Publications by authors named "Miikka Tarkia"

24 Publications

  • Page 1 of 1

Quantification of Myocardial Blood Flow by Machine Learning Analysis of Modified Dual Bolus MRI Examination.

Ann Biomed Eng 2021 Feb 20;49(2):653-662. Epub 2020 Aug 20.

Diagnostic Imaging Center, Kuopio University Hospital, PO Box 100, 70029 KYS, Kuopio, Finland.

Contrast-enhanced magnetic resonance imaging (MRI) is a promising method for estimating myocardial blood flow (MBF). However, it is often affected by noise from imaging artefacts, such as dark rim artefact obscuring relevant features. Machine learning enables extracting important features from such noisy data and is increasingly applied in areas where traditional approaches are limited. In this study, we investigate the capacity of machine learning, particularly support vector machines (SVM) and random forests (RF), for estimating MBF from tissue impulse response signal in an animal model. Domestic pigs (n = 5) were subjected to contrast enhanced first pass MRI (MRI-FP) and the impulse response at different regions of the myocardium (n = 24/pig) were evaluated at rest (n = 120) and stress (n = 96). Reference MBF was then measured using positron emission tomography (PET). Since the impulse response may include artefacts, classification models based on SVM and RF were developed to discriminate noisy signal. In addition, regression models based on SVM, RF and linear regression (for comparison) were developed for estimating MBF from the impulse response at rest and stress. The classification and regression models were trained on data from 4 pigs (n = 168) and tested on 1 pig (n = 48). Models based on SVM and RF outperformed linear regression, with higher correlation (R  = 0.81, R  = 0.74, R  = 0.60; ρ = 0.76, ρ = 0.76, ρ = 0.71) and lower error (RMSE = 0.67 mL/g/min, RMSE = 0.77 mL/g/min, RMSE = 0.96 mL/g/min) for predicting MBF from MRI impulse response signal. Classifier based on SVM was optimal for detecting impulse response signals with artefacts (accuracy = 92%). Modified dual bolus MRI signal, combined with machine learning, has potential for accurately estimating MBF at rest and stress states, even from signals with dark rim artefacts. This could provide a protocol for reliable and easy estimation of MBF, although further research is needed to clinically validate the approach.
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http://dx.doi.org/10.1007/s10439-020-02591-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851105PMC
February 2021

Epicardial transplantation of atrial appendage micrograft patch salvages myocardium after infarction.

J Heart Lung Transplant 2020 07 7;39(7):707-718. Epub 2020 Apr 7.

Department of Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland. Electronic address:

Background: Ischemic heart disease remains the leading cause of mortality and morbidity worldwide despite improved possibilities in medical care. Alongside interventional therapies, such as coronary artery bypass grafting, adjuvant tissue-engineered and cell-based treatments can provide regenerative improvement. Unfortunately, most of these advanced approaches require multiple lengthy and costly preparation stages without delivering significant clinical benefits.

Methods: We evaluated the effect of epicardially delivered minute pieces of atrial appendage tissue material, defined as atrial appendage micrografts (AAMs), in a mouse myocardial infarction model. An extracellular matrix patch was used to cover and fix the AAMs onto the surface of the infarcted heart.

Results: The matrix-covered AAMs salvaged the heart from the infarction-induced loss of functional myocardium and attenuated scarring. Site-selective proteomics of injured ischemic and uninjured distal myocardium from AAMs-treated and -untreated tissue sections revealed increased expression of several cardiac regeneration-associated proteins (i.e., periostin, transglutaminases, and glutathione peroxidases) and activation of pathways responsible for angiogenesis and cardiogenesis in relation to AAMs therapy.

Conclusions: Epicardial delivery of AAMs encased in an extracellular matrix patch scaffold salvages functional cardiac tissue from ischemic injury and restricts fibrosis after myocardial infarction. Our results support the use of AAMs as tissue-based therapy adjuvants for salvaging the ischemic myocardium.
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http://dx.doi.org/10.1016/j.healun.2020.03.023DOI Listing
July 2020

Quantification of porcine myocardial perfusion with modified dual bolus MRI - a prospective study with a PET reference.

BMC Med Imaging 2019 07 26;19(1):58. Epub 2019 Jul 26.

Diagnostic Imaging Center, Kuopio University Hospital, PO Box 100, 70029, Kuopio, KYS, Finland.

Background: The reliable quantification of myocardial blood flow (MBF) with MRI, necessitates the correction of errors in arterial input function (AIF) caused by the T1 saturation effect. The aim of this study was to compare MBF determined by a traditional dual bolus method against a modified dual bolus approach and to evaluate both methods against PET in a porcine model of myocardial ischemia.

Methods: Local myocardial ischemia was induced in five pigs, which were subsequently examined with contrast enhanced MRI (gadoteric acid) and PET (O-15 water). In the determination of MBF, the initial high concentration AIF was corrected using the ratio of low and high contrast AIF areas, normalized according to the corresponding heart rates. MBF was determined from the MRI, during stress and at rest, using the dual bolus and the modified dual bolus methods in 24 segments of the myocardium (total of 240 segments, five pigs in stress and rest). Due to image artifacts and technical problems 53% of the segments had to be rejected from further analyses. These two estimates were later compared against respective rest and stress PET-based MBF measurements.

Results: Values of MBF were determined for 112/240 regions. Correlations for MBF between the modified dual bolus method and PET was r = 0.84, and between the traditional dual bolus method and PET r = 0.79. The intraclass correlation was very good (ICC = 0.85) between the modified dual bolus method and PET, but poor between the traditional dual bolus method and PET (ICC = 0.07).

