Atherosclerosis Pathophysiology Fall 2024 PDF

Atherosclerosis PAT201 FALL 2024 WEEK 11 1  Hypertension There are Orthostatic (postural) hypotension many Aneurysm Thrombus formation diseases of Embolism the Peripheral arterial diseases Atherosc...

Atherosclerosis PAT201 FALL 2024 WEEK 11 1  Hypertension There are Orthostatic (postural) hypotension many Aneurysm Thrombus formation diseases of Embolism the Peripheral arterial diseases Atherosclerosis arteries, Peripheral artery disease but we will Coronary artery disease Myocardial ischemia focus on… Acute coronary syndromes 2  Let’s First Learn About Dyslipidemia! Abnormal Plasma Lipoprotein Concentrations 3 Sooooo…What Are Lipoproteins? Lipoprotein: Lipids, phospholipids, cholesterol, and triglycerides bound to carrier proteins Lipids are needed for the formation/repair of plasma membranes Cholesterol is important component in manufacturing essential substances (e.g., bile acids and steroid hormones) and repairing plasma membranes From diet but body also manufactures it 4 Types of Lipoproteins Four Types of Lipoproteins Very low- High-density Low-density Chylomicrons density lipoproteins lipoproteins (primarily lipoproteins (HDLs) (LDLs) triglycerides) (VLDLs) 5 Composition of Lipoproteins Because lipid molecules are not soluble in plasma, they must be specially packaged for transport through the blood To accomplish this, the body forms complexes called lipoproteins that consist of various amounts of cholesterol, triglycerides, and phospholipids, along with a protein carrier The protein component is called an apoprotein (apo- means “separated from” or “derived from”). Figure 49.2, Adams et al., 2025, p. 786 6 HDL High-density lipoprotein (HDL):returns cholesterol to liver “Reverse cholesterol transport” Cholesterol binds to hepatic receptors (including the LDL receptor) and is processed & eliminated as bile or converted to cholesterol-containing steroids Other functions of HDL include protects LDL from oxidation, preserves endothelial function promotes anti-inflammatory and anti-thrombotic effects 7 LDL and VLDL Low-density lipoprotein (LDL): carries cholesterol to tissues Normally controlled by: Hepatic receptors that bind LDL and limit liver synthesis of this lipoprotein ↑ serum concentration of LDL in combination with risk factors such as age, diabetes, and CKD is an indicator of coronary Very risk low–density lipoproteins (VLDL): carry triglycerides 8 Lipoprotein Receptors LDL delivers cholesterol to tissues Serum LDL is controlled by hepatic receptors Bind to LDL Limit synthesis of LDL in the liver dietary cholesterol genetic predisposition serum cholesterol (e.g.: decreased hepatic receptors) 9 Chylomicrons Transport exogenous lipids from intestine to liver & peripheral cells Dietary fat is packaged into chylomicrons for absorption in the small intestine Primarily contains triglyceride; triglycerides may be removed and either stored by adipose tissue or used by muscle as an energy source Remnants contain cholesterol, which is taken up by the liver 10  Increased LDL: plays a role in endothelial injury, inflammation, and immune Dyslipidemia responses that are important in Is an atherogenesis Indicator of Low levels of HDL: responsible for “reverse cholesterol transport,” which returns excess Coronary cholesterol from the tissues to the liver Risk (& Elevated serum VLDL (triglycerides) Atheroscleros is) Increased lipoprotein(a): enhances cholesterol delivery to injured blood vessels 11  Is a form of arteriosclerosis (thickening of arteries – various causes) Atherosclerosis = thickening and hardening caused by the accumulation of Now…Back to lipid-laden macrophages in the arterial Atherosclerosis! wall = plaque development Occurs throughout the body ischemic syndromes Leading cause of coronary artery and cerebrovascular disease 12 What is Atherosclerosis? *chronic, inflammatory condition *interaction of many pathological processes = damage to arterial walls Progression: endothelial injury/dysfunction fatty streak fibrotic plaque complicated lesions 13  Clinical Depends On The Organ Affected Manifestations -Obstruction of the vessels that