1. ENDOTHELIAL DYSFUNCTION - ED A Marker of Cardio Vascular Disease
Dr.R.V.S.N. Sarma., M.D., M.Sc., (Canada)
Consultant Physician and Chest Specialist
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2. The Endothelium

3. Tunica intima
LUMEN
Tunica adventitia
Tunica media

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

12. The Endothelium As 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 in Health and Disease

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

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

24. Regulatory Functions of the Endothelium Normal 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
 O Endothelial Cells and
 H2O2 Vascular Smooth Muscle
Endothelial Dysfunction
Oxidative Stress: Endothelial Dysfunction and CAD/Renal Risk Factors
A variety of conditions or insults listed at the top of the illustration that are known risk factors for either coronary artery disease (CAD), progressive renal insufficiency, or both, adversely affect endothelial cell or vascular smooth muscle cell function by increasing the formation of reactive oxygen species such as superoxide anion and hydrogen peroxide. The resultant reduction in the actions of endothelium-derived vasodilators/growth inhibitors such as prostacyclin and nitric oxide with maintenance or increased formation of endothelium-derived vasoconstrictors/growth promoters, such as angiotensin II, endothelin-1, and PAI-1, has significant vascular and renal pathophysiological consequences. Some of the mechanisms by which progressive coronary and renal injury occur include increased apoptosis or programmed cell death that contributes to vascular wall remodeling, activation of cell adhesion molecules resulting in adherence of both mononuclear and polymorphonuclear leukocytes to the vascular wall with subsequent infiltration, deposition of oxidized lipids in the vessel wall, vasoconstriction, both hypertrophy and hyperplasia of vascular smooth muscle cells, and a propensity for thrombus formation.
Lipid
deposition
Apoptosis
Thrombosis
VSMC
growth
Leukocyte
adhesion
Vasoconstriction

27. Can We Measure Endothelial Function ??

28. Clinical Methods for Assessing Endothelium - Dependent Dilation
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

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
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 Vasodilation. Baseline. 5 Minutes
Brachial Artery Flow-Mediated Vasodilation Baseline Minutes Post-Occlusion Blood 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 controlled BP (<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

51. Erectile Dysfunction – Today’s concept
Penis is the barometer
of Endothelial Health
Erectile Dysfunction is a
mirror of Cardiovascular Risk
ED = ED

52. Erectile Dysfunction – What is special?
The consistent inability of a man to get or keep an erection satisfactory for sexual intercourse
Affects less than 3% of men under age 45
Incidence increases to 25% by age 65
By age 75, almost 2/3 of men have ED
About 1/3 of men > 65 years suffer from ED
Half of men of 40 to 70 yrs suffer from ED

53. Erectile Dysfunction – Pathophysiology
Excess sympathetic tone
Hypo-responsive endothelium
Venous incompetence
Low testosterone
Elevated prolactin

54. Erectile Dysfunction – What causes it?
Aging
Smoking
Hyperhomocysteinemia
Hyperlipidemia
Hypertension
Diabetes
Prostate surgery

55. Take Home Messages
CVD Risks are ever increasing
Endothelium is the largest endocrine gland
Common under laying pathology is ED
Endothelial Dysfunction can be measured
ED is diagnostic and prognostic
ED can be treated and monitored
ED = ED – So careful evaluation is needed
Penis is the barometer of CV Risk

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