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Cardiomyocyte (CM) nuclei are constantly exposed to mechanical stress, but how they maintain their nuclear shape remains unknown. In this study, we found that ventricular CM nuclei acquire characteristic prominent spatial organizations of heterochromatin (SOH), which are disrupted by high-level expression of H2B-mCherry in mice. SOH disruption was associated with nuclear softening, leading to extreme elongation and rupture under unidirectional mechanical stress. Loosened chromatin then leaks into the cytosol, causing severe inflammation and cardiac dysfunction. Although SOH disruption was accompanied by loosened higher-order genomic structures, the change in gene expression before nuclear deformation was mild, suggesting that SOH play major roles in nuclear structural integrity. Aged CM nuclei consistently exhibited scattered SOH and marked elongation. Furthermore, we provide mechanistic insight into the development and maintenance of SOH driven by chromatin compaction and condensate formation. These results highlight SOH as a safeguard of nuclear shape and genomic integrity against mechanical stress. [Display omitted] • Cardiomyocytes acquire characteristic spatial organizations of heterochromatin (SOH) • High levels of H2B-mCherry disrupt SOH, leading to nuclear elongation in cardiomyocytes • SOH disruption minimally impacts gene expression despite loosening global genome structure • SOH alter with aging, leading to nuclear deformation in ventricular cardiomyocytes Cardiomyocytes exhibit characteristic prominent spatial organizations of heterochromatin (SOH). Fujiwara et al. found that the replacement of endogenous H2B with H2B-mCherry disrupts SOH, leading to extreme elongation of ventricular cardiomyocyte nuclei, resulting in severe heart failure, demonstrating that SOH play a structural role in maintaining nuclear shape against mechanical stress. [ABSTRACT FROM AUTHOR]

Background: The utility of late potentials on signal-averaged electrocardiography (SAECG) for risk stratification in patients with Brugada syndrome (BrS) remains controversial. Late potentials on conventional SAECG with Frank leads may be insufficiently sensitive to detect site-specific late potentials in right precordial leads.Objective: The purpose of this study was to evaluate the utility of site-specific late potentials using a novel unipolar Holter-SAECG system for risk stratification in patients with BrS.Methods: Consecutive symptomatic (n = 20) and asymptomatic (n = 21) patients with BrS who underwent investigation using conventional SAECG and a novel unipolar Holter-SAECG system were enrolled. We evaluated clinical characteristics and outcomes and compared late potentials on the 2 SAECGs between both groups and patients with and without cardiac events (CEs) (sudden cardiac death or sustained ventricular tachyarrhythmias) during the follow-up period.Results: During mean follow-up of 76 months, 10 patients (24%) had CEs. There were no significant differences in late potentials on conventional SAECG between symptomatic and asymptomatic patients. On the Holter-SAECG system, RMS40 in lead V2 in the third intercostal space (3L-V2) at the nighttime was significantly lower in the symptomatic group than in the asymptomatic group (5.5 ± 0.8 μV and 8.2 ± 0.8 μV, respectively; P = .027). Univariate analysis of predictive values for CE showed that hazard ratios of daytime and nighttime RMS40 in lead 3L-V2 of <7.7 μV and <6.1 μV were 7.58 and 6.14, respectively.Conclusion: Site-specific late potentials in lead 3L-V2 measured using the novel Holter-SAECG system may be a useful marker for high-risk patients with BrS. [ABSTRACT FROM AUTHOR]

• The present study compared ex vivo optical frequency domain imaging (OFDI) with histological diagnosis. • The overall agreement correlated with the observers' years of experience. • The interpretation of OFDI scans requires expertise. To date, there have been no data available regarding the diagnostic performance of optical frequency domain imaging (OFDI) for in vivo histological classification of atherosclerotic lesions. This study investigated whether OFDI can be used to diagnose and classify histological atherosclerotic lesions in the coronary artery by ex vivo histological examinations. Three-hundred-fifteen histological cross-sections from 21 autopsy hearts were matched with the OFDI images. Histological cross-sections were classified into six categories: adaptive intimal thickening (AIT), pathological intimal thickening (PIT), fibrous cap atheroma (FA), fibrocalcific plaque (FC), calcified nodule, and healed erosion/rupture. The five observers with different years of experience in the interpretation of OFDI provided a single diagnosis for the OFDI scans of each cross-section according to the aforementioned six histological categories. The diagnostic accuracy and interobserver variability of lesion types for each OFDI observer were determined using histology as the gold standard. The overall agreement rates between OFDI and histopathologic diagnosis for OFDI observers 1–5 were 81%, 70%, 68%, 61%, and 50% (κ values of 0.75, 0.61, 0.58, 0.49, and 0.36), respectively. Although the diagnostic accuracy of OFDI for detecting AIT and FC was excellent for all five observers, the sensitivity, and positive predictive values of OFDI for detecting PIT and FA were low in proportion to years of experience. The diagnostic accuracy of atherosclerotic tissue properties from OFDI scans correlated with the observers' years of experience, especially when lesions contained lipid components. [ABSTRACT FROM AUTHOR]

