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Molecular Imaging of the Heart

Nabil E. Boutagy, Attila Feher, Imran Alkhalil, Nsini Umoh, Albert J. Sinusas

10.1002/cphy.c180007

Source: Volume 9, Issue 2, April 2019

Published online: March 2019

Full Article on Wiley Online Library



ABSTRACT

Multimodality cardiovascular imaging is routinely used to assess cardiac function, structure, and physiological parameters to facilitate the diagnosis, characterization, and phenotyping of numerous cardiovascular diseases (CVD), as well as allows for risk stratification and guidance in medical therapy decision‐making. Although useful, these imaging strategies are unable to assess the underlying cellular and molecular processes that modulate pathophysiological changes. Over the last decade, there have been great advancements in imaging instrumentation and technology that have been paralleled by breakthroughs in probe development and image analysis. These advancements have been merged with discoveries in cellular/molecular cardiovascular biology to burgeon the field of cardiovascular molecular imaging. Cardiovascular molecular imaging aims to noninvasively detect and characterize underlying disease processes to facilitate early diagnosis, improve prognostication, and guide targeted therapy across the continuum of CVD. The most‐widely used approaches for preclinical and clinical molecular imaging include radiotracers that allow for high‐sensitivity in vivo detection and quantification of molecular processes with single photon emission computed tomography and positron emission tomography. This review will describe multimodality molecular imaging instrumentation along with established and novel molecular imaging targets and probes. We will highlight how molecular imaging has provided valuable insights in determining the underlying fundamental biology of a wide variety of CVDs, including: myocardial infarction, cardiac arrhythmias, and nonischemic and ischemic heart failure with reduced and preserved ejection fraction. In addition, the potential of molecular imaging to assist in the characterization and risk stratification of systemic diseases, such as amyloidosis and sarcoidosis will be discussed. © 2019 American Physiological Society. Compr Physiol 9:477‐533, 2019.

