BIOL E162a Fall 2009

Cardiovascular pathophysiology IIIreview section

CO Mendivil, MD

The endothelium is crucial in initiation of atherosclerosis

Advanced age

Dyslipidemia

Hypertension

Diabetes Mellitus

Smoking

Hyperhomocysteinemia

Chronic inflammation

?? Atherosclerosis

Vascular endotheliumVascular endothelium

ENDOTHELIUM = Just “internal lining”of blood vessels?

NONOHemodynamicstimuliHemodynamicstimuli

HormonalenvironmentHormonalenvironment

Endocrine andParacrinesecretion

Vacular tone

Vascularproliferation

Leukocyte andPLT adhesion

ThrombogenesisThrombolysis

Inflammation

Origin of Nitric Oxide

HemodynamicstimuliHemodynamicstimuli

HormonalenvironmentHormonalenvironment

Ca++

CalmodulineNOS Arginine

CitrulinNO

GTP GMPc

Proteinkinase G

Guanilatecyclase

Ca++

Relaxation

Endothelial dysfunction

Principal característica:Lower BIOAVAILABILITY of NOLower 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

How can oxidative stress induce endothelial dysfunction?

Endothelial dysfunction

ONeNOS

O2-

ONOO-

AT1 NADPHOxidase

XANTHINEOXIDASE

XANTHINEOXIDASE

Xanthine

Uric acid

SuperoxideDismutase

(SOD)

SuperoxideDismutase

(SOD)

H2O2

GlutathionPeroxidase

Catalase

Fe++

H2OO2

H2OO2

OH-

Endothelium 2003;10:23-33

Angiotensin receptor

LDLs and endothelial dysfunction

LDL Ox-LDL

ROSROS

Endothelium 2003;10:17-21

Inhibition eNOS

Necrosis

Apoptosis

Remnantlipoproteins

LDL

Endothelial dysfunction and initiation of atherosclerosisEndothelial dysfunction and initiation of atherosclerosis

Monocyte

Macrophage

Healthyartery

Fattystreak

Initiation of atherosclerosisInitiation of atherosclerosis

The additive effects of LDL and inflammation

Expansion of a myocardial infarction

How do we detect it ?

How do we detect it ?

Within minutes Within hours

Within days Within years

Before

The dreaded image

A full-thickness recent myocardial infarction

Q-wavewith no “r”

Elevation ofS-T segment

InvertedT-wave

How do we detect it ?

How do we detect it ?

How do we detect it ?Technecium scan

StressResting

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

STELLAR studySTELLAR studySTELLAR studySTELLAR study

-10%

-20%

-30%

-40%

-50%

-60%

-10%

-20%

-30%

-40%

-50%

-60%

Rosuvastatin 10-40 mg

Atorvastatin 10-80 mg

Simvastatin 10-80 mg

Pravastatin 10-40 mg

20202424

30302828

35353939

4646

37374343

48484646

52525555 5151

n=485n=485

n=648n=648

n=634n=634

n=473n=473

% L

DLc r

ed

ucti

on

10mg 20mg 40mg 80mg10mg 20mg 40mg 80mg

20202424

3030

20202424

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3030

20202424

35353939

3030

20202424

2828

35353939

3030

20202424

3737

2828

35353939

3030

20202424

43433737

2828

35353939

3030

20202424

48484343

3737

2828

35353939

3030

20202424

464648484343

3737

2828

35353939

3030

20202424

5151

464648484343

3737

2828

35353939

3030

20202424

5555 5151

464648484343

3737

2828

35353939

3030

20202424

52525555 5151

464648484343

37373535

3939

30302424

Statins effectively reduce LDLc

Jones PH et al. Am J Cardiol 2003;92:152–160

How to deal with themonce 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