ENDOTHELIAL DYSFUNCTION - ED A Marker of Cardio Vascular Disease

1. ENDOTHELIAL DYSFUNCTION - EDA Marker of Cardio Vascular Disease Dr.R.V.S.N. Sarma., M.D., M.Sc., (Canada) Consultant Physician and Chest Specialist Visit us at : www.drsarma.in

2. The Endothelium

3. Tunica intima LUMEN Tunica adventitia Tunica media

4. LUMEN Can you see the endothelium? What type of tissue is it? Why?

6. Note the individual Endothelial Cells

9. Vasoconstriction and dilatation Normal Vasoconstriction Vasodilatation

10. Vasoconstriction and dilatation ↓Resistance to flow ↑ Resistance to flow Vasodilatation Vasoconstriction

11. Endothelial Apoptosis Apoptosed Normal

12. The EndotheliumAs an Endocrine Organ

13. The Vascular Endothelium • The inner lining of our bloods vessels is the Endothelium • It plays a central role in regulating the vasomotror tone & • Local homeostasis & control of the coagulation process • Endothelial cells have ‘Sensors’ and release ‘Mediators’ • ‘Mediators’ are the functional molecules on the cell surface

14. Oxidative stress and Endothelial dysfunction • Oxidative Stress leads to ED • Endothelial dysfunction is mainly due to reduced bioavailability and bioactivity of Nitric Oxide (NO) • It is also a physiological process • Takes place gradually by age and menopause.

15. The Effects of ED • Oxidant stress and Endothelial dysfunction are major factors for atherosclerosis – the common pathway– • for most of the cardiovascular risk factors including Hypertension, DM, Dyslipidemia and Smoking. • Both endothelial dysfunction and oxidant stress result in clinical conditions - Heart failure, IHD and MI

16. Vascular Endothelial Mediators Include the following • Nitric oxide (NO) • Cycloxygenase (CxO) • Endothelin-1 (ET-1) • Endothelium Depolarisation Factor (EDF) • And many others - thus • It is the largest endocrine gland

17. Nitric Oxide (NO) • Half-life of NO, is affected by its chemical reaction and inactivation by superoxide anion • NO is the most abundant free-radical in the body • It is the only biological molecule in high concentrations to out-compete superoxide dismutase for superoxide • NO has an anti-thrombogenic & anti-atherogenic role

18. Protective actions of NO Endothelial NO has the following actions • Smooth muscle relaxation and vasodilatation • Essential for regulation of blood pressure • Reduces proliferation of vascular smooth muscle • Protects blood vessel intima from injurious consequences of platelet aggregation

19. ED and NO ↓ NO deficiency in the vessel wall promotes • Inflammation • Oxidation of lipoproteins • Smooth muscle proliferation • Accumulation of lipid rich material • Platelet activation and thrombus formation Finally results in atherosclerosis.

20. The Endothelium inHealth and Disease

21. Genes Coronary Risk Factors Endothelial Dysfunction NO ↑ Inflammation ↑ Thrombosis Coronary Heart Disease The Essential Components The Universal Damage

22. (L-NMMA) =N(G)-mono-methyl-L-arginine

24. Regulatory Functions of the EndotheliumNormal Dysfunction Vasodilation Vasoconstriction NO, PGI2, EDHF, BK, C-NP ROS, ET-1, TxA2, A-II, PGH2 Thrombolysis Thrombosis tPA, Protein C, TF-I, vWF PAI-1, TF-α, Tx-A2 Platelet Disaggregation NO, PGI2 Adhesion Molecules CAMs, P,E Selectins Antiproliferation NO, PGI2, TGF-, Hep Growth Factors ET-1, A-II, PDGF, ILGF, ILs Inflammation ROS, NF-B Lipolysis LPL Vogel R

25. Clinical Sequelae

26. Oxidative Stress: Endothelial Dysfunction and CAD/Renal Risk Factors Homocysteine Estrogen deficiency Smoking LDL Diabetes Hypertension O2Endothelial Cells and  H2O2 Vascular Smooth Muscle Endothelial Dysfunction Lipid deposition Thrombosis Apoptosis VSMC growth Leukocyte adhesion Vasoconstriction

27. Can We MeasureEndothelial Function ??

28. Coronary Arteries Epicardial Artery Diameter  with ACh CBF  with ACh Epicardial Artery Diameter  with Adenosine Forearm Brachial Artery Diameter  with Arterial Occlusion FMD Forearm Blood Flow with ACh Clinical Methods for Assessing Endothelium - Dependent Dilation

29. Comparison of Brachial and Coronary Flow-Mediated Vasodilation

30. CVE’s over 7.7 Years in 147 Subjects with CAD According to Coronary Artery Responses to Ach, Cold Pressor, and FMD CVE’s

31. CVE’s over 4 Years in 176 Subjects without CAD as per CVR and CA Diameters Changes with ACh

32. Effect of ACh-Induced Forearm Vasodilation on CVE’s (%) in 225 Never Treated HTN cases

33. CVE’s According to FBF Responses to ACh and I.V. Vitamin C in 281 Subjects with CHD ACh-induced FBF Responses Vitamin C Responses

34. Brachial Artery Flow-Mediated VasodilationBaseline5 MinutesPost-OcclusionBlood Pressure Cuff Occlusion – 1 Minute Release 3.6 mm 3.1 mm

35. Can Endothelial Dysfunction help in Diagnosis of CVD ??

36. CHD Events over 5 Years in 76 CAD Patients According to Brachial Artery FMD

37. 5-Year Outcome in 350 Postmenopausal Hypertensive Women with controlledBP (<140/90) Change in BAFMD  

42. Can Endothelial Dysfunction predict prognosis of CVD ??

46. Can Endothelial Dysfunction predict HTN and T2DM ??

49. What is the Rx. for ED ??

50. What is the Rx. for Endothelial Dysfunction? • Control of all the known CV risk factors • Main focus on the big six – DM, HTN, Lipids, Obesity, Smoking, Sedentary life style • Diet and physical activity are vital in Rx of ED • Statins are the first line treatment for ED • Glitazones have proven value to improve ED • Insulin and Rx. Insulin resistance improves ED