Imaging of αvβ3 integrin expression in experimental myocardial ischemia with [68Ga]NODAGA-RGD positron emission tomography

Abstract

BackgroundRadiolabeled RGD peptides detect αvβ3 integrin expression associated with angiogenesis and extracellular matrix remodeling after myocardial infarction. We studied whether cardiac positron emission tomography (PET) with [68Ga]NODAGA-RGD detects increased αvβ3 integrin expression after induction of flow-limiting coronary stenosis in pigs, and whether αvβ3 integrin is expressed in viable ischemic or injured myocardium.MethodsWe studied 8 Finnish landrace pigs 13 ± 4 days after percutaneous implantation of a bottleneck stent in the proximal left anterior descending coronary artery. Antithrombotic therapy was used to prevent stent occlusion. Myocardial uptake of [68Ga]NODAGA-RGD (290 ± 31 MBq) was evaluated by a 62 min dynamic PET scan. The ischemic area was defined as the regional perfusion abnormality during adenosine-induced stress by [15O]water PET. Guided by triphenyltetrazolium chloride staining, tissue samples from viable and injured myocardial areas were obtained for autoradiography and histology.ResultsStent implantation resulted in a partly reversible myocardial perfusion abnormality. Compared with remote myocardium, [68Ga]NODAGA-RGD PET showed increased tracer uptake in the ischemic area (ischemic-to-remote ratio 1.3 ± 0.20, p = 0.0034). Tissue samples from the injured areas, but not from the viable ischemic areas, showed higher [68Ga]NODAGA-RGD uptake than the remote non-ischemic myocardium. Uptake of [68Ga]NODAGA-RGD correlated with immunohistochemical detection of αvβ3 integrin that was expressed in the injured myocardial areas.ConclusionsCardiac [68Ga]NODAGA-RGD PET demonstrates increased myocardial αvβ3 integrin expression after induction of flow-limiting coronary stenosis in pigs. Localization of [68Ga]NODAGA-RGD uptake indicates that it reflects αvβ3 integrin expression associated with repair of recent myocardial injury.

Angiogenesis PET Tracer Uptake (68Ga-NODAGA-E[(cRGDyK)]2) in Induced Myocardial Infarction and Stromal Cell Treatment in Minipigs

“…Our finding of integrin α v β 3 only in the infarcted area is in line with a recent study (Grönman et al), using the same RGD peptide, but not the same tracer, to detect angiogenesis in pigs after induction of coronary stenosis [ 13 ]. They found integrin α v β 3 and their tracer almost exclusively located in the injured myocardium.…”

Multiparametric PET and MRI of myocardial damage after myocardial infarction: correlation of integrin αvβ3 expression and myocardial blood flow

“…The integrin αvβ3 could therefore represent a novel biomarker after MI to predict adverse LV remodeling processes. Radiolabeled antagonists containing a cyclic Arg-Gly-Asp (RGD) peptide have been used for molecular imaging of αvβ3 integrin expression in oncology and after experimental and human MI using radionuclide imaging [13][14][15][17][18][19][20][21][22][23][24][25][26]. The first PET tracer used clinically for αvβ3 imaging was [ 18 F]Galacto-RGD [27,28].…”

Molecular Imaging to Monitor Left Ventricular Remodeling in Heart Failure

“…Molecular imaging of αvβ3 is based on tracers that contain the RGD peptide subunit (the arginine-glycine-aspartate motif) that binds to the activated αvβ3 integrin. Several PET tracers targeting αvβ3 integrin have been evaluated in experimental models of MI [104,[106][107][108][109][110][111][112][113] and in patients with MI [114][115][116]. Studies have shown increased uptake of RGDbased radiotracers at the site of infarction as early as 3 days, peaking at 1-3 weeks after MI.…”