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CHD Newer Risk Factors

CHD Newer Risk Factors. An over view on Homocystinemia. Dr. R.V.S.N.Sarma M.D., M.Sc., (Canada). All are One. This not about the GOD There is only one disease – Over nutrition Its faces are many such as Over weight / Obesity Diabetes mellitus, IR, Syndrome X

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CHD Newer Risk Factors

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  1. CHDNewer Risk Factors An over view on Homocystinemia Dr. R.V.S.N.Sarma M.D., M.Sc., (Canada)

  2. All are One • This not about the GOD • There is only one disease – Over nutrition • Its faces are many such as • Over weight / Obesity • Diabetes mellitus, IR, Syndrome X • Atherosclerosis – HT- CHD – CVD – RVD – PVD • Hyper lipidemias – endothelial dysfunction • Wear and tear of joints …. So on • What are we to do ? - Avoid over-indulgence

  3. How much is much ? BMI = Weight in kgs Height2 in mts 70 1.65 x 1.65 BMI = = 25.71 Underweight < 20 Over weight > 25 to 30 Normal 20 to 25 Obesity >30 Waist / Hip ratio = 35” /38” = 0.92 Normal for Males < 0.90, Females <0.80

  4. Diets rich in Saturated Fat, Chol Sedentary Life Style Excess body weight/ Obesity Less perfect Genetic make-up Lipid abnormalities Atherosclerotic vascular disease CHD, CVD, PVD Macro-vascular Disease ROS tHcy

  5. AVD – Clinical Manifestations For every thing the common denominator is ED

  6. Lipid Peroxidation LDL, IDL Not normally taken up by the vessel wall ROS – Free radicals and Pro-oxidants Freely enters the vessel wall Oxidized LDL, IDL Macrophages Endothelium Scavenger pathway Foam Cells Cytokines, GF Atherosclerosis

  7. Risk Factors for AVD • Hyperhomocyst(e)inemia • Diabetes mellitus • Hypertension • Dyslipidemia • Positive family history, Smoking, obesity and physical inactivity Oxidative Stress AVD

  8. Free Radical Formation Homolytic fission of a covalent bond Single covalent bond A B Homolytic fission Heterolytic fission B A A B Free radicals Ions

  9. ROS damage biological tissues- membranes Reactive Oxygen Species Lipid peroxidation Protein denaturation DNA Damage Free radicals released Cell Dysfunction and death

  10. Classification • Preventive antioxidants -Ceruloplasmin, transferrin, lactoferrin • Enzyme antioxidants -Superoxide dismutase, catalase, glutathione peroxidase • Scavenging or ‘chain-breaking’ or ‘sacrificial’antioxidants -Vitamins A,C, and E

  11. ROS and their Antioxidants

  12. Reactive Oxygen Species (ROS) ROS are highly reactive….and can damage biological tissues and membranes

  13. What is Homocysteine ? Metabolism Digestion Protein diet Methionine 1)Homocysteine Auto-oxidation Protein synthesis 2)Homocystine 3) Homocysteine thiolactone HS-CH2-CH2-CH-COOH Generation of ROS NH2 Homocysteine • 1+2+3= homocyst(e)ine • homocyst(e)ine = tHcy • Homocyst(e)inemia=hyper - tHcy • Sulfur-containing amino acid • By product of methionine metabolism

  14. Homocysteine : Metabolic Pathways Remethylation Cycle Demethylation Cycle Diet Tetra hydrofolate Methionine Folic acid MTHFR Vitamin B6 (MS) Methyl tetrahydrofolate Homocysteine Vitamin B6 (C beta S) MS – Methionine synthase MTHFR – Methyl tetrahydro folate reductase C beta S – Cystathionine beta synthase Cystathionine Transsulfuration Pathway Cysteine Sulphate Glutathione

  15. Hyperhomocyst(e)inemia Blood Homocyst(e)ine Levels • Moderate to severe hyper – tHcy : established risk factor for AVD 1-4 • Hyper – tHcy • - 5-7 % of the general population • - 12-47 % of patients with AVD

  16. Causes of Hyperhomocyst(e)inemia • Nutritional : Vitamin deficiency Folic Acid Vitamin B12 Vitamin B6 • Genetic : Enzyme Abnormality • Drugs : Methotrexate, Phenytoin, Theophylline

  17. Homocysteine & Pathogenesis of AVD Homocysteine Auto-oxidation Generation of ROS H2O2 OH/O2 Oxidizes LDL Damages endothelium Lipid peroxidation Exposure of smooth muscle, subendothelium ¯ Nitric Oxide formation Foam cells (chol) Proliferation of SM cells, Chemotaxis ¯ Vasodilation Hypertension ATHEROSCLEROSIS

  18. Physicians Health Study • 271 male physicians who had MI and matched controls were studied • Various risk factors were analyzed • Plasma tHcy is significantly higher in those with MI compared to controls • The R.R for tHcy levels above 13 is 3.4 after adjusting for all other risk factors • 482 hyperlipedemic subjects – 72 % with ↑tHcy had atheroscleoris v/s 44 % without

  19. Treatment of Hyperhomocyst(e)inemia • Nutritional : Vitamin Supplimentation Folic Acid – 5 mg daily (Folvite) Supplementation of Vitamin B12 Supplementation of Vitamin B6 • Drugs : Care while using drugs like Methotrexate, Phenytoin, Theophylline C. Role of anti-oxidants – no RCTs

  20. Lp (a) or Little a • Similar to LDL molecule • a single apo-A is attached by a disulfide bond to apo-B 100 • Primary determinant is genetic • Normal value 20 mg %, > 30 high risk • It may compete with plasminogen because of structural similarity and so interfere with plasmin synthesis and thrombolytic pathway • Nicotinic acid, ? Benzafibrate, estrogens lower it

  21. True !

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