16 Pathophysiology of Dyslipidemia and Atherosclerosis.docx

Pathophysiology of Dyslipidemia and Atherosclerosis Learning Objectives Compare and contrast the content, metabolism, and function of each lipoprotein Given a patient case, identify general cardiovascular risk factors Identify normal or desirable levels for the following laboratory parameters: tota...

Pathophysiology of Dyslipidemia and Atherosclerosis Learning Objectives Compare and contrast the content, metabolism, and function of each lipoprotein Given a patient case, identify general cardiovascular risk factors Identify normal or desirable levels for the following laboratory parameters: total cholesterol, non-HDL-C, LDL-C, HDL-C, and triglycerides Recognize common secondary causes of dyslipidemias Describe the “response to injury” hypothesis regarding the pathogenesis of atherosclerosis Dyslipidemia Epidemiology 50% of Americans have elevated total cholesterol levels Lipid abnormalities are a major risk factor for coronary heart disease (CHD) HIGH LDL-C levels and LOW HDL-C levels are associated with an increased CHD risk CHD and other types of atherosclerotic cardiovascular disease is a leading cause of death in the U.S. The total cost of cardiovascular disease exceeded $500 billion in 2016 General Cardiovascular Risk Factors Non-Modifiable Increasing age Males ≥ 45 years old Females ≥ 55 years old Family history of premature heart disease Gender Socioeconomic status Modifiable Tobacco use Stress Diet and physical activity Obesity High blood pressure Lipid disorders Diabetes Etiology Primary (Familial) Dyslipidemia Genetic disorders Hypercholesterolemia Homozygous (HoFH) Heterozygous (HeFH) Hypertriglyceridemia Combined hyperlipidemia HDL-C metabolism disorder Secondary (Acquired) Dyslipidemia The 4D Classification Diet Drugs Disorder Disease Pathophysiology Lipid Functions Cholesterol Cell membrane formation Bile acid precursor Steroid, hormone, and vitamin D synthesis Three sources of cholesterol: In vivo synthesis Extraction from systemic circulation via lipoproteins Diet → modest impact on blood cholesterol levels Triglycerides (TG) Glycerol + fatty acids Derived from the foods that we eat Stored energy in adipose tissue Phospholipids Cellular function Lipid transport Oxidation of lipoproteins in arterial wall In Vivo Synthesis of Cholesterol: Mevalonate or HMG-CoA Reductase Pathway 80% of the body’s total cholesterol is produced in the liver and intestines Other sites of synthesis include: adrenal glands and reproductive system Mevalonate production is the rate-limiting step → statin site of action Coenzyme Q10 production is also limited by HMG-CoA reductase inhibition Extraction from Systemic Circulation: Lipoprotein Overview Cholesterol storage and metabolism occurs in the liver Lipids are water insoluble → packaged within lipoproteins for transport through the bloodstream Lipoproteins are spheres of lipid and protein synthesized in the liver Outer (water soluble): phospholipids, unesterified cholesterol, apolipoproteins Inside (water insoluble): cholesterol esters, TGs Lipoprotein Structure Identified based on density and apolipoproteins Density depends on protein vs. lipid content Apolipoproteins are embedded throughout the lipoprotein Exposed on outside layer based on lipoprotein type → binding activates enzyme systems Atherogenic lipoproteins contain apolipoprotein B (apo B) Lipoprotein Types Chylomicron Very low-density lipoprotein (VLDL) Intermediate-density lipoprotein (IDL) Low-density lipoprotein (LDL) High-density lipoprotein (HDL) Chylomicron Content Very large, derived from diet → 98-99% is TG Also contains bile acids which are involved in absorption of fat from the small intestine Function Transfers TG and cholesterol from gut to liver Metabolism Catabolized by lipoprotein lipase (LPL) into free fatty acids (FFA) and chylomicron remnants Very Low-Density Lipoprotein (VLDL) and Intermediate-Density Lipoprotein (IDL) Content Very large, mostly TG but carries 15-20% of serum cholesterol Contains apo B which is atherogenic Function Both VLDL and IDL are precursors to LDL Metabolism VLDL is catabolized by LPL to form IDL and then further metabolized to LDL Hepatic lipase (HTGL) also has role in converting VLDL → IDL → LDL by removing TG Low-Density Lipoprotein (LDL): Content and Function Carries 60-70% of serum cholesterol to cells; contains Apo B Greatest contributor to atherosclerosis since it attaches to arterial walls via oxidation LDL size and density affects its atherogenicity Small, dense LDL is more atherogenic than large, buoyant LDL Long half life Reduced affinity for LDL receptors that metabolize LDL Rapidly oxidized Low-Density Lipoprotein (LDL): Metabolism Liver removes 70% of LDL from circulation LDL is degraded after interactions with LDL receptors in liver Increased storage of intracellular cholesterol inhibits HMG-CoA reductase Increased excretion of cholesterol into bile portion of stools Eventually, LDL receptors will degrade and downregulate What is the role of PCSK9 in LDL metabolism? PSCK9 promotes LDL receptor degradation which then decreases LDL intake for metabolism Therefore, by inhibiting PSCK9, you increase LDL metabolism High-Density Lipoprotein (HDL) Synthesized in the liver and intestine Carries 20-30% of serum cholesterol Reverse cholesterol transport which removes excess systemic and