Browsing by Subject "Myocardial ischemia"

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  • Grönman, Maria; Tarkia, Miikka; Kiviniemi, Tuomas; Halonen, Paavo; Kuivanen, Antti; Savunen, Timo; Tolvanen, Tuula; Teuho, Jarmo; Käkelä, Meeri; Metsälä, Olli; Pietilä, Mikko; Saukko, Pekka; Ylä-Herttuala, Seppo; Knuuti, Juhani; Roivainen, Anne; Saraste, Antti (BioMed Central, 2017)
    Abstract Background Radiolabeled 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. Methods We 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. Results Stent 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. Conclusions Cardiac [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.
  • Koivula, Kimmo; Eskola, Markku; Viikilä, Juho; Lilleberg, Jyrki; Huhtala, Heini; Birnbaum, Yochai; Nikus, Kjell (2018)
    Background: Grade 3 ischemia (G3I) in the 12 lead electrocardiogram (ECG) predicts poor outcome in patients with ST-elevation myocardial infarction (STEMI). The outcome of G3I in "real-life" patient cohorts is unclear. Methods: The aim of the study was to establish the prognostic significance of grade 2 ischemia (G2I), G3I and the STEMI patients excluded from ischemia grading (No grade of ischemia, NG) in a real-life patient population. We assessed in-hospital, 30-day and 1-year mortality as well as other endpoints. Results: The NG patients had more comorbidities and longer treatment delays than the two other groups. Shortterm and 1-year mortality were highest in patients with NG and lowest in patients with G2I. Maximum troponin level was highest in G3I, followed by NG and G2I. In logistic regression multivariable analysis, NG was independently associated with 1-year mortality. Conclusions: NG predicted poor outcome in STEMI patients. G2I predicted relatively favorable outcome. (C) 2018 Elsevier Inc. All rights reserved.
  • Heliste, Juho; Jokilammi, Anne; Paatero, Ilkka; Chakroborty, Deepankar; Stark, Christoffer; Savunen, Timo; Laaksonen, Maria; Elenius, Klaus (BioMed Central, 2018)
    Abstract Background Receptor tyrosine kinases (RTK) are potential targets for the treatment of ischemic heart disease. The human RTK family consists of 55 members, most of which have not yet been characterized for expression or activity in the ischemic heart. Methods RTK gene expression was analyzed from human heart samples representing healthy tissue, acute myocardial infarction or ischemic cardiomyopathy. As an experimental model, pig heart with ischemia-reperfusion injury, caused by cardiopulmonary bypass, was used, from which phosphorylation status of RTKs was assessed with a phospho-RTK array. Expression and function of one RTK, ROR1, was further validated in pig tissue samples, and in HL-1 cardiomyocytes and H9c2 cardiomyoblasts, exposed to hypoxia and reoxygenation. ROR1 protein level was analyzed by Western blotting. Cell viability after ROR1 siRNA knockdown or activation with Wnt-5a ligand was assessed by MTT assays. Results In addition to previously characterized RTKs, a group of novel active and regulated RTKs was detected in the ischemic heart. ROR1 was the most significantly upregulated RTK in human ischemic cardiomyopathy. However, ROR1 phosphorylation was suppressed in the pig model of ischemia-reperfusion and ROR1 phosphorylation and expression were down-regulated in HL-1 cardiomyocytes subjected to short-term hypoxia in vitro. ROR1 expression in the pig heart was confirmed on protein and mRNA level. Functionally, ROR1 activity was associated with reduced viability of HL-1 cardiomyocytes in both normoxia and during hypoxia-reoxygenation. Conclusions Several novel RTKs were found to be regulated in expression or activity in ischemic heart. ROR1 was one of the most significantly regulated RTKs. The in vitro findings suggest a role for ROR1 as a potential target for the treatment of ischemic heart injury.
  • Heliste, Juho; Jokilammi, Anne; Paatero, Ilkka; Chakroborty, Deepankar; Stark, Christoffer; Savunen, Timo; Laaksonen, Maria; Elenius, Klaus (2018)
    BackgroundReceptor tyrosine kinases (RTK) are potential targets for the treatment of ischemic heart disease. The human RTK family consists of 55 members, most of which have not yet been characterized for expression or activity in the ischemic heart.MethodsRTK gene expression was analyzed from human heart samples representing healthy tissue, acute myocardial infarction or ischemic cardiomyopathy. As an experimental model, pig heart with ischemia-reperfusion injury, caused by cardiopulmonary bypass,was used, from which phosphorylation status of RTKs was assessed with a phospho-RTK array. Expression and function of one RTK, ROR1, was further validated in pig tissue samples, and in HL-1 cardiomyocytes and H9c2 cardiomyoblasts, exposed to hypoxia and reoxygenation. ROR1 protein level was analyzed by Western blotting. Cell viability after ROR1 siRNA knockdown or activation with Wnt-5a ligand was assessed by MTT assays.ResultsIn addition to previously characterized RTKs, a group of novel active and regulated RTKs was detected in the ischemic heart. ROR1 was the most significantly upregulated RTK in human ischemic cardiomyopathy. However, ROR1 phosphorylation was suppressed in the pig model of ischemia-reperfusion and ROR1 phosphorylation and expression were down-regulated in HL-1 cardiomyocytes subjected to short-term hypoxia in vitro. ROR1 expression in the pig heart was confirmed on protein and mRNA level. Functionally, ROR1 activity was associated with reduced viability of HL-1 cardiomyocytes in both normoxia and during hypoxia-reoxygenation.ConclusionsSeveral novel RTKs were found to be regulated in expression or activity in ischemic heart. ROR1 was one of the most significantly regulated RTKs. The in vitro findings suggest a role for ROR1 as a potential target for the treatment of ischemic heart injury.