Abstract 272: Pharmacological Testing Of Novel Atrial-specific Ion Channel Blockers Establishes Human Pluripotent Stem Cell Derived Atrial Cardiomyocytes As A Predictive Pre-clinical Model For Selective Pharmacology
Background: Atrial Fibrillation (AF) is the most prevalent arrhythmia affecting two and half million people in the United States alone. Medical therapy is the choice of treatment in a large number of cases and current drug discovery programs by pharmaceutical industries are aimed at developing atrial-specific ion channel blockers. Most of the current selective pharmacology studies however, are carried out in animal models such as dogs and guinea pigs. Human pluripotent stem cell derived cardiomyocytes provide a promising alternative in this respect.
Aim: To establish an in vitro pre-clinical model of selective pharmacology for testing atrial-specific pharmacological compounds using human pluripotent stem cell (hPSC) derived atrial-like cardiomyocytes.
Methods & Results: We have successfully generated atrial-like cardiomyocytes from differentiating human embryonic stem cells by modulating retinoic acid signaling. Molecular identity of these cardiomyocytes was established by whole genome microarray while the functional identity was confirmed by voltage patch clamp techniques. At the electrophysiological level, hPSC-derived atrial-like cardiomyocytes exhibit shorter action potentials, increased Ito1 density and increased steady state currents (combination of IKr, IKs and IKur) as expected for atrial cardiomyocytes. In order to validate the use of these cells for selective pharmacology, novel IKur and IKACh blockers (currently in clinical trials/pre-clinical development) were tested and their effect was assessed by electrophysiology. hPSC-derived atrial-like cardiomyocytes showed prolongation of action potential in response to IKur and IKACh blockers whereas the effect was minimal on hPSC-derived ventricular-like cardiomyocytes. These findings are being compared against multiple ion-channel blockers such as Dronaderone.
Conclusions: Modulation of retinoic acid signaling drives differentiating human pluripotent stem cells to atrial-like cardiomyocytes which have been validated as a pre-clinical screening model for testing novel atrial-specific pharmacological compounds.
- © 2013 by American Heart Association, Inc.