Blood Vessels and Atherosclerosis (PDF)

BLOOD VESSELS AND ATHEROSCLEROSIS Associate Professor Vinod Gopalan Medical Education & Histopathology School of Medicine & Dentistry Atherosclerosis underlies the pathogenesis of coronary, cerebral and peripheral vascular disease, and causes more morbidity and mortality (roughly half of all deaths)...

BLOOD VESSELS AND ATHEROSCLEROSIS Associate Professor Vinod Gopalan Medical Education & Histopathology School of Medicine & Dentistry Atherosclerosis underlies the pathogenesis of coronary, cerebral and peripheral vascular disease, and causes more morbidity and mortality (roughly half of all deaths) in the Western world than any other disorder. Histology- Blood Vessels Intima Single layer of endothelial cells Media Smooth muscle and elastic fibers Adventitia Connective tissue and nerve fibers protect from trauma and abrasions Histology- Blood Vessels http://www.lab.anhb.uwa.edu.au/mb140/corepages/vascular/vascular.htm Tunica Intima ❑The intima consists of a layer of endothelial cells lining the lumen of the vessel. ❑In arteries, the intima is separated from the media by an internal elastic lamina, which contains maintains integrity fenestrae (windows) through which substances can diffuse to the underlying tissue. Tunica Media layers different with larger vessel ❑The media consists mainly of concentric layers of helically arranged smooth muscle cells, with variable amounts of elastic fibers and reticular fibers. capillary - absent elastic layer strength ❑In larger muscular arteries, an external elastic lamina separates the media from the adventitia. Histology- Blood Vessels http://www.lab.anhb.uwa.edu.au/mb140/corepages/vascular/vascular.htm Tunica Adventitia. ❑The adventitia consists of longitudinally arranged collagen and elastic fibers. stretch + contract ❑The adventitial layer gradually merges with the surrounding connective tissue. ❑In large veins such as the vena cava, bundles of smooth muscle are found in the adventitia. contract and move Histology- Blood Vessels Innervation Most blood vessels that contain smooth muscle in their walls are supplied with a profuse network of unmyelinated sympathetic nerve fibers. Vasa Vasorum In large vessels, vasa vasorum (vessels of the vessels) provide nutrients and oxygen to the adventitia and the media, since these layers are too thick to be nourished solely by diffusion from the lumen. Histology- ARTERY ▪ Arteries are classified according to their size into large elastic arteries, muscular arteries of medium or large diameter and arterioles. ▪ In general the walls of arteries are thicker than the walls of veins of the same diameter and contain more smooth muscle. all have internal elastic lamina Elastic elastic fibres Muscular Arteriole 2-3 layers of SM less formed external elastic lamina http://histology-online.com/ http://faculty.une.edu/com/abell/histo/histolab3a.htm Histology- ARTERY Elastic arteries Muscular arteries Aorta and larger branches, pulmonary artery Coronary, renal, hepatic Small arteries (< 2 mm) Penetrate tissues and organs Arterioles (20-100 m) Regulation of systemic blood pressure ❑The luminal diameter of artery gradually decrease with each branching. Histology- ARTERY Elastic Arteries ❑ Elastic arteries: aorta and larger branches (subclavian, common carotid, iliac aa.), pulmonary a. ❑ These are also called conducting arteries. flexible ❑ Tunica Media with abundant elastic fibers arranged in layers, which alternate with layers of smooth muscle cells Histology- ARTERY Elastic Arteries The intima- consists of single layer of flattened endothelium. The thick subendothelial space contains cells akin to smooth muscle cellsmyointimal cells. like tissue damage first damage Clinical Significance: With increasing age, the myointimal cells accumulate lipid and the intima progressively thickens which can in turn progress in to atherosclerosis. The media- consist of layers of concentrically arranged elastic laminae, which contain perforations to allow diffusion of nutrients from the lumen. Histology- ARTERY Elastic Arteries Histology- ARTERY Elastic Arteries first damage in endothelial cells red blood cells myointimal cells Histology- ARTERY Muscular Arteries Muscular arteries: coronary, renal, hepatic. ❑ In muscular arteries the elastic tissue is largely concentrated as two well defined elastic sheets. 