CTA Characterization of Vulnerable Plaque Minneapolis Heart Institute Robert S. Schwartz, MD Minneapolis Heart Institute

Shareholder/Founder: Atritech Robert S. Schwartz, MD Shareholder/Founder: Atritech

What is a Vulnerable Plaque? Plaque morphology underlying luminal thrombi represents a vulnerable plaque Thin-cap Fibroatheroma – Plaque rupture Pathologic intimal thickening Fibroatheroma Calcified plates with bone formation – Calcified nodule - surface thrombus Plaque Erosion

Causes of Coronary Thrombosis Virmani R, et al. Arterioscler Thromb Vasc Biol 2000;20:1262 Erosion Rupture Calcified nodule Rupture Site Calcified Nodule NC Th Th Th Th NC FC Th Th Th Th

Whither Coronary Calcification ? 5

Very High Coronary Artery Calcium Scores: Extremely Elevated Risk Wayhs R, Zelinger A, Raggi P, JACC 2002;39:225-230 Probability of survival free of events in 98 consecutive asymptomatic subjects with calcium score >1,000 on a screening electron beam tomography scan. 6

Risk of MI Raggi et al. Arterioscler Thromb Vasc Biol 2004;24:1272 Progressors were 17 fold more likely to have a hard cardiac event 7

Event rates relative to Framingham Risk 632 aSx pts Raggi, Am Heart J 2001;141:376 8

Incremental Value of CAC Over Total Risk Factors Budoff, M. J. et al. J Am Coll Cardiol 2007;49:1860-1870

Consecutive Acute MIs at BWH (n=200) Location of MI by Vessel Kuntz et al Consecutive Acute MIs at BWH (n=200)

Distribution of Acute Coronary Occlusions Left Anterior Descending Artery (Normalized Segment Analysis) 35 30 p = 0.003 25 33.3 20.5 20 Percent (%) 16.7 16.7 15 10 6.4 5 3.9 1.3 1.3 10 20 30 40 50 60 70 80 90 100 110 120 130 millimeters (mm) Prox Mid Distal 11

Cumulative Frequency Distribution Distance from Ostium LAD 100 80 60 Percent (%) 40 20 10 20 30 40 50 60 70 80 millimeters (mm) 12

MSCTA: Disease is Proximal There are only a handful of radioisotopes with characteristics suitable for coronary Brachytherapy applications. Radioactive isotopes have a fixed half-life (the time it takes for the activity to drop by half). Their energies are also fixed. These energies are dictated by the nuclear structure and cannot be altered. Therefore to reach a certain target with radioisotopes one must have the right energy. If the conditions between the isotope and the target are changed by the presence of foreign material with different properties than tissue the dose to the target may not be achieved. As I mentioned earlier, beta sources have a limited depth of penetration which is adequate for a millimeter depth. On the other hand due to gamma's penetrating power it delivers a dose well beyond the treatment zone. 13

Gregg W. Stone, MD PROSPECT Investigators 9/11/2018 The PROSPECT Trial Providing Regional Observations to Study Predictors of Events in the Coronary Tree A Natural History Study of Atherosclerosis Using Multimodality Intracoronary Imaging to Prospectively Identify Vulnerable Plaque This is the Main Title Slide There is no Master for this particular slide, as it is used only once for each presentation. To use this slide in your presentation, merely retype the title and the list of participating doctors. Gregg W. Stone, MD PROSPECT Investigators TCT 2008 - DRAFT 14 14

PROSPECT: Conclusions Approximately 20% of pts with successfully treated ACS with stents and medical Rx develop MACE within 3 years Adverse future events are equally attributable to recurrence at originally treated culprit lesions (treatment failure) and to previously untreated coronary segments Approximately 12% of pts develop MACE from non culprit lesions during 3 years of follow-up Patients treated with medical therapy who develop non culprit lesion events present most commonly with progressive or unstable angina, and rarely with cardiac death, cardiac arrest or MI

PROSPECT: Conclusions While plaques responsible for unanticipated future MACE are angiographically mild, most untreated plaques which become symptomatic have a large plaque burden and a small lumen area (which are detectable by IVUS but not by angiography) Only about half of new events due to non culprit lesions exemplify the classic notion of vulnerable plaque (rapid lesion progression of mild angiographic lesions), while half are attributable to unrecognized and untreated severe disease with minimal change over time

PROSPECT: Conclusions The prospective identification of non culprit lesions prone to develop MACE within 3 years can be enhanced by characterization of underlying plaque morphology with virtual histology, with VH-TCFAs representing the highest risk lesion type The combination of large plaque burden (IVUS) and a large necrotic core without a visible cap (VH-TCFA) identifies lesions which are at higher risk for future adverse cardiovascular events

