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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.

Abstract  In order to comprehend the domain structure of two β-tropomyosin (β-Tm) isoforms (skeletal muscle and smooth muscle β-Tm) and the influence of the disease-causing mutation Arg91Gly on it, we studied the thermal unfolding of these tropomyosin species by means of differential scanning calorimetry (DSC). Our results show that the studied point mutation dramatically decreases thermal stability of a significant part of both β-Tm isoforms (about a half of the molecule) that unfolds as a cooperative unit (calorimetric domain). We have assigned this domain to the N-terminal part of the molecule combining, in the case of smooth muscle β-Tm, DSC studies with measurements of temperature dependence of pyrene excimer fluorescence, whose decrease reflects dissociation of two β-Tm chains in the region of pyrene-labeled Cys-36. Interestingly, the destabilizing effect of the mutation spreads along the coiled-coil reflecting the high extent of cooperativity within this part of the β-Tm molecule. [ABSTRACT FROM AUTHOR]