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. Author manuscript; available in PMC: 2016 Nov 1.
Published in final edited form as: Curr Opin Cardiol. 2015 Nov;30(6):671–680. doi: 10.1097/HCO.0000000000000226

Imaging inflammation and neovascularization in atherosclerosis: clinical and translational molecular and structural imaging targets

Eric A Osborn 1,2, Farouc A Jaffer 1,3
PMCID: PMC4632070  NIHMSID: NIHMS729740  PMID: 26398413

Abstract

Purpose of review

To showcase advances in molecular imaging of atheroma biology in living subjects.

Recent findings

18F-fluorodeoxyglucose (FDG) PET/CT continues to be the predominant molecular imaging approach for clinical applications, particularly in the large arterial beds. Recently there has been significant progress in imaging of neovascularization and inflammation to delineate high-risk atheroma, and to evaluate drug efficacy. In addition, new hardware detection technology and imaging agents are enabling in vivo imaging of new targets on diverse imaging platforms.

Summary

In this review, we present recent exciting developments in molecular and structural imaging of atherosclerotic plaque inflammation and neovascularization. Building upon prior studies, these advances develop key technology that will play an important role to propel new diagnostic and therapeutic strategies identifying high-risk plaque phenotypes and assessing new plaque stabilization therapies in clinical trials.

Keywords: atherosclerosis, molecular imaging, inflammation, neovascularization

Introduction

Atherosclerosis is a chronic, systemic inflammatory disease characterized by the accumulation of lipids and inflammatory cells within the artery wall [1]. In the earliest stages, atherosclerosis primarily affects the intima, however, ongoing inflammation impacts deeper layers. Leaky neovessels penetrate from the adventitia, promoting atheroma expansion associated with plaque vulnerability [2]. Inflammation weakens the protective fibrous cap that can lead to plaque rupture responsible for most acute coronary syndromes. Therefore, inflammation and neovascularization are closely interrelated, and serve as key imaging and therapeutic targets to stratify high and low risk atheroma in vivo [3].

Strategies to identify inflammation and neovascularization in human atheroma rely on biology-specific, high-resolution imaging approaches. Conventional imaging can visualize structural plaque features (e.g. calcium, lipid deposits) and the degree of vessel stenosis [4]. Increasingly, molecular imaging approaches that complement structural data are unraveling key biology central to plaque stability [5]. In this review, we highlight exciting recent advances in atherosclerosis molecular and structural imaging of inflammation and neovascularization and its relationship to plaque pathobiology.

Positron Emission Tomography (PET)

FDG-PET: advances in diagnostic image quality

18F-fluorodeoxyglucose (FDG) PET/CT imaging is the most widely utilized clinical imaging strategy to evaluate plaque metabolism secondary to inflammation. FDG is a radiolabeled glucose reporter that accumulates in metabolically active cells, including atheroma. In atheroma, FDG predominately reports on plaque macrophages, although hypoxia [6•,7•], oxidized LDL [8], and other metabolically active components may contribute to plaque FDG signal. Quantitative FDG signal is generally reported as a target-to-background ratios (TBR) or standardized uptake value (SUV). Hyperglycemia. Elevated serum glucose competitively decreases cellular FDG uptake, thus limiting application of FDG-PET in patients with uncontrolled diabetes mellitus, a common and high-risk atherosclerosis population. Data from 195 cardiovascular disease patients demonstrated that a pre-scan glucose level >7.0 mmol/L (126 mg/dL) inversely associated with carotid and aortic wall FDG uptake [9], suggesting that FDG-PET imaging should be avoided in hyperglycemia. Longer timepoint before FDG-PET imaging. Delayed FDG imaging beyond 90 minutes might increase FDG bioavailability and reduce background FDG blood pool. In two studies, delaying FDG-PET imaging to 2.5–3 hours after injection significantly increased the FDG plaque SUV and TBR signal [9•,10], a simple and effective strategy to improve plaque signal-to-noise.

FDG-PET: secondary plaque inflammation readouts

Linking arterial and fat inflammation. Carotid and aortic plaque FDG activity in 173 obese patients was found to correlate significantly with FDG uptake in fatty tissue by multivariate regression analysis [11•]. Furthermore, increasing body weight associated with greater FDG signal in fat. Increased FDG metabolic activity in the spleen, a putative organ source of leukocytes and pro-inflammatory cytokines that can accelerate atherosclerosis, was associated with greater plaque FDG inflammation in 22 acute coronary syndrome patients [12••]. Remarkably, in a separate arm of this study including 464 subjects without known cardiovascular disease, splenic FDG uptake independently associated with future cardiovascular events (hazard ratio 3.3; 95% confidence interval 1.5–7.3; p=0.003) over a median 4 year follow up period (Figure 1). The concept of targeting systemic inflammation to reduce cardiovascular events is currently being tested in multiple large clinical trials (e.g. CIRT: Cardiovascular Inflammation Reduction Trial; CANTOS: Canakinumab Anti-inflammatory Thrombosis Outcomes Study).

Figure 1. FDG-PET imaging and cardiovascular outcomes in acute coronary syndrome (ACS) patients.

