HMN 2025: How Explore the promise of human iPSC-heart cells in understanding fentanyl abuse

In recent years, fentanyl, a synthetic opioid that is 50 to 100 times stronger than morphine, has been a main contributor to the opioid crisis. One of the worst adverse effects of fentanyl abuse is opioid-induced cardiac arrest. Although it is well known that opioid abuse can induce arrhythmias, the effects of fentanyl abuse on heart rhythms have not yet been thoroughly investigated.

In a recent study published in Circulation, first-author Gema Mondéjar-Parreño, Ph.D. and senior author Joseph C. Wu, MD, Ph.D., director of Stanford Cardiovascular Institute, found that human-induced pluripotent stem cells provide an unparalleled opportunity to study patient-specific responses to opioid abuse.

The investigators studied the consequences of fentanyl abuse, specifically those relating to the electrical activity of the heart, which determine how the heart controls its rhythm and pumping. The scientists analyzed 19 toxicology studies between 1994 and 2022 in which the mean estimate of fentanyl concentration was three times higher than for patients with chronic pain. Using the data, the investigators exposed human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) to doses of fentanyl that mimicked circumstances of overdose.

They found that this caused changes in calcium signaling homeostasis in heart muscle cells and slowed down preparation for the next heartbeat, which contributed to beating irregularities. Additionally, since arrhythmias are often more evident when the heart rate increases, the researchers found the combination of fentanyl and isoproterenol, a stimulant used to increase heart rate, can worsen fentanyl-induced arrhythmias.

This study offers evidence that fentanyl abuse can impair the function of cardiac cells, leading to rhythm defects. Together with respiratory depression, fentanyl-induced effects on electrophysiology significantly contribute to cardiac arrest. Further studies will help us better understand fentanyl abuse and its relationship to arrhythmias.