@article{MTMT:34786266, title = {Neural network emulation of the human ventricular cardiomyocyte action potential for more efficient computations in pharmacological studies}, url = {https://m2.mtmt.hu/api/publication/34786266}, author = {Grandits, Thomas and Augustin, Christoph M and Haase, Gundolf and Jost, Norbert László and Mirams, Gary R and Niederer, Steven A and Plank, Gernot and Varró, András and Virág, László and Jung, Alexander}, doi = {10.7554/eLife.91911}, journal-iso = {ELIFE}, journal = {ELIFE}, volume = {12}, unique-id = {34786266}, issn = {2050-084X}, abstract = {Computer models of the human ventricular cardiomyocyte action potential (AP) have reached a level of detail and maturity that has led to an increasing number of applications in the pharmaceutical sector. However, interfacing the models with experimental data can become a significant computational burden. To mitigate the computational burden, the present study introduces a neural network (NN) that emulates the AP for given maximum conductances of selected ion channels, pumps, and exchangers. Its applicability in pharmacological studies was tested on synthetic and experimental data. The NN emulator potentially enables massive speed-ups compared to regular simulations and the forward problem (find drugged AP for pharmacological parameters defined as scaling factors of control maximum conductances) on synthetic data could be solved with average root-mean-square errors (RMSE) of 0.47 mV in normal APs and of 14.5 mV in abnormal APs exhibiting early afterdepolarizations (72.5% of the emulated APs were alining with the abnormality, and the substantial majority of the remaining APs demonstrated pronounced proximity). This demonstrates not only very fast and mostly very accurate AP emulations but also the capability of accounting for discontinuities, a major advantage over existing emulation strategies. Furthermore, the inverse problem (find pharmacological parameters for control and drugged APs through optimization) on synthetic data could be solved with high accuracy shown by a maximum RMSE of 0.22 in the estimated pharmacological parameters. However, notable mismatches were observed between pharmacological parameters estimated from experimental data and distributions obtained from the Comprehensive in vitro Proarrhythmia Assay initiative. This reveals larger inaccuracies which can be attributed particularly to the fact that small tissue preparations were studied while the emulator was trained on single cardiomyocyte data. Overall, our study highlights the potential of NN emulators as powerful tool for an increased efficiency in future quantitative systems pharmacology studies.}, keywords = {human; computer simulation; machine learning; Systems biology; Computational Biology; Computer modeling; CELL BIOLOGY; Cardiac electrophysiology; surrogate modeling}, year = {2024}, eissn = {2050-084X}, orcid-numbers = {Varró, András/0000-0003-0745-3603} } @article{MTMT:34763568, title = {Cellular electrophysiological effects of the citrus flavonoid hesperetin in dog and rabbit cardiac ventricular preparations}, url = {https://m2.mtmt.hu/api/publication/34763568}, author = {Mohammed, Aiman and Mohácsi, Gábor and Naveed, Muhammad and Prorok, János and Jost, Norbert László and Virág, László and Baczkó, István and Topal, Leila and Varró, András}, doi = {10.1038/s41598-024-57828-y}, journal-iso = {SCI REP}, journal = {SCIENTIFIC REPORTS}, volume = {14}, unique-id = {34763568}, issn = {2045-2322}, abstract = {Recent experimental data shows that hesperetin, a citrus flavonoid, affects potassium channels and can prolong the QT c interval in humans. Therefore, in the present study we investigated the effects of