Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes: The New Working Horse in Cardiovascular Pharmacology?

From the beginning of cardiovascular pharmacology, animal tissues have been used to test the effects of putative drugs on mechanical and electrical activity of the heart. However, the exact interplay of ion channels and transporters has shown substantial species differences,1 complicating translation to the situation in humans. Obviously, work with human tissue obtained during open heart surgery could be helpful to bridge that gap.2 However, access is limited and restricted to diseased tissues. The impact of patient's clinical characteristics has to be considered and application of sophisticated statistical methods may be necessary.3 Genetic manipulation of human tissue remains almost impossible. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) provide a novel, human source to study compound effects, avoiding all 3 aforementioned limitations. In fact, hiPSC-CM have been used to study genetic heart disease. In addition, there are a lot of opportunities to use hiPSC-CM in safety pharmacology.4 However, the application of hiPSC-CM in other fields of cardiovascular pharmacology is still rare. There may be several reasons for this situation. In this issue of Journal of Cardiovascular Pharmacology we try to highlight some of them. Automated patch-clamp assessment of drug effects on individual human cardiac currents in recombinant cells has reached an impressive level of standardization.5 Action potential (AP) measurements in hiPSC-CM could be the perfect approach to estimate net effects of a compound on electrical activity of the human heart. However, a major drawback of isolated hiPSC-CM as a model system for electrophysiological studies is their depolarized state, resulting at least in part from an insufficiently low activity of inward rectifier currents (IK1). Verkerk and Wilders6 discuss both biological, as well as technical solutions to overcome this limitation. The authors give an extensive overview of several approaches to compensate for too low IK1 by dynamic current injection. In great detail, they discuss the possibility and impact of injecting different IK1 formulations on the shape of both ventricular and atrial AP recorded in hiPSC-CM. Dynamic current injection of IK1 in a fixed mode has reached commercialization,7 underscoring the wide interest of this research topic. Hortigon-Vinagre et al8 describe a system based on hiPSC-CM clusters from 2-dimensional cultures. Contractions and APs can be recorded simultaneously. An automated analysis algorithm was developed by the authors, allowing for a large number of experiments. Ten test compounds, frequently applied for the validation of hiPSC-CM-based models in the past, have been used successfully. Combined analysis of drug effects on parameters of contractility and APs can be easily performed and is expected to facilitate identification of the mechanisms involved. Lemoine et al focus on hiPSC-CM as a model for atrial fibrillation (AF).9 Retinoic acid has been established by several groups as effective in inducing an atrial phenotype in hiPSC-CM. Artificial expression of channel rhodopsin allows long-term tachypacing. Both results may open up the possibility to replace atrial tachypacing models in large animals to study AF and to investigate genome-specific susceptibility to AF. Results are promising; however, several issues have to be solved. AP shape in retinoic acid–treated hiPSC-CM from controls may resemble closely AP found in human AF. Intensity and duration of tachypacing may need further refinement. Paci et al10 provide an extensive literature review of hiPSC-CM as a tool to model cardiac diseases and drug-screening approaches. It is impressive how many different patient-specific hiPSC-CM have been already investigated, and how the new possibility to screen several compounds genome specifically in vitro might be translated to the patients. Credit goes to the authors in highlighting numerous differences between hiPSC-CM and adult human cardiomyocytes. Some of them have to be considered as a limitation when hiPSC-CM will be used as a pharmacological model. Paci et al discuss also sex-related aspects of hiPSC-CM electrophysiology, an aspect that will become more relevant in the context of individualized medicine. In summary, there is a growing interest to use hiPSC-CM not only in studying rather exotic genetic heart diseases, but also common cardiovascular pharmacology. It remains to be seen, whether hiPSC-CM will have the potential to be the new working horse in cardiovascular pharmacology, closing the zoo of animals used by electrophysiologists so far.1 Hopefully, we can attract the interest of the readers of the Journal of Cardiovascular Pharmacology on the rapidly evolving field of hiPSC-CM applications.