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Endothelial dysfunction in Hypertension.

Endothelial dysfunction in Hypertension. Dr.K.S.Ravindranath MD.DM.DNB Professor of Cardiology Sri Jayadeva Institutue of Cardiology Bangalore. Endothelium:The Largest Living Organ. Tunica adventitia Tunica media Tunica intima. Endothelium Subendothelial connective tissue

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Endothelial dysfunction in Hypertension.

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  1. Endothelial dysfunction in Hypertension. Dr.K.S.RavindranathMD.DM.DNB Professor of Cardiology Sri Jayadeva Institutue of Cardiology Bangalore

  2. Endothelium:The Largest Living Organ Tunica adventitia Tunica media Tunica intima Endothelium Subendothelial connective tissue Internal elastic membrane Smooth muscle cells Elastic/collagen fibers External elastic membrane

  3. The normal endothelium

  4. Endothelium:The Largest Living Organ 1 ½ kg. 6 tennis courts Semi-permeable

  5. Ca2+ Ca2+-calmodulin arginine Citruline + NO Soluble guanylate cyclase SMC GTP cGMP Relaxation, inhibition of proliferation Endothelial nitric oxide production and action Acetyl choline, bradykinin etc High Shear Receptors EC

  6. Control of Vascular Tone

  7. Endothelial Dysfunction- Risk Factors Dyslipedemia Oxidative stress & CHF Insulin resistance Hypertension Diabetes Endothelial dysfunction  Vasoconstriction Inflammation Atherosclerosis ISCHEMIC Thrombosis Plaque rupture ACS Coronary events

  8. Pathophysiologic Effectsof Angiotensin II Cardiac myocyte Fibroblast Peripheral artery Coronary artery Hypertrophy Hyperplasia Vasoconstriction Vasoconstriction Endothelial dysfunction Endothelial dysfunction Apoptosis Collagen synthesis Atherosclerosis Hypertrophy Cell sliding Fibrosis Restenosis Decreased compliance Increased wall stress Increased O2 consumption Thrombosis Impaired relaxation

  9. Effects of Aldosterone Fibroblast Cardiac myocyte Peripheral artery Kidney Vasoconstriction Hypertrophy Potassium loss Hyperplasia Endothelial dysfunction Collagen synthesis Norepinephrine release Sodium retention Fibrosis Hypertrophy Decreased compliance

  10. Dysfunctional Endothelium

  11. Hypertension Oxidative stress plays determining role in ↓ EDNO ↓ Tetrahydrobiopterin  generation of O2ˉˉ Arginine deficiency  ADMA

  12. + - - Reactive oxygen species and endothelial dysfunction Ang II Reduced NO bioactivity NO ROS Macrophages Integrins Chemotaxis factors (MCP-1) Endothelium ICAMs Selectins NO NO Vasodilation NO VSMC Werner N, Nickenig G. Eur Heart J. 2003; 5(suppl A): A9-A13

  13. Endothelial dysfunction and HT • NO inactivation –  of reactive oxygen species, • ↑production of AT II and endothelin, • ↓ availability of NO precursor L-arginine, • Defect in G-protein dependent intracellular signalling pathway.

  14. ED - Hypertension • Primary or secondary not clear • ED – Normotensive offsprings of HTN patients – Could be primary • ED – Reversed by ACEI , Ca antagonists – could be consequence

  15. Normotensive offspring of individuals with essential HT have impaired vasodilator response to Ach, suggests a primary abnormality and genetic basis . • Cirulation 1996,94:1298-1303

  16. ED - HTN • Endothelium dependent vasodilation not only operates in large conductace vessels, but • Is also controls dilation in small ( resistance) vessels, • ED - resistant vessels – Micro vascular Dysfunction – Nephropathy – Microalbuminuria • ED - Peripheral arteries - Coronary Macro & Micro circulation - Renal circulation

  17. How to Assess ED • Endothelium-dependent vasodilation • Acetyl choline or post-ischaemic FMD* • Coronary or forearm arteries • Intima-media thickness (IMT) • Microalbuminuria • Plasma markers • ADMA, CRP, adhesion molecules • Clinical diagnosis • flow-mediated dilatation (FMD) • asymmetric dimethylarginine (ADMA)