peripheral cholesterol Cholesteryl ester transfer protein (CETP) allows for exchange of TG and cholesterol Lecithin-cholesterol acyltransferase (LCAT) allows HDL to collect cholesterol After HDL returns to the liver, the HDL receptors in the liver allow uptake of cholesterol for excretion Origin Intestine Liver Liver (VLDL) Liver (IDL) Intestine, liver Function Transport dietary TG and chol to liver Transport endogenous TG and chol Transport endogenous TG and chol Transport endogenous chol to cells Transport chol from cells to liver Summary: Cholesterol Synthesis and Lipid Metabolism Lipids are essential for cell integrity, steroid and hormone production, and energy storage Cholesterol comes from endogenous and exogenous sources Statins target HMG-CoA reductase during in vivo synthesis Lipoproteins transport circulating lipids to and from the liver LDL is “bad cholesterol” = main contributor to atherosclerosis based on type and excess Other lipoproteins that contain apolipoprotein B (VLDL, IDL) are also atherogenic HDL is “good cholesterol” = reverse cholesterol transport Lipid Abnormalities Classification of Cholesterol Levels A “lipid panel” typically includes total cholesterol, LDL-C, HDL-C, and TG Non-HDL-C measures all atherogenic lipoproteins and is ordered separately Direct LDL-C levels vs. Friedewald equation are more accurate when: Non-fasting TG > 400 mg/dL LDL-C < 70 mg/dL Very High LDL Cholesterol (≥ 190 mg/dL): Often Due to Primary Causes Caused by genetic disorders Familial hypercholesterolemia (FH) Familial defective apolipoprotein B-100 Polygenic hypercholesterolemia FH patients may manifest physical findings including corneal arcus and tendon xanthomas Elevated Total Cholesterol (> 200 mg/dL): Secondary Causes Patient Factors Hypothyroidism Obstructive liver disease Nephrotic syndrome Anorexia nervosa Acute intermittent porphyria Medications Corticosteroids Protease inhibitors Thiazide diuretics Beta-blockers Progestational agents Retinoids (e.g. isotretinoin) Atypical antipsychotics Immunosuppressants (e.g., cyclosporine) Mirtazapine Elevated Triglycerides (≥ 150 mg/dL): Secondary Causes Patient Factors T2DM Obesity Physical inactivity Cigarette smoking Alcohol use High carbohydrate intake Chronic renal failure Pregnancy Medications Corticosteroids Beta-blockers Thiazide diuretics Bile acid sequestrants Atypical antipsychotics Progestational agents Retinoids (i.e. isotretinoin) Protease inhibitors Immunosuppressants (e.g., cyclosporine) Very elevated TG (≥ 500 mg/dL) increases the risk of acute pancreatitis! Low HDL Cholesterol (< 40 mg/dL): Secondary Causes Patient Factors Obesity Physical inactivity Cigarette smoking Elevated triglycerides Type 2 diabetes mellitus High carbohydrate intake Malnutrition Medications Beta-blockers Anabolic steroids Progestin agents Summary: Lipid Abnormalities Lipid disorders are classified by phenotype or laboratory abnormalities Recognize the normal or desirable levels for cholesterols and triglycerides Each specific dyslipidemia is associated with secondary causes including disease states, other patient factors, or medications Very high LDL-C levels > 190 mg/dL is often a primary (genetic) condition Atherosclerosis Overview Plaques in arteries will contain lipids, inflammatory cells, smooth muscle cells, and connective tissue Underlying cause of ASCVD Derived from the Greek words: “athero” = gruel “sclero” = hard The blood vessel’s inner most layer is the site of atherosclerosis The intima contains the endothelium, basement membrane, and elastic tissue Pathogenesis: Response to Injury Hypothesis Injury to Endothelium Increased LDL transport and retention in intima LDL binds to extracellular matrix to increase its “residence time” LDL oxidizes to trigger an inflammatory response Physiologic Responses Plasminogen inhibition → increased coagulation Endothelin expression → vasoconstriction Decreased nitric oxide expression → vasoconstriction Inflammatory Process: Macrophage Accumulation Monocytes are recruited and transformed to macrophages Macrophages accumulate lipids Lipid-filled macrophages are called foam cells Foam cells accumulate to form a fatty streak Fibrous Cap Formation Fatty streak grows after repeated injury and repair, which leads to plaque → symptoms such as chest pain FIRST OCCUR at plaque formation Damaged endothelium disappears, then smooth muscle and extracellular matrix proliferate A fibrous cap forms to protect the core of lipids, macrophages, collagen, and inflammatory cells Plaque Rupture Clot may cause a complete or incomplete arterial occlusion Clots of atherosclerotic origin is NOT the same as venous thromboembolism Consequences include ASCVD: what are some examples? Clinical Atherosclerotic Cardiovascular Disease (ASCVD) Types of ASCVD: Acute coronary syndromes Myocardial infarction Stable or unstable angina Coronary or other arterial revascularization Stroke Transient ischemic attack Peripheral arterial disease Summary: Atherosclerosis Atherosclerosis is defined by plaque in the arterial walls Underlying cause of cardiovascular disease General risk factors for cardiovascular disease are non-modifiable or modifiable The “response to injury hypothesis” has 4 stages Inflammatory process in response to intima injury Symptoms FIRST OCCUR at plaque formation Plaque rupture may result in a complete or incomplete vessel occlusion