Novel Noninvasive Nuclear Medicine Imaging Techniques for Cardiac Inflammation

Purpose of Review

Inflammation is a key player in a wide range of cardiovascular and myocardial diseases. Given the numerous implications of inflammatory processes in disease initiation and progression, functional imaging modalities including positron emission tomography (PET) represent valuable diagnostic, prognostic, and monitoring tools in patient management. Since increased glucose metabolism is a hallmark of inflammation, PET using the radiolabeled glucose analog [¹⁸F]-2-deoxy-2-fluoro-d-glucose (FDG) is the mainstay diagnostic test for nuclear imaging of (cardiac) inflammation. Recently, new approaches using more specific tracers to overcome the limited specificity of FDG have emerged.

Recent Findings

PET imaging has proven its value in a number of inflammatory conditions of the heart including myocarditis, endocarditis, sarcoidosis, or reactive changes after myocardial infarction. In infection-related endocarditis, FDG-PET and white blood cell scintigraphy have been implemented in current guidelines. FDG-PET is considered as nuclear medical gold standard in myocarditis, pericarditis, or sarcoidosis. Novel strategies, including targeting of somatostatin receptors or C-X-C motif chemokine receptor CXCR4, have shown promising results in first studies.

Summary

Nuclear medicine techniques offer valuable information in the assessment of myocardial inflammation. Given the possibility to directly visualize inflammatory activity, they represent useful tools for diagnosis, risk stratification, and therapy monitoring.

     

Molecular Imaging of Cardiac Sarcoidosis

Purpose of Review

Cardiac involvement is increasingly being recognized as a cause of significant morbidity and mortality in patients with sarcoidosis. Unfortunately, imaging cardiac sarcoidosis (CS) remains a challenge and often relies on advanced imaging modalities. The aim of this review is to provide an up-to-date overview of the role of molecular imaging for the diagnosis of cardiac sarcoidosis, with particular emphasis on the use of FDG and non-FDG PET.

Recent Findings

In the last few years, FDG-PET has established itself as an accurate imaging study for the assessment of CS. New diagnostic criteria have recently appeared which incorporate FDG-PET findings in the diagnostic workup for CS. In addition, a joint SNMMI-ASNC Expert Consensus document has appeared on the role of FDG-PET in CS. Recent advances in the field have focused on the role of PET for diagnosis, assessment of therapy, and use of non-FDG tracers to image myocardial inflammation.

Summary

The role of PET is rapidly evolving but is now firmly established as an important component in the imaging assessment of CS.

     

Nuclear Cardiology for the Prediction of Response to Cardiac Resynchronization Therapy

Purpose of Review

About one-third patients selected for cardiac resynchronization therapy (CRT) based on conventional criteria do not show favourable response. Assessment of cardiac mechanical dyssynchrony by nuclear medicine techniques has generated considerable interest in recent years as an additional tool to improve the outcome of patients submitted to CRT.

Recent Findings

Several studies in recent years have shown the utility of equilibrium radionuclide angiography (ERNA) and gated myocardial perfusion SPECT (GMPS) in predicting response to CRT. Both ERNA and GMPS can assess cardiac mechanical dyssynchrony quantitatively; GMPS in addition can also provide information on the presence of scar and site of the latest mechanical activation, thereby determining the optimal site of lead placement. Limited studies have also shown the utility of gated blood-pool SPECT, gated myocardial PET and cardiac autonomic imaging in predicting response to CRT.

Summary

Nuclear medicine techniques are useful for prediction of response to CRT.

     

Improving Quality and Communication in Cardiac Imaging: The Coronary Artery Disease Reporting and Data System (CAD-RADS™)

Purpose of Review

To critically examine the Coronary Artery Disease Reporting and Data System (CAD-RADS?) lexicon and its nuances, with representative case examples provided for each of the major CAD-RADS classification categories and modifiers.

Recent Findings

CAD-RADS is a recently developed multi-disciplinary, multi-society standardized reporting system for coronary CTA based on scientific data and expert consensus from leaders in cardiac imaging.

