Background: Cardiac chamber-selective transcriptional programs underpin the structural and functional differences between atrial and ventricular cardiomyocytes (aCMs and vCMs). The mechanisms responsible for these chamber-selective transcriptional programs remain largely undefined.Methods: We nominated candidate chamber-selective enhancers (CSEs) by determining the genome-wide occupancy of 7 key cardiac transcription factors (GATA4, MEF2A, MEF2C, NKX2-5, SRF, TBX5, TEAD1) and transcriptional coactivator P300 in atria and ventricles. Candidate enhancers were tested using an adeno-associated virus–mediated massively parallel reporter assay. Chromatin features of CSEs were evaluated by performing assay of transposase accessible chromatin sequencing and acetylation of histone H3 at lysine 27-HiChIP on aCMs and vCMs. CSE sequence requirements were determined by systematic tiling mutagenesis of 29 CSEs at 5 bp resolution. Estrogen-related receptor (ERR) function in cardiomyocytes was evaluated by Cre-loxP–mediated inactivation of ERRα and ERRγ in cardiomyocytes.Results: We identified 134 066 and 97 506 regions reproducibly occupied by at least 1 transcription factor or P300, in atria or ventricles, respectively. Enhancer activities of 2639 regions bound by transcription factors or P300 were tested in aCMs and vCMs by adeno-associated virus–mediated massively parallel reporter assay. This identified 1092 active enhancers in aCMs or vCMs. Several overlapped loci associated with cardiovascular disease through genome-wide association studies, and 229 exhibited chamber-selective activity in aCMs or vCMs. Many CSEs exhibited differential chromatin accessibility between aCMs and vCMs, and CSEs were enriched for aCM- or vCM-selective acetylation of histone H3 at lysine 27–anchored loops. Tiling mutagenesis of 29 CSEs identified the binding motif of ERRα/γ as important for ventricular enhancer activity. The requirement of ERRα/γ to activate ventricular CSEs and promote vCM identity was confirmed by loss of the vCM gene profile in ERRα/γ knockout vCMs.Conclusions: We identified 229 CSEs that could be useful research tools or direct therapeutic gene expression. We showed that chamber-selective multi–transcription factor, P300 occupancy, open chromatin, and chromatin looping are predictive features of CSEs. We found that ERRα/γ are essential for maintenance of ventricular identity. Finally, our gene expression, epigenetic, 3-dimensional genome, and enhancer activity atlas provide key resources for future studies of chamber-selective gene regulation.

Fontan surgery by step-wise completing the isolation of originally mixed pulmonary and systemic circulation provides an operative approach for functional single-ventricle patients not amenable to biventricular repair and allows their survival into adulthood. In the absence of a subpulmonic pumping chamber, however, the unphysiological Fontan circulation consequently results in diminished cardiac output and elevated central venous pressure, in which multiple short-term or long-term complications may develop. Current understanding of the Fontan-associated complications, particularly toward etiology and pathophysiology, is extremely incomplete. What’s more, ongoing efforts have been made to manage these complications to weaken the Fontan-associated adverse impact and improve the life quality, but strategies are ill-defined. Herein, this review summarizes recent studies on cardiac and non-cardiac complications associated with Fontan circulation, focusing on significance or severity, etiology, pathophysiology, prevalence, risk factors, surveillance, or diagnosis. From the perspective of surgeons, we also discuss the management of the Fontan circulation based on current evidence, including post-operative administration of antithrombotic agents, ablation, pacemaker implantation, mechanical circulatory support, and final orthotopic heart transplantation, etc., to standardize diagnosis and treatment in the future.

Studying the haemodynamics of the central shunt (CS) and modified Blalock–Taussig shunt (MBTS) benefits the improvement of postoperative recovery for patients with an aorta-pulmonary shunt. Shunt configurations, including CS and MBTS, are virtually reconstructed for infants A and B based on preoperative CT data, and three-dimensional models of A, 11 months after CS, and B, 8 months after MBTS, are reconstructed based on postoperative CT data. A series of parameters including energy loss, wall shear stress, and shunt ratio are computed from simulation to analyse the haemodynamics of CS and MBTS. Our results showed that the shunt ratio of the CS is approximately 30% higher than the MBTS and velocity distribution in the left pulmonary artery (LPA) and right pulmonary artery (RPA) was closer to a natural development in the CS than the MBTS. However, energy loss of the MBTS is lower, and the MBTS can provide more symmetric pulmonary artery (PA) flow than the CS. With the growth of infants A and B, the shunt ratio of infants was decreased, but maximum wall shear stress and the distribution region of high wall shear stress (WSS) were increased, which raises the probability of thrombosis. For infant A, the preoperative abnormal PA structure directly resulted in asymmetric growth of PA after operation, and the LPA/RPA ratio decreased from 0.49 to 0.25. Insufficient reserved length of the MBTS led to traction phenomena with the growth of infant B; on the one hand, it increased the eddy current, and on the other hand, it increased the flow resistance of anastomosis, promoting asymmetric PA flow.

Wnt/β-catenin signaling plays a key role in pathological cardiac remodeling in adults. The identification of a tissue-specific Wnt/β-catenin interaction factor may provide a tissue-specific clinical targeting strategy. Drosophila Pygo encodes the core interaction factor of Wnt/β-catenin. Two Pygo homologs ( Pygo1 and Pygo2) have been identified in mammals. Different from the ubiquitous expression profile of Pygo2, Pygo1 is enriched in cardiac tissue. However, the role of Pygo1 in mammalian cardiac disease is yet to be elucidated. In this study, we found that Pygo1 was upregulated in human cardiac tissues with pathological hypertrophy. Cardiac-specific overexpression of Pygo1 in mice spontaneously led to cardiac hypertrophy accompanied by declined cardiac function, increased heart weight/body weight and heart weight/tibial length ratios, and increased cell size. The canonical β-catenin/T-cell transcription factor 4 (TCF4) complex was abundant in Pygo1 -overexpressing transgenic ( Pygo1 -TG) cardiac tissue, and the downstream genes of Wnt signaling, that is, Axin2, Ephb3, and c-Myc, were upregulated. A tail vein injection of β-catenin inhibitor effectively rescued the phenotype of cardiac failure and pathological myocardial remodeling in Pygo1 -TG mice. Furthermore, in vivo downregulated pygo1 during cardiac hypertrophic condition antagonized agonist-induced cardiac hypertrophy. Therefore, our study is the first to present in vivo evidence demonstrating that Pygo1 regulates pathological cardiac hypertrophy in a canonical Wnt/β-catenin-dependent manner, which may provide new clues for tissue-specific clinical treatment via targeting this pathway. NEW & NOTEWORTHY In this study, we found that Pygo1 is associated with human pathological hypertrophy. Cardiac-specific overexpression of Pygo1 in mice spontaneously led to cardiac hypertrophy. Meanwhile, cardiac function was improved when expression of Pygo1 was interfered in hypertrophy-model mice. Our study is the first to present in vivo evidence demonstrating that Pygo1 regulates pathological cardiac hypertrophy in a canonical Wnt/β-catenin-dependent manner, which may provide new clues for a tissue-specific clinical treatment targeting this pathway.