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Figure 1. Figure 1. Lipid‐based nanoparticles for molecular imaging. (A) Schematic representation of amphiphilic lipids. (I) Amphiphiles consist of a hydrophilic head and a hydrophobic tail. (II) Micelle‐forming lipids have a relatively large head compared with the hydrophobic part, whereas (III) bilayer‐forming lipids usually have two hydrophobic tails. (IV) PEG‐lipids are used to improve pharmacokinetic properties and (V) cholesterol is used to stabilize liposomes. (B) Possible lipid aggregates for in vivo use. (I) Micelles can be prepared from micelle‐forming lipids and from PEG‐lipids. (II) A conventional liposome consists of a phospholipid bilayer. (III) Improved stabilization of liposomes can be achieved by incorporating a small amount of PEG‐lipids and cholesterol. (IV) Microemulsions consist of a surfactant (amphiphile) monolayer covering oil. (V) Micelles can contain a hydrophobic nanoparticle. (VI) Bilayer on nanoparticles of silica, mica, glass, or iron oxide. Modified, with permission, from Mulder WJ, NMR Biomed. 2006 (255).
Figure 2. Figure 2. Schematic representation of the relative strengths of each imaging modality as it relates to multiple facets of cardiovascular imaging. The weight of the connecting arrows on the left indicates the relative strengths of each imaging modality as it relates to anatomical (e.g., spatial resolution), physiological (e.g., flow, function), metabolic and molecular imaging. The connecting arrows on the right links each imaging modality to specific biological targets, including: thrombosis, angiogenesis, inflammation, autonomic nervous system function, the renin angiotensin‐aldosterone system (RAAS), cell death, extracellular matrix, and tracking of cell and gene therapies. CT, computed tomography; MRI, magnetic resonance imaging; MRS, magnetic resonance spectroscopy.
Figure 3. Figure 3. Schematic representation of cardiac metabolic imaging, including imaging of myocardial perfusion, substrate utilization [glycolysis, β‐oxidation, and tricarboxylic acid cycle (TCA) cycle], and high‐energy phosphate metabolism: Myocardial perfusion can be quantified with gadolinium (Gd) using first‐pass MRI or by using PET (15O‐water, 82Rb, or 13NH4) or SPECT (99mTc‐tetrofosmin, 99mTc‐sestamibi or 201Tl) radiotracers. Substrate utilization: Proton‐MRS (1H‐MRS) is used for static measurement of the triglyceride (TG) pool. 13C‐octanoate, 1‐13C‐pyruvate, and 2‐13C‐pyruvate can be used as tracers for hyperpolarized carbon‐MRS (13C‐MRS). 13C‐octanoate can be found downstream as 13C‐acetylcarnitine and can be used as an estimate of fatty acid uptake and oxidation. 1‐13C‐pyruvate will be converted to 13CO2 and 13C‐bicarbonate and can be used to determine the pyruvate dehydrogenase (PDH) fluxes as an estimate of glucose oxidation. By tracing 2‐13C‐pyruvate, the complete TCA cycle can be visualized, as the 13C label will be retained in acetyl‐CoA and downstream in lactate, acetylcarnitine, citrate, and glutamate. Metabolic trapping of β‐methyl‐11C‐heptadecanoic acid (β‐Me‐HA) and 2‐deoxy‐2‐18F‐fluoro‐D‐glucose (FDG‐glucose) enables dynamic estimates of fatty acid and glucose uptake by PET, respectively. 3‐ and 5‐Methyl‐17‐18F‐fluoroheptadecanoic acid (3‐MFHA and 5‐MFHA), 16‐18F‐fluoro‐4‐thiapalmitic acid (FTP), and 14‐18F‐fluoro‐6‐thiaheptadecanoic acid (FTHA) are used to estimate fatty acid uptake and metabolism (although metabolism and kinetics of these traces are not fully elucidated). The metabolically cleared 11C‐palmitate is used for estimation of fatty acid uptake, oxidation, and esterification; 11C‐acetate is used for the assessment of TCA activity coupled to oxygen consumption in the electron transport chain (ETC). 11C‐glucose, which is fully metabolized, enables kinetic modeling of glucose metabolism. Fatty acid tracers for SPECT are the metabolically trapped 123I‐β‐methyl‐p‐iodophenylpentadecanoic acid (BMIPP) and the fully metabolized 123I‐iodophenylpentadecanoic acid (IPPA). High‐energy phosphate metabolism: In the cytoplasm, adenosine diphosphate (ADP), formed by hydrolysis of adenosine triphosphate (ATP), can be resynthesized by cytoplasmatic creatine kinase (MM‐CK) to ATP through hydrolysis of phosphocreatine (PCr). PCr can be quickly resynthesized by mitochondrial creatine kinase (Mi‐CK) through hydrolysis of newly formed ATP in the mitochondria. PCr levels are dependent on cellular creatine (Cr) uptake, as creatine is not synthesized in the heart but actively taken up by cardiomyocytes. 1H‐MRS and phosphorus‐MRS (31P‐MRS) are used for measurement of Cr and PCr/ATP ratio, respectively. Modified, with permission, from van de Weijer T, J Appl Physiol (1985). 2018 (400).
Figure 4. Figure 4. Low‐flow ischemia leads to translocation of GLUT‐4 and GLUT‐1 to the sarcolemma: (I) Immunofluorescence of glucose transporter‐4 (GLUT‐4) and GLUT‐1 in sections from nonischemic (A) and ischemic (C) regions of left ventricle by confocal microscopy. (II) Myocardial extraction (% of arterial) of glucose and lactate in the left anterior descending (LAD) and left circumflex coronary (LCx) regions during the 30 min before ischemia (Baseline) and during the last 30 min of low‐flow ischemia (Low Flow). AV extractions were calculated from quadruplicate time points. * P < 0.01 versus both baseline LAD extraction and LCx extraction during low‐flow ischemia. Values represent mean ± SEM (n = 9). (III) Sarcolemma and intracellular membrane content of GLUT‐4 and GLUT‐1 in myocardium from nonischemic and ischemic regions of the left ventricle. Glucose transporter content was quantified by 125I‐protein A binding (cpm/μg membrane protein) multiplied by yield of membrane fraction. Data for each membrane fraction are expressed as a percentage of total GLUT‐4 or GLUT‐1 content in sarcolemma and intracellular membrane fractions. Values are mean ± SEM (n = 9). * P < 0.05 versus nonischemic myocardium. Modified, with permission, from Young LH, Circulation. 1997 (436).
Figure 5. Figure 5. Correlation of the myocardial free fatty‐acid analog, p‐123I‐iodophenylpentadecanoic acid (IPPA) retention with 2‐[18F] fluoro‐2‐deoxy‐D‐glucose (18F‐FDG) accumulation during experimental low‐flow ischemia: (I) After baseline (BASE) measurements, partial coronary stenosis was created in canines and maintained throughout protocol. Arterial and venous samples were obtained for metabolic measurements, and radiolabeled microspheres were injected at times designated. IPPA was injected 60 min after creation of stenosis. 18F‐FDG was injected 90 min later. (II) Myocardial 123I‐IPPA and 18F‐FDG retained activities expressed as nonischemic percentage for all segments (n = 576). Segments were segregated on basis of normalized flows in segments into 20%‐flow increments. Numbers within each bar represent number of segments falling into each flow range. (III) (A) Serial short‐axis and vertical long (v‐long) axis SPECT 123I‐IPPA images from a representative dog displayed in standard format. Time after injection is designated on left margin. Note perfusion defect in anteroseptal and anteroapical regions, which normalizes over time. (B) Myocardial 123I‐IPPA clearance curves derived from ischemic and nonischemic regions for same dog. (C) Early clearance data for same dog are also displayed as semilogarithmic plot. Early myocardial clearance appears linear on this semilogarithmic plot, suggesting early monoexponential clearance of 123I‐IPPA. Delayed myocardial 123I‐IPPA clearance is seen in ischemic region. This research was originally published in JNM. Shi CQ, Young LH, Daher E, DiBella EV, Liu YH, Heller EN, Zoghbi S, Wackers FJ, Soufer R, and Sinusas AJ. Correlation of myocardial p‐(123)I‐iodophenylpentadecanoic acid retention with (18)F‐FDG accumulation during experimental low‐flow ischemia. J Nucl Med 43: 421‐431, 2002. © SNMMI. (336).
Figure 6. Figure 6. SPECT imaging showing delayed recovery of regional fatty acid metabolism in heart tissue after transient exercise‐induced ischemia (“ischemic memory”): Representative stress and rest short‐axis thallium tomograms after reinjection (left two panels) demonstrate a reversible inferior defect consistent with exercise‐induced myocardial ischemia. Cardiac SPECT of a patient injected with radiolabeled [123I]‐β‐methyl‐p‐iodophenyl‐pentadecanoic acid (BMIPP), acquired at rest 22 h after exercise‐induced ischemia, shows persistent metabolic abnormality in the inferior region despite complete recovery of regional perfusion (center panel). Retention of BMIPP in the heart of a normal adult is shown as a control (right panel). Modified, with permission, from Taegtmeyer H, Nat Clin Pract Cardiovasc Med. 2008 (369).
Figure 7. Figure 7. Quantitative PET imaging detects early metabolic remodeling in a mouse model of pressure‐overload left ventricular hypertrophy in vivo: Gated end‐diastolic transverse 18F‐FDG PET images for sham mice, transverse aortic constriction (TAC) mice, and TAC mice treated with propranolol at baseline, day 1, and day 7 after surgery are shown. All serial scans are from same animals. Images show increase in 18F‐FDG uptake in TAC mice starting at day 1, indicative of metabolic adaptation in pressure‐overload left ventricular hypertrophy. This research was originally published in JNM. Zhong M, Alonso CE, Taegtmeyer H, and Kundu BK. Quantitative PET imaging detects early metabolic remodeling in a mouse model of pressure‐overload left ventricular hypertrophy in vivo. J Nucl Med 54: 609‐615, 2013. © SNMMI. (448).
Figure 8. Figure 8. PET scan showing perfusion–metabolism mismatch in hibernating heart tissue as an example of preserved cardiometabolic reserve: (A) 82Rubidium (82Rb) PET in short‐axis view shows markedly decreased perfusion in the apical, inferior, inferolateral, and septal regions of the left ventricle at rest, which extends from distal to basal slices. (B) Images acquired under glucose‐loaded conditions, labeled with 18F‐fluorodeoxyglucose (18F‐FDG), show perfusion‐metabolism mismatch pattern (the scintigraphic hallmark of hibernation) in all abnormally perfused myocardial regions at rest. An exception is the anteroseptal region, which demonstrates matched perfusion‐metabolism pattern (compatible with scarred myocardium). Modified, with permission, from Taegtmeyer H, Nat Clin Pract Cardiovasc Med. 2008 (369).
Figure 9. Figure 9. Increased 18F‐fluorodeoxyglucose (18F‐FDG) accumulation in right ventricular free wall in patients with pulmonary hypertension and the effect of epoprostenol: Representative midventricular transaxial 18F‐FDG positron emission tomography images of a patient with primary pulmonary hypertension before and after the pulmonary vasodilator therapy with epoprostenol for three months. (A) Before the pulmonary vasodilator therapy, the right ventricular (RV) 18F‐FDG accumulation was highly increased and the corrected RV standardized uptake value (SUV) of 18F‐FDG was 13.4. (B) After the therapy, the corrected RV SUV of 18F‐FDG markedly decreased to 7.5. (Lower panels) Correlations between the percentage change of RV SUV of 18F‐FDG corrected for the partial volume effect and the percentage change of the pulmonary vascular resistance and peak‐systolic wall stress in the RV free wall. Modified, with permission, from Oikawa M, J Am Coll Cardiol. 2005 (286).
Figure 10. Figure 10. Evaluation of the cardioprotective effects of Fv‐HSP72 by Annexin‐V based apoptosis imaging in a rabbit ischemia‐reperfusion model: the effect of a single intravenous dose of Fv‐HSP72 [the heat shock protein‐72 (HSP72) coupled to a single‐chain variable fragment (Fv) of monoclonal antibody 3E10 (3E10Fv)] was tested in rabbits undergoing left coronary artery occlusion for 40 min followed by 3 h reperfusion. Higher and more extensive uptake of 99mTc‐annexin‐V was seen in the control groups compared with the two therapy groups (pre and post ischemia reperfusion) in in vivo sagittal slices of SPECT images obtained 3 h after the injection of 99mTc‐annexin‐V (white circle = apex) and in ex vivo images of excised heart (traced with dotted lines, arrows = high uptake area; asterisk = apex). Modified, with permission, from Tanimoto T, J Am Coll Cardiol. 2017 (381).
Figure 11. Figure 11. Molecular MRI imaging of cardiomyocyte apoptosis with AnxCLIO‐Cy5.5 (A, D, G) and simultaneous delayed enhancement (DE) MRI of necrosis with Gadolinium‐DTPA‐NBD (B, E, H) in a mouse with severe myocardial injury after transient coronary artery ligation (35 min): Images at three slice locations are shown, moving progressively from the midventricular level (A and B) to the left ventricular apex (G and H). (B) At the midventricular level, only a small area in the subendocardium of the lateral wall shows DE (red arrows). (E and H) The extent of DE increases progressively in the more apical slices (red arrows) and is fairly extensive at the apex. Although the accumulation of AnxCLIO‐Cy5.5 is fairly transmural, DE of Gd‐DTPA‐NBD is seen predominantly in the subendocardium. (C, F, and I) Immunohistochemistry for Gd‐DTPA‐NBD confirming the in vivo MRI findings. (C) Control area in the uninjured septum showing no evidence of DE (magnification × 200). (F) (× 200) and (I) (× 400) Sections from the antero‐apical wall of the left ventricle show positive staining for Gd‐DTPA‐NBD in areas of the subendocardium with significant amounts of cardiomyocyte degeneration. Modified, with permission, from Sosnovik DE, Circ Cardiovasc Imaging. 2009 (352).
Figure 12. Figure 12. Ferumoxytol‐enhanced magnetic resonance imaging assessing inflammation after myocardial infarction: examples of myocardial edema and ferumoxytol enhancement in the infarct zone of 3 patients after myocardial infarction (1—anteroseptal, 2—lateral, and 3—inferior). Accumulation of ferumoxytol reduces T2* decay time and creates signal deficits that can be quantified and visualized using T2* MRI. To describe ferumoxytol accumulation, the relaxation rate, R2*, which is the inverse of the mean T2* was calculated for each region of interest, where the higher the value, the greater the ferumoxytol accumulation. The separate columns illustrate late gadolinium enhancement (LGE, first column), ferumoxytol enhancement (R2* map, second and third column) and edema (T2 map, fourth and fifth columns). At early time points (up to 10 days) increased inflammation was detected by ferumoxytol (dark regions on R2* maps) and edema was detected on T2 maps (light region). These changes have improved or have resolved by 3 months. Modified, with permission, from Stirrat CG, Heart. 2017 (363).
Figure 13. Figure 13. Prospective evaluation of 18F‐Fluorodeoxyglucose (18F‐FDG) uptake after acute myocardial infarction by PET/MRI imaging as a prognostic marker of functional outcome: (Left panel) Short‐ and long‐axis views of late gadolinium enhancement (LGE) MRI (left), 18F‐FDG–PET images (middle), and overlay (right) of patients with anterior (A) or inferior (B) myocardial infarction. (Right Panel) (A) Correlation between LGE extent and Δ ejection fraction (EF at follow‐up ‐ EF at initial imaging), Δ end diastolic volume (EDV at follow‐up – EDV at initial imaging), and Δ end‐systolic volume (ESV at follow‐up – ESV at initial imaging). (B) Correlation between postischemic 18F‐FDG uptake in the infarct area mean standard uptake value (SUVmean) and ΔEF, ΔEDV and ΔESV. (C) Segmental analysis of the wall motion recovery at follow‐up. Comparison of LGE transmurality and 18F‐FDG uptake in the infarct (SUVmean). Modified, with permission, from Rischpler C, Circ Cardiovasc Imaging. 2016 (311).
Figure 14. Figure 14. Mitochondrial translocator protein (TSPO)‐targeted positron emission tomography reveals myocardial inflammation and neuroinflammation in patients after acute myocardial infarction (AMI): (A) tomographic images of the heart display elevated TSPO signal in the hypoperfused infarct region in a representative patient (arrows). Images were acquired 4 to 6 days after reperfusion for first AMI. (B) Parametric brain images (statistical parametric mapping) show regional group difference of TSPO signal between infarct patients and healthy volunteers, superimposed to a magnetic resonance imaging template. Elevation of signal is regionally seen in the frontal and temporal cortex. HLA, horizontal long axis; VLA, vertical long axis. Modified, with permission, from Thackeray JT, J Am Coll Cardiol. 2018 (388).
