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Example: Advanced Clinical Foundations Modules Inflammation is the basis for cardiovascular disease Cardiovascular Overview: The Deadliest Disease Cardiovascular Disease kills more New Zealanders a year than any other cause 41% of all New Zealanders are killed my cardiovascular disease 28% deaths result from all Cancers Cardiovascular Risk Factors (Based on the Framingham Study) Symptomatic disease previous angina, MI, PTCA, CHF, TIA, CVA, PVD impaired renal function or left ventricular hypertrophy Major Risk Factors age male gender cigarette smoking hypertension increased total cholesterol diabetes Other Risk Factors family history of early CHD (early MI) physical inactivity obesity Atherogenesis – Atherosclerosis from beginning Old Thought – Atherosclerosis was due to a mechanical cause, similar to a corroded pipe. Increased lipids ► cause deposits ► result in clogged arteries New Knowledge - It appears that an inflammatory reaction is the basis of the pathology. Cholesterol plays a role, but it is not always elevated in people with cardiovascular disease Atherosclerosis Treatment Cardiac and Vascular Protective Antiplatelet Therapy Statin (regardless of LDL) ACE Inhibitor (regardless of BP status) Beta Blocker (regardless of BP status) Smoking Cessation Exercise Hemodynamic/Metabolic Protection Blood Pressure Control (BP <140/90; DM BP <130/80) Lipid Control Diabetes Control (HgA1c <7%) Genesis of atherosclerosis A blood-borne irritant, such as homocysteine (derived from the protein in our diets), produces toxins on contact with plasma, and those toxins injure the arterial wall. Fatty substances (LDL - low density lipoprotein) cholesterol infiltrates the arterial intima (inner layer) at the points of intimal injury. Advanced Cardiovascular Clinical Reasoning © Equinox Health Ltd. 2010 1 Example: Advanced Clinical Foundations Modules Role of LDL in Atherogenesis LDL readily enters the artery wall with the help of apolipid B (APOB). High levels of APOB are associated with increased plaque formation. Once the LDL enters the artery wall (the intima) it is oxidized and modified. The modified LDL is proinflammatory. Endothelial Cell Role in Atherogenesis Endothelial cells have antithrombogenic properties and produce vasodilators and vasoconstrictors. Disruption of the endothelium may cause plaque instability and fissuring which lead to MI. Endothelial cells release potent vasodilator known as Endothelial-derived Relaxing Factor (EDRF) was found to be nitric oxide (it is still under debate if there are others types of EDRF), which is protective. Atherosclerosis replaces EDRF-producing endothelial cells Endothelins are major vasoconstrictors produced by endothelial cells and are elevated in atherosclerosis, MI, CHF and hypertension (HTN). There are many causes of endothelium and disruption and inflammation. These include hyperlipidemia, hyperglycaemia, abdominal obesity, and possibly bacterial or viral infection. Genesis of atherosclerosis Monocytes (circulating immune cells) rush to the site of injury, burrow into the blood vessel walls, mature into macrophages ("big eaters"), gorge themselves on oxidized fatty substances (lipid peroxidation) and die, causing inflammation Fatty streaks form inside the large- and medium-size arteries, often at stress points and where branching occurs or where the wall is already damaged. These deposits thicken, forming an atheroma (a hard mass of fatty tissue) that gradually erodes the wall, narrows the arterial pathway and impairs the flow of blood. An atheroma builds up to form a harder mass called plaque. The fibrous cap of the plaque contains smooth muscle cells, collagen, and intra and extracellular lipids. The lipid-filled "foam cells" are believed to be either monocytes or modified smooth muscle cells. The necrotic core contains cell debris, cholesterol esters and crystals, and calcium. Coronary Heart Disease (CHD) Atherosclerosis can cause disease of the coronary vessels which can cause angina, myocardial infarction, dysrhythmias, conduction defects, heart failure and sudden death. However, CHD is often a silent disorder because at least 75% of the vessel lumen must be occluded before there is a significant reduction in blood flow. Acute MI is usually precipitated by disruption of an atherosclerotic plaque. Emerging Risk Coronary Heart Disease Risk Factors Apolipoprotein B (ApoB): This is the major protein associated with LDL-C, very low density lipoprotein(VLDL) and intermediate density lipoprotein (IDL). ApoB is a good predictor of risk and may be more widely used as assays become standardised. LDL-C Particle Size: Small LDL-C particle size promotes atherogenicity. Triglyceride levels over 1.7 mmol/L are a useful surrogate measure for small dense LDL-C. Advanced Cardiovascular Clinical Reasoning © Equinox Health Ltd. 2010 2 Example: Advanced Clinical Foundations Modules Urinary Albumin/Microalbuminuria: Marker for generalised endothelial damage and urinary albumin excretion correlates with atherosclerotic arterial disease. Microalbuminuria may indicate vascular damage, especially in people with elevated blood pressure, Further data on the effectiveness of interventions in reducing albumin excretion and its impact on cardiovascular outcomes is required before routine measurement can be recommended. However, there is increased risk of cardiovascular events in people with diabetes and microalbuminuria often precedes renal nephropathy. C-Reactive Protein: Discovered in 1929 and is a non-specific marker of inflammation. It is produced in liver in response to Interluken-6 (IL-6) which is released in areas of inflammation. Endolethial cell lining of vessels also produce inflammatory mediators. Levels: 0.1 to 1.0, <1.0 good, >3.0 may indicate inflammation But, it isn’t very specific – rheumatoid arthritis may not have elevated CRP levels. Elevated levels of C-Reactive protein are also correlated with: Total Mortality Heart Attack Stroke Sudden Cardiac Death Type II Diabetes Metabolic Syndrome Body Mass Index Depression Heavy Drinking No Alcohol Drinking Post-Menopause hormone replacement Cigarette Smoking Age Weight Anger/Hostility Decreased C-Reactive protein levels are associated with: Weight Loss Drinking in Moderation Statins (with or without elevated cholesterol levels) Exercise There is no correlation with C-Reactive protein levels with these factors: Cancer Cholesterol Many MI occur in people without significant risk factors Understanding C-reactive protein helps guide us to the most important health promotion activities for patients. Eat a diet high in polyunsaturated oils (including fish) Maintain a desirable weight Increase physical activity Decrease stress Free Radicals: Oxidative stress is caused by the build-up of free radicals which are a by product of oxygen metabolism by mitochondria. These free radicals are highly reactive oxygen molecules that damage DNA, proteins, and lipids and promote the turning on of genes that cause cell death. Anti-Inflammation Diet: Important to reduce high glycaemic foods because the they raise CRP, as well as omega-6 oils found in corn and soybean oil. It is well known that it is also important to reduce Advanced Cardiovascular Clinical Reasoning © Equinox Health Ltd. 2010 3 Example: Advanced Clinical Foundations Modules trans-fatty acids and fried foods. Animal proteins contain arachidonic acid, which the body uses to produce pro-inflammatory prostaglandins. Anti-Inflammation Diets such as the Mediterranean diet and the DASH diet promote eating whole, unprocessed plant foods with plenty of colour and variety. Antioxidants like beta-carotene (found in squash, carrots, and spinach), lycopene (found in tomatoes), and vitamin C (found in broccoli and citrus) are thought to "sweep up" the free radicals. Other foods such as ginger, garlic, onion, turmeric, and rosemary have strong anti-inflammatory properties. Blueberries, cherries, and blackberries are rich in anti-inflammatory flavonoid compounds and omega-3 fatty acids found in wild salmon, herring, flaxseed, and walnuts also have anti-inflammatory qualities. Exercise: an active body revs up production of antioxidants, which "vacuum" the free radicals. However, overly strenuous or weekend-warrior-type exercise can actually boost inflammation levels. In one study, six months of exercising for an average of 2.5 hours a week, people with a known risk of heart disease had a 35% reduction in CRP levels Visceral Fat: It used to be thought of as an inert storage area, but now we known as a dynamic, chemical producing area. Risk for the Insulin Resistance Syndrome BMI ≥25 kg/m2 or waist circumference M >100 cm, F >90 cm Sedentary lifestyle Age >40 years Non-Caucasian ethnicity Family history of Type II Diabetes Hypertension Cardiovascular Disease History of glucose intolerance or gestational diabetes Personal diagnosis of Hypertension High Triglycerides low HDL Cardiovascular Disease Acanthosis nigricans Polycystic ovarian syndrome (PCOS)) Advanced Cardiovascular Clinical Reasoning © Equinox Health Ltd. 2010 4