and lecture notes of Nigel Plummer, Ph.D and Dicken Weatherby, ND 1. Cardiovascular disease (heart attack and stroke) top killer in US 1. Condition that shows ↓HDL; ↑LDL; ↑triglycerides 2. 20% of people who develop CHD before age 60 have this pattern e. Good resource: 1. CVD requires a combination of bad blood fats and blood vessel 2. As inflammation is repaired, low-density cholesterol, combined with macrophage debris, is enmeshed in the repair, causing soft 3. Soft plaque can break off and cause embolism in coronary or a. Hard established plaque wil not break off b. Think of scar tissue (old) versus a scab (new) 4. Heart attack due to stenosis alone accounts for 15% of heart 5. Origin of plaque requires inflammatory agents coming from within 1. Excess fats (in tissue or as triglycerides) a. Release free radicals (oxidative stress) which injures b. Stimulate release of inflammatory cytokines b. Insulin acts like a solvent, telling cell walls to open up so as to transport insulin and other nutrients into cel , while allowing cel ular debris to exit the cel c. Levels should be below 4 about 1-2 hrs after eating d. Accounts for high heart disease in diabetics, who have chronical y elevated insulin due to injections a. IL-6 is inflammatory, until turned off by IL-10 3. Wil increase with sweating exercise, 45-60 minutes 4. Environmental toxins, including heavy metals, chemicals a. These cause oxidative stress (free radical damage) 1. Clostridium, h. pylori, cytomegalovirus, periodontal d. Treatment should focus on inhibition of inflammation as wel as 1. Inflammation starts with cytokine release 1. Secreted by endothelium, leucocytes, macrophages 1. Includes monocytes which become macrophages a. Cytokines increase production and release of monocytes a. Cytokines release acute-phase proteins 3. Functions and facts about cholesterol and triglyceride 1. Total cholesterol: < 200 mg/dL (higher risk: >240) 2. HDL (high density lipoproteins): >45 (higher risk: <35) 3. LDL (low density lipoproteins): <130 (higher risk: >160) a. Keeps membrane soft and porous (permeable) 2. Required for steroid hormone production 3. Necessary for production of bile acids and fat-soluble vitamins (A, 4. Created by liver, intestines, adrenal glands, reproductive organs a. Cholesterol creation is turned off if levels are high 5. Excreted by liver via bile duct to smal intestine 6. All animal fats contain some cholesterol a. Percentage of triglycerides and phospholipids is higher b. Animal source cholesterol not significant in raising total 1. Includes cheese, egg yolks, beef, pork, poultry and 2. Reduction in animal products results in increase of liver making cholesterol, so doesn’t reduce blood c. More is stimulated by trans-fats and saturated fats- 1. Pure animal fat contains saturated fats 1. Function is to transport cholesterol and triglycerides from arteries and tissues back to liver for recycling or excretion 3. Low levels are indicator of higher risk for heart disease a. Hyperlipidemia, atherosclerosis, oxidative stress c. If HDL is only 25% of total cholesterol, high risk of 1. Liver asks for more HDL to protect membranes 3. Not shown to reduce total death rate, but does 3. Pharmacological niacin 1-3 g. increases HDL by 10- 1. “No flush” or ”sustained release” h. Statins have no effect on raising HDL 1. Function is to transport cholesterol and triglycerides from liver a. Cel membranes create LDL receptors so cholesterol can be a. When one is higher, the other is lower 3. Higher levels are associated with CHD. Mechanism: a. Arterial epithelial cel s attract LDL b. With inflammation in the artery wal : 1. Smal dense cholesterol is trapped in repair of 2. Macrophages engulf excess LDL particles and c. Clots are formed > embolism, stroke or heart attack e. Due to high refined carbohydrate and sugar diet 5. Best to have various kinds of LDL enumerated a. Done with VAP test (“Vertical Auto Profile”) b. Not commonly done due to higher cost and fewer labs a. Creates “atheroma”, a mix of macrophage 3. Associated with elevated triglycerides e. Healthiest