Induced Pluripotent Stem Cell-Derived Cardiomyocytes and Long QT Syndrome: Is Personalized Medicine Ready for Prime Time?

Abstract

See related article, pages 841–847 The study by Malan et al1 in this issue of the Circulation Research presents elegant data about induced pluripotent stem cell (iPSC)-derived myocytes2 from a mouse model of long QT syndrome (LQTS) type 3.3 The study is an important contribution that adds to a highly innovative field that is trying to define the role of iPSC technology in the understanding of inherited arrhythmias. In this accompanying editorial, I provide an overview of the previous studies in the field, comment on the contribution of Malan et al,1 and conclude by discussing some of the challenges in the field. The technique to differentiate cardiac myocytes from pluripotent stem cells is quite recent and it was introduced by the seminal article published in 2006 by Takahashi and Yamanaka,2 who used a combination of four retrovirally transduced transcription factors ( Oct3/4 , Sox2 , Klf4 , and c-Myc ) to generate iPSCs from mouse somatic cells. The importance of this technology was immediately recognized and it was rapidly applied to human cells.4 In the past few years, several investigators have refined protocols to optimize differentiation of iPSCs into cardiac myocytes and to characterize their properties. In analogy with myocardial cells derived from human embryonic cells,5 iPSC-derived myocytes differentiate into three cell types: nodal, atrial, and ventricular myocytes and present physiological adaptation of action potential duration to changes in heart rate and normal response to beta adrenergic stimulation.6 Furthermore, the presence of key ion channels7 and regulators of intracellular calcium physiology,8 as well as the preservation of the sarcomeric structure,9 have been confirmed in iPSC-derived myocytes. This comprehensive set of data provided a solid background to test the hypothesis that the differentiation of iPSC-derived cardiac cells from patients with inherited cardiac …