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Atrial fibrosis is an essential contributor to atrial fibrillation (AF). It remains unclear whether atrial endocardial endothelial cells (AEECs) that undergo endothelial-mesenchymal transition (EndMT) are among the sources of atrial fibroblasts. We studied human atria, TGF-[beta]-treated human AEECs, cardiac-specific TGF-[beta]-transgenic mice, and heart failure rabbits to identify the underlying mechanism of EndMT in atrial fibrosis. Using isolated AEECs, we found that miR-181b was induced in TGF-[beta]-treated AEECs, which decreased semaphorin 3A (Sema3A) and increased EndMT markers, and these effects could be reversed by a miR-181b antagomir. Experiments in which Sema3A was increased by a peptide or decreased by a siRNA in AEECs revealed a mechanistic link between Sema3A and LIM-kinase 1/phosphorylated cofilin (LIMK/p-cofilin) signaling and suggested that Sema3A is upstream of LIMK in regulating actin remodeling through p-cofilin. Administration of the miR181b antagomir or recombinant Sema3A to TGF-[beta]-transgenic mice evoked increased Sema3A, reduced EndMT markers, and significantly decreased atrial fibrosis and AF vulnerability. Our study provides a mechanistic link between the induction of EndMT by TGF-[beta] via miR-181b/Sema3A/LIMK/p-cofilin signaling to atrial fibrosis. Blocking miR-181b and increasing Sema3A are potential strategies for AF therapeutic intervention., Introduction Atrial fibrillation (AF) is the most common sustained arrhythmia and results in increased morbidity and mortality. Rhythm control in persistent long-term AF, which is characterized by severe atrial myocyte [...]

Background The sutureless valve has gained popularity for degenerative aortic valve stenosis but not congenital bicuspid aortic valve (BAV) due to anatomical challenges. We reviewed our modified implant techniques for patients with BAV. Methods From June 2015 to June 2019, 66 patients with aortic valve stenosis were treated with the Perceval sutureless valve, 20 of whom had BAV. The demographics, type of BAV (the Sievers classification), and associated pathologies, surgical outcomes, and midterm hemodynamics were recorded. Results The median age was 64 (range: 49–81) years and the Society of Thoracic Surgeons score was 2.186 (range: 0.407–6.384). Annular plication was performed in 9 (75%) of 12 type 0 and 3 (37.5%) of 8 type I, with implanted valve sizes of M, L, and XL in 6, 10, 4 cases, respectively. Three patients, all type 0 in the initial learning periods, required intraoperative redeployment due to malposition of the valve. The final implant was successful in all without conversion to traditional prosthesis. The median extubation time was 4 hours and the durations of intensive care unit and hospital stay were 1 and 6 days. At a median follow-up of 46 (23–72) months, there was one late mortality due to hemorrhagic stroke sequel. The last echo revealed none had more than mild paravalvular leakage and the mean transvalvular pressure gradient remained stable at 9.70 (range: 6.94–15.0) mm Hg. Conclusion The sutureless valve can achieve satisfactory outcomes in BAV without paravalvular leakage and excellent hemodynamics. It may serve as the benchmark for transcatheter aortic valve implantation in this unique population. [ABSTRACT FROM AUTHOR]

Background: Sustained, chronic activation of β-adrenergic receptor (β-AR) signaling leads to cardiac arrhythmias, with exchange proteins directly activated by cAMP (Epac1 and Epac2) as key mediators. This study aimed to evaluate whether CD44, a transmembrane receptor mediating various cellular responses, participates in Epac-dependent arrhythmias. Methods: The heart tissue from CD44 knockout (CD44−/−) mice, cultured HL-1 myocytes and the tissue of human ventricle were used for western blot, co-immunoprecipitaiton and confocal studies. Line-scanning confocal imaging was used for the study of cellular Ca2+ sparks on myocytes. Optical mapping and intra-cardiac pacing were applied for arrhythmia studies on mice's hearts. Results: In mice, isoproterenol, a β-AR agonist, upregulated CD44 and Epac1 and increased the association between CD44 and Epac1. Isoproterenol upregulated the expression of phospho-CaMKII (p-CaMKII), phospho-ryanodine receptor (p-RyR), and phospho-phospholamban (p-PLN) in mice and cultured myocytes; these effects were attenuated in CD44−/− mice compared with wild-type controls. In vitro, isoproterenol, 8-CPT-cAMP (an Epac agonist), and osteopontin (a ligand of CD44) significantly upregulated the expression of p-CaMKII, p-RyR, and p-PLN; this effect was attenuated by CD44 small interfering RNA (siRNA). In myocytes, resting Ca2+ sparks were induced by isoproterenol and overexpressed CD44, which were prevented by inhibiting CD44. Ex vivo optical mapping and in vivo intra-cardiac pacing studies showed isoproterenol-induced triggered events and arrhythmias in ventricles were prevented in CD44−/− mice. The inducibility of ventricular arrhythmias (VAs) was attenuated in CD44−/− HF mice compared with wild-type HF controls. In patients, CD44 were upregulated, and the association between CD44 and Epac1 were increased in ventricles with reduced contractility. Conclusion: CD44 regulates β-AR- and Epac1-mediated Ca2+-handling abnormalities and VAs. Inhibition of CD44 is effective in reducing VAs in HF, which is potentially a novel therapeutic target for preventing the arrhythmias and sudden cardiac death in patients with diseased hearts. [ABSTRACT FROM AUTHOR]