L4_MDSA30160_CRD_2024_Vascular Disease 1_Atherosclerosis_PH_notes_V2.pdf

Vascular disease 1: Atherosclerosis MDSA30160 31/01/2024 Peter Holloway Based on lectures by Drs Jane Dolan & Pat Twomey Cardiovascular system Learning Objectives After studying these topics, you will be able to: – Describe the aetiology (causes) and pathogenesis (development) of ATHEROMA (atheroscl...

Vascular disease 1: Atherosclerosis MDSA30160 31/01/2024 Peter Holloway Based on lectures by Drs Jane Dolan & Pat Twomey Cardiovascular system Learning Objectives After studying these topics, you will be able to: – Describe the aetiology (causes) and pathogenesis (development) of ATHEROMA (atherosclerosis) – Understand and list the main consequences of atheroma in each organ system – Discuss the causes and consequences of ‘vulnerable/unstable’ plaque E-Learning: structures for considering and studying disease 5 Blood vessels as tubes Two modes of failure 1. Blockage (and narrowing) Nothing getting through 2. Burst (and leakage) Everything getting out Not enough getting through Some stuff getting out ATHEROSCLEROSIS significant but incompletely understood disease A vascular disease responsible for more MORBIDITY & MORTALITY in Western World than any other category of disease Incidence increases with age * * Almost universal in middle and old age Extremely uncommon in early years but increasing Though so common, we do not yet(?) fully understand it Atherosclerosis (definition) A complex, multifactorial, incompletely understood degenerative process resulting from the action of environmental stressors on genetic susceptibility (with inflammatory and metabolic components) that affects large and medium sized arteries characterised by intimal plaques containing variable proportions of accumulated lipid and accompanying fibrosis (the lesions are called atheroma, greek athere- porridge, -oma swelling/mass) It is systemic but patchy. Not to be confused with Arteriosclerosis ‘ hardening of the arteries’ Arterial wall thickening and loss of elasticity (more a problem with the media than the intima) Ageing phenomenon Mainly small arteries/arterioles Framingham Study (1948-) Prospective cohort study Risk factors for Atheroma 1 (Framingham Heart study etc) MAJOR MODIFIABLE (multiplicative) 1. DYSLIPIDAEMIA (NB CHOLESTEROL, LDL) 2. HYPERTENSION (IHD Relative Risk 1.6) 3. CIGARETTE SMOKING (IHD Relative Risk 2) 4. DYSGLYCEMIA/Diabetes mellitus (IHD Relative Risk 2) 5. CHRONIC INFLAMMATION (C-reactive protein) Risk Factors for atheroma 2 Major FIXED CONSTITUTIONAL RISK FACTORS * 1. AGE (from 40 to 50 y.o. incidence 5x) 2. Biological sex – male, (postmenopausal female) 3. GENETICS – FAMILY HISTORY (majority, polygenic) Lipoprotein abnormalities (minority, Mendelian) and others Distribution of Atheroma Arteries ONLY >2mm diameter Medium and large arteries Usually starts at branch points Abdominal Aorta * Coronary Arteries Popliteal Arteries Carotids Circle of Willis Figure 11.29 Common sites of atheroma formation, shown in blue. Downloaded from: StudentConsult (on 19 January 2010 01:37 PM) © 2005 Elsevier Normal Arterial Structure Intima(Endothelium, sub-endothelial connective tissue, internal elastic lamina) Media (Smooth Muscle cells,elastic fibres, external elastic lamina) Adventitia (Connective tissue, incl. nerves, vasa vasorum) Atheroma A chronic indolent systemic disease which builds up over decades Typically the complications are sudden, acute and localized Fatty streak – Intracellular lipid (foam cell/macrophages) Transitional plaque – Extracellular lipid Advanced or raised fibrolipid plaque – Lipid, collagen and smooth muscle – +/- stenosis, instability Complicated plaque – Thrombosis (superficial endothelial erosion or deep fissuring) PATHOGENESIS RESPONSE TO INJURY HYPOTHESIS A chronic inflammatory and healing response of the arterial wall to endothelial injury A dynamic process Systemic - simultaneous involvement of many arteries Spatial heterogeneity (focal) PATHOGENESIS Key materials / cells Lesion progression occurs through interaction of circulating – – – – Lipoproteins /lipids Macrophages Precursor stem cells T lymphocytes with the normal constituents of the vessel wall including – endothelium – vascular smooth muscle cells Together with Extracellular matrix formation Plus – angiogenesis (new vessels) – mineralization Endothelium Border control between vascular and extravascular spaces Insults – Physical – Chemical Exogenous: toxins Endogenous: metabolic – Genetic susceptibility – Immunologic/Inflammatory Response to injury hypothesis 1. Endothelial injury/activation 2. Endothelial “stickiness” & permeability – – – Lipid Platelets Macrophages 3. Cellular recruitment – Platelets, Macrophages, Myocytes, T-cells 4. Inflammation – – Macrophage lipid uptake, peroxidation and scavenging with impaired