Advances in Molecular Imaging: Cardiac Regeneration

In addition to the standard cardiovascular pharmacological treatment and catheter-based and surgical procedures, cardiac restorative therapy was recently introduced. Despite the encouraging results obtained in pre-clinical research, cardiac regenerative therapy is still not used in clinical practice, because of the modest effect on cardiac function. To improve cardiac regenerative strategies, the identification of non-invasive powerful tools is required. Due to availability of various radiotracers and acquisition protocols nuclear imaging is the most promising and can be used both in gene and in cell therapy. This review summarizes current status and future role of nuclear imaging in the area of myocardial regeneration.     

Magnetic Resonance Molecular Imaging of Plaque Angiogenesis

Neovascular expansion of the vasa vasorum is an early pathological biomarker of atherosclerosis, preceding endothelial dysfunction. Plaque angiogenesis accompanies intraplaque hemorrhage and plaque rupture, precursors of myocardial infarction and stroke. Molecular imaging of angiogenesis aims to map the expression of neovascular biomarkers on a cellular scale, often utilizing paramagnetic or superparamagnetic MRI contrast agents in order to generate sufficient image enhancement. Both clinically approved extracellular contrast agents and experimental targeted nanoparticles have demonstrated MRI signal enhancement that is proportional to the neovascular density in the vessel wall. Furthermore, targeted contrast agents formulated with anti-angiogenic drugs can be used to quantify drug deposition within the plaque and predict subsequent therapeutic effects. Molecular imaging of plaque angiogenesis has shown promise for interrogating the pathophysiology of atherosclerotic lesions rather than just their physical characteristics, with the ultimate goal of identifying the high-risk plaques that are most likely to cause cardiovascular events.     

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.

     

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.

     

Molecular Imaging of Macrophage Enzyme Activity in Cardiac Inflammation

Molecular imaging is highly advantageous as various insidious inflammatory events can be imaged in a serial and quantitative fashion. Combined with the conventional imaging modalities like computed tomography (CT), magnetic resonance (MR), and nuclear imaging, it helps us resolve the extent of ongoing pathology, quantify inflammation, and predict outcome. Macrophages are increasingly gaining importance as an imaging biomarker in inflammatory cardiovascular diseases. Macrophages, recruited to the site of injury, internalize necrotic or foreign material. Along with phagocytosis, activated macrophages release proteolytic enzymes like matrix metalloproteinases (MMPs) and cathepsins into the extracellular environment. Proinflammatory monocytes and macrophages also induce tissue oxidative damage through the inflammatory enzyme myeloperoxidase (MPO). In this review we will highlight recent advances in molecular macrophage imaging. Particular stress will be given to macrophage functional and enzymatic activity imaging, which targets phagocytosis, proteolysis, and myeloperoxidase activity imaging.     

Molecular Imaging of Stem Cells and Exosomes for Myocardial Regeneration

Purpose of Review

Stem cell therapy is studied for the treatment of ischemic heart disease. Despite high expectations, investigation has yielded mixed results. For further advancement of this field, it is essential to understand the fate of the transplanted stem cells in living subjects. A myriad of tools has been developed to allow for the immediate and longitudinal monitoring of stem cells in vivo. In this review, we outline the most reliable techniques and their implications for cardiac regenerative medicine.

Recent Findings

Direct (e.g., PET/SPECT, MRI) and indirect labeling (e.g., reporter gene) techniques have existed for decades prior to their use in stem cell imaging. In this review, we describe some of the key developments in the context of stem cell therapy for cardiac ischemia, including new contrast agents (MRI, SPECT) and novel reporter genes (e.g., near-infrared fluorescent protein). Furthermore, we discuss innovative techniques that integrate direct and indirect labeling, such as PET reporter gene systems. Finally, we examine the potential of exosomes, a component of the stem cell secretome, which has recently garnered much attention for its potential in myocardial regeneration, and how they may be imaged in vivo.

Summary

This review outlines the most reliable techniques for stem cell imaging in cardiac injury animal models, new and notable advancements in the field, and possible directions for cardiac regenerative medicine.

     

Noninvasive Imaging of Cardiac Gene Expression and Its Future Implications for Molecular Therapy

Innovative approaches for cardiovascular molecular therapy are rapidly evolving, and translational efforts from experimental to clinical application are increasing. Gene and cell therapy hold promise for treatment of heart disease, but despite progress, some basic principles are still under development. Open issues are, e.g., related to the optimal method for delivery, to therapeutic efficacy, to time course and magnitude of gene expression, and to the fate of transplanted cells in target and remote areas. The use of reporter genes and labeled reporter probes for noninvasive imaging provides the methodology to address these questions by assessment of location, magnitude, and persistence of transgene expression in the heart and the whole body. Coexpression of a reporter gene allows for indirect imaging of the expression of a therapeutic gene of choice. Furthermore, reporter genes can be transferred to stem cells prior to transplantation for serial monitoring of cell viability using gene product imaging. Additionally, functional effects of therapy on the tissue level can be identified using established imaging approaches to determine blood flow, metabolism, innervation, or cell death. Measures of transgene expression can then be linked to physiologic effects and will refine the understanding of basic therapeutic mechanisms. Noninvasive gene-targeted imaging will thus enhance the determination of therapeutic effects in cardiovascular molecular therapy in the future.     

