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Review
. 2011 Feb 1;123(4):425-43.
doi: 10.1161/CIRCULATIONAHA.109.916338.

Cardiovascular molecular imaging: focus on clinical translation

Ian Y Chen  1 , Joseph C Wu
Affiliations
Review

Cardiovascular molecular imaging: focus on clinical translation

Ian Y Chen et al. Circulation. .
No abstract available

PubMed Disclaimer

Figures

Figure 1
Figure 1. Essential components of molecular imaging technology
(A) Molecular imaging modalities for small animals with sample applications. Abbreviations: microPET, micro-positron emission tomography; microSPECT, micro-single photon emission computed tomography; MRI, magnetic resonance imaging; microCT, micro-computed tomography. (B) A general platform for imaging cell surface or extracellular targets. A typical probe for imaging cell surface or extracellular targets contains 3 moieties: ligands (L) for recognizing the molecular target (T) of interest, signal elements (SE) for generating signal (S), and a carrier (C) for structurally binding the other 2 moieties. Each moiety can take on many forms as listed. The signal generating mechanism dictates the specific imaging modality needed for signal detection.
Figure 1
Figure 1. Essential components of molecular imaging technology
(A) Molecular imaging modalities for small animals with sample applications. Abbreviations: microPET, micro-positron emission tomography; microSPECT, micro-single photon emission computed tomography; MRI, magnetic resonance imaging; microCT, micro-computed tomography. (B) A general platform for imaging cell surface or extracellular targets. A typical probe for imaging cell surface or extracellular targets contains 3 moieties: ligands (L) for recognizing the molecular target (T) of interest, signal elements (SE) for generating signal (S), and a carrier (C) for structurally binding the other 2 moieties. Each moiety can take on many forms as listed. The signal generating mechanism dictates the specific imaging modality needed for signal detection.
Figure 2
Figure 2. 18F-fluorodeoxyglucose (18F-FDG) uptake of human carotid and aortic atherosclerotic plaques in response to simvastatin therapy
Coronal 18F-FDG-PET images (top 2 rows) of human carotid (upper white arrows) and aortic (lower white arrows) atherosclerotic plaques at baseline (left column) and 3 months after treatment (right column) with either dietary management (top row) or simvastatin (bottom 2 rows). 18F-FDG uptake is attenuated in both carotid and aortic atherosclerotic plaques treated with simvastatin, as clearly demonstrated in the transverse PET/CT images (bottom row) of a left carotid plaque (black box). Plaque 18F-FDG uptake is not influenced by dietary management. Reproduced with permission from Tahara et al.
Figure 3
Figure 3. Ultrasmall superparamagnetic iron oxide (USPIO)-enhanced MRI of macrophage activity associated with human carotid atheroma undergoing atorvastatin therapy
T2*-weighted images of a carotid plaque in a patient receiving daily atorvastatin (80 mg) before (top row) and after (bottom row) USPIO infusion at 0 (left column), 6 (middle column), and 12 weeks (right column). Decreasing USPIO uptake (corresponding to increasing signal intensity) can be seen in the carotid plaque (yellow and blue arrows) over the course of atorvastatin treatment, suggesting drug-mediated reduction in plaque macrophage activity. No USPIO uptake is seen at 6 and 12 weeks prior to USPIO infusion (red arrows), suggesting an adequate clearance of plaque-associated USPIO from the previous scan. Adapted with permission from Tang et al.
Figure 4
Figure 4. Planar 123I-meta-iodo-benzylguanidine (123I-MIBG) imaging of myocardial sympathetic innervation in CHF progression
(A) 123I-MIBG undergoes similar cascades as norepinephrine (NE) at the sympathetic nerve terminal, except that it does not (1) interact with post-synaptic adrenergic (α or β) receptors, (2) undergo post-synaptic metabolism by catechol O-methyl transferase (COMT) into normetanephrine (NMN), or (3) interact with α2c pre-synaptic receptors to regulate NE release. Like NE, 123I-MIBG either (4) escapes the synaptic cleft, potentially spilling over into the blood stream, or (5) undergoes re-uptake by the NE transporter 1 (NET-1) into the exoplasm, where it is transported into a storage vesicle (red circle) by the vesicular monoamine transporter (VMAT). Adapted with permission from Narula et al. (B) Representative anterior planar 123I-MIBG images of patients with increasing NYHA classes and decreasing heart-to-mediastinum (H/M) ratios. Reduced myocardial 123I-MIBG uptake is clearly seen for CHF patients (middle and right images). Images courtesy of Arnold F. Jacobson at GE Healthcare.