Figure 15. Figure 15. Myocardial contrast echocardiographic (MCE) ischemic memory in dogs with selectin‐targeted microbubbles: (A) mean (± SEM) video intensity in the risk and remote areas after selectin‐targeted microbubble administration in dogs undergoing ischemia‐reperfusion, and in both left anterior descending coronary artery and left circumflex territories together in closed‐chest nonischemic controls (n for closed‐chest represents region rather than animal number). (B) Example of MCE from a closed‐chest control animal. (C‐E) Examples of MCE, triphenyltetrazolium chloride staining and risk area by method of intracoronary injection of contrast from a single animal undergoing left circumflex ischemia reperfusion. ANOVA, analysis of variance. Modified, with permission, from Mott B, JACC Cardiovasc Imaging. 2016 (252).
Figure 16. Figure 16. Patients with imaging evidence of active cardiac sarcoidosis on hybrid PET/MRI: late gadolinium enhancement (LGE) MRI images on the left with hybrid 18F‐fluorodeoxyglucose (18F‐FDG) PET/MRI images on the right. (A) Subepicardial (near transmural) LGE in the basal anteroseptum extending in to the right ventricular free wall with increased 18F‐FDG uptake localizing to exactly the same region on fused PET/MRI. (B) Subepicardial LGE in the basal anterolateral wall with increased 18F‐FDG uptake colocalizing to exactly that region on PET/MRI. (C) Patchy midwall LGE in the anterolateral wall with matched increased 18F‐FDG uptake on PET/MRI. (D) Multifocal LGE in the lateral wall with matched increased 18F‐FDG uptake on PET/MRI. Modified, with permission, from Dweck MR, JACC Cardiovasc Imaging. 2018 (107).
Figure 17. Figure 17. 11C‐Methionine PET of myocardial inflammation in a rat model of experimental autoimmune myocarditis (EAM): (A) representative 11C‐methionine PET images in a rat model of EAM 30 min after intravenous tracer administration. Strong focal cardiac 11C‐methionine uptake was observed in EAM rats but not in control animals. Extracardiac tracer accumulation in thymus (asterisk) and the liver (arrowheads) was noted in both EAM and control rats, whereas respective tracer activities in lungs and blood pool were rather low. (B) Cardiac tracer uptake in EAM rats (black bar) was significantly higher than that in control rats (white bar). (C) Representative short‐axis PET images and time‐activity curves of dynamic PET imaging in EAM rat. Ten to 20 min after administration, tracer uptake increased in heart together with rapid clearance of blood activity. Cardiac signals remained stable for 30 to 40 min. Gray scale images serve as reference for location of heart. This research was originally published in JNM. Maya Y, Werner RA, Schutz C, Wakabayashi H, Samnick S, Lapa C, Zechmeister C, Jahns R, Jahns V, and Higuchi T. 11C‐Methionine PET of Myocardial Inflammation in a Rat Model of Experimental Autoimmune Myocarditis. J Nucl Med 57: 1985‐1990, 2016. © SNMMI. (236).
Figure 18. Figure 18. In vivo and ex vivo 111In‐RP748 and 99mTc‐sestamibi (99mTc‐MIBI) images from dogs with chronic infarction: (A) Serial in vivo 111In‐RP748 SPECT short axis, vertical long axis (VLA), and horizontal long axis (HLA) images in a dog 3 weeks after left anterior descending coronary artery (LAD) infarction at 20 min and 75 min after injection in standard format. 111In‐RP748 SPECT images were registered with 99mTc‐MIBI perfusion images (third row). The 75‐min 111In‐RP748 SPECT images were colored red and fused with 99mTc‐MIBI images (green) to better demonstrate localization of 111In‐RP748 activity within the heart (color fusion, bottom row). Right ventricular (RV) and left ventricular (LV) blood pool activity is seen at 20 min. White arrows indicate region of increased 111In‐RP748 uptake in anterior wall. This corresponds to the anteroapical 99mTc‐sestamibi perfusion defect (yellow arrows). (B) Sequential 99mTc‐sestamibi (top row) and 111In‐RP748 in vivo SPECT HLA images at 90 min after injection (middle row) from a dog at 8 h (acute), 1 week, and 3 weeks after LAD infarction. Increased myocardial 111In‐RP748 uptake is seen in the anteroapical wall at all three time points. Color fusion 99mTc‐MIBI (green) and 111In‐RP748 (red) images (bottom row) demonstrate 111In‐RP748 uptake within 99mTc‐MIBI perfusion defect. (C) Ex vivo 99mTc‐sestamibi (left) and 111In‐RP748 (center) images of myocardial slices from a dog 3 weeks after LAD occlusion, with color fusion image on the right. Short axis slices are in the standard orientation. Yellow arrows indicate anterior location of nontransmural perfusion defect region; white arrows indicate corresponding area of increased 111In‐RP748 uptake. Reprinted with permission (241).
Figure 19. Figure 19. Assessment of cardiac αVβ3 integrin expression following acute myocardial infarction in humans by 18F‐Fluciclatide PET imaging: (Left panel) 18F‐Fluciclatide uptake in three patients with recent subendocardial myocardial infarction (MI). (A) Patient 1, 13 days after anterior MI, displaying a short‐axis PET image of the left ventricle with crescentic 18F‐fluciclatide uptake that correlates with the interventricular septum and anterior wall on CT angiography (B). The fused PET/CT‐angiography image (C) shows this uptake to correspond exactly with the region of late gadolinium enhancement (LGE) on magnetic resonance imaging (MRI) (D). Further delineation of myocardial uptake on PET/CT is clearer in the two‐chamber view (E) and on a fused CT/three‐dimensional‐Patlak image, which shows this uptake to follow a watershed‐pattern emerging from the coronary stents present in the left anterior descending coronary artery (F). (G and H) Patient 2, 8 days following anterior MI, displaying focal uptake of 18F‐fluciclatide in the anterior wall and apex in the three‐chamber view on PET/CT (G) which corresponds to the region of infarction on LGE MRI imaging (H). (I and J) Patient 3, showing focal uptake of 18F‐fluciclatide in the inferior wall 19 days following MI on PET/CT (I) that again corresponds to the infarction on MRI LGE imaging (J). (Right Panel) 18F‐Fluciclatide uptake in MI is shown. Uptake of 18F‐fluciclatide in (A) patients with acute MI at 2 and 10 weeks, patients with chronic total occlusion (CTO) and healthy control subjects is shown. Uptake was greatest at 2 weeks after MI (B). 18F‐Fluciclatide uptake in the acute MI group was greater in regions of hypokinesis when compared with sites of normal function or akinesis (C). This translated to a higher 18F‐fluciclatide uptake in those regions, which subsequently improved in function on follow‐up cardiac magnetic resonance (D). CTO, chronic total occlusion; TBR, tissue‐to‐background ratio. WMA, wall motion abnormality. Modified, with permission, from Jenkins WS, Heart. 2017 (178).
Figure 20. Figure 20. Postinfarction myocardial scarring in mice: molecular MRI imaging with use of a collagen‐targeting contrast agent: Midventricular short‐axis double inversion‐recovery gradient‐echo MRI images (A, B, D, and E) and corresponding picrosirius red‐stained histologic sections (C and F) of the mouse left ventricle 6 weeks after left anterior descending artery occlusion‐reperfusion. Arrows point to area of scarring. (A and D) Standard anatomic MR images acquired by using a double inversion‐recovery gradient‐echo sequence. (B and E) Midventricular short‐axis MR images of the left ventricles at two section locations obtained 40 min after injection of a gadolinium‐based collagen‐targeting contrast agent EP‐3533. The regions of contrast enhancement correlate closely with (C and F) photomicrographs of picrosirius red‐stained tissue sections. Modified, with permission, from Helm PA et al. Radiology 2008 (150).
Figure 21. Figure 21. Noninvasive targeted imaging of matrix metalloproteinase activation in a murine model of postinfarction remodeling: hybrid micro‐SPECT/CT reconstructed short‐axis images were acquired without x‐ray contrast (A) in a control sham‐operated mouse (left) and selected mice at 1 week (middle) and 3 weeks (right) after surgical myocardial infarction (MI), after injection of 201Tl (top row, green) and 99mTc‐RP805, (middle row, red). A black‐and‐white and multicolor fusion image is shown on bottom. Control heart demonstrates normal myocardial perfusion and no focal 99mTc‐RP805 uptake within the heart, although some uptake is seen in chest wall at the thoracotomy site (dashed arrows). All post‐MI mice have a large anterolateral 201Tl perfusion defect (yellow arrows) and focal uptake of 99mTc‐RP805 in defect area. A dashed circle is drawn around the heart to demonstrate localization of 99mTc‐RP805, within the infarcted area of the heart. Some activity is also seen in the peri‐infarct border zone. Additional micro‐SPECT/CT images were acquired by use of a higher‐resolution SPECT detector after the administration of x‐ray contrast, at 1 week (B) and 3 weeks (C) after MI. The contrast agent permitted better definition of the LV myocardium, which is highlighted by white dotted line. Representative short‐axis (SA), horizontal long‐axis (HLA), and vertical long‐axis (VLA) images are shown for two additional mice by use of the same format and color scheme. Focal uptake of 99mTc‐RP805 is seen within the central infarct and peri‐infarct regions, which again corresponds to 201Tl perfusion defect. Modified, with permission, from Su H, Circulation. 2005 (364).
Figure 22. Figure 22. Dual‐isotope in vivo SPECT/CT imaging reflecting myocardial perfusion (201Thallium) and matrix metalloproteinase activity (99mTc‐RP805): In vivo Thallium‐201 and 99mTc‐RP805 SPECT/CT images of pigs at 1 week, 2 weeks and 4 weeks post myocardial infarction are shown in transaxial, coronal, and sagittal views. Note the perfusion defect in the lateral wall and the time dependent changes in the intensity of 99mTc‐RP805 retention in the same regions (green arrows). The yellow double arrows point to 99mTc‐RP805 activity in the surgical sternal wound. A known point source (orange arrow) can be used to quantify hotspot uptake. Scale bars: 2 cm. Modified, with permission, from Sahul ZH, Circ Cardiovasc Imaging. 2011 (320)
Figure 23. Figure 23. Positon emission tomography (PET)/computed tomography (CT) of angiotensin II type 1 receptors (AT1R) in healthy pigs: panel A shows anterior maximum intensity projections (MIP, left), transaxial fusion images (middle) and reangulated PET images (right) (SA, short axis; HL, horizontal long axis; VL, vertical long axis), using AT1R ligand [11C]‐KR31173 (top row), and myocardial perfusion tracer [13N]‐ammonia (NH3) (bottom row). Panel B shows myocardial kinetics of [11C]‐KR31173 at baseline, and (panel C) after intravenous AT1R blockade (representative coronal PET slices on top, time activity curves for arterial blood (pink) and myocardium (cyan) on bottom). Modified, with permission, from Fukushima K, J Am Coll Cardiol. 2012 (127).
Figure 24. Figure 24. In vivo visualization of amyloid deposits in the heart with Pittsburgh compound B (11C‐PIB) and PET: short‐axis images of the Pittsburgh compound B (11C‐PIB) retention index and myocardial blood flow (MBF) in (left to right) patients with high, intermediate, and partially increased 11C‐PIB retention and a healthy control. Liver is clearly visible in 11C‐PIB images of the second patient and healthy control and is just outside PET field of view for other 2 patients. Liver uptake is due to biliary excretion of 11C‐PIB and is likely not related to amyloid binding. This research was originally published in JNM. Antoni G, Lubberink M, Estrada S, Axelsson J, Carlson K, Lindsjo L, Kero T, Langstrom B, Granstam SO, Rosengren S, Vedin O, Wassberg C, Wikstrom G, Westermark P, and Sorensen J. In vivo visualization of amyloid deposits in the heart with 11C‐PIB and PET. J Nucl Med 54: 213‐220, 2013. © SNMMI (8).
Figure 25. Figure 25. First‐in‐human study of a novel 18F‐labeled tracer LMI1195 for imaging myocardial sympathetic innervation: Representative series of whole body [18F]‐LMI 1195 coronal images at mid‐myocardial level in a healthy human volunteer acquired 5 hours after injection (average, 193.5  ±  37.4 MBq [5.23  ±  1.01 mCi]). Each whole‐body image is scaled to maximum value within that image. This research was originally published in JNM. Sinusas AJ, Lazewatsky J, Brunetti J, Heller G, Srivastava A, Liu YH, Sparks R, Puretskiy A, Lin SF, Crane P, Carson RE, and Lee LV. Biodistribution and radiation dosimetry of LMI1195: first‐in‐human study of a novel 18F‐labeled tracer for imaging myocardial innervation. J Nucl Med 55: 1445‐1451, 2014. © SNMMI (344).
Figure 26. Figure 26. Depiction of postganglionic sympathetic nervous system (SNS) and parasympathetic nervous system (PNS) nerve endings: (Left panel) The synthesis and release of norepinephrine in postganglionic SNS nerve endings and subsequent binding to postsynaptic receptors on cardiomyocytes. The tracers in red depict SNS pre‐ and postsynaptic radioanalogs. (Right panel) the synthesis and release of acetylcholine in the terminal nerve ending and varicosities of postganglionic PNS nerve endings and subsequent binding to postsynaptic receptors on cardiomyocytes. Tracers in blue depict PNS pre‐ and postsynaptic radioanalogs. AC, adenylyl cyclase; ACh, acetylcholine; AChE, acetylcholinesterase; ATP, adenosine triphosphate; CAT, choline‐acetyl‐transferase; COM, catechol‐O‐methyltransferase; cAMP, cyclic adenosine monophosphate; MAO, monoamine oxidase; mIBG, metaiodobenzylguanidine; MR2, muscarinic receptor 2; NE, norepinephrine; NR, nicotinic receptor; VMAT, vesicular monoamine transporter; 18F‐6F‐DA, 6‐18F‐fluorodopamine; PHEN, phenylephrine; EPI, epinephrine; HED, hydroxyephedrine; MQNB, (R,S)‐N‐[11C]‐methyl‐quinuclidin‐3‐yl benzilate. Modified, with permission, from Boutagy NE, Curr Cardiol Rep. 2017 (45).
Figure 27. Figure 27. 123I‐metaiodobenzylguanidine (123I‐mIBG) imaging for prediction of mortality and potentially fatal events in heart failure: representative 123I‐mIBG images from patients from the ADMIRE‐HFX Study. (A) Image from 37‐year‐old man with nonischemic cardiomyopathy demonstrated 123I‐mIBG heart to mediastinum (H/M) ratio of 1.69. (B) Image from 51‐year‐old woman with ischemic cardiomyopathy showed H/M ratio of 1.80. Right panel shows 2‐year all‐cause mortality rates based on 0.1 increments of H/M indicating progressive decline from maximum of 29.4% for H/M < 1.10. There were no deaths among subjects with H/M ≥1.80. This research was originally published in JNM. Narula J, Gerson M, Thomas GS, Cerqueira MD, and Jacobson AF. 123I‐mIBG imaging for prediction of mortality and potentially fatal events in heart failure: the ADMIRE‐HFX study. Journal of Nuclear Medicine 56: 1011‐1018, 2015 (271).
Figure 28. Figure 28. Regional myocardial sympathetic denervation assessment by [11C]‐meta‐hydroxyephedrine (HED) PET in ischemic cardiomyopathy: (Top panel) PET images from two representative subjects from the PAREPET trial comparing resting flow (measured by 13N‐ammonia [13NH3]), viability (by insulin‐stimulated 18F‐fluorodeoxyglucose [18F‐FDG]), and myocardial sympathetic innervation (by 11C‐HED) are shown. (Bottom panel) Kaplan‐Meier curves show the incidence of sudden cardiac arrest for tertiles of PET‐defined myocardial substrates (median follow‐up 4.1 years). As continuous variables, the total volume of denervated myocardium, as well as viable denervated myocardium, predicted sudden cardiac arrest. Neither infarct volume nor hibernating myocardium was significant as continuous variables. Modified, with permission, from Fallavollita JA, J Am Coll Cardiol. 2014 (114).
Figure 29. Figure 29. Tracking of human induced pluripotent stem cells in a pig model of myocardial infarction: assessment of cell survival, engraftment and distribution by hybrid SPECT/CT imaging of sodium iodide symporter transgene expression: In vivo SPECT/CT imaging ∼1 h following intracoronary injection of 123I demonstrating long‐term surviving derivatives of sodium iodide symporter (NIS) positive (pos) transgenic human induced pluripotent stem cells (NISpos‐hiPSCs, each site 5 × 107 cells) in pig hearts after 5 days and 15 weeks, respectively. Note, NISpos‐hiPSCs were only visualized when co‐injected with an equal number of mesenchymal stem cells (MSC). Immunohistochemical staining of tissue sections of corresponding areas of the left ventricular wall confirmed the presence of hiPSC derivatives, since delivered NISpos‐hiPSCs were also transfected to express the reporter protein, venus. Notably, the vast majority of venus positive iPSC derivatives were found to represent endothelial cells integrated into the cardiac vasculature 15 weeks after cell transplantation. Modified, with permission, from Templin C, Circulation 2012 (385).


