Lecture 3.10 Atherosclerosis (UF College of Pharmacy) - PDF

Lecture 3.10 Atherosclerosis Lihui Yuan, PharmD, Ph.D  Learning Objectives Explain the pathogenesis of atherosclerosis. Discuss the progression of atherosclerosis. List the risk factors and complications for atherosclerosis. Discuss the signs and symptoms of thrombi. List e...

Lecture 3.10 Atherosclerosis Lihui Yuan, PharmD, Ph.D  Learning Objectives Explain the pathogenesis of atherosclerosis. Discuss the progression of atherosclerosis. List the risk factors and complications for atherosclerosis. Discuss the signs and symptoms of thrombi. List examples of vascular inflammatory diseases. Explain how vessel inflammation alters vascular function. Atherosclerosis: Inflammatory disease of vessel wall Initiation may involve endothelial injury Oxidized LDL Excessive homocysteine Immunologic attacks Infection-induced changes Diabetes ↑ C-reactive protein (CRP) reflects inflammation (made by smooth muscle cells, endothelial cells, macrophages, lymphocytes as well as hepatocytes and adipocytes), not unique to atherosclerosis Atherosclerosis Risk factors: Older age (greater than 40 years) Cigarette smoking Diabetes mellitus Hypercholesterolemia Hypertension Hyperhomocysteinemia  Mechanisms of atherosclerosis 3: Macrophages engulf FA, 1: LDL uptake into vessel wall form foam cells LDL oxidation 2: Monocytes taken up Convert to macrophages ↑LDL oxidation ↑Scavenger R 4: Release of chemotactic factors Increase inflammation in lesion 5  Atherosclerosis Inflammation in vessel wall Release of chemo attractants and cytokines Accumulation of lipids, collagen, calcium Accumulation of inflammatory cells such as T- lymphocytes. Accumulation of extracellular matrix and formation of a fibrous plaque (prevents rupture)  Atherosclerosis Changes in function: Increases resistance (esp. small artery, arterioles) Less compliance (if large artery) Decreases flow to tissue leads to complications: clotting, ischemia, etc Changes endothelial function Alters reactivity of smooth muscle – Inability or limited ability to autoregulate – Inability or limited ability to respond to metabolic needs Complicated lesion: hemorrhage, cell necrosis, calcification, thrombosis Complications associated with atherosclerosis Increased blood pressure (↑R) –hypertension Stiffness in vessels- In large arteries- stiffness leads to increased pulse pressure (higher systolic, lower diastolic) Decreased perfusion (affects function) Increased risk of thrombosis (stroke, heart attack) Test of Knowledge Which of the following statement is true about atherosclerosis? A. Atherosclerosis starts with vascular smooth muscle lesion B. Macrophage will convert into monocyte after being taken up C. Foam cells are macrophages with fatty acids D. HDL is taken up in the vessel 10 Why is vascular pathology important? What happens with changes in flow? Symptoms associated with poor perfusion/ ischemia Symptoms depend on location brain- confusion heart –angina, exercise intolerance Peripheral artery- pain at rest or intermittent claudication Intermittent claudication: “limping”; cramp like pains in the legs due to poor perfusion Other possible problems with Peripheral Artery atherosclerosis Fatigue (esp. muscle fatigue) Thrombosis/embolism Severe: muscle atrophy, cyanosis, hair loss Severe (e.g. arteriosclerosis obliterans): bruits, loss of pulses below site, gangrene Thrombosis: What causes thrombosis? Atherosclerosis: disruption of intima starts clotting cascade Aneurysms: pooling of blood Infection/inflammation: invasion of intima, thromboxane production Cardiac valve diseases with calcification or bacterial infection (endocarditis) Signs/Symptoms/Complications of thrombosis Ischemia (obstruction)-pain Tenderness, swelling Skin pale (if arterial) Aneurysms Skin red to deep blue-purple (if venous) Neuralgia: sharp shocking pain of nerve Embolism-organ disruption, necrosis, sepsis  Other vascular disease: Vasculitis Etiology Inflammation of vessel wall due to immune response or autoimmune disease ❖ Reduces tissue perfusion by causing vessel spasms (Raynaud’s) or necrosis, thrombosis ❖ Disrupts normal endothelial responsiveness of vascular lining Examples of inflammatory vessel diseases: Primary Raynaud’s (no known cause, most common, cold/stress) Secondary Raynaud’s (underline illness, autoimmune) Wegner’s granulomatosis (inflammation in vessels in nose, sinuses, throat, lungs and kidneys ) Giant cell arteritis (inflammation in vessel near temples) Buerger’s disease (inflammation commonly in arms and legs)  Summary ✓ Atherosclerosis is an inflammatory disease of the vessel wall which affects functions of both the endothelium and the vascular smooth muscle. ✓ Atherosclerosis is a progressive disease. ✓ Atherosclerosis increases resistance to flow, increases risk of thrombosis and results in further damage to vessel. ✓ Atherosclerosis can alter tissue perfusion and lead to organ related symptoms (e.g. angina or skeletal muscle pain) or organ damage (e.g. cardiac). ✓ Vascular autoimmune or inflammatory diseases also cause disruption of normal vessel function, can result in downstream pathology.