Innovation Interlude: Molecular Imaging in Cardiology. Celestial Doppelgangers and Relativity

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1 Innovation Interlude: Molecular Imaging in Cardiology Jonathan R. Lindner, M.D. M. Lowell Edwards Professor of Cardiology Knight Cardiovascular Institute Oregon National Primate Research Center Oregon Health & Science University Disclosures Off-label use of contrast agents Investigator-initiated Grants from GE Healthcare, Astellas and Bracco Celestial Doppelgangers and Relativity Hubble Telescope QSO Twin Quasar 1

2 The Evolution of Cardiovascular Imaging Structure Function Metabolism/Perfusion Molecular Imaging in Cardiology Atherosclerosis detection and risk -Inflammation -Protease activity -Platelets, VWF -Oxidative stress, oxidized lipids -Vasa vasorum -TF, fibrin Angiogenesis/Regenerative Biology -chemokines and growth factors -Stem cell recruitment/engraftment -endothelial markers Ischemia -Selectins, hypoxic metabolism, C receptors Myocarditis/OHT rejection -Adhesion molecules, inflammatory cells, chemokines, apoptosis Ventricular remodeling -Protease activity, inflammatory cells, apoptosis Arrhythmogenesis -Sympathetic activity -cell jxn molecules 2

3 Examples of Strategies Used for Molecular Imaging 1. Ligand-receptor binding which produces tracer retention or altered kinetics 2. Cellular retention from metabolic uptake or incorporation into metabolic machinery 3. Tracer activation by targeted metabolic or enzymatic process 4. Endogenous signal characteristics without contrast agent Microbubbles for Perfusion Imaging Microbubble Velocity (mm/s) 3 2 Y=.85x+137 p<.1, r= RBC Velocity (mm/s) 3

4 MB Targeting by Surface Targeting Ligand rpsgl-1 or Other targeting ligand PEG stearate DSPC (CH 2 CH 2 O-) 4 (CH 2 CH 2 O-) 7 (CH 2 CH 2 O-) 4 dfb gas core Roles for Molecular Imaging Basic Research & Discovery Uncovering pathophysiology Phenotyping animal models of disease Matching molecular process to anatomy or function Matching gene expression to molecular or anatomic phenotype Pre clinical & Clinical Research Rapid evaluation of new therapies Optimization of therapies Evaluating mechanism of therapy or off target effects Tracking cell or gene therapy Understanding resistance to disease Clinical Medicine Early diagnosis More definitive diagnosis Evaluating response to therapy Customized therapy Monitoring disease progression or prognosis 4

5 Potential Clinical Roles of Molecular Imaging in Ischemia Early detection of infarction and ischemia Risk stratification based on spatial extent of ischemia Detection of ischemia/infarction in those with preexisting perfusion or wall motion abnormalities Salvaging the disaster stress echo. Imaging Strategy and Temporal Resolution Tracer Concentration Free Tracer Total Retained Repeat? Time imaging 5

6 Myocardial Ischemic Memory Imaging Anaerobic Metabolism - BMIPP-SPECT BMIPP CH I (CH 2 ) 12 C H CH 2 COOH FAT/ CD36 BMIPP Acyl-CoA synthetase Lipid pool P-iodophenyl acetic acid BMIPP-CoA -oxidation Mochizuki T, et al. Ann Nucl Med 22;16:563 Mitochondria Aras O, et al. Curr Opin Biotechn 27:18:46 51 P-Selectin Targeting for Ischemic Memory mab SLeX PSGL-1 Lectin EGF PSGL-1 CR n COOH COOH 6

7 Selectin-targeted Ischemic Memory Imaging Risk Area B-Mode Selectin-targeted Wall Motion Davidson BD, et. al. JACC 212;6:169 MB-PS Versus P-selectin Targeting Christiansen JP, et al. Circulation 22;5:1764 Mott B, et al. JACC CV Imag 216;9:937 7

8 Potential Clinical Roles of Molecular Imaging in Atherosclerosis Early detection of aggressive disease Vulnerability to complication (plaque or patient) Selection/optimization of therapy Pre-clinical drug development and early clinical proof-of-mechanism studies Molecular Imaging in Atherosclerosis: Potential Targets Pro-inflammatory cytokines Procoagulant effects proteases apoptosis LDL Monocyte EC Activation Ox-LDL T-cell IFN Th1 GF & Chemok. Differentiation Foam cells OFR Angiogen. IEL SMC 8

9 Aortic FDG-PET Activity For Prediction of Events Stroke, TIA, ACS, Revasc., Angina, PAD, HF, CV death NRI -12% on FRS Figueroa AL, et al., JACC-CVI 213;6:125 Plaque Development in LDL-R -/- and Apobec-1 -/- mice wks 2 wks 4 wks 2-D VCAM-1 Signal Enhancement (AU) Wild Type DKO wk 2wk 4wk wk 2wk 4wk wk 2wk 4wk Control P-selectin VCAM-1 Kaufmann BA, et al., ATVB 2;3:54 9

10 Endothelial Phenotype in Insulin Resistance VCAM-1 B-Mode 12 MHz Signal Intensity P-Selectin Control P-selectin BL Months Chadderdon S, et al., Circulation 214;129:471 Platelets in Non-ACS Atherosclerosis Scanning EM Immunohistochemistry GPIIb Mac-2 5 m m 1. Source for pro-inflammatory cytokines 2. Contribute to monocyte recruitment 3. Source for vasoconstrictor mediators 4. Source for pro-angiogenic cytokines and GFs

11 Plt-Endothelial Interactions in DKO Mice Molecular Imaging of Platelet-Endothelial Interactions VWF active A1 domain (AA ) 2-D B-mode MB-VWF-A MB-VWF-A1 MB-control 12 MB-VWF-A1 MB-control Intensity (IU) 2 15 Intensity (IU) Age (weeks) Shim CY, et. al. Circ CV Imag 215;8:e wk 4 wk plt depl 11

12 Imaging Treatment Effects with NOX Inhibition 4 wk 4 wk Low 4 wk High Liu Y, et al, Circ CV Imaging 213;6:74 m 35 P-selectin 35 VCAM-1 35 GP1b Signal Intensity (VIU) Signal Intensity (VIU) Signal Intensity (VIU) wks Control 2 Low 3 High 4 (n=5) (n=8) (n=7) (n=6) 3 1wks Control 2 Low 3 High 4 (n=5) (n=8) (n=7) (n=6) 3 1wks Control 2 Low 3 High 4 (n=5) (n=8) (n=7) (n=6) 4 wks 4 wks 4 wks 12