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Concerns with Lowering Cholesterol • • •
• Increase risk in cancer Risk of myositis or hepatitis Risk of excessively low cholesterol Economic impact Mean LDL Levels:
Calculating LDL • VLDL = Triglyceride (TG) / 5 • LDL = TC – (VLDL + HDL) • If TG > 400mg/dL, calculation is not accurate • Fractionation able to calculate LDL when TG > 400mg/dL Non-Pharmacologic Treatment of Hypercholesterolemia • •
• ↓ cholesterol intake ↓ saturated fats Avoid hydrogenated unsaturated fats ↑ Fiber (24grams/day) Physical Activity o Walking, stairs o 30 min (mod intensity) 5x/wk (3.5-7kcal/min), OR •
Saturated Fats: Greatest in foods from animals o Fatty cuts of meats, poultry skin, whole-milk dairy, vegetable oils (coconut, palm) Unsaturated fats are preferable over saturated o Olive or canola oil, safflower, corn, sunflower or soybean oils o Reduce trans fatty acids (hydrogenated, partially hydrogenated oils; margarine, shortening)
o ≥20 min of vigorous activity ≥3x/wk (>7kcal/min)
• Smoking Cessation Maintain desirable weight (BMI < 25kg/m2)
Screening Guidelines • • • •
Base treatment on 2 or more measurements Primary screening TC & HDL
o If TC < 160mg/dL recheck in 5 years
Begin screening at 20 yrs of age (controversial) Screening is not recommended > 75 yrs of age
Complete fasting lipid panel for people with known CVD, diabetes, metabolic syndrome, or at high risk Optimal LDL is < 100mg/dL o Some experts recommend no greater than 40mg/dL
o Unless Hx of cardiovascular disease (CVD) or diabetes
10-20%. women =>35) Triglycerides 150mg/dL Blood pressure 130/85 Fasting glucose 110-125mg/dL • • • Total Cholesterol Distribution: CHD vs. Female >55 Family Hx of premature CHD o 1st male <55. Non-CHD Population A TC <200 mg/dL doesn’t mean your risk for CHD is any lower 1/3 of pts still develop CHD .Coronary Heart Disease (CHD) What is it? • • • • Myocardial infarction Unstable or stable angina Coronary artery procedures Angioplasty or Bypass surgery Evidence of myocardial ischemia CHD Risk Equivalents: • • • • • • • Type 2 diabetes mellitus Peripheral arterial disease Abdominal aortic aneurysm Carotid artery disease Transient ischemic attack (TIA) 10-yr risk for CHD ≥20% Metabolic syndrome (not official) • Estimate Risk of CHD • Calculate CHD risk factors Framingham 10-year Risk Calculate 10-yr risk (<10%. or female <65 Current tobacco usage HTN BP >/= 140/90mmHg or receiving tx HDL < 40mg/dL (optional < 70mg/dL) • • HDL (<50 mg/dL) Systolic Blood Pressure CHD Risk Factors Negative: • HDL > 60mg/dL • • • • High & Moderate Risk Factors Metabolic Syndrome: • • • • • • Obesity Physical inactivity Elevated Triglycerides Low HDL Metabolic syndrome Chronic renal failure (not official) • • • Equivalent risk of CVD as patients with type 2 diabetes Presence of 3 or more of the following Waist circumference (men => 40. >20%) based on total points for: • Age • Total Cholesterol • Smoker / Non smoker o 0-1 risk factors 10-yr risk assessment is not necessary o 2 or more risk factors calculate 10-yr risk assessment • Presence of CHD or CHD equivalent o LDL goal is < 100mg/dL o Positive: • Male >45.
Lipid Lowering Therapy GOALS Goals of therapy • • • ↓ risk of CVD ↓ CHOL levels ↓ risk of pancreatitis if TG>800mg/d Individualize tx Minimize adverse effects • • • Utilize cost-effective regimen NCEP III LDL Cholesterol Goals ***KNOW*** CHOLESTEROL GOALS • If “Moderate Risk” (2+ risk factors) calculate Framingham 10-yr risk determine LDL goal: New 2004 NCEP Recommendations LDL goals for HIGH RISK pts: • • Achieve LDL lowering of at least 30-40% If LDL <100mg/dL & presence of elevated TG consider Gemfibrozil VERY High Risk Patients • LDL Goal < 70mg/dL • • • • • • Presence of established CV DISEASE ***PLUS*** Acute coronary syndrome (strongest and only evidence) Multiple major risk factors Severe and poorly controlled risk factors (includes current cigarette smokers) Multiple risk factors of T2DM or metabolic syndrome. esp: TG ≥ 200mg/dL and non-HDL-C ≥ 130mg/dL and low HCL-C < Argue that the LDL goal of 70mg/dL is only in patients with: o Known CVD or Acute coronary syndrome (ACS) ***AND*** o Baseline LDL is between 70100mg/dL (evidence supports 87128mg/dL) .