supplies the of organ -Signs and symptoms are the result of Atherosclerosis inadequate perfusion of tissues Partial vessel obstruction may lead to transient ischemic events, often associated with exercise or stress. Obstruction of peripheral arteries can cause significant pain and disability. CAD caused by atherosclerosis is the major cause of myocardial ischemia Atherosclerotic obstruction of the vessels supplying the brain is the major cause of stroke. Usually more than one vessel is involved so a person may have symptoms from several different ischemic tissues at the same time. Disease in one area may indicate that the individual is at risk for ischemic complications elsewhere. Eg: myocardial infarction and stroke 14  Laboratory tests Lab Values measurement of lipids, blood Diagnostic glucose, and high-sensitivity CRP Imaging & (hs-CRP). Assessment Diagnostic Imaging x-ray films, electrocardiography, ultrasonography, nuclear scanning, CT, MRI, and angiography to identify affected vessels, particularly coronary vessels. Physical Assessment & History complete health history (including risk factors and symptoms of ischemia) Physical examination may reveal evidence of decreased blood flow to tissues. 15  Pathophysiology of Atherosclerosis 16 Progression of Atherosclerosis Endothelium Inflammation of Cytokines Cellular injury endothelium released proliferation Low-density lipoproteins (LDL) Macrophage oxidation (foam Fatty streak Fibrous plaque migration cell formation) with oxidative stress Complicated plaque 17 Development Of Atherosclerosis: DAMAGED ENDOTHELIUM Endothelial cell injury: results from different factors which cause cells to be inflamed - Smoking, hypertension, diabetes, etc. Damaged endothelium: stops making normal antithrombotic and vasodilatory substances (nitric oxide and prostaglandins) - Promotes adhesion of monocytes and other inflammatory cells -Produces reactive oxygen species (formed from O2 and damage molecules) 18 Figure 32.5, Rogers, 2023, p.  Development Of Atherosclerosis: LDL OXIDATION -Low-density lipoprotein (LDL) penetrates the arterial walls & become trapped -Inflammation, oxidative stress and activation of macrophages oxidizes LDL -Activated macrophages engulf oxidized LDL -Macrophages full of LDL transform into foam cells 19 Figure 32.6, Rogers, 2023, p. Development Of Atherosclerosis: FATTY STREAK FORMATION Foam cells accumulate in significant amounts and form a lesion called a fatty streak - Consists of foam cells, smooth muscle cells, and macrophages - Cytokines and other enzymes are released - further injury - Growth factors are released - stimulate smooth muscle cell proliferation - Smooth muscle cells release collagen - Migrate over the fatty streak and can progress to fibrous plaque 20 Figure 32.5, Rogers, 2023, p. Development Of Atherosclerosis: FIBROUS PLAQUE Fibrous plaque: - Calcify & protrude into vessel lumen - obstruct blood flow to distal tissues - esp. during exercise → angina or intermittent claudication (leg cramps) Plaques are unstable & prone to rupture due to: -inflammatory activation of proteinases -apoptosis (death) of cells in the plaque -plaque hemorrhage *plaques are clinically silent until they rupture* 21 Figure 32.5, Rogers, 2023, p. Development Of Atherosclerosis: COMPLICATED LESION Complicated plaque: plaques that have ruptured -expose underlying tissue - platelet adhesion -initiation of clotting cascade -rapid thrombus formation -may suddenly occlude affected vessel -ischemia and infarction - Prevention of complicated plaque: antithrombotic agents (ASA - antiplatelet) 22 Figure 32.5, Rogers, 2023, p. Development of Atherosclerosis: Summary Endothelial Injury Endothelium stops making normal antithrombic and vasodilatory Lipid substances, such as nitric oxide and deposition prostaglandins Leukocytes and macrophages adhere to the endothelium and release Inflammat cytokines ion Oxidation and phagocytosis of LDL (foam cells) Smooth muscle Fatty streak accumulates foam proliferation cells Abnormal Progressive vessel vasoconstriction damage Fibrosis and calcification Plaque Ulceratio Thrombo Rupture n sis 23 Copyright © 2019, Elsevier Inc. All rights reserved. Consequenc es of Atherosclero sis Coronary artery disease (CAD) Peripheral artery disease (PAD) Aortic Aneurysms 24  Atherosclerosis is the most common cause for Coronary Artery Diseases! 