Non-Coronary Cardiac CT Imaging

Cardiac multidetector CT (MDCT) has moved from purely anatomic imaging, to assessment of cardiac function. Significant advances since the advent of multidetector CT now make it feasible to assess not only the coronary arteries, but also ejection fraction, ventricular volumes, myocardial mass and the presence of wall-motion abnormalities. Advances include improvements in EKG-gating, including improvements in temporal resolution, as well as the addition of delayed contrast-enhanced methods. Anatomic imaging has improved as well, with thinner collimation and better reconstruction methods. Three-dimensional software programs now permit excellent surface rendered displays and multiplanar reconstructions suitable as surgical and procedural "road maps."     

Robust Cardiac Regeneration: Fulfilling the Promise of Cardiac Cell Therapy

PurposeWe review the history of cardiac cell therapy, highlighting lessons learned from initial adult stem cell (ASC) clinical trials. We present pluripotent stem cell–derived cardiomyocytes (PSC-CMs) as a leading candidate for robust regeneration of infarcted myocardium but identify several issues that must be addressed before successful clinical translation.MethodsWe conducted an unstructured literature review of PubMed-listed articles, selecting the most comprehensive and relevant research articles, review articles, clinical trials, and basic or translation articles in the field of cardiac cell therapy. Articles were identified using the search terms adult stem cells, pluripotent stem cells, cardiac stem cell, and cardiac regeneration or from references of relevant articles, Articles were prioritized and selected based on their impact, originality, or potential clinical applicability.FindingsSince its inception, the ASC therapy field has been troubled by conflicting preclinical data, academic controversies, and inconsistent trial designs. These issues have damaged perceptions of cardiac cell therapy among investors, the academic community, health care professionals, and, importantly, patients. In hindsight, the key issue underpinning these problems was the inability of these cell types to differentiate directly into genuine cardiomyocytes, rendering them unable to replace damaged myocardium. Despite this, beneficial effects through indirect paracrine or immunomodulatory effects remain possible and continue to be investigated. However, in preclinical models, PSC-CMs have robustly remuscularized infarcted myocardium with functional, force-generating cardiomyocytes. Hence, PSC-CMs have now emerged as a leading candidate for cardiac regeneration, and unpublished reports of first-in-human delivery of these cells have recently surfaced. However, the cardiac cell therapy field's history should serve as a cautionary tale, and we identify several translational hurdles that still remain. Preclinical solutions to issues such as arrhythmogenicity, immunogenicity, and poor engraftment rates are needed, and next-generation clinical trials must draw on robust knowledge of mechanistic principles of the therapy.ImplicationsThe clinical transplantation of functional stem cell–derived heart tissue with seamless integration into native myocardium is a lofty goal. However, considerable advances have been made during the past 2 decades. Currently, PSC-CMs appear to be the best prospect to reach this goal, but several hurdles remain. The history of adult stem cell trials has taught us that shortcuts cannot be taken without dire consequences, and it is essential that progress not be hurried and that a worldwide, cross-disciplinary approach be used to ensure safe and effective clinical translation.     

心脏肿瘤的MRI诊断

本文简述了心脏肿瘤的ＭＲＩ扫描技术，重点按心脏肿瘤的发生部位依次介绍了心内膜肿瘤、心腔壁内肿瘤和心包肿瘤的ＭＲＩ诊断，并对ＭＲＩ诊断心脏肿瘤的能力进行评价。     

Advances in Molecular Imaging: Plaque Imaging

Recent advances in nuclear plaque imaging aim to achieve noninvasive identification of vulnerable atherosclerotic plaques using positron emission tomography (PET) with ¹⁸F-fluorodexoyglucose (FDG) and novel tracers targeting molecular markers of inflammation and other active metabolic processes. Nuclear imaging of atherosclerosis has been demonstrated in multiple vascular beds, including the carotid, aorta, peripheral and coronary arteries—but significant challenges remain, especially for coronary imaging. The advantage of PET over other molecular imaging modalities is its superior sensitivity, however, low spatial resolution means that images must be co-registered with computed tomography (CT) or magnetic resonance imaging (MRI) for precise anatomical localization of the PET signal. Such hybrid techniques provide the best hope for early detection of prospective culprit lesions—which may, in the coronary vasculature, appear falsely low-risk using conventional coronary angiography or stress imaging. Current hot topics in nuclear plaque imaging include the use of FDG-PET for therapeutic monitoring in drug development, identification of imaging biomarkers to evaluate cardiovascular risk, and the development of novel tracers against an array of biologically important markers of atherosclerosis. The purpose of this article is to review these recent advances in nuclear plaque imaging.     