fibrates. ketoconazole. Cerivastatin > Pravastatin. erythromycin. indinavir. verapamil. nelfinavir. • Carbamazepine • 2C9 Fluvastatin itraconazole. cyclosporine. Lovastatin. • 3A4 & glucoronidated o Atorvastatin. • Warfarin Fluvastatin. grape fruit juice. & glucuronidated • Phenytoin. Altoprev) Simvastatin (Zocor) Atorvastatin (Lipitor) Competitive inhibitor of HMG-CoA enzyme (the rate-limiting step in CHOL synthesis) ↓ hepatic CHOL synthesis ↓ intracellular CHOL stimulates upregulation of LDL receptor & ↑ uptake of non-HDL particles from circulation ↓ TC • ↓ LDL ↓ TG (Atorvastatin & Rosuvastatin) • • • Pravastatin (Pravachol) Fluvastatin (Lescol) Rosuvastatin (Crestor) • Therapeutic Effect • • • Comparison Cost and Effectiveness of Statins Prodrugs: • Lovastatin. • Phenobarbital nefazodone. Cerivastatin. 2C19. Lovastatin > Fluvastatin • • Atorvastatin & Rosuvastatin able to ↓ TG up to 40% Choose 1 high potency and 1 low/moderate low cost potency statin (for formularies) Atorvastatin & Pravastatin Simvastatin Rosuvastatin 10-80 mg/day 5-80 mg/day 5-40 mg/day Take at bedtime • Rosuvastatin has more ↓ LDL but costs more • ↑ the dose of a statin does NOT ↓ LDL much more Drug & ↑ levels of: Inihibit metabolism of statins: CYP450: Food Intx • Digoxin • Amiodarone. CNS disturbances elevations of serum dementia?) • Cancer (↓ LDL ↑ cancer) transaminases • Association of statins • GI upset • Pregnancy (cat X) • . diltiazem. increase HDL 3-10% (Rosuvastatin > Atorvastatin > Simvastatin > Lovastatin > Pravastatin) Relative Potency: • Rosuvastatin > Atorvastatin > Simvastatin . Fluvastatin. Simvastatin Hydrophilic: • Pravastatin.40mg/dL Hypercholesterolemia Statins Generic (Trade) Names MOA • • • • Lovastatin (Mevacor. Fluva: BID if >40mg/d) ↑ HDL o Via inhibition of CETP o Inconsistent results. ↓ levels of statins: Simvastatin fluconazole. • 2C9. saquinavir. (3A4 but to a lesser extent) sertraline. zafirlukast • Rifabutin Rosuvastatin o 15-30% of Asians are PMs • Rifampin ↑ risk of myositis: of CYP2C19 start @ ↑ levels of statins: • With above DIs lower doses • Grapefruit juice • Combination w/ Niacin & o 3-6% of Caucasians (>1 quart/day) Gemfibrozil • Pravastatin is glucoronidated ADRs & C/I • Hepatitis CNS Effects: Contraindications: • Insomnia • Acute liver disease • Myositis • Peripheral neuropathy • Rhabdomyolysis • Unexplained persistent • Cognition (↑/↓ risk of • Insomnia. Rosuvastatin Dosing Lovastatin & Fluvastatin 20-80 mg/day (Lova: BID if >20 mg/d. ritonavir.