Figure 1. Lipid‐based nanoparticles for molecular imaging. (A) Schematic representation of amphiphilic lipids. (I) Amphiphiles consist of a hydrophilic head and a hydrophobic tail. (II) Micelle‐forming lipids have a relatively large head compared with the hydrophobic part, whereas (III) bilayer‐forming lipids usually have two hydrophobic tails. (IV) PEG‐lipids are used to improve pharmacokinetic properties and (V) cholesterol is used to stabilize liposomes. (B) Possible lipid aggregates for in vivo use. (I) Micelles can be prepared from micelle‐forming lipids and from PEG‐lipids. (II) A conventional liposome consists of a phospholipid bilayer. (III) Improved stabilization of liposomes can be achieved by incorporating a small amount of PEG‐lipids and cholesterol. (IV) Microemulsions consist of a surfactant (amphiphile) monolayer covering oil. (V) Micelles can contain a hydrophobic nanoparticle. (VI) Bilayer on nanoparticles of silica, mica, glass, or iron oxide. Modified, with permission, from Mulder WJ, NMR Biomed. 2006 (255).


Figure 2. Schematic representation of the relative strengths of each imaging modality as it relates to multiple facets of cardiovascular imaging. The weight of the connecting arrows on the left indicates the relative strengths of each imaging modality as it relates to anatomical (e.g., spatial resolution), physiological (e.g., flow, function), metabolic and molecular imaging. The connecting arrows on the right links each imaging modality to specific biological targets, including: thrombosis, angiogenesis, inflammation, autonomic nervous system function, the renin angiotensin‐aldosterone system (RAAS), cell death, extracellular matrix, and tracking of cell and gene therapies. CT, computed tomography; MRI, magnetic resonance imaging; MRS, magnetic resonance spectroscopy.


Figure 3. Schematic representation of cardiac metabolic imaging, including imaging of myocardial perfusion, substrate utilization [glycolysis, β‐oxidation, and tricarboxylic acid cycle (TCA) cycle], and high‐energy phosphate metabolism: Myocardial perfusion can be quantified with gadolinium (Gd) using first‐pass MRI or by using PET (15O‐water, 82Rb, or 13NH4) or SPECT (99mTc‐tetrofosmin, 99mTc‐sestamibi or 201Tl) radiotracers. Substrate utilization: Proton‐MRS (1H‐MRS) is used for static measurement of the triglyceride (TG) pool. 13C‐octanoate, 1‐13C‐pyruvate, and 2‐13C‐pyruvate can be used as tracers for hyperpolarized carbon‐MRS (13C‐MRS). 13C‐octanoate can be found downstream as 13C‐acetylcarnitine and can be used as an estimate of fatty acid uptake and oxidation. 1‐13C‐pyruvate will be converted to 13CO2 and 13C‐bicarbonate and can be used to determine the pyruvate dehydrogenase (PDH) fluxes as an estimate of glucose oxidation. By tracing 2‐13C‐pyruvate, the complete TCA cycle can be visualized, as the 13C label will be retained in acetyl‐CoA and downstream in lactate, acetylcarnitine, citrate, and glutamate. Metabolic trapping of β‐methyl‐11C‐heptadecanoic acid (β‐Me‐HA) and 2‐deoxy‐2‐18F‐fluoro‐D‐glucose (FDG‐glucose) enables dynamic estimates of fatty acid and glucose uptake by PET, respectively. 3‐ and 5‐Methyl‐17‐18F‐fluoroheptadecanoic acid (3‐MFHA and 5‐MFHA), 16‐18F‐fluoro‐4‐thiapalmitic acid (FTP), and 14‐18F‐fluoro‐6‐thiaheptadecanoic acid (FTHA) are used to estimate fatty acid uptake and metabolism (although metabolism and kinetics of these traces are not fully elucidated). The metabolically cleared 11C‐palmitate is used for estimation of fatty acid uptake, oxidation, and esterification; 11C‐acetate is used for the assessment of TCA activity coupled to oxygen consumption in the electron transport chain (ETC). 11C‐glucose, which is fully metabolized, enables kinetic modeling of glucose metabolism. Fatty acid tracers for SPECT are the metabolically trapped 123I‐β‐methyl‐p‐iodophenylpentadecanoic acid (BMIPP) and the fully metabolized 123I‐iodophenylpentadecanoic acid (IPPA). High‐energy phosphate metabolism: In the cytoplasm, adenosine diphosphate (ADP), formed by hydrolysis of adenosine triphosphate (ATP), can be resynthesized by cytoplasmatic creatine kinase (MM‐CK) to ATP through hydrolysis of phosphocreatine (PCr). PCr can be quickly resynthesized by mitochondrial creatine kinase (Mi‐CK) through hydrolysis of newly formed ATP in the mitochondria. PCr levels are dependent on cellular creatine (Cr) uptake, as creatine is not synthesized in the heart but actively taken up by cardiomyocytes. 1H‐MRS and phosphorus‐MRS (31P‐MRS) are used for measurement of Cr and PCr/ATP ratio, respectively. Modified, with permission, from van de Weijer T, J Appl Physiol (1985). 2018 (400).


Figure 4. Low‐flow ischemia leads to translocation of GLUT‐4 and GLUT‐1 to the sarcolemma: (I) Immunofluorescence of glucose transporter‐4 (GLUT‐4) and GLUT‐1 in sections from nonischemic (A) and ischemic (C) regions of left ventricle by confocal microscopy. (II) Myocardial extraction (% of arterial) of glucose and lactate in the left anterior descending (LAD) and left circumflex coronary (LCx) regions during the 30 min before ischemia (Baseline) and during the last 30 min of low‐flow ischemia (Low Flow). AV extractions were calculated from quadruplicate time points. * P < 0.01 versus both baseline LAD extraction and LCx extraction during low‐flow ischemia. Values represent mean ± SEM (n = 9). (III) Sarcolemma and intracellular membrane content of GLUT‐4 and GLUT‐1 in myocardium from nonischemic and ischemic regions of the left ventricle. Glucose transporter content was quantified by 125I‐protein A binding (cpm/μg membrane protein) multiplied by yield of membrane fraction. Data for each membrane fraction are expressed as a percentage of total GLUT‐4 or GLUT‐1 content in sarcolemma and intracellular membrane fractions. Values are mean ± SEM (n = 9). * P < 0.05 versus nonischemic myocardium. Modified, with permission, from Young LH, Circulation. 1997 (436).


