77 results on '"Zlabinger K"'
Search Results
2. Increased cardiac output and left ventricular contractility in pigs paced with vs. without restored respiratory sinus arrhythmia - proof of principle of a newly developed pacing device
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Riesenhuber, M, primary, Spannbauer, A, additional, Hasimbegovic, E, additional, Muller-Zlabinger, K, additional, Lukovic, D, additional, Hamzaraj, K, additional, Han, E, additional, Hemetsberger, R, additional, Aasmul, S, additional, Leonhardt, M, additional, Kushwah, C, additional, Nogaret, A, additional, Hengstenberg, C, additional, and Gyongyosi, M, additional
- Published
- 2023
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3. P121918F-FDG perfusion-metabolism mismatch 3 days after acute myocardial infarction predicts worse outcome: molecular glucose steel phenomenon visualized by hybrid PET-MRI images
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Pavo, I J, primary, Gyongyosi, M, additional, Jakab, A, additional, Lukovic, D, additional, Zlabinger, K, additional, Gigerell, A, additional, Winkler, J, additional, and Pavo, N, additional
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- 2019
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4. P5990In vivo tracking of long-term survival of xenogeneic porcine mesenchymal stem cells seeded on tissue-engineered heart valve implanted in sheep
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Gyongyosi, M, primary, Lukovic, D, additional, Pavo, N, additional, Gugerell, A, additional, Winkler, J, additional, Spannbauer, A, additional, Pavo, I J, additional, Michel-Behnke, I, additional, Emmert, M Y, additional, Hoerstrup, S P, additional, Marian, T, additional, Balkay, L, additional, Trencsenyi, G, additional, Wu, J C, additional, and Zlabinger, K, additional
- Published
- 2019
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5. P110Effect of MMP-2 on compromised homing of intracoronary delivery of mesenchymal stem cell in a porcine reperfused myocardial infarction: comparison with intramyocardial cell delivery
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Gugerell, A, primary, Zlabinger, K, additional, Lukovic, D, additional, Winkler, J, additional, Hemetsberger, R, additional, Mandic, L J, additional, Traxler, D, additional, Spannbauer, A, additional, Pavo, N, additional, and Gyongyosi, M, additional
- Published
- 2018
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6. P145Distinct alterations between transcriptomic profiles of fibrotic porcine hearts induced by cardiac remodeling, hypertrophy, or cardiotoxicity
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Winkler, J, primary, Lukovic, D, additional, Zlabinger, K, additional, Gugerell, A, additional, Spannbauer, A, additional, Traxler, D, additional, Pavo, N, additional, Bergler-Klein, J, additional, and Gyongyosi, M, additional
- Published
- 2018
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7. P476Intraventricular measurement of electrophysiological parameters in pre- or post-conditioned myocardial infarction
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Spannbauer, A, primary, Traxler, D, additional, Pavo, N, additional, Riesenhuber, M, additional, Mueller, C, additional, Gugerell, A, additional, Winkler, J, additional, Zlabinger, K, additional, Lukovic, D, additional, and Gyongyosi, M, additional
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- 2018
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8. P474Stable PET-reporter gene transfection of MSCs for in vivo long-term cell tracking in xenogeneic transplanted tissue engineered heart valves
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Zlabinger, K, primary, Lukovic, D, additional, Gugerell, A, additional, Winkler, J, additional, Spannbauer, A, additional, Emmert, M, additional, Hoerstrup, S P, additional, and Gyoengyoesi, M, additional
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- 2018
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9. P541Evaluation of plasma exosomal miRNA-1, miRNA-133 and miRNA-208 levels in a porcine model during acute myocardial infarction
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Mueller, C, primary, Spannbauer, A, additional, Traxler, D, additional, Lukovic, D, additional, Borger, A, additional, Zlabinger, K, additional, Winkler, J, additional, Gugerell, A, additional, and Gyongyosi, M, additional
- Published
- 2018
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10. 240Mesenchymal stem cells transfected with minicircle-HIF-1a decreases LV adverse remodelling via release of cardioprotective miRNAs and pro-angiogenic factors
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Gara, E, primary, Ong, S G, additional, Winkler, J, additional, Zlabinger, K, additional, Lukovic, D, additional, Jakab, A, additional, Merkely, B, additional, Wu, J C, additional, Gyongyosi, M, additional, and Pavo, N, additional
- Published
- 2018
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11. P516Systemic clusterin but not neprilysin levels are associated with acute myocardial infarction
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Traxler-Weidenauer, D, primary, Gyongyosi, M, additional, Winkler, J, additional, Zlabinger, K, additional, Gugerell, A, additional, Spannbauer, A, additional, Lukovic, D, additional, and Pavo, N, additional
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- 2018
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12. 403Induction of interferon-related genes limits the cardiotoxicity of liposomal doxorubicin in pigs
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Lukovic, D, primary, Zlabinger, K, additional, Spannbauer, A, additional, Gugerell, A, additional, Pavo, N, additional, Traxler, D, additional, Jakab, A, additional, Bergler-Klein, J, additional, Gyongyosi, M, additional, and Winkler, J, additional
- Published
- 2018
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13. Differential regulation of profibrotic genes responsible for cardiotoxicity after experimental anticancer treatments
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Gyongyosi, M., primary, Zlabinger, K., additional, Lukovic, D., additional, Spannbauer, A., additional, Maurer, G., additional, and Bergler-Klein, J., additional
- Published
- 2016
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14. Rapid Fire Abstract session: new insights in cardiomyopthies434The role of 4D echocardiography and cardiac biomarkers for early detection of chemotherapy induced cardiotoxicity in nonHodgkin lymphoma patients435Identification of proto-oncogenes and genes responsible for myocardial fibrosis and diastolic dysfunction after anticancer treatment under experimental conditions436Wild type transthyretin cardiac amyloidosis: clinical characteristics, echocardiographic findings, and predictors of outcome437A novel echocardiographic index for detection of cardiac amyloidosis.438Left ventricular outflow obstruction is a treatable feature rather than a risk marker in patients with hypertrophic cardiomyopathy439The international stress echo registry in hypertrophic cardiomyopathy440Value of left atrial size and function to risk stratify for new onset atrial fibrillation in hypertrophic cardiomyopathy441Right ventricle ejection fraction by cardiac resonance imaging is superior in discrimination between early phase ARVC and right ventricular outflow tract ventricular tachycardia
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Mihalcea, D, primary, Bergler-Klein, J, primary, Grogan, M, primary, Pagourelias, E, primary, Faber, L, primary, Ciampi, Q, primary, Debonnaire, P, primary, Saberniak, J, primary, Florescu, M, additional, Vladareanu, AM, additional, Mihaila, S, additional, Vinereanu, D, additional, Spannbauer, A, additional, Zlabinger, K, additional, Macejovska, D, additional, Maurer, G, additional, Gyongyosi, M, additional, Scott, C, additional, Lin, G, additional, Klarich, K, additional, Miller, W, additional, Dispenzieri, A, additional, Mirea, OC, additional, Duchenne, J, additional, Vovas, G, additional, Van Aelst, L, additional, Claus, P, additional, Van Cleemput, J, additional, Delforge, M, additional, Bogaert, J, additional, Voigt, JU, additional, Burghardt, A, additional, Seggewiss, H, additional, Van Buuren, F, additional, Horstkotte, D, additional, Olivotto, I, additional, Gardini, C, additional, Monserrat, L, additional, Peteiro, J, additional, Lopes, L, additional, Cotrim, C, additional, Losi, MA, additional, Lazzeroni, DE, additional, Picano, E, additional, Joyce, E, additional, Van Den Brink, OVW, additional, Bax, JJ, additional, Delgado, V, additional, Ajmone Marsan, N, additional, Leren, IS, additional, Haland, TF, additional, Hopp, E, additional, Edvardsen, T, additional, and Haugaa, KH, additional
- Published
- 2015
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15. 1574P - Differential regulation of profibrotic genes responsible for cardiotoxicity after experimental anticancer treatments
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Gyongyosi, M., Zlabinger, K., Lukovic, D., Spannbauer, A., Maurer, G., and Bergler-Klein, J.
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- 2016
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16. Cardiac Stem Cell-based Regenerative Therapy for the Ischemic Injured Heart — a Short Update 2017
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Gyöngyösi Mariann, Lukovic Dominika, Zlabinger Katrin, Mandic Ljubica, Winkler Johannes, and Gugerell Alfred
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stem cells ,ischemic heart diseases ,cardiac regeneration ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
Cell therapy for the ischemic injured heart has been largely investigated in the last two decades, and most of the small cohort and randomized clinical studies, as well as meta-analyses led to the conclusion that cell-based human regenerative therapy is safe and effective in term of reducing adverse clinical outcomes and increasing left ventricular performance. Both the in vitro and in vivo rodent animal models of ischemic heart failure using bone marrow-derived mononuclear cells promised marvelous success in regeneration of the heart suffering from ischemic burden. However, in certain patient groups, stem cell studies failed to reach the primary endpoint, showing no effect of this regenerative therapy. This brief overview addresses the contradictory results between human cardiac regenerative studies and the very positive rodent experiments.
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- 2017
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17. Molecular Imaging of Angiogenesis in Cardiac Regeneration
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Mandic L, Traxler D, Alfred Gugerell, Zlabinger K, Lukovic D, Pavo N, Goliasch G, Spannbauer A, Winkler J, and Gyöngyösi M
18. Rapid Fire Abstract session: new insights in cardiomyopthies
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Mihalcea, D, Florescu, M, Vladareanu, AM, Mihaila, S, Vinereanu, D, Bergler-Klein, J, Spannbauer, A, Zlabinger, K, Macejovska, D, Maurer, G, Gyongyosi, M, Grogan, M, Scott, C, Lin, G, Klarich, K, Miller, W, Dispenzieri, A, Pagourelias, E, Mirea, OC, Duchenne, J, Vovas, G, Van Aelst, L, Claus, P, Van Cleemput, J, Delforge, M, Bogaert, J, Voigt, JU, Faber, L, Burghardt, A, Seggewiss, H, Van Buuren, F, Horstkotte, D, Ciampi, Q, Olivotto, I, Gardini, C, Monserrat, L, Peteiro, J, Lopes, L, Cotrim, C, Losi, MA, Lazzeroni, DE, Picano, E, Debonnaire, P, Joyce, E, Van Den Brink, OVW, Bax, JJ, Delgado, V, Ajmone Marsan, N, Saberniak, J, Leren, IS, Haland, TF, Hopp, E, Edvardsen, T, and Haugaa, KH
- Abstract
CHOP regimen is standard chemotherapy in patients with non-Hodgkin's lymphoma (NHL), but its use is limited by the risk of cardiotoxicity. Aim. To define new parameters, such as 4D echo (4DE) LV deformation or biomarkers, to diagnose early cardiac dysfunction and predict cardiotoxicity. Methods. 37 patients (13 men, 62 ± 12 years) with NHL, without cardiac disease, with EF>53%, scheduled to receive CHOP, were assessed at baseline, after the 2nd and 4th cycle. 4DE was used to assess EF and LV systolic deformation: longitudinal, radial, circumferential, area strain (LS, RS, CS, AS). Troponin I was measured. Cardiotoxicity was defined as a decrease of EF <53%, with >10% from the baseline. Results. After the 4th cycle of CHOP, 10 patients (27%) (group I) developed cardiotoxicity, while 27 patients (group II) didn't. There was a significant reduction of all LV systolic deformation parameters starting with the 2nd cycle, but group I had lower values than group II (Table). The reduction of the LS after the 2nd cycle was the best independent predictor for the decrease of EF after the 4th cycle (R2=0.44, p=0.0001); a decrease of LS with >30% after the 2nd cycle predicted the development of cardiotoxicity after the 4th cycle (sb 100%, sp 85%). Conclusion. Assessment of 4DE myocardial deformation parameters are able to detect early chemotherapy-induced cardiotoxicity and to predict further changes in the EF of patients with NHL.