hesperetin on various transmembrane ionic currents and on ventricular action potentials. Transmembrane current measurements and action potential recordings were performed by patch-clamp and the conventional microelectrode techniques in dog and rabbit ventricular preparations. At 10 µM concentration hesperetin did not, however, at 30 µM significantly decreased the amplitude of the I K1 , I to , I Kr potassium currents. Hesperetin at 3–30 µM significantly and in a concentration-dependent manner reduced the amplitude of the I Ks current. The drug significantly decreased the amplitudes of the I NaL and I CaL currents at 30 µM. Hesperetin (10 and 30 µM) did not change the action potential duration in normal preparations, however, in preparations where the repolarization reserve had been previously attenuated by 100 nM dofetilide and 1 µg/ml veratrine, caused a moderate but significant prolongation of repolarization. These results suggest that hesperetin at close to relevant concentrations inhibits the I Ks outward potassium current and thereby reduces repolarization reserve. This effect in certain specific situations may prolong the QT interval and consequently may enhance proarrhythmic risk.}, year = {2024}, eissn = {2045-2322}, orcid-numbers = {Prorok, János/0000-0001-8419-8859; Baczkó, István/0000-0002-9588-0797; Varró, András/0000-0003-0745-3603} } @article{MTMT:34113182, title = {Selective Inhibition of Cardiac Late Na+ Current Is Based on Fast Offset Kinetics of the Inhibitor}, url = {https://m2.mtmt.hu/api/publication/34113182}, author = {Naveed, Muhammad and Mohammed, Aiman and Topal, Leila and Kovács, Zsigmond Máté and Dienes, Csaba Bálint and Óvári, József and Szentandrássy, Norbert and Magyar, János and Bányász, Tamás and Prorok, János and Jost, Norbert László and Virág, László and Baczkó, István and Varró, András and Nánási, Péter Pál and Horváth, Balázs}, doi = {10.3390/biomedicines11092383}, journal-iso = {BIOMEDICINES}, journal = {BIOMEDICINES}, volume = {11}, unique-id = {34113182}, abstract = {The present study was designed to test the hypothesis that the selectivity of blocking the late Na+ current (INaL) over the peak Na+ current (INaP) is related to the fast offset kinetics of the Na+ channel inhibitor. Therefore, the effects of 1 µM GS967 (INaL inhibitor), 20 µM mexiletine (I/B antiarrhythmic) and 10 µM quinidine (I/A antiarrhythmic) on INaL and INaP were compared in canine ventricular myocardium. INaP was estimated as the maximum velocity of action potential upstroke (V+max). Equal amounts of INaL were dissected by the applied drug concentrations under APVC conditions. The inhibition of INaL by mexiletine and quinidine was comparable under a conventional voltage clamp, while both were smaller than the inhibitory effect of GS967. Under steady-state conditions, the V+max block at the physiological cycle length of 700 ms was 2.3% for GS967, 11.4% for mexiletine and 26.2% for quinidine. The respective offset time constants were 110 ± 6 ms, 456 ± 284 ms and 7.2 ± 0.9 s. These results reveal an inverse relationship between the offset time constant and the selectivity of INaL over INaP inhibition without any influence of the onset rate constant. It is concluded that the selective inhibition of INaL over INaP is related to the fast offset kinetics of the Na+ channel inhibitor.