Abstract
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.
Highlights
Hypertrophic cardiomyopathy (HCM) is an inherited myocardial disease with a prevalence of 1:500 in the general population (Maron et al, 1995)
Since we found increased ICa,L in HCM human-induced pluripotent stem cells (hiPSCs)-CMs and engineered heart tissues (EHTs) compared to Ctrl (Fig 3D and E), we tested whether the mutation in a-actinin 2 might affect the interaction affinity between a-actinin 2 and Cava1.2
The ACTN2 mutation resulted in Action potentials (APs) prolongation and abnormal high ICa,L density
Summary
Hypertrophic cardiomyopathy (HCM) is an inherited myocardial disease with a prevalence of 1:500 in the general population (Maron et al, 1995). It is defined by hypertrophy, mainly seen in the left ventricle (LV) and associated with myocardial disarray, fibrosis, and diastolic dysfunction (Ho, 2010). There is no curative treatment for HCM, which reverses or prevents hypertrophy and dysfunction of the heart (Tardiff et al, 2015). B-adrenoceptor antagonists (b-blockers) and Ca2+-channel blockers are used to reduce heart rate and lengthen LV filling time (Marian, 2009). While these therapeutic approaches address general disease mechanisms independent of the underlying pathophysiology,
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