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Our understanding of the spatiotemporal regulation of cardiogenesis is hindered by the difficulties in modeling this complex organ currently by in vitro models. Here we develop a method to generate heart organoids from mouse embryonic stem cell-derived embryoid bodies. Consecutive morphological changes proceed in a self-organizing manner in the presence of the laminin-entactin (LN/ET) complex and fibroblast growth factor 4 (FGF4), and the resulting in vitro heart organoid possesses atrium- and ventricle-like parts containing cardiac muscle, conducting tissues, smooth muscle and endothelial cells that exhibited myocardial contraction and action potentials. The heart organoids exhibit ultrastructural, histochemical and gene expression characteristics of considerable similarity to those of developmental hearts in vivo. Our results demonstrate that this method not only provides a biomimetic model of the developing heart-like structure with simplified differentiation protocol, but also represents a promising research tool with a broad range of applications, including drug testing. Our understanding of the development of the heart has been limited by a lack of in vitro cellular models. Here, the authors treat mouse embryonic stem cell-derived embryoid bodies with laminin-entactin (to mimic the developing microenvironment) and FGF4 to form heart organoids, with atrial and ventricular-like parts.

Ballistocardiography (BCG) is a noninvasive modality for detecting cardiac activity. This study developed a robust atrial fibrillation (AF) detection algorithm using multiple BCG sensors at different locations and evaluated the improvement in accuracy by combining data from multiple sensors. We recorded the BCG using a piezoelectric rubber sheet sensor and an electrocardiogram in 84 participants (29 with AF and 55 without AF) in the supine position. Four BCGs (BCG1–4) were obtained using sensors placed from the head to the lumbar region (0, 25, 45, and 65 cm from the head). The BCG signals were divided into 32 s blocks and analyzed. After applying fast Fourier transform, we input the power spectrum, focusing on frequencies below 10 Hz, into machine learning (ML) classifiers to distinguish between AF and non-AF with parameter tuning. The AdaBoost classifier for BCG2 exhibited the highest accuracy (0.88) among the ML models for each sensor. When we applied the classifier to other BCGs, it achieved accuracies of 0.92, 0.73, and 0.78 for BCG1, 3, and 4, respectively. The combined model using multiple sensors exhibited an accuracy of 0.92. The optimized model for BCG2 was robust against shifts in the sensor toward the head and lumbar directions. A combined assessment using multiple sensors improved performance.

Takotsubo cardiomyopathy is characterized by temporary ballooning of the left ventricle and may lead to thrombosis, necessitating anticoagulation therapy in high-risk patients. However, no previous studies have compared anticoagulation therapies for this population. We aimed to compare the clinical outcomes of patients treated with direct oral anticoagulants (DOACs) and those treated with heparin. This retrospective study included patients with Takotsubo cardiomyopathy receiving DOACs or heparin within the first 2 days of admission between April 2012 and March 2021, identified from a nationwide in-hospital database in Japan. The primary outcome was in-hospital mortality. The secondary outcomes were ischemic and bleeding events, hospitalization costs, and length of hospital stay. After adjustment with propensity score-based inverse probability weighting, the risks of outcomes were estimated using Poisson regression models. Among 4,813 patients, 530 received DOACs and 4,283 received heparin. The DOAC group was older than the heparin group (mean [standard deviation] 78.1 [9.4] vs. 74.4 [11.2] years). After covariate adjustment, in-hospital mortality (4.0% vs. 3.8%; p = 0.87), ischemic events (1.1% vs. 2.8%; p = 0.067), and bleeding events (0.2% vs. 0.3%; p = 0.67) did not significantly differ between the DOAC and heparin groups. In contrast, the DOAC group had shorter hospital stays (median, 11 days vs. 13 days; p < 0.001) and lower total hospitalization costs ( $5,181 USD vs. $ 6,084 USD; p = 0.003). These findings provide clinicians with valuable insights regarding the use of DOACs for patients with Takotsubo cardiomyopathy.