Summary

CAD-RADS was developed to improve quality and communication in cardiac imaging, and to provide management recommendations based on actionable information from the coronary CTA imaging report. Widespread adoption of CAD-RADS in clinical practice will help maximize the clinical impact of coronary CTA for the care of patients with acute and stable chest pain.

     

Hepatic imaging following intra-arterial embolotherapy

Purpose

To discuss guidelines and salient imaging findings of solid tumors treated with common intra-arterial procedures used in interventional oncology.

Methods

A meticulous literature search of PubMed-indexed articles was conducted. Key words included “imaging + embolization,” “imaging + TACE,” “imaging + radioembolization,” “imaging + Y90,” “mRECIST,” and “EASL.” Representative post-treatment cross-sectional images were obtained from past cases in this institution.

Results

Intra-arterial therapy (IAT) in interventional oncology includes bland embolization, chemoembolization, and radioembolization. Solid tumors of the liver are the primary focus of these procedures. Cross-sectional CT and/or MR are the main modalities used to image tumors after treatment. Traditional size-based response criteria (WHO and RECIST) alone are of limited utility in determining response to IAT; tumoral necrosis and enhancement must be considered. Specifically for HCC, the EASL and mRECIST guidelines are becoming widely adopted response criteria to assess these factors. DWI, FDG-PET, and CEUS are modalities that play an adjunctive but controversial role.

Conclusions

Radiologists must be aware that the different forms of intra-arterial therapy yield characteristic findings on cross-sectional imaging. Knowledge of these findings is integral to accurate assessment of tumor response and progression.

     

Molecular Imaging of Cardiac Amyloidosis

Purpose of Review

Cardiac amyloidosis is an infiltrative cardiomyopathy, most commonly due to light chain amyloidosis [AL] or transthyretin amyloidosis [ATTR]; both cause significant heart failure and mortality. This review is a comprehensive overview of radionuclide molecular imaging in cardiac amyloidosis, highlighting the latest advancements in aiding diagnosis and prognosis.

Recent Findings

Specific bone scintigraphy agents have a high sensitivity and specificity for the diagnosis of transthyretin cardiac amyloidosis. Amyloid-binding radiotracers, originally developed for imaging Alzheimer’s disease, are being employed to image light chain and transthyretin cardiac amyloidosis. There is ongoing research into the use of these tracers for precise quantification of cardiac amyloidosis, which can be used to guide therapy.

Summary

Radionuclide molecular imaging techniques have a vital role in advancing the field of cardiac amyloidosis. With a broadening armamentarium of novel radio tracers and new therapeutic developments, this is an exciting area, with potential breakthroughs on the horizon.

     

Characterization of “γ-Eye”: a Low-Cost Benchtop Mouse-Sized Gamma Camera for Dynamic and Static Imaging Studies

Purpose

Several preclinical imaging systems are commercially available, but their purchase and maintenance costs make them unaffordable for the majority of small- and medium-sized groups. Taking into account the needs of average users, we developed “γ-eye”, a mouse-sized, benchtop γ-camera suitable for in vivo scintigraphic imaging.

Procedures

The γ-eye is based on two position-sensitive photomultiplier tubes, coupled to a CsI(Na) pixelated scintillator and a low-energy lead collimator with parallel hexagonal holes.

Results

The spatial resolution of the system is 2 mm at 0 mm. The energy resolution is 26 % at 140 keV and the maximum recorded sensitivity 210 cps/MBq. The system was evaluated in a proof-of-concept animal study, using three different clinical Tc-99m-labeled radiopharmaceuticals. Phantom and animal studies demonstrate its ability to provide semiquantitative results even for short scans.

Conclusions

Systems’ performance, dimensions, and cost make γ-eye a unique solution for efficient whole-body mouse nuclear imaging.

     

700-nm Zwitterionic Near-Infrared Fluorophores for Dual-Channel Image-Guided Surgery

Purpose

The purpose of this study was to develop a family of 700-nm zwitterionic pentamethine indocyanine near-infrared fluorophores that would permit dual-channel image-guided surgery.

