Disease modeling of a mutation in α-actinin 2 guides clinical therapy in hypertrophic cardiomyopathy

Autor: Nico Kresin, Josefine Busch, Elisabeth Krämer, Felix W. Friedrich, Marc D Lemoine, Thomas Eschenhagen, Giulia Mearini, Jussi T. Koivumäki, Torsten Christ, Saskia Schlossarek, Daniele Catalucci, Sandra D. Laufer, András Horváth, Christian Meyer, Alexander E Volk, Tobias Krause, Julia Münch, Michael Spohn, Antonia T.L. Zech, Monica Patten, Lucie Carrier, Vittoria Di Mauro, Maksymilian Prondzynski, Charles Redwood, Arne Hansen
Přispěvatelé: Tampere University, BioMediTech
Rok vydání: 2019
Předmět:
0301 basic medicine
Medicine (General)
medicine.medical_specialty
Myofilament
human‐induced pluripotent stem cells
Long QT syndrome
macromolecular substances
QH426-470
Left ventricular hypertrophy
Regenerative Medicine
Cardiovascular System
Article
Muscle hypertrophy
03 medical and health sciences
R5-920
0302 clinical medicine
Internal medicine
disease modeling
Genetics
medicine
Animals
Humans
Actinin
Diltiazem
cardiovascular diseases
Precision Medicine
Induced pluripotent stem cell
business.industry
Hypertrophic cardiomyopathy
Atrial fibrillation
Articles
217 Medical engineering
Cardiomyopathy
Hypertrophic
medicine.disease
hypertrophic cardiomyopathy
3. Good health
Addendum
Disease Models
Animal
Long QT Syndrome
030104 developmental biology
Mutation
Cardiology
cardiovascular system
Molecular Medicine
Genetics
Gene Therapy & Genetic Disease
business
030217 neurology & neurosurgery
medicine.drug
Zdroj: EMBO Mol Med
EMBO Molecular Medicine
EMBO Molecular Medicine, Vol 11, Iss 12, Pp n/a-n/a (2019)
ISSN: 1757-4684
Popis: 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 α‐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.
Disease modeling of a rare ACTN2 mutation in iPSC‐derived cardiomyocytes & heart tissues engineering revealed typical features of hypertrophic cardiomyopathy & electrophysiological anomalies. Diltiazem reversed the in vitro phenotypes & guided clinical therapy in the family, reducing QTc intervals.
Databáze: OpenAIRE
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