As atrial fibrillation (AF) progresses from initial paroxysmal episodes to the persistent phase, maintaining sinus rhythm for an extended period through pharmacotherapy and catheter ablation becomes difficult. A major cause of the deteriorated treatment outcome is the atrial structural and electrophysiological heterogeneity, which AF itself can exacerbate. This heterogeneity exists or manifests in various dimensions, including anatomically segmental structural features, the distribution of histological fibrosis and the autonomic nervous system, sarcolemmal ion channels, and electrophysiological properties. All these types of heterogeneity are closely related to the development of AF. Recognizing the heterogeneity provides a valuable approach to comprehending the underlying mechanisms in the complex excitatory patterns of AF and the determining factors that govern the seemingly chaotic propagation. Furthermore, substrate modification based on heterogeneity is a potential therapeutic strategy. This review aims to consolidate the current knowledge on structural and electrophysiological atrial heterogeneity and its relation to the pathogenesis of AF, drawing insights from clinical studies, animal and cell experiments, molecular basis, and computer-based approaches, to advance our understanding of the pathophysiology and management of AF.

Magnetocardiography (MCG) provides a non-invasive, contactless technique for evaluating the magnetic fields generated by cardiac electrical activity, offering unique spatial insights into cardiac electrophysiology. However, conventional MCG systems depend on superconducting quantum interference devices that require cryogenic cooling and magnetic shielded environments, posing considerable impediments to widespread clinical adoption. In this study, we present a novel MCG system utilizing a high-sensitivity, wide-dynamic-range magnetoresistive sensor array operating at room temperature. To mitigate environmental interference, identical sensors were deployed as reference channels, enabling adaptive noise cancellation (ANC) without the need for traditional magnetic shielding. MCG recordings were obtained from 40 healthy participants, with signals processed using ANC, R-peak-synchronized averaging, and Bayesian spatial signal separation. This approach enabled the reliable detection of key cardiac components, including P, QRS, and T waves, from the unshielded MCG recordings. Our findings underscore the feasibility of a cost-effective, portable MCG system suitable for clinical settings, presenting new opportunities for noninvasive cardiac diagnostics and monitoring.

Atrial fibrillation (AF) is the most common sustained arrhythmia, and it causes a high rate of complications such as stroke. It is known that AF begins as paroxysmal form and gradually progresses to persistent form, and sometimes it is difficult to identify paroxysmal AF (PAF) before having stroke. The aim of this study is to evaluate the risk of PAF and stroke using genetic analysis and circulating biomarkers. A total of 600 adult subjects were enrolled (300 from PAF and control groups). Peripheral blood was drawn to identify the genetic variation and biomarkers. Ten single nucleotide polymorphisms (SNPs) were analyzed, and circulating cell-free DNA (cfDNA) was measured from plasma. Four microRNAs (miR-99a-5p, miR-192-5p, miR-214-3p, and miR-342-5p) were quantified in serum using quantitative RT-PCR. Genotyping identified 4 single nucleotide polymorphisms (SNPs) that were significantly associated with AF (rs6817105, rs3807989, rs10824026, and rs2106261), and the genetic risk score using 4 SNPs showed the area under the curve (AUC) of 0.631. Circulating miRNAs and cfDNA did not show significant differences between PAF and control groups. The concentration of cfDNA was significantly higher in patients with a history of stroke, and the AUC was 0.950 to estimate the association with stroke. The risk of AF could be assessed by genetic risk score. Furthermore, the risk of stroke might be evaluated by plasma cfDNA level.

Systemic inflammation is assumed to be the consequence and the cause of atrial fibrillation (AF); however, the underlying mechanism remains unclear. We aimed to evaluate the level of cell-free DNA (cfDNA) in patients with AF and AF mimicking models, and to illuminate its impact on inflammation. Peripheral blood was obtained from 54 patients with AF and 104 non-AF controls, and cfDNA was extracted. We extracted total cfDNA from conditioned medium after rapid pacing to HL-1 cells. Nuclear and mitochondrial DNA were separately extracted and fragmented to simulate nuclear-cfDNA (n-cfDNA) and mitochondrial-cfDNA (mt-cfDNA). The AF group showed higher cfDNA concentration than the non-AF group (12.6 [9.0–17.1] vs. 8.1 [5.3–10.8] [ng/mL], p  < 0.001). The copy numbers of n-cfDNA and mt-cfDNA were higher in AF groups than in non-AF groups; the difference of mt-cfDNA was particularly apparent ( p  = 0.011 and p  < 0.001, respectively). Administration of total cfDNA and mt-cfDNA to macrophages significantly promoted IL-1β and IL-6 expression through TLR9, whereas n-cfDNA did not. Induction of cytokine expression by methylated mt-cfDNA was lower than that by unmethylated mt-cfDNA. Collectively, AF was associated with an increased cfDNA level, especially mt-cfDNA. Sparsely methylated mt-cfDNA released from cardiomyocytes may be involved in sterile systemic inflammation accompanied by AF.