Procedures

Three complementary synthetic schemes were used to produce novel zwitterionic chemical structures. Physicochemical, optical, biodistribution, and clearance properties were compared to Cy5.5, a conventional pentamethine indocyanine now used for biomedical imaging.

Results

ZW700-1a, ZW700-1b, and ZW700-1c were synthesized, purified, and analyzed extensively in vitro and in vivo. All molecules had extinction coefficients ≥199,000 M^?1 cm^?1, emission ≥660 nm, and stability ≥99 % after 24 h in warm serum. In mice, rats, and pigs, ≥80 % of the injected dose was completely eliminated from the body via renal clearance within 4 h. Either alone or conjugated to a tumor targeting ligand, ZW700-1a permitted dual-channel, high SBR, and simultaneous imaging with 800-nm NIR fluorophores using the FLARE® imaging system.

Conclusions

Novel 700-nm zwitterionic NIR fluorophores enable dual-NIR image-guided surgery.

     

Molecular Imaging of Angiogenesis in Cardiac Regeneration

Purpose of Review

Myocardial infarction (MI) leading to heart failure displays an important cause of death worldwide. Adequate restoration of blood flow to prevent this transition is a crucial factor to improve long-term morbidity and mortality. Novel regenerative therapies have been thoroughly investigated within the past decades.

Recent Findings

Increased angiogenesis in infarcted myocardium has shown beneficial effects on the prognosis of MI; therefore, the proangiogenic capacity of currently tested treatments is of specific interest. Molecular imaging to visualize formation of new blood vessels in vivo displays a promising option to monitor proangiogenic effects of regenerative substances.

Summary

Based on encouraging results in preclinical models, molecular angiogenesis imaging has recently been applied in a small set of patients. This article reviews recent literature on noninvasive in vivo molecular imaging of angiogenesis after MI as an integral part of cardiac regeneration.

     

Cardiac CT: Technological Advances in Hardware,Software, and Machine Learning Applications

Purpose of Review

Multidetector row computed tomography (CT) allows noninvasive imaging of the heart and coronary arteries. The purpose of this review is to briefly summarize recent advances in CT hardware and software technology, and machine learning applications for cardiovascular imaging.

Recent Findings

In the last decades, there have been significant improvements in CT hardware focusing on faster gantry rotation resulting in improved temporal resolution. Concurrent hardware improvements include improved spatial resolution and higher coverage of the patient, enabling faster acquisition. Advances in cardiac CT software include methods for measurement of noninvasive FFR, coronary plaque characterization, and adipose tissue characteristics around the heart. Machine learning approaches using cardiac CT have been shown to improve both risk of prognosis and lesion-specific ischemia.

Summary

Recent advances in CT hardware and software have expanded the clinical utility of CT for cardiovascular imaging. In the next decades, continued advances can be anticipated in these areas, and in machine learning applications in cardiac CT, as they are incorporated into clinical routine for image acquisition, image analysis, and prediction of patient outcomes.

     

Molecular Imaging of Atherosclerosis: a Clinical Focus

Purpose of Review

Molecular imaging of cardiovascular disease is a powerful clinical and experimental approach that can inform our understanding of atherosclerosis biology. Complementing cross-sectional imaging techniques that provide detailed anatomical information, molecular imaging can further detect important biological changes occurring within atheroma and refine the prediction of vascular complications.

Recent Findings

Molecular imaging of atherosclerosis can illuminate underlying pathophysiology and serve as a surrogate endpoint in clinical trials of new drugs.

Summary

This review showcases promising molecular approaches for imaging atherosclerosis, with a focus on positron emission tomography (PET), magnetic resonance imaging (MRI), and intravascular near-infrared fluorescence (NIRF) imaging methods that are in the clinic or close-to-clinical usage.

