Pathology of Coronary Artery Disease Seth J. Kligerman, MD Pathology of Coronary Artery Disease Seth Kligerman, MD Assistant Professor Medical Director of MRI University of Maryland Department of Radiology and Nuclear Medicine Coronary Artery Disease (CAD) Leading cause of death in men and women in the Western World Around 450,000 people die each year in US from CAD 1.1 million myocardial infarcts/year in US 40% fatal Heart disease costs $316.4 billion/year CAD- Inflammatory Process Libby etal. The Vascular Biology Atherolseclerosis and Imaging Targets. J Nucl Med 2010; 51:1S 5S Arterial endothelium exposed to Bacterial products Lipids Proinflammatory cytokines Vasoconstrictor hormones Activation of endothelium Overexpression of adhesion molecules Blood leukocytes (mononuclear phagocytes and T-cells) Adhere to endothelium Migrate into intima Leukocytes release inflammatory mediators and cytokines Additional leukocytes and macrophages recruited Smooth muscles cells (SMC) proliferate Coronary Artery Histology 3 layers Intima Media Adventitia http://www.fmh.org/body.cfm?id=687 Intima Role of Endothelium Endothelial cells (E) lining the lumen Bound by internal elastic lamina (IEL) Fenestrated sheet of elastin fibers Thin subendothelial (SE) space in between Elastin and collagen fibers Smooth muscle cells (SMCs) Media E SE E SE E Nonthrombogenic surface Heparin sulfate Prostacyclin Vascular tone and remodeling Nitrous oxide Endothelin Seratonin Platelet activation Thrombus creation and lysis Lipid metabolism Monocyte adhesion Intima Media Adventitia Dalager, S. et al. Stroke 2007;38:2698-2705 477
Modified AHA Classification of Atherosclerotic Lesions Nonpathologic Findings Diffuse Intimal Thickening Type 0 Intimal Xantoma Fatty Streak Type I and II Normal aging process Seen in fetuses and infants Well-organized structure Pathologic factors absent Deposition of lipids Macrophages infiltrate intima Form foam cells SMC proliferation Dalager, S. et al. Stroke 2007;38:2698-2705 Lipid Core, aka Atheroma Type IV Cellular proliferation and death continues Two main components Necrotic Core () SMCs Deposition of extracellular connective tissue matrix Helps form fibrous cap Overlies core of foam cells, extracellular lipid, and Contains inflammatory cells Thickness varies Thick cap Thin cap Thin cap Inflammatory cells thin cap Prone to rupture Vulnerable plaque Avascular Hypocellular Contains Free cholesterol Cholesterol crystals Esterfied cholesterol Circulating lipids Foam cell death Size of directly related to likelihood of plaque rupture Necrotic Core Fibroatheroma on CT Calcified Mixed Noncalcified 478
Coronary Artery Calcification Coronary Artery Calcification Similar to orthotopic bone formation Osteoblast-like like cells derived from SMCs Endochondral ossification Lipid core mineralization Fibrous microcalcification Shao etal. Inflammation and the Osteogenic Regulation of Vascular Calcification: A Review and Perspective. Hypertension 2010, 55:579-592 Strong predictor of incident coronary artery disease Risk stratification Wide-spread screening debate Only detects calcified and mixed plaque Detrano etal. Coronary Calcium as a Predictor of Coronary Events in Four Racial or Ethnic Groups. N Engl J Med 2008; 358:1336-1345 Calcium Score Potential Fibroatheroma Outcomes Growth Regression Atheroma Rupture Erosion Lipid Rich s Expansion of Increasing calcification Intraplaque hemorrhage Healed rupture growth Rupture Site Thrombus Fibrous Cap Nonocclusive thrombus after plaque rupture Neovascularity and Intraplaque Hemorrhage s acquire microvascular network Immature vessels weak and leaky Blood components extravasate into plaque Cholesterol crystal production Oxidant activities Proteolytic activities 150 m thick sections stained with Ulex 479
Outward Growth Positive Remodeling Inward Growth Negative Remodeling Growth Positive Remodeling Outward compensatory remodeling Lumen initially uncompromised Stenosis of >70% to cause flow limitation More than half of MIs occur in arteries narrowed <50% Vulnerable plaques Prone to rupture Acute coronary syndrome Ohayon J, Finet G, Gharib AM etal. Necrotic core thickness and positive arterial remodeling index: emergent biomechanical factors for evaluating the risk of plaque rupture. Am J Physiol Heart Circ Physiol. 2008; 295: H717-H727. Positive Remodeling Positive Remodeling L L Negative Remodeling Luminal stenosis Many plaques with positive remodeling progress to negative remodeling dli Outcomes Often have stable angina Increased risk for ACS Lumen already compromised Potential Outcomes Growth Regression Atheroma Erosion Rupture 480
Thin-cap Fibrous Atheroma Inflammation thins fibrous cap Precursor of plaque rupture >95% of plaque ruptures occur with diameters <65 Thin Fibrous Cap Acute Rupture Type VI lesion Fibrous cap disrupts Highly thrombogenic material pours into lumen Most prevalent Proximal coronary arteries Near branch points Rupture Outcomes Nonocclusive Thrombus Nonocclusive thrombus Progressive luminal narrowing Asymptomatic Stable or unstable angina Occlusive thrombus Acute infarction Sudden cardiac death organization Recanalized Chronically thrombosed Nonocclusive Thrombus Multiple Ruptures Nonocclusive Thrombus 35 year-old man with unstable angina 481
Occlusive Thrombus Acute MI Perfusion Defect LAD Distribution Occlusive Thrombus Sudden Cardiac Death Occlusive Thrombus Chronic Total Occlusion Type IX Potential Outcomes Lipid Poor s Growth Regression Atheroma Erosion Rupture Poorly understood More common in women Progressive intimal thickening Repeated erosions 482
Erosion of endothelial layer Fibrous cap intact Luminal thrombi not due to plaque rupture Mechanism unknown Erosion Fibrous cap intact Thrombus Erosion in without Necrotic Core LAD Occlusion Conclusion Coronary artery disease is complex inflammatory process enlargement and luminal narrowing or occlusion occurs by variety of mechanisms Radiologic imaging of CAD still in infancy Key is distinction between plaques RF intravascular ultrasound Not yet possible on CT, MR, or PET 483