Figure 1

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(Top panel) FDG-PET uptake was significantly enhanced in the aortic wall (left column) and also remote hematopoietic organs (bone marrow, middle column; spleen, right column) in ACS patients over healthy control subjects. (A and B) Compared to those with low FDG uptake, ACS patients with FDG-PET activity greater than the median in the bone marrow and spleen demonstrated increased cardiovascular risk. However, after multivariate adjustment only increased FDG splenic activity remained independently associated with future cardiovascular events (hazard ratio 3.3; 95% confidence interval: 1.5 to 7.3; p=0.003). FDG = 18F-fluorodeoxyglucose; PET = positron emission tomography. Reproduced with permission from reference [12].

FDG-PET: assessment of novel plaque anti-inflammatory therapeutics

In 38 patients with familial hypercholesterolemia, arterial FDG activity modestly correlated with baseline LDL (R=0.37; p=0.03) [13•]. Following lipoprotein apheresis (>50% LDL reduction), FDG uptake significantly diminished within only 3 days, implicating high circulating lipoprotein levels as important direct mediators of chronic plaque inflammation.

A multi-center trial of 72 atherosclerosis patients on low dose statin therapy administered a new p38 mitogen-activate protein kinase (MAPK) inhibitor (BMS-582949) did not show decreased FDG plaque uptake compared to placebo [14]. As a positive control, intensification of statin therapy significantly lowered plaque FDG inflammation. These findings suggest that BMS-582949 may not be a clinically efficacious anti-inflammatory therapy for atherosclerosis. Similarly, an anti-inflammatory 5-lipoxygenase inhibitor VIA-2291 that blocks leukotriene synthesis [15], an oxidized LDL neutralizing antibody MLDL1278A to inhibit immune complex formation [16•], and an Lp-PLA2 inhibitor rilapladib that decreases bioactive inflammatory mediators [17•], all failed to meet the primary endpoints to reduce arterial FDG plaque inflammatory activity. These studies highlight the potential predictive value of FDG plaque imaging in Phase I/II that could have implications for streamlining successful phase III trials.

FDG-PET: advances in PET coronary artery imaging

Diet modulation. Coronary FDG-PET plaque imaging is limited by high background from the adjacent metabolically active myocardium. A randomized trial recently demonstrated that a high-fat, low-carbohydrate meal, followed by 12 hour fast, reliably suppressed myocardial FDG uptake in most subjects [18•]. Quality of suppression was inversely linked to circulating free fatty acid levels, which may help select patients likely to provide high-quality noninvasive FDG-PET images of coronary arteries. Intravascular detectors. To improve spatial resolution, intravascular nuclear scintillating balloon catheter imaging system prototypes have been engineered [19•,20]. The 1–2 µm resolution is a significant advance over the typical 3–5 mm resolution of noninvasive PET, although it remains to be seen if intravascular PET will be a practical option for clinical investigation.

New PET inflammation agents beyond FDG

18F-labeled mannose. 18F-fluoro-D-mannnose (FDM) is a glucose isomer that is transported identically to FDG via glucose receptors but has a more specific targeting profile for anti-inflammatory (M2-like) macrophage populations [21••]. Compared to FDG, FDM-PET improved plaque inflammation detection capabilities with 35% greater radiotracer uptake in rabbit atheroma. The utility of FDM beyond or complementary to FDG is under investigation.

18F-sodium fluoride (NaF) PET imaging. In a major step forward in clinical molecular imaging, NaF-PET, actively used in oncology to assess cancer bone metastases, was applied to detect ostoegenic activity in human coronary atheroma in vivo. NaF has minimal myocardial background compared to FDG, and therefore enables high-quality coronary PET images with good signal-to-noise. In a prospective 40 patient study with myocardial infarction or stable angina, NaF coronary plaque uptake localized to the culprit lesion in 93% of cases (TBR: 1.66 culprit vs. 1.24 non-culprit; p<0.0001), and was associated with high-risk structural plaque features on intravascular ultrasound (Figure 2) [22••]. Comparatively, FDG plaque activity was not significantly different in culprit or non-culprit plaques, likely due to signal contamination from myocardial background. Prospective studies assessing NaF signal with clinical events are underway. It remains unclear if NaF will provide predictive value beyond coronary artery calcium scores, however NaF may detect a biologically more active process.

Figure 2. NaF-PET and FDG-PET coronary atherosclerosis imaging in acute coronary syndromes and stable angina.

Figure 2

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A patient with acute ST elevation myocardial infarction demonstrating (A) angiography with proximal LAD occlusion (red arrow), (B) markedly enhanced NaF uptake at the culprit plaque (red arrow; target-to-background ratio: 2.3 culprit vs. 1.1 reference segment), and (C) no FDG activity at the culprit lesion (red arrow) despite the myocardium (yellow arrow) and esophagus (blue arrow) exhibiting strong FDG metabolism. An acute non-ST elevation myocardial infarction patient with (D) angiography identifying the LAD culprit stenosis (red arrow) and also a non-culprit stenosis (white arrow) in the left circumflex that were both treated with percutaneous coronary intervention. After stent placement, (E) NaF was enhanced in the culprit LAD lesion (red arrow), but not the non-culprit stenosis (white arrow); (F) in contrast, FDG signal was not significantly enhanced in either lesion. A patient with stable angina revealed (G) angiography with diffuse, non-obstructive disease in the right coronary artery (red and yellow lines denote diseased regions) that on (H) NaF-PET coronary imaging showed corresponding areas of high (red line) and low (yellow line) NaF plaque activity. Radiofrequency intravascular ultrasound imaging of plaque composition revealed (I) predominantly fibrotic (green color) and calcific (white color) structure in the low NaF signal plaque, and (J) necrotic core (red color) in the high NaF signal plaque suggesting the presence of high-risk features. NaF = 18F-sodium fluoride; FDG = 18F-fluorodeoxyglucose; PET = positron emission tomography; LAD = left anterior descending coronary artery. Reproduced with permission from reference [22].

