Atherosclerosis: Lipoproteins interact with vessel wall proteoglycans

5. Atherosclerosis: Lipoproteins interact with vessel wall proteoglycans This causes inflammation (so the endothelial cells secrete adhesion molecules for monocytes (type of white blood cell that rolls along the blood vessel wall)) Monocytes migrate into the endothelial tissue and differentiate into macrophages, which take up lipids to try to dispose of them. They become engorged and can die. Lipids are only taken up if they are oxidized (which happens to LDL trapped on the vessel wall) Macrophages secrete cytokines like interleukin-1 and interleukin-6 that trigger an inflammation response (recruit more white blood cells to help dispose of all the trapped lipids) The trapped, engorged, dying macrophages leads to calcification of the atherosclerotic lesion, and the associated inflammation increases risk of thrombosis

6. Lipoproteins interact with vessel wall proteoglycans High [LDL] means more lipid to bind to vessels This causes inflammation (so the endothelial cells secrete adhesion molecules for monocytes (type of white blood cell that rolls along the blood vessel wall)) Monocytes migrate into the endothelial tissue and differentiate into macrophages, which take up lipids to try to dispose of them. They become engorged and can die. Inflammatory/immune state of body can accelerate atherosclerosis Lipids are only taken up if they are oxidized (which happens to LDL trapped on the vessel wall) Smoking, reactive oxygen species. Mediated by LOX-1 Macrophages secrete cytokines like interleukin-1 and interleukin-6 that trigger an inflammation response (recruit more white blood cells to help dispose of all the trapped lipids) Inflammatory marker proteins (like C Reactive Protein) can be detected in the blood The trapped, engorged, dying macrophages leads to calcification of the atherosclerotic lesion, and the associated inflammation increases risk of thrombosis Prostaglandins mediate pro-thrombotic or antithrombotic conditions in the arteries, local inflammation events, and general inflammatory state. Plaque rupture and resulting clot causes myocardial infarction (heart attack)

7. (seeds) (algae, grass) Series 1 Series 2 Series 3 When dietary source of linoleic and a-linolenic acids are equal, relative activities of D6 and D5 desaturases determines relative amounts of these prostaglandins

8. Leukotrienes lead to inflammation (asthma, heart attack, anaphylaxis) EPA-based leukotrienes have much lower activity than their arachidonate-derived counterparts eicosapentaenoic acid (EPA) (w-3 from marine animals) inhibits thromboxane synthesis

9. Some questions I have been thinking about: Greenland Eskimo diet: high cholesterol, high saturated fat, no vegetables (raw fish, blubber, marine animals), and NO heart disease… Typical poor American child diet: sugar, soybean oil, corn oil, white flour…and high chance of developing obesity, heart disease, and diabetes. Does inflammation play a role in health? We have a protein called C reactive protein. It is secreted as a result of inflammatory stimuli, IL-6, IL-1, so reflects the inflammatory state of the body. CRP levels are measured along with cholesterol levels to diagnose risk of heart disease. It seems that CRP also has a role in CAUSING inflammation in the presence of oxidized LDL.

10. hsCRP (Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:1222.) 2008 American Heart Association, Inc. The Time for Cardiovascular Inflammation Reduction Trials Has Arrived. How Low to Go for hsCRP? Paul M Ridker From the Center for Cardiovascular Disease Prevention, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass. That inflammation plays a fundamental role in atherothrombosisand that hsCRP is a clinically effective predictor of risk isno longer controversial.24 If anything, from an epidemiologicalperspective, the attributable risk of coronary heart diseaseassociated with inflammation is as large as that associatedwith hyperlipidemia. It would thus appear that the time forrandomized trials directly testing the inflammatory hypothesisof atherothrombosis has arrived. High-Sensitivity C-Reactive Protein and Coronary Heart Disease in a General Population of Japanese: The Hisayama Study Hisatomi Arima, Michiaki Kubo, Koji Yonemoto, Yasufumi Doi, Toshiharu Ninomiya, Yumihiro Tanizaki, Jun Hata, Kiyoshi Matsumura, Mitsuo Iida, and Yutaka KiyoharaArterioscler. Thromb. Vasc. Biol. 2008 28: 1385-1391. [Abstract][Full Text][PDF] The lower the hsCRP level, the lower the risk of atherothrombosis (heart attack), and the protective levels of hsCRP were much lower than those found in the Women’s Health Study to be protective (the American “healthy” diet still has a ways to go to be healthy). The atheroma is precededby a fatty streak, an accumulation of lipid-laden cells beneaththe endothelium.3 Most of these cells in the fatty streak aremacrophages, together with some T cells. Fatty streaks are prevalentin young people, never cause symptoms, and may progress to atheromataor eventually disappear

11. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005; 352: 1685�1695.[Free Full Text] Studies in animals and humans have shown that hypercholesterolemiacauses focal activation of endothelium in large and medium-sizedarteries. The infiltration and retention of LDL in the arterialintima initiate an inflammatory response in the artery wall13,14(Figure 2). Modification of LDL, through oxidation or enzymaticattack in the intima, leads to the activation of endothelial cells Bacterial endotoxins, apoptotic cell fragments, and oxidizedLDL particles are all taken up and destroyed through this pathway.If cholesterol derived from the uptake of oxidized LDL particlescannot be mobilized from the cell to a sufficient extent, itaccumulates as cytosolic droplets. Ultimately, the cell is transformedinto a foam cell, the prototypical cell in atherosclerosis. Inhibition of the receptor pathways mediating the uptake of oxidized LDL prevents atherosclerosis (EVEN IF HIGH LDL LEVELS!!!!!). Opposing this, stimulation of the oxLDL receptor with C reactive protein accelerates oxLDL uptake and atherosclerotic progression. Inhibition of cytokines mediating the inflammatory response to uptake of oxLDL eliminates atherosclerosis (EVEN IF HIGH LDL LEVELS!!!!!). (Peptido)leukotrienes promote vascular inflammation (but leukotrienes based on marine lipids (w-3) are far less active!!!!!!!).

12. Oxidized LDL receptor LOX-1 binds to C-reactive protein and mediates its vascular effects. Fujita, et al. Clinical Chemistry Feb. 2009 Acute inflammation increases CRP ~1000-fold (300mg/L). Low levels (high-sensitivity CRP) reflect long-term, chronic inflammation CRP appears to function to enhance removal of foreign bodies (bacterial, apoptotic remnants, oxLDL). It apparently binds the oxidized phosphorylcholine on oxLDL… C-reactive protein (CRP) is an acute-phase protein that binds specifically to phosphorylcholine (PC) as a component of microbial capsular polysaccharide and participates in the innate immune response against microorganisms. CRP elevation also is a major risk factor for cardiovascular disease Their Results: LOX-1 binds CRP (0.3mg/L, below recommended concentrations), and mediates its biological effects… Evidence in the paper is pretty clear that the binding occurs. They give good evidence for the mechanism for CRP accelerating the progression of atherosclerosis, which clarifies something that is not well understood in the field.

13. 1: Atherosclerosis. 2008 Sep 2. [Epub ahead of print] Links Reduction in dietary omega-6 polyunsaturated fatty acids: Eicosapentaenoic acid plus docosahexaenoic acid ratio minimizes atherosclerotic lesion formation and inflammatory response in the LDL receptor null mouse. Wang S, Wu D, Matthan NR, Lamon-Fava S, Lecker JL, Lichtenstein AH. Cardiovascular Nutrition Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, 711 Washington Street, Boston, MA 02111, United States. Dietary very long chain omega (omega)-3 polyunsaturated fatty acids (PUFA) have been associated with reduced CVD risk, the mechanisms of which have yet to be fully elucidated. LDL receptor null mice (LDLr-/-) were used to assess the effect of different ratios of dietary omega-6 PUFA to eicosapentaenoic acid plus docosahexaenoic acid (omega-6:EPA+DHA) on atherogenesis and inflammatory response. Mice were fed high saturated fat diets without EPA and DHA (HSF omega-6), or with omega-6:EPA+DHA at ratios of 20:1 (HSF R=20:1), 4:1 (HSF R=4:1), and 1:1 (HSF R=1:1) for 32 weeks. Mice fed the lowest omega-6:EPA+DHA ratio diet had lower circulating concentrations of non-HDL cholesterol (25%, P<0.05) and interleukin-6 (IL-6) (44%, P<0.05) compared to mice fed the HSF omega-6 diet. Aortic and elicited peritoneal macrophage (Mvarphi) total cholesterol were 24% (P=0.07) and 25% (P<0.05) lower, respectively, in HSF R=1:1 compared to HSF omega-6 fed mice. MCP-1 mRNA levels and secretion were 37% (P<0.05) and 38% (P<0.05) lower, respectively, in elicited peritoneal Mvarphi isolated from HSF R=1:1 compared to HSF omega-6 fed mice. mRNA and protein levels of ATP-binding cassette A1, and mRNA levels of TNFalpha were significantly lower in elicited peritoneal Mvarphi isolated from HSF R=1:1 fed mice, whereas there was no significant effect of diets with different omega-6:EPA+DHA ratios on CD36, Mvarphi scavenger receptor 1, scavenger receptor B1 and IL-6 mRNA or protein levels. These data suggest that lower omega-6:EPA+DHA ratio diets lowered some measures of inflammation and Mvarphi cholesterol accumulation, which was associated with less aortic lesion formation in LDLr-/- mice. IL-6 is inflammatory marker