4D deformation parameters CHOP Group I Group II p value (Anova) LS (-%) Baseline 22 ± 2 22 ± 2 0.0001 2nd cycle 10 ± 1 16 ± 2* 0.0001 4th cycle 8 ± 1* 12 ± 2* 0.0001 CS (-%) Baseline 21 ± 2* 21 ± 2* 0.0001 2nd cycle 15 ± 1* 17 ± 2* 0.05 4th cycle 12 ± 3* 15 ± 1* 0.0001 RS (%) Baseline 56 ± 5* 56 ± 5* 0.0001 2nd cycle 40 ± 5* 46 ± 6* 0.05 4th cycle 33 ± 6* 39 ± 6* 0.0001 AS(%) Baseline 35 ± 4* 36 ± 4* 0.0001 2nd cycle 22 ± 5 28 ± 4* 0.0001 4th cycle 17 ± 5* 23 ± 4 0.01 - Published
- 2015
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19. Increased [ 18 F]FDG uptake in the infarcted myocardial area displayed by combined PET/CMR correlates with snRNA-seq-detected inflammatory cell invasion.
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Lukovic D, Gyöngyösi M, Pavo IJ, Mester-Tonczar J, Einzinger P, Zlabinger K, Kastner N, Spannbauer A, Traxler D, Pavo N, Goliasch G, Pils D, Jakab A, Szankai Z, Michel-Behnke I, Zhang L, Devaux Y, Graf S, Beitzke D, and Winkler J
- Abstract
Combined [
18 F]FDG PET-cardiac MRI imaging (PET/CMR) is a useful tool to assess myocardial viability and cardiac function in patients with acute myocardial infarction (AMI). Here, we evaluated the prognostic value of PET/CMR in a porcine closed-chest reperfused AMI (rAMI) model. Late gadolinium enhancement by PET/CMR imaging displayed tracer uptake defect at the infarction site by 3 days after the rAMI in the majority of the animals (group Match, n = 28). Increased [18 F]FDG uptake at the infarcted area (metabolism/contractility mismatch) with reduced tracer uptake in the remote viable myocardium (group Mismatch, n = 12) 3 days after rAMI was observed in the animals with larger infarct size and worse left ventricular ejection fraction (LVEF) (34 ± 8.7 vs 42.0 ± 5.2%), with lower LVEF also at the 1-month follow-up (35.8 ± 9.5 vs 43.0 ± 6.3%). Transcriptome analyses by bulk and single-nuclei RNA sequencing of the infarcted myocardium and border zones (n = 3 of each group, and 3 sham-operated controls) revealed a strong inflammatory response with infiltration of monocytes and macrophages in the infarcted and border areas in Mismatch animals. Our data indicate a high prognostic relevance of combined PET/MRI in the subacute phase of rAMI for subsequent impairment of heart function and underline the adverse effects of an excessive activation of the innate immune system in the initial phase after rAMI., (© 2024. The Author(s).)- Published
- 2024
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20. Improvement of Symptoms and Cardiac Magnetic Resonance Abnormalities in Patients with Post-Acute Sequelae of SARS-CoV-2 Cardiovascular Syndrome (PASC-CVS) after Guideline-Oriented Therapy.
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Gyöngyösi M, Hasimbegovic E, Han E, Zlabinger K, Spannbauer A, Riesenhuber M, Hamzaraj K, Bergler-Klein J, Hengstenberg C, Kammerlander A, Kastl S, Loewe C, and Beitzke D
- Abstract
Cardiac magnetic resonance (CMR) studies reported CMR abnormalities in patients with mild-moderate SARS-CoV-2 infection, suggesting ongoing myocardial inflammation. Patients ( n = 278, 43 ± 13 years, 70.5% female) with post-acute sequelae of SARS-CoV-2 cardiovascular syndrome (PASC-CVS) were included prospectively into the Vienna POSTCOV Registry between March 2021 and March 2023 (clinicaltrials.gov NCT05398952). Clinical, laboratory, and CMR findings were recorded. Patients with abnormal CMR results were classified into isolated chronic pericardial (with/without pleural) effusion, isolated cardiac function impairment, or both (myopericarditis) groups. Medical treatment included a nonsteroidal anti-inflammatory agent (NSAID) for pericardial effusion and a condition-adapted maximal dose of heart failure (HF) treatment. Three months after medical therapy, clinical assessment and CMR were repeated in 82 patients. Laboratory analyses revealed normal hematological, inflammatory, coagulation, and cardiac biomarkers. CMR abnormalities were found in 155 patients (55.8%). Condition-adapted HF treatment led to a significant increase in the left ventricular ejection fraction (LVEF) in patients with initially reduced LVEF (from 49 ± 5% to 56 ± 4%, p = 0.009, n = 25). Low-moderate doses of NSAIDs for 3 months significantly reduced pericardial effusion (from 4/3;5.75/mm to 2/0;3/mm, median/interquartile ranges/ p < 0.001, n = 51). Clinical symptoms improved markedly with a decrease in CMR abnormalities, which might be attributed to the maintenance of NSAID and HF medical treatment for PASC-CVS.
- Published
- 2023
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21. A CircRNA-miRNA-mRNA Network for Exploring Doxorubicin- and Myocet-Induced Cardiotoxicity in a Translational Porcine Model.
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Mester-Tonczar J, Einzinger P, Hasimbegovic E, Kastner N, Schweiger V, Spannbauer A, Han E, Müller-Zlabinger K, Traxler-Weidenauer D, Bergler-Klein J, Gyöngyösi M, and Lukovic D
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- Swine, Animals, RNA, Circular genetics, RNA, Messenger genetics, Doxorubicin toxicity, Cardiotoxicity genetics, Antibiotics, Antineoplastic toxicity, Sus scrofa genetics, Sus scrofa metabolism, MicroRNAs genetics, MicroRNAs metabolism
- Abstract
Despite the widespread use of doxorubicin (DOX) as a chemotherapeutic agent, its severe cumulative cardiotoxicity represents a significant limitation. While the liposomal encapsulation of doxorubicin (Myocet, MYO) reduces cardiotoxicity, it is crucial to understand the molecular background of doxorubicin-induced cardiotoxicity. Here, we examined circular RNA expression in a translational model of pigs treated with either DOX or MYO and its potential impact on the global gene expression pattern in the myocardium. This study furthers our knowledge about the regulatory network of circRNA/miRNA/mRNA and its interaction with chemotherapeutics. Domestic pigs were treated with three cycles of anthracycline drugs (DOX, n = 5; MYO, n = 5) to induce cardiotoxicity. Untreated animals served as controls (control, n = 3). We applied a bulk mRNA-seq approach and the CIRIquant algorithm to identify circRNAs. The most differentially regulated circRNAs were validated under cell culture conditions, following forecasting of the circRNA-miRNA-mRNA network. We identified eight novel significantly regulated circRNAs from exonic and mitochondrial regions in the porcine myocardium. The forecasted circRNA-miRNA-mRNA network suggested candidate circRNAs that sponge miR-17, miR-15b, miR-130b, the let-7 family, and miR125, together with their mRNA targets. The identified circRNA-miRNA-mRNA network provides an updated, coherent view of the mechanisms involved in anthracycline-induced cardiotoxicity.
- Published
- 2023
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22. Effect of monovalent COVID-19 vaccines on viral interference between SARS-CoV-2 and several DNA viruses in patients with long-COVID syndrome.
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Gyöngyösi M, Lukovic D, Mester-Tonczar J, Zlabinger K, Einzinger P, Spannbauer A, Schweiger V, Schefberger K, Samaha E, Bergler-Klein J, Riesenhuber M, Nitsche C, Hengstenberg C, Mucher P, Haslacher H, Breuer M, Strassl R, Puchhammer-Stöckl E, Loewe C, Beitzke D, Hasimbegovic E, and Zelniker TA
- Abstract
Epstein-Barr virus (EBV) reactivation may be involved in long-COVID symptoms, but reactivation of other viruses as a factor has received less attention. Here we evaluated the reactivation of parvovirus-B19 and several members of the Herpesviridae family (DNA viruses) in patients with long-COVID syndrome. We hypothesized that monovalent COVID-19 vaccines inhibit viral interference between SARS-CoV-2 and several DNA viruses in patients with long-COVID syndrome, thereby reducing clinical symptoms. Clinical and laboratory data for 252 consecutive patients with PCR-verified past SARS-CoV-2 infection and long-COVID syndrome (155 vaccinated and 97 non-vaccinated) were recorded during April 2021-May 2022 (median 243 days post-COVID-19 infection). DNA virus-related IgG and IgM titers were compared between vaccinated and non-vaccinated long-COVID patients and with age- and sex-matched non-infected, unvaccinated (pan-negative for spike-antibody) controls. Vaccination with monovalent COVID-19 vaccines was associated with significantly less frequent fatigue and multiorgan symptoms (p < 0.001), significantly less cumulative DNA virus-related IgM positivity, significantly lower levels of plasma IgG subfractions 2 and 4, and significantly lower quantitative cytomegalovirus IgG and IgM and EBV IgM titers. These results indicate that anti-SARS-CoV-2 vaccination may interrupt viral cross-talk in patients with long-COVID syndrome (ClinicalTrials.gov Identifier: NCT05398952)., (© 2023. Springer Nature Limited.)
- Published
- 2023
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23. Plasma Small Extracellular Vesicle Cardiac miRNA Expression in Patients with Ischemic Heart Failure, Randomized to Percutaneous Intramyocardial Treatment of Adipose Derived Stem Cells or Placebo: Subanalysis of the SCIENCE Study.
