Investigation on arrhythmogenic potential of phenanthrene using human induced pluripotent stem cell-derived cardiomyocytes

With the exacerbation of air pollution, the attention towards cardiovascular diseases associated with air pollution has increased. Phenanthrene, a polycyclic aromatic hydrocarbon produced by incomplete combustion, is a widespread pollutant that causes cardiovascular diseases. Previous studies have reported cardiac electrophysiological disturbances caused by phenanthrene in aquatic animals and mouse models; however, its effects on human-relevant models have not been adequately investigated. Although the hERG assay is commonly used to assess arrhythmia risk, it is restricted to assessing a single ion channel and cannot reflect the complexity of the multiple ion channels in the heart. To address this limitation, multielectrode array (MEA) analysis using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) has emerged as a promising method for predicting arrhythmia, offering improved evaluation of electrophysiological disturbances across multiple ion channels.

This study aimed to evaluate the arrhythmogenic potential of phenanthrene through MEA analysis using hiPSC-CMs.

Before measuring, a viability test was performed to confirm that acute exposure to phenanthrene did not affect the cell viability. Field potential (FP) measurements before and after phenanthrene treatment for 25 min revealed a dose-dependent decrease in major parameters, including field potential duration (FPD), corrected FPD (FPDc), beat period (BP), and spike amplitude (SA). The results of hiPSC-CMs exposed to L-type Ca²⁺ channel blocker (nifedipine) and K⁺ channel blocker (quinidine) was analyzed for comparison with phenanthrene treatment. Nifedipine-induced shortening of FPD, FPDc, and BP, while quinidine caused elongation of FPD and FPDc and a decrease in SA. These data imply that phenanthrene inhibit both L-type Ca²⁺ and K⁺ channel in hiPSC-CMs.

In conclusion, our results indicate that acute exposure to phenanthrene causes electrophysiological disruption in hiPSC-CMs, suggesting that phenanthrene has proarrhythmic potential in humans. Given our findings and previous studies, it is urgent to initiate discussions on regulatory standard for phenanthrene.