25 Figure 32.7, Rogers, 2023, p.  Advanced age Non- Male sex or women after menopause Modifiable Risk Factors Family history & genetics for CAD and Family history may contribute to CAD through Atherosclero genetics and shared environmental exposure. many gene polymorphisms have been associated sis with CAD and its risk factors. Aging and menopause are associated with increased exposure to risk factors and poor endothelial healing. 26  Dyslipidemia Modifiable Hypertension Risk Factors Endothelial injury, increase for CAD and in myocardial demand Atherosclero Cigarette smoking sis Vasoconstriction and increase in LDL, decrease in high-density lipoproteins (HDL) 27  Diabetes and insulin resistance Endothelial damage, thickening of the vessel wall Modifiable Obesity or sedentary Risk Factors lifestyle for CAD and Dyslipidemia, hypertension Metabolic syndrome Atherosclero sis (cont.) Atherogenic diet Diets high in salt, fats, trans fats, and carbohydrates have all been implicated 28  Markers of inflammation, ischemia, and thrombosis High-sensitivity C-reactive protein, Troponin I Chronic kidney disease In CKD, dyslipidemia, endothelial dysfunction, vascular calcification, elevated levels of growth factors, and toxic Non- oxygen radicals all contribute to atherogenesis and CAD. traditional Adipokines Adiponectin and leptin Risk Factors Adipokines are a group of hormones released from adipose cells. Weight loss and exercise improve adipokine levels and are correlated with improved cardiovascular risk Medications increase in CAD-related ischemic events can occur within weeks of beginning NSAID use Antirejection drugs and protease inhibitors also increase the risk 29  Air pollution and ionizing radiation Exposure to air pollution is strongly correlated with coronary risk. Non- toxins in pollution may contribute to macrophage activation, oxidation of LDL, traditional autonomic imbalance, thrombosis, and inflammation of vessel walls. Risk Factors Coronary artery calcification, carotid (cont.) wall thickness Can be assessed with vascular imaging Microbiome 30 Microbiome Effects Indirect effects: diet and lifestyle affect the microbiome This has an impact on other risk factors which in turn contribute to atherosclerosis e.g., diabetes, autoimmunity Direct effects: microbiota function Hyperhomocysteinemia (amino acid) linked to cardiovascular risk Thought that the microbiome modulates homocysteine & lipid metabolism and other risk factors for atherosclerosis 31 PAD Atherosclerotic disease of arteries that perfuse limbs, especially lower extremities Lower extremity ischemia from arterial obstruction Prevalent in people with diabetes or who smoke 10-% - 15% people over 60 Significant morbidity & mortality Significant predictor of atherosclerotic disease PAD - 2X risk of coronary artery disease 32 PAD: Intermittent Claudication Gradual Acute Intermittent Claudication: Obstruction of arterial blood flow in the May not be iliofemoral vessels, painful, so can go a thrombus forms undetected for resulting in pain with years ambulation. acute cessation of blood flow with severe pain, loss of pulses, skin colour changes 33 PAD: Diagnosis and Treatment Diagnosis - history and physical examination Measurement of blood flow Treatment – first treat the cause! treatment of diabetes treatment of hypertension treatment of dyslipidemia smoking cessation vasodilators & antiplatelet medications cholesterol lowering medications exercise possible surgery to restore circulation 34 Aortic Aneurysms Aneurysm = localized dilation or outpouching of a vessel wall or cardiac chamber true Aneurysm – involves all 3 layers of artery wall false Aneurysm- extravascular hematoma that creates a break in the vessel wall Weakening of the vessel wall layers from chronic inflammation ½ of people with aneurysms have arteriosclerosis & hypertension Atherosclerosis is a common cause Plaque erodes the vessel wall Loss of smooth muscle cells