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Traxler D, Dannenberg V, Zlabinger K, Gugerell A, Mester-Tonczar J, Lukovic D, Spannbauer A, Hasimbegovic E, Kastrup J, and Gyöngyösi M
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- Humans, Adipose Tissue, Stem Cells, MicroRNAs genetics, Heart Failure, Extracellular Vesicles genetics, Myocardial Ischemia genetics, Myocardial Ischemia therapy
- Abstract
Small extracellular vesicles (EVs) and their cargo are an important component of cell-to-cell communication in cardiac disease. Allogeneic adipose derived stem cells (ADSCs) are thought to be a potential approach for cardiac regenerative therapy in ischemic heart disease. The SCIENCE study investigated the effect of ADSCs administered via intramyocardial injection on cardiac function in patients with ischemic heart disease. The aim of this substudy, based on samples from 15 patients, was to explore small EV miRNA dynamics after treatment with ADSCs compared to a placebo. Small EVs were isolated at several timepoints after the percutaneous intramyocardial application of ADSCs. No significant effect of ADSC treatment on small EV concentration was detected. After 12 months, the expression of miR-126 decreased significantly in ADSC patients, but not in the placebo-treated group. However, all cardiac miRNAs correlated with plasma cardiac biomarkers. In line with the overall negative results of the SCIENCE study, with the exception of one miR, we did not detect any significant regulation of small EV miRNAs in this patient collective.
- Published
- 2023
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24. Identification of Gene Expression Signatures for Phenotype-Specific Drug Targeting of Cardiac Fibrosis.
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Lukovic D, Hasimbegovic E, Winkler J, Mester-Tonczar J, Müller-Zlabinger K, Han E, Spannbauer A, Traxler-Weidenauer D, Bergler-Klein J, Pavo N, Goliasch G, Batkai S, Thum T, Zannad F, and Gyöngyösi M
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- Animals, Transcriptome, Angiotensin Receptor Antagonists, Angiotensin-Converting Enzyme Inhibitors pharmacology, Cardiotoxicity pathology, Doxorubicin pharmacology, Phenotype, Fibrosis, Drug Delivery Systems, Myocardium metabolism, Disease Models, Animal, Cardiomyopathies metabolism, Heart Failure pathology
- Abstract
We have designed translational animal models to investigate cardiac profibrotic gene signatures. Domestic pigs were treated with cardiotoxic drugs (doxorubicin, DOX, n = 5 or Myocet
® , MYO, n = 5) to induce replacement fibrosis via cardiotoxicity. Reactive interstitial fibrosis was triggered by LV pressure overload by artificial isthmus stenosis with stepwise developing myocardial hypertrophy and final fibrosis (Hyper, n = 3) or by LV volume overload in the adverse remodeled LV after myocardial infarction (RemoLV, n = 3). Sham interventions served as controls and healthy animals (Control, n = 3) served as a reference in sequencing study. Myocardial samples from the LV of each group were subjected to RNA sequencing. RNA-seq analysis revealed a clear distinction between the transcriptomes of myocardial fibrosis (MF) models. Cardiotoxic drugs activated the TNF-alpha and adrenergic signaling pathways. Pressure or volume overload led to the activation of FoxO pathway. Significant upregulation of pathway components enabled the identification of potential drug candidates used for the treatment of heart failure, such as ACE inhibitors, ARB, ß-blockers, statins and diuretics specific to the distinct MF models. We identified candidate drugs in the groups of channel blockers, thiostrepton that targets the FOXM1-regulated ACE conversion to ACE2, tyrosine kinases or peroxisome proliferator-activated receptor inhibitors. Our study identified different gene targets involved in the development of distinct preclinical MF protocols enabling tailoring expression signature-based approach for the treatment of MF.- Published
- 2023
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25. Peri-Interventional Triple Therapy with Dabigatran Modifies Vasomotion after Bare-Metal Stent Implantation in a Pig Coronary Artery Model.
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Hemetsberger R, Farhan S, Lukovic D, Zlabinger K, Hajagos-Toth J, Bota J, Garcia-Garcia HM, Ay C, Samaha E, Gaspar R, Garamvölgyi R, Huber K, Spannbauer A, and Gyöngyösi M
- Abstract
(1) Background: Coronary artery stenting leads to local inflammation, disturbs vasomotion, and slows endothelialization, increasing vascular thrombus risk. We used a pig stenting coronary artery model to assess how peri-interventional triple therapy with dabigatran ameliorates these effects. (2) Methods: In a total of 28 pigs bare-metal stents were implanted. Four days before the percutaneous coronary intervention (PCI), we started 16 of the animals on dabigatran, maintained through 4 days after the procedure. As controls, the remaining 12 pigs received no therapy. In both groups, dual antiplatelet therapy (DAPT) (clopidogrel, 75 mg plus aspirin, 100 mg) was administered until animals were euthanized. Just after the PCI and on day 3 after the procedure, we performed optical coherence tomography (OCT) in eight animals in the dabigatran group and four controls and euthanized them. We followed the eight remaining animals in each group with OCT and angiography for one month before euthanizing them and performed in vitro myometry and histology on harvested coronary arteries from all animals. (3) Results: The dabigatran group showed a significantly increased vasoconstriction at 3 days after PCI (10.97 ± 3.85 mN vs. 7.32 ± 5.41 mN, p = 0.03), but we found no differences between endothelium-dependent and -independent vasodilatation. We also found no group differences in OCT, quantitative angiography, or histomorphometry findings. (4) Conclusions: Starting a short course of dabigatran just before PCI and continuing for a 3-day window along with usual post-PCI DAPT is associated with enhanced vasoconstriction after bare-metal stent implantation without reducing neointimal formation at one month.
- Published
- 2023
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26. Cell-Based HIF1α Gene Therapy Reduces Myocardial Scar and Enhances Angiopoietic Proteome, Transcriptomic and miRNA Expression in Experimental Chronic Left Ventricular Dysfunction.
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Gara E, Ong SG, Winkler J, Zlabinger K, Lukovic D, Merkely B, Emmert MY, Wolint P, Hoerstrup SP, Gyöngyösi M, Wu JC, and Pavo N
- Abstract
Recent preclinical investigations and clinical trials with stem cells mostly studied bone-marrow-derived mononuclear cells (BM-MNCs), which so far failed to meet clinically significant functional study endpoints. BM-MNCs containing small proportions of stem cells provide little regenerative potential, while mesenchymal stem cells (MSCs) promise effective therapy via paracrine impact. Genetic engineering for rationally enhancing paracrine effects of implanted stem cells is an attractive option for further development of therapeutic cardiac repair strategies. Non-viral, efficient transfection methods promise improved clinical translation, longevity and a high level of gene delivery. Hypoxia-induced factor 1α is responsible for pro-angiogenic, anti-apoptotic and anti-remodeling mechanisms. Here we aimed to apply a cellular gene therapy model in chronic ischemic heart failure in pigs. A non-viral circular minicircle DNA vector (MiCi) was used for in vitro transfection of porcine MSCs (pMSC) with HIF1α (pMSC-MiCi-HIF-1α). pMSCs-MiCi-HIF-1α were injected endomyocardially into the border zone of an anterior myocardial infarction one month post-reperfused-infarct. Cell injection was guided via 3D-guided NOGA electro-magnetic catheter delivery system. pMSC-MiCi-HIF-1α delivery improved cardiac output and reduced myocardial scar size. Abundances of pro-angiogenic proteins were analyzed 12, 24 h and 1 month after the delivery of the regenerative substances. In a protein array, the significantly increased angiogenesis proteins were Activin A, Angiopoietin, Artemin, Endothelin-1, MCP-1; and remodeling factors ADAMTS1, FGFs, TGFb1, MMPs, and Serpins. In a qPCR analysis, increased levels of angiopeptin, CXCL12, HIF-1α and miR-132 were found 24 h after cell-based gene delivery, compared to those in untreated animals with infarction and in control animals. Expression of angiopeptin increased already 12 h after treatment, and miR-1 expression was reduced at that time point. In total, pMSC overexpressing HIF-1α showed beneficial effects for treatment of ischemic injury, mediated by stimulation of angiogenesis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Gara, Ong, Winkler, Zlabinger, Lukovic, Merkely, Emmert, Wolint, Hoerstrup, Gyöngyösi, Wu and Pavo.)
- Published
- 2022
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27. Peri-interventional Triple Therapy With Dabigatran Improves Vasomotion and Promotes Endothelialization in Porcine Coronary Stenting Model.
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Hemetsberger R, Farhan S, Lukovic D, Zlabinger K, Hajagos-Toth J, Bota J, Garcia-Garcia HM, Ay C, Samaha E, Gaspar R, Garamvölgyi R, Huber K, Gyöngyösi M, and Spannbauer A
- Abstract
Objective: We evaluated the short and long-term effect of peri-interventional dabigatran therapy on vasomotion, endothelialization, and neointimal formation in a porcine coronary artery stenting model. Background: Stenting of coronary arteries induces local inflammation, impairs vasomotion and delays endothelialization. Methods: Twenty-eight animals underwent percutaneous coronary intervention (PCI) with drug eluting stents. Sixteen pigs started dabigatran therapy 4 days prior to PCI and continued for 4 days post-stenting, while 12 animals served as controls. Post-stenting dual antiplatelet therapy (75 mg clopidogrel and 100 mg aspirin) was continued in both groups until termination. Immediately post-stenting and at day 3 optical coherence tomography (OCT) was performed in all animals, followed by euthanasia of 8 dabigatran and 4 control animals. The remaining pigs (8 of each group) were followed up for 1 month, with control angiography and OCT. Tissue burden (degree of peri-strut structure-thrombus and/or fibrin) was evaluated. After euthanasia coronary arteries were harvested for in-vitro myometry and histology. Results: Thrombin generation was lower ( p < 0.001) and tissue burden (0.83 ± 0.98 vs. 3.0 ± 2.45; p = 0.031) was significantly decreased in dabigatran treated animals. After 3 days post-PCI endothelium-dependent vasodilation was significantly improved (77 ± 40% vs. 41 ± 31%, p = 0.02) in dabigatran animals. Neither quantitative angiography nor histomorphometry showed differences between the groups. Endothelialization was faster in the dabigatran group as compared with controls ( p = 0.045). Conclusion: Short-term peri-interventional triple therapy with dabigatran, aspirin, and clopidogrel led to an enhanced endothelium dependent vasodilation and faster endothelialization. However, neointimal formation 1-month after stent implantation was comparable between groups., Competing Interests: KH reports lecture and consultation fees from Astra Zeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo Pfizer, and Sanofi with this manuscript. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hemetsberger, Farhan, Lukovic, Zlabinger, Hajagos-Toth, Bota, Garcia-Garcia, Ay, Samaha, Gaspar, Garamvölgyi, Huber, Gyöngyösi and Spannbauer.)
