Cardiomyopathies are defined as myocardial diseases, which can be due to myocardial infarction, genetic mutation, valvular regurgitation, storage disorder, endocrine disease, and toxicity from chemotherapy or alcohol. This complex disease requires an elaborate model to study the underlying functional mechanism. Recently, iPSCs have been utilized for in vitro
disease modeling of cardiac arrhythmias [57
]. A prominent example of cardiac arrhythmia is the long QT syndrome (LQTS). This rare inborn heart condition has an estimated prevalence of about 1:7000 persons (inherited LQTS), causing ~2000–3000 sudden deaths in children and young adults each year in the US alone [72
]. QT describes a specific interval on an electrocardiogram (ECG), the time from the electrical stimulation (depolarization) of the heart’s pumping ventricles to the end of the recharging of the electrical system (repolarization). The total duration is measured in seconds or milliseconds (ms) and closely approximates the time from the beginning of the ventricles’ contraction until the end of relaxation. The normal QTc interval varies from 350–450 ms. About 95% of people show values between 338–440 ms, which is the range generally considered as the ‘normal’ range [75
In LQTS, delayed repolarization of the heart following a heartbeat increases the risk of episodes of Torsade de Pointes (TdP), a form of irregular heartbeat that originates from the ventricles [77
]. These episodes may lead to palpitation, fainting, and sudden death due to ventricular fibrillation [81
]. It became evident that iPSC lines derived from patients with LQT1, LQT2, and LQT7 (also called Timothy Syndrome) can be differentiated into cardiomyocytes, showing the disease’s characteristic electrophysiological signature [57
] and establishing a convenient and powerful system for studying mechanisms of pathogenesis and therapeutic compound testing. Moretti et al. generated for the first time iPSCs derived from LQT1 patients who are affected by an identified autosomal dominant missense mutation (R190Q) in the long-QT syndrome type 1 (LQT1) gene, which encodes the repolarizing potassium channel that mediates the delayed rectifier IKS
current. Patient-derived iPSCs maintained the disease genotype of LQT1 and were successfully differentiated into functional cardiomyocytes. In “ventricular” and “atrial” cells derived from patients with LQT1, the duration of the action potential was markedly prolonged as compared to cells from control subjects. Interestingly, the R190Q–KCNQ1 mutation in the pathogenesis of LQT1 turned out to be associated with a dominant negative trafficking defect, leading to a 70~80% reduction in IKS
current and altered channel activation as well as deactivation properties. Furthermore, the phenotype of iPSC-derived cardiomyocytes (iPSC-CMs) derived from patients with LQT1 had an increased susceptibility to catecholamine-induced tachyarrhythmia, which was diminished by beta-blockade treatment.
Following the same approach for LQT2, which is caused by a mutation in the KCNH1 gene and encodes the repolarizing potassium channel mediating the delayed rectifier IKr current, two studies generated iPSCs derived from LQT2 patients carrying the missense mutations A614V and G1681A, respectively [57
]. Detailed multielectrode array (MEA) and whole-cell patch clamp studies established a significant reduction of the cardiac potassium current IKr, which in turn can significantly prolong the action potential and cause early-after depolarization (EAD) [84
]. Intriguingly, several existing as well as novel pharmacological agents were tested on this newly established LQT human iPSC-derived cardiac tissue model, including potassium-channel blockers (E-4031), calcium-channel blockers (nifedipine), sodium-channel blockers (ranolazine), KATP-channel openers (pinacidil and nicorandil), stressor (isoprenaline), and β-blockers (propranolol and nadolol).
Collectively, these findings provide a powerful proof-of-principle demonstration that iPSCs can reliably reproduce abnormal cellular phenotypes and behaviors in vitro
, thereby providing crucial mechanistic insights into the disease process [57
]. Furthermore, these studies suggest that iPSCs may serve as a valuable platform for functional analysis of small molecules (). Nevertheless, further optimization of the iPSC technology is required to facilitate its application in drug screening and pharmacological large-scale drug screening. Ongoing research is committed to improving both derivation efficiency and quality of iPSCs and their differentiated target cell progeny. These improvements will be highly beneficial not only for disease modeling research but also potential clinical applications, and for high-content, industrial-scale drug screening approaches.
Schematic representation of cardiac drug screening and toxicity testing with human iPSC technology