Noninvasive Molecular Imaging of Cell Death in Myocardial Infarction using 111In-GSAO

Abstract

Acute insult to the myocardium is associated with substantial loss of cardiomyocytes during the process of myocardial infarction. In this setting, apoptosis (programmed cell death) and necrosis may operate on a continuum. Because the latter is characterized by the loss of sarcolemmal integrity, we propose that an appropriately labeled tracer directed at a ubiquitously present intracellular moiety would allow non-invasive definition of cardiomyocyte necrosis. A trivalent arsenic peptide, GSAO (4-(N-(S-glutathionylacetyl)amino)phenylarsonous acid), is capable of binding to intracellular dithiol molecules such as HSP90 and filamin-A. Since GSAO is membrane impermeable and dithiol molecules abundantly present intracellularly, we propose that myocardial localization would represent sarcolemmal disruption or necrotic cell death. In rabbit and mouse models of myocardial infarction and post-infarct heart failure, we employed In-111-labelled GSAO for noninvasive radionuclide molecular imaging. 111In-GSAO uptake was observed within the regions of apoptosis seeking agent- 99mTc-Annexin A5 uptake, suggesting the colocalization of apoptotic and necrotic cell death processes.

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“…It had been targeted by a small organoarsenical compound, 4-( N -( S -glutathionylacetyl)amino)phenylarsonous acid (GSAO) labeled with fluorophores and radionuclides (Fig. 1) for imaging of cell death in animal models of tumors, traumatic brain injury, and myocardial infarction or ischemia75., 76., 77., 78.. GSAO is a peptide trivalent arsenical that rapidly accumulates in the cytoplasm of dying and dead cells coincident with loss of plasma membrane integrity.…”

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“…Increased accumulation of GSAO fluorophore conjugates in apoptic induced cells led to binding of biotin‐GSAO to 90 kDa heat shock protein (Hsp90), which is abundant, yet inaccessible to GSAO, in the cytoplasm of healthy eukaryotic cells. Furthermore, a rabbit and mouse in vivo model has been developed to image cell death during myocardial infarction . The myocardial accumulation of a radionuclide molecular imaging agent, 111 In–GSAO conjugate, was investigated via single‐photon emission computed tomography/computed tomography (SPECT/CT) and was correlated to both apototic and nectrotic cell death processes ( Figure ).…”

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“…In a previous preclinical study, Tahara and co-investigators first describe results of imaging acute myocardial infarction using 111 In-GSAO. 15 They studied mice and rabbits. In mice, they showed very nicely by dual fluorescence, staining for annexin A5 on the cell membrane and staining for GSAO intracellularly.…”

“…In mice, they showed very nicely by dual fluorescence, staining for annexin A5 on the cell membrane and staining for GSAO intracellularly. 15 In rabbits with reperfused myocardial infarctions, they compared uptake of 111 In-GSAO with 99m Tc-Annexin A5 against histological staining for apoptosis using both TUNEL and caspase staining and found a good correlation in uptake between the two tracers and with the quantitative immunohistology.…”