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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