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Modeling propofol-induced cardiotoxicity in the isolated-perfused newborn mouse heart
Matthew B Barajas1, Aili Wang1, Keren K Griffiths1
1Department of Anesthesiology, Columbia University Medical Center, New York, New York, USA.
Insights
Propofol infusion syndrome (PRIS) affects vulnerable infants and children, causing cardiac issues. This study developed an ex-vivo mouse heart model to study propofol cardiotoxicity, mimicking pediatric PRIS features.
Area of Science:
- Cardiology
- Pediatric Anesthesiology
- Toxicology
Background:
- Propofol infusion syndrome (PRIS) poses significant risks to pediatric patients, with cardiac dysfunction being a primary concern.
- The underlying mechanisms of pediatric PRIS remain poorly understood due to limited research and the absence of a suitable animal model.
- In vivo studies in newborn mice are challenging due to feasibility and confounding factors.
Purpose of the Study:
- To develop and validate an ex-vivo model using isolated-perfused newborn mouse hearts to study propofol-induced cardiotoxicity.
- To investigate whether this model can recapitulate key cardiac features of pediatric PRIS.
- To corroborate previously observed in vitro findings regarding propofol's effects on cardiomyocytes.
Main Methods:
- Isolated newborn mouse hearts were perfused and exposed to a toxic dose of propofol or intralipid for 30 minutes.
- Cardiac function was assessed via surface electrocardiogram, ventricular contractile force, and oxygen extraction.
- Mitochondrial function was evaluated using multiphoton laser imaging for membrane potential and permeability transition pore analysis, alongside propidium iodide uptake for cell death.
Main Results:
- Propofol exposure rapidly induced cardiac dysrhythmias and significantly depressed ventricular contractile function.
- Mitochondrial membrane potential was impaired, and the permeability transition pore's open probability increased in propofol-treated hearts.
- These cardiotoxic effects occurred without inducing significant cell death, mirroring hallmarks of pediatric PRIS.
Conclusions:
- The isolated-perfused newborn mouse heart model effectively replicates critical cardiac aspects of pediatric propofol infusion syndrome.
- This ex-vivo model provides a viable platform for further investigation into the mechanisms of pediatric PRIS.
- Findings support prior in vitro observations and highlight the utility of this model for studying acute propofol cardiotoxicity in developing hearts.
Abstract:
Infants and children are vulnerable to developing propofol infusion syndrome (PRIS) and young age is a risk factor. Cardiac involvement is often prominent and associated with death. However, the mechanisms of pediatric PRIS are poorly understood because of the paucity of investigation and lack of a gold standard animal model. Unfortunately, in vivo modeling of PRIS in a newborn mouse is not feasible and would be complicated by confounders. Thus, we focused on propofol-induced cardiotoxicity and aimed to develop an ex-vivo model in the isolated-perfused newborn mouse heart. We hypothesized that the model would recapitulate the key cardiac features of PRIS seen in infants and children and would corroborate prior in vitro observations. Isolated perfused newborn mouse hearts were exposed to a toxic dose of propofol or intralipid for 30-min. Surface electrocardiogram, ventricular contractile force, and oxygen extraction were measured over time. Real-time multiphoton laser imaging was utilized to quantify calcein and tetramethylrhodamine ethyl ester fluorescence. Propidium iodide uptake was assessed following drug exposure. A toxic dose of propofol rapidly induced dysrhythmias, depressed ventricular contractile function, impaired the mitochondrial membrane potential, and increased open probability of the permeability transition pore in propofol-exposed hearts without causing cell death. These features mimicked the hallmarks of pediatric PRIS and corroborated prior observations made in isolated newborn cardiomyocyte mitochondria. Thus, acute propofol-induced cardiotoxicity in the isolated-perfused developing mouse heart may serve as a relevant ex-vivo model for pediatric PRIS.
