Cardiovascular molecular imaging

doi:10.1053/j.semnuclmed.2004.09.006

Seminars in Nuclear Medicine

Volume 35, Issue 1, January 2005, Pages 73-81

https://doi.org/10.1053/j.semnuclmed.2004.09.006 Get rights and content

The recent introduction of novel gene therapies for treatment of cardiac and noncardiac diseases has caused a remarkable need for noninvasive imaging approaches to evaluate and track the progress of these therapies. In the past we have relied on the evaluation of the physiological consequences of therapeutic interventions. With advances in targeted molecular imaging we now have the ability to evaluate early molecular effects of these therapies. The development of dedicated high resolution small animal imaging systems and the establishment of transgenic animal models has enhanced our understanding of cardiovascular disease and has expedited the development of new gene therapies. Noninvasive targeted molecular imaging will allow us to directly track biochemical processes and signaling events that precede the pathophysiological changes. The examples of targeted molecular imaging outlined in this seminar provide some insight into the bright and growing future of cardiovascular molecular imaging. The success of this new field rests on the development of targeted biological markers of molecular and physiological processes, development of new instruments with improved sensitivity and resolution, and the establishment of multidisciplinary teams of experimental and clinical investigators with a wide range of expertise. Molecular imaging already plays a critical role in the experimental laboratory. We expect that, in the near future, targeted molecular imaging will be routinely used in clinical cardiovascular nuclear medicine laboratories in conjunction with existing imaging modalities for both diagnostic and prognostic purposes, as well as for evaluation of new genetic based therapeutic strategies.

Section snippets

Molecular imaging

The concept and practice of molecular imaging, defined as the in vivo characterization and measurement of biological processes at the cellular and molecular level within living organisms, has been present for decades and originated with targeted nuclear imaging.1 Targeted imaging can be defined in terms of a probe-target interaction, whereas the probe localization and magnitude are directly related to the interaction with the target epitope or peptide. Nuclear medicine is particularly suited

Imaging technology

Significant progress in the technological advancement of imaging instrumentation has been observed during recent decades. However, because of practical limitations of different imaging modalities, the broad use of molecular imaging is restricted to a few techniques (Fig. 1). Nuclear and optical modalities provide remarkable ability to study molecular processes and biological pathways; however, because of their relatively poor spatial resolution, their use in imaging the anatomy is somehow

Imaging of angiogenesis

Angiogenesis represents the formation of new capillaries by cellular outgrowth from existing microvessels.5 It occurs as part of the natural healing process after ischemic injury. The process of angiogenesis includes local proliferation and migration of vascular smooth muscle and endothelial cells as well as potential participation of blood-derived macrophages and circulating stem cells. The principal stimuli for angiogenesis include tissue ischemia and hypoxia, inflammation, and shear stress.

Imaging ofatherosclerosis and vascular injury

Integrins, particularly αvβ3, also have emerged as a promising target for imaging injury-induced vascular remodeling and proliferation. Antagonists of αvβ3 have been shown to limit neointimal hyperplasia and lumen stenosis in experimental models of vascular injury. Sadeghi and coworkers have demonstrated that the novel ¹¹¹In-labeled αvβ3 integrin-specific molecule, RP748 and its homologues bind preferentially to activated αvβ3 on endothelial cells (ECs) in vitro and exhibit favorable binding

Imaging of apoptosis

Apoptosis, or programmed cell death, occurs in association with many cardiovascular diseases. This preprogrammed cell death often occurs in combination with cell death by necrosis. Apoptosis, first described by Kerr and coworkers, is characterized by morphological changes, including cell shrinkage and formation of membrane-bound apoptotic bodies.32 In contrast, necrosis is characterized by an early loss of membrane permeability, cell swelling and random fragmentation of DNA. Cells undergoing

References (37)

H. Tseng et al.
Cardiac receptor physiology and its application to clinical imagingpresent and future
J Nucl Cardiol
(2001)
J.M. Link et al.
PET measures of pre- and post-synaptic cardiac beta adrenergic function
Nucl Med Biol
(2003)
P. Brooks et al.
Integrin alpha v beta 3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels
Cell
(1994)
T.L. Haas et al.
Extracellular matrix-driven matrix metalloproteinase production in endothelial cellsImplications for angiogenesis
Trends Cardiovasc Med
(1999)
A.J. Sinusas
Imaging of angiogenesis
J Nucl Cardiol
(2004)
M. Cerqueira et al.
Lake Tahoe Invitation Meeting 2002
J Nucl Cardiol
(2003)
K. Kopka et al.
Synthesis and preliminary biological evaluation of new radioiodinated MMP inhibitors for imaging MMP activity in vivo
Nucl Med Biol
(2004)
J. Narula et al.
Maximizing radiotracer delivery to experimental atherosclerotic lesions with high-dose, negative charge-modified Z2D3 antibody for immunoscintigraphic targeting
J Nucl Cardiol
(1997)
H. Su et al.
Evaluation of myocardial matrix metalloproteinase (MMP) mediated post-MI remodeling with a novel radiolabeled MMP inhibitor
J Nucl Cardiol
(2004)
I. Vermes et al.
A novel assay for apoptosis. Flow cytometric detection of phosphatidylserine expression on early apoptotic cells using fluorescein labelled Annexin V
J Immunol Methods
(1995)

H.W. Strauss et al.