Figure 5. Correlation of the myocardial free fatty‐acid analog, p‐123I‐iodophenylpentadecanoic acid (IPPA) retention with 2‐[18F] fluoro‐2‐deoxy‐D‐glucose (18F‐FDG) accumulation during experimental low‐flow ischemia: (I) After baseline (BASE) measurements, partial coronary stenosis was created in canines and maintained throughout protocol. Arterial and venous samples were obtained for metabolic measurements, and radiolabeled microspheres were injected at times designated. IPPA was injected 60 min after creation of stenosis. 18F‐FDG was injected 90 min later. (II) Myocardial 123I‐IPPA and 18F‐FDG retained activities expressed as nonischemic percentage for all segments (n = 576). Segments were segregated on basis of normalized flows in segments into 20%‐flow increments. Numbers within each bar represent number of segments falling into each flow range. (III) (A) Serial short‐axis and vertical long (v‐long) axis SPECT 123I‐IPPA images from a representative dog displayed in standard format. Time after injection is designated on left margin. Note perfusion defect in anteroseptal and anteroapical regions, which normalizes over time. (B) Myocardial 123I‐IPPA clearance curves derived from ischemic and nonischemic regions for same dog. (C) Early clearance data for same dog are also displayed as semilogarithmic plot. Early myocardial clearance appears linear on this semilogarithmic plot, suggesting early monoexponential clearance of 123I‐IPPA. Delayed myocardial 123I‐IPPA clearance is seen in ischemic region. This research was originally published in JNM. Shi CQ, Young LH, Daher E, DiBella EV, Liu YH, Heller EN, Zoghbi S, Wackers FJ, Soufer R, and Sinusas AJ. Correlation of myocardial p‐(123)I‐iodophenylpentadecanoic acid retention with (18)F‐FDG accumulation during experimental low‐flow ischemia. J Nucl Med 43: 421‐431, 2002. © SNMMI. (336).


Figure 6. SPECT imaging showing delayed recovery of regional fatty acid metabolism in heart tissue after transient exercise‐induced ischemia (“ischemic memory”): Representative stress and rest short‐axis thallium tomograms after reinjection (left two panels) demonstrate a reversible inferior defect consistent with exercise‐induced myocardial ischemia. Cardiac SPECT of a patient injected with radiolabeled [123I]‐β‐methyl‐p‐iodophenyl‐pentadecanoic acid (BMIPP), acquired at rest 22 h after exercise‐induced ischemia, shows persistent metabolic abnormality in the inferior region despite complete recovery of regional perfusion (center panel). Retention of BMIPP in the heart of a normal adult is shown as a control (right panel). Modified, with permission, from Taegtmeyer H, Nat Clin Pract Cardiovasc Med. 2008 (369).


Figure 7. Quantitative PET imaging detects early metabolic remodeling in a mouse model of pressure‐overload left ventricular hypertrophy in vivo: Gated end‐diastolic transverse 18F‐FDG PET images for sham mice, transverse aortic constriction (TAC) mice, and TAC mice treated with propranolol at baseline, day 1, and day 7 after surgery are shown. All serial scans are from same animals. Images show increase in 18F‐FDG uptake in TAC mice starting at day 1, indicative of metabolic adaptation in pressure‐overload left ventricular hypertrophy. This research was originally published in JNM. Zhong M, Alonso CE, Taegtmeyer H, and Kundu BK. Quantitative PET imaging detects early metabolic remodeling in a mouse model of pressure‐overload left ventricular hypertrophy in vivo. J Nucl Med 54: 609‐615, 2013. © SNMMI. (448).


Figure 8. PET scan showing perfusion–metabolism mismatch in hibernating heart tissue as an example of preserved cardiometabolic reserve: (A) 82Rubidium (82Rb) PET in short‐axis view shows markedly decreased perfusion in the apical, inferior, inferolateral, and septal regions of the left ventricle at rest, which extends from distal to basal slices. (B) Images acquired under glucose‐loaded conditions, labeled with 18F‐fluorodeoxyglucose (18F‐FDG), show perfusion‐metabolism mismatch pattern (the scintigraphic hallmark of hibernation) in all abnormally perfused myocardial regions at rest. An exception is the anteroseptal region, which demonstrates matched perfusion‐metabolism pattern (compatible with scarred myocardium). Modified, with permission, from Taegtmeyer H, Nat Clin Pract Cardiovasc Med. 2008 (369).


Figure 9. Increased 18F‐fluorodeoxyglucose (18F‐FDG) accumulation in right ventricular free wall in patients with pulmonary hypertension and the effect of epoprostenol: Representative midventricular transaxial 18F‐FDG positron emission tomography images of a patient with primary pulmonary hypertension before and after the pulmonary vasodilator therapy with epoprostenol for three months. (A) Before the pulmonary vasodilator therapy, the right ventricular (RV) 18F‐FDG accumulation was highly increased and the corrected RV standardized uptake value (SUV) of 18F‐FDG was 13.4. (B) After the therapy, the corrected RV SUV of 18F‐FDG markedly decreased to 7.5. (Lower panels) Correlations between the percentage change of RV SUV of 18F‐FDG corrected for the partial volume effect and the percentage change of the pulmonary vascular resistance and peak‐systolic wall stress in the RV free wall. Modified, with permission, from Oikawa M, J Am Coll Cardiol. 2005 (286).


Figure 10. Evaluation of the cardioprotective effects of Fv‐HSP72 by Annexin‐V based apoptosis imaging in a rabbit ischemia‐reperfusion model: the effect of a single intravenous dose of Fv‐HSP72 [the heat shock protein‐72 (HSP72) coupled to a single‐chain variable fragment (Fv) of monoclonal antibody 3E10 (3E10Fv)] was tested in rabbits undergoing left coronary artery occlusion for 40 min followed by 3 h reperfusion. Higher and more extensive uptake of 99mTc‐annexin‐V was seen in the control groups compared with the two therapy groups (pre and post ischemia reperfusion) in in vivo sagittal slices of SPECT images obtained 3 h after the injection of 99mTc‐annexin‐V (white circle = apex) and in ex vivo images of excised heart (traced with dotted lines, arrows = high uptake area; asterisk = apex). Modified, with permission, from Tanimoto T, J Am Coll Cardiol. 2017 (381).


Figure 11. Molecular MRI imaging of cardiomyocyte apoptosis with AnxCLIO‐Cy5.5 (A, D, G) and simultaneous delayed enhancement (DE) MRI of necrosis with Gadolinium‐DTPA‐NBD (B, E, H) in a mouse with severe myocardial injury after transient coronary artery ligation (35 min): Images at three slice locations are shown, moving progressively from the midventricular level (A and B) to the left ventricular apex (G and H). (B) At the midventricular level, only a small area in the subendocardium of the lateral wall shows DE (red arrows). (E and H) The extent of DE increases progressively in the more apical slices (red arrows) and is fairly extensive at the apex. Although the accumulation of AnxCLIO‐Cy5.5 is fairly transmural, DE of Gd‐DTPA‐NBD is seen predominantly in the subendocardium. (C, F, and I) Immunohistochemistry for Gd‐DTPA‐NBD confirming the in vivo MRI findings. (C) Control area in the uninjured septum showing no evidence of DE (magnification × 200). (F) (× 200) and (I) (× 400) Sections from the antero‐apical wall of the left ventricle show positive staining for Gd‐DTPA‐NBD in areas of the subendocardium with significant amounts of cardiomyocyte degeneration. Modified, with permission, from Sosnovik DE, Circ Cardiovasc Imaging. 2009 (352).


Figure 12. Ferumoxytol‐enhanced magnetic resonance imaging assessing inflammation after myocardial infarction: examples of myocardial edema and ferumoxytol enhancement in the infarct zone of 3 patients after myocardial infarction (1—anteroseptal, 2—lateral, and 3—inferior). Accumulation of ferumoxytol reduces T2* decay time and creates signal deficits that can be quantified and visualized using T2* MRI. To describe ferumoxytol accumulation, the relaxation rate, R2*, which is the inverse of the mean T2* was calculated for each region of interest, where the higher the value, the greater the ferumoxytol accumulation. The separate columns illustrate late gadolinium enhancement (LGE, first column), ferumoxytol enhancement (R2* map, second and third column) and edema (T2 map, fourth and fifth columns). At early time points (up to 10 days) increased inflammation was detected by ferumoxytol (dark regions on R2* maps) and edema was detected on T2 maps (light region). These changes have improved or have resolved by 3 months. Modified, with permission, from Stirrat CG, Heart. 2017 (363).


Figure 13. Prospective evaluation of 18F‐Fluorodeoxyglucose (18F‐FDG) uptake after acute myocardial infarction by PET/MRI imaging as a prognostic marker of functional outcome: (Left panel) Short‐ and long‐axis views of late gadolinium enhancement (LGE) MRI (left), 18F‐FDG–PET images (middle), and overlay (right) of patients with anterior (A) or inferior (B) myocardial infarction. (Right Panel) (A) Correlation between LGE extent and Δ ejection fraction (EF at follow‐up ‐ EF at initial imaging), Δ end diastolic volume (EDV at follow‐up – EDV at initial imaging), and Δ end‐systolic volume (ESV at follow‐up – ESV at initial imaging). (B) Correlation between postischemic 18F‐FDG uptake in the infarct area mean standard uptake value (SUVmean) and ΔEF, ΔEDV and ΔESV. (C) Segmental analysis of the wall motion recovery at follow‐up. Comparison of LGE transmurality and 18F‐FDG uptake in the infarct (SUVmean). Modified, with permission, from Rischpler C, Circ Cardiovasc Imaging. 2016 (311).


Figure 14. Mitochondrial translocator protein (TSPO)‐targeted positron emission tomography reveals myocardial inflammation and neuroinflammation in patients after acute myocardial infarction (AMI): (A) tomographic images of the heart display elevated TSPO signal in the hypoperfused infarct region in a representative patient (arrows). Images were acquired 4 to 6 days after reperfusion for first AMI. (B) Parametric brain images (statistical parametric mapping) show regional group difference of TSPO signal between infarct patients and healthy volunteers, superimposed to a magnetic resonance imaging template. Elevation of signal is regionally seen in the frontal and temporal cortex. HLA, horizontal long axis; VLA, vertical long axis. Modified, with permission, from Thackeray JT, J Am Coll Cardiol. 2018 (388).


