Author + information
- Received October 18, 2011
- Revision received December 14, 2011
- Accepted December 15, 2011
- Published online March 1, 2012.
- ↵⁎Reprint requests and correspondence:
Dr. Farouc A. Jaffer, Massachusetts General Hospital Cardiovascular Research Center, Simches Research Building 3206, 185 Cambridge Street, Boston, Massachusetts 02114
Molecular imaging is devoted to the discovery and application of specific biological imaging approaches that complement traditional anatomical imaging. This field continues to witness impressive growth, particularly in the study of oncology, neurology, and cardiovascular disease (CVD). Interest in molecular imaging technologies stems from its great potential, not only to heighten our understanding and diagnostic capability of common CVD scenarios, but also to offer the prospect of personalized treatment and early monitoring of therapeutic response. Targeted imaging reporters are now spawning the development of combined diagnostic and therapeutic agents that can deliver therapy to individual cells in affected tissues. Recently, diagnostic imaging probes for myocardial infarction (MI), stem cell tracking, and atherosclerotic vascular disease have demonstrated significant advances in preclinical research and development (also see the Online Appendix). Clinical molecular imaging studies have further expanded into the areas of aortic dissection and aneurysm disease, and have provided new insights into aspects of heart failure and transplant medicine. In this review, we highlight outstanding CVD molecular imaging studies published over the past year. A summary of important clinical and preclinical imaging agents and applications is provided in Table 1.
A major goal of molecular imaging is to foster translation of innovative technology into the clinical arena. Clinical molecular imaging studies of human atherosclerosis remain prominent. In addition, new strategies have been developed for imaging myocardial disease, as well other areas of vascular disease.
The overarching goal of atherosclerosis molecular imaging is to identify features associated with at-risk (vulnerable) plaques that are prone to rupture. Such plaques may harbor inflammation, hemorrhage, thrombus, neovascularization, or apoptotic cells, aspects suitable for molecular imaging. Studies investigating atherosclerosis based on 18-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) imaging of plaque metabolism/inflammation, and possibly hypoxia, lead the efforts in clinical CVD molecular imaging.
18F-FDG PET imaging of carotid plaque inflammation
18F-FDG is a radiolabeled glucose analog transported into metabolically active cells, and its presence is correlated with plaque macrophage content. 18F-FDG PET imaging, therefore, is a surrogate reporter of this critical cell involved in atherogenesis and plaque rupture. On the basis of the commercial availability of the 18F-FDG tracer and clinical PET scanners, 18F-FDG PET has become one of the most widely employed clinical molecular imaging strategies to study the presence and evolution of endovascular inflammation, particularly in the larger arterial beds (i.e., carotid, aorta).
Carotid Plaque Inflammation and Risk of Microemboli
Microemboli emanating from carotid plaques are associated with an increased risk of stroke, as well as larger macrophage-rich areas in carotid atheroma. In a cross-sectional study of 16 patients with recent anterior circulation transient ischemic attack or minor stroke and 50% to 99% ipsilateral carotid stenosis, 18F-FDG PET imaging was performed (1). Carotid microemboli signals (MES) were detected on transcranial Doppler ultrasound (middle cerebral artery, 1-h duration, same day as PET imaging). 18F-FDG PET discriminated between MES+ and MES− plaques (p = 0.005) on the basis of their degree of local inflammation. Notably, plaque percent stenosis did not provide discriminatory power between MES+ and MES− plaques in the pilot study (p = 0.48). Prospective studies are indicated to determine whether 18F-FDG PET imaging of carotid plaque inflammation/metabolism will improve risk prediction of stroke beyond percent stenosis derived from anatomical imaging.
Plaque Inflammation and Cardiovascular Risk Factors
Extending the application of 18F-FDG PET imaging to patients with diabetes mellitus, Kim et al. (2) studied 90 age- and sex-matched subjects without known cardiovascular disease, who were divided evenly between normal, impaired glucose tolerance, and type 2 diabetes. Images revealed that carotid artery 18F-FDG uptake increased incrementally with the degree of glucose intolerance, and the mean and maximum plaque target-to-background ratios (TBRs) correlated with several cardiovascular risk factors and metabolic biomarkers. The same subjects stratified by Framingham Risk Scores of <10%, 10% to 20%, and >20% also showed increasing maximum TBRs of 1.2, 2.0, and 2.3, respectively, (p = 0.001). Interestingly, however, concomitantly obtained carotid intima-media thicknesses were similar among all 3 groups, providing further evidence that inflammation cannot be routinely evaluated using structural-based imaging approaches.
