@article{MTMT:34799327, title = {NASH triggers cardiometabolic HFpEF in aging mice}, url = {https://m2.mtmt.hu/api/publication/34799327}, author = {Kucsera, Dániel and Ruppert, Mihály and Sayour, Viktor Nabil and Tóth, Viktória and Kovács, Tamás and Hegedűs, Zsombor and Onódi, Zsófia and Fábián, Alexandra and Kovács, Attila and Radovits, Tamás and Merkely, Béla Péter and Pacher, Pál and Ferdinandy, Péter and Varga, Zoltán}, doi = {10.1007/s11357-024-01153-9}, journal-iso = {GEROSCIENCE}, journal = {GEROSCIENCE: OFFICIAL JOURNAL OF THE AMERICAN AGING ASSOCIATION (AGE)}, volume = {46}, unique-id = {34799327}, issn = {2509-2715}, abstract = {Both heart failure with preserved ejection fraction (HFpEF) and non-alcoholic fatty liver disease (NAFLD) develop due to metabolic dysregulation, has similar risk factors (e.g., insulin resistance, systemic inflammation) and are unresolved clinical challenges. Therefore, the potential link between the two disease is important to study. We aimed to evaluate whether NASH is an independent factor of cardiac dysfunction and to investigate the age dependent effects of NASH on cardiac function. C57Bl/6 J middle aged (10 months old) and aged mice (24 months old) were fed either control or choline deficient (CDAA) diet for 8 weeks. Before termination, echocardiography was performed. Upon termination, organ samples were isolated for histological and molecular analysis. CDAA diet led to the development of NASH in both age groups, without inducing weight gain, allowing to study the direct effect of NASH on cardiac function. Mice with NASH developed hepatomegaly, fibrosis, and inflammation. Aged animals had increased heart weight. Conventional echocardiography revealed normal systolic function in all cohorts, while increased left ventricular volumes in aged mice. Two-dimensional speckle tracking echocardiography showed subtle systolic and diastolic deterioration in aged mice with NASH. Histologic analyses of cardiac samples showed increased cross-sectional area, pronounced fibrosis and Col1a1 gene expression, and elevated intracardiac CD68 + macrophage count with increased Il1b expression. Conventional echocardiography failed to reveal subtle change in myocardial function; however, 2D speckle tracking echocardiography was able to identify diastolic deterioration. NASH had greater impact on aged animals resulting in cardiac hypertrophy, fibrosis, and inflammation.}, year = {2024}, eissn = {2509-2723}, pages = {4517-4531}, orcid-numbers = {Kucsera, Dániel/0000-0001-9446-847X; Tóth, Viktória/0009-0003-9776-724X; Kovács, Tamás/0000-0003-4127-4545; Onódi, Zsófia/0000-0002-3746-8016; Fábián, Alexandra/0000-0002-8449-0638; Kovács, Attila/0000-0003-2320-6434; Merkely, Béla Péter/0000-0001-6514-0723; Pacher, Pál/0000-0001-7036-8108; Ferdinandy, Péter/0000-0002-6424-6806; Varga, Zoltán/0000-0002-2758-0784} } @article{MTMT:33228693, title = {Characterization of immune checkpoint inhibitor-induced cardiotoxicity reveals interleukin-17A as a driver of cardiac dysfunction after anti-PD-1 treatment}, url = {https://m2.mtmt.hu/api/publication/33228693}, author = {Gergely, Tamás G and Kucsera, Dániel and Tóth, Viktória and Kovács, Tamás and Sayour, Viktor Nabil and Drobni, Zsófia and Ruppert, Mihály and Petrovich, Balázs and Ágg, Bence and Onódi, Zsófia and Fekete, Nóra and Pállinger, Éva and Buzás, Edit Irén and Yousif, Laura I. and Meijers, Wouter C. and Radovits, Tamás and Merkely, Béla Péter and Ferdinandy, Péter and Varga, Zoltán}, doi = {10.1111/bph.15984}, journal-iso = {BR J PHARMACOL}, journal = {BRITISH JOURNAL OF PHARMACOLOGY}, volume = {180}, unique-id = {33228693}, issn = {0007-1188}, year = {2023}, eissn = {1476-5381}, pages = {740-761}, orcid-numbers = {Kucsera, Dániel/0000-0001-9446-847X; Tóth, Viktória/0009-0003-9776-724X; Kovács, Tamás/0000-0003-4127-4545; Drobni, Zsófia/0000-0002-1355-5318; Petrovich, Balázs/0000-0002-9745-0416; Ágg, Bence/0000-0002-6492-0426; Onódi, Zsófia/0000-0002-3746-8016; Pállinger, Éva/0000-0002-5789-0951; Buzás, Edit Irén/0000-0002-3744-206X; Merkely, Béla Péter/0000-0001-6514-0723; Ferdinandy, Péter/0000-0002-6424-6806; Varga, Zoltán/0000-0002-2758-0784} } @article{MTMT:33567171, title = {Effects of Bempedoic Acid in Acute Myocardial Infarction in Rats: No Cardioprotection and No Hidden Cardiotoxicity}, url = {https://m2.mtmt.hu/api/publication/33567171}, author = {Gergely, Tamás G and Brenner, Gábor and Nagy, Regina Norma and Sayour, Viktor Nabil and Makkos, András and Kovácsházi, Csenger and Tian, Huimin and Schulz, Rainer and Giricz, Zoltán and Görbe, Anikó and Ferdinandy, Péter}, doi = {10.3390/ijms24021585}, journal-iso = {INT J MOL SCI}, journal = {INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES}, volume = {24}, unique-id = {33567171}, issn = {1661-6596}, abstract = {Lipid-lowering drugs have been shown to have cardioprotective effects but may have hidden cardiotoxic properties. Therefore, here we aimed to investigate if chronic treatment with the novel lipid-lowering drug bempedoic acid (BA) exerts hidden cardiotoxic and/or cardioprotective effects in a rat model of acute myocardial infarction (AMI). Wistar rats were orally treated with BA or its vehicle for 28 days, anesthetized and randomized to three different groups (vehicle + ischemia/reperfusion (I/R), BA + I/R, and positive control vehicle + ischemic preconditioning (IPC)) and subjected to cardiac 30 min ischemia and 120 min reperfusion. IPC was performed by 3 × 5 min I/R cycles before ischemia. Myocardial function, area at risk, infarct size and arrhythmias were analyzed. Chronic BA pretreatment did not influence cardiac function or infarct size as compared to the vehicle group, while the positive control IPC significantly reduced the infarct size. The incidence of reperfusion-induced arrhythmias was significantly reduced by BA and IPC. This is the first demonstration that BA treatment does not show cardioprotective effect although moderately reduces the incidence of reperfusion-induced arrhythmias. Furthermore, BA does not show hidden cardiotoxic effect in rats with AMI, showing its safety in the ischemic/reperfused heart.}, year = {2023}, eissn = {1422-0067}, orcid-numbers = {Gergely, Tamás G/0000-0003-1972-2065; Brenner, Gábor/0000-0001-7886-2960; Nagy, Regina Norma/0000-0002-3253-5398; Makkos, András/0000-0002-0309-4909; Kovácsházi, Csenger/0000-0003-0283-9486; Schulz, Rainer/0000-0003-3017-0476; Giricz, Zoltán/0000-0003-2036-8665; Görbe, Anikó/0000-0003-4908-1094; Ferdinandy, Péter/0000-0002-6424-6806} } @article{MTMT:33547688, title = {IL-1β neutralization prevents diastolic dysfunction development, but lacks hepatoprotective effect in an aged mouse model of NASH}, url = {https://m2.mtmt.hu/api/publication/33547688}, author = {Kucsera, Dániel and Tóth, Viktória and Sayour, Viktor Nabil and Kovács, Tamás and Gergely, Tamás G and Ruppert, Mihály and Radovits, Tamás and Fábián, Alexandra and Kovács, Attila and Merkely, Béla Péter and Ferdinandy, Péter and Varga, Zoltán}, doi = {10.1038/s41598-022-26896-3}, journal-iso = {SCI REP}, journal = {SCIENTIFIC REPORTS}, volume = {13}, unique-id = {33547688}, abstract = {Interleukin-1β (IL-1β) is a key mediator of non-alcoholic steatohepatitis (NASH), a chronic liver disease, and of systemic inflammation-driven aging. IL-1β contributes to cardio-metabolic decline, and may promote hepatic oncogenic transformation. Therefore, IL-1β is a potential therapeutic target in these pathologies. We aimed to investigate the hepatic and cardiac effects of an IL-1β targeting monoclonal antibody in an aged mouse model of NASH. 24 months old male C57Bl/6J mice were fed with control or choline deficient (CDAA) diet and were treated with isotype control or anti-IL-1β Mab for 8 weeks. Cardiac functions were assessed by conventional—and 2D speckle tracking echocardiography. Liver samples were analyzed by immunohistochemistry and qRT-PCR. Echocardiography revealed improved cardiac diastolic function in anti-IL-1β treated mice with NASH. Marked hepatic fibrosis developed in CDAA-fed group, but IL-1β inhibition affected fibrosis only at transcriptomic level. Hepatic inflammation was not affected by the IL-1β inhibitor. PCNA staining revealed intensive hepatocyte proliferation in CDAA-fed animals, which was not influenced by neutralization of IL-1β. IL-1β inhibition increased hepatic expression of Pd-1 and Ctla4 , while Pd-l1 expression increased in NASH. In conclusion, IL-1β inhibition improved cardiac diastolic function, but did not ameliorate features of NASH; moreover, even promoted hepatic immune checkpoint expression, with concomitant NASH-related hepatocellular proliferation.}, year = {2023}, eissn = {2045-2322}, orcid-numbers = {Kucsera, Dániel/0000-0001-9446-847X; Tóth, Viktória/0009-0003-9776-724X; Kovács, Tamás/0000-0003-4127-4545; Fábián, Alexandra/0000-0002-8449-0638; Kovács, Attila/0000-0003-2320-6434; Merkely, Béla Péter/0000-0001-6514-0723; Ferdinandy, Péter/0000-0002-6424-6806; Varga, Zoltán/0000-0002-2758-0784} } @article{MTMT:34136194, title = {Droplet Digital PCR Is a Novel Screening Method Identifying Potential Cardiac G-Protein-Coupled Receptors as Candidate Pharmacological Targets in a Rat Model of Pressure-Overload-Induced Cardiac Dysfunction}, url = {https://m2.mtmt.hu/api/publication/34136194}, author = {Sayour, Viktor Nabil and Tóth, Viktória and Nagy, Regina Norma and Vörös, Imre and Gergely, Tamás G and Onódi, Zsófia and Nagy, Noémi and Bödör, Csaba and Váradi, Barnabás and Ruppert, Mihály and Radovits, Tamás and Bleckwedel, Federico and Zelarayán, Laura C. and Pacher, Pál and Ágg, Bence and Görbe, Anikó and Ferdinandy, Péter and Varga, Zoltán}, doi = {10.3390/ijms241813826}, journal-iso = {INT J MOL SCI}, journal = {INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES}, volume = {24}, unique-id = {34136194}, issn = {1661-6596}, abstract = {The identification of novel drug targets is needed to improve the outcomes of heart failure (HF). G-protein-coupled receptors (GPCRs) represent the largest family of targets for already approved drugs, thus providing an opportunity for drug repurposing. Here, we aimed (i) to investigate the differential expressions of 288 cardiac GPCRs via droplet digital PCR (ddPCR) and bulk RNA sequencing (RNAseq) in a rat model of left ventricular pressure-overload; (ii) to compare RNAseq findings with those of ddPCR; and (iii) to screen and test for novel, translatable GPCR drug targets in HF. Male Wistar rats subjected to transverse aortic constriction (TAC, n = 5) showed significant systolic dysfunction vs. sham operated animals (SHAM, n = 5) via echocardiography. In TAC vs. SHAM hearts, RNAseq identified 69, and