Study familial hypertrophic cardiomyopathy using patient-specific induced pluripotent stem cells.
Bottom Line: Studying HCM with patient-specific induced pluripotent stem-cell (iPSC)-derived cardiomyocytes (CMs) would benefit the understanding of HCM mechanism, as well as the development of personalized therapeutic strategies.A widespread increase of genes responsible for 'Cell Proliferation' was observed in HCM iPSC-CMs when compared with control iPSC-CMs. Additionally, HCM iPSC-CMs exhibited disorganized sarcomeres and electrophysiological irregularities.Furthermore, disease phenotypes of HCM iPSC-CMs were attenuated with pharmaceutical treatments.
Affiliation: Department of Developmental Biology, University of Pittsburgh School of Medicine, 8117 Rangos Research Center, 530 45th Street, Pittsburgh, PA 15201, USA.Show MeSH
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Mentions: HCM patient iPSC-CMs provide an in vitro model to evaluate therapeutic benefits of pharmaceutical agents. Both control and HCM iPSC-CMs were treated with a β-adrenergic agonist, isoproterenol, which is known to trigger cardiac hypertrophy and heart failure in animals.37,38 Administration of 1 μM isoproterenol (Iso) for 5 days increased the beating frequencies of control and HCM CMs (Figure 6A), and significantly elevated premature beats and irregular beating rates in HCM CMs (Figure 6A, D and Supplementary material online, Figure S5C and D). We next tested the response of HCM CMs to several drug reagents, which are currently in clinical use for HCM therapy. First, β1-adrenergic blocker metoprolol (Meto, 10 μM) was added into HCM CMs post-isoproterenol treatment. Metoprolol significantly decreased beating irregularity and reduced arrhythmia in HCM CMs (Figure 6B, C and E). Because Ca2+ influx through L-type Ca2+ channel contributes importantly to arrhythmia induction,31,39 we next applied a Ca2+ channel blocker, verapamil (100 nM), to HCM CMs post-metoprolol treatment. This continuous treatment with verapamil for additional 4 days completely eliminated irregular beats in HCM CMs (Figure 6B, C and E). Verapamil treatment ameliorated calcium handling abnormalities and depressed beating rhythm irregularity in HCM CMs, probably through decreasing the resting Ca2+ level and shortening Ca2+ transient duration (Supplementary material online, Figure S4E–G). In addition, long-term treatment of verapamil with high concentrations (>250 nM) could induce the cessation of spontaneous beating in iPSC-CMs (data not shown), indicating the feasibility of using human iPSC-CMs for drug safety testing. Lastly, we continuously treated HCM CMs with pinacidil (1 µM) post verapamil. Pinacidil is a KATP channel opener and clinically used as an antihypertensive drug. However, it induced irregular interspike intervals in the HCM CMs (Figure 6C). These results revealed a personalized response of HCM iPSC-CMs to drug reagents and indicate the significance of using patient-specific iPSC-CMs for developing personalized therapeutic strategies for human HCM.Figure 6
Affiliation: Department of Developmental Biology, University of Pittsburgh School of Medicine, 8117 Rangos Research Center, 530 45th Street, Pittsburgh, PA 15201, USA.