Combined inflammation and neovascularization PET imaging

Inflammation and neovascularization have been evaluated together with PET/CT via 18F-Galacto-RGD, which targets the integrin αvβ3 cell membrane receptors expressed on both activated endothelial cells and inflammatory macrophages in atheroma. In 10 patients with carotid stenosis planned for endarterectomy, 18F-Galacto-RGD uptake was significantly enhanced in regions of severe stenosis compared to less stenotic zones (Figure 3), and revealed a strong relationship with αvβ3 integrin expression on ex vivo analysis (R=0.73, p=0.04) [23•]. While correlations of 18F-Galacto-RGD with macrophages (CD68 immunostaining; R=0.37) and microvessel density (CD-31 immunostaining; R=0.48) were less robust, and a difference between symptomatic and asymptomatic carotid plaques could not be demonstrated in this small study, investigations in larger numbers of high-risk atheroma patients are warranted. New translatable PET agents with improved binding affinity to enhance αvβ3 integrin detection, such as 64Cu-NOTA-3-4A based on a labeled cysteine knot peptide [24], and in vivo albumin radiolabeling techniques to identify leaky neovasculature [25], are also being developed preclinically.

Figure 3. Clinical neovascularization and inflammation imaging of carotid stenosis in vivo with 18F-Galacto-RGD PET imaging.

Figure 3

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Multimodality images paired with ex vivo histology from two patients (1 patient per row of images) with severe carotid artery stenosis. (A, E) Magnetic resonance angiography demonstrates high-grade stenosis of the internal carotid artery (open arrows). Despite a similar degree of stenosis, 18F-Galacto-RGD PET (B) and fusion PET/CT (C) imaging shows enhanced 18F-Galacto-RGD uptake in the patient in the top row (open arrow) that was (F, G) absent in the other patient. As control, both patients revealed salivary gland and pharyngeal mucosa uptake (closed arrows in images B, C, F, and G). (D, H) Immunostaining for αvβ3 integrin expression demonstrated greater αvβ3 presence in the patient in the top row with high 18F-Galacto-RGD activity, providing histological validation for the in vivo imaging results (* = vessel lumen). PET = positron emission tomography; CT = computed tomography. Reproduced with permission from reference [23].

Single Photon Emission Computerized Tomography (SPECT)

SPECT imaging offers lower resolution than PET (10 mm vs. 5 mm), but similar high-sensitivity reporting. Typically, SPECT employs 99mTc, a radiolabel with short blood half-life and low absorbed radiation dose. IL-2 receptor imaging. In 10 symptomatic carotid stenosis patients, a 99mTc-labeled interleukin-2 reporter (99mTc-HYNIC-IL-2) that targets upregulated IL-2 receptor expression on plaque T-lymphocytes, was safe, readily detectable in vivo, and localized specifically on ex vivo analysis [26]. Folate receptor-β imaging. Human carotid endarterectomy specimens incubated with 99mTc-folate, directed at the folate receptor-β expressed on activated macrophages, suggested that 99mTc-folate detects the reparative (M2-like) subpopulation of plaque macrophages [27•], a property shared by targeted FDM-PET imaging [21]. Folate-targeted receptors have been previously reported for clinical optical fluorescence detection [28], and are also being developed for PET [29]. Validation of specific leukocyte molecular imaging markers beyond global macrophages may highlight a deeper understanding of in vivo plaque pathobiology.

Leukocyte trafficking. SPECT imaging has also been utilized to track leukocyte homing to inflamed plaques in vivo. After baseline MRI and FDG-PET/CT characterization of carotid plaque, 10 cardiovascular disease patients were administered 99mTc-labeled autologous peripheral blood mononuclear cells (PBMC) followed by serial in vivo SPECT/CT imaging over 6 hours [30•]. Compared to healthy controls, 99mTc-PBMC uptake was greater in diseased arteries (TBR 2.1 vs. 1.5; p=0.04). Importantly, 99mTc-PBMC showed a strong correlation (R=0.88; p<0.001) with FDG-PET metabolic activity, implying that already inflamed plaques preferentially recruit leukocytes (Figure 4). Through improved understanding of leukocyte migration from organ reservoirs, new therapies designed to mitigate inflammatory enhancement of atheroma, such as targeted delivery of plaque-stabilizing payloads coupled to labeled leukocytes, may be realized.

Figure 4. Tracking accumulation of peripheral blood mononuclear cells (PBMC) to atheroma in humans with SPECT/CT imaging.

Figure 4

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Patients with cardiovascular disease (A) or healthy controls (B) were injected with 99mTc-labeled PBMC and serial SPECT imaging 3 to 6 hours after injection performed to visualize localization of PBMC in the aorta (red). Patients with cardiovascular disease demonstrated significantly increased PBMC accumulation that correlated with FDG-PET disease severity, which was not observed in control subjects. SPECT = single-photon emission computed tomography; CT = computed tomography. Reproduced with permission from reference [30].