Conclusions: The modified dual bolus method showed a better agreement with PET than the traditional dual bolus method. The modified dual bolus method was found to be more reliable than the traditional dual bolus method, especially when there was variation in the heart rate. However, the difference between the MBF values estimated with either of the two MRI-based dual-bolus methods and those estimated with the gold-standard PET method were statistically significant.
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http://dx.doi.org/10.1186/s12880-019-0359-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6660956PMC
July 2019

Assessment of myocardial viability with [O]water PET: A validation study in experimental myocardial infarction.

J Nucl Cardiol 2019 Jul 17. Epub 2019 Jul 17.

Turku PET Centre, University of Turku, Turku, Finland.

Background: Assessment of myocardial viability is often needed in patients with chest pain and reduced ejection fraction. We evaluated the performance of reduced resting MBF, perfusable tissue fraction (PTF), and perfusable tissue index (PTI) in the assessment of myocardial viability in a pig model of myocardial infarction (MI).

Methods And Results: Pigs underwent resting [O]water PET perfusion study 12 weeks after surgical (n = 16) or 2 weeks after catheter-based (n = 4) occlusion of the proximal left anterior descending coronary artery. MBF, PTF, and PTI were compared with volume fraction of MI in matched segments as assessed by triphenyl tetrazolium chloride staining of LV slices. MBF and PTF were lower in infarcted than non-infarcted segments. Segmental analysis of MBF showed similar area under the curve (AUC) of 0.85, 0.86, and 0.90 with relative MBF, PTF, and PTI for the detection of viable myocardium defined as infarct volume fraction of < 75%. Cut-off values of relative MBF of ≥ 67% and PTF of ≥ 66% resulted in accuracies of 90% and 81%, respectively.

Conclusions: Our results indicate that resting MBF, PTF, and PTI based on [O]water PET perfusion imaging are useful for the assessment of myocardial viability.
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http://dx.doi.org/10.1007/s12350-019-01818-5DOI Listing
July 2019

Determinants of Myocardial Strain in Experimental Chronic Myocardial Infarction.

Ultrasound Med Biol 2019 02 19;45(2):568-578. Epub 2018 Nov 19.

Turku PET Centre, University of Turku and Turku University Hospital, Turku, Finland; Heart Center, Turku University Hospital and University of Turku, Turku, Finland; Institute of Clinical Medicine, University of Turku, Turku, Finland.

We evaluated the relationships between regional myocardial strain measured by speckle tracking echocardiography and viability, fibrosis, hypertrophy and oxygen consumption in the infarcted or remote myocardium in a pig model of chronic myocardial infarction (MI). Thirteen farm pigs with surgical occlusion of the left anterior descending coronary artery and five sham-operated pigs were studied 3 mo post-MI. Computed tomography revealed significant left ventricle remodeling. Reduced radial or circumferential strain identified areas of transmural infarction (area under the curve: 0.82 and 0.79, respectively). In the remote non-infarcted area, radial strain correlated inversely with the amount of fibrosis (r = -0.66, p = 0.04) and myocyte hypertrophy (r = -0.68, p = 0.03). Radial strain rate inversely correlated with myocardial resting oxygen consumption assessed with C-labeled acetate positron emission tomography (r = -0.71, p = 0.006). In conclusion, myocardial strain and strain rate reflect fibrosis, hypertrophy and oxygen consumption of the remote areas after MI.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2018.10.005DOI Listing
February 2019

Aluminum fluoride-18 labeled folate enables in vivo detection of atherosclerotic plaque inflammation by positron emission tomography.

Sci Rep 2018 06 26;8(1):9720. Epub 2018 Jun 26.

Turku PET Centre, University of Turku, Turku, Finland.

Inflammation plays an important role in the development of atherosclerosis and its complications. Because the folate receptor β (FR-β) is selectively expressed on macrophages, an FR targeted imaging agent could be useful for assessment of atherosclerotic inflammation. We investigated aluminum fluoride-18-labeled 1,4,7-triazacyclononane-1,4,7-triacetic acid conjugated folate (F-FOL) for the detection of atherosclerotic plaque inflammation. We studied atherosclerotic plaques in mice, rabbits, and human tissue samples using F-FOL positron emission tomography/computed tomography (PET/CT). Compound 2-deoxy-2-[F]fluoro-D-glucose (F-FDG) was used as a comparison. Firstly, we found that the in vitro binding of F-FOL co-localized with FR-β-positive macrophages in carotid endarterectomy samples from patients with recent ischemic symptoms. We then demonstrated specific accumulation of intravenously administered F-FOL in atherosclerotic plaques in mice and rabbits using PET/CT. We noticed that the F-FOL uptake correlated with the density of macrophages in plaques and provided a target-to-background ratio as high as F-FDG, but with considerably lower myocardial uptake. Thus, F-FOL PET/CT targeting of FR-β-positive macrophages presents a promising new tool for the in vivo imaging of atherosclerotic inflammation.
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http://dx.doi.org/10.1038/s41598-018-27618-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6018703PMC
June 2018

Characterizing the Key Metabolic Pathways of the Neonatal Mouse Heart Using a Quantitative Combinatorial Omics Approach.

Front Physiol 2018 11;9:365. Epub 2018 Apr 11.

Medicum, Department of Pharmacology, Faculty of Medicine, PB63, University of Helsinki, Helsinki, Finland.