Relationship Between Carotid Plaque Inflammation and Plaque Echogenicity
The association between carotid plaque ultrasound echogenicity and 18F-FDG PET inflammation was evaluated prospectively in 33 patients with symptomatic carotid arterial disease (3). Although echogenic lesions demonstrated minimal 18F-FDG uptake, echolucent atheroma, a putative ultrasound marker of vulnerable carotid plaques, exhibited a wide range of 18F-FDG–assessed inflammation. Plaque inflammation in vivo correlated positively with CD68+ macrophages on endarterectomy histopathology specimens (r = 0.501). Therefore, within a range of suspected high-risk plaques based on echolucency, 18F-FDG PET may further stratify at-risk lesions by their degree of local inflammation. Stated another way, this study shows that all echolucent plaques are not inflamed. In addition, similar to other studies, stenosis was not significantly associated with the degree of plaque inflammation, or with plaque echogenicity.
Plaque Inflammation and New Biomarkers
In a validation study, Yoo et al. (4) positively correlated elevated circulating blood adipocyte fatty acid binding protein with carotid 18F-FDG PET uptake in a cross-sectional study of 87 men without previously diagnosed CVD or diabetes. Multiple regression analysis accounting for other CVD risk factors further identified adipocyte fatty acid binding protein as an independent predictor of 18F-FDG–determined vascular inflammation. This study demonstrates the ability of molecular imaging strategies to validate potential biomarkers in human subjects.
Natural History of 18F-FDG PET Inflammation Signals
A prospective study has demonstrated the stability of 18F-FDG plaque signal over a 2-week period; however, longer-term data are limited. In a retrospective study, Menezes et al. (5) examined the records of 50 patients that had at least 4 PET/computed tomography (CT) scans performed over a mean follow-up period of 27 months. The authors measured aortic and carotid 18F-FDG PET uptake, as well as CT-determined Hounsfield unit tissue density (i.e., calcification). Notably, no initial 18F-FDG–positive site remained positive on subsequent PET studies, suggesting that inflammation in a particular plaque may not persist for years. Prospective studies are needed to better understand the natural history of plaque inflammation, and these data may arise from ongoing serial imaging trials assessing the inflammatory-modulating effects of new pharmacotherapeutics.
18F-FDG PET imaging of coronary plaque inflammation
A noninvasive method to detect coronary arterial inflammation could be highly useful. Major challenges for 18F-FDG PET imaging include relatively low spatial resolution and high background signal from metabolically active myocardium underlying the coronary bed. Encouragingly, there has been recent progress in this area, aided by dietary manipulations that can suppress background myocardial 18F-FDG signal.
Coronary Plaque Inflammation in Patients with Acute Coronary Syndromes and Stable Angina
Rogers et al. (6) examined ascending aorta and left main coronary artery 18F-FDG PET uptake in 25 patients 1 to 2 weeks after presenting with acute coronary syndrome (ACS) or stable angina. In the left main coronary artery, greater 18F-FDG–based inflammatory activity was present in subjects with ACS compared with stable angina (Fig. 1) (plaque TBR: 2.48 vs. 2.00, p = 0.03). In stented epicardial coronary artery segments, similar findings were observed, with plaque TBRs in ACS patients higher than those with stable angina (TBR: 2.61 vs. 1.74, p = 0.02). Impressively, 96% of coronary PET segments were analyzable after dietary-based suppression of background myocardial signal, including 89% of stented culprit lesions. The results demonstrate that hybrid molecular PET/CT may have utility for noninvasive evaluation of left main coronary arterial inflammation, as the left main is larger, more remote from myocardium, and less mobile, leading to improved image quality and co-registration with coronary CT angiography.
