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

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.

Case Report on: Very Early Afterdepolarizations in HiPSC-Cardiomyocytes—An Artifact by Big Conductance Calcium Activated Potassium Current (Ibk,Ca)

“…In some APs the notch was followed by a peculiar oscillation during plateau phase of the AP. This peculiarity of notch/oscillation was only observed in some of independent differentiation batches of the C25 cell line, but never in any other of three in-house cell lines or five commercial cell lines investigated with sharp microelectrodes as previously described [5,9,[27][28][29][30]. When the notch/oscillation was detected in one EHT, all impalements showed this peculiarity including all EHTs from this differentiation batch.…”

“…Other genes related to KCNMA1 did not show major alterations in expression. Immunofluorescence analysis of hiPSC-CMs revealed the expression of the alpha-1 subunit of the BK Ca channel in the C25 cell line with enhanced signal intensity at cell-cell contacts, whereas no signal was detected in the control cell line [30] (Supplementary Figure S5).…”

The Emergence of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes (hiPSC-CMs) as a Platform to Model Arrhythmogenic Diseases

“…For example, most HCM mutations are found in the MYH7 gene, which is the main β-myosin heavy chain isoform in the human heart, but not in small animals such as rodents. This is a major limitation that can now be addressed using HCM patient-specific hiPSC-CMs, which have been shown to recapitulate the human phenotype: impaired relaxation, increased myofilament Ca sensitivity, APD prolongation, and larger L-type Ca current [124]. In the clinic, and in contrast to HCM, dilated cardiomyopathy (DCM) is characterized by ventricular dilatation and left ventricular systolic dysfunction, which can result in progressive heart failure and arrhythmias [125].…”

Transcriptome Profiling across Five Tissues of Giant Panda

“…TRDN is required for the triplet connection of normal tissues, where the T-tube and sarcoplasmic reticulum terminal cisternae are in close contact and are required for normal skeletal muscle strength [ 65 – 68 ]. ACTN2 is linked with heart failure [ 69 ], especially its mutation that can cause hypertrophic cardiomyopathy [ 70 , 71 ]. FGA first produces monomers from protease thrombin cleavage and then polymerizes with fibrinogen beta (FGB) and fibrinogen gamma (FGG) to form an insoluble fibrin matrix, and fibrin plays an important role in hemostasis as one of the main components of blood clots [ 72 ].…”