14. The hot topic in fats today is the ratio of 6s to 3s, and the effect of that ratio on our health. The typical American diet has too much omega-6 and not nearly enough omega-3. Studies have shown these essential oils are critical to healthy skin, nerve cells, and brain function, including prevention of depression. We also know that Omega-3s are important to the proper development of the fetus and infant. Omega-3s can reduce the clotting factors that precipitate stroke and heart disease, and they can lower the LDLs while increasing HDLs in our cholesterol levels. This essential fatty acid is also known to be effective in treatment of inflammatory diseases such as arthritis and allergies. Inadequate Omega-3s, and or excess Omega-6s in relation to 3s can contribute to a host of other chronic diseases as well, such as cancer, obesity, insulin resistance and diabetes. Omega-3s in beef that feed on grass is 7% of the total fat content, compared to 1% in grain-only fed beef. Grain-fed beef can have an omega-6 to omega-3 ratio higher than 20:1, well exceeding the 4:1 ratio where health problems begin to show up because of the essential fatty acid imbalance.  Grass-fed beef can have an omega-6 to omega-3 ratio of 1:1.

15. TABLE I - Chemical Composition (per 100 g) of Raw Chicken and Beef Beef cuts Semimembranosus Biceps femoris Dark chicken meat Moisture (g)c 74.48 ± 1.08 72.48 ± 1.57 77.49 ± 1.04 Protein (g) c 21.17 ± 0.16 20.97 ± 0.04 18.83 ± 0.09 Fat (g) c 3.08 ± 0.07 8.75 ± 1.12 4.08 ± 0.60 Cholesterol (mg)g 51.97 ± 1.40 63.02 ± 3.62 80.30 ± 2.83

17. Chicken meat is a significant source of polyunsaturated fat. Chickens that forage for insects and eat clover and other greens have better -6: -3 ratios in their meat and eggs. Organic, free range, natural, cage free chickens still live in warehouses with thousands of other chickens and eat grain (and whatever else the food manufacturer wants to put in there, like other animal byproducts, recently DHA, etc.). Cattle lose their -3 fatty acids soon after being sent to the feedlot to eat sugar and grain until slaughter. Cows evolved to eat grass (ruminant digestion), but humans have been fattening them on grain as long as we have had grain to feed them. Modern industrial agriculture simply goes to extremes with the grain-fed process. Monsanto bred Round-up Ready Soy with almost no -3, since it is prone to oxidation (goes rancid). Soybean oil is about 60% polyunsaturated, with up to a 60:1 ratio of w-6:w-3. Soybean oil is used in many restaurants and processed food, since it is the oil we produce on our factory farms. Olive oil has a 3:1 up to 10:1 ratio of w-6:w-3, which is borderline okay, but it is only about 10% polyunsaturated.

18. Discussion points: What is the biggest source of w-6 fat in our diets? Where can we get w-3 fats? What is nutritionism? Are we practising nutritionism by obsessing about w-3 fats? Eating plenty of grass-fed beef is a good solution, right? Before the modern food era -- and before nutritionism -- people relied for guidance about what to eat on their national or ethnic or regional cultures. Where can we seek guidance on our food?

19. Jeff’s Wednesday food intake and PUFA analysis: the peanut butter contributes the most to the high w-6:w-3 ratio!! Breakfast: Oatmeal, blueberries, 50mL whole milk, 1Tbsp butter (88% of 15g plus 4% of 50g = 13.2g+2g = 15.2g total butterfat) Bufferfat is ~3% w-6, so 3% of 15.2 = 0.46g w-6 Butterfat is ~1% w-3, so 1% of 15.2 = 0.15g w-3. Lunch: 2 peanut butter sandwiches, 1 apple 1Tbsp butter = 0.4g w-6, 0.13g w-3 3Tbsp peanut butter = 21g fat, and 33% of 21g = 7g w-6 Peanut oil is 0.5% w-3, giving 0.5%*22.5g = 0.11g w-3 Dinner: 150g pork sausage, salad with 1Tbsp olive oil vinaigrette, sauerkraut, potatoes, 5g lard Sausage is ~20% fat, so 150g * 20% = 30g pork fat + 5 extra = 35g lard, which is 10% w-6 (3.5g) W-3 is 1% of the 35g, or 0.35g Dessert: 8oz hot chocolate 200mL whole milk (4% of 220g =8.8g butterfat*3% = 0.26g w-6) 8.8g * 1% = 0.09g w-3 Total omega-6 = 0.46+7+3.5+0.26 = 11.2g Total omega-3 = 0.15+0.11+0.35+.09=0.7g Ratio: 16:1!!!!!!!! Plus 1tsp fish oil (1.2g w-3), 11.2 w-6 / 1.9 w-3 = 5.8:1 Total fat for day: 15.2+45g+35g+8.8g=104g fat Total calories: 900 fat, 1319 calories carbs (329g), 55g protein 220 calories=2340 total calories