The heart of a newborn mouse has an exceptional capacity to regenerate from myocardial injury that is lost within the first week of its life. In order to elucidate the molecular mechanisms taking place in the mouse heart during this critical period we applied an untargeted combinatory multiomics approach using large-scale mass spectrometry-based quantitative proteomics, metabolomics and mRNA sequencing on hearts from 1-day-old and 7-day-old mice. As a result, we quantified 1.937 proteins (366 differentially expressed), 612 metabolites (263 differentially regulated) and revealed 2.586 differentially expressed gene loci (2.175 annotated genes). The analyses pinpointed the fructose-induced glycolysis-pathway to be markedly active in 1-day-old neonatal mice. Integrated analysis of the data convincingly demonstrated cardiac metabolic reprogramming from glycolysis to oxidative phosphorylation in 7-days old mice, with increases of key enzymes and metabolites in fatty acid transport (acylcarnitines) and β-oxidation. An upsurge in the formation of reactive oxygen species and an increase in oxidative stress markers, e.g., lipid peroxidation, altered sphingolipid and plasmalogen metabolism were also evident in 7-days mice. maintenance of physiological fetal hypoxic conditions retained the proliferative capacity of cardiomyocytes isolated from newborn mice hearts. In summary, we provide here a holistic, multiomics view toward early postnatal changes associated with loss of a tissue regenerative capacity in the neonatal mouse heart. These results may provide insight into mechanisms of human cardiac diseases associated with tissue regenerative incapacity at the molecular level, and offer a prospect to discovery of novel therapeutic targets.
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http://dx.doi.org/10.3389/fphys.2018.00365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5904546PMC
April 2018

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

J Transl Med 2017 06 19;15(1):144. Epub 2017 Jun 19.

Turku PET Centre, University of Turku, 20521, Turku, Finland.

Background: Radiolabeled RGD peptides detect αβ integrin expression associated with angiogenesis and extracellular matrix remodeling after myocardial infarction. We studied whether cardiac positron emission tomography (PET) with [Ga]NODAGA-RGD detects increased αβ integrin expression after induction of flow-limiting coronary stenosis in pigs, and whether αβ 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 [Ga]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 [O]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, [Ga]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 [Ga]NODAGA-RGD uptake than the remote non-ischemic myocardium. Uptake of [Ga]NODAGA-RGD correlated with immunohistochemical detection of αβ integrin that was expressed in the injured myocardial areas.

Conclusions: Cardiac [Ga]NODAGA-RGD PET demonstrates increased myocardial αβ integrin expression after induction of flow-limiting coronary stenosis in pigs. Localization of [Ga]NODAGA-RGD uptake indicates that it reflects αβ integrin expression associated with repair of recent myocardial injury.
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http://dx.doi.org/10.1186/s12967-017-1245-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5477135PMC
June 2017

Accuracy of echocardiographic area-length method in chronic myocardial infarction: comparison with cardiac CT in pigs.

Cardiovasc Ultrasound 2017 Jan 9;15(1). Epub 2017 Jan 9.

Turku PET Centre, University of Turku and Turku University Hospital, Kiinamyllynkatu 4-8, Turku, 20520, Finland.

Background: We evaluated echocardiographic area-length methods to measure left ventricle (LV) volumes and ejection fraction (EF) in parasternal short axis views in comparison with cardiac computed tomography (CT) in pigs with chronic myocardial infarction (MI).

Methods: Male farm pigs with surgical occlusion of the left anterior descending coronary artery (n = 9) or sham operation (n = 5) had transthoracic echocardiography and cardiac-CT 3 months after surgery. We measured length of the LV in parasternal long axis view, and both systolic and diastolic LV areas in parasternal short axis views at the level of mitral valve, papillary muscles and apex. Volumes and EF of the LV were calculated using Simpson's method of discs (tri-plane area) or Cylinder-hemiellipsoid method (single plane area).

Results: The pigs with coronary occlusion had anterior MI scars and reduced EF (average EF 42 ± 10%) by CT. Measurements of LV volumes and EF were reproducible by echocardiography. Compared with CT, end-diastolic volume (EDV) measured by echocardiography showed good correlation and agreement using either Simpson's method (r = 0.90; mean difference -2, 95% CI -47 to 43 mL) or Cylinder-hemiellipsoid method (r = 0.94; mean difference 3, 95% CI -44 to 49 mL). Furthermore, End-systolic volume (ESV) measured by echocardiography showed also good correlation and agreement using either Simpson's method (r = 0.94; mean difference 12 ml, 95% CI: -16 to 40) or Cylinder-hemiellipsoid method (r = 0.97; mean difference:13 ml, 95% CI: -8 to 33). EF was underestimated using either Simpson's method (r = 0.78; mean difference -6, 95% CI -11 to 1%) or Cylinder-hemiellipsoid method (r = 0.74; mean difference -4, 95% CI-10 to 2%).

Conclusion: Our results indicate that measurement of LV volumes may be accurate, but EF is underestimated using either three or single parasternal short axis planes by echocardiography in a large animal model of chronic MI.
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http://dx.doi.org/10.1186/s12947-016-0093-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5223339PMC
January 2017

Low kidney uptake of GLP-1R-targeting, beta cell-specific PET tracer, F-labeled [Nle,Lys]exendin-4 analog, shows promise for clinical imaging.

EJNMMI Res 2016 Dec 13;6(1):91. Epub 2016 Dec 13.

Turku PET Centre, University of Turku, Turku, Finland.

Background: Several radiometal-labeled, exendin-based tracers that target glucagon-like peptide-1 receptors (GLP-1R) have been intensively explored for β cell imaging. The main obstacle has been the high uptake of tracer in the kidneys. This study aimed to develop a novel GLP1-R-specific tracer, with fluorine-18 attached to exendin-4, to label β cells for clinical imaging with PET (positron emission tomography). We hypothesized that this tracer would undergo reduced kidney uptake. F-labeled [Nle,Lys]exendin-4 analog ([F]exendin-4) was produced via Cu-catalyzed click chemistry. The biodistribution of [F]exendin-4 was assessed with ex vivo organ γ-counting and in vivo PET imaging. We also tested the in vivo stability of the radiotracer. The localization of F radioactivity in rat and human pancreatic tissue sections was investigated with autoradiography. Receptor specificity was assessed with unlabeled exendin-3. Islet labeling was confirmed with immunohistochemistry. The doses of radiation in humans were estimated based on biodistribution results in rats.