Figure 15. Myocardial contrast echocardiographic (MCE) ischemic memory in dogs with selectin‐targeted microbubbles: (A) mean (± SEM) video intensity in the risk and remote areas after selectin‐targeted microbubble administration in dogs undergoing ischemia‐reperfusion, and in both left anterior descending coronary artery and left circumflex territories together in closed‐chest nonischemic controls (n for closed‐chest represents region rather than animal number). (B) Example of MCE from a closed‐chest control animal. (C‐E) Examples of MCE, triphenyltetrazolium chloride staining and risk area by method of intracoronary injection of contrast from a single animal undergoing left circumflex ischemia reperfusion. ANOVA, analysis of variance. Modified, with permission, from Mott B, JACC Cardiovasc Imaging. 2016 (252).


Figure 16. Patients with imaging evidence of active cardiac sarcoidosis on hybrid PET/MRI: late gadolinium enhancement (LGE) MRI images on the left with hybrid 18F‐fluorodeoxyglucose (18F‐FDG) PET/MRI images on the right. (A) Subepicardial (near transmural) LGE in the basal anteroseptum extending in to the right ventricular free wall with increased 18F‐FDG uptake localizing to exactly the same region on fused PET/MRI. (B) Subepicardial LGE in the basal anterolateral wall with increased 18F‐FDG uptake colocalizing to exactly that region on PET/MRI. (C) Patchy midwall LGE in the anterolateral wall with matched increased 18F‐FDG uptake on PET/MRI. (D) Multifocal LGE in the lateral wall with matched increased 18F‐FDG uptake on PET/MRI. Modified, with permission, from Dweck MR, JACC Cardiovasc Imaging. 2018 (107).


Figure 17. 11C‐Methionine PET of myocardial inflammation in a rat model of experimental autoimmune myocarditis (EAM): (A) representative 11C‐methionine PET images in a rat model of EAM 30 min after intravenous tracer administration. Strong focal cardiac 11C‐methionine uptake was observed in EAM rats but not in control animals. Extracardiac tracer accumulation in thymus (asterisk) and the liver (arrowheads) was noted in both EAM and control rats, whereas respective tracer activities in lungs and blood pool were rather low. (B) Cardiac tracer uptake in EAM rats (black bar) was significantly higher than that in control rats (white bar). (C) Representative short‐axis PET images and time‐activity curves of dynamic PET imaging in EAM rat. Ten to 20 min after administration, tracer uptake increased in heart together with rapid clearance of blood activity. Cardiac signals remained stable for 30 to 40 min. Gray scale images serve as reference for location of heart. This research was originally published in JNM. Maya Y, Werner RA, Schutz C, Wakabayashi H, Samnick S, Lapa C, Zechmeister C, Jahns R, Jahns V, and Higuchi T. 11C‐Methionine PET of Myocardial Inflammation in a Rat Model of Experimental Autoimmune Myocarditis. J Nucl Med 57: 1985‐1990, 2016. © SNMMI. (236).


Figure 18. In vivo and ex vivo 111In‐RP748 and 99mTc‐sestamibi (99mTc‐MIBI) images from dogs with chronic infarction: (A) Serial in vivo 111In‐RP748 SPECT short axis, vertical long axis (VLA), and horizontal long axis (HLA) images in a dog 3 weeks after left anterior descending coronary artery (LAD) infarction at 20 min and 75 min after injection in standard format. 111In‐RP748 SPECT images were registered with 99mTc‐MIBI perfusion images (third row). The 75‐min 111In‐RP748 SPECT images were colored red and fused with 99mTc‐MIBI images (green) to better demonstrate localization of 111In‐RP748 activity within the heart (color fusion, bottom row). Right ventricular (RV) and left ventricular (LV) blood pool activity is seen at 20 min. White arrows indicate region of increased 111In‐RP748 uptake in anterior wall. This corresponds to the anteroapical 99mTc‐sestamibi perfusion defect (yellow arrows). (B) Sequential 99mTc‐sestamibi (top row) and 111In‐RP748 in vivo SPECT HLA images at 90 min after injection (middle row) from a dog at 8 h (acute), 1 week, and 3 weeks after LAD infarction. Increased myocardial 111In‐RP748 uptake is seen in the anteroapical wall at all three time points. Color fusion 99mTc‐MIBI (green) and 111In‐RP748 (red) images (bottom row) demonstrate 111In‐RP748 uptake within 99mTc‐MIBI perfusion defect. (C) Ex vivo 99mTc‐sestamibi (left) and 111In‐RP748 (center) images of myocardial slices from a dog 3 weeks after LAD occlusion, with color fusion image on the right. Short axis slices are in the standard orientation. Yellow arrows indicate anterior location of nontransmural perfusion defect region; white arrows indicate corresponding area of increased 111In‐RP748 uptake. Reprinted with permission (241).


Figure 19. Assessment of cardiac αVβ3 integrin expression following acute myocardial infarction in humans by 18F‐Fluciclatide PET imaging: (Left panel) 18F‐Fluciclatide uptake in three patients with recent subendocardial myocardial infarction (MI). (A) Patient 1, 13 days after anterior MI, displaying a short‐axis PET image of the left ventricle with crescentic 18F‐fluciclatide uptake that correlates with the interventricular septum and anterior wall on CT angiography (B). The fused PET/CT‐angiography image (C) shows this uptake to correspond exactly with the region of late gadolinium enhancement (LGE) on magnetic resonance imaging (MRI) (D). Further delineation of myocardial uptake on PET/CT is clearer in the two‐chamber view (E) and on a fused CT/three‐dimensional‐Patlak image, which shows this uptake to follow a watershed‐pattern emerging from the coronary stents present in the left anterior descending coronary artery (F). (G and H) Patient 2, 8 days following anterior MI, displaying focal uptake of 18F‐fluciclatide in the anterior wall and apex in the three‐chamber view on PET/CT (G) which corresponds to the region of infarction on LGE MRI imaging (H). (I and J) Patient 3, showing focal uptake of 18F‐fluciclatide in the inferior wall 19 days following MI on PET/CT (I) that again corresponds to the infarction on MRI LGE imaging (J). (Right Panel) 18F‐Fluciclatide uptake in MI is shown. Uptake of 18F‐fluciclatide in (A) patients with acute MI at 2 and 10 weeks, patients with chronic total occlusion (CTO) and healthy control subjects is shown. Uptake was greatest at 2 weeks after MI (B). 18F‐Fluciclatide uptake in the acute MI group was greater in regions of hypokinesis when compared with sites of normal function or akinesis (C). This translated to a higher 18F‐fluciclatide uptake in those regions, which subsequently improved in function on follow‐up cardiac magnetic resonance (D). CTO, chronic total occlusion; TBR, tissue‐to‐background ratio. WMA, wall motion abnormality. Modified, with permission, from Jenkins WS, Heart. 2017 (178).


Figure 20. Postinfarction myocardial scarring in mice: molecular MRI imaging with use of a collagen‐targeting contrast agent: Midventricular short‐axis double inversion‐recovery gradient‐echo MRI images (A, B, D, and E) and corresponding picrosirius red‐stained histologic sections (C and F) of the mouse left ventricle 6 weeks after left anterior descending artery occlusion‐reperfusion. Arrows point to area of scarring. (A and D) Standard anatomic MR images acquired by using a double inversion‐recovery gradient‐echo sequence. (B and E) Midventricular short‐axis MR images of the left ventricles at two section locations obtained 40 min after injection of a gadolinium‐based collagen‐targeting contrast agent EP‐3533. The regions of contrast enhancement correlate closely with (C and F) photomicrographs of picrosirius red‐stained tissue sections. Modified, with permission, from Helm PA et al. Radiology 2008 (150).


Figure 21. Noninvasive targeted imaging of matrix metalloproteinase activation in a murine model of postinfarction remodeling: hybrid micro‐SPECT/CT reconstructed short‐axis images were acquired without x‐ray contrast (A) in a control sham‐operated mouse (left) and selected mice at 1 week (middle) and 3 weeks (right) after surgical myocardial infarction (MI), after injection of 201Tl (top row, green) and 99mTc‐RP805, (middle row, red). A black‐and‐white and multicolor fusion image is shown on bottom. Control heart demonstrates normal myocardial perfusion and no focal 99mTc‐RP805 uptake within the heart, although some uptake is seen in chest wall at the thoracotomy site (dashed arrows). All post‐MI mice have a large anterolateral 201Tl perfusion defect (yellow arrows) and focal uptake of 99mTc‐RP805 in defect area. A dashed circle is drawn around the heart to demonstrate localization of 99mTc‐RP805, within the infarcted area of the heart. Some activity is also seen in the peri‐infarct border zone. Additional micro‐SPECT/CT images were acquired by use of a higher‐resolution SPECT detector after the administration of x‐ray contrast, at 1 week (B) and 3 weeks (C) after MI. The contrast agent permitted better definition of the LV myocardium, which is highlighted by white dotted line. Representative short‐axis (SA), horizontal long‐axis (HLA), and vertical long‐axis (VLA) images are shown for two additional mice by use of the same format and color scheme. Focal uptake of 99mTc‐RP805 is seen within the central infarct and peri‐infarct regions, which again corresponds to 201Tl perfusion defect. Modified, with permission, from Su H, Circulation. 2005 (364).


Figure 22. Dual‐isotope in vivo SPECT/CT imaging reflecting myocardial perfusion (201Thallium) and matrix metalloproteinase activity (99mTc‐RP805): In vivo Thallium‐201 and 99mTc‐RP805 SPECT/CT images of pigs at 1 week, 2 weeks and 4 weeks post myocardial infarction are shown in transaxial, coronal, and sagittal views. Note the perfusion defect in the lateral wall and the time dependent changes in the intensity of 99mTc‐RP805 retention in the same regions (green arrows). The yellow double arrows point to 99mTc‐RP805 activity in the surgical sternal wound. A known point source (orange arrow) can be used to quantify hotspot uptake. Scale bars: 2 cm. Modified, with permission, from Sahul ZH, Circ Cardiovasc Imaging. 2011 (320)


Figure 23. Positon emission tomography (PET)/computed tomography (CT) of angiotensin II type 1 receptors (AT1R) in healthy pigs: panel A shows anterior maximum intensity projections (MIP, left), transaxial fusion images (middle) and reangulated PET images (right) (SA, short axis; HL, horizontal long axis; VL, vertical long axis), using AT1R ligand [11C]‐KR31173 (top row), and myocardial perfusion tracer [13N]‐ammonia (NH3) (bottom row). Panel B shows myocardial kinetics of [11C]‐KR31173 at baseline, and (panel C) after intravenous AT1R blockade (representative coronal PET slices on top, time activity curves for arterial blood (pink) and myocardium (cyan) on bottom). Modified, with permission, from Fukushima K, J Am Coll Cardiol. 2012 (127).