and accumulation of inflammatory cells 35 Aortic Aneurysms (cont.) Aneurysms commonly occur in thoracic or abdominal aorta Aorta is very susceptible due to constant stress on the vessel wall Inflammation, plaques cause erosion of vessel = Loss of elasticity & thinning Prone to rupture = surgical emergency Aortic Dissection – splitting of the aorta – DEADLY! Abdominal Aortic Aneurysm (AAA) Common Causes: Inflammation = smooth muscle cell death loss of medial elastic lamellae and thinning Infections, such as syphilis Collagen disorders Traumatic injury to the chest or abdomen Genetic susceptibility 36  37 Figure 32.4, Rogers, 2023, p. Abdominal Aortic Aneurysms - In the abdominal Diagnosis aorta ultrasonography, CT, MRI, or angiography Treatment - Goal = keep low blood volume & low blood pressure to decrease mechanical force Slow Growing aneurysms Smoking cessation Beta adrenergic blockers Acute Aortic Syndromes Vessel rupture Aortic Dissection - deadly Ascending – type A – emergency – immediate surgery Any other part of aorta –Type B – can managed with medical therapy pain behind neck, jaw, chest, back or abdomen urgent CT scan, echo and MRI 38 Management of Lipid Disorders and Atherosclerosis 39 Lipid Disorders Goal: Maximize HDL and Minimize LDL Clients with lipid disorders are often Pharmacotherapy for asymptomatic until hyperlipidemia focuses on reducing progressing to more LDL and increasing HDL serious Reducing cholesterol in liver cells cardiovascular can contribute to lowering LDL in disorders Managing Hyperlipidemia with Lifestyle Changes Diet Reduce intake of saturated fats and cholesterol Non- Increase intake of soluble Pharmacolog fiber ical Increase intake of plant Management sterols Eliminate tobacco, alcohol Exercise regularly Regular monitoring of blood lipids, HDL and LDL Management of Atherosclerosis Focuses on reducing risk factors removing initial causes of vessel damage preventing lesion progression promoting exercising, smoking cessation, and controlling hypertension and diabetes when appropriate reducing LDL cholesterol levels by diet or drugs or both 42 Pharmacotherapy of Atherosclerosis Classification Drug HMG-CoA reductase inhibitors atorvastatin Antidepressants amitriptyline 43 What are “Statins”? Class of antihyperlipidemics that interferes with a critical enzyme (HMG-CoA reductase) in the synthesis of cholesterol Cholesterol is manufactured in the liver by a series of more than 25 metabolic steps, beginning with acetyl coenzyme A (acetyl CoA) HMG-CoA reductase regulates cholesterol biosynthesis 44 What are “statins” (cont.) Statins inhibit HMG-CoA reductase! This enzyme is required for the synthesis of cholesterol Statins cause liver to make less cholesterol Liver also responds by making more LDL receptors on surface of liver cells More LDL receptors on surface of liver cells → ↑ removal of LDL from blood 45 Results in reduction of both cholesterol and LDL! Cholestero l Biosynthes is And Excretion Figure 49.3, Adams et al., 2025, p. 788 46  HMG-CoA Reductase Inhibitors: Atorvastatin First choice of drug for decreasing lipid levels Figure 49.4, Adams et al., 2025, p. 790 47 HMG-CoA Reductase Inhibitors: Atorvastatin 48 e q u ires rr L i v e G - C oA HM s e to ct a redu duce Indications for use p ro o… r ol. S ? Hypercholesterolemia es t chol inhibit e it Mechanisms of action if w e Inhibit HMG-CoA reductase, enzyme needed for cholesterol biosynthesis, so ↓ cholesterol ↑ number of LDL receptors on liver cells so ↑ removal of LDL from blood Desired effect ↓ cholesterol levels and ↓ LDL; ↑ HDL levels Can also ↓ triglyceride and VLDL levels Adverse effects Can cause liver damage Rare but serious: rhabdomyolysis (breakdown of muscle fibres) where muscle cells spill into systemic circulation, which can clog the kidneys and cause potential fatal acute renal failure REMEMBER: grapefruit juice inactivates metabolizing enzymes → sustained levels of unmetabolized statin drug →↑risk for major drug toxicity Nursing Implications for Practice Use Your C linical Judg Given your ement! understand atorvastatin in g of , what nurs implication in g s for practic e would you consid er? 49