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![Saturday, August 21, 2021
Homocysteine
Homocysteine degrades and inhibits the formation of the three main structural
components of arteries: collagen, elastin and proteoglycans. In proteins, homocysteine
permanently degrades cysteine disulfide bridges and lysine amino acid
residues,[7] affecting structure and function.](https://image.slidesharecdn.com/1797027-231009001036-774d32d1/85/17970_27-1Atherosclerosis-pptx-20-320.jpg)
17970_27.1Atherosclerosis.pptx
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- 2. • PA 27.1:Describe the pathogenesis of atherosclerosis • PA 27.5 Describe the epidemiology,risk factors of Ischemic Heart Disease Saturday, August 21, 2021
- 3. SPECIFIC LEARNING OBJECTIVES •Define atherosclerosis, enumerate risk factors of and outline the steps of the proposed pathogenesis • Describe the morphology of atherosclerosis with special reference to the morphologic changes in a complicated plaques • Discuss the systemic effects ( organ specific) and the clinical significance (complications) of atherosclerosis Saturday, August 21, 2021
- 4. Atherosclerosis is characterized byintimal lesions called atheromas that protrude into vessel lumens. A plaque consists of a raised lesion with a soft, yellow pasty gruelike or grumous core of lipid (mainly cholesterol and cholesterol esters) covered by a white fibrous cap FIBROUS CAP NECROTIC CENTER MEDIA
- 5. Major Risk Factors forAtherosclerosis CONSTITUTIONAL • Increasing age • Male gender (premenopausal women are relatively protected against atherosclerosis) • Family history of premature CAD • Genetic abnormalities MODIFIABLE • Dyslipidemia (LDL; HDL) • Hypertension • Cigarette smoking • Diabetes • C-reactive protein • Obesity • Lack of Exercise • Others: lipoprotein a; homocystinemia; infection
- 6. Age & Gender • clinicallymanifests in middle age or later. Between ages 40 and 60 the incidence of MI increases fivefold. • premenopausal women are relatively protected against atherosclerosis . • After menopause, the incidence increases and at older ages actually exceeds that of men. • Family history is the most significant independent risk factor for atherosclerosis. • Familial predisposition to atherosclerosis and IHD is usually multifactorial. • Certain mendelian disorders (e.g., familial hypercholesterolemia)are associated with small % of atherosclerosis.
- 7. Hyperlipidemia • hypercholesterolemia—is amajor risk factor for atherosclerosis; • The major component associated with increased risk is • Low-density lipoprotein (LDL) cholesterol (“bad cholesterol”); • higher levels of HDL correlate with reduced risk. • High dietary intake of cholesterol, saturated fats (present in egg yolks, animal fats, and butter, for example), trans-unsaturated fats Raises plasma cholesterol levels. • Conversely, diets with higher ratios of polyunsaturated fats & Omega-3 fatty acids Lower cholesterol
- 8. Saturday, August 21,2021 Ratio of total Cholesterol to HDL Ratio of LDL to HDL Risk Men women Men Women Very low (1/2 average) <3.4 <3.3 1 1.5 low risk 4.0 3.8 Average risk 5.0 4.5 3.6 3.2 Moderate (2x average) 9.5 7.0 6.3 5.0 High risk (3x risk) >23 >11 8 6.1 Risk LDL Total C Triglycerides HDL Optimal <100 Undesirable <40 Near optimal 100-129 Desirable >60 Desirable <200 < 130 (All in mg/dL) Normal < 150 Borderline 130-159 200-239 150-199 High 160-189 >240 200-499 Very High >190 >= 500
- 9. Hypertension • both systolic& diastolic levels are important. • On its own, hypertension increases the risk of IHD by approximately 60% • Hypertension is the most important cause of left ventricular hypertrophy Cigarette smoking • Uncombustable ROS, Nic, Actn of endothelium • well-established risk factor. • Prolonged (years) smoking of one pack of cigarettes or more daily doubles the death rate from IHD. • Cessation of Smoking reduces the risk.
