Cardiovascular Imaging (eBook)

Foreword 6
References 9
Preface 12
Contents 14
Part I: Preclinical Imaging of Mechanisms of Atherosclerosis and Its Complications 16
1: Pathobiology and Mechanisms of Atherosclerosis 17
1.1 Introduction 19
1.2 Plaque Formation 20
1.3 Plaque Progression 22
1.4 Plaque Complications 24
1.4.1 Plaque Rupture 24
1.4.2 Plaque Erosion 25
1.4.3 Intraplaque Hemorrhage (IPH) 25
1.5 Atherosclerosis Imaging 26
1.6 Anatomic Atherosclerotic Plaque Imaging 26
1.6.1 X-Ray Computed Tomography 26
1.6.2 Magnetic Resonance Imaging 28
1.6.3 Angiography 28
1.6.4 Angioscopy 29
1.6.5 Intravascular Ultrasound 29
1.6.6 Optical Coherence Tomography 30
1.7 Functional Atherosclerotic Plaque Imaging 31
1.7.1 Cell Activation Imaging 32
1.7.2 Phagocytosis Imaging 34
1.7.3 Imaging of Lipid Uptake/Foam Cell Formation 35
1.7.4 Imaging Metabolic Activity 35
1.7.5 Apoptosis Imaging 36
1.7.6 Oxidative Stress Imaging 37
1.7.7 Angiogenesis Imaging 37
1.7.8 Proteinase Imaging 38
1.7.9 Imaging Thrombosis 39
1.7.10 Imaging Calcification 39
Conclusion 40
References 40
2: Ultrasound Molecular Imaging of Endothelial Cell Activation and Damage in Atherosclerosis 53
2.1 B-Mode Ultrasound Imaging of Atherosclerosis 54
2.1.1 Focused Review of Ultrasound Physics 54
2.1.2 Ultrasound of Imaging of Plaque Burden 55
2.1.3 Imaging Plaque Composition 56
2.1.4 Mechanical Properties 58
2.1.5 Vasa Vasorum and Plaque Neovessel Imaging 59
2.2 Ultrasound Molecular Imaging of Atherosclerosis 61
2.2.1 Basics of Ultrasound Molecular Imaging 61
2.2.1.1 Ultrasound Contrast Agents 61
2.2.1.2 Targeted Microbubble Contrast Agents 62
2.2.1.3 Targeted Contrast-Enhanced Ultrasound Molecular Imaging 63
2.2.2 Molecular Targets of Atherosclerosis Accessible to Ultrasound Contrast Agents 65
2.2.3 Ultrasound Molecular Imaging of Atherosclerosis 66
2.2.3.1 Non-ligand Microbubble Targeting 66
2.2.3.2 Endothelial Cell Adhesion Molecules 67
P-Selectin 67
ICAM-1 and VCAM-1 68
Platelets and Thrombus 71
2.3 Summary 72
References 74
3: Molecular Imaging of Macrophages in Atherosclerosis 78
3.1 Conventional Imaging Modalities for Atherosclerotic Vascular Diseases 79
3.2 Macrophages in Atherosclerotic Diseases 79
3.3 Molecular Imaging 80
3.4 Macrophage Imaging by Iron-Based Nanomaterials 80
3.5 Macrophage Imaging by Nuclear Medicine 82
3.6 Imaging of Macrophage-Derived Proteases in Atherosclerotic Plaques 83
3.7 Imaging of Plaque Macrophages by HDL-Based Probes 85
3.8 Macrophage Imaging in Other Cardiovascular Diseases 85
3.9 Macrophage Imaging in Fat Tissue 87
3.10 Future Perspectives 87
References 88
4: Intravascular Molecular Imaging of Proteolytic Activity 92
4.1 Background 93
4.2 High-Risk Plaque Features 94
4.2.1 Plaque Proteolytic Activity 96
4.3 Coronary Artery Molecular Imaging 96
4.3.1 Clinical Trials 96
4.4 Intravascular NIRF Imaging 98
4.4.1 Intravascular NIRF Imaging Platforms 98
4.4.1.1 One-Dimensional In Vivo Intravascular NIRF Sensing 99
4.4.1.2 Two-Dimensional In Vivo Intravascular NIRF Imaging 100
4.4.1.3 In Vivo Intravascular NIRF-OFDI Molecular-Structural Imaging 100