muscle aches/cramps. anorexia. dark urine. jaundice • Avoid excessive ETOH Asymptomatic ↑ in LFT in the absence of elevated bilirubin: • May be due to reduced cholesterol in hepatocytes • Preexisting liver abnormalities: o Non ETOH fatty liver infiltrate o Diabetes. Hyperlipidemia. weight loss.000 IU/L Risks of Myositis: • ↑ statin levels (drug intx) • Renal insufficiency • Hepatic insufficiency • Combo w/ Fibrates or Niacin • Age • ETOH abuse • Hypothyroidism • Diabetes • Muscle disorders Myositis Statin Dose Limits: • Combo w/ Cyclosporine. 12 wks and periodically • Caution with active liver disease or heavy ETOH Consult provider/pharmacist if develop hepatitis: • Prolonged fatigue or “flu like” symptoms. mevolonate) necessary for mitochondria fxn o Impairs protein synthesis o Coenzyme Q supplemenation (benefit not established) • Combo w/ Amiodarone & Verapamil o o o Fluvastatin 40mg Qd Lovastatin 40mg Qd Simvastatin 20mg Qd • Renal Insufficiency o o o o o Fluvastatin 40mg Qd Lovastatin 20mg Qday Pravastatin 10mg Qd Simvastatin 5mg Qd Rosuvastatin 10mg Qday Proteinuria monitoring • • Statins may cause proteinuria o Inhibit HMG CoA reductase in the proximal tubule Inconsistent data for Rosuvastatin and Cerivastatin Rosuvastatin • o If using >40 mg daily monitor for proteinuria . severe stomach pain • Serious can cause death (esp w/ Cerivastatin) • Statins block HMG-CoA reductase o Inhibits cholesterol intermediates (ubiquinone CoenzymeQ. Fibrates & Niacin o o o o o Fluvastatin 40mg Qd Lovastatin 20mg Qd Pravastatin 20mg Qd Rosuvastatin 5-10mg Qd Simvastatin 5-10mg Qd Myositis = Inflammation of the muscle • Fever. reduced libido and cognitive impairment may be idiosyncratic • Breast-feeding Statin Monitoring Hepatotoxicity monitoring Monitor liver function tests (LFTs): • At baseline.• • • Thrombocytopenia Gynecomastia Impotency. Obesity o ETOH o Viral Hepatitis • Little evidence that isolated asymptomatic ↑ in LFTs leads to hepatotoxicity Monitoring LFT’s: If LFT ↑ ≤ 3x normal & asymptomatic: • Continue and f/u monitoring in 1 month If LFT ↑ 3-5x normal: • Continue and f/u monitoring in 1-2 weeks • Reduce dose and recheck in 2 weeks If LFT ↑ > 5x normal: • D/c and recheck LFT • Reduce dose and recheck in 1-2 weeks *If symptomatic stop dose & recheck Myositis monitoring Monitor Creatine Phosphokinase (CPK): • Myositis = CPK 5-10x normal • Rhabdomyolysis = CPK >20. fever. 6 wks.
phenytoin. tetracycline. penicillin. Questran) Colestipol (Colestid) • Colesevelam (WelChol) o Improved SE profile o ↓ LDL by approximately 15% o Requires 4-6 tablets daily (large pill) MOA • Binds bile acid which stimulates synthesis of bile acid from cholesterol Cholestyramine: • Inhibits enterohepatic reuptake of intestinal bile salts and thereby increases the fecal loss of bile saltbound LDL-C Binds with bile acids forms an insoluble complex that is eliminated in feces • • ↓ LDL (by 15-30% not as potent as statins at lowering LDL) No effect on HDL May ↑ TG when used alone o Avoid if TG’s > 400 mg/dL o Dysbetalipoproteinemia Use w/ a STATIN Colestipol: • Therapeutic Effect • Dosing • • • • • • Mix powder with water or other fluid prior to administration. sulphonylureas. D. thiazides. not to be taken in dry form Cholestyramine: 4 g 1-2x/day (to a max of 16-24 g/day) & a max of 6x/day Colestipol: 5-30 g/day given once or in divided doses 2-4x/day o Initial dose: 5 g 1-2x/day. furosemide. iron.to 2-month intervals Binding & ↓ absorption (of other meds. exacerbation of hemorrhoids and diverticulitis Malabsorption of fat soluble vitamins (A. nausea. mycophenolate.o Asian or elderly patients initiate at 5mg/day 15-30% Asians are poor metabolizers of CYP2C19 3-6% Caucasians Pravastatin and Simvastatin are associated with ↓ proteinuria Hypercholesterolemia • Bile Acid Resins Generic (Trade) Names • • Cholestyramine (Prevalite. levothyroxine. K) and folate RARE elevations of LFTs No big systemis SEs but doesn’t really ↓ LDL much Drug Intx ADRs & C/I • • • • • • • • Complete biliary obstruction Bowel obstruction • . fat soluble vitamins Dose 1 hour before or 4 hours after administration of other medications Contraindications: Sandy gritty texture Constipation Bloating. digoxin. Ca. & folic acid) ASA. flatulence. warfarin. imipramine. increase by 5g at 1. E.