Vascular cell adhesion molecule (VCAM)-1. In a preclinical study, a 99mTc-labeled single domain antibody fragment (99mTc-cAbVCAM1-5) specific to VCAM-1, a surface receptor expressed on inflamed endothelium, revealed enhanced in vivo uptake in murine atheroma [31]. 99mTc-cAbVCAM1-5 plaque uptake associated with histological VCAM-1 expression, and decreased in response to atorvastatin treatment. Single domain antibody labeled agents such as 99mTc-cAbVCAM1-5 represent new molecular imaging compounds that retain antibody sensitivity and specificity in a smaller package, can be functionalized with reporters for multiple imaging platforms, and humanized for translation.

Magnetic Resonance Imaging (MRI)

Dynamic contrast-enhancement (DCE). DCE-MRI is a structural imaging modality that determines the extent and permeability of plaque neovasculature via the transfer coefficient Ktrans, which represents movement of gadolinium into the extracellular space. In an intriguing non-invasive study assessing both neovascularization and inflammation, 32 carotid stenosis patients underwent DCE-MRI and FDG-PET/CT to measure Ktrans and TBR, respectively [32••]. In histologically confirmed regions of high plaque inflammation and microvessels, multivariate regression modeling identified a significant link between plaque Ktrans and TBR (β=2.63; p<0.0001) that was independent of the severity of anatomic stenosis or the presence of clinical symptoms. However, a separate 41 subject imaging-only study showed strong association only in symptomatic carotid stenosis patients [33•], indicating that larger sample sizes may be needed to overcome patient and plaque diversity. This work provides confirmation that plaque inflammation and neovascularization are highly intertwined in vivo, and identifies a potential population of vulnerable plaques for future outcomes studies.

Ultrasound Imaging

Vascular ultrasound is a safe plaque assessment technique with high temporal resolution, albeit tempered by relatively low spatial resolution. Nontargeted microbubbles. Non-targeted ultrasound contrast agents composed of gas-filled protein, lipid, or biopolymer microbubbles (MB) confined to the blood pool can identify plaque neovessels. When excited, high-frequency MB size oscillations produce a unique acoustic signal for optimized detection. In 13 patients with carotid atheroma, quantitative non-targeted MB contrast enhancement correlated well with FDG plaque inflammation from a non-concurrent scan within 3 months (R=0.67, p<0.02), demonstrating co-localization of inflammation and neovascularization [34•].

Targeted microbubbles. To probe plaque pathology beyond structure, MB may be labeled with an antibody or small molecule that reports on a biologically-relevant process. In hypercholesterolemic primates imaged serially every 4 months for 2 years, P-selectin and VCAM-1 targeted MB identified carotid artery endothelial activation (5–7 fold enhanced MB attachment) that was in proportion to the duration of insulin resistance and prior to ultrasound-detectable plaque formation [35•]. Further preclinical evidence suggests that VCAM-1 targeted MB can serially monitor endothelial damage recovery, such as occurs after percutaneous intervention [36•]. Whether activated endothelial inflammation detected by targeted MB can be replicated in humans, is predictive of future cardiovascular events, or can be reversed prior atheroma formation, remains to be tested.

Optical Imaging

Optical coherence tomography (OCT). Light-based imaging strategies are gaining hold in clinical use due to their safety, speed and capacity for high-resolution plaque imaging. Intravascular OCT is the mainstay of current clinical optical imaging platforms, generating unsurpassed 10–20 µm resolution images of plaque structural constituents such as thrombus, thin fibrous caps, macrophages, and neovessels during rapid, automated catheter pullback at rates ≤40 mm/sec. In 40 patients with mild coronary disease, OCT-identified coronary plaque macrophage accumulations and vasa vasorum neovessels correlated positively with endothelial dysfunction, defined as acetylcholine-induced vasoconstriction [37•]. This study strengthens the relationship among endothelial dysfunction, inflammation, and neovascularization in atherosclerosis, Technological innovations in OCT continue, including demonstration of µOCT imaging (1 µm resolution) that can detect cholesterol crystals within the cytoplasm of plaque macrophages [38•], and the reporting of an integrated OCT and intravascular ultrasound imaging catheter [39•].

Near-infrared fluorescence (NIRF). NIRF is an evolving translational optical imaging approach utilizing targets labeled with near-infrared fluorophores [40]. NIRF is quantitative and sensitive, and can be performed through blood without flushing with excellent signal-to-noise due to the low tissue autofluorescence present at near-infrared wavelengths. In preclinical studies, NIRF imaging of atheroma inflammation with protease- or macrophage-targeted agents has demonstrated translational potential to detect high-risk plaque features. Building upon prior work [41,42], a high-speed intravascular NIRF-OCT catheter for combined molecular and structural plaque imaging was recently tested in rabbit atheroma to detect plaque inflammation using indocyanine green, a FDA-approved NIRF reporter [43•]. In an important step towards clinical translation, an integrated clinical NIRF-OCT imaging system recently approved under FDA investigational device exemption has successfully measured coronary artery plaque near-infrared autofluorescence in a first-in-human study [44•], propelling the near term prospects of a human intracoronary NIRF-OCT imaging trial. Improved automated image processing algorithms for intravascular NIRF analysis will serve to accelerate this process [45•].

