Myosin heavy chain 7 (MYH7) is a major causative gene for hypertrophic cardiomyopathy, but the affected signaling pathways and therapeutics remain elusive. In this research, we identified ventricle myosin heavy chain like ( vmhcl ) as a zebrafish homolog of human MYH7 , and we generated vmhcl frameshift mutants. We noted vmhcl -based embryonic cardiac dysfunction (VEC) in the vmhcl homozygous mutants and vmhcl -based adult cardiomyopathy (VAC) phenotypes in the vmhcl heterozygous mutants. Using the VEC model, we assessed 7 known cardiomyopathy signaling pathways pharmacologically and 11 candidate genes genetically via CRISPR/Cas9 genome editing technology based on microhomology-mediated end joining (MMEJ). Both studies converged on therapeutic benefits of mTOR or mitogen-activated protein kinase (MAPK) inhibition of VEC. While mTOR inhibition rescued the enlarged nuclear size of cardiomyocytes, MAPK inhibition restored the prolonged cell shape in the VEC model. The therapeutic effects of mTOR and MAPK inhibition were later validated in the VAC model. Together, vmhcl/myh7 loss of function is sufficient to induce cardiomyopathy in zebrafish. The VEC and VAC models in zebrafish are amenable to both efficient genetic and chemical genetic tools, offering a rapid in vivo platform for discovering candidate signaling pathways of MYH7 cardiomyopathy.

Traditional percutaneous device closure of perimembranous ventricular septal defects (PmVSDs) is a minimally invasive technique, but can result in high radiation exposure and can result in potential arterial complications. Here, we aimed to assess the safety and feasibility of device closure of PmVSDs via the femoral vein approach under transesophageal echocardiography (TEE) guidance in children. From January 2014 to December 2017, a total of 46 PmVSD patients (mean age, 6.5 ± 2.3 years [range, 4.2–12.0 years]; mean body weight 22.1 ± 6.6 kg [range, 16.0–38.5 kg]; VSD diameter, 4.1 ± 0.6 mm [range, 3.2–5.0 mm]) underwent attempted transcatheter closure via the femoral vein approach under the guidance of TEE without fluoroscopy. The transcatheter occlusion procedure under TEE guidance was successful in 44 (95.7%) patients. Surgery was necessary in 2 (4.3%) patients. The procedure duration was 28.2 ± 8.7 min (range, 12.0–42.0 min). One patient had immediate post-operative trivial residual shunt and three patients had immediate incomplete right bundle branch block (IRBBB) after operation; the new IRBBB in 1 case was noted in the first postoperative month. No residual shunt was noted at 3 months after the procedure, and no intervention related complications were detected at 1–24 months follow-up. Percutaneous device closure of PmVSDs under TEE guidance solely by femoral vein approach is effective and safe, avoids radiation exposure, potential arterial complications and a surgical incision.

Background: Although most cases of atrial septal defect (ASD) are sporadic, familial cases have been reported, which may be caused by mutation of transcription factor GATA binding protein 4 (GATA4). Herein we combined whole-exome sequencing and bioinformatics strategies to identify a novel mutation inGATA4accounting for the etiology in a Chinese family with ASD.Methods: We identified kindred spanning 3 generations in which 3 of 12 (25.0%) individuals had ASD. Punctilious records for the subjects included complete physical examination, transthoracic echocardiography, electrocardiograph and surgical confirming. Whole-exome capture and high-throughput sequencing were performed on the proband III.1. Sanger sequencing was used to validate the candidate variants, and segregation analyses were performed in the family members.Results: Direct sequencing ofGATA4from the genomic DNA of family members identified a T-to-C transition at nucleotide 929 in exon 5 that predicted a methionine to threonine substitution at codon 310 (M310T) in the nuclear localization signal (NLS) region. Two affected members (II.2 and III.3) and the proband (III.1) who was recognized as a carrier exhibited this mutation, whereas the other unaffected family members or control individuals did not. More importantly, the mutationGATA4(c.T929C: p.M310T) has not been reported previously in either familial or sporadic cases of congenital heart defects (CHD).Conclusions: We identified for the first time a novel M310T mutation in theGATA4gene that is located in the NLS region and leads to family ASD with arrhythmias. However, the mechanism by which this pathogenic mutation contributes to the development of heart defect and tachyarrhythmias remains to be ascertained.