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Endothelial function.aha.

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Endothelial function.aha.

  1. 1. Systemic markers of endothelial function Arshed A. Quyyumi M.D. Professor of Medicine Emory Univesrity School of Medicine
  2. 2. ATHEROSCLEROSIS Cardiovascular events RISK FACTORS OXIDATIVE STRESS ENDOTHELIAL DYSFUNCTION INFLAMMATION
  3. 3. ENDOTHELIUM SMOOTH MUSCLE PLATELETS - - Shear Stress 2 EDHF PGI L-NMMA - Relaxation GTP cGMP Guanylate cyclase (inactive) Nitric Oxide Guanylate cyclase (active) L-ARGININE Nitric Oxide NOS L-citrulline R BradykininAcetylcholine
  4. 4. Endothelium-dependent probes: •Acetylcholine, •Bradykinin, •Substance P, •L-NMMA, •Shear Stress Endothelium- independent probes: •Sodium nitroprusside, •Adenosine Measurements: •Coronary blood flow and resistance •Epicardial Diameter Assessment of Coronary Vascular Function
  5. 5. Acetylcholine Baseline Normal Endothelial Function
  6. 6. Acetylcholine Endothelial Dysfunction Baseline
  7. 7. Nitroprusside Endothelial Dysfunction Acetylcholine
  8. 8. Microcirculatory endothelial function assessment
  9. 9. Brachial artery reactivity • Flow-mediated vasodilation (FMD) – Endothelium-dependent • Baseline measurements • Reactive Hyperemia • Sublingual Nitroglycerin response (NTG) – Endothelium-independent RestRest ReactiveReactive HyperemiaHyperemia
  10. 10. CP914474- 11 10 min 5 min 10 min 10 min Cuff inflation 60 mm Hg > systole pressure Cuff deflation NTG SL Pulsatile arterial tonometry (PAT)Pulsatile arterial tonometry (PAT) CP989904-9
  11. 11. CP914474- 12 PAT Hyperemic Response – Mayo StudyPAT Hyperemic Response – Mayo Study Compared to Intra Coronary Blood Flow Response to AcetylcholineCompared to Intra Coronary Blood Flow Response to Acetylcholine N=94N=94 1 1.2 1.4 1.6 1.8 2 Abnornmal coron resp Normal coron resp PATIndex p<.00001n=55 n=39 Mayo Clinic (Abnormal if CBF<50% or CAD<-20%) Lerman et al
  12. 12. CP914474- 13 The Effect of Nitric PWAFollowing Re 0 20 40 60 80 100 120 140 160 180 1 2 3 4 5 Control L-NAME
  13. 13. Endothelial dysfunction No atherosclerosis • Sedentary lifestyle •Hypertension • Hypercholesterolemia • Diabetes • Heart failure • Estrogen withdrawal • Age • Smoking • Homocystinuria • Prinzmetal's angina Atherosclerosis Platelet activation tPA ↓ , PAI-1 ↑ •thrombosis •Adhesion molecule expression •Cytokine release •Growth factors ↑ •progression of atherosclerosis Abnormal vasomotion •myocardial ischemia •coronary spasm •hypertension
  14. 14. Endothelial function is an independentEndothelial function is an independent determinant of long term prognosisdeterminant of long term prognosis
  15. 15. CP914474- 17CP1137788-2 -8.0 -6.0 -4.0 -2.0 0.0 2.0 4.0 6.0 8.0 Suwaidi et al, 2000 Schanginger et al, 2000 Neunteufl et al, 2000 Perticone et al, 2001 Heitzer et al, 2001 Halcox et al, 2002 Modena et al, 2002 Schindler et al, 2003 Gokce et al, 2003 Targonski et al, 2003 Relative risk: Dysfunction vs. normal function Prediction of future cardiovascular eventsPrediction of future cardiovascular events by measurement of endothelial functionby measurement of endothelial function
  16. 16. Event-Free Survival According to Coronary Vascular Function (Death, myocardial infarction, unstable angina, stroke) Acetylcholine Highest tertile Mid tertile Lower tertile Months 0 12 24 36 48 60 72 84 96 EventFreeSurvival(%) 0 50 60 70 80 90 100 Microvascular vasodilation Greatest Intermediate Least Vasodilation p=0.047 Months 0 12 24 36 48 60 72 84 96 EventFreeSurvival(%) 0 50 60 70 80 90 100 Dilation Constriction Epicardial changes p=0.003 Halcox J, Quyyumi A Circulation 2002 308 patients
  17. 17. CAD Event-Free Survival According to Coronary Vascular Function 308 patients undergoing catheterization with and without CAD/follow-up 44±2 months Events: Death, CVA, Myocardial infarction, Unstable angina Normal Coronaries Months 0 12 24 36 48 60 72 84 96 Event Free Survival (%) 0 20 40 60 80 100 Highest Mid + Lowest Tertiles of Acetylcholine Response p=0.035 Halcox, Quyyumi, Circulation 2002