Left Anterior Descending Arterial Inflammation
In an attempt to extend 18F-FDG to the proximal coronary arteries, Saam et al. (7) examined 18F-FDG uptake in the proximal left anterior descending coronary artery (LAD) in a consecutive series of oncology patients. The authors found a modest, but significant, correlation with various cardiac risk factors (R ≈ 0.2), and further noted that patients with a TBR in the upper tertile had a larger calcified plaque burden and higher pericardial fat volume than patients in the lower tertile. However, LAD data from 45% of the patients were not usable due to background myocardial 18F-FDG uptake, limiting image analysis. Further advances, possibly such as electrocardiogram-based triggering of CT acquisitions, are needed to extend 18F-FDG reliably into the non–left main coronary tree.
Statin pharmacotherapy and 18F-FDG PET plaque activity
The effect of increasing statin dose on 18F-FDG PET atheroma uptake was prospectively evaluated in 30 coronary artery disease patients randomized to atorvastatin 5 mg versus 20 mg daily (8). All patients were scheduled for percutaneous coronary intervention to treat stable angina symptoms, and none of them had received lipid-lowering medications for at least the previous 12 months. The day after percutaneous coronary intervention, baseline 18F-FDG PET/CT imaging was performed, and the 18F-FDG activity in the aorta and femoral artery quantified. The patients were then randomized to high- or low-dose statin therapy, with a follow-up 18F-FDG PET imaging study performed 6 months later. The arterial 18F-FDG TBR was significantly reduced in the high-dose statin arm (aorta baseline TBR: 1.15 vs. 1.05, p = 0.007; femoral baseline TBR: 1.12 vs. 1.02, p = 0.012). Although there were similar significant reductions in low-density lipoprotein and high-sensitivity C-reactive protein levels in both the high-dose and the low-dose statin groups, the low-dose group did not show significant changes in arterial 18F-FDG uptake. This suggests that higher statin doses may be required to reduce plaque inflammation.
Near-infrared fluorescence imaging of carotid plaque protease activity
Augmented inflammatory protease activity is a marker of vulnerable plaques. Using near-infrared fluorescence (NIRF) imaging systems in concert with protease-activatable NIRF imaging agents, Kim et al. (9) investigated ex vivo matrix metalloproteinase and cysteine protease activity in samples obtained from 56 subjects undergoing either carotid endarterectomy or carotid stenting with filter devices. On macroscopic NIRF imaging, enhanced cathepsin B and MMP 2/9 protease activity were identified both in retrieved emboli and in bifurcations of carotid endarterectomy specimens (Fig. 2). Plaques demonstrated unstable histopathological features (rupture with thrombus, hemorrhage, and thin, inflamed cap). Symptomatic patients (ipsilateral stroke within 1 month) harbored plaques with greater protease activity compared with asymptomatic patients. Intriguingly, cathepsin B protease activity was diminished in patients taking statins, consistent with the anti-inflammatory properties associated with this medication class. Protease signal correlated modestly with anatomic stenosis or ultrasound echolucency, a suggested marker of plaque instability, indicating that protease-identified inflammation likely provides independent, complementary data on plaque stability. Although NIRF molecular imaging agents are not yet approved for clinical study, the current data, along with a recent report of a clinical targeted fluorescence imaging trial (10), provide momentum for future clinical testing of NIRF protease sensors in human subjects.
Following irreversible myocardial damage, necrotic muscle is replaced by collagen-dense scar that may promote maladaptive tissue remodeling, myocardial dysfunction, and clinical heart failure and malignant arrhythmias. Typically, the true degree of dysfunction and scar burden are not fully realized until months after the index event, at a time when there may be little reversibility. Therefore, early detection of these changes may allow subsequent intervention to prevent adverse outcomes.