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- 2021
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28. Secondary mitral regurgitation-Insights from microRNA assessment.
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Spinka G, Bartko PE, Pavo N, Freitag C, Zlabinger K, Prausmüller S, Arfsten H, Heitzinger G, Mascherbauer J, Hengstenberg C, Gyöngyösi M, Hülsmann M, and Goliasch G
- Subjects
- Aged, Case-Control Studies, Echocardiography, Female, Heart Failure complications, Heart Failure diagnostic imaging, Heart Failure physiopathology, Humans, Male, Middle Aged, Mitral Valve Insufficiency diagnostic imaging, Mitral Valve Insufficiency etiology, Mitral Valve Insufficiency physiopathology, Stroke Volume physiology, Heart Failure genetics, MicroRNAs metabolism, Mitral Valve Insufficiency genetics
- Abstract
Background: While secondary mitral regurgitation (sMR) is associated with adverse outcome in heart failure with reduced ejection fraction (HFrEF), key pathophysiologic mechanisms remain poorly understood and might be elucidated by microRNAs (miRNA/miR), that were recently related to cardiac remodelling. This study sought to assess (i) the differences of miRNA profiles in patients with severe sMR compared to matched disease controls, (ii) the correlation between circulating miRNAs and surrogates of sMR severity as well as (iii) the prognostic implications of miRNA levels in severe sMR., Materials and Methods: Sixty-six HFrEF patients were included, of these 44 patients with severe sMR 2:1 matched to HFrEF controls with no/mild sMR. A comprehensive set of miRNAs (miR-21, miR-29a, miR-122, miR-132, miR-133a, miR-let7i) were measured and correlated to echocardiographic sMR severity., Results: miRNA patterns differed distinctly between patients with severe sMR and HFrEF controls (P < .05). Among the panel of assessed miRNAs, miR-133a correlated most strongly with surrogates of sMR severity (r = -0.41, P = .001 with sMR vena contracta width). Interestingly, elevated levels of miR-133 were associated with an increased risk for cardiovascular death and/or HF hospitalizations with and adjusted HR of 1.85 (95% CI 1.24-2.76, P = .003)., Conclusions: This study unveils distinct pathophysiologic maladaptions at a cellular level in patients with severe sMR compared to no/mild sMR by showing significant differences in miRNA profiles and correlations with sMR severity, supporting the concept that sMR drives cardiac remodelling in heart failure. Moreover, the increased risk for adverse outcome in HFrEF patients with severe sMR conveyed by miR-133a might indicate irreversible myocardial damage., (© The Authors. European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)
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- 2021
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29. Novel Identified Circular Transcript of RCAN2, circ-RCAN2, Shows Deviated Expression Pattern in Pig Reperfused Infarcted Myocardium and Hypoxic Porcine Cardiac Progenitor Cells In Vitro.
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Mester-Tonczar J, Einzinger P, Winkler J, Kastner N, Spannbauer A, Zlabinger K, Traxler D, Lukovic D, Hasimbegovic E, Goliasch G, Pavo N, and Gyöngyösi M
- Subjects
- Animals, Cell Hypoxia genetics, Computational Biology, Coronary Angiography, Disease Models, Animal, Down-Regulation, Female, Humans, Myoblasts, Cardiac metabolism, Myocardial Infarction diagnosis, Myocardial Infarction genetics, Myocardial Reperfusion Injury diagnosis, Myocardial Reperfusion Injury pathology, Myocardium pathology, RNA-Seq, Sus scrofa, Up-Regulation, Gene Regulatory Networks, Myoblasts, Cardiac pathology, Myocardial Infarction complications, Myocardial Reperfusion Injury genetics, RNA, Circular metabolism
- Abstract
Circular RNAs (circRNAs) are crucial in gene regulatory networks and disease development, yet circRNA expression in myocardial infarction (MI) is poorly understood. Here, we harvested myocardium samples from domestic pigs 3 days after closed-chest reperfused MI or sham surgery. Cardiac circRNAs were identified by RNA-sequencing of rRNA-depleted RNA from infarcted and healthy myocardium tissue samples. Bioinformatics analysis was performed using the CIRIfull and KNIFE algorithms, and circRNAs identified with both algorithms were subjected to differential expression (DE) analysis and validation by qPCR. Circ-RCAN2 and circ-C12orf29 expressions were significantly downregulated in infarcted tissue compared to healthy pig heart. Sanger sequencing was performed to identify the backsplice junctions of circular transcripts. Finally, we compared the expressions of circ-C12orf29 and circ-RCAN2 between porcine cardiac progenitor cells (pCPCs) that were incubated in a hypoxia chamber for different time periods versus normoxic pCPCs. Circ-C12orf29 did not show significant DE in vitro, whereas circ-RCAN2 exhibited significant ischemia-time-dependent upregulation in hypoxic pCPCs. Overall, our results revealed novel cardiac circRNAs with DE patterns in pCPCs, and in infarcted and healthy myocardium. Circ-RCAN2 exhibited differential regulation by myocardial infarction in vivo and by hypoxia in vitro. These results will improve our understanding of circRNA regulation during acute MI.
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- 2021
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30. CDR132L improves systolic and diastolic function in a large animal model of chronic heart failure.
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Batkai S, Genschel C, Viereck J, Rump S, Bär C, Borchert T, Traxler D, Riesenhuber M, Spannbauer A, Lukovic D, Zlabinger K, Hašimbegović E, Winkler J, Garamvölgyi R, Neitzel S, Gyöngyösi M, and Thum T
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- Animals, Diastole, Disease Models, Animal, Swine, Ventricular Remodeling, Heart Failure drug therapy, Myocardial Infarction drug therapy
- Abstract
Aims: Cardiac miR-132 activation leads to adverse remodelling and pathological hypertrophy. CDR132L is a synthetic lead-optimized oligonucleotide inhibitor with proven preclinical efficacy and safety in heart failure (HF) early after myocardial infarction (MI), and recently completed clinical evaluation in a Phase 1b study (NCT04045405). The aim of the current study was to assess safety and efficacy of CDR132L in a clinically relevant large animal (pig) model of chronic heart failure following MI., Methods and Results: In a chronic model of post-MI HF, slow-growing pigs underwent 90 min left anterior descending artery occlusion followed by reperfusion. Animals were randomized and treatment started 1-month post-MI. Monthly intravenous (IV) treatments of CDR132L over 3 or 5 months (3× or 5×) were applied in a blinded randomized placebo-controlled fashion. Efficacy was evaluated based on serial magnetic resonance imaging, haemodynamic, and biomarker analyses. The treatment regime provided sufficient tissue exposure and CDR132L was well tolerated. Overall, CDR132L treatment significantly improved cardiac function and reversed cardiac remodelling. In addition to the systolic recovery, diastolic function was also ameliorated in this chronic model of HF., Conclusion: Monthly repeated dosing of CDR132L is safe and adequate to provide clinically relevant exposure and therapeutic efficacy in a model of chronic post-MI HF. CDR132L thus should be explored as treatment for the broad area of chronic heart failure., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)
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- 2021
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31. Comparative Effect of MSC Secretome to MSC Co-culture on Cardiomyocyte Gene Expression Under Hypoxic Conditions in vitro .
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Kastner N, Mester-Tonczar J, Winkler J, Traxler D, Spannbauer A, Rüger BM, Goliasch G, Pavo N, Gyöngyösi M, and Zlabinger K
- Abstract
Introduction: Despite major leaps in regenerative medicine, the regeneration of cardiomyocytes after ischemic conditions remains to elucidate. It is crucial to understand hypoxia induced cellular mechanisms to provide advanced treatment options, including the use of stem cell paracrine factors for myocardial regeneration., Materials and Methods: In this study, the regenerative potential of hypoxic human cardiomyocytes (group Hyp-CMC) in vitro was evaluated when co-cultured with human bone-marrow derived MSC (group Hyp-CMC-MSC) or stimulated with the secretome of MSC (group Hyp-CMC-S
MSC ). The secretome of normoxic MSC and CMC, and the hypoxic CMC was analyzed with a cytokine panel. Gene expression changes of HIF-1 α, proliferation marker Ki-67 and cytokinesis marker RhoA over different reoxygenation time periods of 4, 8, 24, 48, and 72 h were analyzed in comparison to normoxic CMC and MSC. Further, the proinflammatory cytokine IL-18 protein expression change, metabolic activity and proliferation was assessed in all experimental setups., Results and Conclusion: HIF-1 α was persistently overexpressed in Hyp-CMC-SMSC as compared to Hyp-CMC (except at 72 h). Hyp-CMC-MSC showed a weaker HIF-1 α expression than Hyp-CMC-SMSC in most tested time points, except after 8 h. The Ki-67 expression showed the strongest upregulation in Hyp-CMC after 24 and 48 h incubation, then returned to baseline level, while a temporary increase in Ki-67 expression in Hyp-CMC-MSC at 4 and 8 h and at 48 h in Hyp-CMC-SMSC could be observed. RhoA was increased in normoxic MSCs and in Hyp-CMC-SMSC over time, but not in Hyp-CMC-MSC. A temporary increase in IL-18 protein expression was detected in Hyp-CMC-SMSC and Hyp-CMC. Our study demonstrates timely dynamic changes in expression of different ischemia and regeneration-related genes of CMCs, depending from the culture condition, with stronger expression of HIF-1 α, RhoA and IL-18 if the hypoxic CMC were subjected to the secretome of MSCs., (Copyright © 2020 Kastner, Mester-Tonczar, Winkler, Traxler, Spannbauer, Rüger, Goliasch, Pavo, Gyöngyösi and Zlabinger.)- Published
- 2020
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32. Large Animal Models of Cell-Free Cardiac Regeneration.
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Spannbauer A, Mester-Tonczar J, Traxler D, Kastner N, Zlabinger K, Hašimbegović E, Riesenhuber M, Pavo N, Goliasch G, and Gyöngyösi M
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- Animals, Disease Models, Animal, Heart physiopathology, Humans, Myocardial Infarction physiopathology, Myocytes, Cardiac metabolism, Swine genetics, Swine physiology, Cell-Free System, Heart growth & development, Myocardial Infarction therapy, Regeneration genetics
- Abstract
The adult mammalian heart lacks the ability to sufficiently regenerate itself, leading to the progressive deterioration of function and heart failure after ischemic injuries such as myocardial infarction. Thus far, cell-based therapies have delivered unsatisfactory results, prompting the search for cell-free alternatives that can induce the heart to repair itself through cardiomyocyte proliferation, angiogenesis, and advantageous remodeling. Large animal models are an invaluable step toward translating basic research into clinical applications. In this review, we give an overview of the state-of-the-art in cell-free cardiac regeneration therapies that have been tested in large animal models, mainly pigs. Cell-free cardiac regeneration therapies involve stem cell secretome- and extracellular vesicles (including exosomes)-induced cardiac repair, RNA-based therapies, mainly regarding microRNAs, but also modified mRNA (modRNA) as well as other molecules including growth factors and extracellular matrix components. Various methods for the delivery of regenerative substances are used, including adenoviral vectors (AAVs), microencapsulation, and microparticles. Physical stimulation methods and direct cardiac reprogramming approaches are also discussed.
