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Frequency-Dependent Multi-Well Cardiotoxicity Screening Enabled by Optogenetic Stimulation.

Susanne Rehnelt1, Daniela Malan2, Krisztina Juhasz3,4

  • 1Institute of Physiology I, Medical Faculty, University of Bonn, 53127 Bonn, Germany. s4surehn@uni-bonn.de.

International Journal of Molecular Sciences
|December 7, 2017
PubMed
Summary
This summary is machine-generated.

A new optogenetic system automates cardiac ion channel screening in human cardiomyocytes. This allows for faster, frequency-dependent analysis of drug cardiotoxicity, reducing risks associated with drug development.

Keywords:
cardiomyocytescardiotoxicity screeningfield potentialheart rateinduced pluripotent stem cellslong QT syndromeoptogenetics

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Area of Science:

  • Biomedical Engineering
  • Cardiovascular Pharmacology
  • Optogenetics

Background:

  • Drug-induced cardiac ion channel dysfunction can cause lethal arrhythmias, leading to market withdrawals.
  • Current field potential (FP) recording methods for cardiotoxicity assessment are limited by spontaneous beating and manual analysis.

Purpose of the Study:

  • To develop a novel optogenetic system for automated, parallel, frequency-dependent analysis of drug effects on cardiomyocyte electrophysiology.
  • To enable high-throughput preclinical screening of drug candidates for cardiotoxicity.

Main Methods:

  • Optimized viral transduction and mRNA transfection for Channelrhodopsin-2 expression in human-induced pluripotent stem cell-derived cardiomyocytes.
  • Utilized a novel LED lid for optical stimulation in a 96-well FP recording system.
  • Implemented automated recording and analysis of field potentials.

Main Results:

  • Successfully achieved reliable pacing at physiological heart rates and robust FP recording.
  • Detected rate-dependent drug effects on Na+, Ca2+, and K+ channel function via FP prolongation, shortening, and downstroke changes.
  • Observed drug-induced afterdepolarizations, indicating potential arrhythmogenic effects.

Conclusions:

  • The presented optogenetic system offers a scalable and automated approach for preclinical cardiotoxicity screening.
  • This technology facilitates frequency-dependent analysis of cardiac electrophysiology, improving drug safety assessment.
  • The system is readily available using commercial components, promoting widespread adoption.