}, keywords = {Dog myocytes; RATE-DEPENDENT BLOCK; LATE NA+ CURRENT; GS967; class I antiarrhythmics}, year = {2023}, eissn = {2227-9059}, orcid-numbers = {Szentandrássy, Norbert/0000-0003-0197-9567; Prorok, János/0000-0001-8419-8859; Baczkó, István/0000-0002-9588-0797; Varró, András/0000-0003-0745-3603; Horváth, Balázs/0000-0003-2562-8446} } @article{MTMT:33834230, title = {A szív repolarizációs és celluláris elektrofiziológiai eltéréseinek vizsgálata krónikus tesztoszteron szupplementációt követően nagyállat modellben = Altered cardiac repolarization associated with cellular electrophysiological remodeling following chronic testosterone administration in a large animal model}, url = {https://m2.mtmt.hu/api/publication/33834230}, author = {Topal, Leila and Pintér, Jenő Antal and Farkas, Attila and Farkas, András and Virág, László and Jost, Norbert László and Baczkó, István and Varró, András}, journal-iso = {CARDIOL HUNG}, journal = {CARDIOLOGIA HUNGARICA}, volume = {53}, unique-id = {33834230}, issn = {0133-5596}, year = {2023}, eissn = {1588-0230}, pages = {A330-A330}, orcid-numbers = {Baczkó, István/0000-0002-9588-0797; Varró, András/0000-0003-0745-3603} } @article{MTMT:33834219, title = {A hesperetin szívelektrofiziológiai hatásai csökkenthetik a repolarizációs tartalékot = Cardiac electrophysiological effects of hesperetin can decrease the repolarization reserve}, url = {https://m2.mtmt.hu/api/publication/33834219}, author = {Prorok, János and Naveed, Muhammad and Mohácsi, G and Mohammed, Aiman and Topal, Leila and Jost, Norbert László and Virág, László and Baczkó, István and Varró, András}, journal-iso = {CARDIOL HUNG}, journal = {CARDIOLOGIA HUNGARICA}, volume = {53}, unique-id = {33834219}, issn = {0133-5596}, year = {2023}, eissn = {1588-0230}, pages = {A329-A329}, orcid-numbers = {Prorok, János/0000-0001-8419-8859; Baczkó, István/0000-0002-9588-0797; Varró, András/0000-0003-0745-3603} } @article{MTMT:33834195, title = {A tartós állóképességi tréning elektorfiziológiai hatásainak vizsgálata kutya sportszív-modellen = Electrophysiological effects of endurance training in a canine sports heart model}, url = {https://m2.mtmt.hu/api/publication/33834195}, author = {Polyák, Alexandra Júlia and Topal, Leila and Pintér, Jenő Antal and Husti, Zoltán and Hornyik, Tibor and Nagy, Norbert and Jost, Norbert László and Virág, László and Farkas, András and Baczkó, István and Farkas, Attila and Varró, András}, journal-iso = {CARDIOL HUNG}, journal = {CARDIOLOGIA HUNGARICA}, volume = {53}, unique-id = {33834195}, issn = {0133-5596}, year = {2023}, eissn = {1588-0230}, pages = {A328-A328}, orcid-numbers = {Baczkó, István/0000-0002-9588-0797; Varró, András/0000-0003-0745-3603} } @article{MTMT:33685694, title = {Cardiac electrophysiological remodeling associated with enhanced arrhythmia susceptibility in a canine model of elite exercise}, url = {https://m2.mtmt.hu/api/publication/33685694}, author = {Polyák, Alexandra Júlia and Topal, Leila and Zombori-Tóth, Noémi and Tóth, Noémi and Prorok, János and Kohajda, Zsófia and Déri, Szilvia and Demeter-Haludka, Vivien and Hegyi, Péter and Venglovecz, Viktória and Ágoston, Gergely and Husti, Zoltán and Gazdag, Péter and Szlovák, Jozefina and Árpádffy-Lovas, Tamás and Naveed, Muhammad and Sarusi, Annamária and Jost, Norbert László and Virág, László and Nagy, Norbert and Baczkó, István and Farkas, Attila and Varró, András}, doi = {10.7554/eLife.80710}, journal-iso = {ELIFE}, journal = {ELIFE}, volume = {12}, unique-id = {33685694}, issn = {2050-084X}, abstract = {The health benefits of regular physical exercise are well known. Even so, there is increasing evidence that the exercise regimes of elite athletes can evoke cardiac arrhythmias including ventricular fibrillation and even sudden cardiac death (SCD). The mechanism of exercise-induced arrhythmia and SCD is poorly understood. Here, we show that chronic training in a canine model (12 sedentary and 12 trained dogs) that mimics the regime of elite athletes induces electrophysiological remodeling (measured by ECG, patch-clamp and immunocytochemical techniques) resulting