Molecular Imaging in Synthetic Biology,and Synthetic Biology in Molecular Imaging

Biomedical synthetic biology is an emerging field in which cells are engineered at the genetic level to carry out novel functions with relevance to biomedical and industrial applications. This approach promises new treatments, imaging tools, and diagnostics for diseases ranging from gastrointestinal inflammatory syndromes to cancer, diabetes, and neurodegeneration. As these cellular technologies undergo pre-clinical and clinical development, it is becoming essential to monitor their location and function in vivo, necessitating appropriate molecular imaging strategies, and therefore, we have created an interest group within the World Molecular Imaging Society focusing on synthetic biology and reporter gene technologies. Here, we highlight recent advances in biomedical synthetic biology, including bacterial therapy, immunotherapy, and regenerative medicine. We then discuss emerging molecular imaging approaches to facilitate in vivo applications, focusing on reporter genes for noninvasive modalities such as magnetic resonance, ultrasound, photoacoustic imaging, bioluminescence, and radionuclear imaging. Because reporter genes can be incorporated directly into engineered genetic circuits, they are particularly well suited to imaging synthetic biological constructs, and developing them provides opportunities for creative molecular and genetic engineering.     

Advances in Molecular Imaging: Innervation Imaging

Cardiac autonomic nervous system plays a major role in maintaining hemodynamic and electrophysiological stability to changing demands. There is increasing evidence showing that imaging cardiac autonomic nervous system can evaluate patients with different cardiac conditions, including ischemic heart disease, arrhythmias and heart failure (HF), with high prognostic value, thus providing a potential tool for improving patient management. Excellent reviews on cardiac autonomic imaging with SPECT and PET tracers have been recently published. This review is aimed to bring the reader up-to-date on the subject with particular emphasis on the major findings of recent years.     

Cardiac CT: Imaging of and Through Cardiac Devices

For patients with cardiac devices, cardiac computed tomography (CT) remains the mainstay for imaging due to its superior resolution as compared with echocardiography and nuclear studies and no contraindication to metal as with cardiac magnetic resonance imaging. This review focuses on the evaluation and pitfalls of coronary arterial imaging in patients with devices, such as pacemakers, implantable defibrillators, cardiac resynchronization therapy (CRT), as well as complications such as lead perforation and safety concerns of CT interference. We discuss both pre- and post-procedural CRT assessment for coronary venous imaging and pre-procedural myocardial scar assessment to localize regions of scar and peri-infarct zone to facilitate ventricular tachycardia ablation in patients with devices. We describe potential new research on dyssynchrony and integration with myocardial scar and site of latest activation for patients with or being considered for CRT. We detail the utility of CT for the assessment of proper function and complications in patients with left ventricular assist device implantation.     

Advances in Imaging of Cardiac Allograft Rejection

Endomyocardial biopsy with its inherent invasiveness and morbidity calls for the development of noninvasive imaging methods to evaluate heart transplant recipients. While conventional imaging technologies report on anatomical and metabolic changes in heart grafts, macrophage-targeted imaging could allow disease detection before gross anatomical and functional changes have occurred. One important approach in magnetic resonance–based molecular imaging exploits an increased T2/T2* relaxation effect, occurring when phagocytic cells localized in the heart graft take up iron-oxide nanoparticles. This methodology of nanoparticle reporting on immune cell accumulation in the graft combined with precise functional and morphological information of cardiac MRI has potential to supplant endomyocardial biopsy. The use of multifunctional nanoparticles fit for multiple imaging modalities (magnetic, optical, and nuclear) will help improve methods of ex vivo and in vitro imaging of allograft rejection and also further our knowledge of allograft rejection by providing a tool for nondestructive serial in vivo assessment.     

Imaging Cell Therapy for Myocardial Regeneration

Noninvasive or minimally invasive imaging techniques are essential for developing strategies and assessing outcomes of cell-based therapies for myocardial regeneration, also referred to as cellular cardiomyoplasty. Imaging-based monitoring of cell survival is useful for selection of optimal cell type and evaluating strategies to enhance engraftment. Imaging-derived surrogate end points including global and regional contractile function, myocardial blood flow, or perfusion and bioenergetics have been used in clinical trials or in relevant large animal models to evaluate the therapeutic effect and mechanisms of action of cellular cardiomyoplasty. New techniques are emerging to assess electrical integration of donor cells with host cardiomyocytes. This review will summarize and highlight important and informative findings revealed by imaging in clinical and preclinical cellular cardiomyoplasty studies over the past 3 years.