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- 2020
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33. Circular RNAs in Cardiac Regeneration: Cardiac Cell Proliferation, Differentiation, Survival, and Reprogramming.
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Mester-Tonczar J, Hašimbegović E, Spannbauer A, Traxler D, Kastner N, Zlabinger K, Einzinger P, Pavo N, Goliasch G, and Gyöngyösi M
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Circular RNAs (circRNAs) are classified as long non-coding RNAs (lncRNAs) that are characterized by a covalent closed-loop structure. This closed-loop shape is the result of a backsplicing event in which the 3' and 5' splice sites are ligated. Through the lack of 3' poly(A) tails and 5' cap structures, circRNAs are more stable than linear RNAs because these adjustments make the circular loop less susceptible to exonucleases. The majority of identified circRNAs possess cell- and tissue-specific expression patterns. In addition, high-throughput RNA-sequencing combined with novel bioinformatics algorithms revealed that circRNA sequences are often conserved across different species suggesting a positive evolutionary pressure. Implicated as regulators of protein turnover, micro RNA (miRNA) sponges, or broad effectors in cell differentiation, proliferation, and senescence, research of circRNA has increased in recent years. Particularly in cardiovascular research, circRNA-related discoveries have opened the door for the development of potential diagnostic and therapeutic tools. Increasing evidence links deviating circRNA expression patterns to various cardiovascular diseases including ischemic heart failure. In this mini-review, we summarize the current state of knowledge on circRNAs in cardiac regeneration with a focus on cardiac cell proliferation, differentiation, cardiomyocyte survival, and cardiac reprogramming., (Copyright © 2020 Mester-Tonczar, Hašimbegović, Spannbauer, Traxler, Kastner, Zlabinger, Einzinger, Pavo, Goliasch and Gyöngyösi.)
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- 2020
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34. New Insights and Current Approaches in Cardiac Hypertrophy Cell Culture, Tissue Engineering Models, and Novel Pathways Involving Non-Coding RNA.
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Kastner N, Zlabinger K, Spannbauer A, Traxler D, Mester-Tonczar J, Hašimbegović E, and Gyöngyösi M
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Cardiac hypertrophy is an ongoing clinical challenge, as risk factors such as obesity, smoking and increasing age become more widespread, which lead to an increasing prevalence of developing hypertrophy. Pathological hypertrophy is a maladaptive response to stress conditions, such as pressure overload, and involve a number of changes in cellular mechanisms, gene expression and pathway regulations. Although several important pathways involved in the remodeling and hypertrophy process have been identified, further research is needed to achieve a better understanding and explore new and better treatment options. More recently discovered pathways showed the involvement of several non-coding RNAs, including micro RNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), which either promote or inhibit the remodeling process and pose a possible target for novel therapy approaches. In vitro modeling serves as a vital tool for this further pathway analysis and treatment testing and has vastly improved over the recent years, providing a less costly and labor-intensive alternative to in vivo animal models., (Copyright © 2020 Kastner, Zlabinger, Spannbauer, Traxler, Mester-Tonczar, Hašimbegović and Gyöngyösi.)
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- 2020
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35. Association between Circular RNA CDR1as and Post-Infarction Cardiac Function in Pig Ischemic Heart Failure: Influence of the Anti-Fibrotic Natural Compounds Bufalin and Lycorine.
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Mester-Tonczar J, Winkler J, Einzinger P, Hasimbegovic E, Kastner N, Lukovic D, Zlabinger K, Spannbauer A, Traxler D, Batkai S, Thum T, and Gyöngyösi M
- Subjects
- Amaryllidaceae Alkaloids pharmacology, Animals, Bufanolides pharmacology, Disease Models, Animal, Humans, Injections, Subcutaneous, Male, Myocardial Infarction etiology, Myocardial Infarction genetics, Myocardial Infarction physiopathology, Phenanthridines pharmacology, Stroke Volume drug effects, Swine, Treatment Outcome, Up-Regulation drug effects, Amaryllidaceae Alkaloids administration & dosage, Bufanolides administration & dosage, Myocardial Infarction drug therapy, Phenanthridines administration & dosage, RNA, Circular genetics, RNA, Long Noncoding economics, Ventricular Remodeling drug effects
- Abstract
Anti-fibrotic therapies are of increasing interest to combat cardiac remodeling and heart failure progression. Recently, anti-fibrotic circular RNAs (circRNAs) have been identified in human and rodent cardiac tissue. In vivo (rodent) experiments proved cardiac anti-fibrotic effects of the natural compounds bufalin and lycorine by downregulating miRNA-671-5p, associated with a theoretic increase in the tissue level of circRNA CDR1as. Accordingly, we hypothesized that both anti-fibrotic drugs may inhibit focal myocardial fibrosis of the remodeled left ventricle (LV) also in a translational large animal model of heart failure (HF). Domestic pigs were repeatedly treated with subcutaneous injections of either bufalin, lycorine, or saline, (n = 5/group) between days 7-21 post acute myocardial infarction (AMI). At the 2-month follow-up, both bufalin and lycorine led to significantly reduced cardiac fibrosis. Bufalin treatment additionally led to smaller end-diastolic volumes, higher LV ejection fraction (EF), and increased expression of CDR1as of the AMI region. Elevated tissue levels of the circRNA CDR1as in the AMI region of the pig heart correlated significantly with LV and right ventricular EF, LV stroke volume, and negatively with infarct size. In conclusion, we successfully identified the circRNA CDR1as in pig hearts and show a significant association with improved LV and RV function by anti-fibrotic therapies in a translational animal model of HF.
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- 2020
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36. Heart Failure With Reduced Ejection Fraction Is Characterized by Systemic NEP Downregulation.
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Pavo IJ, Pavo N, Kastner N, Traxler D, Lukovic D, Zlabinger K, Spannbauer A, Riesenhuber M, Lorant D, Bartko PE, Goliasch G, Hülsmann M, Winkler J, and Gyöngyösi M
- Abstract
Based on the investigation of neprilysin (NEP) regulation in a translational porcine model of chronic heart failure (HF), this study concluded: 1) that kidneys might play a crucial part in systemic NEP regulation based on 20 to 100 higher NEP content and/or activity compared with any other organ; 2) NEP seems to be downregulated under HF conditions; and 3) that the value of plasma NEP concentrations and activity as biomarkers is questionable. For the first time, these data provide basic knowledge on HF-related pathophysiological alterations of the NEP system and contribute to understanding the mechanism of action of angiotensin-receptor neprilysin-inhibitors, which remains elusive despite broad clinical applications., (© 2020 The Authors.)
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- 2020
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37. Reduced histologic neo in-stent restenosis after use of a paclitaxel-coated cutting balloon in porcine coronary arteries.
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Traxler D, Hemetsberger R, Spannbauer A, Zlabinger K, Gugerell A, Lukovic D, Mandic L, Pavo N, Winkler J, and Gyöngyösi M
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- Animals, Sus scrofa, Angioplasty, Balloon, Coronary instrumentation, Coronary Artery Disease pathology, Coronary Restenosis prevention & control, Drug-Eluting Stents, Paclitaxel pharmacology
- Abstract
The incidence of in-stent restenosis (ISR) has declined dramatically, but once it develops, no current treatment option, such as drug-eluting stents, drug-coated balloons, or cutting balloons (CBs), prevents re-narrowing of the stented atherosclerotic artery. In this preclinical study, we aimed to improve the efficacy of ISR treatment by coating CBs with paclitaxel (paclitaxel-eluting cutting balloon; PECB) and to characterize the histological features of neo-ISRs that arise after ISR treatment. ISR was induced by bare metal stent (BMS) implantation in coronary arteries in pigs. After one month of follow-up, the BMS-induced ISR was treated with either CB or PECB. After another month, we performed quantitative coronary angiography, explanted the treated arteries and assessed histopathological and histomorphometric parameters. In addition, we compared the histological features of neo-ISRs with pre-treatment ISRs. Injury, inflammation, fibrin deposition, and endothelialization scores were similar between the CB and PECB groups at one month after ISR treatment. Neointimal area (0.87±0.61 vs. 1.95±1.14 mm², p=0.02), mean neointimal thickness (0.40±0.39 vs. 0.99±0.56 mm, p=0.01), and percent area stenosis (27.3±20.4 vs. 48.3±22.9%, p=0.04) were decreased in PECB-treated coronary arteries compared to CB-treated arteries, respectively. Density of cells (predominantly smooth muscle cells; SMCs) was increased in neo-ISRs (3.51±3.05×10³ vs. 6.35±2.57×10³ cells/mm², p<0.01), but significantly more CD68⁺ and CD20⁺ cells were found in the pre-treatment ISRs. In conclusion, PECB treatment of ISRs led to better results in terms of smaller neointimal area and %area stenosis of the neo-ISR. SMC density was increased in neo-ISRs in contrast with higher percentage of CD68⁺ and CD20⁺ cells in pre-treatment ISRs.
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- 2020
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38. Early Elevation of Systemic Plasma Clusterin after Reperfused Acute Myocardial Infarction in a Preclinical Porcine Model of Ischemic Heart Disease.
