Molecular Imaging In Cardiovascular Disease Research Articles

Molecular imaging of cardiovascular disease: Current status and future perspective.

Advancements in knowledge of cardiovascular disease, pharmacology, and chemistry have led to the development of newer radiopharmaceuticals and targets for new and more suitable molecules. Molecular imaging encompasses multiple imaging techniques for identifying the characteristics of key components involved in disease. Despite its limitations in spatial resolution, the affinity for key molecules compensates for disadvantages in diagnosing diseases and elucidating their pathophysiology. This review introduce established molecular tracers involved in clinical practice and emerging tracers already applied in clinical studies, classifying the key component in A: artery, specifically those vulnerable plaque (A-I) inflammatory cells [18F-FDG]; A-II) lipid/fatty acid; A-III) hypoxia; A-IV) angiogenesis; A-V) protease [18F/68Ga-FAPI]; A-VI) thrombus/hemorrhage; A-VII) apoptosis and A-VIII) microcalcification [18F-NaF]) and B: myocardium, including myocardial ischemia, infarction and myocardiopathy (BI) myocardial ischemia; B-II) myocardial infarction (myocardial damage and fibrosis); B-III) myocarditis and endocarditis; B-IV) sarcoidosis; BV) amyloidosis; B-VI) metabolism; B-VII) innervation imaging). In addition to cardiovascular-specific tracers tested in animal models, many radiotracers may have been developed in other areas, such as oncology imaging or neuroimaging. While this review does not cover all available tracers, some of them hold potential for future use assessing cardiovascular disease. Advances in molecular biology, pharmaceuticals, and imaging sciences will facilitate the identification of precise disease mechanisms, enabling precise diagnoses, better assessment of disease status, and enhanced therapeutic evaluation in this multi-modality era.

Molecular nanoprobe for diagnosis of cardiovascular diseases

Cardiovascular disease (CVD) remains the most leading cause of disease-related death worldwide. Current diagnostic modalities such as biomarkers and electrocardiography are relatively limited, which urgently develop new and effective techniques. Recently, molecular imaging has gained extensive attention in CVD diagnosis due to its ability to non-invasively visualize and quantify physio-pathological processes. However, the current mainstream imaging agents are limited by low specificity, short retention time, and severe side effects. Fortunately, with the development of nanomedicine, nanomaterials could play an important role in molecular imaging and CVD diagnosis. Here, we first summarize the concepts and characteristics of different molecular imaging, then focus on the application of nanoprobes as imaging agents in molecular imaging of CVD, and finally briefly introduce the challenges and prospects of nanomaterials-based molecular imaging.

Targeted Molecular Imaging of Cardiovascular Diseases by Iron Oxide Nanoparticles.

Cardiovascular disease is one of the major contributors to global disease burden. Atherosclerosis is an inflammatory process that involves the accumulation of lipids and fibrous elements in the large arteries, forming an atherosclerotic plaque. Rupture of unstable plaques leads to thrombosis that triggers life-threatening complications such as myocardial infarction. Current diagnostic methods are invasive as they require insertion of a catheter into the coronary artery. Molecular imaging techniques, such as magnetic resonance imaging, have been developed to image atherosclerotic plaques and thrombosis due to its high spatial resolution and safety. The sensitivity of magnetic resonance imaging can be improved with contrast agents, such as iron oxide nanoparticles. This review presents the most recent advances in atherosclerosis, thrombosis, and myocardial infarction molecular imaging using iron oxide-based nanoparticles. While some studies have shown their effectiveness, many are yet to undertake comprehensive testing of biocompatibility. There are still potential hazards to address and complications to diagnosis, therefore strategies for overcoming these challenges are required.

Magnetic resonance imaging for pathobiological assessment and interventional treatment of the coronary arteries.

