Cardiovascular pathophysiology III
BIOL E162a Fall 2009 Cardiovascular pathophysiology III review section CO Mendivil, MD ? The endothelium is crucial in initiation of atherosclerosis
Advanced age Dyslipidemia ? Hypertension Diabetes Mellitus Smoking Atherosclerosis Hyperhomocysteinemia Vascular endothelium Chronic inflammation Just internal lining
= 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 Origin of Nitric Oxide Ca++ Ca++ NO Calmodulin Hemodynamic stimuli
Guanilate cyclase Ca++ GTP GMPc Calmodulin eNOS Arginine Protein kinase G NO Hemodynamic stimuli Citrulin Ca++ Hormonal environment Relaxation Endothelial dysfunction
Principal caracterstica: Lower BIOAVAILABILITY of NO 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: O2- ON ONOO- Endothelial dysfunction eNOS H2O2
How can oxidative stress induce endothelial dysfunction? Angiotensin receptor AT1 NADPH Oxidase Xanthine H2O O2 Glutathion Peroxidase Superoxide Dismutase (SOD) XANTHINE OXIDASE H2O O2 H2O2 O2- Catalase Uric acid Fe++ OH- ON ONOO- eNOS Endothelium 2003;10:23-33 LDLs and endothelial dysfunction
Necrosis ROS Apoptosis LDL Ox-LDL Inhibition eNOS Endothelium 2003;10:17-21 Endothelial dysfunction and initiation of atherosclerosis
Remnant lipoproteins Monocyte LDL Macrophage Initiation of atherosclerosis
Healthy artery Fatty streak The additive effects of LDL and inflammation Expansion of a myocardial infarction How do we detect it ? How do we detect it ? Before Within minutes Within hours Within days
Within years The dreaded image A full-thickness recent myocardial infarction
Elevation of S-T segment Inverted T-wave Q-wave with no r A full-thickness recent myocardial infarction How do we detect it ? How do we detect it ? How do we detect it ? Technecium scan Resting Stress How do we detect it ? Coronary angiography How to prevent them from occurring ?
Controlling risk factors for atherosclerosis: Lipids Blood pressure Glycemia Smoking Homocysteine Body weight - Chronic inflammation Jones PH et al. Am J Cardiol 2003;92:152160
Statins effectively reduce LDLc STELLAR study 10mg mg mg mg Rosuvastatin mg Atorvastatin mg Simvastatin mg Pravastatin 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 n=648 30 30 30 30 30 30 30 30 30 30 30 30 % LDLc reduction 35 35 35 35 35 35 35 35 35 35 37 37 37 37 37 37 37 37 n=634 39 39 39 39 39 39 39 39 39 39 39 43 43 43 43 43 43 43 46 48 48 48 48 48 48 46 46 46 46 46 n=473 52 52 51 51 51 51 55 55 55 Jones PH et al. Am J Cardiol 2003;92:152160 How to deal with them once they have occurred ? Stents Drug-eluting stents How to deal with them once they have occurred ?
Installation of a coronary stent Before Installation After How to deal with them once they have occurred ? What happens later ? Heart failure Heart failure