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Updated: Mar 26, 2026
Analysis of Cardiac Contractile Dysfunction and Ca2+ Transients in Rodent Myocytes
Published on: May 25, 2022
Analysis of Tyrosine Kinase Inhibitor-Mediated Decline in Contractile Force in Rat Engineered Heart Tissue
Fabian Jacob1, Amina Y Yonis2, Friederike Cuello1
1Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany.
Introduction:
Left ventricular dysfunction is a frequent and potentially severe side effect of many tyrosine kinase inhibitors (TKI). The mode of toxicity is not identified, but may include impairment of mitochondrial or sarcomeric function, autophagy or angiogenesis, either as an on-target or off-target mechanism.
Methods And Results:
We studied concentration-response curves and time courses for nine TKIs in three-dimensional, force generating engineered heart tissue (EHT) from neonatal rat heart cells. We detected a concentration- and time-dependent decline in contractile force for gefitinib, lapatinib, sunitinib, imatinib, sorafenib, vandetanib and lestaurtinib and no decline in contractile force for erlotinib and dasatinib after 96 hours of incubation. The decline in contractile force was associated with an impairment of autophagy (LC3 Western blot) and appearance of autophagolysosomes (transmission electron microscopy).
Conclusion:
This study demonstrates the feasibility to study TKI-mediated force effects in EHTs and identifies an association between a decline in contractility and inhibition of autophagic flux.
Insights
Many tyrosine kinase inhibitors (TKIs) cause heart dysfunction. This study found that several TKIs impair cardiac contractility by inhibiting autophagy in engineered heart tissue, providing a new model for TKI toxicity research.
Area of Science:
- Cardiovascular Toxicology
- Pharmacology
- Biochemistry
Background:
- Left ventricular dysfunction is a significant side effect of tyrosine kinase inhibitors (TKIs).
- The precise mechanisms of TKI-induced cardiotoxicity remain unclear.
- Potential mechanisms include impaired mitochondrial function, sarcomeric function, autophagy, or angiogenesis.
Purpose of the Study:
- To investigate the cardiotoxic effects of various TKIs.
- To explore the underlying mechanisms of TKI-induced cardiac dysfunction.
- To establish a novel model for studying TKI cardiotoxicity.
Main Methods:
- Utilized three-dimensional, force-generating engineered heart tissues (EHTs) from neonatal rat cardiomyocytes.
- Assessed concentration- and time-dependent effects of nine different TKIs on contractile force.
- Analyzed autophagy impairment using LC3 Western blot and transmission electron microscopy.
Main Results:
- Seven out of nine TKIs (gefitinib, lapatinib, sunitinib, imatinib, sorafenib, vandetanib, lestaurtinib) caused a concentration- and time-dependent decline in contractile force.
- Erlotinib and dasatinib did not affect contractile force after 96 hours.
- Declined contractility correlated with impaired autophagic flux and autophagolysosome accumulation.
Conclusions:
- Engineered heart tissues (EHTs) provide a feasible platform for studying TKI-mediated cardiac effects.
- An association was identified between reduced cardiac contractility and inhibited autophagic flux induced by TKIs.
