BIOL E162a Fall 2009

1. BIOL E162a Fall 2009 Cardiovascular pathophysiology III review section CO Mendivil, MD

2. The endothelium is crucial in initiation of atherosclerosis Advanced age Dyslipidemia ? Hypertension Diabetes Mellitus Atherosclerosis Smoking Hyperhomocysteinemia Vascular endothelium Chronic inflammation

3. = Just “internal lining” of blood vessels? ENDOTHELIUM NO Vacular tone Hemodynamic stimuli Vascular proliferation Endocrine and Paracrine secretion Leukocyte and PLT adhesion Thrombogenesis Thrombolysis Hormonal environment Inflammation

4. Ca++ Ca++ GTP Origin of Nitric Oxide Guanilate cyclase GMPc Calmodulin eNOS Arginine Protein kinase G NO Citrulin Hemodynamic stimuli Hormonal environment Relaxation

5. Endothelial dysfunction Lower BIOAVAILABILITY of NO Principal característica: LOWER PRODUCTION GREATER DEGRADATION • Vasoconstricting hormonal • environment • ADMA • Insulin resistance: • - MAPK inactivation • - eNOS inactivation • Oxidative stress states: • Hypercholesterolemia (cLDL) • Low HDLc • High Angiotensin activity • - High concentration of FFA Curr Atherosclerosis Rep 2003;5:506-513

6. NADPH Oxidase AT1 H2O H2O O2 O2 Endothelial dysfunction How can oxidative stress induce endothelial dysfunction? Angiotensin receptor Xanthine Glutathion Peroxidase Superoxide Dismutase (SOD) XANTHINE OXIDASE H2O2 O2- Catalase Uric acid Fe++ OH- ON ONOO- eNOS Endothelium 2003;10:23-33

7. LDLs and endothelial dysfunction Necrosis ROS Apoptosis LDL Ox-LDL Inhibition eNOS Endothelium 2003;10:17-21

8. Endothelial dysfunction and initiation of atherosclerosis Remnant lipoproteins Monocyte LDL Macrophage

9. Initiation of atherosclerosis Fatty streak Healthy artery

11. The additive effects of LDL and inflammation

12. Expansion of a myocardial infarction

13. How do we detect it ?

14. How do we detect it ? Within hours Before Within minutes Within days Within years

15. The dreaded image Elevation of S-T segment Inverted T-wave Q-wave with no “r” A full-thickness recent myocardial infarction

16. How do we detect it ?

17. How do we detect it ?

18. How do we detect it ? Technecium scan Resting Stress

19. How do we detect it ? Coronary angiography

20. How to prevent them from occurring ? Controlling risk factors for atherosclerosis: Lipids Blood pressure Glycemia Smoking Homocysteine Body weight - Chronic inflammation

21. Statins effectively reduce LDLc STELLAR study 10mg 20mg 40mg 80mg Rosuvastatin 10-40 mg Atorvastatin 10-80 mg Simvastatin 10-80 mg Pravastatin 10-40 mg -10% -20% -30% -40% -50% -60% 20 20 20 20 20 20 20 20 20 20 20 20 n=485 24 24 24 24 24 24 24 24 24 24 24 24 24 28 28 28 28 28 28 28 28 30 30 30 30 30 30 30 30 30 30 30 30 n=648 % LDLc reduction 35 35 35 35 35 35 35 35 35 35 37 37 37 37 37 37 37 37 39 39 39 39 39 39 39 39 39 39 39 n=634 43 43 43 43 43 43 43 46 46 46 46 46 46 48 48 48 48 48 48 n=473 52 52 51 51 51 51 55 55 55 Jones PH et al. Am J Cardiol 2003;92:152–160

23. How to deal with them once they have occurred ? Stents

24. Drug-eluting stents

25. How to deal with them once they have occurred ? Installation of a coronary stent Before Installation After

26. How to deal with them once they have occurred ?

27. What happens later ?

28. Heart failure

29. Heart failure