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Traxler D, Spannbauer A, Einzinger P, Mester-Tonczar J, Lukovic D, Winkler J, Zlabinger K, Gugerell A, Mandic L, Gyöngyösi M, and Pavo N
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- Animals, Female, Myocardial Infarction blood, Myocardial Infarction therapy, Myocardial Ischemia blood, Myocardial Ischemia therapy, Reperfusion, Stroke Volume, Swine, Transcriptome, Ventricular Remodeling, Clusterin blood, Disease Models, Animal, Myocardial Infarction pathology, Myocardial Ischemia pathology
- Abstract
Clusterin exerts anti-inflammatory, cytoprotective and anti-apoptotic effects. Both an increase and decrease of clusterin in acute myocardial infarction (AMI) has been reported. We aimed to clarify the role of clusterin as a systemic biomarker in AMI. AMI was induced by percutaneous left anterior artery (LAD) occlusion for 90 min followed by reperfusion in 24 pigs. Contrast ventriculography was performed after reperfusion to assess left ventricular ejection fraction (LVEF), left ventricular end diastolic volume (LVEDV) and left ventricular end systolic volume (LVESV) and additional cMRI + late enhancement to measure infarct size and LV functions at day 3 and week 6 post-MI. Blood samples were collected at prespecified timepoints. Plasma clusterin and other biomarkers (cTnT, NT-proBNP, neprilysin, NGAL, ET-1, osteopontin, miR21, miR29) were measured by ELISA and qPCR. Gene expression profiles of infarcted and remote region 3 h ( n = 5) and 3 days ( n = 5) after AMI onset were analysed by RNA-sequencing. AMI led to an increase in LVEDV and LVESV during 6-week, with concomitant elevation of NT-proBNP 3-weeks after AMI. Plasma clusterin levels were increased immediately after AMI and returned to normal levels until 3-weeks. Plasma NGAL, ET-1 and miR29 was significantly elevated at 3 weeks follow-up, miR21 increased after reperfusion and at 3 weeks post-AMI, while circulating neprilysin levels did not change. Elevated plasma clusterin levels 120 min after AMI onset suggest that clusterin might be an additional early biomarker of myocardial ischemia., Competing Interests: The authors declare no conflict of interest.
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- 2020
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39. Multimarker Approach to Identify Patients with Coronary Artery Disease at High Risk for Subsequent Cardiac Adverse Events: The Multi-Biomarker Study.
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Giurgea GA, Zlabinger K, Gugerell A, Lukovic D, Syeda B, Mandic L, Pavo N, Mester-Tonczar J, Traxler-Weidenauer D, Spannbauer A, Kastner N, Müller C, Anvari A, Bergler-Klein J, and Gyöngyösi M
- Subjects
- Aged, Aged, 80 and over, Cohort Studies, Comorbidity, Coronary Artery Disease complications, Coronary Artery Disease therapy, Death, Female, Hospitalization statistics & numerical data, Humans, Male, Middle Aged, Myocardial Infarction diagnosis, Myocardial Infarction etiology, Myocardial Infarction mortality, Percutaneous Coronary Intervention, Prognosis, Prospective Studies, Risk Assessment, Risk Factors, Stroke diagnosis, Stroke etiology, Biomarkers analysis, Coronary Artery Disease diagnosis, Coronary Artery Disease epidemiology
- Abstract
In our prospective non-randomized, single-center cohort study ( n = 161), we have evaluated a multimarker approach including S100 calcium binding protein A12 (S100A1), interleukin 1 like-receptor-4 (IL1R4), adrenomedullin, copeptin, neutrophil gelatinase-associated lipocalin (NGAL), soluble urokinase plasminogen activator receptor (suPAR), and ischemia modified albumin (IMA) in prediction of subsequent cardiac adverse events (AE) during 1-year follow-up in patients with coronary artery disease. The primary endpoint was to assess the combined discriminatory predictive value of the selected 7 biomarkers in prediction of AE (myocardial infarction, coronary revascularization, death, stroke, and hospitalization) by canonical discriminant function analysis. The main secondary endpoints were the levels of the 7 biomarkers in the groups with/without AE; comparison of the calculated discriminant score of the biomarkers with traditional logistic regression and C-statistics. The canonical correlation coefficient was 0.642, with a Wilk's lambda value of 0.78 and p < 0.001. By using the calculated discriminant equation with the weighted mean discriminant score (centroid), the sensitivity and specificity of our model were 79.4% and 74.3% in prediction of AE. These values were higher than that of the calculated C-statistics if traditional risk factors with/without biomarkers were used for AE prediction. In conclusion, canonical discriminant analysis of the multimarker approach is able to define the risk threshold at the individual patient level for personalized medicine., Competing Interests: The authors declare no conflict of interest.
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- 2020
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40. Quantitative Hybrid Cardiac [ 18 F]FDG-PET-MRI Images for Assessment of Cardiac Repair by Preconditioned Cardiosphere-Derived Cells.
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Winkler J, Lukovic D, Mester-Tonczar J, Zlabinger K, Gugerell A, Pavo N, Jakab A, Szankai Z, Traxler D, Müller C, Spannbauer A, Riesenhuber M, Hašimbegović E, Dawkins J, Zimmermann M, Ankersmit HJ, Marbán E, and Gyöngyösi M
- Abstract
Cardiosphere-derived cells (CDCs) are progenitor cells derived from heart tissue and have shown promising results in preclinical models. APOSEC, the secretome of irradiated peripheral blood mononuclear cells, has decreased infarct size in acute and chronic experimental myocardial infarction (MI). We enhanced the effect of CDCs with APOSEC preconditioning (apoCDC) and investigated the reparative effect in a translational pig model of reperfused MI. Supernatants of CDCs, assessed by proteomic analysis, revealed reduced production of extracellular matrix proteins after in vitro APOSEC preconditioning. In a porcine model of catheter-based reperfused anterior acute MI (AMI), CDCs with (apoCDC, n = 8) or without APOSEC preconditioning (CDC, n = 6) were infused intracoronary, 15 min after the start of reperfusion. Untreated AMI animals (n = 7) and sham procedures (n = 5) functioned as controls. 2-deoxy-2-(18 F)-fluoro-D-glucose-positron emission tomography-magnetic resonance imaging ([
18 F]FDG-PET-MRI), with late enhancement after 1 month, showed reduced scar volume and lower transmurality of the infarcted area in CDC and apoCDC compared to AMI controls. Segmental quantitative PET images displayed indicated more residual viability in apoCDC. The left-ventricle (LV) ejection fraction was improved nonsignificantly to 45.8% ± 8.6% for apoCDC and 43.5% ± 7.1% for CDCs compared to 38.5% ± 4.4% for untreated AMI. Quantitative hybrid [18 F]FDG-PET-MRI demonstrated improved metabolic and functional recovery after CDC administration, whereas apoCDCs induced preservation of viability of the infarcted area., (© 2020 The Author(s).)- Published
- 2020
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41. Liposomal doxorubicin attenuates cardiotoxicity via induction of interferon-related DNA damage resistance.
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Gyöngyösi M, Lukovic D, Zlabinger K, Spannbauer A, Gugerell A, Pavo N, Traxler D, Pils D, Maurer G, Jakab A, Riesenhuber M, Pircher A, Winkler J, and Bergler-Klein J
- Subjects
- Animals, Antibiotics, Antineoplastic pharmacokinetics, Cardiomyopathies chemically induced, Cardiomyopathies metabolism, Cardiomyopathies physiopathology, Cardiotoxicity, Cells, Cultured, Collagen genetics, Collagen metabolism, Dose-Response Relationship, Drug, Doxorubicin pharmacokinetics, Doxorubicin toxicity, Drug Compounding, Epirubicin toxicity, Female, Fibrosis, Humans, Interferon Regulatory Factors genetics, Myocytes, Cardiac metabolism, Myocytes, Cardiac pathology, Polyethylene Glycols pharmacokinetics, Polyethylene Glycols toxicity, Sus scrofa, Transcriptome drug effects, Ventricular Function, Left drug effects, Ventricular Function, Right drug effects, Ventricular Remodeling drug effects, Antibiotics, Antineoplastic toxicity, Cardiomyopathies prevention & control, DNA Damage, Doxorubicin analogs & derivatives, Interferon Regulatory Factors metabolism, Myocytes, Cardiac drug effects
- Abstract
Aims: The clinical application of doxorubicin (DOX) is severely compromised by its cardiotoxic effects, which limit the therapeutic index and the cumulative dose. Liposomal encapsulation of DOX (Myocet®) provides a certain protective effect against cardiotoxicity by reducing myocardial drug accumulation. We aimed to evaluate transcriptomic responses to anthracyclines with different cardiotoxicity profiles in a translational large animal model for identifying potential alleviation strategies., Methods and Results: We treated domestic pigs with either DOX, epirubicin (EPI), or liposomal DOX and compared the cardiac, laboratory, and haemodynamic effects with saline-treated animals. Cardiotoxicity was encountered in all groups, reflected by an increase of plasma markers N-terminal pro-brain-natriuretic peptide and Troponin I and an impact on body weight. High morbidity of EPI-treated animals impeded further evaluation. Cardiac magnetic resonance imaging with gadolinium late enhancement and transthoracic echocardiography showed stronger reduction of the left and right ventricular systolic function and stronger myocardial fibrosis in DOX-treated animals than in those treated with the liposomal formulation. Gene expression profiles of the left and right ventricles were analysed by RNA-sequencing and validated by qPCR. Interferon-stimulated genes (ISGs), linked to DNA damage repair and cell survival, were downregulated by DOX, but upregulated by liposomal DOX in both the left and right ventricle. The expression of cardioprotective translocator protein (TSPO) was inhibited by DOX, but not its liposomal formulation. Cardiac fibrosis with activation of collagen was found in all treatment groups., Conclusions: All anthracycline-derivatives resulted in transcriptional activation of collagen synthesis and processing. Liposomal packaging of DOX-induced ISGs in association with lower cardiotoxicity, which is of high clinical importance in anticancer treatment. Our study identified potential mechanisms for rational development of strategies to mitigate anthracycline-induced cardiomyopathy., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.)
- Published
- 2020
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42. Preclinical development of a miR-132 inhibitor for heart failure treatment.
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Foinquinos A, Batkai S, Genschel C, Viereck J, Rump S, Gyöngyösi M, Traxler D, Riesenhuber M, Spannbauer A, Lukovic D, Weber N, Zlabinger K, Hašimbegović E, Winkler J, Fiedler J, Dangwal S, Fischer M, de la Roche J, Wojciechowski D, Kraft T, Garamvölgyi R, Neitzel S, Chatterjee S, Yin X, Bär C, Mayr M, Xiao K, and Thum T
- Subjects
- Animals, Drug Evaluation, Preclinical, Female, Gene Expression Regulation, Heart Failure metabolism, Humans, MicroRNAs metabolism, Myocytes, Cardiac metabolism, Oligonucleotides, Antisense metabolism, Oligonucleotides, Antisense pharmacokinetics, Swine, Genetic Therapy methods, Heart Failure genetics, Heart Failure therapy, MicroRNAs genetics, Oligonucleotides, Antisense genetics
- Abstract
Despite proven efficacy of pharmacotherapies targeting primarily global neurohormonal dysregulation, heart failure (HF) is a growing pandemic with increasing burden. Treatments mechanistically focusing at the cardiomyocyte level are lacking. MicroRNAs (miRNA) are transcriptional regulators and essential drivers of disease progression. We previously demonstrated that miR-132 is both necessary and sufficient to drive the pathological cardiomyocytes growth, a hallmark of adverse cardiac remodelling. Therefore, miR-132 may serve as a target for HF therapy. Here we report further mechanistic insight of the mode of action and translational evidence for an optimized, synthetic locked nucleic acid antisense oligonucleotide inhibitor (antimiR-132). We reveal the compound's therapeutic efficacy in various models, including a clinically highly relevant pig model of HF. We demonstrate favourable pharmacokinetics, safety, tolerability, dose-dependent PK/PD relationships and high clinical potential for the antimiR-132 treatment scheme.
