More than 33 million people worldwide suffer from atrial fibrillation, an irregular and often rapid heart rate that can increase risk of stroke, heart failure and other cardiac complications. Studying atrial biology may offer insight into treatment development.
One obstacle to the development of anti-arrhythmic drugs is the difficulty of isolating and maintaining human atrial cardiomyocytes (cardiac muscle cells). Atrial cardiomyocytes, together with the ventricular cardiomyocytes, form the muscular walls of the heart — the myocardium — and make an important contribution to the refilling of ventricles with blood, which enhances the subsequent ejection of blood from the heart. Because animal models do not accurately represent human cardiac physiology, cardiomyocytes derived from human induced pluripotent stem cells (hiPSC) may represent a solution for evaluating potential drugs.
With this in mind, scientists from Germany and the UK have evaluated the suitability of hiPSC-derived atrial-like cardiomyocytes (hiPSC-CMs) as a 3D model of the human atrium. A 3D model offers a physiological cell environment and allows the study of heart function parameters. The findings of this study offer a new platform for the investigation of heart function parameters and pharmacological responses (Stem Cell Reports 10.1016/j.stemcr.2018.10.008).
Model creation
To generate a 3D model of the human atrial heart muscle, the authors induced an atrial phenotype in hiPSC-CMs using previously established retinoic acid (RA) protocols. RA is a vitamin A metabolite involved in the switch between cell proliferation and differentiation.
The RA treatment caused the hiPSC-CMs to achieve properties characteristic of the atrial heart muscle: a decrease in cell size, together with an increase in gene expression and protein level of atrial-specific markers (especially MLC2A, a protein that modulates cardiac development and contractility) and ion channels (potassium channels). These markers indicate that RA promotes atrial-like cardiomyocytes to develop instead of ventricular-like cardiomyocytes. Moreover, the authors noticed that the hiPSC-CMs beat and contracted faster upon RA treatment.
Electrophysiological characteristics
The team used electrophysiological characteristics, such as the action potential duration and the repolarization fraction, to distinguish between atrial and ventricular-type functionalities. RA treatment resulted in a reduced action potential duration and an increased repolarization fraction in hiPSC-CMs, which correspond to an atrial-like electrophysiological phenotype.
In the human heart, two potassium currents are predominantly expressed: the acetylcholine-activated potassium current and the ultrarapidly activating delayed rectifier potassium current (IKur). When the researchers added carbachol, a drug that activates and binds acetylcholine receptors, they observed a shortening of action potential duration in the RA-engineered heart tissue. In addition, when they applied 4-aminopyridine (the inhibitor for IKur), the expected changes in action potential morphology were observed in the RA-engineered heart tissue. These findings suggest that following RA treatment, a more atrial-like electrophysiological phenotype was obtained for the engineered heart tissue.
This study indicates that RA-treated hiPSC-CMs develop an atrial phenotype and form spontaneously beating engineered heart tissue. This tissue shows characteristic atrial heart muscle features, in terms of gene expression, contraction kinetics, action potential features, and pharmacological responses to potassium current blockers and activators. The 3D engineered atrial heart may serve as a useful model in preclinical drug development.
