Investigating the Risk of Arrhythmogenesis Associated with Fentanyl Abuse Using Mice and Human iPSC-Derived Cardiomyocytes

The rise in synthetic opioid use, particularly fentanyl, has severely exacerbated the opioid epidemic and its impact surged dramatically during the COVID-19 pandemic. Fentanyl, a prescription opioid used for anesthesia and analgesia, is 50-100x stronger than morphine. Opioid-induced cardiac arrest represents the most dramatic manifestation of the opioid use disorder. Fentanyl primarily targets opioid receptors (ORs) in the nervous system, but its misuse also adversely depresses the pulmonary and cardiovascular systems. The proarrhythmic effects of other opioids were reported; however, the electrophysiological consequences of fentanyl abuse have not been studied. Our analysis of 19 toxicology studies conducted between 1994 and 2022 found that the average blood concentration of fentanyl in abuse or overdose cases is 30±1 ng/mL (89 nM), ~3-fold higher than in chronic pain or ~7.5-fold higher than in occasionally exposed patients. Advances in human induced pluripotent stem cell (iPSC) technology provide unprecedented opportunities to study patient‐specific responses to opioid abuse. Human iPSC-derived cardiomyocytes (iPSC-CMs) from 3 healthy donors were exposed to three doses of 89 nM fentanyl for 5 days. Then, we investigated whether fentanyl abuse has any consequences on cardiac electrophysiology. Human iPSC-derived cardiomyocytes (iPSC-CMs) from 2 healthy donors were exposed to three doses of 89 nM fentanyl for 5 days.