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 Visit us at : www.drsarma.in

The Endothelium

Tunica intima LUMEN Tunica adventitia Tunica media

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?

Note the individual Endothelial Cells

Vasoconstriction and dilatation Normal Vasoconstriction Vasodilatation

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

Endothelial Apoptosis Normal Apoptosed

The Endothelium As an Endocrine Organ

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

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.

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

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

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

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

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.

The Endothelium in Health and Disease

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

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

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

Clinical Sequelae

Oxidative Stress: Endothelial Dysfunction and CAD/Renal Risk Factors Homocysteine Estrogen deficiency Smoking LDL Diabetes Hypertension  O2 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

Can We Measure Endothelial 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 CVE’s

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

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

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

Brachial Artery Flow-Mediated Vasodilation. Baseline. 5 Minutes Brachial Artery Flow-Mediated Vasodilation Baseline 5 Minutes Post-Occlusion Blood Pressure Cuff Occlusion – 1 Minute Release 3.6 mm 3.1 mm

Can Endothelial Dysfunction help in Diagnosis of CVD ??

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

5-Year Outcome in 350 Postmenopausal Hypertensive Women with controlled BP (<140/90) Change in BAFMD  

Can Endothelial Dysfunction predict prognosis of CVD ??

Can Endothelial Dysfunction predict HTN and T2DM ??

What is the Rx. for ED ??

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

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

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

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

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