Extinguishing Inflammation: A Practical Guide
Part 2 of a 2-Part Series
Part 2: How to shut down inflammation
Inflammation drives coronary plaque growth. It's also the trigger for plaque rupture that
results in heart attack. Inflammation is like a fire—one that you can put out.
Fish oil and omega-3 fatty acids
Fish oil should be the mainstay of your program.
Abundant data over the past 10 years has demonstrated the power of omega-3 fatty acids in fish oil to suppress multiple steps in the inflammatory process, including IL-1, IL-2, tumor necrosis factor, COX-2 and others. Among the most persuasive observations are in trials in inflammatory joint diseases like rheumatoid arthritis, in which inflammatory factors are markedly reduced and the severity of arthritis lessened by fish oil. Some authorities have speculated that fish oil's anti-inflammatory benefits are responsible for the dramatic reduction in death from heart disease observed with fish oil supplementation.
The effective dose starts at a minimum of 4000 mg per day (providing 1200 mg of the omega-3 fatty acids EPA + DHA). CRP reductions of approximately 30% are generally achieved.24–26
Flavonoids
Flavonoids are important naturally-occurring food factors that suppress inflammation.
Most Americans obtain around 25 mg per day total flavonoids from foods. Of the 4000 flavonoids identified, several stand out for anti-inflammatory effects. Quercetin is among the most potent for turning off inflammation. Several hundred studies have confirmed its potent health effects. This flavonoid, found in apples and onions, suppresses the inflammatory enzymes cyclooxygenase and lipoxygenase responsible for prostaglandin-driven inflammation. Quercetin also suppresses tyrosine kinase and nuclear factor-kappa B, proteins that participate in inflammation and cancer development. Nuclear factor-kappa B, in particular, is a critical control point for many other inflammatory proteins.27 Despite the wealth of experimental data, limited human studies are available. The existing data, however, have shown that doses of 1000 mg per day are safe.28
The proanthocyanidin class of flavonoids from blueberries, raspberries, cherries, and red onions are enjoyed in abundance by populations with low occurrence of cancer and heart disease. Not surprisingly, proanthocyanidins have potent anti-inflammatory properties. Like quercetin, the proanthocyanidins curb inflammatory proteins including cyclooxygenase, MMP, and NF kappa B. Grape seed extract supplements take advantage of the high concentration of proanthocyanidins in the seeds of grapes. Proanthocyanidins are also available in concentrated form as pycnogenol (from pine bark) and bilberry concentrate. Doses of several hundred milligrams per day appear to be safe and reproduce the quantity obtained by the healthiest populations.29,30
The catechin variety of flavonoids, found in green and black tea, command center stage due to their benefits in anti-oxidation, cancer prevention, and weight loss. They have also demonstrated broad anti-inflammatory effects in numerous experimental settings. The active ingredients in tea are principally attributable to epigallocatechin-3-gallate and theaflavin, present in quantities of approximately 30–50 mg per 6 oz cup of green or black tea. The green tea catechins are gaining special popularity for modest weight-loss enhancing effects, in addition to anti-inflammatory benefits. Green tea catechins at a dose of 270 mg per day as a supplement, or approximately 2–3 cups of brewed tea, has been shown to provide these effects.30–33
Chocolate lovers have cause to rejoice with the finding that chocolate procyanidins, most plentiful in dark chocolate and cocoa, are impressive suppressors of inflammation. A University of California study in 10 healthy volunteers showed that chocolate containing 148 mg of procyanidins (the equivalent of approximately 6 oz of dark chocolate34) caused a 29% decrease in inflammatory leukotrienes and a 32% increase in prostacyclin, yielding a net decrease in the plasma leukotriene-prostacyclin ratio, a measure of proinflammatory-antiinflammatory eicosanoid balance. The investigators also noted that these benefits largely dissipated by six hours after subjects ingested the chocolate, suggesting that consumption of flavonoid sources several times a day may yield maximum benefit.35
Resveratrol, the flavonoid found in grape skins and concentrated in red wine, is a close relative of quercetin. It exhibits many of the same beneficial anti-inflammatory properties through suppression of cyclooxygenase and nuclear factor kappa B.36
Resveratrol may be one of the factors responsible for the marked reduction in heart attack experienced by people following the Mediterranean diet. Resveratrol powerfully inhibits the matrix metalloproteinase enzyme, MMP, that may be the trigger for rupture of atherosclerotic plaque resulting in heart attack and stroke.37 Resveratrol content in red wines varies enormously depending on type of grape, soil characteristics, etc., but averages around 1 mg per liter. If you're a non-drinker, resveratrol is available as a supplement, often mixed with other flavonoids.