Radioimaging to identify myocardial cell death and probably injury

Lancet

(2000)

T.F. Massoud et al.

Molecular imaging in living subjectsSeeing fundamental biological processes in a new light

Genes Dev

(2003)

C.L. Brumley et al.

Radiolabeled monoclonal antibodies

Aorn J

(1995)

E.J. Battegay

AngiogenesisMechanistic insights, neovascular diseases, and therapeutic prospects

J Mol Med

(1995)

P. Brooks et al.

Requirement of vascular integrin alpha v beta 3 for angiogenesis

Science

(1994)

M. Schwartz et al.

Integrins: Emerging paradigms of signal transduction. I

Annu Rev Cell Dev Biol

(1995)

N. Ferrara et al.

The biology of vascular endothelial growth factor

Endocr Rev

(1997)

N. Ferrara et al.

The biology of VEGF and its receptors

Nat Med

(2003)

Cited by (27)

Noninvasive imaging of cardiovascular injury related to the treatment of cancer
2014, JACC: Cardiovascular Imaging
Citation Excerpt :
For those treated for cancer, data pertaining to the association of LGE with cancer treatment are mostly anecdotal or observational, and somewhat conflicting in regard to reported results. In a chemotoxic cardiomyopathy study by Catalano et al. (87), mid-myocardial LGE is shown in the mid-basal septum and anterior, basal anterolateral, and mid-inferior walls after treatment with anthracycline/cyclophosphamide, and a study by Fallah-Rad et al. (79,88) demonstrates mid-myocardial LGE patterns in the lateral wall after treatment with trastuzumab for 12 months. By contrast, Neilan et al. (78) determined that LGE is an infrequent finding occurring in only 6% (5 cases/91 cases) of patients treated with anthracycline-base chemotherapy despite a reduced LVEF.
The introduction of multiple treatments for cancer, including chemotherapeutic agents and radiation therapy, has significantly reduced cancer-related morbidity and mortality. However, these therapies can promote a variety of toxicities, among the most severe being the ones involving the cardiovascular system. Currently, for many surviving cancer patients, cardiovascular (CV) events represent the primary cause of morbidity and mortality. Recent data suggest that CV injury occurs early during cancer treatment, creating a substrate for subsequent cardiovascular events. Researchers have investigated the utility of noninvasive imaging strategies to detect the presence of CV injury during and after completion of cancer treatment because it starts early during cancer therapy, often preceding the development of chemotherapy or cancer therapeutics related cardiac dysfunction. In this State-of-the-Art Paper, we review the utility of current clinical and investigative CV noninvasive modalities for the identification and characterization of cancer treatment-related CV toxicity.
Non FDG PET
2010, Clinical Radiology
Citation Excerpt :
Apoptosis, or programmed cell death, occurs in association with many cardiovascular diseases. Cells undergoing apoptosis express on their cell membrane phosphatidylserine, which is a favourable target for imaging of apoptotic processes.85 Annexin-V is a medium-sized physiological human protein with a high Ca2+-dependent affinity for the phosphatidylserine on the outer leaflet of the cell membrane.
2- [¹⁸F]-fluoro-2-deoxy-d-glucose (FDG) is the radiopharmaceutical most frequently used for clinical positron emission tomography (PET). However, FDG cannot be used for many oncological, cardiological, or neurological conditions, either because the abnormal tissue does not concentrate it, or because the tissues under investigation demonstrate high physiological glucose uptake. Consequently, alternative PET tracers have been produced and introduced into clinical practice. The most important compounds in routine practice are ¹¹C-choline and ¹⁸F-choline, mainly for the evaluation of prostate cancer; ¹C-methionine for brain tumours; ¹¹⁸F-DOPA (¹⁸F- deoxiphenilalanine) for neuroendocrine tumours and movement disorders; ⁶⁸Ga-DOTANOC (tetraazacyclododecanetetraacetic acid-[1-Nal3]-octreotide) and other somatostatin analogues for neuroendocrine tumours; 11C-acetate for prostate cancer and hepatic masses and 18F-FLT (3ٰ-deoxy-3ٰ-fluorothymidine) for a number of malignant tumours.
Another impetus for the development of new tracers is to enable the investigation of biological processes in tumours other than glucose metabolism. This is especially important in the field of response assessment, where there are new agents that are targeted more specifically at angiogenesis, hypoxia, apoptosis and other processes.
Dual targeting improves microbubble contrast agent adhesion to VCAM-1 and P-selectin under flow
2009, Journal of Controlled Release