- Published
- 2020
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43. MiR-21, MiR-29a, GATA4, and MEF2c Expression Changes in Endothelin-1 and Angiotensin II Cardiac Hypertrophy Stimulated Isl-1 + Sca-1 + c-kit + Porcine Cardiac Progenitor Cells In Vitro.
- Author
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Zlabinger K, Spannbauer A, Traxler D, Gugerell A, Lukovic D, Winkler J, Mester-Tonczar J, Podesser B, and Gyöngyösi M
- Subjects
- Angiotensin II genetics, Angiotensin II metabolism, Animals, Antigens, Surface metabolism, Cardiomegaly pathology, Cells, Cultured, Cellular Reprogramming genetics, Connexin 43 genetics, Connexin 43 metabolism, Endothelin-1 genetics, Endothelin-1 metabolism, GATA4 Transcription Factor genetics, Genetic Predisposition to Disease, Immunophenotyping, MEF2 Transcription Factors genetics, MicroRNAs genetics, Phenotype, Swine, Ventricular Remodeling genetics, Biomarkers, Cardiomegaly etiology, Cardiomegaly metabolism, Disease Susceptibility, Myoblasts, Cardiac metabolism
- Abstract
Cost- and time-intensive porcine translational disease models offer great opportunities to test drugs and therapies for pathological cardiac hypertrophy and can be supported by porcine cell culture models that provide further insights into basic disease mechanisms. Cardiac progenitor cells (CPCs) residing in the adult heart have been shown to differentiate in vitro into cardiomyocytes and could contribute to cardiac regeneration. Therefore, it is important to evaluate their changes on the cellular level caused by disease. We successfully isolated Isl1
+ Sca1+ cKit+ porcine CPCs (pCPCs) from pig hearts and stimulated them with endothelin-1 (ET-1) and angiotensin II (Ang II) in vitro. We also performed a cardiac reprogramming transfection and tested the same conditions. Our results show that undifferentiated Isl1+ Sca1+ cKit+ pCPCs were significantly upregulated in GATA4, MEF2c, and miR-29a gene expressions and in BNP and MCP-1 protein expressions with Ang II stimulation, but they showed no significant changes in miR-29a and MCP-1 when stimulated with ET-1. Differentiated Isl1+ Sca1+ cKit+ pCPCs exhibited significantly higher levels of MEF2c, GATA4, miR-29a, and miR-21 as well as Cx43 and BNP with Ang II stimulation. pMx-MGT -transfected Isl1+ Sca1+ cKit+ pCPCs showed significant elevations in MEF2c, GATA4, and BNP expressions when stimulated with ET-1. Our model demonstrates that in vitro stimulation leads to successful Isl1+ Sca1+ cKit+ pCPC hypertrophy with upregulation of cardiac remodeling associated genes and profibrotic miRNAs and offers great possibilities for further investigations of disease mechanisms and treatment.- Published
- 2019
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44. Large Animal Models of Heart Failure With Reduced Ejection Fraction (HFrEF).
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Spannbauer A, Traxler D, Zlabinger K, Gugerell A, Winkler J, Mester-Tonczar J, Lukovic D, Müller C, Riesenhuber M, Pavo N, and Gyöngyösi M
- Abstract
Heart failure with reduced ejection fraction (HFrEF) is defined by an ejection fraction (EF) below 40%. Many distinct disease processes culminate in HFrEF, among them acute and chronic ischemia, pressure overload, volume overload, cytotoxic medication, and arrhythmia. To study these different etiologies the development of accurate animal models is vital. While small animal models are generally cheaper, allow for larger sample sizes and offer a greater variety of transgenic models, they have important limitations in the context of HFrEF research. Small mammals have much higher heart rates and distinct ion channels. They also have much higher basal metabolic rates and their physiology in many ways does not reflect that of humans. The size of their organs also puts practical constraints on experiments. Therefore, large animal models have been developed to accurately simulate human HFrEF. This review aims to give a short overview of the currently established large animal models of HFrEF. The main animal models discussed are dogs, pigs, and sheep. Furthermore, multiple approaches for modeling the different etiologies of HF are discussed, namely models of acute and chronic ischemia, pressure overload, volume overload as well as cytotoxic, and tachycardic pacing approaches.
- Published
- 2019
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45. Effect of Ischemic Preconditioning and Postconditioning on Exosome-Rich Fraction microRNA Levels, in Relation with Electrophysiological Parameters and Ventricular Arrhythmia in Experimental Closed-Chest Reperfused Myocardial Infarction.
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Spannbauer A, Traxler D, Lukovic D, Zlabinger K, Winkler J, Gugerell A, Ferdinandy P, Hausenloy DJ, Pavo N, Emmert MY, Hoerstrup SP, Jakab A, Gyöngyösi M, and Riesenhuber M
- Subjects
- Animals, Female, Heart Ventricles metabolism, MicroRNAs genetics, Myocardial Infarction complications, Myocardial Infarction therapy, Swine, Ventricular Fibrillation etiology, Ventricular Fibrillation therapy, Ventricular Function, Exosomes metabolism, Ischemic Postconditioning, Ischemic Preconditioning, Myocardial, MicroRNAs metabolism, Myocardial Infarction metabolism, Ventricular Fibrillation metabolism
- Abstract
We investigated the antiarrhythmic effects of ischemic preconditioning (IPC) and postconditioning (PostC) by intracardiac electrocardiogram (ECG) and measured circulating microRNAs (miRs) that are related to cardiac conduction. Domestic pigs underwent 90-min. percutaneous occlusion of the mid left anterior coronary artery, followed by reperfusion. The animals were divided into three groups: acute myocardial infarction (AMI, n = 7), ischemic preconditioning-acute myocardial infarction (IPC-AMI) ( n = 9), or AMI-PostC ( n = 5). IPC was induced by three 5-min. episodes of repetitive ischemia/reperfusion cycles (rI/R) before AMI. PostC was induced by six 30-s rI/R immediately after induction of reperfusion 90 min after occlusion. Before the angiographic procedure, a NOGA endocardial mapping catheter was placed again the distal anterior ventricular endocardium to record the intracardiac electrogram (R-amplitude, ST-Elevation, ST-area under the curve (AUC), QRS width, and corrected QT time (QTc)) during the entire procedure. An arrhythmia score was calculated. Cardiac MRI was performed after one-month. IPC led to significantly lower ST-elevation, heart rate, and arrhythmia score during ischemia. PostC induced a rapid recovery of R-amplitude, decrease in QTc, and lower arrhythmia score during reperfusion. Slightly higher levels of miR-26 and miR-133 were observed in AMI compared to groups IPC-AMI and AMI-PostC. Significantly lower levels of miR-1, miR-208, and miR-328 were measured in the AMI-PostC group as compared to animals in group AMI and IPC-AMI. The arrhythmia score was not significantly associated with miRNA plasma levels. Cardiac MRI showed significantly smaller infarct size in the IPC-AMI group when compared to the AMI and AMI-PostC groups. Thus, IPC led to better left ventricular ejection fraction at one-month and it exerted antiarrhythmic effects during ischemia, whereas PostC exhibited antiarrhythmic properties after reperfusion, with significant downregulaton of ischemia-related miRNAs.
- Published
- 2019
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46. Transcriptional Alterations by Ischaemic Postconditioning in a Pig Infarction Model: Impact on Microvascular Protection.
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Lukovic D, Gugerell A, Zlabinger K, Winkler J, Pavo N, Baranyai T, Giricz Z, Varga ZV, Riesenhuber M, Spannbauer A, Traxler D, Jakab A, Garamvölgyi R, Petnehazy Ö, Pils D, Tóth L, Schulz R, Ferdinandy P, and Gyöngyösi M
- Subjects
- Animals, Cell Size, Cluster Analysis, Disease Models, Animal, Focal Adhesions metabolism, High-Throughput Nucleotide Sequencing, Myocardial Reperfusion Injury genetics, Myocardial Reperfusion Injury pathology, RNA, Messenger genetics, RNA, Messenger metabolism, Reproducibility of Results, Survival Analysis, Swine, Ischemic Postconditioning, Microvessels pathology, Myocardial Infarction genetics, Myocardial Infarction pathology, Transcription, Genetic
- Abstract
Although the application of cardioprotective ischaemia/reperfusion (I/R) stimuli after myocardial infarction (MI) is a promising concept for salvaging the myocardium, translation to a clinical scenario has not fulfilled expectations. We have previously shown that in pigs, ischaemic postconditioning (IPostC) reduces myocardial oedema and microvascular obstruction (MVO), without influencing myocardial infarct size. In the present study, we analyzed the mechanisms underlying the IPostC-induced microvascular protection by transcriptomic analysis, followed by pathway analysis. Closed-chest reperfused MI was induced by 90 min percutaneous balloon occlusion of the left anterior descending coronary artery, followed by balloon deflation in anaesthetised pigs. Animals were randomised to IPostC ( n = 8), MI (non-conditioned, n = 8), or Control (sham-operated, n = 4) groups. After three hours or three days follow-up, myocardial tissue samples were harvested and subjected to RNA-seq analysis. Although the transcriptome analysis revealed similar expression between IPostC and MI in transcripts involved in cardioprotective pathways, we identified gene expression changes responding to IPostC at the three days follow-up. Focal adhesion signaling, downregulated genes participating in cardiomyopathy and activation of blood cells may have critical consequences for microvascular protection. Specific analyses of the gene subsets enriched in the endothelium of the infarcted area, revealed strong deregulation of transcriptional functional clusters, DNA processing, replication and repair, cell proliferation, and focal adhesion, suggesting sustentative function in the endothelial cell layer protection and integrity. The spatial and time-dependent transcriptome analysis of porcine myocardium supports a protective effect of IPostC on coronary microvasculature post-MI., Competing Interests: P.F. is the founder and CEO of Pharmahungary, a group of R&D companies. The other authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.
- Published
- 2019
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47. Matrix Metalloproteinase-2 Impairs Homing of Intracoronary Delivered Mesenchymal Stem Cells in a Porcine Reperfused Myocardial Infarction: Comparison With Intramyocardial Cell Delivery.
