Atherosclerosis (3)

Arteriosclerosis due to HTN: Characterized by....

Characterized by intimal thickening: SMC growth, ECM synthesis, thickening of the vascular wall

Lipoprotein metabolic pathways: lipid transport is dependent on.....

Lipid Transportation is dependent on source of Lipid production 1. Exogenous (dietary) a) Transports lipids from intestine to the periphery + liver 2. Endogenous (made by the liver) a) Transports hepatic lipids to the periphery

Additional risk factors of atherosclerosis

Roughly 20% of cardiovascular events occur in the absence of identifiable risk factors, other contributors include: 1. Inflammation 2. Hyperhomocysteinemia 3. Metabolic Syndrome 4. Lipoprotein (a) levels 5. Elevated levels of procoagulants 6. Clonal Hematopoiesis 7. Other: lack of exercise, stressful lifestyle

Transport of intestinally derived dietary lipids

*Lipoprotein Responsible for transport of dietary lipids = CHYLOMICRONS* 1. Vital for efficient transport of dietary lipids from the intestines to tissues that require fatty acids for energy or store/metabolize lipids 2. Dietary lipids are hydrolyzed by lipases in the small intestinal lumen & emulsified by bile acids 3. Dietary cholesterol, fatty acids, and fat-soluble vitamins are absorbed in the small intestine 4. Chylomicrons are formed & TGs are packaged with apo—48, cholesterol esters, phospholipids 5. Chylomicrons from the intestine are secreted into intestinal lymph --> delivered to the thoracic duct --> go into systemic circulation --> get processed by peripheral tissues --> ultimately make it to the liver a) While in the periphery, TG get hydrolyzed by lipoprotein lipase --> release of FFA --> Myocytes & adipocytes take up the FFA b) HDL will transfer apoliporoteins to chylomicrons to increase lipoprotein lipase activation c) During this process, chylomicrons shrink, and the apoliporoteins on the particle surface are transferred back to HDL 6. *Chylomicrons are then merely remnants --> rapidly removed from the circulation by the liver (are often not presents after 12-hr fast)*

Apolipoproteins 1. what are they? 2. required for.... 3. ApoB 4. APoA-1

1. *Apolipoproteins = the proteins associated with lipoproteins* 2. Required for the assembly, structure, function, and metabolism of lipoporoteins a) Activate enzymes important in lipoprotein metabolism b) Act as ligands for cell surface receptors 3. ApoB = large protein, major structural protein of chylomicrons, VLDLs, LDLs, and IDLs a) There are multiple type of ApoB, 2 main ones are --apoB-48 = associated with chylomicrons synthesized in the gut --apoB-100 = associated with VLDLs, IDL,s and LDLd synthesized by the liver 4. HDL's have different apolipoproteins, most importantly apoA-I a) Synthesized in the liver & intestine, found in all HDL particles

Inflammation and atherosclerosis/CVD risk- C reactive protein (CRP)

1. *C-reactive protein has emerged as a new marker of inflammation + is being studied as a marker of underlying asymptomatic atherosclerosis* a) CRP = an acute-phase reactant synthesized by the liver in response to a variety of inflammatory cytokines b) *Some studies show CRP levels independently predict risk* of MI, CVA, PAD, sudden cardiac death in otherwise healthy adults c) Unclear if CRP levels are a marker or a result of plaque inflammation --CRP may be a marker for underlying asymptomatic atherosclerosis d) CRP is reduced by smoking cessation, weight loss, exercise 2. Of note: no evidence that lowering CRP diminished cardiovascular risk

Disorders of elevated cholesterol and TG's: Pathways that regulate lipoprotein metabolism and are dysfunctional in specific dyslipidemias include: 1. Excessive production of _______ by the liver = common cause of dyslipidemia a) increased _______ is associated with..... b) Risk factors associated...... c) increased ______ secretion occurs with: d) Genetic: 2. Impaired ________ of the TGs in TG-rich lipoproteins a) LPL = b) produced by.... c) Impaired by.....

1. *Excessive production of VLDL by the liver = common cause of dyslipidemia* a) increased VLDL is associated with increased TG levels, low HDL b) Risk factors associated with VLDL overproduction: obesity, glucose intolerance, insulin resistance, hypertension (metabolic syndrome) c) increased VLDL secretion occurs with: alcohol use, obesity, high-carbohydrate diet, *metabolic syndrome, Cushing syndrome* d) Genetic: Familial combined hyperlipidemia --> increase TG/LDL, low HDL 2. *Impaired lipolysis of the TGs in TG-rich lipoproteins* a) *LPL = key enzyme responsible for hydrolyzing TGs* b) Produced by adipocytes, skeletal myocytes, and cardiomyocytes c) LPL is impaired by: insulin resistance, obesity, T2DM

Disorders of elevated cholesterol and TG's: Pathways that regulate lipoprotein metabolism and are dysfunctional in specific dyslipidemias include: 1. Impaired _______ uptake of..... a) The LDL receptor on the liver = b) _______-regulation of..... c) LDL activity is influenced by: 2. Genetic: a) High LDL, with _______ TG b) Cause: c) Keys to Dx: d) Often hard to control LDL levels and require......

