Effects of cigarette smoke extracts (combustible and heated tobacco) on rat and human iPS cell-derived cardiomyocytes.

Abstract

Smoking is a risk factor of cardiovascular diseases. However, direct effects on cardiomyocytes, especially on intracellular Ca2+ dynamics and on human cardiomyocytes, are not fully elucidated. In addition, the effects of heated cigarettes, which have been increasingly used in recent years, on human diseases have not been extensively studied. In this study, we compared the effects of cigarette smoke extracts (CSEs) from heated (Ploom X, IQOS) and combustible cigarettes (1R6F, Hi-Lite) on cell viability, contractile function and intracellular Ca2+ dynamics in rat and human iPS cell-derived cardiomyocytes. MTS assays indicated that all CSEs reduced cell viability of cultured myocytes, with toxicity in the order of combustible > heated CSEs. Functional analysis showed that 1% CSE significantly reduced the spontaneous beating rate of cultured cardiomyocytes only in the combustible cigarette group. In contrast, in freshly isolated cardiomyocytes, cell shortening was reduced in all CSE-treated groups. Intracellular Ca2+ measurement revealed that abnormal Ca2+ dynamics are induced by combustible CSEs. Kinetic analysis of Ca2+ transients suggests that CSE accelerates the rate of Ca2+ uptake into the sarcoplasmic reticulum (SR), but also causes excessive Ca2+ leakage from the SR, leading to diastolic Ca2+ overload. Similar contractile dysfunction (reduced spontaneous beating rate and contractility) was also observed in human iPS-derived cardiomyocytes. These results indicate that combustible cigarettes attenuate contractile function by altering intracellular Ca2+ dynamics. On the other hand, heated cigarettes were also found to exhibit myocardial toxic effects, albeit to a lesser degree than combustible cigarettes, suggesting the need for caution when smoking cigarettes.