PMID- 35983280
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20230730
IS  - 2575-9108 (Electronic)
IS  - 2575-9108 (Linking)
VI  - 5
IP  - 8
DP  - 2022 Aug 12
TI  - Validating the Arrhythmogenic Potential of High-, Intermediate-, and Low-Risk 
      Drugs in a Human-Induced Pluripotent Stem Cell-Derived Cardiac Microphysiological 
      System.
PG  - 652-667
LID - 10.1021/acsptsci.2c00088 [doi]
AB  - Evaluation of arrhythmogenic drugs is required by regulatory agencies before any 
      new compound can obtain market approval. Despite rigorous review, cardiac 
      disorders remain the second most common cause for safety-related market 
      withdrawal. On the other hand, false-positive preclinical findings prohibit 
      potentially beneficial candidates from moving forward in the development 
      pipeline. Complex in vitro models using cardiomyocytes derived from human-induced 
      pluripotent stem cells (hiPSC-CM) have been identified as a useful tool that 
      allows for rapid and cost-efficient screening of proarrhythmic drug risk. 
      Currently available hiPSC-CM models employ simple two-dimensional (2D) culture 
      formats with limited structural and functional relevance to the human heart 
      muscle. Here, we present the use of our 3D cardiac microphysiological system 
      (MPS), composed of a hiPSC-derived heart micromuscle, as a platform for 
      arrhythmia risk assessment. We employed two different hiPSC lines and tested 
      seven drugs with known ion channel effects and known clinical risk: dofetilide 
      and bepridil (high risk); amiodarone and terfenadine (intermediate risk); and 
      nifedipine, mexiletine, and lidocaine (low risk). The cardiac MPS successfully 
      predicted drug cardiotoxicity risks based on changes in action potential 
      duration, beat waveform (i.e., shape), and occurrence of proarrhythmic events of 
      healthy patient hiPSC lines in the absence of risk cofactors. We showcase 
      examples where the cardiac MPS outperformed existing hiPSC-CM 2D models.
CI  - (c) 2022 American Chemical Society.
FAU - Charwat, Verena
AU  - Charwat V
AUID- ORCID: 0000-0002-2222-3702
AD  - Department of Bioengineering and California Institute for Quantitative 
      Biosciences (QB3), University of California at Berkeley, Berkeley, California 
      94720, United States.
FAU - Charrez, Berenice
AU  - Charrez B
AD  - Department of Bioengineering and California Institute for Quantitative 
      Biosciences (QB3), University of California at Berkeley, Berkeley, California 
      94720, United States.
FAU - Siemons, Brian A
AU  - Siemons BA
AD  - Department of Bioengineering and California Institute for Quantitative 
      Biosciences (QB3), University of California at Berkeley, Berkeley, California 
      94720, United States.
FAU - Finsberg, Henrik
AU  - Finsberg H
AUID- ORCID: 0000-0003-3766-2393
AD  - Simula Research Laboratory, 0164 Oslo, Norway.
FAU - Jaeger, Karoline H
AU  - Jaeger KH
AUID- ORCID: 0000-0003-4234-9094
AD  - Simula Research Laboratory, 0164 Oslo, Norway.
FAU - Edwards, Andrew G
AU  - Edwards AG
AD  - Simula Research Laboratory, 0164 Oslo, Norway.
FAU - Huebsch, Nathaniel
AU  - Huebsch N
AUID- ORCID: 0000-0002-3329-0214
AD  - Department of Bioengineering and California Institute for Quantitative 
      Biosciences (QB3), University of California at Berkeley, Berkeley, California 
      94720, United States.
FAU - Wall, Samuel
AU  - Wall S
AUID- ORCID: 0000-0002-2487-703X
AD  - Simula Research Laboratory, 0164 Oslo, Norway.
FAU - Miller, Evan
AU  - Miller E
AUID- ORCID: 0000-0002-6556-7679
AD  - Department of Chemistry, University of California at Berkeley, Berkeley, 
      California 94720, United States.
FAU - Tveito, Aslak
AU  - Tveito A
AD  - Simula Research Laboratory, 0164 Oslo, Norway.
FAU - Healy, Kevin E
AU  - Healy KE
AUID- ORCID: 0000-0002-8524-3671
AD  - Department of Bioengineering and California Institute for Quantitative 
      Biosciences (QB3), University of California at Berkeley, Berkeley, California 
      94720, United States.
AD  - Department of Materials Science and Engineering, University of California at 
      Berkeley, Berkeley, California 94720, United States.
LA  - eng
GR  - 75N92020D00019/HL/NHLBI NIH HHS/United States
GR  - R01 HL130417/HL/NHLBI NIH HHS/United States
PT  - Journal Article
DEP - 20220729
PL  - United States
TA  - ACS Pharmacol Transl Sci
JT  - ACS pharmacology & translational science
JID - 101721411
PMC - PMC9380217
COIS- The authors declare the following competing financial interest(s): KEH, VC, BAS, 
      HF, KHJ, AGE, NH, SW and AT have a financial relationship with Organos Inc., and 
      they and the company may benefit from commercialization of the results of this 
      research.
EDAT- 2022/08/20 06:00
MHDA- 2022/08/20 06:01
PMCR- 2023/07/29
CRDT- 2022/08/19 02:17
PHST- 2022/05/10 00:00 [received]
PHST- 2022/08/19 02:17 [entrez]
PHST- 2022/08/20 06:00 [pubmed]
PHST- 2022/08/20 06:01 [medline]
PHST- 2023/07/29 00:00 [pmc-release]
AID - 10.1021/acsptsci.2c00088 [doi]
PST - epublish
SO  - ACS Pharmacol Transl Sci. 2022 Jul 29;5(8):652-667. doi: 
      10.1021/acsptsci.2c00088. eCollection 2022 Aug 12.