X-ray-based fluoroscopy is the standard tool for diagnostics and intervention in coronary artery disease. In recent years, computed tomography has emerged as a non-invasive alternative to coronary angiography offering detection of coronary calcification and imaging of the vessel lumen by the use of iodinated contrast agents. Even though currently available invasive or non-invasive techniques can show the degree of vessel stenosis, they are unable to provide information about biofunctional plaque properties, e.g. plaque inflammation. Furthermore, the use of radiation and the necessity of iodinated contrast agents remain unfavourable prerequisites. Magnetic resonance imaging (MRI) is a radiation-free alternative to X-ray which offers anatomical and functional imaging contrasts fostering the idea of non-invasive biofunctional assessment of the coronary vessel wall. In combination with molecular contrast agents that target-specific epitopes of the vessel wall, MRI might reveal unique plaque properties rendering it, for example, ‘vulnerable and prone to rupture’. Early detection of these lesions may allow for early or prophylactic treatment even before an adverse coronary event occurs. Besides diagnostic imaging, advances in real-time image acquisition and motion compensation now provide grounds for MRI-guided coronary interventions. In this article, we summarize our research on MRI-based molecular imaging in cardiovascular disease and feature our advances towards real-time MRI-based coronary interventions in a porcine model.

Molecular Imaging of Cardiovascular Disease

The ability to visualize morphology and function of the heart plays a central role in cardiology practice today. However, clinical tools to diagnose processes in an early phase on a molecular level in order to prevent dysmorphy or dysfunction are still lacking. There is a need for early diagnosis of molecular processes on a pre-disease level and the ability to monitor existing and novel treatments enabling personalized medicine. Molecular imaging is emerging in research and early clinical trials as a very promising approach in diagnosis and monitoring of heart disease. In this review we aim to discuss the potential of molecular imaging in cardiovascular disease.

Molecular Imaging of Atherosclerosis: A Clinical Focus.

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. In addition, molecular imaging of atherosclerosis can illuminate underlying pathophysiology and serve as a surrogate end-point in clinical trials of new drugs. This review showcases promising molecular approaches for imaging atherosclerosis, with a focus on PET, MRI, and intravascular near-infrared fluorescence (NIRF) imaging methods that are in the clinic or close-to-clinical usage.

Translational applications of molecular imaging in cardiovascular disease and stem cell therapy.

Cardiovascular disease (CVD) is the leading cause of mortality and morbidity worldwide. Molecular imaging techniques provide valuable information at cellular and molecular level, as opposed to anatomical and structural layers acquired from traditional imaging modalities. More specifically, molecular imaging employs imaging probes which interact with specific molecular targets and therefore makes it possible to visualize biological processes in vivo. Molecular imaging technology is now progressing towards preclinical and clinical application that gives an integral and comprehensive guidance for the investigation of cardiovascular disease. In addition, cardiac stem cell therapy holds great promise for clinical translation. Undoubtedly, combining stem cell therapy with molecular imaging technology will bring a broad prospect for the study and treatment of cardiac disease. This review will focus on the progresses of molecular imaging strategies in cardiovascular disease and cardiac stem cell therapy. Furthermore, the perspective on the future role of molecular imaging in clinical translation and potential strategies in defining safety and efficacy of cardiac stem cell therapies will be discussed.

In vivo Optical Molecular Imaging of Cardiovascular Diseases: Long Road Ahead

Optical molecular imaging is a powerful imaging method, which can in vivo monitor physiological and pathobiological processes at the cellular and molecular levels, as opposed to the anatomical level, bridging the gap between imaging and biological processes. Because of its relevance in cardiovascular diseases research, the use of this technology for imaging of cardiovascular diseases advances at a rapid pace in the past decade. This review summarizes the optical molecular imaging methods for imaging the specific targets in cardiovascular diseases, which hold promise for in vivo applications in cardiovascular diseases research. Collectively, in vivo optical molecular imaging may be highly suitable for discriminating targets that play key roles in the occurrence and development of the instable atherosclerosis, thrombogenesis, myocardial infarction, myocardial apoptosis, angiogenesis, as well as in cardiac cell transplantation. Keywords: Bioluminescent imaging, cardiovascular diseases, fluorescence molecular tomography, near-infrared fluorescence imaging, optical imaging.

Molecular imaging in cardiovascular diseases.