     

Quantitative [<Superscript>18</Superscript>F]FMISO PET Imaging Shows Reduction of Hypoxia Following Trastuzumab in a Murine Model of HER2+ Breast Cancer

Purpose

Evaluation of [¹⁸F]fluoromisonidazole ([¹⁸F]FMISO)-positron emission tomography (PET) imaging as a metric for evaluating early response to trastuzumab therapy with histological validation in a murine model of HER2+ breast cancer.

Procedures

Mice with BT474, HER2+ tumors, were imaged with [¹⁸F]FMISO-PET during trastuzumab therapy. Pimonidazole staining was used to confirm hypoxia from imaging.

Results

[¹⁸F]FMISO-PET indicated significant decreases in hypoxia beginning on day 3 (P?<?0.01) prior to changes in tumor size. These results were confirmed with pimonidazole staining on day 7 (P?<?0.01); additionally, there was a significant positive linear correlation between histology and PET imaging (r ² ?=?0.85).

Conclusions

[¹⁸F]FMISO-PET is a clinically relevant modality which provides the opportunity to (1) predict response to HER2+ therapy before changes in tumor size and (2) identify decreases in hypoxia which has the potential to guide subsequent therapy.

     

Role of CT Imaging for Coronary and Non-coronary Interventions

Purpose of Review

Pre-procedural imaging is essential for successful planning and performance of several cardiac interventions. Cardiac computed tomography (CT) is a non-invasive imaging modality capable of providing precise information required for different coronary and non-coronary interventions. The role of cardiac CT for the guidance of different cardiac interventions will be described in this review.

Recent Findings

Contrast-enhanced computed tomography imaging is increasingly being used for guiding transcatheter cardiac interventions. Anatomical and functional information provided by CT helps in successful planning and performance of several cardiac interventions.

Summary

Over the last decade, the continuous growth of interventional cardiology has been associated with widespread acknowledgment that CT is particularly useful for pre-interventional imaging with increasing implementation in clinical routine.

     

Comparative Study of Tumor Targeting and Biodistribution of pH (Low) Insertion Peptides (pHLIP<Superscript>®</Superscript> Peptides) Conjugated with Different Fluorescent Dyes

Purpose

Acidification of extracellular space promotes tumor development, progression, and invasiveness. pH (low) insertion peptides (pHLIP^® peptides) belong to the class of pH-sensitive membrane peptides, which target acidic tumors and deliver imaging and/or therapeutic agents to cancer cells within tumors.

Procedures

Ex vivo fluorescent imaging of tissue and organs collected at various time points after administration of different pHLIP^® variants conjugated with fluorescent dyes of various polarity was performed. Methods of multivariate statistical analyses were employed to establish classification between fluorescently labeled pHLIP^® variants in multidimensional space of spectral parameters.

Results

The fluorescently labeled pHLIP^® variants were classified based on their biodistribution profile and ability of targeting of primary tumors. Also, submillimeter-sized metastatic lesions in lungs were identified by ex vivo imaging after intravenous administration of fluorescent pHLIP^® peptide.

Conclusions

Different cargo molecules conjugated with pHLIP^® peptides can alter biodistribution and tumor targeting. The obtained knowledge is essential for the design of novel pHLIP^®-based diagnostic and therapeutic agents targeting primary tumors and metastatic lesions.

     

Imaging Options in Cardiac Amyloidosis: Differentiating AL from ATTR

Purpose of Review

Cardiac amyloidosis (CA) results from the myocardial deposition of abnormally folded endogenous proteins leading to significant morbidity and mortality. Accurate and timely non-invasive diagnosis of cardiac amyloidosis and the correct identification of amyloid type are critical for choosing appropriate therapy. Disease type is defined by the precursor protein and most typically involves light chain (AL) or transthyretin (ATTR). Traditionally, cardiac amyloidosis has been suspected on the basis of characteristic echocardiographic features and confirmed with endomyocardial biopsy. Recent advances in echocardiography, cardiovascular magnetic resonance (CMR), and nuclear imaging now permit the non-invasive diagnosis of CA with a high degree of confidence and, in some cases, assignment of amyloid types.