CONCLUSIONS

Atherosclerosis continues to be a major cause of death and disability globally despite significant advances in detection and treatment. While structural imaging has substantially enabled this growth, new biological molecular imaging approaches will improve our understanding of atherosclerosis pathobiology and offer venues to pursue new targeted therapeutic strategies. Inflammation and neovascularization, two key high-risk atheroma features, are being investigated in vivo via an expansion of imaging strategies, and are being harnessed as imaging endpoints in trials testing novel anti-atherosclerotic treatments. Future studies will aim to demonstrate the benefit of combined molecular and structural plaque imaging in predicting adverse cardiovascular outcomes. Overall, atherosclerosis plaque imaging is growing rapidly with an exciting outlook to allow earlier detection of atherosclerosis, enable personalized therapy in patients with established disease, and improve current paradigms for cardiovascular disease treatment.

Key Points.

  • *

    High-risk atherosclerotic plaques are characterized by chronic inflammation and leaky neovessels.

  • *

    Molecular and structural imaging of neovascularization and inflammation are important diagnostic and therapeutic plaque imaging targets.

  • *

    FDG-PET/CT remains a leading strategy for plaque inflammation imaging in human clinical studies.

  • *

    Other imaging modalities including SPECT, MRI, optical, ultrasound, and MRI for high-risk plaque imaging are available.

  • *

    New imaging agents for molecular detection of plaque inflammation and neovascularization continue to be developed.

ACKNOWLEDGEMENTS

None.

FINANCIAL SUPPORT AND SPONSORSHIP

This work was supported by National Institutes of Health R01 HL108229 and R01 HL122388-01A1, American Heart Association Grant-in-Aid #13GRNT1760040 (FAJ); Harvard Catalyst Medical Research Investigator Training Award / National Institutes of Health KL2 TR001100 (EAO).

FAJ has received research grants from Abbott Vascular, Merck, and Kowa.

Footnotes

CONFLICTS OF INTEREST

EAO has no conflicts to declare.