1. *Impaired hepatic uptake of apoB-containing lipoproteins (VLDL/LDL)* a) The LDL receptor on the liver = vital to uptake LDL + remnant particles by the liver b) Down-regulation of LDL receptor activity (or genetic variation) can reduce activity of the LDL receptor on hepatocytes --> elevation in LDL-C c) LDL activity is influenced by: diet high in saturated & trans fats, hypothyroidism, estrogen deficiency 2. Genetic: Familial hypercholesterolemia (Autosomal dominant hypercholesterolemia) a) High LDL, with normal TG b) Cause: mutations in the LDL-receptor --> reduced clearance of LDL from circulation c) Keys to Dx: family history &/or premature CAD, & absence of secondary etiology d) Often hard to control LDL levels and require multiple medications & strict diet

Reduced HDL cholesterol levels 1. Low levels of HDL-C = 2. HDL metabolism is strongly influenced by: 3. Etiology: a) Key risk factors = b) Possible mechanism: 4. Despite a target as a risk of ASCVD.....

1. *Low levels of HDL-C = an important independent predictor of increased cardiovascular risk* 2. HDL metabolism is strongly influenced by: a) TG metabolism, insulin resistance, inflammation b) It integrates multiple CVD risk factors 3. Etiology: genetic predisposition + environmental factors a) Key risk factors = *obesity + insulin resistance have strong suppressive effects on HDL-C* b) Possible mechanism: accelerated catabolism of HDL 4. *Despite a target as a risk of ASCVD, improving HDL levels has not shown to improve outcomes for ASCVD risk*

Vascular smooth muscle cells 1. Predominant cell of the _______ 2. Properties of SMCs: a) _________ cells in response to _______ 3. In injury: SMCs can migrate from the _______ into the ______ and ______ a) When this occurs: they lose _______ property + gain the capacity to....... b) Migrator + _________ activities of SMC's are regulated by:

1. *Predominant cell of the media* 2. Properties of SMCs: a) Contractile cells (Vasoconstriction or vasodilation) in response to stimuli 3. In injury: SMCs can migrate from the media into the intima and proliferate a) When this occurs: they lose contractile property + gain the capacity to divide, proliferate, and synthesize: --ECM collagen, elastin, GF (PDGF), cytokines b) Migrator + Proliferative activities of SMC's are regulated by: --PDGF, endothelin, thrombin, FGF, inflammatory mediators (IL-1, IFN-y)

Acute plaque change: What extrinsic factors are important?

1. Adrenergic stimulation (i.e. with intense emotions): a) Can increase systemic blood pressure b) Induce local vasoconstriction c) And increase mechanical stress on a given plaque 2. One explanation for the pronounced circadian periodicity in the onset of heart attacks (peak incidence between 6 am and noon) is the adrenergic surge associated with waking & risking (enough to cause BP spikes & heightened platelet reactivity)

Transport of hepatically derived lipids (VLDL/LDL) 1. another key role of lipoproteins 2. purpose:

1. Another key role of lipoproteins = the transport of hepatic lipids from the liver to the periphery 2. Purpose: provides energy source during fasting states a) During fasting state: TG's generate FFA à transported to the liver b) Liver esterifies fatty acids into TG's which are packaged into VLDL particles (with apoB-100) with cholesterol esters, phospholipids c) Secreted into the plasma as VLDL d) TGs get hydrolyzed by LPL (heart, muscle, adipose) e) VLDL become TG depleted and are referred to as IDLs f) The liver removes ~40% to 60% of IDL by endocytosis g) Remainder of IDL will form LDL

Metabolic syndrome and atherosclerosis/CVD risk 1. associated with 2. criteria 3. associated with.... 4. higher risk of.....

