Open AccessDisease modeling of a mutation in α‐actinin 2 guides clinical therapy in hypertrophic cardiomyopathy
Author(s) -
Prondzynski Maksymilian,
Lemoine Marc D,
Zech Antonia TL,
Horváth András,
Di Mauro Vittoria,
Koivumäki Jussi T,
Kresin Nico,
Busch Josefine,
Krause Tobias,
Krämer Elisabeth,
Schlossarek Saskia,
Spohn Michael,
Friedrich Felix W,
Münch Julia,
Laufer Sandra D,
Redwood Charles,
Volk Alexander E,
Hansen Arne,
Mearini Giulia,
Catalucci Daniele,
Meyer Christian,
Christ Torsten,
Patten Monica,
Eschenhagen Thomas,
Carrier Lucie
Publication year - 2019
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201911115
Subject(s) - hypertrophic cardiomyopathy , cardiology , medicine , myofilament , cardiomyopathy , myocyte , induced pluripotent stem cell , sarcomere , atrial fibrillation , muscle hypertrophy , heart failure , diltiazem , biology , genetics , calcium , gene , embryonic stem cell
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 ACTN 2 , 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 (hi PSC s) and show that hi PSC ‐derived cardiomyocytes and engineered heart tissues recapitulated several hallmarks of HCM , such as hypertrophy, myofibrillar disarray, hypercontractility, impaired relaxation, and higher myofilament Ca 2+ sensitivity, and also prolonged action potential duration and enhanced L‐type Ca 2+ current. The L‐type Ca 2+ 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 QT c interval in HCM ‐affected son and sister of the index patient. These data provide evidence for this ACTN 2 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 hi PSC for personalized treatment of cardiomyopathies.