ZnO Nanoparticles induce acute arrhythmia and heart failure in mice by disturbing cardiac ion channels

Xuexue Liu^1,2Zijuan Zhao²Kailong Ma²Shan Wen^2,3Xinyu Wang²Yanfei Du¹Chang LI²JUN LI²Guangqin Zhang³Xiaobo Zhou²Tuck Wah Soong⁴Ziqi Yuan³Jian Feng²Guang Li^2*

• ¹The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
• ²Southwest Medical University, Luzhou, China
• ³China Pharmaceutical University, Nanjing, Jiangsu Province, China
• ⁴National University of Singapore, Singapore, Singapore

The extensive application of zinc oxide nanoparticles (ZnO NPs) has raised concerns regarding their impact on environmental safety and human health. In this study, we systematically assessed the cardiac effects of acute exposure to different sizes of ZnO NPs (40 nm and 100 nm). Our results unveiled that acute exposure to ZnO NPs causes acute arrhythmia in mice. Mechanistically, ZnO NP exposure had no significant effects on IK1 but significantly decreased INa and ICa-L currents, resulting in a reduced amplitude and shortened duration of action potential in cardiomyocytes. These changes not only caused prolonged PR-interval and blocked A-V conduction that triggered cardiac arrhythmia, but also caused reduced calcium transient that led to heart failure. The downregulation of calcium transient upon ZnO NP exposure was further verified in cardiomyocytes derived from human induced pluripotent stem cells. Meanwhile, acute exposure to ZnO NPs did not induce endocytosis, nor impair membrane integrity or promote ROS production in the mitochondria of cardiomyocytes.Collectively, acute ZnO NP exposure causes heart failure and arrhythmia in mice by directly affecting ion channel function.