1. Associated with central obesity 2. Definition, 3 of the 5 criteria (ATP III): a) Increased Waist circumference (waist circumference: males ³ 102 cm or 40 in, females ³ 88cm or 35 in) b) Triglyceride level ³ 150 mg/dL, or drug tx for elevated triglycerides c) Fasting Serum glucose ³ 100 mg/dL, or drug treatment for elevated blood glucose d) Blood pressure ³ 130/85 mmHg, or drug treatment for elevated blood pressure e) Low HDL levels (male < 40 mg/dL, female < 50 mg/dL) 3. Associated with a pro-inflammatory state, likely due to cytokine release from adipocytes. 4. Higher risk of endothelial dysfunction and/or thrombosis

Hypercholesterolemia in atherogenesis

1. Dominant lipids in atheromatous plaques are cholesterol + cholesterol esters 2. Genetic defects in lipoprotein uptake & metabolism that cause hyperlipoproteinemia are associated with *accelerated atherosclerosis* (early onset MI, as young as age 20's) 3. Other genetic/acquired disorders (DM, hypothyroidism) that cause hypercholesterolemia lead to premature atherosclerosis 4. Epidemiologic analysis (Framingham study): demonstrate a significant correlation between levels of total plasma cholesterol or LDL & severity of atherosclerosis 5. Lowering serum cholesterol by diet/drugs slows rate of progression of atherosclerosis, causes regression of plaques, and may reduce risk of CV events

Atherosclerotic stenosis 1. At early stages...... a) but there are _____ to ________ 2. Eventually the expanding atheroma may impinge...... 3. Critical stenosis = a) In coronary circulations: this typically occurs when the vessel is ______% occluded b) Chronic arterial _________ in __________ due to atherosclerosis can cause:

1. At early stages, remodeling of the media tends to preserve the luminal diameter by increasing overall vessel circumferences a) but there are limits to remodeling 2. Eventually the expanding atheroma may impinge blood flow (occurs gradually)(most commonly, impingement on blood flow is due to acute plaque change) 3. Critical stenosis = chronic occlusion limits flow so severely that tissue demand > tissue supply a) In coronary circulations: this typically occurs when the vessel is >70% occluded (usually asymptomatic at rest, but with exertion, the demand > supply and they develop symptoms) b) Chronic arterial hypoperfusion in vascular beds due to atherosclerosis can cause: --Bowel ischemia, sudden cardiac death, chronic IHD, ischemic encephalopathy, intermittent claudication

Atherosclerosis pathogenesis overview 1. Atheromatous plaques = a) Lesions can enlarge --> obstruction of the vascular ________ --> _______ b) Lesions can _________ --> *thrombosis + sudden occlusion of the vessel* c) _______ lesions can thicken --> impede perfusion to the ________ --> __________ to SMC/ECM --> weakening of the vessel wall --> __________

1. Atheromatous plaques = raised lesions composed of *soft friable* (grumous) *lipid cores* (mainly cholesterol, cholesterol esters, necrotic debris) covered by *fibrous caps* a) Lesions can enlarge --> obstruction of the vascular lumina --> *stenosis* b) Lesions can rupture --> *thrombosis + sudden occlusion of the vessel* c) Intimal lesions can thicken --> impede perfusion to the media --> ischemia to SMC/ECM --> weakening of the vessel wall --> *aneurysm formation*

Epidemiology of atherosclerosis 1. Atherosclerosis is becoming more _______ throughout the world & is ubiquitous among ________ nations 2. Epidemiologic data related to atherosclerosis- a) Mortality rate of IHD in the U.S. is among the __________ in the world 3. The prevalence and severity of atherosclerosis + IHD have been correlated with...... a) Hallmark Study = b) Important in identifying ______ factors c) _______ factors have roughly ________ effects

1. Atherosclerosis is becoming more prevalent throughout the world & is ubiquitous among developed nations 2. Epidemiologic data related to atherosclerosis-related mortality typically reflects death caused by ischemic heart disease (IHD, MI - accounts for ~ 1/4th of all deaths in the U.S.) a) Mortality rate of IHD in the U.S. is among the highest in the world 3. The prevalence and severity of atherosclerosis + IHD have been correlated with a number of risk factors in several prospective analyses a) Hallmark Study = The Framingham Heart Study b) Important in identifying risk factors (constitutional + acquired/modifiable behaviors) c) Risk factors have roughly multiplicative effects --2 factors for MI ~4-fold, 3 risk factors risk of IHD by a factor of 7

2 main pathologic changes contribute to the clinical consequences of atherosclerosis:

1. Atherosclerotic stenosis 2. Acute Plaque change

What are some inducers of endothelial activation?