Results: [F]exendin-4 was synthesized with high yield and high specific activity. Results showed specific, sustained [F]exendin-4 uptake in pancreatic islets. In contrast to previous studies that tested radiometal-labeled exendin-based tracers, we observed rapid renal clearance of [F]exendin-4.

Conclusions: [F]exendin-4 showed promise as a tracer for clinical imaging of pancreatic β cells, due to its high specific uptake in native β cells and its concomitant low kidney radioactivity uptake.
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http://dx.doi.org/10.1186/s13550-016-0243-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5153397PMC
December 2016

Systemic Dosing of Thymosin Beta 4 before and after Ischemia Does Not Attenuate Global Myocardial Ischemia-Reperfusion Injury in Pigs.

Front Pharmacol 2016 3;7:115. Epub 2016 May 3.

Research Center of Applied and Preventive Cardiovascular Medicine, University of Turku Turku, Finland.

The use of cardiopulmonary bypass (CPB) and aortic cross-clamping causes myocardial ischemia-reperfusion injury (I-RI) and can lead to reduced postoperative cardiac function. We investigated whether this injury could be attenuated by thymosin beta 4 (TB4), a peptide which has showed cardioprotective effects. Pigs received either TB4 or vehicle and underwent CPB and aortic cross-clamping for 60 min with cold intermittent blood-cardioplegia and were then followed for 30 h. Myocardial function and blood flow was studied by cardiac magnetic resonance and PET imaging. Tissue and plasma samples were analyzed to determine the amount of cardiomyocyte necrosis and apoptosis as well as pharmacokinetics of the peptide. In vitro studies were performed to assess its influence on blood coagulation and vasomotor tone. Serum levels of the peptide were increased after administration compared to control samples. TB4 did not decrease the amount of cell death. Cardiac function and global myocardial blood flow was similar between the study groups. At high doses a vasoconstrictor effect on mesentery arteries and a vasodilator effect on coronary arteries was observed and blood clot firmness was reduced when tested in the presence of an antiplatelet agent. Despite promising results in previous trials the cardioprotective effect of TB4 was not demonstrated in this model for global myocardial I-RI.
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http://dx.doi.org/10.3389/fphar.2016.00115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4853610PMC
May 2016

AdVEGF-B186 and AdVEGF-DΔNΔC induce angiogenesis and increase perfusion in porcine myocardium.

Heart 2016 11 12;102(21):1716-1720. Epub 2016 May 12.

Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland Science Service Center, Kuopio University Hospital, Kuopio, Finland Gene Therapy Unit, Kuopio University Hospital, Kuopio, Finland.

Objective: Coronary heart disease remains a significant clinical problem, and new therapies are needed especially for patients with refractory angina for whom the current therapies do not provide sufficient relief. The aim of this study was to find out if angiogenic gene therapy using new members of the vascular endothelial growth factor (VEGF) family, VEGF-B and VEGF-D, increase myocardial perfusion as measured by the positron emission tomography (PET) O-imaging, and whether there would be coronary steal effect to the contralateral side. Furthermore, safety of intramyocardial angiogenic adenoviral gene transfer was evaluated.

Methods: Intramyocardial adenoviral (Ad) VEGF-B or AdVEGF-D gene transfers were given endovascularly into the porcine posterolateral wall of the left ventricle (n=34). Six days later, PET O-imaging for myocardial perfusion and coronary angiography were performed.

Results: AdVEGF-B and AdVEGF-D induced angiogenesis and increased total microvascular area 1.8-fold (95% CI 0.2 to 3.5) and 2.8-fold (95% CI 1.4 to 4.3), respectively. At rest, perfusion was maintained at normal levels, but at stress, relative perfusion was increased 1.4-fold (95% CI 1.1 to 1.7) for AdVEGF-B and 1.3-fold (95% CI 1.0 to 1.7) for AdVEGF-D, without causing coronary steal effect in the control area. The therapy was well tolerated and did not lead to any significant changes in laboratory safety parameters.

Conclusions: Both AdVEGF-B and AdVEGF-D gene transfers induced efficient angiogenesis in the myocardium resulting in an increased myocardial perfusion measured by PET. Importantly, local perfusion increase did not induce any coronary steal effect. As such, both treatments seem suitable new candidates for the induction of therapeutic angiogenesis for the treatment of refractory angina.
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http://dx.doi.org/10.1136/heartjnl-2016-309373DOI Listing
November 2016

Effect of levosimendan therapy on myocardial infarct size and left ventricular function after acute coronary occlusion.

Heart 2016 Mar 13;102(6):465-71. Epub 2016 Jan 13.

Turku PET Centre, University of Turku and Turku University Hospital, Turku, Finland.

Background: Levosimendan is an inotropic agent with cardioprotective and vasodilating properties used for the management of acutely decompensated heart failure. We studied the effects of levosimendan treatment on the size of myocardial infarction (MI) and left ventricular (LV) function in experimental pig model of post MI heart failure.

Methods: After occlusion of the left anterior descending (LAD) coronary artery, animals received levosimendan 5 mg/kg/day orally for 8 weeks (n=7) or no treatment (n=18). One week after stopping treatment, transthoracic echocardiography, CT scan and positron emission tomography were performed to evaluate myocardial function, perfusion and oxidative metabolism. Histology was used to confirm the size of MI and features of LV remodelling.