Atrial remodeling is a major pathophysiological mechanism of atrial fibrillation (AF). Atrial remodeling progresses with aging and background diseases, including hypertension, heart failure, and AF itself. However, its mechanism of action and reversibility have not been completely elucidated. In this study, we investigated the involvement of DNA methylation in atrial remodeling. Mice underwent transverse aortic constriction (TAC) to generate a pressure overload model. After 14 days, the TAC-operated mice showed a significant increase in the atrium/body weight ratio and deposition of collagen fibers in the atria. A comprehensive analysis using RNA-sequencing (RNA-Seq) and methyl-CpG-binding domain sequencing (MBD-Seq) in the left atrial tissue identified Hif3a and Ifltd1 as showing increased DNA methylation in their promoter regions and decreased RNA expression. In addition, we created a transient pressure overload model by removing the aortic constriction 3 or 7 days after the initial TAC procedure (R3 or R7 groups). A reduction in RNA expression was achieved at R3 for Hif3a and at R7 for Ifltd1. Heterozygous Dnmt1 gene-targeting mice (Dnmt1 mut ) showed disappearance of the reduction in RNA expression and an increase in the atrium/body weight ratio. Altogether, DNA methylation contributed to at least part of atrial remodeling in the pressure overload mouse model.

Dilated cardiomyopathy (DCM) is a fatal heart disease characterized by left ventricular dilatation and cardiac dysfunction. Recent genetic studies on DCM have identified causative mutations in over 60 genes, including RBM20 , which encodes a regulator of heart-specific splicing. DCM patients with RBM20 mutations have been reported to present with more severe cardiac phenotypes, including impaired cardiac function, atrial fibrillation (AF), and ventricular arrhythmias leading to sudden cardiac death, compared to those with mutations in the other genes. An RSRSP stretch of RBM20, a hotspot of missense mutations found in patients with idiopathic DCM, functions as a crucial part of its nuclear localization signals. However, the relationship between mutations in the RSRSP stretch and cardiac phenotypes has never been assessed in an animal model. Here, we show that Rbm20 mutant mice harboring a missense mutation S637A in the RSRSP stretch, mimicking that in a DCM patient, demonstrated severe cardiac dysfunction and spontaneous AF and ventricular arrhythmias mimicking the clinical state in patients. In contrast, Rbm20 mutant mice with frame-shifting deletion demonstrated less severe phenotypes, although loss of RBM20-dependent alternative splicing was indistinguishable. RBM20 S637A protein cannot be localized to the nuclear speckles, but accumulated in cytoplasmic, perinuclear granule-like structures in cardiomyocytes, which might contribute to the more severe cardiac phenotypes.

Atrial fibrillation (AF) is the most common cardiac arrhythmia, and both metabolic reprogramming and autophagy have been implicated in its pathogenesis. However, the expression pattern of autophagy-related genes during metabolic reprogramming in AF remains elusive. We aimed to characterize the expression profiles of autophagy- and metabolic reprogramming-related genes in atrial tissue to gain pathophysiological insights into AF. Three datasets obtained from the Gene Expression Omnibus (GSE2240, GSE79768, and GSE14975) that included atrial tissue samples from patients with or without AF were subjected to a bioinformatics analysis, which identified 2812 differentially expressed genes. Eight autophagy- and metabolic reprogramming-related differentially expressed genes (A&MRRDEGs) were identified as key candidates through least absolute shrinkage and selection operator regression combined with the random forest approach. Meanwhile, mice underwent transverse aortic constriction (TAC) for 2 weeks in an AF model, and gene expression in atrial tissue was analyzed. In atrial tissues from TAC mice, only Akt1 and Hspa5 of the eight A&MRRDEGs exhibited expression changes concordant with the human datasets, while Glud1 showed discordant regulation. Collectively, these cross-species findings highlight that the eight A&MRRDEGs, particularly AKT1 and HSPA5, are potentially involved in autophagy and metabolic reprogramming during AF pathogenesis.