validate new imaging technology 15m Robert L Wilensky, M.D. - PowerPoint PPT Presentation

Atherosclerotic animal models: a way to validate new imaging technology 15m Robert L Wilensky, M.D. University of Pennsylvania

Is there a suitable animal model of human atherosclerosis and vulnerable plaque? • Human atherosclerosis develops over decades while we use a model that develops over weeks to months. • Incidence of coronary artery disease is variable despite similar risk factors. • Do we fully understand the process leading from vulnerable plaque to plaque rupture?

The ideal animal model for vulnerable plaque assessment • Similar morphology and physiological characteristics to human disease. • High percentage of high-risk coronary artery lesions. • Variable lesion development. • The lesion phenotype can be modified.

Advantages of porcine models • Aged pigs develop atherosclerosis. • Serial intraluminal evaluations of atherosclerotic lesions are possible. • Lesions are similar to human lesions. • Have been used in diagnostic, pharmacologic and interventional studies

Porcine models of accelerated coronary atherosclerosis Model Advantages Limitations Well characterized. Type I diabetic model. Diabetes/ Reproducible human like Variable development of atherosclerosis. hypercholesterolemic atherosclerosis. Expensive Results obtained from diagnostic and pharmacologic treatment studies corroborate data obtained in humans. Complex lesions detectable as early as 6 months after induction. Well characterized Long induction period for Rapacz familial Models a known human disease atherosclerosis. hypercholesterolemic state. Large size of animals (although genetic modified mini-pig has been developed). Expensive Small size. Limited commercial availability. PCSK9 gain of Models a known human disease state Relatively long term induction period (12 function Reproducible lesions. months) Only model of metabolic syndrome Limited commercial availability. Ossabaw induced atherosclerosis. Questionable development of severe Small size. lesions. Relatively short induction period after a high fat diet regimen. Hamamdzic & Wilensky. J Diabetes Res 2013:761415

Thin cap Large plaque burden Large necrotic core Expansive remodelling Inflammation of the fibrous cap Schaar JA et al. Eur Heart J 2004;25:1077

Rapacz mini-pig: Coronary artery at 13 months Courtesy of E. Falk in J Diabetes Res 2013:761415

PSCK-9-transgenic Yucatan mini-pig: Coronary artery at13 months of atherogenic diet Courtesy of E. Falk in J Diabetes Res 2013:761415

Ossabaw feral pigs

Diffuse atherosclerosis in Ossabaw pigs Neeb ZP et al. Comp Med 2010;60:300

Coronary artery from Ossabaw pig Courtesy of M Sturek in J Diabetes Res 2013:761415

DM/HC causes increased coronary artery lesion complexity Proximal LAD lesions: 7 months Wilensky et al Nat Med 2008;14:1059

Higher lipid content is associated with coronary events. • Culprit lesions in ACS are more likely to have a high lipid core than non-culprit lesions by NIRS (84.4% vs 52.8%) Circ Cardiovasc Intervent 2012;5:55. • Non-culprit lesions in ACS have a higher lipid core than patients with stable angina by NIRS Circ Cardiovasc Intervent 2012;5:55 • Culprit lesions in STEMI have higher lipid core burden index compared to non-culprit lesions by NIRS Arterioscler Thromb Vasc Biol 2016;36:1010 d

Increased early lipid deposition in arteries developing a TCFA Figure 3: TCFA present TCFA absent LCBI: 45 LCBI: 16 3 months LCBI: 306 LCBI: 5 6 months 9 months 300 µm 300 µm 300 µm Saybolt et al Euro Invent 2016;11:1612

DM/HC porcine model: The vulnerable artery Arteries containing TCFA Arteries containing no TCFAs P=0.04 P=0.97 LCBI LCBI Saybolt et al Euro Invent 2016;11:1612

Early NIRS+ predicts future TCFA and fibroatheroma development by histology (9 months) . Number of histology sections 152 32 38 16 TCFAs 100 90 + at 3-m or 6-m P=0.007 80 % of histology sections 70 + 6-m only P=0.004 60 + at 3-m & 6-m P=0.03 50 40 Fibroatheromas 30 20 + at 3-m or 6-m P=0.0001 10 + 6-m only P=0.0001 0 3 mth NEG POS NEG POS 6 mth NEG NEG POS POS + at 3-m & 6-m P=0.0004 TCFA ThCFA PIT Normal/IH Patel et al ATVB 2013;33:346