Figure 5
Figure 5. Cell labeling strategies for imaging stem cells
Direct cell labeling: (A) FI: cell incubation with arginine-glycine-aspartic acid (RGD) peptide-conjugated quantum dots (QDs) leads to their endocytosis via integrin (αvβ3) receptors, followed by sequestration in early endosomes (EE). Excitation of endocytosed QDs with a light source (yellow λ) leads to fluorescence emission (pink λ) as cell signal. (B) SPECT: cell incubation with 111In-oxine molecules leads to their passive diffusion into the cytosol, where each molecule dissociates into 111In-In3+ and an oxine ion (Ox-), both of which can efflux from the cell, but only the former can bind reversibly to intracellular proteins. Gamma ray (γ) emission from intracellular 111In radioisotope is detected as cell signal by SPECT. (C) PET: cell exposure to 18F-FDG molecules leads to their uptake through the glucose transporter type 1 (GLUT1) into the cytosol, where each molecule undergoes phosphorylation by hexokinase and becomes trapped intracellularly. Positron (+) emitted from 18F radioisotope annihilates with a nearby electron (−) to produce oppositely directed γ rays, which can be detected as cell signal by PET. 18F-FDG uptake mimics that of glucose (Glc), except that the phosphorylated product of Glc, glucose-6-phosphate (Glc-6-P), is further converted to pyruvate (Pyr), which enters the TCA cycle. (D) MRI: cell incubation with SPIOs previously complexed with transfection agents (TAs) leads to SPIO uptake via non-specific endocytosis and subsequent storage in endosomes. The water protons (1H) surrounding each SPIO can emit RF wave (gray) as MR cell signal if excited with an RF wave (black) in the presence of a static magnetic field (B0; not shown). Reporter gene/probe labeling: (E) FI and BLI: transcription of the firefly luciferase reporter gene (fluc) under the regulation of a promoter (P), followed by translation of its messenger RNA (mRNA), leads to accumulation of firefly luciferase enzyme (FLuc), which catalyzes the oxidation of its substrate, D-Luciferin, into oxyluciferin, accompanied by emission of bioluminescent light (yellow orange λ) as cell signal. Expression of the enhanced green fluorescent protein reporter gene (eGFP) leads to cytosolic retention of enhanced green fluorescent protein (EGFP), which emits fluorescent light (green λ) as signal when excited with a light source (blue λ). (F) PET: transgene expression of a mutant herpes simplex virus type 1 thymidine kinase (HSV-sr39tk) reporter gene leads to the thymidine kinase enzyme (HSV1-sr39TK), which phosphorylates the PET reporter probe 9-(4-18F-fluoro-3-hydroxymethylbutyl)guanine (FHBG) and traps it intracellularly. Radioactive decay of 18F leads to positron (+) emission and subsequent annihilation with a nearby electron (−) to produce 2 oppositely directed gamma rays as cell signal. (G) SPECT: expression of sodium iodide symporter (NIS) reporter gene leads to insertion of sodium iodide symporters into the cell membrane, where they import either 123I- or technetium pertechnetate (99mTcO4-) as reporter probe, along with sodium ion (Na+), into the cytosol. Radioactive probes within the cytosol emit gamma rays as cell signal and can slowly efflux from the cell over time. Sodium ions are pumped out of the cell by sodium potassium exchangers (Na/K ATPase). (H) MRI: transgene expression of either ferritin heavy chain (FTH) or ferritin light chain (FTL) MR reporter gene leads to the assembly of ferritin (FT) proteins, which can individually sequester intracellular iron (Fe), triggering an up-regulation of transferring receptor (TfR) to internalize Fe-bound transferrin (Tf) into endosomes, where Fe is further transferred to FT for storage, with TfR recycled to the cell surface. Water protons (1H) within the local magnetic field of FT-sequestered iron molecules emits RF wave (gray) as cell signal when excited by an RF wave (black) in the presence of a static magnetic field (B0; not shown).
Figure 5
Figure 5. Cell labeling strategies for imaging stem cells
