Between 1990 and 2006 one third of all safety-related drug withdrawals were due to cardiotoxicity, and cardiac liability continues to be a major hurdle in drug development. Within the pharmaceutical industry, academic institutions, and regulatory agencies there are ongoing efforts to develop higher throughput and more predictive assays that can be used earlier in the drug discovery/development pipeline to minimize both cost and risk.
As described elsewhere in our technology overview, xCELLigence provides a non-invasive and label-free means of evaluating the effect of drugs on cardiomyocyte mechanical beating (Cardio system) and/or electrical activity (CardioECR system). In the below example human iPSc-derived cardiomyocytes were exposed to a variety of compounds with known arrhythmogenic activity and impedance was subsequently monitored on the millisecond time scale. Compared to DMSO (vehicle) and aspirin (negative control), the arrhythmogenic compounds and non-Torsade de Pointes arrhythmogenic compounds (aconitine and quabain) produce distinct impedance profiles indicative of abnormal contraction/relaxation cycles (Figure 1).
Figure 1. Drug-induced arrhythmia. Human iPS-derived cardiomyocytes (iCells) were treated with the indicated compounds and beating was monitored using impedance at millisecond time intervals. Known arrythmogenic compounds were administered as follows: alfuzosin (10 μM), cisapride (1 μM), dofetilide (0.01 μM), erythromycin (30 μM), flecainide (3 μM), quinidine (10 μM), sotalol (100 μM), terfenadine (1 μM), and thioridazine (3 μM). Compounds associated with non-Torsade de Pointes arrhythmia, aconitine (0.03 μM) and quabain (0.03 μM), induced tachycardia- or fibrillation-like arrhythmia. DMSO (0.1%) and 100 μM aspirin serve as vehicle and negative control, respectively. (Data and figures adapted from Guo L, et. al., 2011).
KEY BENEFITS OF USING XCELLIGENCE FOR STUDYING DRUG-INDUCED ARRHYTHMIA:
- Data display excellent correlation with known clinical arrhythmogenic risk.
- Monitor cardiotoxicity over short (seconds) and/or long (days/weeks) time scales.
- More thorough understanding of drug mechanism of action.
Drug-Induced Arrhythmia Supporting Information:
- Cell lines Tested:
Human iPSC iCELL® cardiomyocyte (Cellular Dynamics International), mouse ESC Cor.At® cardiomyocyte (Axiogenesis), human iPSC Cor.4U cardiomyocytes (Axiogenesis), human iPSC Pluricyte® Cardiomyocyte (Pluriomics), rat neonatal cardiomyocyte, murine ES D3 α-pig44 derived cardiomyocyte, mouse iPS derived cardiomyocyte (University of Cologne)
- Compatible xCELLigence Systems
- Drug-Induced Arrhythmia Publications:
- Impedance-based detection of beating rhythm and proarrhythmic effects of compounds on stem cell-derived cardiomyocytes. Jonsson MK, Wang QD, Becker B. Assay Drug Dev Technol. 2011 Dec;9(6):589-99. (Roche R&D, Sweden)
- Functional cardiotoxicity profiling and screening using the xCELLigence RTCA Cardio System. Xi B, Wang T, Li N, Ouyang W, Zhang W, Wu J, Xu X, Wang X, Abassi YA. J Lab Autom. 2011 Dec;16(6):415-21. (ACEA Biosciences, Inc., USA)
- Estimating the risk of drug-induced proarrhythmia using human induced pluripotent stem cell-derived cardiomyocytes. Guo L, Abrams RM, Babiarz JE, Cohen JD, Kameoka S, Sanders MJ, Chiao E, Kolaja KL. Toxicol Sci. 2011 Sep;123(1):281-9. (Hoffmann-La Roche, Nutley, USA)
- In vitro model for assessing arrhythmogenic properties of drugs based on high-resolution impedance measurements. Nguemo F, Šarić T, Pfannkuche K, Watzele M, Reppel M, Hescheler J. Cell Physiol Biochem. 2012;29(5-6):819-32. (University of Cologne, Germany)
- Dynamic monitoring of beating periodicity of stem cell-derived cardiomyocytes as a predictive tool for preclinical safety assessment. Abassi YA, Xi B, Li N, Ouyang W, Seiler A, Watzele M, Kettenhofen R, Bohlen H, Ehlich A, Kolossov E, Wang X, Xu X. Br J Pharmacol. 2012 Mar;165(5):1424-41. (ACEA Biosciences, Inc.,USA)
- Drug-induced functional cardiotoxicity screening in stem cell-derived human and mouse cardiomyocytes: effects of reference compounds. Himmel HM. J Pharmacol Toxicol Methods. 2013 Jul-Aug;68(1):97-111. (Bayer Pharma AG, Germany)
- Refining the human iPSC cardiomyocyte arrhythmic risk assessment model. Guo L, Coyle L, Abrams RM, Kemper R, Chiao ET, Kolaja KL. Toxicol Sci. 2013 Dec;136(2):581-94. (Hoffmann-La Roche, Inc., Nutley, USA)
- The proliferative and chronotropic effects of Brillantaisia nitens Lindau (Acanthaceae) extracts on pluripotent stem cells and their cardiomyocytes derivatives. Nembo EN, Dimo T, Bopda OS, Hescheler J, Nguemo F. J Ethnopharmacol. 2014 Oct 28;156:73-81. (University of Cologne, Germany)
- Chapter 16: Label-Free Impedance Measurements for Profiling Drug- Induced Cardiotoxicity. Nguemo F, Semmler J, Hescheler J. Label-Free Biosensor Methods in Drug Discovery 2015 (University of Cologne, Germany)