ddPCR identified 27 significantly differentially expressed GPCR mRNAs, 8 of which were identified using both methods, thus showing a correlation between the two methods. Of these, Prostaglandin-F2α-receptor (Ptgfr) was further investigated and localized on cardiomyocytes and fibroblasts in murine hearts via RNA-Scope. Antagonizing Ptgfr via AL-8810 reverted angiotensin-II-induced cardiomyocyte hypertrophy in vitro. In conclusion, using ddPCR as a novel screening method, we were able to identify GPCR targets in HF. We also show that the antagonism of Ptgfr could be a novel target in HF by alleviating cardiomyocyte hypertrophy.}, year = {2023}, eissn = {1422-0067}, orcid-numbers = {Tóth, Viktória/0009-0003-9776-724X; Nagy, Regina Norma/0000-0002-3253-5398; Vörös, Imre/0000-0001-5922-6109; Onódi, Zsófia/0000-0002-3746-8016; Bödör, Csaba/0000-0002-0729-692X; Bleckwedel, Federico/0000-0002-3015-951X; Pacher, Pál/0000-0001-7036-8108; Ágg, Bence/0000-0002-6492-0426; Görbe, Anikó/0000-0003-4908-1094; Ferdinandy, Péter/0000-0002-6424-6806; Varga, Zoltán/0000-0002-2758-0784} } @article{MTMT:31643621, title = {CDR132L improves systolic and diastolic function in a large animal model of chronic heart failure}, url = {https://m2.mtmt.hu/api/publication/31643621}, author = {Batkai, Sandor and Genschel, Celina and Viereck, Janika and Rump, Steffen and Bär, Christian and Borchert, Tobias and Traxler, Denise and Riesenhuber, Martin and Spannbauer, Andreas and Lukovic, Dominika and Zlabinger, Katrin and Hašimbegović, Ena and Winkler, Johannes and Garamvölgyi, Rita and Neitzel, Sonja and Gyöngyösi, Mariann and Thum, Thomas}, doi = {10.1093/eurheartj/ehaa791}, journal-iso = {EUR HEART J}, journal = {EUROPEAN HEART JOURNAL}, volume = {42}, unique-id = {31643621}, issn = {0195-668X}, abstract = {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.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.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.}, keywords = {myocardial infarction; MICRORNAS; Contractile function; Chronic heart failure; Cardiac remodelling; translational studies}, year = {2021}, eissn = {1522-9645}, pages = {192-201}, orcid-numbers = {Garamvölgyi, Rita/0000-0001-7243-7808} } @article{MTMT:31992276, title = {Post-Myocardial Infarction Heart Failure in Closed-chest Coronary Occlusion/Reperfusion Model in Göttingen Minipigs and Landrace Pigs}, url = {https://m2.mtmt.hu/api/publication/31992276}, author = {Brenner, Gábor and Giricz, Zoltán and Garamvölgyi, Rita and Makkos, András and Onódi, Zsófia and Sayour, Viktor Nabil and Gergely, Tamás G and Baranyai, Tamás and Petneházy, Örs and Kőrösi, Dénes and Szabó, P. Gergő and Vágó, Hajnalka and Dohy, Zsófia and Czimbalmos, Csilla and Merkely, Béla Péter and Boldin-Adamsky, Swetlana and Feinstein, Elena and Horváth, Iván and Ferdinandy, Péter}, doi = {10.3791/61901}, journal-iso = {JOVE-J VIS EXP}, journal = {JOVE-JOURNAL OF VISUALIZED EXPERIMENTS}, volume = {2021}, unique-id = {31992276}, issn = {1940-087X}, year = {2021}, eissn = {1940-087X}, orcid-numbers = {Brenner, Gábor/0000-0001-7886-2960; Giricz, Zoltán/0000-0003-2036-8665; Garamvölgyi, Rita/0000-0001-7243-7808; Makkos, András/0000-0002-0309-4909; Onódi, Zsófia/0000-0002-3746-8016; Baranyai, Tamás/0000-0002-9378-8938; Petneházy, Örs/0000-0001-9698-5753; Vágó, Hajnalka/0000-0002-3568-3572; Dohy, Zsófia/0000-0002-0706-5179; Czimbalmos, Csilla/0000-0001-6311-9920; Merkely, Béla Péter/0000-0001-6514-0723; Ferdinandy, Péter/0000-0002-6424-6806} } @article{MTMT:32277097, title = {Towards standardization of