Figure 24. In vivo visualization of amyloid deposits in the heart with Pittsburgh compound B (11C‐PIB) and PET: short‐axis images of the Pittsburgh compound B (11C‐PIB) retention index and myocardial blood flow (MBF) in (left to right) patients with high, intermediate, and partially increased 11C‐PIB retention and a healthy control. Liver is clearly visible in 11C‐PIB images of the second patient and healthy control and is just outside PET field of view for other 2 patients. Liver uptake is due to biliary excretion of 11C‐PIB and is likely not related to amyloid binding. This research was originally published in JNM. Antoni G, Lubberink M, Estrada S, Axelsson J, Carlson K, Lindsjo L, Kero T, Langstrom B, Granstam SO, Rosengren S, Vedin O, Wassberg C, Wikstrom G, Westermark P, and Sorensen J. In vivo visualization of amyloid deposits in the heart with 11C‐PIB and PET. J Nucl Med 54: 213‐220, 2013. © SNMMI (8).


Figure 25. First‐in‐human study of a novel 18F‐labeled tracer LMI1195 for imaging myocardial sympathetic innervation: Representative series of whole body [18F]‐LMI 1195 coronal images at mid‐myocardial level in a healthy human volunteer acquired 5 hours after injection (average, 193.5  ±  37.4 MBq [5.23  ±  1.01 mCi]). Each whole‐body image is scaled to maximum value within that image. This research was originally published in JNM. Sinusas AJ, Lazewatsky J, Brunetti J, Heller G, Srivastava A, Liu YH, Sparks R, Puretskiy A, Lin SF, Crane P, Carson RE, and Lee LV. Biodistribution and radiation dosimetry of LMI1195: first‐in‐human study of a novel 18F‐labeled tracer for imaging myocardial innervation. J Nucl Med 55: 1445‐1451, 2014. © SNMMI (344).


Figure 26. Depiction of postganglionic sympathetic nervous system (SNS) and parasympathetic nervous system (PNS) nerve endings: (Left panel) The synthesis and release of norepinephrine in postganglionic SNS nerve endings and subsequent binding to postsynaptic receptors on cardiomyocytes. The tracers in red depict SNS pre‐ and postsynaptic radioanalogs. (Right panel) the synthesis and release of acetylcholine in the terminal nerve ending and varicosities of postganglionic PNS nerve endings and subsequent binding to postsynaptic receptors on cardiomyocytes. Tracers in blue depict PNS pre‐ and postsynaptic radioanalogs. AC, adenylyl cyclase; ACh, acetylcholine; AChE, acetylcholinesterase; ATP, adenosine triphosphate; CAT, choline‐acetyl‐transferase; COM, catechol‐O‐methyltransferase; cAMP, cyclic adenosine monophosphate; MAO, monoamine oxidase; mIBG, metaiodobenzylguanidine; MR2, muscarinic receptor 2; NE, norepinephrine; NR, nicotinic receptor; VMAT, vesicular monoamine transporter; 18F‐6F‐DA, 6‐18F‐fluorodopamine; PHEN, phenylephrine; EPI, epinephrine; HED, hydroxyephedrine; MQNB, (R,S)‐N‐[11C]‐methyl‐quinuclidin‐3‐yl benzilate. Modified, with permission, from Boutagy NE, Curr Cardiol Rep. 2017 (45).


Figure 27. 123I‐metaiodobenzylguanidine (123I‐mIBG) imaging for prediction of mortality and potentially fatal events in heart failure: representative 123I‐mIBG images from patients from the ADMIRE‐HFX Study. (A) Image from 37‐year‐old man with nonischemic cardiomyopathy demonstrated 123I‐mIBG heart to mediastinum (H/M) ratio of 1.69. (B) Image from 51‐year‐old woman with ischemic cardiomyopathy showed H/M ratio of 1.80. Right panel shows 2‐year all‐cause mortality rates based on 0.1 increments of H/M indicating progressive decline from maximum of 29.4% for H/M < 1.10. There were no deaths among subjects with H/M ≥1.80. This research was originally published in JNM. Narula J, Gerson M, Thomas GS, Cerqueira MD, and Jacobson AF. 123I‐mIBG imaging for prediction of mortality and potentially fatal events in heart failure: the ADMIRE‐HFX study. Journal of Nuclear Medicine 56: 1011‐1018, 2015 (271).


Figure 28. Regional myocardial sympathetic denervation assessment by [11C]‐meta‐hydroxyephedrine (HED) PET in ischemic cardiomyopathy: (Top panel) PET images from two representative subjects from the PAREPET trial comparing resting flow (measured by 13N‐ammonia [13NH3]), viability (by insulin‐stimulated 18F‐fluorodeoxyglucose [18F‐FDG]), and myocardial sympathetic innervation (by 11C‐HED) are shown. (Bottom panel) Kaplan‐Meier curves show the incidence of sudden cardiac arrest for tertiles of PET‐defined myocardial substrates (median follow‐up 4.1 years). As continuous variables, the total volume of denervated myocardium, as well as viable denervated myocardium, predicted sudden cardiac arrest. Neither infarct volume nor hibernating myocardium was significant as continuous variables. Modified, with permission, from Fallavollita JA, J Am Coll Cardiol. 2014 (114).


Figure 29. Tracking of human induced pluripotent stem cells in a pig model of myocardial infarction: assessment of cell survival, engraftment and distribution by hybrid SPECT/CT imaging of sodium iodide symporter transgene expression: In vivo SPECT/CT imaging ∼1 h following intracoronary injection of 123I demonstrating long‐term surviving derivatives of sodium iodide symporter (NIS) positive (pos) transgenic human induced pluripotent stem cells (NISpos‐hiPSCs, each site 5 × 107 cells) in pig hearts after 5 days and 15 weeks, respectively. Note, NISpos‐hiPSCs were only visualized when co‐injected with an equal number of mesenchymal stem cells (MSC). Immunohistochemical staining of tissue sections of corresponding areas of the left ventricular wall confirmed the presence of hiPSC derivatives, since delivered NISpos‐hiPSCs were also transfected to express the reporter protein, venus. Notably, the vast majority of venus positive iPSC derivatives were found to represent endothelial cells integrated into the cardiac vasculature 15 weeks after cell transplantation. Modified, with permission, from Templin C, Circulation 2012 (385).
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Teaching Material

N. E. Boutagy, A. Feher, I. Alkhalil, N. Umoh, A. J. Sinusas. Molecular Imaging of the Heart. Compr Physiol 9: 2019, 477-533.

Didactic Synopsis

Major Teaching Points:

  • Molecular imaging refers to the visualization, characterization, and noninvasive measurement of biological processes at the molecular and cellular levels in humans and other living systems.
  • The nuclear imaging systems, single-photon emission tomography (SPECT) and position emission tomography (PET) are the most commonly used modalities for molecular imaging.
  • Nanoparticles, contrast agents and microbubbles are used to enhance the molecular imaging capability of computed tomography (CT), magnetic resonance imaging (MRI) and ultrasound that have inherently lower sensitivity for detection of these molecular processes.
  • Molecular imaging has provided valuable insights in determining the underlying pathophysiology and molecular processes associated with many cardiovascular diseases (CVDs), including: ischemic, hypertrophic, infiltrative or inflammatory heart disease, and complicating arrhythmias and heart failure (HF)
  • Cardiac molecular imaging is already currently used as a sensitive tool in the diagnosis of certain CVDs, such as cardiac sarcoidosis and amyloidosis.
  • Molecular imaging of the heart has the capability to provide early detection of disease, improve the understanding of the mechanisms of disease progression and allows for risk stratification.

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1 This figure illustrates the structure of lipid-based nanoparticles currently used in molecular imaging. Amphiphilic lipids are used to assemble nanoparticles. Major lipid aggregates currently used for in vivo molecular imaging include: micelles, conventional liposomes, stabilized liposomes, microemulsions, micelles and bilayer on nanoparticles.

Figure 2 This figure illustrates the limitations and strengths of each imaging modality as it relates to multiple facets of cardiovascular imaging and also links these imaging modalities to specific biological targets, including; thrombosis, angiogenesis, inflammation, autonomic nervous system function, the renin angiotensin-aldosterone system (RAAS), cell death, extracellular matrix, and tracking of cell and gene therapies.

Figure 3 This figure illustrates the main aspects of cardiac metabolic imaging. Myocardial perfusion can be quantified with gadolinium using first-pass magnetic resonance imaging (MRI) or by using positron emission tomography (PET) or single photon emission tomography (SPECT) radiotracers. Substrate utilization can be assessed by using metabolically trapped or fully metabolized tracers to evaluate glycolysis, β-oxidation, and the tricarboxylic acid cycle with the help of PET, SPECT or hyperpolarized carbon-13 magnetic resonance spectroscopy (MRS). Proton-MRS and phosphorus-31 MRS are used for the evaluation of high-energy phosphate metabolism

Figure 4 This figure illustrates the first report of the translocation of the glucose transporter (GLUT)-4 and GLUT-1 to the sarcolemma of myocytes under low-flow ischemia. Myocardial extraction of glucose dramatically increases in the ischemic region during low-flow ischemia. There is a 200% increase in GLUT-4 and a 40% increase in GLUT-1 expression in the sarcolemma in the ischemic myocardial tissue.

Figure 5 This figure illustrates the shift in myocardial metabolism during low-flow ischemia with nuclear imaging. This figure shows the correlation between the myocardial free fatty-acid analog p-123I-iodophenylpentadecanoic acid (IPPA) retention with 2-[18F] fluoro-2-deoxy-D-glucose (18F-FDG) accumulation during experimental low-flow ischemia created by partial coronary stenosis in canines. Serial IPPA single photon emission tomography (SPECT) images show an initial defect in the ischemic region, which normalizes within 48 min because of the slower IPPA clearance from the ischemic region.

Figure 6 This figure illustrates ‘ischemic memory’, or the delayed recovery normal fatty acid metabolism after transient exercise-induced ischemia. The example shows cardiac single photon emission tomography (SPECT) images of a patient injected with radiolabeled [123I]-β-methyl-p-iodophenyl-pentadecanoic acid (BMIPP, fatty acid metabolism), acquired at rest 22 hours after exercise-induced ischemia, shows persistent metabolic abnormality despite complete recovery of regional perfusion demonstrated by thallium-201 imaging.

