Vulnerable Plaque 분당서울대학교병원 심장센터 연 태 진

Causes / mediators of atherothrombosis Endothelial dysfunction Fatty streak Fibrous plaque Unstable Fibrous plaque Plaque rupture/ fissure & thrombosis Acute coronary syndrome Cardiovascular death Ross R. NEJM 1999; 340: Inflammation Vascular risk factors Genes, BP, Smoking, Chol., Diabetes Upregulation of adhesion molecules  permeability to pl. lipoproteins (NO, A II, PDGF) Leucocytes migrate into artery wall (ox. LDL, PDGF) Lipid-laden macrophages (foam cells) T lymphocyte activation Smooth muscle cells migrate & lipid laden Fibrous cap Necrotic core (apoptosis of lipid & WBC) Expansion at shoulders as leucocytes adhere & enter (ox. LDL, PDGF) Thinning/fissuring of fibrous cap Large, lipid core Influx & activation of macrophages - release metalloproteinases Haemorrhage from - vasa vasorum - lumen of artery …… …….. Atherogenesis Atherothrombosi Angina

Stable and Rupture-prone plaque

Rupture of a coronary plaque The fibrous cap ruptures and the lipid core is exposed to the blood stream

Platelets aggregate around the exposed lipid core and initiate thrombus formation Rupture of a coronary plaque- Thrombosis

Thrombosis propagation v v

Underlying pathology of acute coronary syndrome (unstable angina, acute MI) and sudden cardiac death

 Ruptured plaques (~ 70%) Stenotic (~ 20%) Nonstenotic (~ 50%)  Nonruptured plaques (~ 30%) Erosion Calcified nodule Others/Unknown *Adapted from Falk and associates,6 Davies,7 and Virmani and colleagues.7 Underlying Pathologies of "Culprit" Coronary Lesions Naghavi et al. Circulation. 2003;108:1664

Different Types of Vulnerable Plaques Major Underlying Cause of Acute Coronary Events Normal Rupture-prone Fissured Eroded Critical Stenosis Hemorrhage

Rupture-prone plaque

Eroded plaque with thrombosis

Calcified nodule

The Challenge of Terminology  Culprit Plaque; A Retrospective Term  Vulnerable Plaque; A Prospective Term  Vulnerable Plaque (high-risk plaque) = Future Culprit Plaque  좁은 의미 : Rupture-prone plaque  넓은 의미 : Plaque that is at increased risk of thrombosis and rapid stenosis progression Naghavi et al. Circulation. 2003;108:1664

Criteria for Defining Vulnerable Plaque Based on the Study of Culprit Plaques  Major criteria. Active inflammation (monocyte/macrophage and sometimes T- cell infiltration). Thin cap with large lipid core. Endothelial denudation with superficial platelet aggregation. Fissured plaque. Stenosis 90%  Minor criteria. Superficial calcified nodule. Glistening yellow. Intraplaque hemorrhage. Endothelial dysfunction. Outward (positive) remodeling

Markers of Vulnerability at the Plaque/Artery Level  Plaque Morphology/Structure. Plaque cap thickness. Plaque lipid core size. Plaque stenosis (luminal narrowing). Remodeling (expansive vs constrictive remodeling). Color (yellow, glistening yellow, red, etc). Collagen content versus lipid content, mechanical stability (stiffness and elasticity). Calcification burden and pattern (nodule vs scattered, superficial vs deep, etc). Shear stress (flow pattern throughout the coronary artery)

 Activity/Function. Plaque inflammation (macrophage density, rate of monocyte infiltration and density of activated T cell). Endothelial denudation or dysfunction (local NO production, anti-/procoagulation properties of the endothelium). Plaque oxidative stress. Superficial platelet aggregation and fibrin deposition (residual mural thrombus). Rate of apoptosis (apoptosis protein markers, coronary microsatellite, etc). Angiogenesis, leaking vasa vasorum, and intraplaque hemorrhage. Matrix-digesting enzyme activity in the cap (MMPs 2, 3, 9, etc). Certain microbial antigens (eg, HSP60, C. pneumoniae) Markers of Vulnerability at the Plaque/Artery Level

 Pan-Arterial. Transcoronary gradient of serum markers of vulnerability. Total coronary calcium burden. Total coronary vasoreactivity (endothelial function). Total arterial burden of plaque including peripheral (eg, carotid IMT) Markers of Vulnerability at the Plaque/Artery Level

Diagnostic technique

Intravascular Ultrasound (IVUS)  Advantage:  Reveals the morphology of the plaque  Disadvantages:  Low spatial resolution (~ 200  m)  Limited information about the plaque composition

IVUS

IVUS-radiofrequency data Virtual histologyElastography

Morphological Lesion size Lesion shape % Stenosis Cap thickness Chemical Lipid, Protein, Water Calcium Collagen Physiological Flow disturbances CFR, FFR Spectroscopy Polarization Grey Scale (2-D, L-Mode) Doppler  infrared light wave reflection Optical Coherence Tomography (OCT)

lp Homogeneous, Signal-rich Fibrous Lipid Echolucent, Diffuse Borders Echolucent, Sharp Borders Calcific 500 µm OCT characteristics

Histology OCT High lipid content Fibro-fatty plaque Thin Cap OCT

 Advantage:  High resolution  improved visualization of fibrous caps and plaque components  Possibility to detect inflammation  Disadvantages:  Limited penetration OCT

Angioscopy

 Advantages:  Direct visualization of the plaque surface  Disadvantages:  Visualizes only the surface of the plaque  Requires a proximal occluding balloon  Subjective interpretation Angioscopy

Intravascular Thermography

 Advantages:  Gives information about plaque inflammation  Disadvantages:  Overlap in temperature heterogeneity b/w stable and unstable presentations  Plaque temperature may be affected by the blood flow

Spectroscopy  Advantage:  Chemical compounds detection  Disadvantage:  lack of structural definition  may needs combination with imaging techniques  Analyze the light scattered from the tissue

Others  Intravascular MRI  Intravascular nuclear imaging  MRI  Electron Beam Computed Tomography (EBCT)

Therapeutic options  Focal  Regional  Systemic: medical tx. (aspirin, statins, beta-blocker, ACE inhibitor …..) PCI in selected case Under investigations cryoplasty sonotherapy photodynamic therapy …..