1. Internal elastic lamina between the tunica intima and the tunica media. strong elastic lamina 2. External elastic lamina which lies between the tunica media and the adventia. ❑ The tunica media is composed of concentrically arranged smooth muscle fibres with scanty elastic fibres between them. CORONARY ARTERY coagulation endothelial SM nuclei - elastic external elastic lamina internal elastic lamina external elastic lamina and SM fibres http://histology.med.umich.edu/medical/cardiovascular-system Muscular Arteries- Function ▪ The function of the muscular distributing arteries is to furnish blood to the various organs. ▪The muscle layer in these arteries can control the flow of blood by contracting, or not contracting, in response to local chemical or neural input. Artery-Histology Arteriole ▪These generally contain 1 to 3 layers of concentrically arranged smooth muscle cells in the media. ▪They contain a prominent internal elastic lamina, but no external elastic lamina. ▪The intima consists of the endothelial cells lying on a thin subendothelial layer. The adventitia is thin. http://faculty.une.edu/com/abell/histo/histolab3a.htm BLOOD VESSELS -CAPILLARIES Capillaries are composed of a single layer of endothelial cells rolled up in the form of a tube. Their diameter is so small (less than 10µm) that red blood cells must pass through in single file. Capillaries connect arterioles to venules. flow from artery to vein http://www.histology.leeds.ac.uk/circulatory/capillaries.php good tight junction No SM fibres single RBC inside http://www.histology.leeds.ac.uk/circula tory/capillaries.php myocontractile cells - pericytes contract to move blood BLOOD VESSELS -CAPILLARIES pericyte RBC http://www.histology.leeds.ac.uk/circulatory/capillaries.php Capillary in adipose tissue. The delicate capillary wall is supported by fine peri-vascular connective tissue. Note the single erythrocyte within the capillary's lumen. BLOOD VESSELS -CAPILLARIES Capillary in Liver. Sinusoids in liver act as capillary channels for driving blood cells towards central vein sinus - capillaries Hepatocytes Artery vs Vein Artery Vein no well formed tunica intima more collapsed # Internal elastic lamina is absent SELF ASSESSMENT Identify the structure arrowed A-Muscular artery B- Elastic artery C- Arteriole D- Large capillary SELF ASSESSMENT Identify the structure arrowed A-Endothelial cells B- Internal elastic lamina C- Monocyte D- Myointimal cells ATHEROSCLEROSIS ATHEROSCLEROSIS The likelihood of atherosclerosis is determined by the combination of acquired (e.g., cholesterol levels, smoking, hypertension) and inherited (e.g., LDL receptor gene mutations) risk factors. intima larger w/ atheroma ischaemia in tunica media They cause intimal lesions called atheromas (also called atheromatous or atherosclerotic plaques) that protrude into vessel lumens Besides mechanically obstructing blood flow, atherosclerotic plaques can rupture leading to catastrophic obstructive vascular thrombosis. lead to aneurism Atherosclerotic plaque can also increase the diffusion distance from the lumen to the media, leading to ischemic injury and weakening of the vessel wall, changes that may result in aneurysm formation. ATHEROSCLEROSIS Patchy intimal thickening with deposition of lipid and fibrosis, causing narrowing of the lumen. It can rupture and cause sudden occlusion. Mainly affects large arteries (aorta) & medium-sized arteries (coronary & cerebral arteries) Coronary artery atheroma atheroma intima ATHEROSCLEROSIS Atheromatous plaques are raised lesions composed of soft friable (grumous) lipid cores (mainly cholesterol and cholesterol esters, with necrotic debris) covered by fibrous caps. Atherosclerotic plaques also are prone to rupture, an event that may result in thrombosis and sudden occlusion of the vessel lots of necrotic tissue has a cap - stable weak - risk of rupture to lumen - thrombus Atheromatous plaque. ATHEROSCLEROSIS RISK FACTORS & MULTIPLICATIVE EFFECT Two factors increase risk approximately four-fold, and three (i.e., hyperlipidemia, hypertension, and smoking), increase risk by a factor of seven. AETIOPATHOGENESIS HYPERLIPIDEMIA The major component of serum cholesterol associated with increased risk is low-density lipoprotein (LDL) cholesterol (“bad cholesterol”). LDL is the complex that delivers