Synergistic effects of nicotine and hyperlipidemia induce cardiac damage via dynamic cardiomyocyte-based biosensing

Cigarette smoking and hyperlipidemia are major risk factors for cardiovascular disease. However, the mechanisms underlying their synergistic cardiotoxic effects remain insufficiently elucidated, particularly at the cellular electrophysiological level. To address this, we developed an electrophysiological biosensing platform to establish a real-time co-exposure model that simulates the combined stress of nicotine and palmitic acid-induced hyperlipidemia on the primary rat cardiomyocytes. This model enabled continuous, non-invasive monitoring and quantitative analysis of field potential under individual and combined conditions. Our results revealed a distinct concentration-dependent effect of nicotine on cardiomyocytes: low-dose nicotine induced transient and reversible electrophysiological suppression, while high concentrations triggered severe arrhythmias and cell death. Critically, the co-exposure model revealed that a hyperlipidemic state significantly sensitizes cardiomyocytes to nicotine, markedly exacerbating arrhythmogenesis and compromising cell viability compared to nicotine alone. Moreover, nicotine withdrawal experiments showed that the electrophysiological damage induced by moderate nicotine exposure was reversible, whereas the adverse effects of high-dose nicotine exposure were largely irreversible. This study establishes an in vitro model to investigate the multifactorial cardiotoxicity, and provides a predictive platform for risk stratification and therapeutic intervention in smoking- and/or diet-related cardiovascular diseases.