Abstract 136: Novel Disease Analysis Using Long QT Syndrome-Specific Induced Pluripotent Stem Cells
[Background] Although previous reports have indicated that long QT syndrome-specific iPS cells (LQTS-iPSCs)-derived cardiomyocytes recapitulated disease phenotypes, those patients were previously diagnosed with mutated channel profiles. In reality, most patients have no such specific information. To address whether iPSCs could be used for personalized disease characterization, we generated iPSCs from a sporadic LQTS patient with unknown disease cause.
[Methods and Results] 1 We generated iPSCs from control (n = 2) and a patient with LQTS, and differentiated into cardiomyocytes through embryoid body (EB) formation. 2 Electrophysiological analysis of the LQTS-iPSCs-derived EBs using multi electrode array system revealed that the duration of the field potential (FPD) was markedly prolonged compared with the control (388.9 ± 44.3 msec vs 202.3 ± 16.3 msec, P<0.01). 3 We tested several drugs affecting QT prolongation to clarify the electrophysiological properties. The IKr blocker E4031 significantly prolonged FPD (% change 1.21 ± 0.02, P<0.01) and induced frequent severe arrhythmia, not only early-after depolarization (n = 8/16 vs n = 1/16) but also torsades de pointes-like arrhythmia, only in LQTS (n = 4/16 vs n = 0/16). The IKs blocker, chromanol 293B did not prolong FPD in LQTS but it significantly prolonged FPD in the control (% change 1.09 ± 0.04, NS vs 1.44 ± 0.07, P<0.01), suggesting the involvement of IKs disturbance in the patient. Isoproterenol induced ventricular tachycardia-like arrhythmia only in LQTS, which was blocked by propranolol. These data strongly suggested a functional impairment in the patient’s IKs channel; genotype analysis for KCNQ1 gene revealed a novel heterozygous mutation, 1893delC. 4 Patch clamp analysis and immunostaining confirmed a dominant-negative role for 1893delC in IKs channel through a trafficking deficiency.
[Conclusions]LQTS-iPSCs-derived cardiomyocytes recapitulated the disease phenotypes, and they can be utilized for identification of the disease cause and genotype. This study demonstrated that iPSCs could be useful to characterize the disease, drug responses, diagnosis and genotyping in patients with sporadic LQTS, which in turn may facilitate medical therapies in the clinical settings.
- © 2012 by American Heart Association, Inc.