NIRS positivity is associated with increased inflammation NIRS+ NIRS- Patel et al. ATVB 2013;33:346

Movat’s P-S red Cat S NIRS+ TCFA Cat S TUNEL Ki-67 Movat’s Cat S P-S red NIRS- ThCFA Cat S TUNEL Ki-67 Patel et al ATVB 2013;33:346

3-m Progression of IVUS/NIRS results over time 1 2 3 4 1 2 3 4 6-m 1 2 3 4 9-m 1 2 3 4 2 3 4 1 Patel et al. ATVB 2013;33:346

Sudden death due to ACS in pig 4 months after DM/HC induction

AtheroRemo:Time-to-event for all-cause mortality or non-fatal ACS Median LCBI 43 Oemrawsingh RM et al JACC 2014;64:2510

DM/HC pigs demonstrate increased plaque burden, lipid content and inflammation in lesions exhibiting very low endothelial shear stress. Chatzizisis YS et al. Circulation 2008;117:993

PREDICTION: Large plaque burden and low endothelial shear stress predict progression of lesions (6-10 months). Stone PH et al. Circulation 2012;126:172

PREDICTION: Large plaque burden and low endothelial shear stress independently predict progression of plaque burden. Stone PH et al. Circulation 2012;126:172

Induction of DM/HC causes more severe and less variable atherosclerosis in the abdominal aortae compared to the coronary arteries Coronary Artery Abdominal Aorta Coronary Artery Abdominal Aorta 200 um 500 um 100 um 500 um Thin fibrous cap Medial destruction Calcification Intra-plaque hemorrhage 3 4 1 2 100 um 25 um 100 um 100 um Fenning RS et al JAHA 2015;4:e001477

In DM/HC pigs, abdominal aortic disease severity correlates with glucose and cholesterol levels while coronary artery disease severity does not. Control Control P = 0.0043 P = 0.0014 Darapladib Treated Darapladib Treated 70 Abdominal aortae 70 AA Mean Lesion Size (mm^2) 60 AA Mean Lesion Size (mm^2) 60 50 50 40 40 30 30 20 20 10 10 0 0 200 250 300 350 400 450 500 400 500 600 700 800 900 1000 1100 Total Plasma Glucose Levels (mg/dL) Total Plasma Cholesterol Levels (mg/dL) Control Control P = 0.579 P = 0.843 Darapladib Treated Darapladib Treated 3,5 3,5 Coronary Mean Leion Size (mm^2) Coronary Mean Leion Size (mm^2) Coronary arteries 3 3 2,5 2,5 2 2 1,5 1,5 1 1 0,5 0,5 0 0 400 500 600 700 800 900 1000 1100 200 250 300 350 400 450 500 Total Plasma Cholesterol Levels (mg/dL) Total Plasma Glucose Levels (mg/dL)

Darapladib reduces c oronary artery lesion complexity compared to control - 2 worst proximal LAD lesions Control Treated Wilensky et al Nat Med 2008;14:1059

Kaplan – Meier curves for the primary end point of death from cardiovascular causes, myocardial infarction, or stroke. STABILITY. N Engl J Med 2014;370:1702

STABILITY: Randomization and follow-up. 7924 patients in treatment group were included in the analysis, however, only 5322 were taking darapladib (67.2%) The majority of patients were being treated with 4 cardiac medications STABILITY. N Engl J Med 2014;370:1702

STABILITY: Primary and secondary efficacy end points. STABILITY. N Engl J Med 2014;370:1702

Selective inhibition of Lp-PLA 2 does not reduce development of AA atherosclerosis DM/HC control DM/HC darapladib Fenning RS et al JAHA 2015;4:e001477

Summary • Animal models are not perfect replications of human disease. • Pre-clinical testing of the vulnerable plaque should make use of coronary arteries as the atherosclerotic process may differ in other arterial beds. • Surrogate markers should include necrotic core size, fibrous cap thickness, and vascular inflammation (genes and/or cells). Serial imaging may be of particular importance.