Single-photon emission computed tomography imaging of fibrogenesis post-MI, and its relationship to final infarct size at 1 year
In 10 patients presenting with MI, Verjans et al. (11) serially evaluated changes in interstitial extracellular matrix via an intravenous injection of an integrin receptor–targeted arginine-glycine-aspartic acid–radiolabeled imaging peptide (RIP). RIP has been shown previously to target up-regulated integrin expression (e.g., αvβ3) found on myofibroblasts that manufacture collagen. At 3 and 8 weeks post-MI, 99mTc-RIP–enhanced single-photon emission computed tomography (SPECT) imaging revealed uptake in 70% of patients involving the infarct zone identified on myocardial perfusion imaging. Importantly, RIP-based SPECT signal typically extended beyond the fixed perfusion defect. At 1-year follow-up, the pattern of early myocardial RIP uptake was observed to be similar to the final infarct size as measured by cardiac magnetic resonance (CMR) late gadolinium enhancement (Fig. 3). RIP imaging early after infarction may therefore predict the final extent of post-MI myocardial scarring, and offer opportunities for earlier intervention.
Heart Failure and Transplant Medicine
Sarcoid cardiomyopathy and inflammation imaging by 18F-FDG PET
Congestive heart failure is a wide-reaching condition and a leading cause of hospitalization and death. Sarcoid cardiomyopathy is a relatively uncommon, but important, cause of heart failure that may be successfully treated if detected early. Tahara et al. (12) studied cardiac inflammation in 24 patients with systemic sarcoid disease, of which half had recognized cardiac involvement by endomyocardial biopsy or clinical criteria. Compared with healthy normal subjects or age-matched controls with dilated cardiomyopathy, fasting 18F-FDG uptake in cardiac sarcoidosis patients showed significantly more heterogeneous myocardial signal. Heterogeneity was quantified by the coefficient of variation, defined as the 18F-FDG standard deviation divided by the mean uptake in a 17-segment cardiac model. At a cutoff coefficient of variation value of 0.18, this metric demonstrated excellent operating characteristics, with 100% sensitivity and 97% specificity. Following corticosteroid therapy, serial repeat 18F-FDG PET assessment over 12 months follow-up confirmed that the 18F-FDG uptake variation returned to that of control subjects (Fig. 4). Thus, 18F-FDG PET imaging might provide useful diagnostic and treatment responsiveness in patients with sarcoid cardiomyopathy.
Detecting infected left ventricular assist devices using integrated SPECT/CT of leukocyte foci
The noninvasive diagnosis of left ventricular assist device (LVAD) infection, a potentially life-threatening condition, remains challenging. Imaging modalities such as CT or magnetic resonance imaging (MRI) are limited due to metallic artifacts and contraindications. A noninvasive imaging approach may avoid additional testing and treatment that in certain cases may be costly and unnecessary. Furthermore, such an imaging approach could help assess the response to antibiotic therapy in the LVAD itself. Within this context, Litzler et al. (13) performed a clinical cellular imaging study in 8 consecutive patients with suspected LVAD infection, using 99mTc-exametazime–labeled radioactive leukocytes (≥99% viability with 90% labeling efficacy) and hybrid SPECT/CT imaging. At 4 and 24 h after injection of the radiolabeled autologous leukocytes, pockets of infection were identified in all patients. Images discriminated superficial from deep infection, and depicted the extent of LVAD involvement and any remote involved sites. On the basis of the location and severity of the 99mTc-labeled leukocyte uptake, the duration of antibiotic therapy could be effectively tailored, with follow-up scans in 5 subjects demonstrating infection resolution in the LVAD or in a non–LVAD-related source.
Abdominal aortic aneurysm
Inflammation and weakening of the vessel wall may lead to frank rupture, especially in aneurysms that rapidly expand or reach a critical size. New molecular imaging methods are being directed to evaluate aneurysm markers of instability such as inflammation, hemorrhage, and neovascularization.
CMR of Macrophages in Aortic Aneurysm
Fourteen patients with infrarenal abdominal aortic aneurysm (4.0- to 5.5-cm diameter) underwent CMR of aneurysm inflammation following intravenous injection of Sinerem (ferumoxtran, Guerbet, Villepinte, France) 2.6 mg Fe/kg, an ultrasmall superparamagnetic iron oxide (USPIO) nanoparticle agent phagocytosed by resident macrophages (14). Compared with pre-USPIO injection, post-injection CMR aneurysm signals were significantly lower in macrophage-rich atherosclerotic areas. If validated prospectively, USPIO-enhanced CMR could identify high-risk subjects with aneurysm inflammation more likely to expand or rupture, motivating increased surveillance and/or earlier treatment.