Results: The size of MI was significantly smaller in the levosimendan group than in the controls (12±13% vs 27±15% of the LV, p=0.03). End-diastolic volume (EDV) and end-systolic volume (ESV) were smaller in the levosimendan than in the control group (EDV 161±29 mL vs 245±84 mL, p=0.06; ESV 81±18 mL vs 149±67 mL, p=0.03), whereas ejection fraction tended to be higher in the levosimendan group (50±6% vs 41±8%, p=0.06).

Conclusions: Eight weeks of levosimendan therapy after recent LAD occlusion decreases the size of MI and leads to better preservation of LV function as well as reduced LV remodelling.
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http://dx.doi.org/10.1136/heartjnl-2015-308137DOI Listing
March 2016

[18F]FDG Accumulation in Early Coronary Atherosclerotic Lesions in Pigs.

PLoS One 2015 29;10(6):e0131332. Epub 2015 Jun 29.

Turku PET Centre, University of Turku and Turku University Hospital, Turku, Finland.

Objective: Inflammation is an important contributor to atherosclerosis progression. A glucose analogue 18F-fluorodeoxyglucose ([18F]FDG) has been used to detect atherosclerotic inflammation. However, it is not known to what extent [18F]FDG is taken up in different stages of atherosclerosis. We aimed to study the uptake of [18F]FDG to various stages of coronary plaques in a pig model.

Methods: First, diabetes was caused by streptozotocin injections (50 mg/kg for 3 days) in farm pigs (n = 10). After 6 months on high-fat diet, pigs underwent dual-gated cardiac PET/CT to measure [18F]FDG uptake in coronary arteries. Coronary segments (n = 33) were harvested for ex vivo measurement of radioactivity and autoradiography (ARG).

Results: Intimal thickening was observed in 16 segments and atheroma type plaques in 10 segments. Compared with the normal vessel wall, ARG showed 1.7±0.7 times higher [18F]FDG accumulation in the intimal thickening and 4.1±2.3 times higher in the atheromas (P = 0.004 and P = 0.003, respectively). Ex vivo mean vessel-to-blood ratio was higher in segments with atheroma than those without atherosclerosis (2.6±1.2 vs. 1.3±0.7, P = 0.04). In vivo PET imaging showed the highest target-to-background ratio (TBR) of 2.7. However, maximum TBR was not significantly different in segments without atherosclerosis (1.1±0.5) and either intimal thickening (1.2±0.4, P = 1.0) or atheroma (1.6±0.6, P = 0.4).

Conclusions: We found increased uptake of [18F]FDG in coronary atherosclerotic lesions in a pig model. However, uptake in these early stage lesions was not detectable with in vivo PET imaging. Further studies are needed to clarify whether visible [18F]FDG uptake in coronary arteries represents more advanced, highly inflamed plaques.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0131332PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4487365PMC
March 2016

Cardiac remodeling in a new pig model of chronic heart failure: Assessment of left ventricular functional, metabolic, and structural changes using PET, CT, and echocardiography.

J Nucl Cardiol 2015 Aug 20;22(4):655-65. Epub 2015 Feb 20.

Turku PET Centre, University of Turku and Turku University Hospital, Kiinamyllynkatu 4-8, 20521, Turku, Finland,

Aims: Large animal models are needed to study disease mechanisms in heart failure (HF). In the present study we characterized the functional, metabolic, and structural changes of myocardium in a novel pig model of chronic myocardial infarction (MI) by using multimodality imaging and histology.

Methods And Results: Male farm pigs underwent a two-step occlusion of the left anterior descending coronary artery with concurrent distal ligation and implantation of a proximal ameroid constrictor (HF group), or sham operation (control group). Three months after the operation, cardiac output and wall stress were measured by echocardiography. Left ventricle (LV) volumes and mass were measured by computed tomography (CT). Myocardial perfusion was evaluated by [(15)O]water and oxygen consumption using [(11)C]acetate positron emission tomography, and the efficiency of myocardial work was calculated. Histological examinations were conducted to detect MI, hypertrophy, and fibrosis. Animals in the HF group had a large anterior MI scar. CT showed larger LV diastolic volume and lower ejection fraction in HF pigs than in controls. Perfusion and oxygen consumption in the remote non-infarcted myocardium were preserved in HF pigs as compared to controls. Global LV work and efficiency were significantly lower in HF than control pigs and was associated with increased wall stress. Histology showed myocyte hypertrophy but not increased interstitial fibrosis in the remote segments in HF pigs.

Conclusions: The chronic post-infarction model of HF is suitable for studies aimed to evaluate LV remodeling and changes in oxidative metabolism and can be useful for testing new therapies for HF.
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http://dx.doi.org/10.1007/s12350-015-0068-9DOI Listing
August 2015

Intracranial biodegradable silica-based nimodipine drug release implant for treating vasospasm in subarachnoid hemorrhage in an experimental healthy pig and dog model.

Biomed Res Int 2015 22;2015:715752. Epub 2015 Jan 22.

Clinical Neurosciences, Department of Neurosurgery, Turku University Hospital, P.O. Box 52, Hämeentie 11, 20521 Turku, Finland.