1. Bacterial products 2. Inflammatory cytokines 3. Hemodynamic stress 4. Lipid products (atherosclerosis) 5. Advanced glycation end products (DM vascular injury) 6. Viruses 7. Complement 8. Hypoxia

1. what is arteriosclerosis 2. 4 distinct types a) arteriosclerosis b) mockeberg medial sclerosis c) fibromuscular intimal hyperplasia d) atherosclerosis

1. Definition = "hardening of the arteries" a) Generic term for: *arterial wall thickening + loss of elasticity* 2. 4 Distinct Types (due to clinical + pathologic causes) of arteriosclerosis a) Arteriosclerosis = affects small arteries + arterioles, can cause downstream ischemic injury --Hyaline + hyperplastic arteriosclerosis - occurs in hypertension b) Mockeberg medial sclerosis = presence of calcific deposits in muscular arteries (usually on the internal elastic lamina) --Often age > 50, lesions do not encroach on the vessel lumen, not typically clinically significant c) Fibromuscular intimal hyperplasia = non-atherosclerotic process occurs in muscular a. larger than arterioles --Predominantly a SMC- and ECM- rich lesion driven by *inflammation, mechanical injury* (angioplasty) --> stenosis of a vessel --A major contributor to in-stent restenosis d) Atherosclerosis = intimal lesions called atheromas that impinge on the vascular lumen

1. what is atherosclerosis 2. this underlies the pathogenesis of.... 3. this causes more....

1. Definition = characterized by intimal lesions called *atheromas* (or atheromatous or atherosclerotic plaques) that impinge on the vascular lumen, can rupture, + cause a sudden occlusion 2. This underlies the pathogenesis of: a) Coronary artery disease b) Cerebral vascular disease c) Peripheral arterial (vascular) disease 3. Causes more morbidity + mortality (roughly half of all deaths) in the Western world

Disorders of elevated cholesterol and TGs 1. Disorders of lipoprotein metabolism = _______________ 2. Characterized clinically by: 3. Etiology: 4. Many patients with ________ are at increased risk for _______ a) Patients with markedly TG levels may be at risk for.......

1. Disorders of lipoprotein metabolism = dyslipidemias 2. Characterized clinically by: a) increased plasma levels of cholesterol or TG's, or both, b) decreased levels of HDL cholesterol 3. Etiology: a) Genetic predisposition b) Environmental contribution (diet, lifestyle, medical condition, drug) 4. Many patients with dyslipidemia are at risk for ASCVD a) Patients with markedly TG levels may be at risk for acute pancreatitis

Risk factor of atherosclerosis 1. nonmodifiable (constitutional) risk factors: 2. modifiable risk factors 3. risk for CAD

1. Nonmodifiable (Constitutional) Risk Factors: a) Genetic abnormalities b) Family History c) Increasing Age d) Male gender 2. Modifiable Risk Factors: a) Hyperlipidemia b) Hypertension c) Cigarette smoking d) Diabetes e) Inflammation 3. Estimated 10-year risk for CAD in 55-year-old men and women

Endothelial cell injury 1. EC injury= 2. EC loss due to.. 3. this leads to: 4. dysfunctional EC exhibit: 5. triggers:

1. EC injury = the cornerstone of the response to injury hypothesis 2. EC loss due to any kind of injury (mechanical denudation, hemodynamic forces, immune complex deposition, irradiation, or chemicals) --> intimal thickening 3. Intimal thickening + *high presence of high-lipid diets (or dyslipidemia) --> atheromas form* 4. Dysfunctional Endothelial Cells exhibit: a) Increased permeability b) Enhanced leukocytes adhesion c) Altered gene expression 5. Triggers: hypertension, hyperlipidemia, toxins from cigarette smoke, homocysteinemia, etc. . .

Inflammation contributions to atherogenesis 1. what cells contribute? 2. a ______ inflammatory state occurs:

1. Endothelial Cell dysfunction promotes chemotaxis: a) Monocytes differentiate into macrophages where they: --Engulf lipoproteins (including oxidized LDL) & small cholesterol crystals --Further instigates inflammation through activation & release of cytokines (IL-1) --Activated macrophages also produce toxic ROS that further drive LDL oxidation & elaborate GF that stimulate SMC proliferation b) T Lymphocytes: --Are recruited to the intima & elaborate the inflammatory response and augments macrophage, ECs, SMC proliferation/activation) --Contribute to chronic inflammation (unclear what antigen T cells are responding to) 2. A chronic inflammatory state occur: a) Activate leukocytes b) Vascular wall cells release growth factors that promote SMC proliferation and matrix synthesis

What is the response to endothelial activation?