presentation is smal amounts of Pattern A and a. Px: high LDLs are treated with statins 3. By 2003, Lipitor was the best-sel ing 4. MDs recommend statins if LDL is > 130 mg/dL b. People with no other risk factors can wait until >190, but should undertake lifestyle 1. This oxidation is the inflammatory stress that leads a. Composed of triglycerides, cholesterol and apolipoproteins 2. Acts as an internal transport system of lipids a. Transports cholesterol, phospholipids and triglycerides b. Triglycerides is released from VLDL to be used as energy 1. Eventual y, converted in bloodstream to LDL 3. Elevated VLDL = elevated triglycerides c. Rx: statins, nicotinic acid, Lopid (fibrate) 1. Most abundant fat in the blood stream and tissues a. An ester derived from glycerol and 3 fatty acids b. Excess calories are converted to triglycerides c. Triglycerides cannot enter cel directly 1. Broken into 3 fatty acids which are absorbed, and then reformed into intra-cel ular triglyceride a. Forms when there is excess blood glucose 1. Excess carbohydrates are turned into glucose 2. Glucose is used for energy production by cel s b. Any excess glucose is sent back to liver and converted to 1. Glycogen circulates in blood and is stored in b. Acts as energy reserve to release glucose 2. Muscles can retain only smal amounts of glycogen 3. Excess glycogen is sent back to the liver where it is 4. Triglycerides are stored as fat, or circulate in blood 4. Triglycerides are energy source for cel a. Twice as much energy as protein or carbohydrates c. Glycerol component can be converted into glucose for 5. Higher levels correspond with greater likelihood of heart attack, a. Excess levels thicken blood, which increases possibility of 1. Triglyceride fats may be trapped in blood vessel 1. This can act as reservoir of chronic inflammation d. Usual y indicative of Metabolic Syndrome a. Testing must be done with at least 8 hrs of fasting g. If low (<40) may be indicative of auto-immune disorder a. Diets high in sugars and refined carbohydrates > elevated d. Rx that can induce hypertriglyceridemia: 1. Steroids, beta blockers, diuretics, estrogen, a. Dietary caloric restriction, especial y refined carbohydrates, b. Exercise – enough to burn up the fats 1. 45-60 minutes a day of sweating exercise 2. Once blood triglycerides come down, then stored 3. Much scientific evidence to show that fish oil lowers 1. Amino acid that moves fats into cel ular 2. Effective if combined with sweating exercise g. Rx: Statins with Fibrates (Tricor, Lopid) 1. The combined approach has many side effects 2. If you lower cholesterol too much, cel membranes 1. Lipoprotein similar in structure to LDL 2. Elevated amounts is a strong risk factor for: a. Coronary heart disease, cerebrovascular disease, 3. Lp(a) increases coagulation and triples CVD risk (!) 4. Elevated amounts are usual y due to hereditary c. People with low Lp(a) appear to be healthy a. Desirable: < 14 mg/dL (< 35 nmol/l) b. High risk: 31 - 50 mg/dL (75 - 125 nmol/l) c. Very high risk: > 50 mg/dL (> 125 nmol/l) d. African-Americans often have 2-3 fold increase of these b. Niacin (nicotinic acid), fish oil and aspirin beneficial c. Moderate alcohol consumption reduces level 1. Excessive plasma levels of LDL leads to some accumulating in a. Tunica intima (or just intima) is the innermost layer of an 2. Fatty acids in “trapped” LDL undergo oxidation a. Proteins of LDL undergo oxidation and glycation 3. Oxidized LDL is not recognized in intima a. Macrophages produce and induce endothelial cel s to b. This stimulates endothelial cel s to produce adhesion c. Macrophages increase, and engulf oxidized LDL and 1. Foam cel s are unique to LDL and blood vessel 2. Foam cel s produce fatty like streaks 3. Typical y line the tunica intima of the vasculature 4. T-cel s (Th-1) migrate to fatty streak and perpetuate 5. Monocytes, macrophages, endothelial cel s and smooth muscle cel s secrete chemokines (smal cytokines) to form fibrous a. The smooth cel s release adhesive factors to recruit 1. Monocytes migrate under cel to become 2. Macrophage