cholesterol to peripheral tissues; in contrast, high-density lipoprotein (HDL) is the complex that mobilizes cholesterol from the periphery (including atheromas) and transports it to the liver for excretion in the bile. macrophages - release free radicals HYPERTENSION Contributes to the risk of atherosclerosis and coronary artery disease due to the added force against the artery walls. This pressure can initiate endothelial damage and in turn narrowing of the arterial wall which can later enhance cholesterol plaque buildup. AETIOPATHOGENESIS CIGARETTE SMOKING Free radicles directly from the smoke (or by activating endogenous free radicles) will increase oxidative stress and this later triggers the leukocyte and platelet activation and thus initiate atherosclerotic process. neutrophil -elastase J Am Coll Cardiol 2004;43:1731–7) DIABETES MELLITUS Induces hypercholesterolemia and markedly increases the risk of atherosclerosis. There is also an increased risk of stroke and a 100-fold increased risk of atherosclerosisgas gangrene - clostridium induced gangrene of the lower extremities. dry gangrene some internal organs - wet gangrene INFLAMMATION Inflammation is present during all stages of atherogenesis and is intimately linked with atherosclerotic plaque formation and rupture. C-reactive protein (CRP) is one of the most sensitive circulating markers of inflammation to correlate ischemic heart disease release endothelin Cardiovascular Research 71 (2006) 30 – 39 risk. helps chemokines and lymphocytes CRP increases the release of endothelin-1 and upregulates adhesion molecules and chemoattractant chemokines in endothelial cells and vascular smooth muscle cells. ATHEROSCLEROSIS- PATHOGENESIS “RESPONSE TO INJURY” HYPOTHESIS This model views atherosclerosis as a chronic inflammatory and healing response of the arterial wall to endothelial injury. Lesion progression occurs through interaction of modified lipoproteins, monocyte-derived macrophages, and T lymphocytes with endothelial cells and smooth muscle cells of the arterial wall. ATHEROSCLEROSIS- PATHOGENESIS first step of atherosclerosis Step 1 Step 4 fibrous cap injury Step 2 Step 5 Step 3 migrates ATHEROSCLEROSIS- PATHOGENESIS Endothelial injury and dysfunction, causing (among other things) increased vascular permeability, leukocyte adhesion, and thrombosis Accumulation of lipoproteins (mainly LDL and its oxidized forms) in the vessel wall Monocyte adhesion to the endothelium, followed by migration into the intima and transformation into macrophages and foam cells Platelet adhesion Factor release from activated platelets, macrophages, and vascular wall cells, inducing smooth muscle cell recruitment, either from the media or from circulating precursors Smooth muscle cell proliferation, extracellular matrix production, and recruitment of T cells Lipid accumulation both extracellularly and within cells (macrophages and smooth muscle cell) ATHEROSCLEROSIS- PATHOGENESIS sequence of events Endothelial injury/dysfunction Endothelial injury makes the endothelial cells dysfunctional. This will leads to increased permeability, enhanced leukocyte adhesion, and altered gene expression in the endothelium. Two major causes 1. hemodynamic disturbances and 2. hypercholesterolemia. LDL oxidised Sequence of cellular interactions in atherosclerosis ATHEROSCLEROSIS- PATHOGENESIS Hemodynamic disturbances Non-turbulent laminar flow leads to the induction of endothelial genes whose products protect against atherosclerosis. Turbulent blood flow can induce changes in gene expression (atheroprotective genes) can leads to endothelial damage. Hypercholesterolemia Leads to endothelial dysfunction by increasing local oxygen free radical production. Lipoproteins which accumulate in T.initma generate oxidized LDL and cholesterol crystals. LDL is oxidized through the action of oxygen free radicals generated locally by macrophages or ECs and ingested by macrophages- Foamy macrophages. Small extracellular cholesterol crystals can activate innate immune cells such as monocytes and macrophages to produce IL-1 and other pro-inflammatory mediators. ATHEROSCLEROSIS- PATHOLOGY GROSS (MACROSCOPIC) PATHOLOGY Fatty streaks Fatty streaks are composed of lipid-filled foamy macrophages. These lesions are not sufficiently raised to cause any significant flow disturbances. Some but