Cardiovascular diseases remain the leading cause of morbidity and mortality in industrialized and developing countries. In clinical practice, the in-vivo identification of atherosclerotic lesions, which can lead to complications such as heart attack or stroke, remains difficult. Imaging techniques provide the reference standard for the detection of clinically significant atherosclerotic changes in the coronary and carotid arteries. The assessment of the luminal narrowing is feasible, while the differentiation of stable and potentially unstable or vulnerable atherosclerotic plaques is currently not possible using non-invasive imaging. With high spatial resolution and high soft tissue contrast, magnetic resonance imaging (MRI) is a suitable method for the evaluation of the thin arterial wall. In clinical practice, native MRI of the vessel wall already allows the differentiation and characterization of components of atherosclerotic plaques in the carotid arteries and the aorta. Additional diagnostic information can be gained by the use of non-specific MRI contrast agents. With the development of targeted molecular probes, that highlight specific molecules or cells, pathological processes can be visualized at a molecular level with high spatial resolution. In this review article, the development of pathophysiological changes leading to the development of the arterial wall are introduced and discussed. Additionally, principles of contrast enhanced imaging with non-specific contrast agents and molecular probes will be discussed and latest developments in the field of molecular imaging of the vascular wall will be introduced. Molecular magnetic resonance imaging has great potential to improve the in vivo characterization of atherosclerotic plaques. Based on the molecular information is feasible to enable a better differentiation of stable and unstable (vulnerable) atherosclerotic plaques.

日本心臓血管内視鏡学会を創立して29 年

On 5 February 1986, a committee meeting was held at Hilltop Congress Hall of Tokyo University to establish Japanese Society for Angioscopy and Laser Angioplasty. The members of the committee were Drs. Hitoshi Koyanagi, Syoichi Takekawa, Syunichi Hoshino, Masayoshi Okada, Komei Sugimoto, and Yasumi Uchida (myself). I was recommended as the representative of this society. On 26 September 1987, the first annual meeting of this society was held at the Hilltop Congress Hall. Dr. George Abela was invited as a guest speaker on laser angioplasty of the peripheral artery. On 17 September 1988, the second annual meeting, too, was held successfully at the same Hall. Since then, the meeting was held in Autumn every year. Since 1991, proceedings of the meeting were published in English every year. In 1998, the name of this society was changed to Japanese Association for Cardioangioscopy, and Dr. Uchida was elected as the president. In 2007, Dr. Kyoichi Mizuno was elected as the next president. During the past 29 years, angioscopy was applied clinically not only to coronary artery but also to cardiac chambers and valves, peripheral vessels and great vessels, and many hitherto unrecognized mechanisms of vascular disease were discovered. Many valuable papers were published in famous journals not only in Japan but also in abroad. Angioscopy and cardioscopy both conventional and fluorescent are now directed to cellular and molecular imaging of cardiovascular diseases, and also for guidance of intravascular and intracardiac surgery. This imaging technique will further contribute to diagnosis and evaluation of medical and surgical therapies of cardiovascular diseases.

Molecular imaging in cardiovascular disease: Which methods, which diseases?

Techniques for in vivo assessment of disease-related molecular changes are being developed for all forms of non-invasive cardiovascular imaging. The ability to evaluate tissue molecular or cellular phenotype in patients has the potential to not only improve diagnostic capabilities but to enhance clinical care either by detecting disease at an earlier stage when it is more amenable to therapy, or by guiding most appropriate therapies. These new techniques also can be used in research programs in order to characterize pathophysiology and as a surrogate endpoint for therapeutic efficacy. The most common approach for molecular imaging involves the creation of novel-targeted contrast agents that are designed so that their kinetic properties are different in disease tissues. The main focus of this review is not to describe all the different molecular imaging approaches that have been developed, but rather to describe the status of the field and highlight some of the clinical and research applications that molecular imaging will likely provide meaningful benefit. Specific target areas include assessment of atherosclerotic disease, tissue ischemia, and ventricular and vascular remodeling.

Targeted Nanoparticles for Cardiovascular Molecular Imaging

Molecular imaging is aimed at noninvasive visualization of fundamental (disease) biomarkers in living organisms. Molecular imaging holds great promise in facilitating patient-specific disease diagnosis, treatment planning, monitoring of local drug delivery, and early evaluation of therapy. This paper reviews recent major accomplishments in the field of molecular imaging of cardiovascular disease, with particular focus on the use of nanoparticles as signal beacons for target-specific imaging.

