Ionic Basis of Repolarization of Atrial and Ventricular Specific Cell Types Derived from Human Induced Pluripotent Stem Cells

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Cardiomyocytes derived from human induced pluripotent stem cells (hIPSC-CMs) are an innovative cellular system for understanding human cardiac pathology and physiology. However, hIPSC-CMs express low levels of inward rectifying potassium channel (IK1) relative to native cardiac cells. The lack of this current deforms the action potential (AP) and leads to a depolarized or spontaneous diastolic potential. We used electronic expression of IK1 via dynamic clamp to restore the resting membrane potential back to physiological levels. This resulted in an improved AP morphology, including a reduction in variability and a rate dependent spike and dome shape. There were several significant differences between atrial and ventricular cells including differences in cell capacitance, sodium current magnitude and kinetics and most prominently differences in the transient outward currents. The late components of outward current, cells with atrial APs had a significantly larger sustained outward IKUR or Kv1.5-like component at +50 mV than ventricular shaped APs (in pA/pF: 3.71 ± 0.55 (n=5) vs 1.00 ± 0.10 (n=16),P<0.05) but similar peak outward currents: (6.89 ± 0.50 (n=5) vs. 6.58 ± 0 .67 (n=14),P=N.S). This plateau current is strongly inhibited by 50 micro molar 4-aminopyridine(4-AP). Similarly, atrial-like APs took on a ventricular like shape when treated with 4-AP while the ventricular myocytes APs were 4-AP insensitive. A cloned Kv1.5 current was expressed in oocytes and was used through the electronic expression system to add an IKur to the ventricular myocytes. Addition of this current changed the action potential morphology from ventricle to atrial like. This strongly suggests that IKur is the major determinant of atrial action potential morphology.