echocardiography for the evaluation of left ventricular function in adult rodents: a position paper of the ESC Working Group on Myocardial Function}, url = {https://m2.mtmt.hu/api/publication/32277097}, author = {Zacchigna, Serena and Paldino, Alessia and Falcao-Pires, Ines and Daskalopoulos, Evangelos P. and Dal, Ferro Matteo and Vodret, Simone and Lesizza, Pierluigi and Cannata, Antonio and Miranda-Silva, Daniela and Lourenco, Andre P. and Pinamonti, Bruno and Sinagra, Gianfranco and Weinberger, Florian and Eschenhagen, Thomas and Carrier, Lucie and Kehat, Izhak and Tocchetti, Carlo G. and Russo, Michele and Ghigo, Alessandra and Cimino, James and Hirsch, Emilio and Dawson, Dana and Ciccarelli, Michele and Oliveti, Marco and Linke, Wolfgang A. and Cuijpers, Ilona and Heymans, Stephane and Hamdani, Nazha and de, Boer Martine and Duncker, Dirk J. and Kuster, Diederik and van, der Velden Jolanda and Beauloye, Christophe and Bertrand, Luc and Mayr, Manuel and Giacca, Mauro and Leuschner, Florian and Backs, Johannes and Thum, Thomas}, doi = {10.1093/cvr/cvaa110}, journal-iso = {CARDIOVASC RES}, journal = {CARDIOVASCULAR RESEARCH}, volume = {117}, unique-id = {32277097}, issn = {0008-6363}, abstract = {Echocardiography is a reliable and reproducible method to assess non-invasively cardiac function in clinical and experimental research. Significant progress in the development of echocardiographic equipment and transducers has led to the successful translation of this methodology from humans to rodents, allowing for the scoring of disease severity and progression, testing of new drugs, and monitoring cardiac function in genetically modified or pharmacologically treated animals. However, as yet, there is no standardization in the procedure to acquire echocardiographic measurements in small animals. This position paper focuses on the appropriate acquisition and analysis of echocardiographic parameters in adult mice and rats, and provides reference values, representative images, and videos for the accurate and reproducible quantification of left ventricular function in healthy and pathological conditions. [GRAPHICS] .}, keywords = {STANDARDIZATION; Echocardiography; animal models; SYSTOLIC FUNCTION}, year = {2021}, eissn = {1755-3245}, pages = {43-59}, orcid-numbers = {Lesizza, Pierluigi/0000-0002-1663-373X; Cannata, Antonio/0000-0001-7609-6297; Ciccarelli, Michele/0000-0003-2379-1960; Cuijpers, Ilona/0000-0001-8163-1573; Hamdani, Nazha/0000-0002-3053-0008; Kuster, Diederik/0000-0003-1498-6862; Bertrand, Luc/0000-0003-0655-7099; Mayr, Manuel/0000-0002-0597-829X} } @article{MTMT:31158972, title = {Preclinical development of a miR-132 inhibitor for heart failure treatment}, url = {https://m2.mtmt.hu/api/publication/31158972}, author = {Foinquinos, Ariana and Batkai, Sandor and Genschel, Celina and Viereck, Janika and Rump, Steffen and Gyöngyösi, Mariann and Traxler, Denise and Riesenhuber, Martin and Spannbauer, Andreas and Lukovic, Dominika and Weber, Natalie and Zlabinger, Katrin and Hašimbegović, Ena and Winkler, Johannes and Fiedler, Jan and Dangwal, Seema and Fischer, Martin and Roche, Jeanne de la and Wojciechowski, Daniel and Kraft, Theresia and Garamvölgyi, Rita and Neitzel, Sonja and Chatterjee, Shambhabi and Yin, Xiaoke and Bär, Christian and Mayr, Manuel and Xiao, Ke and Thum, Thomas}, doi = {10.1038/s41467-020-14349-2}, journal-iso = {NAT COMMUN}, journal = {NATURE COMMUNICATIONS}, volume = {11}, unique-id = {31158972}, year = {2020}, eissn = {2041-1723}, orcid-numbers = {Garamvölgyi, Rita/0000-0001-7243-7808} }