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Detection of increased myocardial integrin alphaVbeta3 expression in a pig model of inducible myocardial ischemia using [68Ga]-NODAGA-RGD PET




List of Authors: Grönman Maria, Tarkia Miikka, Käkelä Meeri, Halonen Paavo, Kiviniemi Tuomas, Pietilä Mikko, Ylä-Herttuala Seppo, Knuuti Juhani, Roivainen Anne, Saraste Antti
Publication year: 2015
Journal: EHJ Cardiovascular Imaging / European Heart Journal - Cardiovascular Imaging
Volume number: 16

Abstract


Purpose: Increased integrin αvβ3 expression can be detected by radiolabeled arginine-glycine-aspartic acid (RGD) peptides in the myocardium after an acute myocardial infarction (MI). However, RGD uptake in chronic myocardial ischemia is unknown. Therefore, we studied the feasibility of non-invasive imaging of integrin αvβ3 expression with the use of 68Ga-NODAGA-RGD PET in a pig model of chronic flow-limiting stenosis induced by a bottleneck stent.



Methods: A flow-limiting bottleneck stent was implanted under fluoroscopy guidance in the proximal left anterior descending (LAD) artery of 11 Finnish landrace pigs ageing 12 weeks. Antithrombotic therapy was used to prevent stent thrombosis. After 1 week, myocardial perfusion was evaluated by 15O-water PET at rest and during adenosine-induced stress. Ischemic area-at-risk was defined as perfusion defect (<70% of maximum) during adenosine-induced stress. A 60-min PET study was performed after injection of 300±31 MBq of 68Ga-NODAGA-RGD. Then, the heart was sliced and based on triphenyltetrazolium chloride (TTC) staining, tissue samples from the viable and non-viable myocardium at the ischemic area-at-risk were obtained for ex vivo measurement of tracer uptake and autoradiography.



Results: Eight pigs had ischemic area-at-risk (average area 19 % of the left ventricle) based on PET perfusion imaging during adenosine-induced stress. In 5 of these, there was also a resting perfusion defect (average area 45% of the ischemic area-at-risk) where TTC showed non-viable myocardium. In PET imaging, myocardial 68Ga-NODAGA-RGD uptake was higher in the ischemic area-at-risk than in the remote myocardium (ischemic-to-remote ratio 1.45±0.26; p=0.004). ). To further asses the location and mechanism of the 68Ga-NODAGA-RGD accumulation, ex vivo analyses were performed separately for the viable and non-viable myocardial regions inside the ischemic area-at-risk. The highest 68Ga-NODAGA-RGD uptake was found in the damaged myocardial areas (non-viable myocardium-to-remote ratio 1.88±0.81; p=0.044) but it was not increased in viable regions.



Conclusions: 68Ga-NODAGA-RGD PET demonstrates increased integrin αvβ3 expression in the ischemic myocardium in a pig model of flow limiting stenosis. This increase, however, appears to be co-localized in the non-viable myocardial areas while no increase was seen in regions with inducible ischemia but no scar. The results suggest that increased integrin αvβ3 expression and 68Ga-NODAGA-RGD uptake are markers of myocardial ischemic injury.



Last updated on 2019-29-01 at 12:54