not all fatty streaks can evolve into plaques. small streaks of fat tissue no obstruction become a mass Atherosclerotic Plaque. Plaques are formed with intimal thickening and lipid accumulation. Atheromatous plaques are white-yellow and encroach on the lumen of the artery. Plaques vary in size but can coalesce to form larger masses. intimal thickening - filled ATHEROSCLEROSIS- PATHOLOGY ATHEROMA Cholesterol clefts in the atheroma MICROSCOPIC PATHOLOGY 1. Fibrous cap – collagen rich connective under tunica intima tissue 2. Intra-intimal collections of plasma derived lipid 3. Basal zone of necrosis, rich in lipid 4. Lipid (cholesterol clefts and foamy macrophages) Stable plaques tend to have a dense fibrous cap, minimal lipid accumulation and little inflammation, whereas unstable plaques have thin caps, large lipid cores, and relatively dense inflammatory infiltrates. ATHEROSCLEROSIS- LIVE PATHOLOGY DEMONSTRATION CLICK for E-slide collagen elongated fibres some necrosis foamy macrophages dark, round yellow deposits droplets, bubbles ischaemia led by plaque take out plaque SELF ASSESSMENT ATHEROSCLEROTIC PLAQUE unstable Discuss the differences between atherosclerotic plaques shown in image A and B plaque rupture The arrow shown is indicative of___________________ Discuss the LIKELY complication or natural history embolism risk stroke ATHEROSCLEROSIS- COMPLICATIONS Complications of Atheroma stable at the moment Haemorrhage Ulceration Calcification Thrombosis fatal Aneurysms ATHEROSCLEROSIS- COMPLICATIONS CLINICAL EFFECTS 1. Obstruction of blood flow → ischaemia 2. Injury to plaque → thrombosis 3. Medial weakening beneath the plaque → aneurysm ATHEROSCLEROSIS- SUMMARY Atherosclerosis is an intimal-based lesion composed of a fibrous cap and an atheromatous core; the constituents of the plaque include smooth muscle cells, extracellular matrices, inflammatory cells, lipids, and necrotic debris. Atherogenesis is driven by an interplay of vessel wall injury and inflammation. The multiple risk factors for atherosclerosis all cause endothelial cell dysfunction and influence inflammatory cell and smooth muscle cell recruitment and stimulation. Atherosclerotic plaques develop and grow slowly over decades. Stable plaques can produce symptoms related to chronic ischemia by narrowing vessel lumens, whereas unstable plaques can cause dramatic and potentially fatal ischemic complications related to acute plaque rupture, thrombosis, or embolization. SELF ASSESSMENT SELF ASSESSMENT Among the pathological features below, list the appropriate ones for fatty streak and atherosclerotic plaque below. A. Luminal narrowing B. Endothelial dysfunction C. Foam cell formation D. Smooth muscle proliferation E. Lipoprotein entry F. Fibrous capsule Pathology Fatty streak Atherosclerotic Plaque progression KEY FEATURES (In order) BEC BECDFA SELF ASSESSMENT An 80-year-old man with a lengthy history of smoking survived a small myocardial infarction several years ago. He now reports chest and leg pain during exercise. On physical examination, his vital signs include temperature of 36.9°C, pulse 81/min, respirations 15/min, and blood pressure 165/100 mm Hg. Peripheral pulses are poor in the lower extremities. There is a 7-cm pulsating mass in the midline of the lower abdomen. Which of the pathogenic mechanism is responsible for the pulsating mass in the lower abdomen. aneurism - make media weakened, blood flow needs to be there aneurism A. Loosening of tunica media B. Loosening of tunica media and plaque formation C. Fatty streaks formation in the abdominal aorta N D. Occlusion of vascular lumen by plaque formation E. Mural thrombosis possible SELF ASSESSMENT Dysfunction of which of the following cell types is most important in the initial formation of atherosclerotic lesions? A. B. C. D. E. Macrophages Endoepithelial cells Internal elastic lamina Endothelial cells Smooth muscle cells SELF ASSESSMENT 5 This image shows one of the complications of atherosclerosis. Which of the following would be the most likely one Aorta D A. B. C. D. E. Ulceration Calcification Thrombosis Aneurysm Rupture REFERENCES 1. 2. 3. 4. 5. Functional Histology 2e, Jeffrey B Kerr WHEATER’S functional histology 5E Robbin’s textbook of Pathology Dr Mary An- Anatomical Pathologist, GCUH Referred websites- Images Thank You Email: [email protected]