Abstract 20782: Arrhythmic Risk Evaluation of Native and Combusted Tobacco Flavor Additives in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes

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Introduction: Tobacco and e-cigarette products are flavored to enhance appeal and increase consumption. While many flavor chemicals are conventional food additives and generally regarded as safe, little is known regarding their impact on human cardiac function. Moreover, how heating/combustion of these compounds affects their toxicity is completely unknown.

Objective: To test the in vitro cardiotoxicity of commonly used electronic cigarette flavorings and their thermal degradation products.

Methods and Results: We examined the effects of fifteen flavor compounds (parent and products of heating to 175 or 700°C) on contractile and electrical properties of human induced pluripotent stem cell-derived cardiomyocytes using cellular impedance assays and patch clamp electrophysiology. Of the compounds tested, we found that eugenol (clove), cinnamaldehyde (cinnamon), citronellol (floral), and limonene (citrus) produced significant alterations in impedance parameters with a magnitude of ≥20% relative to controls (P<0.05; EtOH or medium; n = 3). Specifically, cinnamaldehyde (100 μM) significantly reduced cell index (~70% at 48 hrs), while eugenol, citronellol and limonene (100 μM) resulted in transient and acute (~1-3 hrs) increases (+30-40%) in cardiomyocyte beat rate. These effects were significantly attenuated or abolished upon heating. In patch clamp experiments, we found that cinnamaldehyde (100 μM) resulted in progressive membrane potential depolarization and loss of rhythmicity following 5 min of exposure, but did not acutely (≤2 min) alter the action potential waveform, consistent with time-dependent cytotoxic effects of this compound. Application of eugenol produced a concentration-dependent (1-100 μM) decrease in dV/dTmaxand a reversible cessation of spontaneous activity at 1 mM. Consistent with results of impedance analyses, action potential parameters were not significantly altered by eugenol or cinnamaldehyde after heating.

Conclusions: Our results identify several popular flavor additives (i.e., cinnamaldehyde, citronellol, eugenol, limonene) as potentially cardiotoxic. Moreover, the pathophysiological effects of these compounds on cardiac electrical and contractile function may become altered by pyrolysis.

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