Future Applications of Contrast Echocardiography

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1 Future Applications of Contrast Echocardiography Jonathan R. Lindner, M.D. Knight Cardiovascular Institute Oregon Health & Science University Portland, Oregon, USA Disclosures: Investigator-initiated grant from GEHC

2 The Evolution of Cardiovascular Imaging Structure Function Metabolism/Perfusion

3 Molecular Imaging in Cancer Medicine 18F-NOTA-Alfatide Wan L et al. J Nucl Med, 2013; 54(5):691-8

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

4 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

5 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

6 MB Targeting by Surface Targeting Ligand rpsgl-1 or Other targeting ligand PEG stearate DSPC (CH 2 CH 2 O-) 40 (CH 2 CH 2 O-) 70 (CH 2 CH 2 O-) 40 dfb gas core

7 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.

Myocardial Ischemic Memory Imaging Anaerobic Metabolism - BMIPP-SPECT BMIPP CH 3 125 I (CH 2 ) 12 C H CH 2 COOH FAT/ CD36 Acyl-CoA synthetase BMIPP Lipid

8 Myocardial Ischemic Memory Imaging Anaerobic Metabolism - BMIPP-SPECT BMIPP CH I (CH 2 ) 12 C H CH 2 COOH FAT/ CD36 Acyl-CoA synthetase BMIPP Lipid pool P-iodophenyl acetic acid BMIPP-CoA b-oxidation Mochizuki T, et al. Ann Nucl Med 2002;16:563 Mitochondria Aras O, et al. Curr Opin Biotechn 2007:18:46 51

9 123 I-BMIPP in 448 Patients with CP Sensitivity 73% (43% for clinical) NPV 78% (62% for clinical) Kontos MC, et al. JACC 2010;56:290

10 P-Selectin Targeting for Ischemic Memory mab SLeX PSGL-1 Lectin EGF PSGL-1 CR n COOH COOH

11 Selectin-targeted Ischemic Memory Imaging Risk Area B-Mode Selectin-targeted Wall Motion Davidson BD, et. al. JACC 2012;60:1690

12 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

13 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

14 Disease Severity Atherosclerotic Disease Progression ACS and Ischemic Dysfxn Obstructive Symptoms Anatomic disease Pre-clinical Disease Age

15 Vascular Inflammation with 18 FDG-PET Wildgruber M, et al. Theranostics :865

16 Signal Enhancement (AU) Plaque Development in LDL-R -/- and Apobec-1 -/- mice 10 wks 20 wks 40 wks 2-D VCAM Wild Type DKO wk 20wk 40wk 10wk 20wk 40wk 10wk 20wk 40wk Control P-selectin VCAM-1 Kaufmann BA, et al., ATVB 2010;30:54

17 Signal Intensity CIMT (mm) Endothelial Phenotype in Insulin Resistance Avg. 260 μm BL Months on HFD VCAM-1 B-Mode 12 MHz P-Selectin Control P-selectin BL Months Chadderdon S, et al., Circulation 2014;129:471

18 Biologic target identification Defining or refining pathophysiology Screening by bioassay In vivo testing of candidate agent In vivo imaging in animal models Pre-clinical Optimization and Dose-ranging Full characterization of effects IND Phase 1 clinical trials Surrogate end-point Clinical Phase 2 and 3 clinical trials NDA

19 Customizing Atherosclerotic Therapy Drugs in Development Related to Phenotype Anti-OxLDL Anti-Lp-PLA2 Cytokine/Chemokine Antagonists 5-LO Inhibitors TLR/LTB4 Inhibitors ECAM Inhibitors NADPH-Ox Inhibitors Protease Inhibitors GPIb and PAR Antagonists Angiogenesis Inhibitors 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

20 Force (N) The Power of Bubbles: The Mantis Shrimp Time (ms) Shiela Patek U.Mass

21 Therapeutic Contrast Ultrasound: Entraining the Bioeffects Thrombolysis Perfusion ( NO?) Bioeffects Gene or protein delivery Tumor/tissue ablation

22 Gene Delivery Drug Delivery Co-mixture Surface conjugation Innerlamellar Surface conjugation Liposome conjugation

23 Ultrasound Gene Delivery Venule Christiansen JP, et al., Ultrasound Med Bio 2003;29:1759 Xie Aet al., JACC CV Imag (in press)

A 120 100 Muscle Perfusion (2 10 8 MB, 1.3 MHz) y=95(1-exp 1.

18X ) 20 Control Exposed 0 0 2 4 6 8 10 12 14 Exposed (MI 1.

01 D 180 160 140 Control Exposed p<0.01 p<0.05 120 b-value (s -1 ) 1.0 0.

24 A Muscle Perfusion ( MB, 1.3 MHz) y=95(1-exp 1.57X ) B Control T 0 T 1s T 3s T 5s T 8s Intensity Time (s) y=59(1-exp 0.18X ) 20 Control Exposed Exposed (MI 1.3, +MB) T 0 T 1s T 3s T 5s T 8s C Control Exposed p<0.001 p<0.01 D Control Exposed p<0.01 p< b-value (s -1 ) MBF (AXb) MI Pulsed MB MI Pulsed MB Belcik JT, et al. Circ CV imaging 2015;

25 Coronary Recanalization in MI (porcine) Xie, F. et al. Circulation 2009;119:1378

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

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