4.4.1.4 In Vivo Intravascular NIRF-IVUS Imaging 101
4.4.2 Intravascular NIRF Imaging Applications to Atherosclerosis 102
4.4.2.1 NIRF Imaging of Cysteine Protease Activity in Inflamed Plaques 102
4.4.2.2 Stand-Alone In Vivo Intravascular NIRF Sensing 103
4.4.2.3 In Vivo Intravascular NIRF-OFDI 105
4.4.2.4 NIRF Imaging of Lipid-Rich, Inflamed Plaques with Indocyanine Green 107
4.4.3 Intravascular NIRF Imaging of Proteolytic Activity in Coronary Stents 108
4.4.3.1 NIRF Imaging of Stent Inflammatory Proteolytic Activity 110
4.4.3.2 NIRF Imaging of Stent Fibrin Deposition 110
Conclusion 113
References 113
5: Optical Molecular Imaging of Inflammation and Calcification in Atherosclerosis 120
5.1 Imaging Criteria for Atherosclerotic Inflammation and Calcification 121
5.2 Optical Molecular Imaging Strategies 122
5.3 Leukocyte Infiltration via Endothelial Cell Activation 123
5.4 Proteolytic Activity and Matrix Remodeling 125
5.5 Inflammation, Osteogenesis, and Calcification 127
5.6 Future Perspectives 129
References 131
6: Molecular Imaging of Oxidation-­Specific Epitopes to Detect High-Risk Atherosclerotic Plaques 134
6.1 Introduction 135
6.2 Antibodies and Peptides to Oxidation-Specific Epitopes 136
6.3 The Role of OSE in Atherogenesis and Disease Progression 144
6.4 Molecular Imaging Probes for In Vivo OSE Detection 144
6.5 Paramagnetic Probes for In Vivo OSE Imaging 149
6.5.1 Gd OSE-Targeted Micelles 152
6.5.2 Manganese OSE-Targeted Micelles 154
6.5.3 OSE-Targeted, Lipid-Coated, Superparamagnetic Iron Oxide Particles (SPIOs) 156
6.5.4 Manganese OSE-Targeted Dendrimers 158
Conclusions 161
References 163
7: Live Cell Multiphoton Microscopy of Atherosclerotic Plaques in Mouse Aortas 168
7.1 Introduction 169
7.1.1 Atherosclerosis 169
7.1.2 Live Cell Microscopy 170
7.1.2.1 Epifluorescence Microscopy 170
7.1.2.2 Confocal Microscopy 171
7.1.2.3 Multiphoton Microscopy 171
7.1.3 Choice of Multiphoton Microscopy for Studying Atherosclerosis 172
7.2 Materials and Methods 172
7.2.1 Aorta Harvest 172
7.2.1.1 Background 172
7.2.1.2 Method 172
7.2.2 T Cell Harvest 173
7.2.2.1 Background 173
7.2.2.2 Method 175
7.2.3 Tissue Maintenance During Imaging 175
7.2.4 Microscopy and Hardware 176
7.2.5 Image Processing 179
7.3 Results 179
7.4 Conclusion and Future Work 181
References 181
8: Imaging of Complications in Atherosclerosis: Thrombosis and Platelet Aggregation 184
8.1 Introduction 185
8.2 The Significance of Fluorescent Live Imaging 186
8.3 Visualization of In Vivo Cell Kinetics with High Time Resolution and Spatial Resolution 187
8.3.1 Fluorescent Probes (Dyes) 187
8.3.2 Fluorescent Protein 188
8.3.3 Nonstaining Approaches 188
8.4 Application of Fluorescence Imaging to Cardiovascular Diseases 189
8.5 Imaging of Thrombus 190
8.6 Visualizing Platelets In Vivo 191
8.7 Reactive Oxygen Species (ROS)-Induced Thrombosis Models 192
8.8 Ex Vivo Imaging Techniques 193
8.9 Applications for Visualization Techniques for Metabolic Diseases 194
8.10 Summary and Conclusions 194
References 196
Part II: Imaging Insights into Mechanisms of Calcific Aortic Valve Disease (CAVD) and Calcification 198