dies and accumulates, coating the b. Becomes like a forest on the artery wal interior surface c. Stable caps form with a mesh of col agen fibres 6. Continued inflammation in intima al ows macrophages and foam cel s to secrete matrix-degrading enzymes c. “Platelet tissue factor” (strong clotting agent) is activated, 1. Also prevents clearance of the clot by normal d. This breaks off to cause heart attack or stroke b. Due to normal cholesterol plus inflammation 1. Chronic inflammation can form the same process, if enough a. Rheumatoid arthritis patients, for example, usual y die of 2. Chronic cytokine production (IL-1, TNF, and IL-6) wil also lead to c. Direct effects of cytokines towards heart failure 1. Heart failure used to be thought of as a disease of the 2. Now, the inflammatory model is considered the underlying a. TNF and IL-6 are elevated in proportion to severity of heart b. Raise IL-6 can affect pulmonary and ventricular functions 1. A soluble plasma glycoprotein, synthesized by the liver, that is converted by thrombin into fibrin during blood coagulation b. Binds to LDL and converts to fibrin mesh c. This decreases blood flow and al ows platelet aggregation 3. Elevated levels correlate with CVD, Metabolic syndrome, obesity 6. Effective therapies: fish oil, Nattokinase, niacin, beta carotene, 2. Produced in liver during inflammation 6. Elevated trans-fats in diet wil make it rise significantly 9. People with chronic periodontal disease have higher levels c. Elevates with smoking, hypertension, BC pil s, HRT 1. Elevations can be inflammation anywhere in body e. Ask for hs-CRP, highly sensitive c-reactive protein 2. Optimal: Men: <0.55 mg/L; women, <1.5 mg/L c. Erythrocyte sedimentation rate (ESR, Sed rate) a. Rate at which red blood cel s precipitate in a period of 1 hour b. Acts as a non-specific marker for inflammation c. Governed by balance between pro-sedimentation factors, mainly fibrinogen, and factors resisting sedimentation, namely the d. When an inflammatory process is present, the high proportion of fibrinogen in the blood causes red blood cel s to stick to each e. The ESR is increased by any cause or focus of inflammation b. Elevated levels of homocysteine linked to cardiovascular disease 2. Elevated levels associated with plaque build-up a. Causes endothelial dysfunction and damage b. Attracts LDL and blood particles to form scab 3. Lowering homocysteine levels may not improve outcome c. Can be lowered with folic acid, B6 and B12 1. Normal, men: 4.3-15.3 umol/L; women: 3.3-11.6 umol/L 3. > 15 has 24.6 % risk of dying in 3.9-5.3 years 4. > 11 has 74% increased risk of stroke 1. Increased levels good marker for increased inflammation or b. Optimal: men, <5.9; women, <5.5 1. Elevated levels can show tissue damage or tissue breakdown a. Especial y if total protein is elevated 2. Often aggravated by B12 and folate deficiency a. Lipoprotein-associated phospholipase A2 1. Also known as platelet-activating factor acetylhydrolase b. Enzyme which is activated in the presence of inflammation and oxidized phospholipids of LDL cholesterol c. Excel ent marker for degree of soft plaque 2. Powerful predictor of stroke and heart attack risk 3. Based on a meta-analysis involving a total of 79,036 d. Available from Berkeley Heart Lab: 3. VAP and other labs wil measure some or al of these, which 1. Measures the ratio of arachidonic acid (AA) to eicosapentaenoic a. AA is produced by excess Omega-6 fatty acids b. EPA is produced by Omega-3 fatty acid 2. This ratio of the principle omega-3 and omega-6 fatty acids is a measure of the body's eicosanoid balance a. Eicosanoids are produced by both Omega-3 and Omega-6 b. Eicosanoids produced by Omega-6 are more inflammatory c. Aspirin and NSAIDs down-regulate eicosanoid levels b. Medical people have been satisfied with <10 4. Performed by Metametrix Labs; Rocky Mtn Analytical Lab a. Low free testosterone is a cardiac risk factor k. “The Perfect Storm for Heart Disease” 6. Effective Therapies Against Soft Plaque and Heart Disease 1. Fish oil contains Omega 3 fatty acids EPA and DHA c. These are precursors to eicosanoids which reduce 2. Fish do not produce Omega-3 fatty acids, but accumulate them through the food chain, their origin being seaweed and micro-algae a. Best source is sardines and anchovies b. Larger fatty fish high in the food chain accumulate heavy 3. Most effective treatment for cardiovascular disease a. Study: 2.3 g reduces mortality rate 29% (without any b. Beneficial to both high risk and low risk patients 1. 