction patients. Lancet 1996;347:849-853. Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, Faas FH, Linares E, Schaefer EJ, Schectman G, Wilt TJ, Wittes J, for the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med 1999;341:410-418. The BIP Study Group. Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease: the Bezafibrate Infarction Prevention (BIP) Study. Circulation 2000;102:21-27.
- By adding a statin to ezetimibe therapy, we take advantage of two mechanisms. First, the statin promotes clearance of LDL particles from blood into the liver as shown by the white arrow. Second, statins reduce the compensatory response whereby the liver upregulates synthesis to compensate for the reduced flux of cholesterol from the intestine to the liver. The combination of these two therapies would be expected to lead to potent reductions in plasma LDL cholesterol concentrations.
- Fatty fish – salmon, tuna, halibut Walnuts, flaxsees