Aims Type 3 iodothyronine deiodinase (D3), which converts thyroxine (T 4 ) and 3,5,3′-triiodothyronine (T 3 ) to 3,3′,5′-triiodothyronine (rT 3 ) and 3,3′-diiodothyronine (T 2 ), respectively, inactivates thyroid hormones. We investigated the expression and regulation of D3 in human cardiomyocytes which were differentiated from human induced pluripotent stem cells (hiPSCs). Main methods We characterized D3 activity using liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. D3, myosine heavy chain α and β (MHCα and β, respectively), sarcoplasmic reticulum calcium ATPase (SERCA), and phospholamban (PLB) mRNA levels were analyzed by quantitative real-time PCR (qPCR) in hiPSC-derived cardiomyocytes (hiPS-CMs). Key findings We identified enzyme activity that catalyzes the conversion of T 3 to T 2 in both hiPS-CMs and hiPSCs, which showed characteristics compatible with those for D3. D3 mRNA was identified in these cells using qPCR analysis. T 3 and hypoxia mimetics such as CoCl 2 and DFO, increased the D3 mRNA level in both hiPS-CMs and hiPSCs. Addition of iopanoic acid, a competitive inhibitor of iodothyronine deiodination, in the culture medium of hiPS-CMs, increased the mRNA levels such as MHCα and β, SERCA, and PLB induced by T 3 . Significants Our findings indicate that D3 is expressed in hiPS-CMs, and may decrease the intracellular T 3 concentration, and may decrease the expression of cardiac genes such as MHCα and β, SERCA, and PLB in hiPS-CMs. [ABSTRACT FROM AUTHOR]

Abstract: A patient without any known congenital cardiac abnormalities who suffered from ventricular tachycardia was taken to the emergency room following successful resuscitation. Transthoracic echocardiography showed diffuse left ventricle dysfunction and mild aortic regurgitation. Coronary angiography demonstrated intact coronary and suspected morphological abnormalities of the aortic valve. In addition, transesophageal echocardiography revealed a rare quadricuspid aortic valve malformation. After controlling ventricular tachycardia and congestive heart failure with optimal medical therapy, the patient had an uneventful course and was subsequently discharged 3 weeks after admission. To our knowledge, this is the first report of quadricuspid aortic valve associated with idiopathic dilated cardiomyopathy. [Copyright &y& Elsevier]

Growth factors, insulin signaling, and nutrients are important regulators of β-cell mass and function. The events linking these signals to the regulation of β-cell mass are not completely understood. The mTOR pathway integrates signals from growth factors and nutrients. Here, we evaluated the role of the mTORI raptor (mTORC1) signaling in proliferative conditions induced by controlled activation of Akt signaling. These experiments show that the mTORC1 is a major regulator of β-cell cycle progression by modulation of cyclin D2, D3, and Cdk4 activity. The regulation of cell cycle progression by mTORC1 signaling resulted from modulation of the synthesis and stability of cyclin D2, a critical regulator of β-cell cycle, proliferation, and mass. These studies provide novel insights into the regulation of cell cycle by the mTORC1, provide a mechanism for the antiproliferative effects of rapamycin, and imply that the use of rapamycin could negatively impact the success of islet transplantation and the adaptation of β-cells to insulin resistance. [ABSTRACT FROM AUTHOR]