Research in "chemoprevention", or cancer prevention, has shown that isoflavones, a class of flavonoids from soy products, are effective inhibitors of pathways leading to both cancer and inflammation. The isoflavones, genistein and daidzein, block the nuclear factor kappa-B pathway.38,39 Other studies show that soy-based meal replacements, which are primarily soy protein powder that contain isoflavones, also reduce CRP. A UCLA study in diabetic patients showed that soy-based meal replacements reduced CRP by 25%, in addition to achieving significant loss of weight and drops in blood sugar.40
Magnesium is now recognized as a mediator of inflammation, possibly through its effects on suppressing the MMP enzyme.41 Two large studies, including the nearly 12,000 participant Women's Health Study, have shown that people who fail to take the recommended adequate intake of magnesium of 310–420 mg per day are more prone to have both metabolic syndrome and increased CRP.42,43 Magnesium deficiency is exceptionally common and perhaps becoming an even larger societal issue as people turn to bottled water, which contains nearly zero magnesium content. Daily deficiencies of 30% or more each and every day are frighteningly common. In the cities with the highest magnesium water content, only 30% of the RDA can be obtained by drinking two liters of tap water per day.
A confident dose for supplementation is 500 mg per day of "elemental" magnesium. This is the quantity of magnesium regardless of the form you take (e.g., magnesium citrate, magnesium lactate, etc.), usually listed on the bottle as "elemental magnesium." Avoid magnesium oxide, as it is very poorly absorbed and tends to cause more loose stools than other forms. Doses are best taken distributed throughout the day in order to avoid diarrhea.
Vitamin D is gaining recognition as a crucial modulator of inflammation. Most of us are deprived of sun exposure that activates vitamin D in the skin, particularly if you live in a northern climate or work indoors. Less sunlight exposure has been associated with greater cancer and heart attack risk. Some estimates put 70% or more of Americans as deficient in vitamin D, and supplementation can be among the most potent anti-inflammatory strategies available. A British study from the University of London demonstrated a dramatic reduction in the inflammatory proteins, CRP and matrix metalloproteinase (MMP). An astounding 68% reduction in MMP was observed with vitamin D replacement.44 The recently recognized potent tumor-inhibiting effects of vitamin D have also led to observations of prostaglandin suppressing activity.45 The ideal dose is still being debated but is probably is in the vicinity of 2000 units per day.46
HDL is a blood lipoprotein that has tremendous anti-inflammatory properties. People with higher HDL experience far less heart attack, stroke, cancer, and are more likely to live longer, with HDL's in the >90 mg range predicting extreme longevity. HDL has repeatedly shown an inverse correlation with CRP and other inflammatory measures in several studies. Fascinating work from the group at the Heart Research Institute of Australia has shown that CRP induces inflammatory adhesive molecules in cells (vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and E-selectin), a crucial step in atherosclerotic plaque development. HDL cholesterol particles completely shut down this effect of CRP.47 HDL also induces the anti-inflammatory prostaglandin, prostacyclin.48 Raising HDL may therefore be an indirect method to oppose inflammation in your body. Niacin is the number one supplement for raising HDL, beginning at doses of 250 mg per day. (Doses exceeding 500 mg per day should be taken under the supervision of your doctor.)