1. Endothelial Cells change shape 2. Express Adhesion molecules a) (integrin, selectin) 3. Produce cytokines, chemokines 4. Produce Growth Factors 5. Produce procoagulant and anti-coagulant factors

Atherosclerosis results from the following pathogenic events..... 1. __________ cell injury - causing....... 2. Accumulation of ______ 3. ____________ adhesion 4. ________ adhesion to..... 5. ______ accumulation within __________ which causes release of.... 6. _________ recruitment due to..... 7. ____ proliferation and _____ production

1. Endothelial cell injury - causing endothelial dysfunction causes increased permeability, leukocyte adhesion, and thrombosis 2. Accumulation of lipoproteins (mainly oxidized LDL & cholesterol crystals) in the vessel wall 3. Platelet adhesion 4. Monocyte adhesion to the endothelium, migration to the intima, & differentiation into macrophage and foam cells 5. Lipid accumulation within macrophages which causes release of inflammatory cytokines 6. SMC recruitment due to factors released from activated platelets, macrophages, and vascular walls 7. SMC proliferation and ECM production

Acute plaque ruptur 1. factors that influence plaque change a) intrinsic factors = b) extrinsic factors = 2. these factors can _____ and ______ the integrity of the ______, making i unable to.....

1. Factors that influence plaque change (are very complex) a) Intrinsic factors = plaque structure and composition b) Extrinsic factors = blood pressure 2. These factors can combine and weaken the integrity of the plaque, making it unable to withstand vascular shear forces

Morphologic changes of atherosclerosis and plaques

1. Fatty Streaks: minute yellow, flat macules that coalesce into elongated lesions 2. Composition = lipid—filled foamy macrophages, do not cause significant flow disturbance 3. Not all fatty streaks are destined to progress to atherosclerotic plaques (and can be common) 4. Atherosclerosis plaques: white-yellow RAISED lesions, can coalesque, patchy a) Key Features =* intimal thickening & lipid accumulation*

Foam cell progression ---> plaque

1. Formation of Foam cells (lipid-laden macrophages) 2. Accumulation of Foam cells --> *fatty streak* (focal thickening of the intima) 3. Smooth muscle proliferation (within the intima) & collagen production 4. Fibrous Cap (plaques with a defined lipid core) 5. Fibrous plaque a) Stable b) Unstable --rupture, erosion, ulceration ---If occurs: exposure of underlying tissue --> platelet adhesion, initiation of the clotting cascade & rapid thrombus formation c) Hemorrhage into the plaque d) Atheroembolism e) Aneurysm formation

2 important causes of endothelial dysfunction

1. Hemodynamic Disturbances a) Plaques tend to occur at sites of *turbulent blood flow*: ostia of exiting vessels (branch points) & along the posterior wall of the abdominal aorta 2. Hypercholesterolemia/ dyslipidemia a) Primary etiology: genetic alterations that cause increased production of VLDL, impaired LDL-receptor uptake, or metabolism of lipoproteins b) Secondary influences on lipid metabolism: nephrotic syndrome, alcoholism, hypothyroidism, DM c) increased LDL-C, decreased HDL-C, increased Lp(a), increased TG

Influences on serum cholesterol levels 1. what has high dietary intake? 2. what can be beneficial 3. trans-unsaturated fats 4. exercise 5. smoking and obesity 6. statins

1. High dietary intake of cholesterol + saturated fats a) Egg yolks, animal fats, butter = plasma cholesterol levels b) Diets low in cholesterol can lower plasma cholesterol levels 2. Omega-3 fatty acids (abundant in fish oils) = beneficial 3. Trans-unsaturated fats (produced by artificial hydrogenation of polyunsaturated oils) = adversely affect cholesterol profiles 4. Exercise = *raises HDL levels* 5. Obesity + smoking: *lowers HDL levels* 6. Statins = lower circulating cholesterol levels by inhibiting hydroxymethylgutaryl coenzyme A (HMG-CoA) reductase = the rate limiting enzyme in hepatic cholesterol biosynthesis

Morphologic changes of HTN 1. Hyaline arteriosclerosis 2. Hyperplastic arteriosclerosis

1. Hyaline arteriosclerosis a) Hyaline thickening of the *arteriolar* walls, loss of structural detail + luminal narrowing 2. Hyperplastic arteriosclerosis a) Concentric, laminated thickening of arteriolar walls b) Vessels exhibit "onion skin" appearance c) Laminations = SMCs & thickened reduplicated BM

Modifiable risk factors: hyperlipidemia 1. what is hyperlipidemia a) can induce _____ in the absence of other RFs 2. main component associated with increased risk = a) distributes ____ to _______ tissues 3. what is HDL? a) how does it work? b) high levels correlate with

1. Hyperlipidemia: especially hypercholesterolemia = *major risk factor for atherosclerosis* a) *Can induce lesions in the absence of other risk factors* 2. Main component associated with increased risk = *low-density lipoprotein (LDL)*, LDL function: a) Distributes cholesterol to peripheral tissues 3. HDL = High-density lipoprotein ("good cholesterol") = protective a) Mobilizes cholesterol from developing + existing vascular plaques + *transports it to the liver for biliary excretion* b) HIGH LEVELS OF HDL CORRELATE WITH *REDUCED RISK*

1. inflammation contributes to..... 2. remember: a) normal vessels do _____ bind ____________ cells b) dysfunctional ECs express....

