AHA- Nov 12, 2005 , Dallas

P.K.Shah, MDDirector of Cardiology and Atherosclerosis Research Center,

Cedars-Sinai Medical Center, Professor of Medicine,

David Geffen School of Medicine at UCLA

Los Angeles, California

Imperative to Detect Subclinical Atherosclerosis

Coronary Artery Disease

4 out of every 10 individuals who developa heart attack or sudden death from

coronary artery diseasehave no prior warning or symptoms

CVD Risk Assessment in Asymptomatic Normal SubjectsLimitations of the Traditional Approach

PKS- CSMC

*One or more “Risk Factor” Accounts for 80-90% ofCHD Events

*Therefore Risk Factors can Predict most CHD Events

CVD Risk Assessment in Asymptomatic Normal SubjectsLimitations of the Traditional Approach

PKS- CSMC

0

10

20

30

40

50

60

70

80

90

100

Death Death/MI

% with > 1 Risk Factors

No Death/MINo Death

men

women

Pathophysiologic Paradigm in AtherosclerosisPathophysiologic Paradigm in Atherosclerosis

Oxidant StressOxidant Stress

Inflammatory Gene ActivationInflammatory Gene Activation

AtherosclerosisAtherosclerosis

Inflammatory Cell Recruitment/ActivationInflammatory Cell Recruitment/Activation

Modified LDL

Other mechanismsOther mechanisms

Oth

er m

echa

nism

s

Other mechanisms

Plaque-disruption/ThrombosisPlaque-disruption/Thrombosis

Genes Genes

Price M and Shah PK: Harrison’s Textbook of Medicne Online 2002

LDL , HDL , Diabetes-IRS-Metabolic Synd , Hypertension , Genetics, Others

Lipoproteins

Entry into Subendothelial Space

Lipoprotein Binding and Retention

Lipoprotein Modification (oxidation)

Inflammatory Gene Induction

InflammationImmune Activation

Athero-prone sites

LDL with Reduced Binding Affinity to Subendothelial Matrix is AssociatedWith Reduced Atherosclerosis Despite Severe Hypercholesterolemia

Skalen K et al: Nature 417:750:2002

Defective LDL

Normal LDL

CSMC--PKS

0

2

4

6

8

10

12

0

1

2

3

4

5

6

7

MyD88 +/+ +/- -/- Genotype Normal Partial Complete Deficiency Absence

Cholesterol

(mg/dl) 943 913 760

Cholesterol

(mg/dl) 943 913 760

Genetic Ablation of Myeloid Differentiation Factor (MyD88) Reduces Atherosclerosis and Plaque Inflammation in Apo E Null Mice Despite Hypercholesterolemia

P<0.01P<0.01

% Macrophage Immunoreactivity% Aortic Surface with Plaque

Michelsen, Wong, Shah, Arditi : PNAS 2004

MyD88 +/+ +/- -/- Genotype Normal Partial Complete Deficiency Absence

+ Risk Factors

+ Disease

+ Events

AtherosclerosisAnd/or

(Pre-atherosclerosis)

Impaired Flow Dynamics

Increased Stiffness

Disease Activity(Biomarkers,

Plaque Phenotype)

Vaso-occlusive Clinical Events

*EBCT*IMT*MRI

Function

Stress TestEndothelial Function*CRP,LP-PLA2

*Gene SNP , Proteomics*Plaque Composition

CVD Risk Assessment: A Different Paradigm

Traditional Risk Factor Based Disease Modification

Imaging for Identification of Subclinical AtherosclerosisEBCT-MSCT, Carotid IMT, MRI

Non-invasive Assessment of Vascular FunctionBART, ABI, Compliance , Stress Test

Markers for Disease Activity Inflammatory and other Biomarkers

PKS- CSMC