then increase • Fibrates activate pyruvate dehydrongenase kinase (PDK4) to therapeutic dose • ↓ TG and FAs Myositis Increase w/ renal insufficiency or statins • Results in the ↑ utilization of Risk of gallstones • amino acids from protein and Decrease libido leads to protein breakdown Breast tenderness Hepatitis (rare) Do NOT use if CrCl ≤30 ml/min • . TriCor. Gemfibrozil may ↑ LDL 5-10% ↑ HDL (10-15%) Shifts the density of LDL particles towards more bouyant particles Gemfibrozil vs Fenofibrate: Fibrate + Statin: • Gemfibrozil: • Fibrate ↓ TG o 1st line • Statin ↓ LDL o Cheaper & easier to tolerate by GI • Low incidence of myositis w/ statin + fibrate o May ↑ LDL (minor = 5-10%) • Use combination with caution (if normal • Fenofibrate: renal fxn ok. just warn pts of SEs) o 2nd line (if GI upset from Gem) • Monitor for signs and Sxs of myositis o ↓ TG by 40-60%. abdominal discomfort. Antara. 30 min before breakfast & dinner Fenofibrate: Initial: Antara: 43-130 mg/day Lipofen: 50-150 mg/day (max 150mg/day) Lofibra: 67 mg/day w/ meals (max 200mg/d) TriCor: 48 mg/day.Hypercholesterolemia Fibrates Generic (Trade) Names MOA Therapeutic Effects • • • • • • • Gemfibrozil (Lopid) Fenofibrate (Lofibra. diarrhea. up to 145 mg/day Triglide: 50-160 mg/day Maintenance: Antara: 130 mg/day Lipofen: 150 mg/day Lofibra: 200 mg/day w/ meals TriCor: 145 mg/day Triglide: 160 mg/day Drug Intx All Fibrates: • • • ADRs & C/I • • ↑ levels of statins & warfarin Statin + Fibrates ↑ risk of myositis ↓ dose or use with caution in the presence of renal insufficiency Gemfibrozil: • Blocks glucoronidation pathway • CYP 2C8 inhibitor • • • • Fenofibrate: • CYP 2C9 (mild-moderate inhibitor) • CYP 2C19. 2CA6 (weak) Use with caution with active hepatic disease Myositis: Nausea. Triglide) ↑ activity of lipoprotein lipase (LPL) to ↑ the clearance of triglycerides Use ↓ TG (40-60%) ↓ LDL (Fenofibrate by 10-15%). flatulence o Initiate at low dose for 3-7 days. LDL 25% • Avoid w/ Cerivastatin higher incidence of o May possess added benefit of greater rhabdomyoysis LDL reduction vs Gemfibrozil Dosing Gemfibrozil: 1200 mg/day in 2 divided doses. Lipofen.
Niaspan. LDL & apoB Inhibits adipose tissue lipolysis Increases lipoprotein lipase activity • • Niacin (vitamin B3) (Niacin-Time. Niacor.Contraindications: Monitoring • • • • • Significant hepatic or renal dysfxn Primary biliary cirrhosis Pre-existing gallbladder disease Serum cholesterol LFTs Hypercholesterolemia Niacin/Nicotinic Acid Generic (Trade) Names MOA • • • Decreases hepatic production of VLDL. diarrhea • Gout (hyperuricemia) Hyperglycemia • Uncontrolled diabetes Hyperuricemia • Peptic ulcer disease Hepatitis Blood glucose Other LFTs (pretreatment and every 6-12 weeks for first year then periodically) • Lipid profile Niaspan Laropiprant Glycemic control • • Extended release form • Prostaglandin D2 receptor antagonist • If diabetes is controlled & pt has failed statins (& needs . itching and warmth associated with niacin Administer prior or 30min before niacin dose o Dose ASA daily 81-325mg o May require ASA dosing before each dose of niacin 325mg is more effective than 81mg 1) Fibrates (better ↓ TG) 2) Niacin (better ↑ HDL) Drug Intx ADRs • • • • • • • • Monitoring • No significant difference btwn 325mg & 625mg Bile acid sequestrants may ↓the absorption of niacin. separate administration by 4-6 hrs Flushing. itching (due to release of Not advised in pts w/: prostaglandins) • Hepatic insufficiency Nausea. Slo-Niacin [OTC]) Niaspan + Lovastatin (Advicor) Therapeutic Effect • • • • • • ↓ TG by 30-50% ↓ LDL by 15-40% ↑ HDL by 10-30% Initiate and increase dose gradually to minimize flushing and GI SEs Limit dose to 2-3 gms daily For ↓ TG: Aspirin: Use/Dosing • • Reduces flushing.