- 10. Diabetes mellitus Induces • Hypercholesterolemia& glycation end prdts • increases the risk of atherosclerosis. • the incidence of MI is twice as high • increased risk of stroke • 100-fold increased risk of atherosclerosis-induced gangrene of the lower extremities. Others • Inflammation: is present during all stages of atherogenesis. CRP levels are used in risk stratification algorithms • Hyperhomocystinemia. Degrades fibers • The metabolic syndrome: abnormalities associated with insulin resistance and adipose tissue signaling • Lipoprotein (a) (altered LDL that contains apolipoprotein B – 100 portion of LDL linked with APO LP-A levels are associated with coronary and cerebrovascular disease risk.
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- 12. Pathogenesis ❖ Endothelial injury, ✓Accumulation of lipoproteins (mainly LDL and its oxidized forms) in the vessel wall ❑ Monocyte by migration into the intima and transformation into macrophages and foam cells • Platelet adhesion • Factor release from activated platelets, macrophages, and vascular wall cells, • Smooth muscle proliferation and ECM production • Lipid accumulation both extracellularly and within cells (macrophages and smooth muscle cells) Saturday, August 21, 2021
- 13. (Oxidized LDL) Response toinjury in atherogenesis
- 14. Saturday, August 21,2021 MORPHOLOGY
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- 16. Fatty Streak –?Is It Pathological ! Fatty streaks with formation of oxidised LDL is an evolutionary adaptation in the foetus; Antibodies developed against oxLDL protects the foetus against streptococcus pneumoniae sepsis Almost every north American child over the age of 3y has some degree of aortic fatty streaks; Coronary streaks appear 5 – 10 years later Fatty streaks are the earliest lesions in atherosclerosis. They are composed of lipid-filled foamy macrophages & form elongated flat streaks 1 cm or more in length.
- 17. Saturday, August 21,2021 Fatty Streak – When Does It Become Pathological? • When endothelium becomes dysfunctional • When there is excessive oxidation of LDL (atheroma) • When macrophages/foam cells become activated (recruits)
- 18. Saturday, August 21,2021 Foam Cell Formation N Engl J Med 1999;340:115-126 LDL LDL Endothelium Vessel Lumen Monocyte Macrophage Scavenger receptor Adhesion Molecules Foam Cell Intima Modified LDL Cytokines Cell Proliferation (Smooth muscle) Matrix Degradation Growth Factors Metalloproteinases MCP-1
- 19. Saturday, August 21,2021 Role of HDL (also Apo A1 – Milano) LDL LDL Endothelium Vessel Lumen Monocyte Modified LDL Macrophage MCP-1 Adhesion Molecules Cytokines Intima HDL Inhibit Oxidation of LDL HDL Inhibit Adhesion Molecule Expression Foam Cell HDL Promote Cholesterol Efflux “Inflammation impairs reverse cholesterol transport in vivo” Cockerill GW et al. Arterioscler Thromb Vasc Biol 1995;15:1987-1994. Circulation. 2009 Mar 3;119(8):1135-45. Epub 2009 Feb 16. http://my.clevelandclinic.org/heart/news/hot/hdlapoa1.aspx
- 20. Saturday, August 21,2021 Homocysteine Homocysteine degrades and inhibits the formation of the three main structural components of arteries: collagen, elastin and proteoglycans. In proteins, homocysteine permanently degrades cysteine disulfide bridges and lysine amino acid residues,[7] affecting structure and function.
- 21. Saturday, August 21,2021 Atheromatous Plaque
- 22. Vulnerable Plaques generallyhave three histologic hallmarks compared to stable plaques 1.a larger lipid core (>40 percent of total lesion area), 2. a thinner fibrous cap (65 to 150 micro-meters), and 3. many inflammatory cells Vulnerable Plaque
- 23. Atherosclerotic plaque rupture.Acute coronary thrombosis superimposed on an atherosclerotic plaque with focal disruption of the fibrous cap, triggering fatal myocardial infarction. An arrow points to the site of plaque rupture. Plaque Rupture
- 24. clinically important changesin Atherosclerotic plaques • thrombosis. • Haemorrhage into a plaque. • Atheroembolism. • Aneurysm formation. Saturday, August 21, 2021
- 25. • Large elasticarteries (e.g., the aorta, carotid, and iliac arteries) and large and medium-sized muscular arteries (e.g., coronary and popliteal arteries) are the major targets of atherosclerosis.
- 26. Summary of thenatural history, morphologic features, main pathogenic events, and clinical complications of atherosclerosis.