in increases of both the trigger and the substrate for ventricular arrhythmias. Thus, 4 months sustained training lengthened ventricular repolarization (QTc: 237.1±3.4 ms vs. 213.6±2.8 ms, n=12; APD90: 472.8±29.6 ms vs. 370.1±32.7 ms, n=29 vs. 25), decreased transient outward potassium current (6.4±0.5 pA/pF vs. 8.8±0.9 pA/pF at 50 mV, n=54 vs. 42) and increased the short term variability of repolarization (29.5±3.8 ms vs. 17.5±4.0 ms, n=27 vs. 18). Left ventricular fibrosis and HCN4 protein expression were also enhanced. These changes were associated with enhanced ectopic activity (number of escape beats from 0/hour to 29.7±20.3/hour) in vivo and arrhythmia susceptibility (elicited ventricular fibrillation: 3 of 10 sedentary dogs vs. 6 of 10 trained dogs). Our findings provide in vivo, cellular electrophysiological and molecular biological evidence for the enhanced susceptibility to ventricular arrhythmia in an experimental large animal model of endurance training.}, keywords = {MEDICINE}, year = {2023}, eissn = {2050-084X}, orcid-numbers = {Prorok, János/0000-0001-8419-8859; Hegyi, Péter/0000-0003-0399-7259; Venglovecz, Viktória/0000-0002-2316-7247; Ágoston, Gergely/0000-0002-8513-5750; Baczkó, István/0000-0002-9588-0797; Varró, András/0000-0003-0745-3603} } @article{MTMT:33744836, title = {MiRP2 rescues long QT syndrome type 5}, url = {https://m2.mtmt.hu/api/publication/33744836}, author = {Déri, Szilvia and Hartai, Teodóra and Virág, László and Jost, Norbert László and Labro, Alain J. and Varró, András and Baczkó, István and Nattel, Stanley and Ördög, Balázs}, doi = {10.1016/j.yjmcc.2022.08.175}, journal-iso = {J MOL CELL CARDIOL}, journal = {JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY}, volume = {173}, unique-id = {33744836}, issn = {0022-2828}, year = {2022}, eissn = {1095-8584}, pages = {S87-S88}, orcid-numbers = {Varró, András/0000-0003-0745-3603; Baczkó, István/0000-0002-9588-0797; Ördög, Balázs/0000-0002-8971-3079} } @article{MTMT:33707927, title = {Endurance training induced cellular electrophysiological remodeling in a small and a large animal athlete’s heart model}, url = {https://m2.mtmt.hu/api/publication/33707927}, author = {Topal, Leila and Polyák, Alexandra Júlia and Tóth, Noémi and Zombori-Toth, N and Déri, Szilvia and Virág, László and Jost, Norbert László and Farkas, András and Baczkó, István and Farkas, Attila and Varró, András}, doi = {10.1093/europace/euac053.554}, journal-iso = {EUROPACE}, journal = {EUROPACE}, volume = {24}, unique-id = {33707927}, issn = {1099-5129}, year = {2022}, eissn = {1532-2092}, pages = {i811-i811}, orcid-numbers = {Baczkó, István/0000-0002-9588-0797; Varró, András/0000-0003-0745-3603} } @{MTMT:33702328, title = {New wine in an old bottle or old wine in a new bottle?" in vivo and cellular antiarrhythmic and cardiac electrophysiological effects of desethylamiodarone in dogs}, url = {https://m2.mtmt.hu/api/publication/33702328}, author = {Jost, Norbert László and Kohajda, Zsófia and Virág, László and Hornyik, Tibor and Husti, Zoltán and Sztojkov-Ivanov, A and Nagy, Norbert and Prorok, János and Tóth, Noémi and Tamás, AL and Koncz, Istvan and Déri, Szilvia and Demeter-Haludka, Vivien and Ördög, Balázs and Patfalusi, M and Tálosi, László and Tiszlavicz, László and Földesi, Imre and Baczkó, István and Varró, András}, booktitle = {New Frontiers in Basic Cardiovascular Research Meeting : France – New EU members}, unique-id = {33702328}, year = {2022}, pages = {38-38}, orcid-numbers = {Prorok, János/0000-0001-8419-8859; Ördög, Balázs/0000-0002-8971-3079; Tiszlavicz, László/0000-0003-1134-6587; Földesi, Imre/0000-0002-3329-8136; Baczkó, István/0000-0002-9588-0797; Varró, András/0000-0003-0745-3603} }