Backache. Diarrhea • Hepatitis.• ↓ risk of flushing but still significant o 77% Niaspan + Placebo o 53-61% Niaspan + ASA • • • Glucoronidated Combined with Niaspan Moderate flushing: o 49% Niaspan o 27% Niaspan + Laropiprant • niacin) give it a shot Compared to placebo: o Glucose only ↑10 mg/dL o HbA1c only ↑0. ↑ LFTs • Arthralgia. Myalgia • Anaphylaxis. Angioedema • Headache • Drug-induced myopathy (Very rarely) • Sinusitis • Rhabdomyolysis (Very rarely) • Increase dose every 4-8 weeks until goal is achieved • May be more aggressive in patients experiencing symptoms or hx of CAD • May be less aggressive with primary prevention • Obtain LFT’s at baseline. then periodically • • . after initiation or dose increase at 6 weeks and 12 weeks.4 Niaspan + Lovastatin (Advicor) Theoretical Benefits: (NOT proven) • ↑ HDL • ↓ TG (49%) • ↓ dense LDL particles Hypercholesterolemia New Targets for Cholesterol • • Cholesterol esterification inhibitors (ACAT inhibitors) o Avasimibe (CI-1011) Cholesterol ester transfer protein (CETP) inhibitors o TORCETRAPIB o Anacetrapib (MK-0859) • • • Microsomal transfer protein (MTP) inhibitors Intestinal bile acid transporter (IBAT) inhibitors Cholesterol absorption inhibitors (CAIs) o Ezetimibe Ezetimibe (Zetia) Generic (Trade) Names MOA • • • Ezetimibe (Zetia) Ezetimibe + Simvastatin (Vytorin) [10 mg/10-80 mg once daily] Inhibits the absorption of cholesterol by the small intestine o ↓ delivery of intestinal cholesterol to the liver o ↓ hepatic cholesterol stores & ↑ clearance of cholesterol from the blood • • • Localizes on the brush border membrane of intestinal epithelial cells. primarily as glucoronidated derivative Systemically absorbed Enterohepatic circulation o Reduces systemic exposure o Long active half-life Monotherapy may not achieve goals Combination may allow reduced dose of niacin or resin and statin Consider increasing the dose or adding additional agent Consider cost of agents Dosing Strategies Drug Intx ADRs Monitoring 10 mg/day • Non-linear dose response (↑ dose no ↑ LDL • reduction) • Initiate at high dose or lower dose? • o If aggressive high dose OK • o Primary prevention use low dose • Risk of myositis with statins may limit dose • Cyclosporine increases levels of Ezetimibe 12-fold • Gemfibrozil & Fenofibrate increase levels of Ezetimibe 2-fold Common: Serious: • Abdominal pain.
TG (Diabetic) Low HDL Statin. Niacin. Hepatic transaminase levels (particularly ALT) should be monitored periodically Combination Therapy Lipid Abnormality ↑ LDL Combination Options Monotherapy Statin. Statin ↑ LDL. Fibrate Pros • • ↓ LDL-C. Lovasa) MOA Active ingredients: • Eicosapentaenoic Acid (EPA) • Docosahexaenoic Acid (DHA) Use • Adjunct to diet in adults w/ TG levels 500 mg/dL or higher • Take w/ food Therapeutic Fish oil capsules Omacor Effects & • ↓ TG (30%) • ↓ TG (45%) Dosing • 1-6 gms daily • ↑ LDL (34%) • 1 gm (1 cap) qid • S/p MI ~↓ CVD events & mortality ADRs & Caution: • Burping Drug Intx • Fish allergy: Use with caution • Indigestion • Prolongation of bleeding time: Use caution w/ anti• Taste sense altered coagulants & NSAIDs • Inhibits the synthesis of TGs • • • Angina Monitoring Triglycerides and other lipids (LDL-C) should be monitored at baseline and periodically. Niacin w/ caution Niacin. ↑ HDL-C May ↓Lp(a) (niacin) Cons • • Increased adverse effects (rhabdomyolysis) Drug interactions . TG (Non-Diabetic) Niacin.Vytorin ENHANCE trial: • Vytorin vs. Resin Combination Statin + Resin Statin + Niacin Statin + Ezetimibe Statin + Niacin Statin + Fibrate Niacin + Fibrate Fibrate + Ezetimibe Statin + Fibrate Statin + Niacin Fibrate + Resin Statin + Niacin Niacin + Fibrate (1st Choice) ↑ LDL. Simvastatin • Endpoint = mean change in carotid intima media thickness • Results: o ↓ LDL (in 2 yrs): Vytorin (58%) & Simvastatin (42%) o ↑ HDL: in Vytorin group o No significant difference in thickness • Surrogate endpoint used so not a good study b/c can’t really tell if Vytorin is beneficial Hypercholesterolemia Omega-3 Fatty Acids (Omacor. ↓ TG.