9: Pathobiology and Optical Molecular Imaging of Calcific Aortic Valve Disease 199
9.1 Aortic Valve Structure, Function, and Disease 200
9.2 Imaging Criteria for Aortic Valve Disease 201
9.3 Valve Endothelial Cell Activation and Migration 203
9.4 Macrophages and Proteolytic Activity 205
9.5 Myofibroblast Activation, Osteogenic Differentiation, and Calcification 207
9.6 Future Perspectives 208
References 208
10: PET/CT Imaging of Inflammation and Calcification in CAVD: Clinical Studies 212
10.1 Introduction 213
10.2 PET/CT 214
10.3 CAVD Pathology and PET Radiotracer Choice 215
10.4 PET/CT for Imaging Inflammation in CAVD 217
10.4.1 Background 217
10.4.2 Clinical Studies 218
10.4.3 Relationship Between FDG Uptake and Lesion Severity 220
10.4.4 Predicting Outcome and Disease Progression 220
10.4.5 Reproducibility and Methodological Strengths and Weaknesses 222
10.4.6 Validation of Valvular 18F-FDG Uptake 223
10.4.7 Summary 223
10.5 PET/CT for Imaging Calcification in CAVD 224
10.5.1 Background 224
10.5.2 Validation of Valvular 18F-Fluoride Uptake 225
10.5.3 Clinical Studies 228
10.5.4 Relationship Between 18F-Fluoride and Lesion Severity 228
10.5.5 Predicting Outcome and Disease Progression with 18F-Fluoride 228
10.5.6 Reproducibility and Methodological Strengths and Weaknesses 229
10.5.7 Summary 230
10.6 Conclusions and the Future 230
References 231
11: Ultrasound Imaging of Calcific Aortic Valve Disease 235
11.1 Introduction 236
11.2 Echocardiography Evaluation of CAVD Severity 236
11.2.1 Anatomy 236
11.2.2 Velocity and Pressure Gradients 238
11.2.3 Aortic Valve Area 240
11.2.4 Additional Measurements of Hemodynamic Severity 242
11.3 Echocardiography and CAVD Outcomes 244
11.3.1 Aortic Valve Sclerosis and Cardiovascular Outcomes 244
11.3.2 Aortic Stenosis and Valvular Outcomes 245
11.4 CAVD Pathophysiology and Echocardiography 248
11.4.1 Ventricular Changes 248
11.4.1.1 Hypertrophy 248
11.4.1.2 Diastolic Dysfunction 248
11.4.1.3 Speckle-Tracking Strain 250
11.4.2 Stress Testing 250
11.4.2.1 Normal EF 251
11.4.2.2 Reduced EF 252
11.4.3 Low-Flow, Low-Gradient AS with Normal EF 254
References 254
12: Innovations in Microscopic Imaging of Atherosclerosis and Valvular Disease 260
12.1 Introduction 261
12.2 OCT 262
12.3 ?OCT Technology 263
12.4 Calcific Aortic Valve Disease (CAVD) 264
12.4.1 Current Status: A Still Unsolved Medical Problem 264
12.4.2 Mechanism of Aortic Valve Calcification 264
12.4.3 ?OCT Imaging of Aortic Valves 265
12.4.4 Extracellular Matrix 266
12.4.5 Cells 267
12.4.6 Cholesterol 269
12.4.7 Microcalcification 271
12.5 Limitations of ?OCT 271
12.6 Conclusion and Future Perspective 272
References 273
Part III: Clinical Imaging of Cardiovascular Inflammation and Calcification 275
13: Molecular MR Imaging of Atherosclerosis 276
13.1 Introduction 277
13.1.1 Application Areas for Molecular Imaging 278
13.1.2 Molecular and Cellular Processes in Atherogenesis 279
13.1.3 Animal Models of Atherosclerosis 281
13.1.4 Magnetic Resonance Imaging 281
13.2 Inflammation 284
13.2.1 Active Targeting 284
13.2.2 Passive Targeting 285