Nimodipine is a widely used medication for treating delayed cerebral ischemia (DCI) after subarachnoid hemorrhage. When administrated orally or intravenously, systemic hypotension is an undesirable side effect. Intracranial subarachnoid delivery of nimodipine during aneurysm clipping may be more efficient way of preventing vasospasm and DCI due to higher concentration of nimodipine in cerebrospinal fluid (CSF). The risk of systemic hypotension may also be decreased with intracranial delivery. We used animal models to evaluate the feasibility of surgically implanting a silica-based nimodipine releasing implant into the subarachnoid space through a frontotemporal craniotomy. Concentrations of released nimodipine were measured from plasma samples and CSF samples. Implant degradation was followed using CT imaging. After completing the recovery period, full histological examination was performed on the brain and meninges. The in vitro characteristics of the implant were determined. Our results show that the biodegradable silica-based implant can be used for an intracranial drug delivery system and no major histopathological foreign body reactions were observed. CT imaging is a feasible method for determining the degradation of silica implants in vivo. The sustained release profiles of nimodipine in CSF were achieved. Compared to a traditional treatment, higher nimodipine CSF/plasma ratios can be obtained with the implant.
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http://dx.doi.org/10.1155/2015/715752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4317635PMC
November 2015

Absorption, elimination and cerebrospinal fluid concentrations of nimodipine in healthy beagle dogs receiving human intravenous and oral formulation.

Eur J Drug Metab Pharmacokinet 2016 Jun 5;41(3):295-300. Epub 2015 Feb 5.

Clinical Neurosciences, Department of Neurosurgery, Turku University Central Hospital, Hämeentie 11, P.O. Box 52, 20521, Turku, Finland.

Nimodipine is an L-type calcium channel blocker and is used to treat vasospasm in patients with subarachnoid hemorrhage. Its putative mechanism of action is relaxation of smooth muscle cells in cerebral arteries. In addition, nimodipine may have pleiotropic effects against vasospasm. Systemic hypotension is an adverse effect when patients are treated with oral or intravenous nimodipine. Intracranial administration of nimodipine formulations may produce higher concentration of nimodipine in the cerebrospinal fluid (CSF) than is possible to achieve orally or intravenously, while resulting in lower incidence of systemic hypotension. The aim of this study was to provide information on plasma and CSF levels of nimodipine in beagle dogs as a comparative data for development of experimental intracranial treatment modalities. Plasma levels of nimodipine were measured after current 30 and 60 mg single oral dose of nimodipine (Nimotop(®) 30 mg tablets), a single intravenous bolus 0.72 mg/dog of nimodipine (Nimotop(®) 0.2 mg/ml infusion solution) and CSF levels after 60 mg single oral dose of nimodipine. CSF/Plasma concentration ratio of nimodipine after oral administration of 60 mg at 1 h was 0.013 ± 0.0005. The mean terminal elimination half-life of nimodipine after i.v. bolus dose 0.72 mg was 1.8 h and mean plasma clearance was 40.3 and 3.4 l/h/kg. Absolute bioavailability was 22 %. Maximum plasma concentration and area under the plasma concentration-time curve from time of administration until the last measurable plasma concentration increased in a dose-proportional manner comparing the exposure parameters at oral doses of 30 and 60 mg. Individual variation in the kinetic profile of nimodipine was measured.
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http://dx.doi.org/10.1007/s13318-015-0258-5DOI Listing
June 2016

Assessment of blood flow with (68)Ga-DOTA PET in experimental inflammation: a validation study using (15)O-water.

Am J Nucl Med Mol Imaging 2014 6;4(6):571-9. Epub 2014 Sep 6.

Turku PET Centre Turku, Finland ; Turku Center for Disease Modeling, University of Turku Turku, Finland.

Increased blood flow and vascular permeability are key events in inflammation. Based on the fact that Gadolinium-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (Gd-DOTA) is commonly used in magnetic resonance (MR) imaging of blood flow (perfusion), we evaluated the feasibility of its Gallium-68 labeled DOTA analog ((68)Ga-DOTA) for positron emission tomography (PET) imaging of blood flow in experimental inflammation. Adult, male Sprague-Dawley rats with turpentine oil induced sterile skin/muscle inflammation were anesthetized with isoflurane, and imaged under rest and adenosine-induced hyperemia by means of dynamic 2-min Oxygen-15 labeled water (H2 (15)O) and 30-min (68)Ga-DOTA PET. For the quantification of PET data, regions of interest (ROIs) were defined in the focus of inflammation, healthy muscle, myocardium and heart left ventricle. Radioactivity concentration in the ROIs versus time after injection was determined for both tracers and blood flow was calculated using image-derived input. According to the H2 (15)O PET, blood flow was 0.69 ± 0.15 ml/min/g for inflammation and 0.15 ± 0.03 ml/min/g for muscle during rest. The blood flow remained unchanged during adenosine-induced hyperemia 0.67 ± 0.11 and 0.12 ± 0.03 ml/min/g for inflammation and muscle, respectively, indicating that adenosine has little effect on blood flow in peripheral tissues in rats. High focal uptake of (68)Ga-DOTA was seen at the site of inflammation throughout the 30-min PET imaging. According to the (68)Ga-DOTA PET, blood flow measured as the blood-to-tissue transport rate (K1) was 0.60 ± 0.07 ml/min/g for inflammation and 0.14 ± 0.06 ml/min/g for muscle during rest and 0.63 ± 0.08 ml/min/g for inflammation and 0.09 ± 0.04 ml/min/g for muscle during adenosine-induced hyperemia. The H2 (15)O-based blood flow and (68)Ga-DOTA-based K1 values correlated well (r = 0.94, P < 0.0001). These results show that (68)Ga-DOTA PET imaging is useful for the quantification of increased blood flow induced by inflammation.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4171843PMC
September 2014

Pancreatic metabolism, blood flow, and β-cell function in obese humans.

J Clin Endocrinol Metab 2014 Jun 14;99(6):E981-90. Epub 2014 Feb 14.

