Why the study?
Understanding preclinical-to-clinical translation is important for novel compound safety, requiring evaluation of primary human cardiomyocytes compared with animal models for profiling drug effects on sarcomere shortening and calcium dynamics.
Do primary human ventricular myocytes and dog cardiomyocytes exhibit similar pharmacological responses to positive inotropes in terms of sarcomere shortening and calcium transients?
Do primary human ventricular myocytes and dog cardiomyocytes exhibit similar pharmacological responses to positive inotropes in terms of sarcomere shortening and calcium transients?
Primary human ventricular myocytes and dog cardiomyocytes demonstrate similar pharmacological responses to positive inotropes, supporting the use of human donor heart myocytes as a non-animal alternative for assessing drug-induced cardiac effects.
Human donor CMs may enable non-animal cardiac safety screening; leaves open clinical translation.
Understanding translation from preclinical observations to clinical findings is important for evaluating the efficacy and safety of novel compounds. Of relevance to cardiac safety is profiling drug effects on cardiomyocyte (CM) sarcomere shortening and intracellular Ca2+ dynamics. Although CM from different animal species have been used to assess such effects, primary human CM isolated from human organ donor heart represent an ideal non-animal alternative approach. We performed a study to evaluate primary human CM and have them compared to freshly isolated dog cardiomyocytes for their basic function and responses to positive inotropes with well-known mechanisms. Our data showed that simultaneous assessment of sarcomere shortening and Ca2+-transient can be performed with both myocytes using the IonOptix system. Amplitude of sarcomere shortening and Ca2+-transient (CaT) were significantly higher in dog compared to human CM in the basic condition (absence of treatment), while longer duration of sarcomere shortening and CaT were observed in human cells. We observed that human and dog CMs have similar pharmacological responses to five inotropes with different mechanisms, including dobutamine and isoproterenol (β-adrenergic stimulation), milrinone (PDE3 inhibition), pimobendan and levosimendan (increase of Ca2+sensitization as well as PDE3 inhibition). In conclusion, our study suggests that myocytes obtained from both human donor hearts and dog hearts can be used to simultaneously assess drug-induced effects on sarcomere shortening and CaT using the IonOptix platform.
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Gao et al. (2023) studied this question.
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