REFERENCES

  • 1.Libby P. Inflammation in atherosclerosis. Arterioscler Thromb Vasc Biol. 2012;32:2045–2051. doi: 10.1161/ATVBAHA.108.179705. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Herrmann J, Lerman LO, Mukhopadhyay D, et al. Angiogenesis in atherogenesis. Arterioscler Thromb Vasc Biol. 2006;26:1948–1957. doi: 10.1161/01.ATV.0000233387.90257.9b. [DOI] [PubMed] [Google Scholar]
  • 3.Sadat U, Jaffer FA, van Zandvoort MA, et al. Inflammation and neovascularization intertwined in atherosclerosis: imaging of structural and molecular imaging targets. Circulation. 2014;130:786–794. doi: 10.1161/CIRCULATIONAHA.114.010369. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Osborn EA, Jaffer FA. Imaging atherosclerosis and risk of plaque rupture. Current Atherosclerosis Reports. 2013;15:359. doi: 10.1007/s11883-013-0359-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Osborn EA, Jaffer FA. The Advancing Clinical Impact of Molecular Imaging in CVD. JACC Cardiovasc Imaging. 2013;6:1327–1341. doi: 10.1016/j.jcmg.2013.09.014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6. Mateo J, Izquierdo-Garcia D, Badimon JJ, et al. Noninvasive assessment of hypoxia in rabbit advanced atherosclerosis using (1)(8)F-fluoromisonidazole positron emission tomographic imaging. Circ Cardiovasc Imaging. 2014;7:312–320. doi: 10.1161/CIRCIMAGING.113.001084. This study demonstrated that plaque hypoxia increases in inflamed, macrophage-rich lesions with neovascularization in a preclnical atheroma model using a hypoxia-sensitive PET marker.
  • 7. Folco EJ, Sukhova GK, Quillard T, Libby P. Moderate hypoxia potentiates interleukin-1beta production in activated human macrophages. Circ Res. 2014;115:875–883. doi: 10.1161/CIRCRESAHA.115.304437. This preclinical study reported a novel mechanism for how plaque hypoxia leads to inflammatory cytokine production.
  • 8.Lee SJ, Thien Quach CH, Jung KH, et al. Oxidized low-density lipoprotein stimulates macrophage 18F-FDG uptake via hypoxia-inducible factor-1alpha activation through Nox2-dependent reactive oxygen species generation. J Nucl Med. 2014;55:1699–1705. doi: 10.2967/jnumed.114.139428. [DOI] [PubMed] [Google Scholar]
  • 9. Bucerius J, Mani V, Moncrieff C, et al. Optimizing 18F-FDG PET/CT imaging of vessel wall inflammation: the impact of 18F-FDG circulation time, injected dose, uptake parameters, and fasting blood glucose levels. Eur J Nucl Med Mol Imaging. 2014;41:369–383. doi: 10.1007/s00259-013-2569-6. This study identified pre-scan glucose and FDG circulation times as key factors in optimial FDG-PET imaging, with FDG injected dose being less important.
  • 10.Blomberg BA, Thomassen A, Takx RA, et al. Delayed 18F-fluorodeoxyglucose PET/CT imaging improves quantitation of atherosclerotic plaque inflammation: results from the CAMONA study. J Nucl Cardiol. 2014;21:588–597. doi: 10.1007/s12350-014-9884-6. [DOI] [PubMed] [Google Scholar]
  • 11. Bucerius J, Mani V, Wong S, et al. Arterial and fat tissue inflammation are highly correlated: a prospective 18F-FDG PET/CT study. Eur J Nucl Med Mol Imaging. 2014;41:934–945. doi: 10.1007/s00259-013-2653-y. This study linked carotid arterial and fat (neck, pre-sternal, pericardium) FDG inflammation in cardiovascular disease patients.
  • 12. Emami H, Singh P, MacNabb M, et al. Splenic metabolic activity predicts risk of future cardiovascular events: demonstration of a cardiosplenic axis in humans. JACC Cardiovasc Imaging. 2015;8:121–130. doi: 10.1016/j.jcmg.2014.10.009. The concept of a cardiosplenic axis, where proinflammatory leukocytes liberated from the spleen migrate to areas of vascular injury to accelerate disease, was tested in acute coronary syndrome patients with FDG-PET. Importantly, not only was FDG activity enhanced in the spleen, but increased FDG activity independently predicted greater cardiovascular events over 4 years follow up, demonstrating association between FDG molecular imaging and patient outcomes.
  • 13. van Wijk DF, Sjouke B, Figueroa A, et al. Nonpharmacological lipoprotein apheresis reduces arterial inflammation in familial hypercholesterolemia. J Am Coll Cardiol. 2014;64:1418–1426. doi: 10.1016/j.jacc.2014.01.088. Arterial FDG uptake was diminished within days following lipoprotein aphresis in a high-risk patient population, implying that atherogenic lipoproteins are direct mediators of plaque inflammation.
  • 14.Emami H, Vucic E, Subramanian S, et al. The effect of BMS-582949, a P38 mitogen-activated protein kinase (P38 MAPK) inhibitor on arterial inflammation: A multicenter FDG-PET trial. Atherosclerosis. 2015;240:490–496. doi: 10.1016/j.atherosclerosis.2015.03.039. [DOI] [PubMed] [Google Scholar]
  • 15.Gaztanaga J, Farkouh M, Rudd JH, et al. A phase 2 randomized, double-blind, placebo-controlled study of the effect of VIA-2291, a 5-lipoxygenase inhibitor, on vascular inflammation in patients after an acute coronary syndrome. Atherosclerosis. 2015;240:53–60. doi: 10.1016/j.atherosclerosis.2015.02.027. [DOI] [PubMed] [Google Scholar]
  • 16. Lehrer-Graiwer J, Singh P, Abdelbaky A, et al. FDG-PET Imaging for Oxidized LDL in Stable Atherosclerotic Disease: A Phase II Study of Safety, Tolerability, and Anti-Inflammatory Activity. JACC Cardiovasc Imaging. 2015;8:493–494. doi: 10.1016/j.jcmg.2014.06.021. While this multicenter randomized trial of an oxidized LDL antibody did not demonstrate an anti-inflammatory effect by FDG-PET, it represents an example of early phase clinical testing using molecular imaging readouts.
  • 17. Tawakol A, Singh P, Rudd JH, et al. Effect of treatment for 12 weeks with rilapladib, a lipoprotein-associated phospholipase A2 inhibitor, on arterial inflammation as assessed with 18F-fluorodeoxyglucose-positron emission tomography imaging. J Am Coll Cardiol. 2014;63:86–88. doi: 10.1016/j.jacc.2013.07.050. This randomized controlled study utilized FDG-PET molecular imaging to evaluate the novel anti-inflammatory agent rilapladib, an oral lipoprotein-associated phospholipase A2 inhibitor.
