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AHA- Nov 12, 2005 , Dallas

AHA- Nov 12, 2005 , Dallas. Imperative to Detect Subclinical Atherosclerosis. P.K.Shah, MD Director of Cardiology and Atherosclerosis Research Center, Cedars-Sinai Medical Center, Professor of Medicine, David Geffen School of Medicine at UCLA Los Angeles, California.

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AHA- Nov 12, 2005 , Dallas

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  1. AHA- Nov 12, 2005 , Dallas Imperative to Detect Subclinical Atherosclerosis P.K.Shah, MD Director of Cardiology and Atherosclerosis Research Center, Cedars-Sinai Medical Center, Professor of Medicine, David Geffen School of Medicine at UCLA Los Angeles, California

  2. Coronary Artery Disease 4out of every 10 individuals who develop a heart attack or sudden death from coronary artery disease have no prior warning or symptoms

  3. CVD Risk Assessment in Asymptomatic Normal Subjects Limitations of the Traditional Approach *One or more “Risk Factor” Accounts for 80-90% of CHD Events *Therefore Risk Factors can Predict most CHD Events PKS- CSMC

  4. CVD Risk Assessment in Asymptomatic Normal Subjects Limitations of the Traditional Approach % with > 1 Risk Factors men women Death Death/MI No Death No Death/MI PKS- CSMC

  5. Pathophysiologic Paradigm in Atherosclerosis Price M and Shah PK: Harrison’s Textbook of Medicne Online 2002 LDL , HDL , Diabetes-IRS-Metabolic Synd , Hypertension , Genetics, Others Modified LDL Oxidant Stress Other mechanisms Other mechanisms Inflammatory Gene Activation Genes Genes Inflammatory Cell Recruitment/Activation Atherosclerosis Other mechanisms Other mechanisms Plaque-disruption/Thrombosis

  6. Athero-prone sites Lipoproteins Entry into Subendothelial Space Lipoprotein Binding and Retention Lipoprotein Modification (oxidation) Inflammatory Gene Induction Inflammation Immune Activation

  7. LDL with Reduced Binding Affinity to Subendothelial Matrix is Associated With Reduced Atherosclerosis Despite Severe Hypercholesterolemia Normal LDL Defective LDL Skalen K et al: Nature 417:750:2002

  8. Genetic Ablation of Myeloid Differentiation Factor (MyD88) Reduces Atherosclerosis and Plaque Inflammation in Apo E Null Mice Despite Hypercholesterolemia Michelsen, Wong, Shah, Arditi : PNAS 2004 % Aortic Surface with Plaque % Macrophage Immunoreactivity P<0.01 P<0.01 MyD88 +/+ +/- -/- Genotype Normal Partial Complete Deficiency Absence MyD88 +/+ +/- -/- Genotype Normal Partial Complete Deficiency Absence Cholesterol (mg/dl) 943 913 760 Cholesterol (mg/dl) 943 913 760

  9. + Risk Factors + Disease + Events

  10. Atherosclerosis And/or (Pre-atherosclerosis) Impaired Flow Dynamics Increased Stiffness *EBCT *IMT *MRI Function Disease Activity (Biomarkers, Plaque Phenotype) Stress Test Endothelial Function *CRP,LP-PLA2 *Gene SNP , Proteomics *Plaque Composition Vaso-occlusive Clinical Events

  11. CVD Risk Assessment: A Different Paradigm Imaging for Identification of Subclinical Atherosclerosis EBCT-MSCT, Carotid IMT, MRI Non-invasive Assessment of Vascular Function BART, ABI, Compliance , Stress Test Markers for Disease Activity Inflammatory and other Biomarkers Traditional Risk Factor Based Disease Modification PKS- CSMC

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