  18. Serum Markers • Endothelin - I, Angiotensin- II, CRP • VWF / Ros / Cytokines • t-PA • PAI-I • ICAM • VCAM • E-Selectin & P Selectin • ADMA • Endothelial progenitor cells (EPCs)

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

  20. Impaired EDNO bioactivity in HT.

  21. Murakami T et al. J Am Coll Cardiol 2001;37:294ACVE’s over 4 Years in 480 Patients with Suspected CAD According to Brachial Artery FMD

  22. Predictors of MACE in symptomatic population with coronary risk factors ( Park et al )

  23. Negative correlation between the rise of SBP and endothelium dependent vasodilation due to NO/cGMP pathway • Rather than a benign process, exercise induced HT may predict possible CVS morbidity due to evolving endothelial dysfunction. • Also seen in white coat hypertension Yonsei Med J vol 44 no 6 ,2003

  24. Correcting Endothelial Dysfunction • Risk factor modification ( BP, DM, Smoking) • Exercise and weight loss • Blockade of the RAS- ACE Θ / ARB • LDL reduction, HDL augmentation. • PPAR-γ agonists • Antioxidants • Reducing homocysteine levels • Improving insulin sensitivity • Lowering CRP • L-arginine.

  25. Statins- Myocardial neovascularization Hypertension / Dyslipidemia 1 Mobilization (VEGF-R) EPC EPC EPC EPC EPC Bone Marrow 2 Peripheral blood Endothelial dysfunction  eNO Migration Ischemia 3

  26. Vascular protection • ACEI vs placebo • HOPE • EUROPA

  27. Reduction in oxidative stress with ACE inhibition ACE inhibition Tissue ACE activity Ang II  p22phox O2 – degradation  rac-1 p47 phox ecSOD  NADPH oxidase  O2 – production  NO availability  Landmesser U, Drexler H. Eur Heart J. 2003; 5(suppl A): A3-A7.

  28. Endothelial dysfunction and HT • Hypertensive patients with DM have endothelial dysfunction that can be related to microalbuminuria ,as well as modified by antihypertensive therapy. • J. Hum. Hyperten 2005

  29. HOPE – Primary outcomes • Effects beyond baseline therapy • Aspirin • Beta-blockers • Lipid-lowering agents • Diuretics • Other antiplatelets • Calcium channel blockers % RR + Ramipril 10 mg • * p = 0 0001 • p = 0.005 The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000;342: 145-153

  30. HOPE Impact of ramipril on stroke based on baseline BP BMJ 2002;324:1-5

  31. Angiotensin Receptor Blockers Mechanism of Action RENIN Angiotensin IANGIOTENSIN II Angiotensinogen ACE Other paths AT1 Receptor Blocker RECEPTORS AT1 AT2 Vasoconstriction Proliferative Action Vasodilatation Antiproliferative Action

  32. Improved endothelial function with Losartan but not with atenolol

  33. LIFE study BP during Follow -up mmHg Time ( Months )

  34. ARB in hypertension – LIFE Study

  35. How Could Losartan Reduce the Risk of Stroke “Beyond Blood Pressure”? Potential Sites of Action Cardiac remodeling/enlargement Vascular remodeling Endothelial dysfunction Prothrombotic state

  36. Cardiovascular diseases in men according to BP Lancet 2006;367:168-176

  37. TROPHY Trial • 30 to 65 (inclusive) years of age • Not treated for hypertension • First visit BP not exceeding 155/99 mm Hg • Average BP ≤139/85-89 or 130-139/≤89 mm Hg (3 visits) as determined by an automatedBP measurement device Julius et al. N Engl J Med 2006

  38. Development of clinicalhypertension Cumulative incidence % 1.0 Placebo 0.9 Candesartan 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 1 2 3 4 Years in study Numbers of hypertension-free individuals Candesartan 391 356 309 191 128 Placebo 381 269 184 118 85 Julius et al. N Engl J Med 2006

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