Induced pluripotent stem cell derived cardiomyocytes as models for cardiac arrhythmias

Abstract

Cardiac arrhythmias are a major cause of morbidity and mortality. In younger patients, the majority of sudden cardiac deaths have an underlying Mendelian genetic cause. Over the last 15 years, enormous progress has been made in identifying the distinct clinical phenotypes and in studying the basic cellular and genetic mechanisms associated with the primary Mendelian (monogenic) arrhythmia syndromes. Investigation of the electrophysiological consequences of an ion channel mutation is ideally done in the native cardiomyocyte (CM) environment. However, the majority of such studies so far have relied on heterologous expression systems in which single ion channel genes are expressed in non-cardiac cells. In some cases, transgenic mouse models have been generated, but these also have significant shortcomings, primarily related to species differences. The discovery that somatic cells can be reprogrammed to pluripotency as induced pluripotent stem cells (iPSC) has generated much interest since it presents an opportunity to generate patient- and disease-specific cell lines from which normal and diseased human CMs can be obtained These genetically diverse human model systems can be studied in vitro and used to decipher mechanisms of disease and identify strategies and reagents for new therapies. Here, we review the present state of the art with respect to cardiac disease models already generated using IPSC technology and which have been (partially) characterized. Human iPSC (hiPSC) models have been described for the cardiac arrhythmia syndromes, including LQT1, LQT2, LQT3-Brugada Syndrome, LQT8/Timothy syndrome and catecholaminergic polymorphic ventricular tachycardia (CPVT). In most cases, the hiPSC-derived cardiomyoctes recapitulate the disease phenotype and have already provided opportunities for novel insight into cardiac pathophysiology. It is expected that the lines will be useful in the development of pharmacological agents for the management of these disorders.

Integrating cardiomyocytes from human pluripotent stem cells in safety pharmacology: has the time come?

“…Even though Ca 2 + ‐handling features appear conserved in independent hiPSC‐CM cultures from different research groups (Hwang et al , 2015a, 2015b; Kane and Terracciano, 2015), heterogeneity has been widely observed in other electrophysiological properties such as the APD (Figure 3), upstroke velocity and current densities (Hoekstra et al , 2012). Inconsistent results on the mechanism of hiPSC‐CM automaticity have also been noted: Kim et al reported a Ca 2 + clock mechanism, consistent with ivabradine having no effect on beating frequency (Kim et al , 2015).…”

Inherited heart disease – what can we expect from the second decade of human iPS cell research?

“…Of note, however, the literature reports a wide range of values in the basic electrophysiological properties of hiPSC‐CMs, action potentials differing an order of magnitude and beating rates anywhere between 0.5 and 1.5 Hz, but also specific ion currents (e.g. the slow I Ks , and the rapid I Kr components of the delayed rectifier potassium currents, the sodium current I Na , and the L‐type calcium current I CaL ) varying widely even among wild‐type control hiPSC‐CMs 55, 56. Most notably, very different levels of I Ks have been described (ranging from ~ 0.3 to ~ 2.5 pA/pF 5, 57), variable observation leading to controversial conclusions: on the one hand, I Ks recapitulates physiological behaviour in playing a major role when repolarisation reserve is attenuated 58, 59; on the other, it seems to contribute to repolarisation in hiPSC‐CMs even in the absence of sympathetic stimulation 5, 36, 60, 61.…”

Stem Cell–Derived Nodal-Like Cardiomyocytes as a Novel Pharmacologic Tool: Insights from Sinoatrial Node Development and Function

“…A detailed discussion of protocols and potential pitfalls in the production and use of human iPSCs is beyond the scope of this article but has been the subject of recent reviews and editorials Yamanaka, 2010, 2011;Mummery, 2011;Xu et al, 2011;Sinnecker et al, 2012). With respect to the specific issue of electrophysiologic characteristics of these cells, there also have been several recent reviews (Poon et al, 2011;Hoekstra et al, 2012;Zeevi-Levin et al, 2012). In the following discussion, we focus specifically on reports concerning aspects of automaticity and the presence of nodal-like cells in these preparations since that is most relevant to the current topic.…”