CardioMotion: identification of functional and structural cardiotoxic liabilities in small molecules through brightfield kinetic imaging

• DOI: 10.1093/toxsci/kfad065
• Publication Date: 2023-07-18T15:28:06Z
• Authors: William Stebbeds; Kavita Raniga; David Standing; Iona Wallace; James Bayliss; Andrew Brown; Richard Kasprowicz; Deidre Dalmas Wilk; Julianna Deakyne; Peter Clements; Khuram W Chaudhary; Eric I Rossman; Anthony Bahinski; Jo Francis
• Keywords: Cardiotoxicity; Safety pharmacology; In vitro toxicology; Drug Development

Cardiovascular toxicity is an important cause of drug failures in the later stages development, early clinical safety assessment, and even postmarket withdrawals. Early-stage vitro assessment potential cardiovascular liabilities pharmaceutical industry involves interactions with cardiac ion channels, as well induced pluripotent stem cell-derived cardiomyocyte-based functional assays, such calcium flux multielectrode-array assays. These methods are appropriate for identification acute cardiotoxicity but structural cardiotoxicity, which manifests effects after chronic exposure, often only captured vivo. CardioMotion a novel, label-free, high throughput, assay analysis pipeline records assesses spontaneous beating cardiomyocytes identifies compounds impact beating. This achieved through acquisition brightfield images at framerate, combined optical flow-based python transforms into waveform data then parameterized. Validation this large dataset showed that cardioactive diverse known direct mechanisms-of-action on identified (sensitivity = 72.9%), importantly, cardiotoxins also disrupt cardiomyocyte 86%) method. Furthermore, method presents specificity 82.5%.