| Autor: |
James G.W. Smith, Thomas Owen, Jamie R. Bhagwan, Diogo Mosqueira, Elizabeth Scott, Ingra Mannhardt, Asha Patel, Roberto Barriales-Villa, Lorenzo Monserrat, Arne Hansen, Thomas Eschenhagen, Sian E. Harding, Steve Marston, Chris Denning |
| Jazyk: |
angličtina |
| Rok vydání: |
2018 |
| Předmět: |
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| Zdroj: |
Stem Cell Reports, Vol 11, Iss 5, Pp 1226-1243 (2018) |
| Druh dokumentu: |
article |
| ISSN: |
2213-6711 |
| DOI: |
10.1016/j.stemcr.2018.10.006 |
| Popis: |
Summary: Hypertrophic cardiomyopathy (HCM) is a primary disorder of contractility in heart muscle. To gain mechanistic insight and guide pharmacological rescue, this study models HCM using isogenic pairs of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) carrying the E99K-ACTC1 cardiac actin mutation. In both 3D engineered heart tissues and 2D monolayers, arrhythmogenesis was evident in all E99K-ACTC1 hiPSC-CMs. Aberrant phenotypes were most common in hiPSC-CMs produced from the heterozygote father. Unexpectedly, pathological phenotypes were less evident in E99K-expressing hiPSC-CMs from the two sons. Mechanistic insight from Ca2+ handling expression studies prompted pharmacological rescue experiments, wherein dual dantroline/ranolazine treatment was most effective. Our data are consistent with E99K mutant protein being a central cause of HCM but the three-way interaction between the primary genetic lesion, background (epi)genetics, and donor patient age may influence the pathogenic phenotype. This illustrates the value of isogenic hiPSC-CMs in genotype-phenotype correlations. : In this article Smith, Denning and colleagues show that the E99K-ACTC1 cardiac actin mutation is a central cause of HCM, but the three-way interaction between the primary genetic lesion, background genetics, and donor patient age may influence the pathogenic phenotype. Pharmacological rescue experiments demonstrated dual dantroline/ranolazine to be an effective treatment. Keywords: arrhythmia, contractile function, hypertrophy, cardiomyopathy |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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