Journal
EMBO MOLECULAR MEDICINE
Volume 11, Issue 12, Pages -Publisher
WILEY
DOI: 10.15252/emmm.201911115
Keywords
disease modeling; human-induced pluripotent stem cells; hypertrophic cardiomyopathy; long QT syndrome; precision medicine
Categories
Funding
- German Centre for Cardiovascular Research (DZHK)
- German Ministry of Research Education (BMBF)
- Deutsche Herzstiftung [F/15/17]
- Helmut und Charlotte Kassau Stiftung
- German Research Foundation (DFG) [3423/5-1]
- European Research Council Advanced Grant (IndivuHeart) [340248]
- European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant (AFib-TrainNet) [675351]
- Research Promotion Fund of the Faculty of Medicine (Hamburg)
- Pirkanmaa Regional Fund of the Finnish Cultural Foundation
- Academy of Finland Centre of Excellence in Body-on-Chip Research
- European Research Council (ERC) [340248] Funding Source: European Research Council (ERC)
Ask authors/readers for more resources
Hypertrophic cardiomyopathy (HCM) is a cardiac genetic disease accompanied by structural and contractile alterations. We identified a rare c.740C>T (p.T247M) mutation in ACTN2, encoding alpha-actinin 2 in a HCM patient, who presented with left ventricular hypertrophy, outflow tract obstruction, and atrial fibrillation. We generated patient-derived human-induced pluripotent stem cells (hiPSCs) and show that hiPSC-derived cardiomyocytes and engineered heart tissues recapitulated several hallmarks of HCM, such as hypertrophy, myofibrillar disarray, hypercontractility, impaired relaxation, and higher myofilament Ca2+ sensitivity, and also prolonged action potential duration and enhanced L-type Ca2+ current. The L-type Ca2+ channel blocker diltiazem reduced force amplitude, relaxation, and action potential duration to a greater extent in HCM than in isogenic control. We translated our findings to patient care and showed that diltiazem application ameliorated the prolonged QTc interval in HCM-affected son and sister of the index patient. These data provide evidence for this ACTN2 mutation to be disease-causing in cardiomyocytes, guiding clinical therapy in this HCM family. This study may serve as a proof-of-principle for the use of hiPSC for personalized treatment of cardiomyopathies.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available