20. Nutrition analysis by Eve Vodden-Thornton Nutrient Total Rec. %Rec Calories 2248.75 2900 77.54% Pro (g) 73.63 63 116.87% Fat (g) 117.55 96.67 121.6% Carb (g) 245.91 -- Fiber (g) 26.33 30 87.77% Cal (mg) 644.65 1000 64.47% Iron (mg) 19.46 10 194.6% Na (mg) 4126.85 2400 171.95% Pot (mg) 3852.85 -- Phos(mg) 1207.13 700 172.45% Ash (g) 17.52 -- vitA (IU) 2270.32 5000 45.41% vitC (mg) 92.42 90 102.69% Thia (mg) 2.33 1.2 194.17% Ribo (mg) 1.88 1.3 144.62% Nia (mg) 27.03 16 168.94% H2O % 39.61 Male 31-50 -- satF (g) 41.4 32.22 128.49% monoF(g) 44.29 32.22 137.46% polyF (g) 15.51 32.22 48.14% Chol (mg) 212.74 300 70.91%1 B1 (thiamine) B3 (nicotinamide)

21. Michael Pollan describes a grass-based chicken production system in his Omnivore’s Dilemma that humanely produces chickens and eggs that are much healthier for you to eat (Polyface Farm, which also sells cows, pigs, rabbits, turkeys). The USDA regulations on butchering these animals are very restrictive, and forces farmers like Polyface to ship their animals hundreds of miles to be slaughtered at a registered facility. Pierce County just received funding for a mobile abattoir (slaughterhouse on wheels) that will travel around to small farmers in Pierce, King, Kitsap and a few other counties to enable them to slaughter their animals on-site. This is the single biggest impediment to a return to local animal farming, and Pierce county has one of the first of these facilities (soon) in the nation!

22. He also gives a philosophical discussion on the ethics of eating meat, and one of his conclusions on the issue is that feeding our world’s fields requires nitrogen, and one sustainable way to feed our fields is to use manure. If we have farms that produce their fields’ fertility onsite, they should be able to sustain themselves without chemical input or pollution. Local farmers who are doing this include: 1. Bruce Dunlop, Lopez Island Farms, who comes to the Proctor’s Farmer’s market (maybe this year he will only sell to you if you are on his list…) 2. Jubilee Farm east of Seattle along the Snoqualmie River near Duvall (Farmer Erick writes wonderful newsletters online, and is a huge proponent of local agriculture, see www.jubileefarm.org 3. Zestful Gardens, Tacoma (I get my weekly veggie box from them June1-Nov30). 4. Left-foot organics (Olympia, also runs a weekly CSA box) Terry’s Berries, Tacoma (CSA, eggs) Cheryl the Pig Lady in Tacoma (who supplies pigs sometimes to the Primo Grill and she visits the 6th ave and downtown farmers’ markets), Stokesberry Farms (in Olympia, supplies chickens to the Primo Grill, and may visit 6th ave farmers’ market) Skagit River Ranch, sells their beef and pork at Marlene’s market S. 38th St. Meat Shop of Tacoma (near Ft. Lewis) Thundering Hooves, near Walla Walla, WA.

23. Other reading: Michael Pollan, In Defense of Food. An expanded version of his NYTimes article “Unhappy Meals”, about nutritionism, the problems with what we Americans eat, and how to think about what a good diet is. Nina Planck, Real Food. She collects an impressive amount of data on what real dairy, meat, vegetables, etc. are, and research on how they affect our health. Sally Fallon, Nourishing Traditions. The cookbook that challenges politically correct nutrition. Bone broth, organ meats, traditional fermented foods, and lots of excerpts from Weston Price’s book.