Turku PET Centre (H.H., J.C.H., M.T., H.K., V.S., K.M., V.O., M.H.-S., A.R., R.P., P.N.), University of Turku, Turku 20520, Finland; Division of Digestive Surgery and Urology (P.S.) and Department of Endocrinology (P.N., M.S.), Turku University Hospital, Turku 20520, Finland; Faculty of Medicine (N.K.), University of Kagawa, Kagawa 760-0016, Japan; Department of Radiology (R.P.), University of Tampere, Tampere 33014, Finland; Institute of Biomedical Engineering (P.I.), National Research Council, 35128 Padua, Italy; and Institute of Clinical Physiology (P.I.), National Research Council, 56124 Pisa, Italy.

Context: Glucolipotoxicity is believed to induce pancreatic β-cell dysfunction in obesity. Previously, it has not been possible to study pancreatic metabolism and blood flow in humans.

Objective: The objective of the study was to investigate whether pancreatic metabolism and blood flow are altered in obesity using positron emission tomography (PET). In the preclinical part, the method was validated in animals.

Design: This was a cross-sectional study.

Setting: The study was conducted in a clinical research center.

Participants: Human studies consisted of 52 morbidly obese and 25 healthy age-matched control subjects. Validation experiments were done with rodents and pigs.

Interventions: PET and magnetic resonance imaging studies using a glucose analog ([(18)F]fluoro-2-deoxy-d-glucose), a palmitate analog [14(R,S)-[(18)F]fluoro-6-thia-heptadecanoic acid], and radiowater ([(15)O]H2O) were performed. In animals, a comparison between ex vivo and in vivo data was performed.

Main Outcome Measures: Pancreatic glucose/fatty acid (FA) uptake, fat accumulation, and blood flow parameters of β-cell function were measured.

Results: PET proved to be a feasible method to measure pancreatic metabolism. Compared with healthy participants, obese participants had elevated pancreatic FA uptake (P < .0001), more fat accumulation (P = .0001), lowered glucose uptake both during fasting and euglycemic hyperinsulinemia, and blunted blood flow (P < .01) in the pancreas. Blood flow, FA uptake, and fat accumulation were negatively associated with multiple markers of β-cell function.

Conclusions: Obesity leads to changes in pancreatic energy metabolism with a substrate shift from glucose to FAs. In morbidly obese humans, impaired pancreatic blood flow may contribute to β-cell dysfunction and in the pathogenesis of type 2 diabetes.
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http://dx.doi.org/10.1210/jc.2013-4369DOI Listing
June 2014

Vertebral bone marrow glucose uptake is inversely associated with bone marrow fat in diabetic and healthy pigs: [(18)F]FDG-PET and MRI study.

Bone 2014 Apr 3;61:33-8. Epub 2014 Jan 3.

Department of Radiology, Tampere University and Tampere University Hospital, PL 2000, 33521 Tampere, Finland; Department of Radiology, University of Turku, Medical Imaging Centre of Southwest Finland and Turku University Hospital, Kiinamyllynkatu 4-8, 20520 Turku, Finland. Electronic address:

Objectives: Diabetes induces osteoporosis and during osteoporosis, vertebral bone marrow (VBM) adipose tissue amount increases. The association between this adiposity and bone marrow metabolism is unclear. Here, we compared VBM glucose metabolism and fat content in healthy and diabetic pigs, in vivo, using positron emission tomography (PET), in-phase and out-of-phase magnetic resonance imaging and magnetic resonance proton spectroscopy ((1)H MR spectroscopy).

Materials/methods: Eleven pigs (n=11) were used. The intervention group had five diabetic and the control group had six healthy pigs. To measure metabolism, PET-imaging with [(18)F]fluoro-deoxy-glucose ([(18)F]FDG) intravenous tracer was used. 1.5-T MRI with (1)H spectroscopy, in-phase and out-of-phase imaging and chemical TAG analysis of the VBM were performed.

Results: We found a significant inverse correlation between VBM glucose uptake (GU) and VBM fat content (R=-0.800, p<0.01) and TAG concentration assay (R=-0.846, p<0.05). There was a trend, although non-significant, of a linear correlation between VBM (1)H MR spectroscopy and TAG concentration (R=0.661) and (1)H MR spectroscopy and in-phase and out-of-phase MR imaging (R=0.635).

Conclusions: VBM glucose metabolism coupled with VBM fat content may impact diabetic induced osteoporosis.
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http://dx.doi.org/10.1016/j.bone.2013.12.022DOI Listing
April 2014

The bottleneck stent model for chronic myocardial ischemia and heart failure in pigs.

Am J Physiol Heart Circ Physiol 2013 Nov 30;305(9):H1297-308. Epub 2013 Aug 30.

Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland;

A large animal model of chronic myocardial ischemia and heart failure is crucial for the development of novel therapeutic approaches. In this study we developed a novel percutaneous one- and two-vessel model for chronic myocardial ischemia using a stent coated with a polytetrafluoroethylene tube formed in a bottleneck shape. The bottleneck stent was implanted in the proximal left anterior descending (LAD) or proximal circumflex artery (LCX), or in both proximal LCX and mid LAD 1 wk later (2-vessel model), and pigs were followed for 4-5 wk. Ejection fraction (EF), infarct size, collateral growth, and myocardial perfusion were assessed. Pigs were given antiarrhythmic medication to prevent sudden death. The occlusion time of the bottleneck stent and the timing of myocardial infarction could be modulated by the duration of antiplatelet medication. Fractional flow reserve measurements and positron emission tomography imaging showed severe ischemia after bottleneck stenting covering over 50% of the left ventricle in the proximal LAD model. Complete coronary occlusion was necessary for significant collateral growth, which mostly had occurred already during the first wk after the stent occlusion. Dynamic and competitive collateral growth patterns were observed. EF declined from 64 to 41% in the LCX model and to 44% in the LAD model 4 wk after stenting with 12 and 21% infarcted left ventricle in the LCX and LAD models, respectively. The mortality was 32 and 37% in the LCX and LAD models but very (71%) high in the two-vessel disease model. The implantation of a novel bottleneck stent in the proximal LAD or LCX is a novel porcine model of reversible myocardial ischemia (open stent) and ischemic heart failure (occluded stent) and is feasible for the development of new therapeutic approaches.
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http://dx.doi.org/10.1152/ajpheart.00561.2013DOI Listing
November 2013

Therapeutic potential of thymosin β4 in myocardial infarct and heart failure.

