HiPSC-cardiomyocyte monolayers and spheroids show different cardiotoxic responses to anti-cancer treatment

Clicks: 1
ID: 323507
2026
Free PDF
Article Quality & Performance Metrics
Overall Quality
Not rated
Combines reader engagement with the AI quality analysis. This article has not been analysed, so there is no overall score — reader engagement is measured and shown alongside.
AI Quality Assessment
Not analyzed
Readership in this journal

Ranked #272 of 282 articles by views in European heart journal supplements : journal of the European Society of Cardiology

Most read Least read

Bar heights use a square-root scale. Only the 120 most-read articles are drawn; the journal has 282 in total.

Mint this article as an NFT
Not yet minted

Create a permanent, verifiable on-chain record of this article on the Scimatic Network. The NFT is held in your Journament account, and you can withdraw it to your own wallet at any time.

5 SUSD one-off · no wallet required
Sign in to mint
Abstract
Abstract Background Cardiotoxic effects of anti-cancer therapies (ACT) is an increasing concern, particularly in the context of dramatic improvements in cancer survival. Preclinical in vitro models are essential in early phase cardiotoxicity screening and can provide early mechanistic insights relevant to patients(1). Use of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) allows assessment of ACTs in a high throughput system with fewer ethical concerns than in vivo testing, an intact human genome and promise of patient specific testing. Innovations such as 3D hiPSC-CM spheroids are intended to more closely recapitulate in vivo conditions than recognised 2D models by increasing maturation, paracrine signalling and mechanistic translation into clinic(2). However, few comparisons of cardiotoxic responses have established pros and cons of monolayers (2D) vs spheroids (3D) to ACT treatment. Aims We compare cardiotoxic responses between hiPSC-CM 2D and 3D models during exposure to clinically relevant doses of doxorubicin (Dox) to inform the role of 2D/3D in in vitro cardiotoxicity screens. Methods Commercial hiPSC-CMs from a healthy male donor were used. Cells were plated in 2D (50k cells/well; 96-well plate) or 3D (5k cells/well; U-bottom ultra-low attachment plates) and Dox (50,100,300,600,1000nM) or 0.1% DMSO vehicle treated for 6-days with media changes every 48hrs. Baseline electrophysiology (fluorescence) and contraction were recorded at baseline and after 24,48,72 and 144hrs Dox treatment. Lactate dehydrogenase (LDH) release in media was measured daily to estimate cytotoxicity. Results Dox caused dose-dependent shortening of action potential duration (APD) in 2D (48hr %ΔΔAPD50; 300nM Dox -33.9±2.4 p<0.05, Fig 1). In the 3D equivalent Dox treatment caused an initial phase of APD prolongation before a decrease in APD50 over chronic treatment (72hr %ΔΔAPD50; 300nM Dox 32.1±1.8 p<0.05, 144hr ΔAPD50; -5.6±5.5 p<0.05). Contractile dysfunction was significant >300nM Dox in 2D and 3D whereas cytotoxicity was evident ≥1000nM Dox. We developed a model (Fig 2) from three empirical functions: APD decrease, APD increase and an excitability limit defining CM non-functionality to estimate QT-interval change and myocardial non-excitability. Applying the model to a Dox patient plasma concentration profile (75mg/m2 dose) predicts no significant changes to QT, and a 5% loss of functional myocardium (3). DISCUSSION: Structural differences may confound divergent APD responses to Dox in 2D vs 3D. Recently glycolytic activation (GA) was shown to be a druggable target for Dox cardiotoxicity(4). Our data suggests APD increase in 3D may be induced by extracellular acidosis from lactate efflux into limited extracellular space, which is not replicated in 2D as the extracellular space is significantly larger(5). Our data suggest 3D better informs complex metabolic-structural-functional cardiotoxic axes, potentiating better mechanistic translation into clinic.Figure 1 Figure 2
Reference Key
openalex_W7172250267 Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors K Shead, E Huethorst, F L Burton, R C Myles, N N Lang, G L Smith
Journal European heart journal supplements : journal of the European Society of Cardiology
Year 2026
DOI
10.1093/eurheartjsupp/suag097.210
URL
https://doi.org/10.1093/eurheartjsupp/suag097.210
Keywords Keywords not found

Citations

No citations found. To add a citation, contact the admin at info@scimatic.org

Comments

No comments yet. Be the first to comment on this article.