monocytes and leukocytes • Barrier against LDL cholesterol by producing lipoprotein lipase .5mm Endothelium Endothelial cells: 1) Regulate vascular tone and structure 2) Regulate inflammation 3) Regulate growth factors 4) Maintain non-thrombogenic environment 1) Regulates vascular tone and structure: • Constricting substances: o endothelin-1 o angiotensin II o thromboxane A2 Relaxation substances: o Prostacyclin o Endothelium-derived relaxation factors (EDRF or nitric oxide) • 4) Maintains non-thrombogenic environment by regulating hemostasis and fibrinolysis: • Alignment of endothelial cells to produce a flat surface • Retards adhesion of platelets.• • • ↑ LDL particle size ↓ Fibrinogen (fibrate) Angiographic data • • • Increase cost Lack of outcome studies Adherence Summary ↓ LDL ↓ TG ↑ HDL • • • • • Statin > Niacin > Bile acid sequestrants > Ezetimibe Gemfibrozil > Niacin > Omega FA > > Statin (Rosuvastatin & possibly Atrovastatin) ↓ TG ↓ pancreatitis Niacin > Gemfibrozil > Statin Low HDL ↑ risk of CVD Contribution of Cholesterol to Atherosclerosis Contribution of Cholesterol to Atherosclerosis • • • • • • • • Endothelium Accumulation of low-density lipoproteins (LDL) Oxidation of LDL Development of “foam cells” Development of fatty plaques Fissure and rupture of plaques Thrombosis cascade and infarction Small diameter o Small changes in diameters results in significant changes in blood flow o Minor improvement in regression of stenosis will result in significant improvement in Diameters of Coronary Arteries • • • Left main coronary artery = 5mm Left anterior descending = 3.3mm Left circumflex = 3.
estrogen. vasopressin) • Bradykinin. histamine • Platelet derived factors (ADP. hypertriglyceridemia. C pneumoniae or herpes infection and homocysteine • Abnormal vascular tone • • High LDL ↓ EDRF Reduced LDL restored levels of EDRF • Excess in production of growth promoters • ↑ platelet adhesion • ↑ leukocyte adherence • ↑ in lipid deposition • ↓ in production of growth inhibitors Contribution of Cholesterol to Atherosclerosis Development of Atherosclerosis LDL crosses endothelium and accumulates in the arterial wall LDL undergoes oxidation (LDL modification) Stimulates monocytes Monocytes ingest the modified LDL and form LDL laden macrophages Macrophages become Foam Cells Foam cells attract T-Lymphocytes that create a chronic inflammatory reaction Macrophages & Foam Cells: Differentiation of Monocytes into Macrophages Express Growth Factors and Proteinases 1) 2) 3) 4) 5) 6) Atherosclerotic Plaque and Thrombus The Anatomy of Atherosclerotic Plaque • • • Foam cells die and form necrotic lipid accumulations o Foam cells contain lipid deposits and smooth muscle cells o Develop into a necrotic center The lipid accumulations and thrombus organize into an atherosclerotic plaque Macrophages accumulate near the edges of the plaque Characteristics of Plaques Prone to Rupture Fissure and Rupture of Plaques . diabetes. obesity. stress.2) Regulates inflammation: • Endothelial cells are involved in the recruitment of leukocytes by secreting chemokines and adhesion molecules 3) Regulates growth factors: • Fibroblast growth factor and plateletderived growth factor Stimulants of endothelium dependent relaxation: • Shear stress (exercise) • Hormones (acetylcholine. insulin resistance. free radicals caused by cigarette smoking. serotonin) • Thrombin Endothelium-dependent relaxation factor: Endothelial Dysfunction LDL cholesterol. insulin. HTN.