13.3 Lipids 288
13.4 Fibrous Cap and ECM Components 288
13.5 Thrombus and Intra-plaque Hemorrhage 291
13.6 Apoptosis 296
13.7 Neovascularization 296
13.8 Conclusions and Future Perspective 297
References 299
14: Cardiac PET Imaging in Coronary Artery Disease 304
14.1 Technical Considerations 305
14.1.1 Multidimensional PET/CT Imaging 306
14.1.1.1 CT Scans 306
14.1.1.2 Emission Scans 306
14.1.2 Radiopharmaceuticals 307
14.2 Imaging Markers of Coronary Artery Disease from Hybrid PET/CT 308
14.2.1 Atherosclerotic Burden 308
14.2.2 Myocardial Perfusion and Metabolism 310
14.2.3 Myocardial Neuronal Function 311
14.2.4 Left Ventricular Function 311
14.3 Use of PET/CT Imaging Markers in Translational Research and Clinical Practice with a Focus in Atherosclerosis 311
14.3.1 Preclinical Characterization of Atherosclerosis 311
14.3.1.1 Coronary Artery Calcification 311
14.3.1.2 Coronary Vasomotor Dysfunction 312
14.3.1.3 Interaction Between CAC and Coronary Vasomotor Dysfunction 312
14.3.2 Evaluation of Symptomatic Patients with Suspected or Known CAD 315
14.3.2.1 Diagnosis of Obstructive Coronary Artery Disease 315
14.3.2.2 Identification of Patients with Symptoms Due to Diffuse Atherosclerosis and Coronary Microvascular Dysfunction 316
14.3.2.3 Risk Stratification 317
Incremental Value of Coronary Flow Reserve 319
Integrating CAC and CT Coronary Angiography and Myocardial Perfusion Imaging 321
Neuronal Imaging to Identify Patients at Risk for Sudden Cardiac Death 323
14.3.2.4 Directing Therapy 324
Ischemia Burden to Guide Revascularization 324
Myocardial Viability Imaging to Guide Revascularization in Patients with Ischemic Heart Failure 324
Conclusions 327
References 327
15: PET/CT Imaging of Inflammation and Calcification 334
15.1 Introduction 335
15.2 FDG-PET/CT Imaging of Oncologic Processes and Inflammation 336
15.3 FDG-PET/CT Imaging of Arterial inflammation 340
15.4 Relationship Between Arterial Inflammation, Disease Progression, and Risk of Cardiovascular Events 342
15.5 PET/CT Measures of Arterial Calcification 345
15.6 Utility of Noninvasive Imaging of Arterial Inflammation to Assess Effectiveness of Therapies 345
15.7 Imaging of Arterial Inflammation to Develop Physiologic Insights 350
15.8 Extra-arterial FDG-PET/CT Inflammatory Imaging 351
15.9 FDG-PET/CT Imaging of the Coronary Arteries and Future Directions 353
Conclusion 356
References 356
16: Clinical Feasibility and Monitoring of the Effects of Anti-inflammatory Therapy in Atherosclerosis 361
16.1 Introduction 362
16.2 Vulnerable Plaques 363
16.3 Molecular Imaging 364
16.4 Vascular FDG-PET Imaging for Clinical Feasibility 365
16.5 FDG-Verified High-Risk Plaques 365
16.6 Efficacy of Drugs in the Treatment of Atherosclerosis 366
16.6.1 HMG-CoA Reductase Inhibitors (Statins) 366
16.6.2 Peroxisome Proliferator-Activated Receptor (PPAR) Agonists 367
16.7 Monitoring of the Effects of Anti-inflammatory Therapy on Atherosclerosis 368
16.8 New Drugs to Increase HDL-C Levels 373
16.9 Measuring FDG Activity in the Coronary Artery 375
16.10 Concluding Remarks 377
References 378
Index 386