A similarly sized study by Nchimi et al. (15) detected biologically active macrophages within intraluminal thrombi of abdominal aortic aneurysms via the superparamagnetic iron oxide (SPIO) agent Endorem (ferumoxide, Guerbet, Villepinte, France). Compared with USPIO, SPIO have relatively larger size and shorter circulation half-life due to rapid hepatic clearance, restricting distribution to luminal surface targets and other well-perfused tissues. Exploiting these properties, SPIO localized in leukocyte-dense intraluminal thrombi 1 h after injection, much earlier than the 24 to 36 h necessitated by longer-circulating USPIOs. Ex vivo CMR and histopathology of excised surgical specimens obtained within 2 weeks of in vivo imaging confirmed thrombus inflammatory cell infiltration with iron particle retention, as well as elevated matrix metalloproteinase 9 (MMP-9) enzymatic activity.
Disruption of the aortic wall is a life-threatening event that often requires immediate surgical intervention. However, autopsy series indicate that incidental aortic dissection is present in up to 1% to 2% of subjects, suggesting that many chronic aortic dissections can be managed conservatively. Because anatomic imaging modalities do not reliably distinguish acute from chronic dissections, new imaging strategies are needed.
18F-FDG PET Imaging of Inflammation in Acute Versus Chronic Aortic Dissection
Reeps et al. (16) evaluated 18F-FDG PET imaging to discriminate acute from chronic type B aortic dissection in 18 patients. 18F-FDG enhancement was observed at the injured aortic wall in all acute dissection patients 3 to 13 days after presentation (Fig. 5). Quantitative analysis revealed that the standardized uptake value (SUV) ratio, or TBR, performed significantly better in discriminating acute from chronic stable dissection (SUV ratio: 2.20 vs. 1.24, respectively, p < 0.001) than simply measuring maximum SUV at the site of injury, which suffered from false-negative and false-positive outliers. This preliminary study suggests that 18F-FDG PET may help distinguish acute from chronic aortic dissection on the basis of the degree of vessel wall inflammation.
18F-FDG and Aortic Dissection Prognosis
The prognostic value of 18F-FDG uptake in medically managed acute aortic dissection was addressed in 28 patients. PET scans were obtained approximately 2 weeks after CT diagnosis (17). All patients had type B dissections except for 2 poor surgical candidates with type A. Over 6 months, there were 8 unfavorable outcomes (death, surgical repair, or dissection progression), predicted by the initial inflammatory 18F-FDG uptake at the dissection site with an odds ratio of 7.72 for adverse events on multivariate analysis. 18F-FDG provided a sensitivity and specificity of 75% and 70%, respectively, for mean SUV > 3.029. Furthermore, in patients with favorable outcomes, a lower 18F-FDG uptake corresponded to a greater likelihood of dissection healing or regression. These results provide intriguing preliminary evidence that 18F-FDG PET imaging may risk-stratify aortic dissection populations that benefit from aggressive earlier surgical intervention.
Giant cell arteritis and Takayasu arteritis are large-vessel inflammatory diseases that can result in arterial occlusion, thrombosis, aneurysm, and accelerated atherosclerosis. New approaches are needed to understand the pathogenesis of these diseases in vivo.
PET Imaging of Macrophages in Vasculitis Using [11C]-PK11195
Pugliese et al. (18) tested the PET imaging probe [11C]-PK11195, an established human neuroimaging agent that selectively binds the benzodiazepine receptor on activated macrophages. Six patients with giant cell arteritis or Takayasu arteritis were compared with 9 asymptomatic controls. Symptomatic subjects exhibited enhanced [11C]-PK11195 signal on vascular PET scans (TBR: 2.41 vs. 0.98 for asymptomatic patients, p = 0.001). In 1 patient treated with 20 weeks of corticosteroid therapy, a follow-up [11C]-PK11195 PET scan demonstrated markedly reduced vascular PET signal (TBR decreased from 1.63 to 0.87), associated with symptomatic improvement and decreased inflammatory biomarkers. Compared with 18F-FDG, which reports on all metabolically active cells, [11C]-PK11195 PET may provide a more macrophage-specific readout, given its ligand selectivity. In addition, [11C]- or [18F]-PK11195 may also improve coronary atherosclerosis PET imaging of inflammation, because background uptake by metabolically active myocytes should be lower than in 18F-FDG PET imaging.