1. Inflammation contributes to the initiation, progression, and complications of atherosclerotic lesions 2. Remember: a) normal vessels do not bind inflammatory cells b) Dysfunctional ECs express *adhesion molecules* that promote *leukocyte adhesion* (esp. monocytes and T cells which migrate into the intima under the influence of chemokines)

Lesions of atherosclerosis

1. Infrarenal abdominal aorta 2. Coronary arteries 3. Popliteal arteries 4. Internal carotid arteries 5. Vessels of the circle of Willis 6. Other vessels that can be affected: a) Mesenteric arteries, renal arteries, arteries of the upper extremities

SMC proliferation and matrix synthesis 1. Intimal SMC proliferation & ECM deposition --> 2. The __________ can mature into an _________ and progression of atherosclerotic lesions 3. Several growth factors are implicated in SMC proliferation & matrix synthesis

1. Intimal SMC proliferation & ECM deposition --> conversion of the earliest lesion = FATTY STREAK 2. The fatty streak can mature into an atheroma and progression of atherosclerotic lesions 3. Several growth factors are implicated in SMC proliferation & matrix synthesis a) PDGF, Fibroblast growth factor, TGF-alpha b) Collagen is produced which stabilized atherosclerotic plaques c) However, activated inflammatory cells in atheromas also can cause intimal SMC *apoptosis & breakdown of matrix --> Unstable plaques*

Secondary causes of Dyslipidemia 1. LDL 2. HDL 3. VLDL

1. LDL a) Elevated: hypothyroidism, nephrotic syndrome, cholestasis, anorexia, drugs (thiazide) b) Reduced: severe liver disease, malabsorption, malnutrition,hyperthyroidism 2. HDL: a) Elevated: alcohol, exercise, estrogen b) Reduced: smoking, T2DM, obesity, malnutrition, anabolic steroids, beta-blockers 3. VLDL a) Elevated: obesity, T2DM, nephrotic syndrome, hepatitis, alcohol, renal failure, sepsis, cushing's syndrome, glucocorticoids

Lipoproteins 1. composition 2. 5 major classes

1. Lipoprotein Composition: a) Hydrophobic lipid core (TGs and cholesterol esters) b) Surrounded by a shell of hydrophilic lipids (phospholipids, unesterified cholesterol) & proteins (called *apolipoproteins*) that interact with body fluids 2. 5 Major Classes of lipoproteins based on *relative density* a) Chylomicrons = *large particles that carry dietary lipid* b) Very low-density lipoprotein (VLDL) = carries the majority of TG c) Intermediate density lipoprotein (IDL) d) Low-density lipoprotein (LDL) = carries the majority of cholesterol e) High-density lipoprotein (HDL) Remember: lipid density < H2O density *density is primarily determined by amount of lipid per particle*

Lipoproteins 1. what are they? 2. disorders of lipoprotein metabolism 3. lipoprotein functions

1. Lipoproteins = complexes of lipids + proteins, essential for transport of cholesterol, triglycerides (TG), and fat-soluble vitamins in the blood 2. Disorders of lipoprotein metabolism: a) Primary + secondary conditions that increase or decrease circulating lipids or lipoproteins 3. Lipoprotein Function a) Transport poorly soluble lipids (primarily TGs, cholesterol, Fat-soluble vitamins) through body fluids to and from tissues b) Essential in absorption of dietary cholesterol, fatty-acids, & fat-soluble vitamins c) They carry TG, cholesterol, fat-soluble vitamins from the liver --> peripheral tissues d) And carry cholesterol from the peripheral tissues --> liver

Lipoprotein (a) 1. what is it? 2. elevated serum LP(a) = a risk factor for........ by: 3. LP(a) excess =

1. Lp(a) = a low-density lipoprotein, contains apoB-100 linked to apo(a) 2. Elevated serum Lp(a) = *a risk factor for atherosclerotic cardiovascular disease (ASCVD), Lp(a) promotes atherosclerosis + thrombosis by:* a) Interfering with fibrinolysis - Lp(a) has similar structure to plasminogen --> directly competes for binding sites and impairs plasminogen activity & fibrinolysis b) Binds to macrophages --> *promotes foam cell formation & deposition of cholesterol in atheromas* c) Binds to endothelium & ECM --> contributes to endothelial dysfunction d) increases expression of intercellular adhesion molecule-1 --> recruits monocytes to arterial wall & binding to macrophages --> *promotes foam cell formation* e) Enhances the susceptibility of LDL to oxidative modification 3. Lp(a) excess = *independent risk factor for ASCVD*