  18. 18. Endothelial function and risk of developing hypertension 952 healthy post menopausal women Age 44 to 60 years Baseline normal BP Follow-up for mean 3.6 years Results:Results: 112 developed hypertension Relative risk of developing HTN during follow-up was 5.8 fold in those in the lowest FMD tertile compared to the highest tertile. Rossi R J Am Coll Cardiol 2004;44:1636
  19. 19. Endothelial function and risk of developing diabetes FMD tertile Highest Mid Lowest FMD % >5.6 4.4-5.5 <4.3 Incident diabetes 9 35 58 Incident rate (per 1000 person years) 2.0 7.9 14.4 Multiple adjusted RR 1 2.85 5.4 840 healthy non-obese post- menopausal women Mean age 53 years Baseline normal glucose and OGTT Follow-up for mean 3.9 years Results:Results: 102 developed Type II diabetes Relative risk of developing diabetes during follow-up was 5.9 fold in those in the lowest FMD tertile compared to the highest tertile. Rossi R J Diabetes Care 2005;2: 702
  20. 20. Endothelial Function Predicts Future Development of Coronary Artery Disease • >10 year FU of 42 women with chest pain, normal CAs, positive SPECT thallium scans, who also underwent endothelial function testing • 22 patients had vasoconstriction and 20 dilation with acetylcholine • In ACH + group; 1 death, 13 continued pain •13 patients in the ACH + group developed CAD by angiography • In ACH – group; resolution of CP after 6 to 36 months, SPECT negative, no CAD by angiography after 10 years Bugiardini Circulation 2004;109;2018
  21. 21. Is improvement in endothelial dysfunction an indicator of improved prognosis? 0 2 4 6 8 10 12 14 16 18 20 CVE Hosp/CHF TIA's Δ FMD < 10%* Δ FMD >10%* * change in FMD from baseline ** no difference in type of Rx or end Rx BP Modena et al, JACC, 2002 400 hypertensive post-menopausal women Responders: FMD improved >10% (4 to 7.1%) in 250 Non-responders: FMD change <10% (4 to 4.1%) in 150
  22. 22. ATHEROSCLEROSIS Cardiovascular events RISK FACTORS OXIDATIVE STRESS ENDOTHELIAL DYSFUNCTION INFLAMMATION
  23. 23. ROS O2 ·- H2O2 HOCl OONO- NO LO· LOO· HO· Glutathione GSH GSSG GPX H2O2 NO2- Ox-Hb met-HbNO-Hb NO3- LDL Apo B E E E E E Protein oxidation Lipid oxidation LOH LOOH LONO LOONO Isoprostanes TBARS HNE MDA oxLDL oxLDL Aby’s Cysteine Cystine
  24. 24. Endothelial function and markers ofEndothelial function and markers of oxidative stressoxidative stress 126 healthy non-smokers EhCys/CySS -73 -72.5 -72 -71.5 -71 -70.5 -70 -69.5 -69 -68.5 -68 FMD <7% FMD >7% Endothelial Function P=0.03 -72.7±8 -69.7±8 Cysteine redox 290 300 310 320 330 340 350 360 370 380 FMD <7% FMD >7%FORT(Carrunits) Endothelial Function P=0.02 377±20 319±17 FORT
  25. 25. EPCs and vascular diseases Risk Factors Endothelial injury Endothelial dysfunction, Inflammation AtherogenesisAtherogenesis Vascular RepairVascular Repair Endothelial Progenitor CellsEndothelial Progenitor Cells Oxidative stress
  26. 26. Endothelial Progenitor Cell Colony Forming Assay • Measure of progenitor cell capacity • Density gradient separation of PBMCs • Fibronectin plate – 1million cells per well/24 well • Colony counts after 7days • Simple and reproducible Hill, Quyyumi, Finkel N Engl J Med 2003;13:593
  27. 27. Endothelial Progenitor Cell Colony Formation and Cardiovascular Risk Profile EPC-CFUEPC-CFU Framingham Risk ScoreFramingham Risk Score Hill, Quyyumi, Finkel N Engl J Med 2003;13:593 45 Healthy Males, >21 years (mean age 50.3±1.7) without cardiovascular diseases
  28. 28. Relation between endothelium- dependent function and EPCs EPC-CFUEPC-CFU Flow mediated dilation –FMDFlow mediated dilation –FMD Hill, Quyyumi, Finkel N Engl J Med 2003;13:593 45 Healthy Males, >21 years (mean age 50.3±1.7) without cardiovascular diseases RestRest ReactiveReactive HyperemiaHyperemia •Flow-mediated vasodilation (FMD) EPC-CFUEPC-CFU
  29. 29. Systemic markers of endothelial function Arshed A. Quyyumi M.D. Professor of Medicine Emory Univesrity School of Medicine

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