2–4 grams is better, esp with marked inflammation 2. Average American intake is < .2g/day 4. Beneficial effects (based on research) 1. Increases action of lipoprotein lipase 2. Increases fatty acid oxidation in liver 3. Study: 2.3 GLA and 2.4 g. EPA for 6 months in d. Regulates and smoothes rhythmic beat of heart 1. Fatal arrhythmias cause 250,000 cardiac deaths 2. Polyunsaturated fatty acids (PUFA) from EPA and 3. PUFAs dampen response of cel s to electrical stimuli 1. 4 g/ day of FO gave further significant reductions of plasma triglycerides and total cholesterol 1. Countries highest in fish oil in their diet have lowest a. Arachidonic acid is main Omega 6 fatty acid 1. Sits at head of arachidonic acid cascade 2. Twenty different signaling paths that control a wide array of functions involving inflammation and the 3. Most AA in the human body derives from dietary b. Omega 3 fatty acids (polyunsaturated oils) form cascades that compete with the arachidonic acid cascade, and are (eicosapentaenoic acid) and DHA (docosahexaenoic 2. EPA provides the most important competing a. Comes from oily fish, hemp oil and flax oil c. GLA (gamma-linolenic acid) also provides anti-inflammation d. Low dietary intake of these essential fatty acids is associated with a variety of inflammation-related diseases 1. Our hunter-gatherer ancestors had much higher 2. Evidence that increase of dietary Omega 3 reduces inflammatory diseases as well as psychiatric 2. In large doses can reverse atherosclerosis a. It lowers the levels of LDL, VLDL, total cholesterol, a. Doses above 1.5 can induce facial flushing 1. One gains tolerance within a short time b. These doses are not recommended during pregnancy 4. “No-flush” niacin is actual y inositol hexanicotinate 5. Nicotinic acid is available as Rx, and from Xymogen and Vital 1. Produced in skin with exposure to UV sunlight 2. Used by macrophages to fight microbes and pre-cancer cel s 3. Synthesized in kidney to regulate calcium and phosphate 4. Low levels associated with blood clots 5. Research shows conflicting conclusions on heart disease a. Human body can make up to 20,000 mg a day 3. Helps generate ATP energy in mitochondria a. Also helps neutralize free radical damage 4. Beneficial in cardiovascular heart disease a. Helpful to supplement patients on statins 6. Supplement is manufactured by fermenting beets and sugar cane a. High levels damage coronary arteries and form clots 3. Stroke has lowered 15% since folate fortification required 1. An enzyme extracted and purified from Natto, a food made from a. Uses the bacterium Bacillus natto to produce Nattokinase b. Only Natto contains Nattokinase enzyme 2. Japanese believes it has clot-busting effects similar to aspirin 2. Prevents oxidation of LDL and Lp(a) by 75% a. An important catalyst for healthy dilation of blood vessels, 2. L-Arginine improves nitric oxide production by vascular endothelial b. Inhibits platelet and monocyte adhesiveness 3. Not recommended fol owing a heart attack a. Enhances metabolism of fats and triglycerides when a. Statins (HMG-CoA reductase inhibitors) 1. Reduces cholesterol by inhibiting the enzyme HMG-CoA reductase a. This plays a central role in the production of cholesterol in b. Lovastatin (Mevacor, Altocor, Altoprev) c. If you lower cholesterol too much, cell membranes are 4. A smal group of scientists argue that elevated cholesterol has not a. Question large numbers of patients being put on statins a. Inhibits the production of thromboxane, which binds b. Creates a patch which covers damage to blood vessel wal s


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