Figure 7 This figure illustrates early metabolic remodeling in a mouse model of pressure-overload left ventricular hypertrophy. Positron emission tomography (PET) images show increased 2-[18F] fluoro-2-deoxy-D-glucose (18F-FDG) uptake after pressure overload starting at day 1 following experimental pressure-overload, which is prevented by beta blocker treatment.

Figure 8 This figure illustrates the perfusion–metabolism mismatch in hibernating heart tissue indicating preserved metabolism, despite a reduction in tissue perfusion. 82Rubidium PET images show markedly decreased perfusion, whereas 2-[18F] fluoro-2-deoxy-D-glucose (18F-FDG) images show increase glucose uptake, demonstrating the classic perfusion–metabolism mismatch pattern commensurate with hibernating myocardium in abnormally perfused regions at rest.

Figure 9 This figure illustrates increased 2-[18F] fluoro-2-deoxy-D-glucose (18F-FDG) accumulation in the right ventricular free wall of patients with pulmonary hypertension. Before pulmonary vasodilator therapy, a patient had markedly elevated right ventricular 18F-FDG accumulation, which was significantly reduced after epoprosterenol therapy. The percentage change of right ventricular of 18F-FDG uptake, expressed as standardized uptake value (SUV), was correlated with the percentage change of the pulmonary vascular resistance and peak-systolic wall stress in the right ventricular free wall.

Figure 10 This figure illustrates the evaluation of the cardioprotective effects of Fv-HSP72 (the heat shock protein-72 [HSP72] coupled to a single-chain variable fragment [Fv] of monoclonal antibody 3E10) by Annexin-V based apoptosis imaging in a rabbit ischemia-reperfusion model. Higher and more extensive uptake of 99mTc-annexin-V was seen in the control groups compared with rabbits treated with Fv-HSP72 in in vivo and in ex vivo single photon emission tomography (SPECT) images.

Figure 11 This figure illustrates molecular magnetic resonance imaging (MRI) of cardiomyocyte apoptosis with AnxCLIO-Cy5.5 and simultaneous delayed enhancement MRI of Gadolinium-DTPA-NBD in a mouse with severe myocardial injury after transient coronary artery ligation (35 minutes). Although the accumulation of AnxCLIO-Cy5.5 is fairly transmural, delayed enhancement of Gd-DTPA-NBD is seen predominantly in the subendocardium.

Figure 12 This figure illustrates inflammation imaging by ferumoxytol-enhanced magnetic resonance imaging (MRI) after myocardial infarction. Accumulation of ferumoxytol reduces T2* decay time and creates signal deficits that can be quantified and visualized by using T2* MRI. At early timepoints (up to 10 days) increased inflammation was detected by ferumoxytol and edema was detected on T2 maps. These changes have improved or have resolved by 3 months.

Figure 13 This figure illustrates the use of 2-[18F] fluoro-2-deoxy-D-glucose (18F-FDG) uptake imaging by hybrid positron emission tomography (PET) magnetic resonance imaging (MRI) after acute myocardial infarction as a prognostic marker of functional outcome. 18F-FDG uptake in the infarcted myocardium was highest in areas with transmural scar. The change in ejection fraction, end-diastolic volume and end-systolic volume was inversely correlated to the extent of late gadolinium enhancement (LGE) and to the post-ischemic 18F-FDG uptake in the infarct area. LGE transmurality and 18F-FDG uptake in the infarct correlated with wall motion recovery at follow-up.

Figure 14 This figure illustrates mitochondrial translocator protein (TSPO)-targeted positron emission tomography (PET) imaging of myocardial inflammation and neuroinflammation in patients after acute myocardial infarction. Tomographic images of the heart display elevated TSPO signal in the hypoperfused infarct region. Parametric brain images show regional group difference of TSPO signal between infarct patients and healthy volunteers, with elevation of signal regionally seen in the frontal and temporal cortex.

Figure 15 This figure illustrates the evaluation of ischemic memory in dogs with selectin-targeted microbubbles by using myocardial contrast echocardiography. Signal in the risk area was > 5-fold higher than in closed-chest control myocardium after selectin-targeted microbubble administration in dogs that underwent experimental ischemia-reperfusion injury.

Figure 16 This figure illustrates hybrid position emission tomography (PET)/magnetic resonance imaging (MRI) of patients with active cardiac sarcoidosis by using late gadolinium enhancement MRI combined with 2-[18F] fluoro-2-deoxy-D-glucose (18F-FDG) imaging.

Figure 17 This figure illustrates 11C-methionine positron emission tomography (PET) imaging of myocardial inflammation in a rat model of experimental autoimmune myocarditis. Strong focal cardiac 11C-methionine uptake was observed in experimental autoimmune myocarditis rats, but not in control animals. Ten to 20 minutes after administration, tracer uptake increased in heart together with rapid clearance of blood activity. Cardiac signals remained stable for 30–40 min.

Figure 18 This figure illustrates in vivo and ex vivo 111In-RP748 (angiogenesis) and 99mTc-sestamibi (perfusion) single photon emission tomography (SPECT) images from dogs with chronic myocardial infarction. Increased 111In-RP748 uptake was observed in regions corresponding to perfusion defect on 99mTc-sestamibi images. Increased myocardial 111In-RP748 uptake was seen in the infarct region at 8 hours, 1 week, and 3 weeks after experimental myocardial infarction.

Figure 19 This figure illustrates the assessment of cardiac αVβ3 integrin expression in humans by 18F-Fluciclatide positron emission tomography (PET) imaging following acute myocardial infarction. 18F-Fluciclatide uptake was increased at sites of acute infarction compared with the remote, non-infarcted myocardium. 18F-Fluciclatide uptake in the acute myocardial infarction group was greater in regions of hypokinesis when compared with sites of normal function or akinesis. The areas with higher 18F-fluciclatide uptake had a higher propensity to improve function, as assessed by cardiac magnetic resonance imaging (MRI), on follow-up.

Figure 20 This figure illustrates the use of a collagen-targeting contrast agent imaged by molecular magnetic resonance imaging (MRI) for the evaluation of post-infarction myocardial scarring in mice. The regions of contrast enhancement correlated closely with photomicrographs of picrosirius red–stained (collagen) tissue sections.

Figure 21 This figure illustrates noninvasive targeted single photon emission tomography (SPECT) imaging of matrix metalloproteinase (MMP) activation (99mTc-RP805) in a murine model of post-infarction remodeling. All post-myocardial infarction mice had a large thallium-201 perfusion defect with corresponding focal uptake of 99mTc-RP805 in defect area, with some 99mTc-RP805 uptake also seen in the peri-infarct border zone.

Figure 22 This figure illustrates dual-isotope in vivo single photon emission tomography (SPECT)/computed tomography (CT) imaging assessing myocardial perfusion (Thallium-201) and matrix metalloproteinase activity (99mTc-RP805) in a porcine model of myocardial infarction. MMP activation was increased within the infarct region at 1-week post-myocardial infarction and remained elevated up to 4 weeks post-myocardial infarction.

Figure 23 This figure illustrates positron emission tomography (PET)/computed tomography (CT) evaluation of angiotensin II type 1 receptors (AT1R) by using [11C]-KR31173 in healthy pigs. Myocardial [11C]-KR31173 retention was detectable, regionally homogeneous, and specific for AT1R, as confirmed by in vivo blocking experiments.

Figure 24 This figure illustrates in vivo visualization of amyloid deposits in the heart with Pittsburgh Compound B (11C-PIB) and positron emission tomography (PET). Myocardial 11C-PIB uptake was visually evident in patients with cardiac amyloidosis and was not seen in healthy volunteers.

Figure 25 This figure illustrates the first-in-human study of a novel 18F-labeled tracer LMI1195 for imaging myocardial innervation with positron emission tomography (PET). After 18F-LMI1195 injection, blood radioactivity cleared quickly, whereas myocardial uptake remained stable and uniform throughout the heart for up to 4 hours. Liver and lung activity cleared relatively rapidly, thus providing favorable target-to-background ratios for cardiac imaging.

Figure 26 This figure illustrates the postganglionic sympathetic nervous system (SNS) and parasympathetic nervous system (PNS) nerve endings. The synthesis and release of norepinephrine in postganglionic SNS nerve endings and subsequent binding to postsynaptic receptors on cardiomyocytes is also shown. The tracers in red depict both single photon emission tomography (SPECT) and positron emission tomography (PET) SNS pre- and postsynaptic radio-analogs. The synthesis and release of acetylcholine in the terminal nerve ending and varicosities of postganglionic PNS nerve endings and subsequent binding to postsynaptic receptors on cardiomyocytes is also shown with tracers in blue depicting PNS pre- and postsynaptic PET radioanalogs.

Figure 27 This figure illustrates the use of 123I-metaiodobenzylguanidine (123I-mIBG) single photon emission tomography (SPECT) imaging for the prediction of mortality and potentially fatal events in heart failure. Two-year all-cause mortality rates based on 0.1 increments of heart to mediastinum (H/M) ratio indicated progressive decline from maximum of 29.4% for H/M < 1.10. There were no deaths among subjects with H/M ≥ 1.80.

Figure 28 This figure illustrates the assessment of regional myocardial sympathetic denervation by [11C]-meta-hydroxyephedrine (HED) positron emission tomography (PET) in ischemic cardiomyopathy from the PARAPET trial. As continuous variables, the total volume of denervated myocardium, as well as viable denervated myocardium, predicted sudden cardiac arrest. Neither infarct volume nor hibernating myocardium were significant predictors of sudden cardiac death as continuous variables.

Figure 29 This figure illustrates the tracking of human induced pluripotent stem cells (hiPSCs) by hybrid single photon emission tomography (SPECT)/computed tomography (CT) imaging of sodium iodide symporter (NIS) transgene expression in a pig model of myocardial infarction. In vivo SPECT/CT imaging ∼ 1 hour following intracoronary injection of 123I demonstrated long-term surviving derivatives of NIS positive transgenic hiPSCs in pig hearts after 5 days and 15 weeks following transplantation. To note, NIS positive hiPSCs were only visualized when co-injected with an equal number of mesenchymal stem cells.

 


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How to Cite

Nabil E. Boutagy, Attila Feher, Imran Alkhalil, Nsini Umoh, Albert J. Sinusas. Molecular Imaging of the Heart. Compr Physiol 2019, 9: 477-533. doi: 10.1002/cphy.c180007