To improve ultrasound contrast agents targeted to the adhesion molecules P-selectin and VCAM-1 for the purpose of molecular imaging of atherosclerotic plaques, perfluorocarbon-filled phospholipid microbubble contrast agents were coupled by a polyethylene glycol–biotin–streptavidin bridge with mAb MVCAM.A(429), a sialyl Lewis^x polymer (PAA-sLe^x), or both (dual). Approximately three hundred thousand antibody molecules were coupled to the surface of each microbubble. Recombinant mouse P-selectin and/or VCAM-1 coated on flow chambers showed saturation of binding at approximately 15 ng/μl, resulting in 800 and 1200 molecules/µm² for P-selectin and VCAM-1, respectively. Dual substrates coated with equal concentrations of P-selectin and VCAM-1 had site densities between 50 and 60% of single substrates. When microbubbles were perfused through flow chambers at 5 × 10⁶ microbubbles/ml (wall shear stress from 1.5 to 6 dyn/cm²) dual-targeted microbubbles adhered almost twice as efficiently as single-targeted microbubbles at 6 dyn/cm². The present study suggests that dual-targeted contrast agents may be useful for atherosclerotic plaque detection at physiologically relevant shear stresses.
Labeling Techniques with 123I: Application to Clinical Settings
2009, Comprehensive Handbook of Iodine: Nutritional, Biochemical, Pathological and Therapeutic Aspects
This chapter deals with the various available labeling techniques using ¹²³I and the applications of some of the compounds obtained. Many molecules of biological, diagnostic, or pharmaceutical interest are labeled with ¹²³I to assess metabolism and receptor function. Indeed, this isotope of iodine, routinely available and with suitable nuclear properties allows good imaging with gamma cameras without significantly altering the physico-chemical and biological properties of the original molecule, when carefully labeled. The various iodinating agents employed and labeling techniques with ¹²³I, from simple isotopic exchange to the use of prosthetic groups, are reviewed here, with emphasis on their respective advantages and disadvantages. ¹²³I is commercially available and widely used as the most suitable cyclotron-produced radionuclide for SPECT. Four routes of production are used, while about 25 have been suggested and investigated. Many methods of labelling have been described, but only a few allow radiopharmaceutical preparation with good labeling and high specific activity. Furthermore, the relative importance of the various methods varies with time, depending on new synthetic pathways and progress, notably in organometallic chemistry, and no method combines all advantages. During labeling and storage, different factors are responsible for the degradation of radioiodinated tracers, among which are radiolysis and the presence of trace impurities. Iodine loss can occur due to oxygen, light, heat, pH, or solvents.
Applications of Small Animal Imaging with PET, PET/CT, and PET/MR Imaging
2008, PET Clinics
Small animal techniques of PET, MR imaging, and CT are most frequently applied in preclinical oncology research, but cardiovascular and neurologic research protocols can also take advantage of these innovative approaches. PET is used to provide functional information about disease activity. Using small animal PET and MR imaging, one can observe the response of a disease condition to a new therapeutic agent or the development of disease, significantly reducing the number of animals employed and increasing the reliability of the results. By employing the same technology (PET, MR imaging, or CT) in the experimental setting and in clinical practice, the step between preclinical science and clinical applications in human patients is shortened.
Molecular imaging will replace perfusion imaging: The impossible dream
2008, Journal of Nuclear Cardiology

View all citing articles on Scopus

View full text

Cardiovascular molecular imaging

Section snippets

Molecular imaging

Imaging technology

Imaging of angiogenesis

Imaging ofatherosclerosis and vascular injury

Imaging of apoptosis

J Nucl Cardiol

Nucl Med Biol

Cell

Trends Cardiovasc Med

J Nucl Cardiol

J Nucl Cardiol

Nucl Med Biol

J Nucl Cardiol

J Nucl Cardiol

J Immunol Methods

Lancet

Molecular imaging in living subjectsSeeing fundamental biological processes in a new light

Genes Dev

Radiolabeled monoclonal antibodies

Aorn J

AngiogenesisMechanistic insights, neovascular diseases, and therapeutic prospects

J Mol Med

Requirement of vascular integrin alpha v beta 3 for angiogenesis

Science

Integrins: Emerging paradigms of signal transduction. I

Annu Rev Cell Dev Biol

The biology of vascular endothelial growth factor

Endocr Rev

The biology of VEGF and its receptors

Nat Med