Molecular Imaging of Thrombus

For some time, scientists with expertise in medical imaging, cell biology, and chemical engineering have teamed together with the goal of producing targeted contrast agents for molecular imaging in cardiovascular disease. The goal of these efforts is to bring about techniques for noninvasively detecting and quantifying specific molecular processes that play a role in the pathophysiology of cardiovascular disease. Although there has been a tendency in the scientific literature to focus on how molecular imaging has been achieved, it is equally important to review why. Article see p 3117 In the clinical setting, molecular imaging is likely to enhance and expand the diagnostic capabilities of current imaging applications. Nowhere has this been more successful than in cancer imaging, where targeted contrast agents can detect otherwise nonapparent primary or metastatic disease or be used to select appropriate therapies based on tumor or tumor microvascular phenotype.1 There are several areas of focus where molecular imaging could play an important role for early diagnosis and to guide patient management in cardiovascular disease. Imaging the cellular or molecular profile in atherosclerotic disease could yield important information on susceptibility for acute atherothrombotic complications.2 In the future, it could also potentially be used to determine appropriateness for emerging therapies such as new drugs that interrupt the inflammatory response, which will likely be expensive and have adverse effects. Recent myocardial ischemia can be detected by molecular imaging of either a reduction in myocyte fatty acid utilization or postischemic inflammatory activation of the microvascular endothelium.3,4 This approach could be used for rapid diagnosis in patients with chest pain of unclear origin and allow spatial assessment of the postischemic region even hours after resolution. Large-scale clinical trials with imaging of labeled branched-chain fatty acids have already been completed showing that the technique can accelerate …

Over a Hump for Imaging Atherosclerosis

The “Holy Grail” in molecular imaging of cardiovascular disease is sensitive, specific, economic, and radiation-free detection of atheromata prone to produce thrombotic complications.1,2 In this issue of Circulation Research , Broisat et al3 describe another step on the path toward noninvasive molecular imaging of inflammation in atherosclerotic plaque. Although still unproven, the early detection of trouble looming ahead could trigger steps for intervention, possibly involving the aggressive modulation of risk factors. Imaging might even help to define individual risk and to guide appropriate local therapy.4 Article, see p 927 The field has provided proof-of-concept studies for a variety of molecular targets. While searching for suitable approaches, imaging scientists have perused the work of molecular biologists and immunologists working in atherosclerosis. The recognition that inflammation drives the development and complication of atherosclerosis offers several potential imaging targets. Adhesion molecules, innate immune cells (monocytes/macrophages), extracellular matrix, oxidized lipids, and proteases all have received scrutiny,4 but vascular cell adhesion molecule-1 (VCAM-1)5 has gained considerable attention in this regard. …

Ultrasound Molecular Imaging of Cardiovascular Disease

Molecular imaging with ultrasound contrast agents relies on the detection of microbubbles within diseased tissue. Microbubbles produce an acoustic signal owing to their resonant properties in an ultrasound field. Microbubble targeting is accomplished by either manipulating the microbubble shell for attachment of microbubbles to activated leukocytes, or by conjugation of disease-specific ligands to the microbubble surface. Inflammation, angiogenesis, and thrombus formation are central pathophysiologic processes in many cardiovascular diseases and produce phenotypic changes in the vascular compartment that can be imaged with targeted ultrasound contrast agents. In the future, targeted contrast ultrasound could aid in the diagnosis of atherosclerosis, myocardial ischemia, transplant rejection, and thrombosis syndromes and could be used for assessing angiogenesis.

A Novel Biotechnological Approach for Targeted Regenerative Cell Therapy and Molecular Imaging of Atherothrombosis

Targeted delivery increases the efficacy of drugs and regenerative cell therapy while reducing the dose required along with negative side effects. Similarly, targeted delivery of imaging agents will localise and retain them at the disease sites, enhancing the sensitivity and accuracy of current imaging techniques. Here we report a novel method employing Staphylococcus aureus sortase A enzyme for the conjugation of a single-chain antibody (scFv), anti-GPIIb/IIIa-scFv to nanoparticles and cells for imaging and cell delivery in cardiovascular disease. This scFv specifically binds to activated platelets, which play a pivotal role in atherosclerosis, thrombosis and inflammation. The scFv was successfully conjugated to magnetic particles of iron oxide, which are powerful contrast agents for MR imaging and also to model cells (CHO). The conjugation efficiency was between 50–70% and the bioactivity of the scFv after coupling was preserved. The targeting of scFv-coupled CHO cells and nanoparticles to activated platelets was strong as demonstrated in in vitro static adhesion assay, under shear stress in a flow chamber system and in intravital microscopy experiments. This unique biotechnological approach combining biological and chemical coupling provides a highly useful tool for regenerative cell therapy (e.g. stem cells) as well as targeted molecular imaging in cardiovascular disease and beyond. View Large Image Figure Viewer Download Hi-res image

A novel high resolution, high sensitivity SPECT detector for molecular imaging of cardiovascular diseases