Clinicopathologic consequences of atherosclerosis 1. most common arteries involved..... 2. most likely to present with signs/sx related to ______ 3. major clinical consequences:

1. Most common arteries involved in atherosclerosis = *large elastic a. & medium-sized muscular a.* (coronary, renal, popliteal a.) 2. Atherosclerosis is most likely to present with signs/symptoms related to ischemia 3. The major clinical consequences of atherosclerosis are a) Myocardial infarction (heart attack) b) Cerebral infarction (stroke) c) Aortic aneurysm d) Peripheral vascular disease (gangrene of extremities)

Atherosclerotic plaques 1. Most commonly atherosclerotic plaques contain the following: 2. The periphery of the lesion often shows __________________ 3. Plaques generally progressively......

1. Most commonly atherosclerotic plaques contain the following: a) Superficial fibrous cap = SMCs & collagen b) The Cap meets the vessel wall where macrophages, T cells, and SMCs are present c) Necrotic core (containing lipid, necrotic debris, lipid-laden macrophages, SMCs, fibrin 2. The periphery of the lesion often shows neovascularization 3. Plaques generally progressively enlarge over time through cell death & degeneration with synthesis & Degradation of the ECM (remodeling) & thrombus organization

Acute plaque change: 1. Not all plaque ruptures result in....... 2. Silent plaque disruption & ensuing superficial platelet aggregation & thrombosis probably occur ________ & ________ in those with atherosclerosis 3. Healing of these subclinical plaque disruptions (and their overlying thromboses) is an important mechanism of.......

1. Not all plaque ruptures result in occlusive thrombosis with catastrophic consequences 2. Silent plaque disruption & ensuing superficial platelet aggregation & thrombosis probably occur frequently & repeatedly in those with atherosclerosis 3. Healing of these subclinical plaque disruptions (and their overlying thromboses) is an important mechanism of atheroma enlargement

Acute plaque rupture 1. Plaque erosion or rupture typically triggers _______ --> leads to...... 2. There are 3 main types of plaque changes 3. Plaques are often ________ until...... 4. Sx are triggered by......

1. Plaque erosion or rupture typically triggers thrombosis --> leads to partial or complete vascular obstruction and often tissue infarction. 2. There are 3 main types of plaque changes a) Rupture/fissuring = exposes highly thrombogenic plaque constituents b) Erosion/ulceration = exposes thrombogenic subendothelial basement membrane to blood c) Hemorrhage into the atheroma = expands its volume 3. Plaques are often *asymptomatic* until an acute event occurs 4. Sx are triggered by thrombosis on a lesion that previously did not have significant luminal occlusion

Vulnerable and stable plaque 1. plaque inflammation increases ______________ and reduces __________ 2. how are statins beneficial?

1. Plaque inflammation increases collagen degradation & reduces collagen synthesis --> *destabilizes the mechanical integrity of the cap* a) Statins may have a beneficial effect not only by reducing circulating cholesterol levels but also by stabilizing plaques through a reduction in plaque inflammation

What plaques are at higher risk of rupturing?

1. Plaques with high risk of rupture = *vulnerable plaques* 2. Plaques that contain large numbers of foam cells 3. Plaques with abundant extracellular lipid 4. Plaques that have a thin fibrous cap containing few SMCs a) The fibrous cap also undergoes continuous remodeling b) Its mechanical strength & stability are proportional to its collagen content c) If there is loss of SMCs --> cap weakening 5. Plaques that contain clusters of inflammatory cells

Screening and diagnosis of dyslipidemia 1. what labs do we use? 2. goals

1. Plasma lipid levels (preferably after 12-hour overnight fast) a) Screen children between 9 - 11 years of age 2. Goal: identify the class of lipoproteins that are increased or decreased a) Rule out secondary causes (obtain fasting glucose, FH, renal function, LFTs, TSH) b) Severe LDL elevation: consider familial etiology c) Severe hypertriglyceridemia: TG > 500 (some say > 750 mg/dL) : consider familial etiology

Nonthrombogenic EC lining 1. Requires _________ flow 2. presence of.... 3. Firm adhesion to...... 4. What 4 things risks the non-thrombogenic state and causes "endothelial activation"?

1. Requires laminar flow 2. presence of certain Growth Factors (VEGF) 3. Firm adhesion to the underlying basement membrane 4. What risks the non-thrombogenic state and causes "endothelial activation"? a) Trauma b) Injury c) Inflammation d) Leads to vasoconstriction, risk of thrombosis

Hyperhomocysteinemia and atherosclerosis/CVD risk 1. serum homocystein levels correlate wth..... 2. however, lowering homocystein levels has not been shown to..... 3. we do not.....