Advances in Preclinical Imaging Approaches
In the last year, new atherosclerosis-targeted imaging agents and devices have been developed to sense plaque inflammation, angiogenesis, and oxidative stress. In vivo studies of pharmacotherapeutic efficacy, as well as the area of integrated therapeutic and diagnostic targeted imaging (“theranostics”), particularly via nanotechnological approaches, are also in a growth phase.
Macrophages are pivotal cells in atherogenesis, driving plaque expansion and plaque complications. Macrophages are the most established imaging target for atherosclerosis molecular imaging studies, with clinical detection of plaque macrophages enabled by 18F-FDG PET and USPIO-enhanced CMR. Although these approaches have proven valuable, new reporter agents are diversifying imaging platforms and aiming to improve sensitivity.
The positron emitter [11C]-PK11195 has been studied to image activated macrophages in clinical vasculitis, as discussed in the previous text. 11C-choline, a source of cell membrane lipids found in high levels in proliferating cells, including plaque macrophages (19), was shown to colocalize with murine plaques by autoradiography, and was able to distinguish noninflamed and inflamed, macrophage-rich plaques (20). A head-to-head comparison with 18F-FDG may be informative in understanding any potential advantages with respect to achievable TBRs.
Folate receptor beta is expressed on activated macrophages and thus offers another molecular imaging target for atherosclerosis. The SPECT tracer 99mTc-labeled folate-targeted probe (99mTc-EC20) was investigated in murine atherosclerosis (21). In vivo SPECT imaging demonstrated greater SPECT signal in animals on a high-cholesterol diet compared with a regular chow diet. Uptake of 99mTc-EC20 was also reduced in animals treated with clodronate liposomes, a macrophage apoptosis–inducing therapeutic agent. Whether the additional macrophage specificity conferred by a folate receptor–based SPECT approach is advantageous compared with 18F-FDG remains to be tested in clinical subjects.
Based on the natural affinity of macrophages for ferritin, targeted imaging agents comprised of bioengineered polypeptide apoferritin (iron-free ferritin) cages were developed as NIRF or CMR agents by coupling apoferritin to the NIR fluorochrome cyanine 5.5 or to magnetite nanoparticles, respectively (22). In diabetic, high-fat diet–fed mice, the imaging agents localized to the macrophage-rich lesions of ligated carotid arteries. Loading of other imaging agents or even therapeutic drugs into the apoferritin protein cage architecture is possible, providing versatility for this macrophage-avid agent.
Maiseyeu et al. (23) synthesized gadolinium-containing anionic vesicles comprised of phosphatidylserine and a novel synthetic oxidized cholesterol ester derivative that avidly binds low-density lipoprotein. Reporter vesicles were internalized by macrophages via scavenger receptors in culture, and in rabbit atheroma in vivo, as shown by 1.5-T CMR. This liposomal agent can also be formulated with fluorescently labeled lipids, and has potential advantages for a good safety profile, easy manufacturing, and scalability that could facilitate clinical testing.
Dual-Modal PET-MRI Reporters
Extending prior work with PET-MRI high-resolution/high-sensitivity macrophage reporters based on 64Cu-labeled crosslinked iron oxide (CLIO-64Cu), Jarrett et al. (24) tested CLIO-64Cu, as well as gadolinium/64Cu-labeled maleylated bovine serum albumin for targeting of the macrophage scavenger receptor A (SRA). Macrophages in injured carotid arteries in 3 different rodent models were visualized with both 64Cu-based PET reporters, as well as by 7-T MR (T1-weighted for gadolinium-based agents, T2-weighted for CLIO-based agents) for higher-resolution imaging.
Although coronary CT imaging has demonstrated substantial clinical utility, few molecular imaging agents are available for CT platforms. Using a high-density lipoprotein (HDL)-based macrophage-targeted gold nanoparticle coupled with spectral (“multicolor”) CT, a multienergy imaging approach based on the discrimination of x-ray energy attenuation differentials, Cormode et al. (25) imaged plaque macrophages in apoE−/− mice. Capitalizing on the multispectral capabilities, in addition to macrophage detection, simultaneous co-registered images of calcification (bones) and iodinated contrast (angiography) were obtained in the same mice (Fig. 6). These results expand the selection of current nanoparticle CT agents for macrophages (e.g., N1177), and may accelerate the use of CT as a molecular and anatomical imaging approach for coronary atherosclerosis.
