Transcript
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
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