Drugs that reduce inflammation
Abundant data show that the statin cholesterol drugs reduce C-reactive protein around 30% over several months. Lipitor® appears to be the stand-out for this effect when compared to other statins. However, the drug manufacturers are trying to make their products the number one choice to reduce inflammation, an approach we strongly disagree with. Ezetimibe (Zetia®) is another agent, usually used in combination with statins, that adds to the CRP-reducing effect.
The glitazones (Actos® and Avandia®) for diabetes or insulin resistance can lower C-reactive protein. Aspirin also lowers C-reactive protein modestly.
Create your own anti-inflammation program
For most of us, turning off inflammation is within easy grasp.
Weight loss to achieve your ideal weight should be the start of an inflammation management program. This alone achieves an impressive correction of hidden inflammation, not to mention marked reduction of risk for all associated diseases like heart disease and cancer. Following a healthy diet low in saturated fat and high in healthy monounsaturated oils; fibers; deeply colored vegetables and fruits; and lean proteins can help you maintain weight and suppress inflammation. Foods to include in your diet as often as possible to reduce CRP include:
* Oat bran—1/4 cup (uncooked) per day added to yogurt, fruit or protein smoothies, or as a hot breakfast cereal. Oat bran has twice the beta-glucan of oatmeal. Alternatively, a similar quantity of ground flaxseed can be substituted. This packs a huge amount of fiber into your diet, similar to the effect of the "diet portfolio" (See Extinguishing Inflammation: Part I.)
* Soy protein powder—3–6 tbsp/day as a protein shake or added to oatmeal, oat bran, yogurt. Other convenient sources of soy protein include soy milk, soy cheese, soy butter, and some low-carb pastas.
* Almonds—34 or approximately 2 handfuls/day. Another great source of healthy fiber.
* Citrus fruits—leave as much rind on as possible, or add ground rind to foods for its pectin content.
* Green or black tea—1–3 cups per day for catechins.
* Dark chocolate—2–4 oz per day for chocolate procyanidins.
* Red wine–1–2 glasses per day for resveratrol and other wine flavonoids.
Supplements can carry a lot of clout and further suppress CRP and inflammation. Your first choices should be:
* Fish oil 4000–6000 mg per day (providing 1200–1800 mg EPA+DHA)
* Vitamin D 2000 units per day
* Magnesium–500 mg elemental magnesium per day
Any of the supplemental flavonoid preparations might be considered, also, to further boost your program, including reseveratrol, quercetin, or grape seed extract.
Selected References:
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23. Ciubotaru I, Lee YS, Wander RC. Dietary fish oil decreases C-reactive protein, interleukin-6, and triacylglycerol to HDL-cholesterol ratio in postmenopausal women on HRT. J Nutr Biochem 2003 Sep;14(9):513–521.
24. Adam O, Beringer C, Kless T et al. Anti-inflammatory effects of a low arachidonic acid diet and fish oil in patients with rheumatoid arthritis. Rheumatol Int 2003 Jan;23(1):27-36. Epub 2002 Sep 6.
25. Nijveldt RJ, van Nood E, van Hoorn DEC, Boelens PG, van Norren K, van Leeuwen PAM. Flavonoids: a review of probable mechanisms of action and potential applications. Am J Clin Nutr 2001;74:418–425.
26. Clifton PM. Effect of grape seed extract and quercetin on cardiovascular and endothelial parameters in high-risk subjects. J Biomed Biotech 2004;5(2004):272–278.
27. De-Xing Hou, Fujii M, Terahara N, Yoshimoto M. Molecular mechanisms behind the chemopreventive effects of anthocyanidins. J Biomed Biotech 2004:5(2004)321–325.
28. Aldini G, Carini M, Piccoli A, Rossoni G, Facin o RM. Procyanidins from grape seeds protect endothelial cells from peroxynitrite damage and enhance endothelium-dependent relaxation in human artery: new evidences for cardio-protection. Life Sci 2003 Oct 17;73(22):2883–2898.