Ann N Y Acad Sci 2012 Oct;1269:117-24

Department of Surgery, Turku University Central Hospital, Turku, Finland.

Thymosin β4 (Tβ4) is a peptide known for its abilities to protect and facilitate regeneration in a number of tissues following injury. Its cardioprotective effects have been evaluated in different animal models and, currently, a clinical trial is being planned in patients suffering from acute myocardial infarction. This paper focuses on the effects of Tβ4 on cardiac function in animal studies utilizing different imaging modalities for outcome measurements.
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http://dx.doi.org/10.1111/j.1749-6632.2012.06695.xDOI Listing
October 2012

Evaluation of 68Ga-labeled tracers for PET imaging of myocardial perfusion in pigs.

Nucl Med Biol 2012 Jul 20;39(5):715-23. Epub 2012 Jan 20.

Turku PET Centre, Department of Medicine, University of Turku and Turku University Hospital, FI-20521 Turku, Finland.

Purpose: We evaluated four potential gallium-68 (68Ga)-labeled tracers for positron emission tomography (PET) imaging of myocardial perfusion in comparison with oxygen-15-labeled water ([15O]water) in healthy pigs. Four hexadentate salicylaldimine ligands derived from bis(3-aminopropyl)ethylenediamine (BAPEN) that showed promise in previous rat experiments were selected for this study.

Methods: Following an evaluation of myocardial blood flow with [15O]water PET, the pigs (total n=14) underwent a dynamic 90-min PET study with one of four 68Ga-labeled BAPEN derivatives (n=3-5 per tracer) either at rest or under adenosine stress. Serial arterial blood samples were collected during the imaging for the measurements of total radioactivity, radiometabolites, plasma protein binding and blood-to-plasma ratio for the 68Ga chelates. Time-activity curves of the left ventricular blood pool and myocardium were derived from PET images, and metabolite-corrected arterial input function was used for kinetic modeling. Also, ex vivo biodistribution of 68Ga radioactivity was analyzed.

Results: All four 68Ga tracers showed undesirably slow myocardial accumulation over time, but their in vivo stability, clearance from blood and the kinetics of the myocardium uptake varied. [68Ga][Ga-(sal)2BAPDMEN]1+ showed the highest myocardial uptake in PET images and tissue samples (myocardium-to-blood ratio 7.63±1.89, myocardium-to-lung ratio 3.03±0.33 and myocardium-to-liver ratio 1.80±0.82). However, there was no correlation between the myocardial perfusion measured with [15O]water and the net uptake rates or K1 values of the 68Ga chelates.

Conclusion: Our results revealed that myocardial accumulation of the 68Ga chelates proposed for myocardial perfusion imaging with PET was slow and not determined by myocardial perfusion in a large animal model. These findings suggest that the studied tracers are not suitable for clinical imaging of myocardial perfusion.
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http://dx.doi.org/10.1016/j.nucmedbio.2011.11.007DOI Listing
July 2012

Cross-validation of input functions obtained by H₂ 15O PET imaging of rat heart and a blood flow-through detector.

Mol Imaging Biol 2012 Aug;14(4):509-16

Turku PET Centre, University of Turku and Turku University Hospital, Finland.

Purpose: Positron emission tomography (PET) with ¹⁵O-labeled water (H₂ ¹⁵O) facilitates the visualization and quantification of blood flow in clinical investigations and also in small animals. The quantification of blood flow requires an input function, which is generally obtained by measuring radioactivity in arterial blood withdrawn during PET scanning. However, this approach is not always feasible, because abundant blood sampling may affect the physiological process being measured. The purpose of the present study was to develop and cross-validate two methods, namely, a blood- and an image-based method for obtaining the input function for blood flow studies from rat H₂ ¹⁵O PET.

Methods: The study material consisted of two separate groups of rats. Group 1 rats were imaged twice by a high-resolution research tomograph PET camera at resting condition for a test-retest study (n = 4), and group 2 rats were imaged with and without adenosine infusion for a rest-stress study (n = 4). In group 1, radioactivity concentration in arterial blood was measured with a new flow-through detector during imaging and a blood-based input function was obtained. The image-based input function was estimated using time-activity curves from the left ventricle and myocardial regions. To validate the two input function methods, myocardial blood flow (MBF) and cerebral blood flow (CBF) were computed, and the methods were tested for reproducibility (test-retest study) and changes (rest-stress study).

Results: The blood- and image-based input functions were similar, and the corresponding CBF values differed only by -6.9 ± 8.1%. In the test-retest study, both MBF and CBF showed good reproducibility, and in the rest-stress study, adenosine significantly increased both MBF (P = 0.035) and CBF (P = 0.029), compared with the resting condition.

Conclusion: It is possible both to measure the input function from rat arteria femoralis during H₂ ¹⁵O PET imaging and to estimate the input function from rat H₂ ¹⁵O PET images, thereby facilitating the assessment of blood flow in organs visible in PET images.
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http://dx.doi.org/10.1007/s11307-011-0511-5DOI Listing
August 2012