Characterization of Noncalcified Coronary Plaques and Identification of Culprit Lesions in Patients With Acute Coronary Syndrome by 64-Slice Computed Tomography Toshiro Kitagawa et al Objectives: We sought to characterize noncalcified coronary atherosclerotic  plaques in culprit and remote coronary atherosclerotic lesions in patients with acute coronary syndrome (ACS) with 64-slice computed tomography (CT). Background: Lower CT density, positive remodeling, and adjacent spotty coronary calcium are characteristic vessel changes in unstable coronary plaques. Methods: Of 147 consecutive patients who underwent contrast-enhanced 64-slice CT examination for coronary artery visualization, 101 (ACS; n = 21, non-ACS; n = 80) having 228 noncalcified coronaryatherosclerotic plaques (NCPs) were studied. Each NCP detected within the vessel wall was evaluated by determining minimum CT density, vascular remodeling index (RI), and morphology of adjacent calcium deposits. Results: The CT visualized more NCPs in ACS patients (65 lesions, 3.1 ± 1.2/patient) than in non-ACS patients (163 lesions, 2.0 ± 1.1/patient). Minimum CT density (24 ± 22 vs. 42 ± 29 Hounsfield units [HU], p < 0.01), RI (1.14 ± 0.18 vs. 1.08 ± 0.19, p = 0.02), and frequency of adjacent spotty calcium of NCPs (60% vs. 38%, p < 0.01) were significantly different between ACS and non-ACS patients. Frequency of NCPs with minimum CT density <40 HU, RI >1.05, and adjacent spotty calcium was approximately 2-fold higher in the ACS group than in the non-ACS group (43% vs. 22%, p <0.01). In the ACS group, only RI was significantly different between 21 culprit and 44 nonculprit lesions (1.26 ± 0.16 vs. 1.09 ± 0.17, p < 0.01), and a larger RI ( 1.23) was independently related to the culprit lesions (odds ratio: 12.3; 95% confidential interval: 2.9 to 68.7, p < 0.01), but there was a substantial overlap of the distribution of RI values in these 2 groups of lesions.

Comparison of RI Between ACS Culprit and Nonculprit Lesions Kitagawa, T. et al. J Am Coll Cardiol Img 2009;2:153-160 Copyright ©2009 American College of Cardiology Foundation. Restrictions may apply.

Gold NanoParticles for Vulnerability Cormode et al Radiology August 2010

Multislice Computed Tomographic Characteristics of Coronary Lesions in Acute Coronary Syndromes Motoyama JACC, 50:4, 24 July 2007, p319-326 295 ACS vs 149 SAP Abstract: ObjectivesTo evaluate the feasibility of noninvasive assessment of the characteristics of disrupted atherosclerotic plaques, the authors interrogated the culprit lesions in acute coronary syndromes (ACS) by multislice computed tomography (CT).BackgroundDisrupted atherosclerotic plaques responsible for ACS histopathologically demonstrate large lipid cores and positive vascular remodeling. It is expected that plaques vulnerable to rupture should bear similar imaging signatures by CT.MethodsEither 0.5-mm × 16-slice or 64-slice CT was performed in 38 patients with ACS and compared with 33 patients with stable angina pectoris (SAP) before percutaneous coronary intervention. The coronary plaques in ACS and SAP were evaluated for the CT plaque characteristics, including vessel remodeling, consistency of noncalcified plaque (NCP <30 HU or 30 HU <NCP <150 HU), and spotty or large calcification.ResultsIn the CT profile of culprit ACS and SAP lesions, the frequency of 30 HU <NCP <150 HU (100% vs. 100%, p = NS) was not different, and large calcification (22% vs. 55%, p = 0.004) was significantly more frequent in the stable lesions. Positive remodeling (87% vs. 12%, p < 0.0001), NCP <30 HU (79% vs. 9%, p < 0.0001), and spotty calcification (63% vs. 21%, p = 0.0005) were significantly more frequent in the ACS lesions. Presence of all 3 (i.e., positive remodeling, NCP <30 HU, and spotty calcification) showed a high positive predictive value, and absence of all 3 showed a high negative predictive value for the culprit plaques associated with ACS. Conclusion: CT characteristics of plaques associated with ACS include positive vascular remodeling, low plaque density, and spotty calcification. It is logical to presume that plaques vulnerable to rupture harbor similar characteristics.

Uncalcified Plaque 124 pts Calcium Score Zero 45% No Plaque 55% with Noncalcified plaque only 55% NCP Only

Risk Factor Assessment No NCP Normal Cors n (%) NCP Mild stenosis Mod-severe stenosis P Value Number of patients 55 (44.4) 63 (50.8) 6 (4.84) Female 36 (65.5) 36 (57.1) 4 (66.7) ns Age (avg +/- SD) 50.2 +/- 11.8 50.7 +/- 11.6 49.8 +/- 8.4 Family history of CHD 32 (58.2) 47 (74.6) 5 (83.3) Hyperlipidemia 43 (68.3) Curr / Former smoker 9 (16.4) 26 (41.3) 0.023* Diabetes Mellitus 1 (1.82) 3 (4.76) 1 (16.7) HTN 15 (27.3) 27 (42.9) Obesity (BMI ≥ 27) 25 (45.5) 34 (54.0) 6 (100) *No NCP vs (NCP mild stenosis + NCP sig stenosis)

59 yo male with Sudden Cardiac Death 11 months post CTA

Importance of Remodeling Remodeling Index ~ 1.40 HU ~60

CTA Characterization of Vulnerable Plaque Minneapolis Heart Institute Robert S. Schwartz, MD Minneapolis Heart Institute 26