Recent Findings

CMR techniques including late gadolinium enhancement and new protocols such as T1 mapping and extra-cellular volume (ECV) quantification have afforded insight into the diagnosis and pathophysiology of cardiac amyloidosis, while bone-avid nuclear tracers can identify ATTR with a high degree of accuracy.

Summary

We highlight the recent advances in imaging techniques that can identify cardiac amyloidosis with a special emphasis on nuclear modalities used for differentiating light chain from transthyretin disease.

     

Non-invasive Macrophage Tracking Using Novel Porphysome Nanoparticles in the Post-myocardial Infarction Murine Heart

Purpose

We generated a folate-conjugated porphyrin nanoparticle (porphysome) suitable for multimodal non-invasive active macrophage tracking post-myocardial infarction (MI).

Procedures

Macrophage uptake of folate-conjugated porphysomes was selective. Folate-porphysome cardiac macrophage tracking was detected in vivo using radioligand and fluorescent imaging. To track post-MI macrophage mobilization, cardiac fluorescence signal in folate-porphysome-injected mice was measured for 9 day post-MI. Active macrophage phenotype was assessed using immunohistochemistry.

Results

Heart active macrophage presence peaked on day 1, returned to baseline by day 3, and peaked again on day 7 post-MI. Macrophages were distributed throughout the left ventricle at day 1, but aggregated within scar tissue at day 7. Macrophage phenotype was pro-inflammatory (TNFα⁺) at day 1, whereas scar-resident macrophages expressed anti-inflammatory markers (IL-10, TGFβ) at day 7. However, day 7 macrophages outside the scar expressed neither pro- nor anti-inflammatory markers.

Conclusions

We established that folate-porphysomes are suitable for non-invasive imaging of macrophages and used it to investigate active macrophage behavior in the infarcted heart.

     

Cardiac CT for Guiding Mitral Valve Interventions

Purpose of Review

The purpose of this paper is to review the current role of contrast-enhanced cardiac computed tomography (CT) in the peri-procedural planning of mitral valve (MV) repair.

Recent Findings

Cardiac CT is increasingly implemented in the peri-interventional management of patients undergoing MV repair or MV replacement due to its widespread availability and its ability to provide detailed information on the complex cardiac and valvular anatomy.

Summary

The complex anatomy of the MV challenges the management of minimally invasive MV repair with respect to device sizing and procedural planning. Advances in CT have enabled cardiac CT to provide critical information for the pre-procedural planning and post-procedural follow-up of MV repair. Therefore, it represents a key element in the improvement of the post-procedural outcome, the efficiency of implanted devices, and the prevention as well as advanced diagnostics of post-procedural complications. However, particular expertise is required to select adequate imaging protocols, perform comprehensive post-processing features, and to achieve specific quantitative image evaluation.

     

Repeatability of Radiomic Features in Non-Small-Cell Lung Cancer [<Superscript>18</Superscript>F]FDG-PET/CT Studies: Impact of Reconstruction and Delineation

Purpose

To assess (1) the repeatability and (2) the impact of reconstruction methods and delineation on the repeatability of 105 radiomic features in non-small-cell lung cancer (NSCLC) 2-deoxy-2-[¹⁸F]fluoro-D-glucose ([¹⁸F]FDG) positron emission tomorgraphy/computed tomography (PET/CT) studies.

Procedures

Eleven NSCLC patients received two baseline whole-body PET/CT scans. Each scan was reconstructed twice, once using the point spread function (PSF) and once complying with the European Association for Nuclear Medicine (EANM) guidelines for tumor PET imaging. Volumes of interest (n?=?19) were delineated twice, once on PET and once on CT images.

Results

Sixty-three features showed an intraclass correlation coefficient?≥?0.90 independent of delineation or reconstruction. More features were sensitive to a change in delineation than to a change in reconstruction (25 and 3 features, respectively).

Conclusions

The majority of features in NSCLC [¹⁸F]FDG-PET/CT studies show a high level of repeatability that is similar or better compared to simple standardized uptake value measures.