  • 18. Demeure F, Hanin FX, Bol A, et al. A randomized trial on the optimization of 18F-FDG myocardial uptake suppression: implications for vulnerable coronary plaque imaging. J Nucl Med. 2014;55:1629–1635. doi: 10.2967/jnumed.114.138594. The authors demonstrated that, in addition to a pre-scan high-fat low-carbohydrate diet, high circulating free fatty acid levels may predict patients with adequate myocardial suppression for successful coronary FDG-PET imaging.
  • 19. Zaman RT, Kosuge H, Carpenter C, et al. Scintillating balloon-enabled fiber-optic system for radionuclide imaging of atherosclerotic plaques. J Nucl Med. 2015;56:771–777. doi: 10.2967/jnumed.114.153239. New technology in devleopment for PET imaging using an intravascular scintillating balloon imaging system could enable high-resolution plaque FDG molecular imaging.
  • 20.Zaman RT, Kosuge H, Pratx G, et al. Fiber-optic system for dual-modality imaging of glucose probes 18F-FDG and 6-NBDG in atherosclerotic plaques. PLoS One. 2014;9:e108108. doi: 10.1371/journal.pone.0108108. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21. Tahara N, Mukherjee J, de Haas HJ, et al. 2-deoxy-2-[18F]fluoro-D-mannose positron emission tomography imaging in atherosclerosis. Nat Med. 2014;20:215–219. doi: 10.1038/nm.3437. As an alternative to FDG-PET, this study investigated use of targeted imaging of the glucose isomer mannose with 18F-fluoro-D-mannnose (FDM) PET in atherosclerotic rabbits. The authors demonstrate the feasibilty of mannose imaging with FDM-PET that may selectively identify reparative macrophage subsets (M2 phenotype) associated with high-risk plaques.
  • 22. Joshi NV, Vesey AT, Williams MC, et al. 18F-fluoride positron emission tomography for identification of ruptured and high-risk coronary atherosclerotic plaques: a prospective clinical trial. Lancet. 2014;383:705–713. doi: 10.1016/S0140-6736(13)61754-7. In a comparative study of 18F-sodium fluoride (NaF) and FDG non-invasive PET coronary plaque imaging, NaF uptake localized to culprit lesions in acute coronary syndrome patients while FDG activity was absent. As NaF is not limited by background myocardial uptake that confounds FDG coronary atheroma assessment, NaF-PET holds significant promise for high-risk plaque detection based on plaque osteogenic activity.
  • 23. Beer AJ, Pelisek J, Heider P, et al. PET/CT imaging of integrin alphavbeta3 expression in human carotid atherosclerosis. JACC Cardiovasc Imaging. 2014;7:178–187. doi: 10.1016/j.jcmg.2013.12.003. This study demonstrated specific uptake of 18F-Galacto-RGD in human carotid atheroma, a molecular imaging marker of endothelial inflammation and neovascularization with potential to delineate high-risk atheroma.
  • 24.Jiang L, Tu Y, Kimura R, et al. 64Cu-Labeled Divalent Cystine Knot Peptide for Imaging Carotid Atherosclerotic Plaques. J Nucl Med. 2015 doi: 10.2967/jnumed.115.155176. [DOI] [PubMed] [Google Scholar]
  • 25.Niu G, Lang L, Kiesewetter DO, et al. In Vivo Labeling of Serum Albumin for PET. J Nucl Med. 2014;55:1150–1156. doi: 10.2967/jnumed.114.139642. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Glaudemans AW, Bonanno E, Galli F, et al. In vivo and in vitro evidence that 99mTc-HYNIC-interleukin-2 is able to detect T lymphocytes in vulnerable atherosclerotic plaques of the carotid artery. Eur J Nucl Med Mol Imaging. 2014;41:1710–1719. doi: 10.1007/s00259-014-2764-0. [DOI] [PubMed] [Google Scholar]
  • 27. Jager NA, Westra J, Golestani R, et al. Folate receptor-beta imaging using 99mTc-folate to explore distribution of polarized macrophage populations in human atherosclerotic plaque. J Nucl Med. 2014;55:1945–1951. doi: 10.2967/jnumed.114.143180. This ex vivo study of carotid endarterectomy specimens incubated with 99mTc-folate demonstrates that SPECT imaging of folate receptor-β can identify M2-like macrophage subpopulations resident in vulnerable plaques.
  • 28.van Dam GM, Themelis G, Crane LMA, et al. Intraoperative tumor-specific fluorescence imaging in ovarian cancer by folate receptor-α targeting: first in-human results. Nat Med. 2011;17:1315–1319. doi: 10.1038/nm.2472. [DOI] [PubMed] [Google Scholar]
  • 29.Muller A, Beck K, Rancic Z, et al. Imaging atherosclerotic plaque inflammation via folate receptor targeting using a novel 18F-folate radiotracer. Mol Imaging. 2014;13:1–11. [PubMed] [Google Scholar]
  • 30. van der Valk FM, Kroon J, Potters WV, et al. In vivo imaging of enhanced leukocyte accumulation in atherosclerotic lesions in humans. J Am Coll Cardiol. 2014;64:1019–1029. doi: 10.1016/j.jacc.2014.06.1171. In this non-invasive clincal molecular imaging study, inflamed atheroma identified by FDG-PET imaging accumulated greater exogenously administered 99mTc-labeled peripheral blood mononuclear cells on SPECT imaging. New treatments aimed at attenuating leukocyte recruitment to inflamed plaques may be beneficial for plaque stabilization.
  • 31.Broisat A, Toczek J, Dumas LS, et al. 99mTc-cAbVCAM1-5 imaging is a sensitive and reproducible tool for the detection of inflamed atherosclerotic lesions in mice. J Nucl Med. 2014;55:1678–1684. doi: 10.2967/jnumed.114.143792. [DOI] [PubMed] [Google Scholar]
  • Taqueti VR, Di Carli MF, Jerosch-Herold M, et al. Increased microvascularization and vessel permeability associate with active inflammation in human atheromata. Circ Cardiovasc Imaging. 2014;7:920–929. doi: 10.1161/CIRCIMAGING.114.002113. Inflamed carotid plaques with higher FDG-PET activity were associated with greater MR evidence of microvessel formation, and furthermore the association was independent of the degree of arterial stenosis and clinical symptom profile.
  • 33. Wang J, Liu H, Sun J, et al. Varying correlation between 18F-fluorodeoxyglucose positron emission tomography and dynamic contrast-enhanced MRI in carotid atherosclerosis: implications for plaque inflammation. Stroke. 2014;45:1842–1845. doi: 10.1161/STROKEAHA.114.005147. This study showed a correlation between FDG-PET signals and dynamic contrast enhanced MR plaque imaging only in patients with symptomatic carotid stenosis.
