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04. - 06.06.2022 | EWGCCE

220604 event image EWGCCE 2022

Conference Venue:
Palacio de congresos de toledo el greco
Paseo del Miradero s/n
45001 Toledo
Spain

Go to the Conference website here.


Meet András Horvath and Elena Dragicevic 

Nanion Application Scientist, András Horvath and Senior Sales and Alliance Manager, Elena Dragicevic will each present a poster. Fitzwilliam Seibertz (University Medical Center Göttingen) will present a poster in collaboration with scientists from the Nanion team.

Presenter: Elena Dragicevic 
Title: Comprehensive electrophysiological analysis of cardiomyocytes 

Abstract:

Fundamental insights into the electrical and mechanical dynamics of the human heart can uncover the complexity of cardiac physiology and disease. Uniting automated patch clamp (APC), impedance, contractile force, and electrical MEA-like recording readouts from cardiac cells, such as hiPSCs cardiomyocytes, gives valuable insight into cellular phenotypes. This holistic approach establishes a more predictive model for cardiovascular risk assessment and opens the way for better screening of new drug candidates. 

We investigated cardiac ion channels in cell models, including hiPSCs, using APC systems in current-, voltage- and dynamic clamp-mode then validated the data on 2D cell monolayers in cell monitoring systems. Additionally, we developed a label-free, pro-maturation physiological environment by recording hiPSCs on flexible substrates, with successful mechanical stimulation.  

We show the evaluation of ion currents, action potentials, maturation, and contractile force after compound or mechanical stimulation. Ion channel currents and myocyte repolarization data were investigated using 20 reference compounds such as “high risk” hERG blockers dofetilide and E-4031 and compounds acting on sodium and calcium channels. Data demonstrate that high-risk compounds prolong the FPD (field potential duration), intermediate risk compounds induced arrhythmia in almost all cases at the highest dose, and low-risk compounds either decreased FPD or had no impact. By developing flexible substrate technology, we show that classical ionotropic compounds (S-Bay-K8644, isoproterenol) induce mature, positive inotropic responses without additional external stimulation. Application of different levels of static pressure potentiating membrane stretching resulted in higher contraction amplitudes. This finding confirmed the reproducibility of the Frank-Starling mechanism. In addition, cyclic stretching resulted in a significant increase in beat amplitude (2.7±0.2 a.u. vs. 1.4±0.3 a.u) and rate (87.7±1.2 bpm vs. 70.2±3 bpm) compared to non-stimulated cells. 

In summary, we show a comprehensive overview of data obtained using three complementary electrophysiology technologies, enabling recordings of cardiac channels and contractility of hiPSCs. 


Presenter: András Horvath
Title: Reliable and straightforward cardiac safety liability and proarrhythmic assessment using automated patch clamp.

Abstract:

Automated patch clamp (APC) devices have become important, higher throughput alternatives to manual patch clamp for cardiac safety testing and for studying ion channel mutations and pharmacology. As hiPSC-CMs are shown to well recapitulate cardiac physiology, there is growing interest to use them on those platforms, triggering the development of optimized tools and assays to enable action potential (AP) recordings in addition to the classical voltage clamp recordings. Here, we developed a range of APC assays for commercially available hiPSC-CM lines, aiming to establish routine recordings in APC.

Recordings were performed in voltage clamp or current clamp mode combined with dynamic clamp to obtain reliable AP pharmacology recordings on APC. We studied the effects of known calcium, sodium, late sodium and hERG channel modulators on AP parameters. hERG pharmacology experiments were performed at room temperature and at 37°C.

Class 1/C blocker flecainide effectively inhibited the sodium current and accordingly reduced the AP amplitude (APA) of hiPSC-CMs in a concentration-dependent manner; Class 1/B blocker mexiletine also showed the expected concentration-response curve (IC50: 5.6 µM). The late sodium channel inhibitor ranolazine significantly reduced the APA (14%), upstroke velocity (24%) and AP duration (APD90) at high concentrations. Increasing the pacing rate from 0.5 Hz to 3Hz resulted in more pronounced effects on APA, as expected. Selective hERG blocker dofetilide prolonged the APD90 and increased the short-term variability of the APs. L-type calcium channel showed sensitivity to blockers (nifedipine and diltiazem), while channel activator BayK 8644 prolonged APD90 in a concentration-dependent manner, which could be reversed by nifedipine.

Our data demonstrate that cardiac ion channel pharmacology can be successfully recorded using hiPSC-CMs in APC, providing a reliable tool for cardiac safety screening and the study of cardiac ion channel diseases in a model system closer to in vivo physiology than heterologous expression systems.


Presenter: Fitzwilliam Seibertz (University Medical Center Göttingen)
Title: High performance automated patch-clamp of mammalian atrial cardiomyocytes


About the ESC Working Group on Cardiac Cellular Electrophysiology

The ESC Working Group on Cardiac Cellular Electrophysiology provides a friendly and informal environment favouring free exchange of ideas in the fields of cardiac ion channel physiology, excitation-contraction coupling, myocardial electrophysiology and related fields of cardiac physiology and pathophysiology.


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