Direct cell labeling: (A) FI: cell incubation with arginine-glycine-aspartic acid (RGD) peptide-conjugated quantum dots (QDs) leads to their endocytosis via integrin (αvβ3) receptors, followed by sequestration in early endosomes (EE). Excitation of endocytosed QDs with a light source (yellow λ) leads to fluorescence emission (pink λ) as cell signal. (B) SPECT: cell incubation with 111In-oxine molecules leads to their passive diffusion into the cytosol, where each molecule dissociates into 111In-In3+ and an oxine ion (Ox-), both of which can efflux from the cell, but only the former can bind reversibly to intracellular proteins. Gamma ray (γ) emission from intracellular 111In radioisotope is detected as cell signal by SPECT. (C) PET: cell exposure to 18F-FDG molecules leads to their uptake through the glucose transporter type 1 (GLUT1) into the cytosol, where each molecule undergoes phosphorylation by hexokinase and becomes trapped intracellularly. Positron (+) emitted from 18F radioisotope annihilates with a nearby electron (−) to produce oppositely directed γ rays, which can be detected as cell signal by PET. 18F-FDG uptake mimics that of glucose (Glc), except that the phosphorylated product of Glc, glucose-6-phosphate (Glc-6-P), is further converted to pyruvate (Pyr), which enters the TCA cycle. (D) MRI: cell incubation with SPIOs previously complexed with transfection agents (TAs) leads to SPIO uptake via non-specific endocytosis and subsequent storage in endosomes. The water protons (1H) surrounding each SPIO can emit RF wave (gray) as MR cell signal if excited with an RF wave (black) in the presence of a static magnetic field (B0; not shown). Reporter gene/probe labeling: (E) FI and BLI: transcription of the firefly luciferase reporter gene (fluc) under the regulation of a promoter (P), followed by translation of its messenger RNA (mRNA), leads to accumulation of firefly luciferase enzyme (FLuc), which catalyzes the oxidation of its substrate, D-Luciferin, into oxyluciferin, accompanied by emission of bioluminescent light (yellow orange λ) as cell signal. Expression of the enhanced green fluorescent protein reporter gene (eGFP) leads to cytosolic retention of enhanced green fluorescent protein (EGFP), which emits fluorescent light (green λ) as signal when excited with a light source (blue λ). (F) PET: transgene expression of a mutant herpes simplex virus type 1 thymidine kinase (HSV-sr39tk) reporter gene leads to the thymidine kinase enzyme (HSV1-sr39TK), which phosphorylates the PET reporter probe 9-(4-18F-fluoro-3-hydroxymethylbutyl)guanine (FHBG) and traps it intracellularly. Radioactive decay of 18F leads to positron (+) emission and subsequent annihilation with a nearby electron (−) to produce 2 oppositely directed gamma rays as cell signal. (G) SPECT: expression of sodium iodide symporter (NIS) reporter gene leads to insertion of sodium iodide symporters into the cell membrane, where they import either 123I- or technetium pertechnetate (99mTcO4-) as reporter probe, along with sodium ion (Na+), into the cytosol. Radioactive probes within the cytosol emit gamma rays as cell signal and can slowly efflux from the cell over time. Sodium ions are pumped out of the cell by sodium potassium exchangers (Na/K ATPase). (H) MRI: transgene expression of either ferritin heavy chain (FTH) or ferritin light chain (FTL) MR reporter gene leads to the assembly of ferritin (FT) proteins, which can individually sequester intracellular iron (Fe), triggering an up-regulation of transferring receptor (TfR) to internalize Fe-bound transferrin (Tf) into endosomes, where Fe is further transferred to FT for storage, with TfR recycled to the cell surface. Water protons (1H) within the local magnetic field of FT-sequestered iron molecules emits RF wave (gray) as cell signal when excited by an RF wave (black) in the presence of a static magnetic field (B0; not shown).
Figure 6
Figure 6. Clinical and pre-clinical PET imaging of stem cell transplantation
(A) Human PET imaging of the engraftment of 18F-FDG-labeled circulating progenitor cells (CPCs) following intracoronary infusion. Representative coronal PET (left), transverse PET (top middle), and transverse PET/CT (bottom middle) images of 18F-FDG-labeled CPCs 4 hours after intracoronary infusion via the left anterior descending (LAD) artery in a patient with 92-day-old anteroseptal wall infarction. Cell accumulation (grayscale for the coronal image; colorscale for the transverse images) is clearly visualized in the anterospetal wall of heart (H; 2% at 4 hours), liver (L), spleen (S), and bone marrow within the skeleton. Images courtesy of Won Jun Kang at Yonsei University, South Korea. (B) PET imaging of reporter gene/probe-labeled embryonic stem cells. A mouse underwent intramyocardial injection of mouse embryonic stem cells expressing HSV1-sr39tk PET reporter gene, followed by 18F-FHBG and 18F-FDG scans 2 weeks later to assess for cell viability and myocardial glucose metabolism. Representative transverse 18F-FHBG (top right), 18F-FDG (middle right), and 18F-FHBG/18F-FDG fusion (bottom right) images show the location of implanted cells (arrows) in the anterolateral wall of left ventricle, where cells were implanted. Reproduced with permission from Cao et al.
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