Post-MI healing involves an orchestrated immune response. Hypo- or hyperimmune cell infiltration following MI can impair myocardial healing, and may promote mechanical complications (rupture) or adverse left ventricular (LV) remodeling (progressive dilation). Methods to study key effector cells and molecules in post-MI healing may shed important insight into this process in vivo, and potentially offer new therapeutic strategies.
Inflammation and myocardial healing
The Effects of Hyperlipidemia on Post-MI Inflammation and Healing
In wild-type and apolipoprotein E–negative (apoE−/−) hyperlipidemic mice, Panizzi et al. (26) first quantified monocyte recruitment post-MI by mapping the pro- and anti-inflammatory subtypes Ly-6Chi and Ly-6Clo via flow cytometry. ApoE−/− mice showed significantly increased levels of inflammatory Ly-6Chi monocytes, cells that secrete degradative enzymes. Using noninvasive, dual-channel fluorescence molecular tomography–CT molecular imaging of post-MI mice (Fig. 7), the authors found that in vivo inflammatory cathepsin enzymatic activity (activatable agent ProSense680, PerkinElmer, Waltham, Massachusetts) and macrophage activity (reporter agent CLIO-750) was also greater in apoE−/− mice (26). Atherosclerotic mice had 10-fold greater Ly-6Chi monocyte infiltration in the infarct zone 5 days post-MI than wild-type controls, as assessed by histopathology, and was associated with increased inflammatory markers, proteolysis, and phagocytosis. In addition, serial CMR showed that apoE−/− mice with MI developed greater ventricular dilation compared with wild-type mice, despite having similar infarct sizes initially. Furthermore, induction of Ly-6Chi monocytosis alone by intraperitoneal lipopolysaccharide injection in wild-type mice without hyperlipidemia or atherosclerosis recapitulated a similar post-MI inflammatory state. This work concludes that the Ly-6Chi monocyte may be a therapeutic cellular target in the post-MI setting.
Please see the Online Appendix for additional high-impact preclinical imaging studies.
Molecular imaging studies are shedding important light on the cellular and molecular biology underlying important cardiovascular diseases. Excitingly, this last year witnessed a growth in clinical molecular investigations, particularly in the areas of atherosclerosis, aneurysm disease, and MI. In the short term, we anticipate continued expansion of 18F-FDG PET–based molecular imaging applications of vascular disease. Insights from 18F-FDG PET should prove useful in predicting which atherosclerosis therapeutics will likely be efficacious and safe. Across many areas of CVD, molecular imaging data studies will continue to elucidate the in vivo pathogenesis of disease, and will provide the foundation for improved risk assessment of key CVD events, such as acute plaque rupture and adverse LV remodeling.
Due to lower imaging agent dose requirements, new strategies for PET and SPECT may be clinically available in the next 2 years. In addition, select fluorescence agents may enter the clinical arena within the next 1 to 3 years. These trends will enable new clinical molecular imaging studies of CVD, and will be spurred further by advances in clinical imaging systems, especially in the emerging areas of fluorescence imaging and multispectral CT imaging. As more agents transition from the bench to the patient bedside, molecular imaging studies should prove helpful in the clinical management of CVD.
For supplementary information on advances in preclinical imaging approaches, please see the online version of this paper.
This study was funded by National Institutes of Health grant R01 HL108229, American Heart Association Scientist Development Grant #0830352N, and a Howard Hughes Medical Institute Career Development Award. Dr. Jaffer has received honoraria from Boston Scientific Corporation, GE Medical Systems, and Merck & Co. Dr. Osborn has reported that he has no relationships relevant to the contents of this paper to disclose. Review period: January 1-December 31, 2010.
- Received October 18, 2011.
- Revision received December 14, 2011.
- Accepted December 15, 2011.
- American College of Cardiology Foundation
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