lipid recycling (foam cells) and toxicity, myocyte proliferation IL-1 recruits T-cells which affect myocyte functioning and apoptosis 5. Cellular proliferation (PDGF and TGFα) – Neo-intimal myocytes 6. Remodelling – – Cells:Myocytes, fibroblast & T-lymphocytes Matrix 7. Stenosis (narrowing) +/or acute plaque change: rupture, ulceration, erosion, thrombosis, intraplaque haemorrhage, atheroembolism, aneurysm formation PATHOGENESIS 1 REACTION TO INJURY HYPOTHESIS InitiationENDOTHELIAL DAMAGE Reduced Nitric Oxide is earliest sign of endothelial damage © 2005 Elsevier PATHOGENESIS 2 ENDOTHELIAL INJURY leads to changes ON the vessel wall 1.Enhanced expression of cellular adhesion molecules on endothelium- monocytes in blood adhere and enter wall 2.Increased thrombogenicity with platelet adhesion 1.Increased LDL permeability – LDLs enter © 2005 Elsevier PATHOGENESIS 3 RESPONSE OF VESSEL WALL TO INJURY leads to – changes IN the vessel wall 1.Growth factors (PDGF) secreted by platelets, endothelium, macrophages, smooth muscle cells. 2.Myointimal cells proliferate 3. Macrophages (from blood) and smooth muscle cells (from media) migrate into the intima 4.Smooth muscle cells in intima synthesize extracellular matrix including collagen Atheroma: vascular smooth muscle cells (VSMCs) Schematic of intimal thickening, emphasizing smooth muscle cell migration and proliferation within the intima, with associated ECM synthesis. Intimal smooth muscle cells may derive from the underlying media or may be recruited from circulating precursors; they are shown in a different color from the medial cells to emphasize that they have a proliferative, synthetic, and noncontractile phenotype distinct from medial smooth muscle cells Downloaded from: StudentConsult (on 23 October 2011 11:51 PM) © 2005 Elsevier PATHOGENESIS 4 LIPID ACCUMULATION 1. Macrophages and myointimal cells engulf lipid, forming foam cells. Some die and extracellular lipid accumulates. 2. Oxidized lipids accumulate and cause further damage. 3. Activated MACROPHAGES1.recruit more macrophages 2.produce a) Free radicals which aggravate lipid oxidation b) Growth factors which stimulate VSMCs c) factors which induce death of VSMCs © 2005 Elsevier ANGIOGENESIS (neovascularization) facilitates: PATHOGENESIS 5 1.Lesion expansion 2.Monocyte trafficking 3.Hemorrhage into plaque VASCULAR SMOOTH MUSCLE CELLS 1.Synthesize COLLAGEN; fibrous cap is formed. 2.Secrete Bone Morphometric Protein with CALCIUM deposition, fragile/brittle cap © 2005 Elsevier Structure of the Atheromatous Plaque Soft yellow, lipid rich centre covered by a fibrous cap Core Cholesterol Necrotic debris FOAM cells (derived from macrophages and smooth muscle cells) © 2005 Elsevier Atheromatous Plaque in coronary artery π Poiseuille’s law: flow= pressure x x r4 8 x length x viscosity lumen lumen calcification © 2005 Elsevier Consequences/Complications of Atheroma Atherosclerotic stenosis (narrowing) and loss of vasodilation (loss of adaptive increased diameter and flow when needed) – Symptoms with activity/demand. Predictable? Acute plaque change (rupture, ulceration, thrombosis, haemorrhage) – Spontaneous (persistent?) symptoms. Unpredictable? Thrombosis Occlusion Growth of the plaque Embolus from the thrombus Vasoconstriction – Many local factors Vascular dilation/ectasia (due to structural weakness) aneurysm * Complications Complication of Atherosclerosis Atherosclerotic stenosis – Critical stenosis in coronaries:  70% occlusion angina, myocardial infarction  chronic Ischaemic Heart Disease – Mesenteric: ischaemic bowel – Cerebrovascular disease: Ischemic encephalopathy and stroke – Peripheral vascular disease: Intermittent claudication, rest pain and gangrene – Renovascular disease – Aortic aneurysm: * Acute plaque change: Plaque rupture and thrombosis of coronary Hemorrhage into the plaque (sudden expansion) © 2005 Elsevier ‘Vulnerable’ v ‘Stable’ plaque Atheroma is a dynamic process shoulder: mechanical stress riser in face of caliber changes Thin Thick Characteristics of Vulnerable plaquesthey are prone to complications Thin fibrous caps – The fibrous cap undergoes continuous remodeling – Collagen synthesis v collagen remodeling (role of inflammation and statins) – Loss of vascular smooth muscle cells (? due to lymphocyte mediated apoptosis) thinner cap – Matrix Metalloproteases (macrophages) versus TissueInhibitorsMPs (endos, VMSCs) and collagen balance Large lipid cores Increased inflammation Influences outside the vessel wall – adrenergic activity Learning Objectives After studying these topics, you will be able to: – Describe the aetiology (causes) and pathogenesis (development) of ATHEROMA (atherosclerosis) – Understand and list the main consequences of atheroma in each organ system – Discuss the causes and consequences of ‘vulnerable/unstable’ plaque 37