and HDL o Transported to tissue and stored for energy o Affected by diet. LDL. LDL. TGs • Chylomicrons o Triglycerides 85-88% o Phospholipids 8% o Cholesterol <1% o Apolipoproteins Regression of lesions Reduction in foam cell accumulation Restoration of endothelial-derived relaxing factor (EDRF) Decrease in platelet thrombogenicity Benefits of Lowering Cholesterol • • • • • Transport dietary TGs and cholesterol • 70% produced hepatically • 30% absorbed from consumption • Required for cell membranes and hormones • Supply energy for cells to function • Transported through the blood by lipoproteins Lipoprotein Metabolism Lipoproteins • VLDL: Transports total cholesterol and Triglycerides (TG) to the liver • TG are removed by lipoprotein lipase to form Intermediate density lipoproteins (IDL) LDL: Apolipoprotein B. 48% cholesterol ester HDL: Produced in the liver and intestine o Removes CHOL from the blood & returns to the liver o Liver excretes cholesterol in the form of bile acids • • • TG: Composed of fatty acids. 15% TG. glycerol. sugars. HDL. binds to protein to form VLDL. exercise. ETOH Lipoprotein (a): is similar to LDL but contains an additional protein called apolipoprotein a • .• • • • • Plaques are weakest at the edges where macrophages are concentrated Macrophages release proteolytic enzymes & inflammatory cells Local hemorrhage occurs Release of vasocontrictive substances thromboxane and serotonin Thrombus formation Stenosis turbulent flow weakens the walls & ↑ pressure of blood flow weakens the plaque possible rupture • Rupture leads to hemorrhage and thrombus • Activation of platelets leads to the formation of free arachidonic acid Plaque Size • MI & Mortality caused mainly by low-grade stenosis (50-75%) • Angina & silent MI caused mainly by larger plaques (>75%) • Stenosis size doesn’t really matter compared to it’s location & stability Contribution of Cholesterol to Atherosclerosis Cholesterol • VLDL.
↑ TG. T2DM.Lipoproteins Additional Risks for Atherosclerosis • Apolipoprotein AI (Apo A-I) o Found in HDL o Prevents accumulation of cholesterol bound macrophages located in arterial wall as foam cells o ↓ Apo A-I assoc. w/ increased CVD • o Apo A-I Milano (mutation) reduces CVD o Apo A-II promotes visceral fat accumulation • Lp (a) Apolipoprotein B (Apo B) o 90% of LDL is composed of Apo B o ↑ the capacity of LDL deposition to the arterial wall o Theorized to be a sensitive marker for atherosclerosis o ↑ Apo B is associated with ↑ CVD Cholesterol ester transfer protein (CETP) • • • Assists with the movement of cholesterol esters from HDL LDL and VLDL Results in ↓ HDL and ↑ VLDL LDL particles become dense Contribution of Cholesterol to Atherosclerosis Should all efforts be directed towards lowering LDL? • • • • • • Atherosclerosis is an inflammatory disease Inflammation can promote thrombosis 35% of patients with cardiovascular disease have “normal” cholesterol panels Other inflammatory factors need to be considered Are other lipoproteins responsible for atherosclerosis? Should we be searching for other lipoproteins as more sensitive risk factors for cardiovascular disease? LDL Subfractionations • Small Dense LDL higher risk of CHD o o o More susceptible to oxidation Associated w/ CHD. ↓ HDL • Large Buoyant LDL less risk for CHD o Less atherogenic • Niacin & fibrates may be able to shift dense buoyant HDL Subfractions . metabolic syndrome Class B Pattern = marker for heart disease ↑ small dense LDL.
• • HDL subfractions range from 1–6 Subfractions 2 & 3 beneficial Familial Disorders Familial hypercholesterolemia (FH): • Autosomal dominant disorder Associated with premature coronary artery disease Malfunctioning LDL receptors Familial Hypertriglyceridemia: • • • Elevated TG Normal LDL Low HDL • • Familial combined hypercholesterolemia (FCHL): • Associated with premature coronary artery disease • • • Combined elevations of TG. VLDL and LDL Increased LDL Isolated elevation of triglycerides Familial defective apolipoprotein B-100: • Impaired binding of LDL to the LDL receptor .
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