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Zlabinger K, Lukovic D, Hemetsberger R, Gugerell A, Winkler J, Mandic L, Traxler D, Spannbauer A, Wolbank S, Zanoni G, Kaun C, Posa A, Gyenes A, Petrasi Z, Petnehazy Ö, Repa I, Hofer-Warbinek R, de Martin R, Gruber F, Charwat S, Huber K, Pavo N, Pavo IJ, Nyolczas N, Kraitchman DL, and Gyöngyösi M
- Abstract
Background: Intracoronary (IC) injection of mesenchymal stem cells (MSCs) results in a prompt decrease of absolute myocardial blood flow (AMF) with late and incomplete recovery of myocardial tissue perfusion. Here, we investigated the effect of decreased AMF on oxidative stress marker matrix metalloproteinase-2 (MMP-2) and its influence on the fate and homing and paracrine character of MSCs after IC or intramyocardial cell delivery in a closed-chest reperfused myocardial infarction (MI) model in pigs., Methods: Porcine MSCs were transiently transfected with Ad-Luc and Ad-green fluorescent protein (GFP). One week after MI, the GFP-Luc-MSCs were injected either IC (group IC, 11.00 ± 1.07 × 10
6 ) or intramyocardially (group IM, 9.88 ± 1.44 × 106 ). AMF was measured before, immediately after, and 24 h post GFP-Luc-MSC delivery. In vitro bioluminescence signal was used to identify tissue samples containing GFP-Luc-MSCs. Myocardial tissue MMP-2 and CXCR4 receptor expression (index of homing signal) were measured in bioluminescence positive and negative infarcted and border, and non-ischemic myocardial areas 1-day post cell transfer. At 7-day follow-up, myocardial homing (cadherin, CXCR4, and stromal derived factor-1alpha) and angiogenic [fibroblast growth factor 2 (FGF2) and VEGF] were quantified by ELISA of homogenized myocardial tissues from the bioluminescence positive and negative infarcted and border, and non-ischemic myocardium. Biodistribution of the implanted cells was quantified by using Luciferase assay and confirmed by fluorescence immunochemistry. Global left ventricular ejection fraction (LVEF) was measured at baseline and 1-month post cell therapy using magnet resonance image., Results: AMF decreased immediately after IC cell delivery, while no change in tissue perfusion was found in the IM group (42.6 ± 11.7 vs. 56.9 ± 16.7 ml/min, p = 0.018). IC delivery led to a significant increase in myocardial MMP-2 64 kD expression (448 ± 88 vs. 315 ± 54 intensity × mm2 , p = 0.021), and decreased expression of CXCR4 (592 ± 50 vs. 714 ± 54 pg/tissue/ml, p = 0.006), with significant exponential decay between MMP-2 and CXCR4 ( r = 0.679, p < 0.001). FGF2 and VEGF of the bioluminescence infarcted and border zone of homogenized tissues were significantly elevated in the IM goups as compared to IC group. LVEF increase was significantly higher in IM group (0.8 ± 8.4 vs 5.3 ± 5.2%, p = 0.046) at the 1-month follow up., Conclusion: Intracoronary stem cell delivery decreased AMF, with consequent increase in myocardial expression of MMP-2 and reduced CXCR4 expression with lower level of myocardial homing and angiogenic factor release as compared to IM cell delivery.- Published
- 2018
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48. Porcine model of progressive cardiac hypertrophy and fibrosis with secondary postcapillary pulmonary hypertension.
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Gyöngyösi M, Pavo N, Lukovic D, Zlabinger K, Spannbauer A, Traxler D, Goliasch G, Mandic L, Bergler-Klein J, Gugerell A, Jakab A, Szankai Z, Toth L, Garamvölgyi R, Maurer G, Jaisser F, Zannad F, Thum T, Bátkai S, and Winkler J
- Subjects
- Animals, Aortic Valve Stenosis blood, Aortic Valve Stenosis complications, Aortic Valve Stenosis pathology, Aortic Valve Stenosis physiopathology, Biomarkers blood, Capillaries physiopathology, Cardiomegaly blood, Cardiomegaly physiopathology, Diastole, Disease Models, Animal, Fibrosis, Gene Expression Regulation, Neoplastic, Heart Ventricles pathology, Heart Ventricles physiopathology, Hypertension, Pulmonary blood, Hypertension, Pulmonary physiopathology, Magnetic Resonance Imaging, Cine, Male, Myocardium pathology, Pressure, Sus scrofa, Systole, Capillaries pathology, Cardiomegaly complications, Cardiomegaly pathology, Disease Progression, Hypertension, Pulmonary complications, Hypertension, Pulmonary pathology
- Abstract
Background: Meaningful translational large animal models for cardiac diseases are indispensable for studying disease mechanisms, development of novel therapeutic strategies, and evaluation of potential drugs., Methods: For induction of heart failure, cardiac hypertrophy and fibrosis, a bare metal stent was implanted in the descending aorta of growing pigs (n = 7), inducing pressure stress on the left ventricle (group HYPI). The constant stent size in growing pigs resulted in antegrade partial obstruction of the aortic flow with a gradual increase in afterload. Five pigs with sham intervention served as control. Serial haemodynamic, pressure-volume loop measurements and transthoracic echocardiography (TTE) were performed to detect developing pressure overload of the LV and cardiac MRI with late enhancement for measuring LV and RV mass and ejection fraction., Results: At 5-month follow-up, CT and contrast aortography, and intraluminal echocardiography confirmed aortic isthmus stenosis with a mean trans-stenotic gradient of 64 ± 13.9 mmHg. Invasive haemodynamic measurements revealed a secondary increase in pulmonary artery pressure (44.6 ± 5.1 vs 25.9 ± 6.2 mmHg, HYPI vs control, p < 0.05). TTE and ex vivo analyses confirmed severe concentric LV hypertrophy (mean circumferential wall thickness, 19.4 ± 3.1, n = 7 vs 11.4 ± 1.0 mm, n = 5, HYPI vs controls, p < 0.05). The LV and RV mass increased significantly, paralleled by increased isovolumic relaxation constant (tau). Histological analyses confirmed substantial fibrosis and myocyte hypertrophy in both LV and RV. Expressions of ANP, BNP, and miRNA-29a were up-regulated, while SERCA2a and miRNA-1 were down-regulated. Plasma NGAL levels increased gradually, while the elevation of NT-proBNP was detected only at the 5-month FUP., Conclusion: These data prove that percutaneous artificial aortic stenosis in pigs is useful for inducing clinically relevant progredient heart failure based on myocardial hypertrophy and fibrosis.
- Published
- 2017
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49. Intrinsic remote conditioning of the myocardium as a comprehensive cardiac response to ischemia and reperfusion.
- Author
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Pavo N, Lukovic D, Zlabinger K, Lorant D, Goliasch G, Winkler J, Pils D, Auer K, Ankersmit HJ, Giricz Z, Sárközy M, Jakab A, Garamvölgyi R, Emmert MY, Hoerstrup SP, Hausenloy DJ, Ferdinandy P, Maurer G, and Gyöngyösi M
- Abstract
We have previously shown that distal anterior wall ischemia/reperfusion induces gene expression changes in the proximal anterior myocardial area, involving genes responsible for cardiac remodeling. Here we investigated the molecular signals of the ischemia non-affected remote lateral and posterior regions and present gene expression profiles of the entire left ventricle by using our novel and straightforward method of 2D and 3D image reconstruction. Five or 24h after repetitive 10min ischemia/reperfusion without subsequent infarction, pig hearts were explanted and myocardial samples from 52 equally distributed locations of the left ventricle were collected. Expressional changes of seven genes of interest (HIF-1α; caspase-3, transcription factor GATA4; myocyte enhancer factor 2C /MEF2c/; hexokinase 2 /HK2/; clusterin /CLU/ and excision repair cross-complementation group 4 /ERCC4/) were measured by qPCR. 2D and 3D gene expression maps were constructed by projecting the fold changes on the NOGA anatomical mapping coordinates. Caspase-3, GATA4, HK2, CLU, and ERCC4 were up-regulated region-specifically in the ischemic zone at 5 h post ischemia/reperfusion injury. Overexpression of GATA4, clusterin and ERCC4 persisted after 24 h. HK2 showed strong up-regulation in the ischemic zone and down-regulation in remote areas at 5 h, and was severely reduced in all heart regions at 24 h. These results indicate a quick onset of regulation of apoptosis-related genes, which is partially reversed in the late phase of ischemia/reperfusion cardioprotection, and highlight variations between ischemic and unaffected myocardium over time. The NOGA 2D and 3D construction system is an attractive method to visualize expressional variations in the myocardium., Competing Interests: CONFLICTS OF INTEREST None.
- Published
- 2017
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50. Sequential activation of different pathway networks in ischemia-affected and non-affected myocardium, inducing intrinsic remote conditioning to prevent left ventricular remodeling.
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Pavo N, Lukovic D, Zlabinger K, Zimba A, Lorant D, Goliasch G, Winkler J, Pils D, Auer K, Jan Ankersmit H, Giricz Z, Baranyai T, Sárközy M, Jakab A, Garamvölgyi R, Emmert MY, Hoerstrup SP, Hausenloy DJ, Ferdinandy P, Maurer G, and Gyöngyösi M
- Subjects
- Animals, Computational Biology, Disease Models, Animal, Gene Expression Profiling, High-Throughput Nucleotide Sequencing, Neprilysin biosynthesis, STAT1 Transcription Factor biosynthesis, STAT3 Transcription Factor biosynthesis, Sus scrofa, Gene Regulatory Networks, Ischemia pathology, Myocardial Reperfusion Injury pathology, Physical Conditioning, Animal methods, Signal Transduction, Ventricular Remodeling
- Abstract
We have analyzed the pathway networks of ischemia-affected and remote myocardial areas after repetitive ischemia/reperfusion (r-I/R) injury without ensuing myocardial infarction (MI) to elaborate a spatial- and chronologic model of cardioprotective gene networks to prevent left ventricular (LV) adverse remodeling. Domestic pigs underwent three cycles of 10/10 min r-I/R by percutaneous intracoronary balloon inflation/deflation in the mid left anterior descending artery, without consecutive MI. Sham interventions (n = 8) served as controls. Hearts were explanted at 5 h (n = 6) and 24 h (n = 6), and transcriptomic profiling of the distal (ischemia-affected) and proximal (non-affected) anterior myocardial regions were analyzed by next generation sequencing (NGS) and post-processing with signaling pathway impact and pathway network analyses. In ischemic region, r-I/R induced early activation of Ca-, adipocytokine and insulin signaling pathways with key regulator STAT3, which was also upregulated in the remote areas together with clusterin (CLU) and TNF-alpha. During the late phase of cardioprotection, antigen immunomodulatory pathways were activated with upregulation of STAT1 and CASP3 and downregulation of neprilysin in both zones, suggesting r-I/R induced intrinsic remote conditioning. The temporo-spatially differently activated pathways revealed a global myocardial response, and neprilysin and the STAT family as key regulators of intrinsic remote conditioning for prevention of adverse remodeling.
- Published
- 2017
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