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Reversibility of etomidate-induced contractile arrest through activation of myocardial autophagy

ABSTRACT: Anesthetic management of heart failure patients undergoing noncardiac surgery remains challenging due to cardiac suppressive properties of anesthetics. Due to varying electrophysiological properties, small and large animals are not good models for studying human myocardial anesthetic responses. Here we use hypertrophic (HCM), dilated (DCM) and healthy human induced pluripotent stem cells derived cardiomyocytes (hiPSC-CMs) to evaluate the cardiac suppression of propofol and etomidate. We demonstrate that propofol and etomidate act through GABAA receptors and contractile inhibition can occur without cell-cell junction. At supraphysiological dosage (100mM), we discovered that cardiac suppression induced by etomidate is reversible while propofol is not. Using transcriptome profiling, we uncover that etomidate was capable of inducing autophagy, likely through induction of cytosolic calcium. Lack of autophagy induction in propofol treated cardiomyocytes were associated with increased apoptosis. Together, we provide the robustness of using hiPSC-CMs as an in vitro cardiotoxicity platform for anesthetics. To delineate how etomidate confers cardioprotection during contraction inhibition, we performed transcriptome profiling on DCM hiPSC-CMs treated with either 10 μM propofol, 10 μM etomidate or DMSO control.

ORGANISM(S): Homo sapiens

PROVIDER: GSE212044 | GEO | 2022/08/30

REPOSITORIES: GEO

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Project description:ABSTRACT Background: Viral myocarditis is a life-threatening illness that may lead to heart failure or cardiac arrhythmias. This study examined whether human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) could be used to model the pathogenic processes of coxsackievirus-induced viral myocarditis and to screen antiviral therapeutics for efficacy. Methods and Results: Human iPSC-CMs were infected with a luciferase-expressing mutant of the coxsackievirus B3 strain (CVB3-Luc). Brightfield microscopy, immunofluorescence, and calcium imaging were used to characterize virally infected hiPSC-CMs. Viral proliferation on hiPSC-CMs was subsequently quantified using bioluminescence imaging. For drug screening, select antiviral compounds including interferon beta 1 (IFNβ1), ribavirin, pyrrolidine dithiocarbamate (PDTC), and fluoxetine were tested for their capacity to abrogate CVB3-Luc proliferation in hiPSC-CMs in vitro. The ability of some of these compounds to reduce CVB3-Luc proliferation in hiPSC-CMs was consistent with the reported drug effects in previous studies. Finally, mechanistic analyses via gene expression profiling of hiPSC-CMs infected with CVB3-Luc revealed an activation of viral RNA and protein clearance pathways within these hiPSC-CMs after IFNβ1 treatment. Conclusions: This study demonstrates that hiPSC-CMs express the coxsackievirus and adenovirus receptor, are susceptible to coxsackievirus infection, and can be used to confirm antiviral drug efficacy. Our results suggest that the hiPSC-CM/CVB3-Luc assay is a sensitive platform that could be used to screen novel antiviral therapeutics for their effectiveness in a high-throughput fashion. For this experiment, human induced pluripotent stem cell derived cardiomyocytes were infected with coxsackievirus at multiplicity of infection (MOI) of 5 for 8 hours. Cells were treated with and without interferon beta 1 in order to determine if treatment activates antiviral response genes and/or viral clearance pathways. 4 total samples (2 for each condition) were analyzed

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Reversibility of etomidate-induced contractile arrest through activation of myocardial autophagy

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