期刊
CARDIOVASCULAR RESEARCH
卷 95, 期 4, 页码 419-429出版社
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvs206
关键词
Long QT syndrome; Drug examination; iPS cells; Cardiomyocytes; Personalized medicine
资金
- Ministry of Education, Science and Culture, Japan
- Programme for Promotion of Fundamental Studies in Health Science of the National Institute of Biomedical Innovation and Health Labour Sciences Research Grant
- Grants-in-Aid for Scientific Research [22136007, 22590813, 24390199, 23590297, 24591086, 22590779, 22689027, 23136503, 11J30002, 23790873] Funding Source: KAKEN
Long QT syndrome (LQTS) is an inheritable and life-threatening disease; however, it is often difficult to determine disease characteristics in sporadic cases with novel mutations, and more precise analysis is necessary for the successful development of evidence-based clinical therapies. This study thus sought to better characterize ion channel cardiac disorders using induced pluripotent stem cells (iPSCs). We reprogrammed somatic cells from a patient with sporadic LQTS and from controls, and differentiated them into cardiomyocytes through embryoid body (EB) formation. Electrophysiological analysis of the LQTS-iPSC-derived EBs using a multi-electrode array (MEA) system revealed a markedly prolonged field potential duration (FPD). The IKr blocker E4031 significantly prolonged FPD in control- and LQTS-iPSC-derived EBs and induced frequent severe arrhythmia only in LQTS-iPSC-derived EBs. The IKs blocker chromanol 293B did not prolong FPD in the LQTS-iPSC-derived EBs, but significantly prolonged FPD in the control EBs, suggesting the involvement of IKs disturbance in the patient. Patch-clamp analysis and immunostaining confirmed a dominant-negative role for 1893delC in IKs channels due to a trafficking deficiency in iPSC-derived cardiomyocytes and human embryonic kidney (HEK) cells. This study demonstrated that iPSCs could be useful to characterize LQTS disease as well as drug responses in the LQTS patient with a novel mutation. Such analyses may in turn lead to future progress in personalized medicine.
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