Cardiovascular diseases are the most common cause of death in western countries. Understanding the rupture of vulnerable atherosclerotic plaques and monitoring the effect of innovative therapies of heart failure is of fundamental importance. A flexible, high resolution, high sensitivity detector system for molecular imaging with radionuclides on small animal models has been designed for this aim. A prototype has been built using tungsten pinhole and LaBr 3 ( Ce ) scintillator coupled to Hamamatsu Flat Panel PMTs. Compact individual-channel readout has been designed, built and tested. Measurements with phantoms as well as pilot studies on mice have been performed, the results show that the myocardial perfusion in mice can be determined with sufficient precision. The detector will be improved replacing the Hamamatsu Flat Panel with Silicon Photomultipliers (SiPMs) to allow integration of the system with MRI scanners. Application of LaBr 3 ( Ce ) scintillator coupled to photosensor with high photon detection efficiency and excellent energy resolution will allow dual-label imaging to monitor simultaneously the cardiac perfusion and the molecular targets under investigation during the heart therapy.

Molecular imaging in cardiovascular disease: targets and opportunities

The practice of clinical cardiology employs many imaging techniques for diagnosis, risk stratification and therapeutic monitoring. These imaging modalities largely provide anatomical or structural information, and only indirectly reflect underlying molecular events. Molecular imaging techniques report on entities or processes that can be defined at the molecular, as opposed to the anatomical, level. For example, molecular imaging can reveal the expression or activity of a specific protein, the fate or localization of a biomolecule, or the activity of a biological pathway. This Review highlights key processes and molecular targets that are currently being investigated experimentally by molecular imaging probes in vivo. Collectively, these targets have an important role in the development of atherosclerosis and acute plaque rupture, as well as in myocardial disease. Molecular imaging technology is now progressing towards clinical application in humans and has the potential to guide diagnosis, risk assessment and treatment response. Imaging-based surrogate end points could speed the development of new drugs, particularly those with novel mechanisms of action. More broadly, by noninvasively reporting on molecular processes in vivo, molecular imaging can reveal how specific proteins or pathways function in their native context, thus contributing to a systems-level understanding of cardiovascular disease biology.

Drug-Eluting Stents in Animals and Patients

Four legs good, two legs better. — —George Orwell, Animal Farm, 1945 Since the earliest use of coronary stents for treating symptomatic coronary stenosis, maintaining patent arteries after treatment has remained an elusive goal. Although the first bare metal stents opened stenotic arteries, they injured the arterial wall. The buildup of intimal scar tissue caused restenosis, a frustrating problem for prevention or treatment. After a dozen years of research, however, drug-eluting stents were developed; armed with polymer coating and paclitaxel or sirolimus, they prevented restenosis and were hailed as a major therapeutic breakthrough. Article see p 141 Not long afterward, however, questions about the safety and efficacy of drug-eluting stents surfaced as reports of late stent thrombosis began to appear.1,2 Cardiologists wondered if prevention of restenosis was always a good thing. If no protective cellular layer formed over the struts of the drug-eluting stent—even months or years after implantation—would thrombus develop on the exposed metal scaffolding or other damaged or inflamed areas on the blood vessel wall? Over months or years, would progressive inflammation or late “catchup” tissue growth cause drug-eluting stents to lose their early advantage over bare metal stents? The pendulum in this debate has swung back and forth as clinical trials first raised concern about increased thrombosis and then later quelled our fears as our understanding of how drug-eluting stents work in real life has matured. An important issue has been the increased use of stents in patients with more complex coronary and other disorders, raising the question of whether the established standards of safety and efficacy still apply. Answers for these challenging questions have come from 2 worlds: clinical studies of patients with stents …

Molecular imaging of cardiovascular disease with contrast-enhanced ultrasonography

Techniques for noninvasive imaging of specific disease-related molecular changes are being developed to enhance diagnosis and therapeutic decision making in the clinical setting, and to facilitate research efforts. Molecular imaging with contrast-enhanced ultrasonography relies on the detection of the acoustic signal produced by microbubble or nanoparticle agents that are targeted to sites of disease. This Review describes the basis for ultrasound molecular imaging, the unique features of contrast agent behavior or detector performance in relation to clinical or research needs, and the progress that has been made to date in imaging key events in cardiovascular medicine, such as atherosclerosis, postischemic inflammation, angiogenesis, transplant rejection and thrombus formation.