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 característica: 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;5:506-513

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;92:152–160 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 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;92:152–160

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