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30. Westerterp-Plantenga MS, Lejeune MP, Kovacs EM. Body weight loss and weight maintenance in relation to habitual caffeine intake and green tea supplementation. Obes Res 2005 Jul;13(7):1195-204.
31. Kaszkin M, Beck K, Eberhardt W, Pfeilschifter J. Unravelling green tea's mechanisms of action: more than meets the eye. Mol Pharmacol 2004;65:15–17.
32. USDA Database for the Flavonoid Content of Selected Foods–2003.
33. Schramm DD, Wang JF, Holt RR et al. Chocolate procyanidins decrease the leukotriene-prostacyclin ratio in humans and human aortic endothelial cells. Am J Clin Nutr 2001;73:36–40.
34. Donnelly LE, Newton R, Kennedy GE et al. Anti-inflammatory effects of resveratrol in lung epithelial cells: molecular mechanisms. Am J Physiol Lung Cell Mol Physiol 2004;287:L774–783.
35. Oak MH, El Bedoui J, Anglard P, Schini-Kerth VB. Red wine polyphenolic compounds strongly inhibit pro-matrix metalloproteinase-2 expression and its activation in response to thrombin via direct inhibition of membrane type 1-matrix metalloproteinase in vascular smooth muscle cells. Circulation 2004 Sep 28;110(13):1861–1867.
36. Sarkar FH, Li Y. Soy isoflavones and cancer prevention. Cancer Invest 2003;21(5):744–757.
37. Valachovicova T, Slivova V, Bergman H, Shuherk J, Sliva D. Soy isoflavones suppress invasiveness of breast cancer cells by the inhibition o fNF-kappaB/AP-1-dependent and –independent pathways. Int J Oncol 2004 Nov 25(5):1389–1395.
38. Li Z, Hong K, Saltsman P, DeShields S et al. Long-term efficacy of soy-based meal replacements vs an individualized diet plan in obese type II DM patients: relative effects on weight loss, metabolic parameters, and C-reactive protein. Eur J Clin Nutr 2005 Mar;59(3):411–418.
39. Yue H, Lee JD, Shimizu H, Uzui H, Mitsuke Y, Yeda T. Effects of magnesium on the production of extracellular matrix metalloproteinases in cultured rat vascular smooth muscle cells. Atherosclerosis 2003 Feb;166(2):271–277.
40. King DE, Mainous GA 3rd, Geesey ME, Woolson RF. Dietary magnesium and C-reactive protein levels. J Am Coll Nutr 2005 Jun;24(3):166–171.
41. Song Y, Ridker PM, Manson JE, Cook NR, Buring JE, Liu S. Magnesium intake, C-reactive protein, and the prevalence of metabolic syndrome in middle-aged and older U.S. women. Diabetes Care 2005 Jun;28(6):1438–1444.
42. Timms PM, Mannan N, Hitman GA, Noonan K et al. Circulating MMP9, vitamin D and variation in the TIMP-1 response with VDR genotype: mechanisms for inflammatory damage in chronic disorders? Q J Med 2002;95:787–796.
43. Moreno J, Krishnan AV, Swami S, Nonn L, Peehl DM, Feldman D. Regulation of prostaglandin metabolism by calcitriol attenuates growth stimulation in prostate cancer cells. Cancer Res 2005 Sep 1;65(17):7917-25.
44. Holick MF. Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis. Am J Clin Nutr. 2004 Mar;79(3):362-71.
45. Wadham C, Albanese N, Roberts J et al. High-density lipoproteins neutralize c-reactive protein proinflammatory activity. Circulation 2004;109:2116–2122.
46. Vinals M, Martinez-Gonzales J, Badimon L. Regulatory effects of HDL on smooth muscle cell prostacyclin release. Arterioscler Thromb Vasc Biol 1999;19:2405–2411.
47. Stroes E. Statins and LDL-cholesterol lowering: an overview. Curr Med Res Opin 2005;21 Suppl 6:S9-16
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