1. Serum homocysteine levels correlate with coronary atherosclerosis, PAD, stroke, and venous thrombosis a) According to a meta-analysis evaluating data from 12 prospective studies found: --25% lower homocysteine levels was associated with lower risk of ischemic heart disease, stroke b) Another study showed: --Independent of Framingham risk factors, each 5 micromol/L higher homocysteine levels was associated with a 20% greater risk of CHD 2. However, lowering homocysteine levels has not been show to improve ASCVD risk, prevent future cardiovascular events (possible exception is stroke) a) i.e. Supplemental vitamin ingestion does not affect the incidence of CVD 3. We do not routinely measure homocysteine levels in patients without known vascular disease

Vascular smooth muscle cells 1. Smooth Muscle Cells: participate in both _________and _________ processes 2. Under stimulation by various factors, SMCs can do the following:

1. Smooth Muscle Cells: *participate in both normal vascular repair and pathologic processes* (i.e. atherosclerosis) 2. Under stimulation by various factors, SMCs can do the following: a) Proliferate (hypertrophy) b) Upregulate ECM collagen, elastin, and proteoglycan production c) Elaborate growth factors and cytokines d) Mediate *vasoconstriction or vasodilation* (in response to physiologic/pharmacologic stimuli)

HDL metabolism and reverse cholesterol transport

1. The transportation of excess cholesterol from the periphery back to the liver for excretion in the bile 2. HDL is produced by the liver (and intestines) 3. It collects free cholesterol from the periphery (macrophages/peripheral cells) & recruits cholesterol from circulating lipoproteins a) It esterifies cholesterol à forms a hydrophobic core, and then will re-recruit apolipoproteins for lipolysis 4. HDLs undergo continual peripheral remodeling due to lipid transfer protein/lipases 5. Eventually are picked up by the liver and cholesterol esters can by hydrolyzed and excreted into bile or into bile acids and excreted into the intestinal lumen

Pathogenesis of atherosclerotic lesion formation- The response to injury hypothesis:

1. This model views atherosclerosis as a chronic inflammatory response of the arterial wall to endothelial injury 2. Lesion progression involves the interaction of: a) Modified lipoproteins b) Monocyte-derived macrophages c) T lymphocytes d) Endothelial cells of the arterial wall

What are the steps of damaged endothelium leading to formation of foam cells?

1. endothelial dysfunction and inflammation a) inability to produce normal amounts antithrombotic and vasodilating cytokines 2. release of inflammatory cytokines (TNF-a, interferon-y, IL-1, toxic oxygen radicals) 3. hyperlipidemia + oxidative stress 4. proinflammatory lipids that cause adhesion and entry of monocytes which differentiate into macrophages a) they release growth factors that encourage further atherosclerosis 5. leads to foam cell formation

Chronic hyperlipidemia 1. impairs _____ function --> 2. lipoproteins ______ within the _____ where 2 pathogenic derivatives are generated:

1. impairs EC function ( local ROS, ROS accelerate NO decay --> impairs *vasodilator activity)* 2. Lipoproteins accumulate within the intima where 2 pathogenic derivatives are generated: a) Oxidized LDL --> *foam cell formation* --EC & macrophages produce ROS --Oxygen free radicals oxidize LDL --> oxidized LDL --Oxidized LDL gets ingested by macrophages --> *FOAM CELL FORMATION* --Oxidized LDL & Foam cell formation --> cytokines, growth factors, chemokines = *cytotoxic to ECs & SMCs* b) Cholesterol crystals --Minute extracellular cholesterol crystals can activate immune cells (monocytes/macrophages) to produce IL-1 and other pro-inflammatory mediators (*important instigators of inflammation*)

Obesity and insulin resistance effect on lipid metabolism 1. _______ TG levels, _____ HDL levels, ________ LDL) 2. increase ________ mass + increased ______ resistance --> altered.... a) increase _____ production and delivery to liver --> form ____ b) ____ are packaged into ______ for secretion into the circulation 3. Insulin _____ also increases ________ synthesis in the liver which contributes to...... 4. Insulin ________ also decreases ________ activity which leads to.....

Obesity & insulin resistance are frequently accompanied by dyslipidemia with: 1. increased TG levels, decreased HDL levels, variable LDL (but increased # small dense LDL particles) 2. increased adipocyte mass + increased insulin resistance --> altered lipid metabolism a) increased FFA production & delivery to the liver --> form TGs b) TGs are packaged into VLDL for secretion into the circulation 3. Insulin resistance also increases fatty acid synthesis in the liver which contributes to VLDL production 4 Insulin resistance also decreases LPL activity --> decreased catabolism of chylomicrons & VLDLs --> increased Triglyceridemia