  • 34. Hjelmgren O, Johansson L, Prahl U, et al. A study of plaque vascularization and inflammation using quantitative contrast-enhanced US and PET/CT. Eur J Radiol. 2014;83:1184–1189. doi: 10.1016/j.ejrad.2014.03.021. This study demonstrated moderate association between plaque neovessel formation identified by contrast-enhanced vascular ultrasound and plaque inflammation assessed by FDG-PET, further linking these two high-risk plaque features in human atheroma.
  • 35. Chadderdon SM, Belcik JT, Bader L, et al. Proinflammatory endothelial activation detected by molecular imaging in obese nonhuman primates coincides with onset of insulin resistance and progressively increases with duration of insulin resistance. Circulation. 2014;129:471–478. doi: 10.1161/CIRCULATIONAHA.113.003645. In atherosclerotic primates, serial ultrasound imaging over 2 years with targeted microbubble assessment of endothelial inflammatory markers revealed increased endothelial inflammation, in proportion to the degree of insulin resistance that occurred prior to detectable carotid plaque formation. Targeted microbubble ultrasound may enable early detection of atherogenesis for potential new therapeutics.
  • 36. Curaj A, Wu Z, Fokong S, et al. Noninvasive Molecular Ultrasound Monitoring of Vessel Healing After Intravascular Surgical Procedures in a Preclinical Setup. Arterioscler Thromb Vasc Biol. 2015;35:1366–1373. doi: 10.1161/ATVBAHA.114.304857. Ultrasound targeted microbubbles to detect VCAM-1 were successfully utilized to track endothelial repair following mechanical injury. Intravascularly-constrained targeted microbubbles could allow safe, non-invasive assessment of vascular healing in ultrasound accessible regions.
  • 37. Choi BJ, Matsuo Y, Aoki T, et al. Coronary endothelial dysfunction is associated with inflammation and vasa vasorum proliferation in patients with early atherosclerosis. Arterioscler Thromb Vasc Biol. 2014;34:2473–2477. doi: 10.1161/ATVBAHA.114.304445. This study demonstrated a positive linkage between human coronary endothlial dysfunction measured by vasoactive acetylcholine response and the presence of high-risk plaque features - macrophage accumulations and neovessels - on intravascular OCT imaging.
  • 38. Kashiwagi M, Liu L, Chu KK, et al. Feasibility of the assessment of cholesterol crystals in human macrophages using micro optical coherence tomography. PLoS One. 2014;9:e102669. doi: 10.1371/journal.pone.0102669. In a significant technological advancement, micro-OCT imaging with 1 µm spatial resolution was demonstrated to resolve the presence of cholesterol crystals within human macrophages. Further development may advance current intravascular clinical OCT detection systems to identify plaque cellular constituents.
  • 39. Li J, Li X, Mohar D, et al. Integrated IVUS-OCT for real-time imaging of coronary atherosclerosis. JACC Cardiovasc Imaging. 2014;7:101–103. doi: 10.1016/j.jcmg.2013.07.012. The authors report engineering a prototype hybrid IVUS-OCT imaging catheter. This system takes advantage of both imaging modality strengths such as the high near-field resolution of OCT for stent evaluation, and the penetration depth of IVUS for plaque burden assessment.
  • 40.Mulder WJ, Jaffer FA, Fayad ZA, Nahrendorf M. Imaging and nanomedicine in inflammatory atherosclerosis. Sci Transl Med. 2014;6:239sr231. doi: 10.1126/scitranslmed.3005101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Vinegoni C, Botnaru I, Aikawa E, et al. Indocyanine green enables near-infrared fluorescence imaging of lipid-rich, inflamed atherosclerotic plaques. Sci Transl Med. 2011;3:84ra45. doi: 10.1126/scitranslmed.3001577. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Yoo H, Kim JW, Shishkov M, et al. Intra-arterial catheter for simultaneous microstructural and molecular imaging in vivo. Nat Med. 2011;17:1680–1684. doi: 10.1038/nm.2555. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43. Lee S, Lee MW, Cho HS, et al. Fully integrated high-speed intravascular optical coherence tomography/near-infrared fluorescence structural/molecular imaging in vivo using a clinically available near-infrared fluorescence-emitting indocyanine green to detect inflamed lipid-rich atheromata in coronary-sized vessels. Circ Cardiovasc Interv. 2014;7:560–569. doi: 10.1161/CIRCINTERVENTIONS.114.001498. A NIRF-OCT imaging catheter with high-speed pullback capabilities could detect the FDA-approved NIRF imaging agent indocyanine green in experimental atheroscelerosis. ICG was shown previously to target plaque macrophages and lipid deposits [41]. Combined structural and molecular imaging strategies for coronary plaque imaging hold great translational promise for understand high-risk plaque biology in vivo.
  • 44. Ughi GJ, Osborn E, Hara T, et al. Transcatheter Cardiovascular Therapeutics. Washington, D.C.: 2014. Next-Generation Intravascular Imaging: Dual-Modality OCT and Near-Infrared Auto-Fluorescence (NIRAF) for the Simultaneous Acquisition of Microstructural and Molecular/Chemical Information Within the Coronary Vasculature: Early Human Clinical Experience. The authors reported a first-in-human experience measuring plaque near-infrared autofluorescence (NIRAF) in human coronary arteries with an integrated NIRAF-OCT molecular-structural imaging system.
  • 45. Ughi GJ, Verjans J, Fard AM, et al. Dual modality intravascular optical coherence tomography (OCT) and near-infrared fluorescence (NIRF) imaging: a fully automated algorithm for the distance-calibration of NIRF signal intensity for quantitative molecular imaging. Int J Cardiovasc Imaging. 2015;31:259–268. doi: 10.1007/s10554-014-0556-z. This study developed an automated image processing technique to distance-calibrate intravascular NIRF measurements based on OCT image segmentation for quantitative NIRF reporting. For clinical translation of NIRF-OCT imaging technology, robust automated image segmentation methodology is critical to enable efficient data processing.

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