ENDOTHELIAL DYSFUNCTION - EDENDOTHELIAL DYSFUNCTION - ED

A Marker of Cardio Vascular DiseaseA 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

The EndotheliumThe Endothelium

LUMEN

Tunica adventitia

Tunica media

Tunica intima

Can you see the endothelium?

What type of tissue is it? Why?

LUMEN

Note the individual Endothelial Cells

Vasoconstriction and dilatation

Normal Vasoconstriction Vasodilatation

VasoconstrictionVasodilatation

Vasoconstriction and dilatation

↓ Resistance to flow ↑ Resistance to flow

Endothelial Apoptosis

Normal Apoptosed

The EndotheliumAs an Endocrine Organ

• 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

The Vascular Endothelium

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.

• 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

The Effects of ED

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

• 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

Nitric Oxide (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

Protective actions of 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.

ED and NO ↓

The Endothelium inHealth and Disease

The Universal Damage

Coronary Coronary Heart Heart

DiseaseDisease

Endothelial Endothelial DysfunctionDysfunction

NO NO ↑ ↑ Inflammation Inflammation ↑ Thrombosis↑ Thrombosis

GenesGenes

Coronary Risk Factors

The Essential Components

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

Regulatory Functions of the EndotheliumNormal Dysfunction

Vasodilation VasoconstrictionNO, PGI2, EDHF,

BK, C-NPROS, ET-1, TxA2,

A-II, PGH2

Thrombolysis Thrombosis

Platelet Disaggregation

NO, PGI2

Adhesion Molecules

CAMs, P,E Selectins

Antiproliferation

NO, PGI2, TGF-, Hep

Growth Factors

ET-1, A-II, PDGF, ILGF, ILs

Lipolysis Inflammation

ROS, NF-B

PAI-1, TF-α, Tx-A2tPA, Protein C, TF-I, vWF

LPLVogel R

Clinical Sequelae

O2 Endothelial Cells and

H2O2 Vascular Smooth Muscle

Oxidative Stress: Endothelial Oxidative Stress: Endothelial Dysfunction and CAD/Renal Risk Dysfunction and CAD/Renal Risk

FactorsFactors

Endothelial Dysfunction

Apoptosis

VasoconstrictionLeukocyteadhesion

Lipiddeposition

ThrombosisVSMCgrowth

HypertensionSmokingDiabetes LDL Homocysteine Estrogen

deficiency

Can We MeasureEndothelial Function ??

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

Comparison of Brachial and Coronary Flow-Mediated Vasodilation

CVE’s over 7.7 Years in 147 Subjects with CAD According to Coronary Artery Responses

to Ach, Cold Pressor, and FMD

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

Ach CP FMD

VasodilVasoconFMD >19%FMD 10-19%FMD <10%

CV

E’s

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

0%

5%

10%

15%

20%

25%

30%

Cor Vasc ResChange Ach

CA DiameterChange Ach

vasodil or T1 CVR

vasocon or T2,3 CVR

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

0

1

2

3

4

5

6

7

8

Tertile 1 Tertile 2 Tertile 3

ACh FBF%CVE's

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

Vitamin C ResponsesACh-induced FBF Responses

Brachial Artery Flow-Mediated Vasodilation

Baseline 5 Minutes Post-OcclusionBlood Pressure CuffOcclusion – 1 Minute Release

3.1 mm 3.6 mm

Can Endothelial Dysfunction help in Diagnosis of CVD ??

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

0%5%

10%15%20%25%30%35%40%45%50%

PTCA CABG MI ANY EVENT

FMD >10%FMD <10%

5-Year Outcome in 350 Postmenopausal Hypertensive Women with controlled

BP (<140/90) Change in BAFMD

0%

2%

4%

6%

8%

10%

12%

14%

16%

18%

20%

CVE's Hosp-CHF TIA's

d-FMD <10%

d-FMD >10%

Can Endothelial Dysfunction predict prognosis of CVD ??

Can Endothelial Dysfunction predict HTN and T2DM ??

What is the Rx. for ED ??

• 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

What is the Rx. for Endothelial Dysfunction?

Erectile Dysfunction – Today’s concept

Penis is the barometer of Endothelial Health

Erectile Dysfunction is amirror of Cardiovascular Risk

ED = ED

• 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

Erectile Dysfunction – What is special?

Erectile Dysfunction – Pathophysiology

• Excess sympathetic tone

• Hypo-responsive endothelium

• Venous incompetence

• Low testosterone

• Elevated prolactin

Erectile Dysfunction – What causes it?

• Aging

• Smoking

• Hyperhomocysteinemia

• Hyperlipidemia

• Hypertension

• Diabetes

• Prostate surgery

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

Thank You All

Visit us at : www.drsarma.in