Arteriosclerosis & Atherosclerosis Ali Al Khader, M.D. Faculty of Medicine Al-Balqa’ Applied University Email: ali.alkhader@bau.edu.jo

Arteriosclerosis = hardening of arteries = arterial wall thickening + loss of elasticity …3 types: -Arteriolosclerosis -Monckeberg medial sclerosis -Atherosclerosis

Arteriosclerosis, cont’d Arteriolosclerosis, 2 types: Hyaline Hyperplastic …Both may cause ischemia Monckeberg medial sclerosis: - Calcific deposits in muscular arteries With age older than 50 years Clinically not significant

Atherosclerosis characterized by -intimal lesions called atheromas (or atheromatous or atherosclerotic plaques) …Atheromatous plaques are: raised lesions composed of soft lipid cores (mainly cholesterol and cholesterol esters, with necrotic debris) covered by fibrous caps

Atherosclerosis, epidemiology CAD (IHD) and atherosclerosis Developed more than developing USA more than Japan…but increasing now in Japan Vessels?

Atherosclerosis, risk factors -High dietary intake of cholesterol and saturated fats (present in egg yolks, animal fats, and butter, for example) raises plasma cholesterol levels. Conversely, diets low in cholesterol, and/or containing higher ratios of polyunsaturated fats, lower plasma cholesterol levels. -Omega-3 fatty acids (abundant in fish oils) are beneficial, whereas (trans)-unsaturated fats produced by artificial hydrogenation of polyunsaturated oils adversely affect cholesterol profiles. -Exercise and moderate consumption of ethanol raise HDL levels, whereas obesity and smoking lower them. -Statins are a widely used class of drugs that lower circulating cholesterol levels by inhibiting hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in hepatic cholesterol biosynthesis …The most important …e.g., familial hypercholesterolemia …small percentage of the cases but strongly associated …AD …mostly polygenic (when associated with HTN, DM..etc.) > 40 20%: no identified risk factors …For example, in previously healthy women more than 75% of cardiovascular events occur in those with LDL cholesterol levels below 160 mg/dL (a cut-off value generally considered to connote low risk) Increases cholesterol

Atherosclerosis risk factors, cont’d Inflammation is very important and present in all stages …so CRP level is important CRP levels strongly and independently predict the risk of myocardial infarction, stroke, peripheral arterial disease, and sudden cardiac death, even among apparently healthy persons Also locally, CRP secreted by cells within atherosclerotic plaques can activate endothelial cells, increasing adhesiveness and inducing a prothrombotic state CRP is reduced by smoking cessation, weight loss, and exercise statins reduce CRP levels independent of their LDL cholesterol-lowering effects, suggesting a possible anti-inflammatory action of these agents

Atherosclerosis risk factors, cont’d Hyperhomocysteinemia …Homocystinuria, due to rare inborn errors of metabolism …early-onset vascular disease …although low folate and vitamin B12 levels can increase homocysteine, supplemental vitamin ingestion does not affect the incidence of cardiovascular disease Metabolic syndrome: Insulin resistance hypertension dyslipidemia (elevated LDL and depressed HDL) hypercoagulability Proinflammatory state

Atherosclerosis risk factors, cont’d Lipoprotein(a) levels …an LDL-like particle…apolipoprotein B-100 linked to apolipoprotein A Elevated levels of procoagulants …thrombin initiates inflammation through cleavage of protease-activated receptors (PARs) on leukocytes, endothelium, and other cells, may be particularly atherogenic lack of exercise and living a competitive, stressful life style (“type A personality”)

Atherosclerosis, pathogenesis Hemodynamic disturbances are very important …plaques tend to occur at ostia of exiting vessels, at branch points, and along the posterior wall of the abdominal aorta, where there is turbulent blood flow -increased LDL cholesterol levels -decreased HDL cholesterol levels -Increased levels of lipoprotein(a) nephrotic syndrome, alcoholism, hypothyroidism, or diabetes mellitus…are causes of abnormal lipid metabolism

Atherosclerosis, pathogenesis Chronic hyperlipidemia, particularly hypercholesterolemia: -impaired endothelial cell function by increasing local oxygen free radical production …also oxygen free radicals accelerate NO decay, damping its vasodilator activity -lipoproteins accumulate within the intima, where they are hypothesized to generate two pathogenic derivatives, oxidized LDL and cholesterol crystals. -LDL is oxidized through the action of oxygen free radicals generated locally by macrophages or endothelial cells and ingested by macrophages through the scavenger receptor, resulting in foam cell formation. -Oxidized LDL stimulates the local release of growth factors, cytokines, and chemokines, increasing monocyte recruitment, and also is cytotoxic to endothelial cells and smooth muscle cells

Atherosclerosis, pathogenesis Dysfunctional endothelial cells…more adhesion to WBCs and more inflammation Engulfment of lipids by macrophages…more activation of WBCs and more oxidation of LDL T cells interact with macrophages…chronic inflammation …the result of released mediators is: proliferation of smooth muscle & deposition of ECM in the intima …PDGF, TGF-alpha & FGF…proliferation of SM cells …this will convert the lesion from fatty streak to atheroma

Atherosclerosis, morphology 1- Fatty streaks: -minute yellow, flat macules that coalesce into elongated lesions, 1 cm or more in length -composed of lipid-filled foamy macrophages but are only minimally raised and do not cause any significant flow disturbance -although fatty streaks may evolve into plaques, not all are destined to progress -Fatty streaks can appear in the aortas of infants younger than 1 year of age and are present in virtually all children older than 10 years

2- Atherosclerotic Plaque

Atherosclerotic plaques have three principal components: (1) cells, including smooth muscle cells, macrophages, and T cells (2) extracellular matrix, including collagen, elastic fibers, and proteoglycans (3) intracellular and extracellular lipid

Overview

Clinical consequences of atherosclerosis Ischemia and aneurysms Mainly large elastic arteries (aorta, carotid and iliac) and muscular arteries Risk of rupture depends on multiple factors

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