Summary: Endothelial cells in growing tumors express activated Akt, which when modeled by transgenic endothelial expression of myrAkt1 was sufficient to recapitulate the abnormal structural and functional features of tumor blood vessels in nontumor tissues. Sustained endothelial Akt activation caused increased blood vessel size and generalized edema from chronic vascular permeability, while acute permeability in response to VEGF-A was unaffected. These changes were reversible, demonstrating an ongoing requirement for Akt signaling for the maintenance of these phenotypes. Furthermore, rapamycin inhibited endothelial Akt signaling, vascular changes from myrAkt1, tumor growth, and tumor vascular permeability. Akt signaling in the tumor vascular stroma was sensitive to rapamycin, suggesting that rapamycin may affect tumor growth in part by acting as a vascular Akt inhibitor. [Copyright &y& Elsevier]

Although signaling mechanisms inducing cardiac hypertrophy have been extensively studied, little is known about the mechanisms that reverse cardiac hypertrophy. Here, we describe the existence of a similar Akt/forkhead signaling axis in cardiac myocytes in vitro and in vivo, which is regulated by insulin, insulin-like growth factor (IGF), stretch, pressure overload, and angiotensin II stimulation. FOXO3a gene transfer prevented both IGF and stretch-induced hypertrophy in rat neonatal cardiac myocyte cultures in vitro. Transduction with FOXO3a also caused a significant reduction in cardiomyocyte size in mouse hearts in vivo. Akt/FOXO signaling regulated the expression of multiple atrophy-related genes "atrogenes," including the ubiquitin ligase atrogin-1 (MAFbx). In cardiac myocyte cultures, transduction with constitutively active Akt or treatment with IGF suppressed atrogin-1 mRNA expression, whereas transduction with FOXO3a stimulated its expression. FOXO3a transduction activated the atrogin-1 promoter in both cultured myocytes and mouse heart. Thus, in cardiomyocytes, as in skeletal muscle, FOXO3a activates an atrogene transcriptional program, which retards or prevents hypertrophy and is down-regulated by multiple physiological and pathological stimuli of myocyte growth. [ABSTRACT FROM AUTHOR]

In the heart, insulin stimulates a variety of kinase cascades and controls glucose utilization. Because insulin is able to activate Akt and inactivate AMP-activated protein kinase (AMPK) in the heart, we hypothesized that Akt can regulate the activity of AMPK. To address the potential existence of this novel signaling pathway, we used a number of experimental protocols to activate Akt in cardiac myocytes and monitored the activation status of AMPK. Mouse hearts perfused in the presence of insulin demonstrated accelerated glycolysis and glucose oxidation rates as compared with non-insulin-perfused hearts. In addition, insulin caused an increase in Akt phosphorylation and a decrease in AMPK phosphorylation at its major regulatory site (threonine 172 of the α catalytic subunit). Transgenic mice overexpressing a constitutively active mutant form of Akt1 displayed decreased phosphorylation of cardiac α-AMPK. Isolated neonatal cardiac myocytes infected with an adenovirus expressing constitutively active mutant forms of either Akt1 or Akt2 also suppressed AMPK phosphorylation. However, Akt-dependent depression of α-AMPK phosphorylation could be overcome in the presence of the AMPK activator, metformin, suggesting that an override mechanism exists that can restore AMPK activity. Taken together, this study suggests that there is crosstalk between the AMPK and Akt pathways and that Akt activation can lead to decreased AMPK activity. In addition, our data suggest that the ability of insulin to inhibit AMPK may be controlled via an Akt-mediated mechanism. [ABSTRACT FROM AUTHOR]

Akt is an important regulator of cell survival, growth, and glucose metabolism in many cell types, but the role of this signaling molecule in hematopoietic stem cells is poorly defined. Side population (SP) cells are enriched for hematopoietic stem cell activity and are defined by their ability to efficiently efflux Hoechst 33342. Bone marrow from Akt1-null mice exhibited a reduced SP fraction. However, bone marrow cellularity, growth factor-responsive progenitor cultures, and engraftable stem cells were normal in these mice. Treatment of bone marrow with LY294002, an inhibitor of the Akt effector protein phosphatidylinositol 3-kinase, led to a reversible loss of the SP fraction. Bcrp1, which encodes the Hoechst dye transporter, was translocated from the membrane to the intracellular compartment under conditions that promote the SP-depleted state. Lentivirus-mediated overexpression of Akt1 in bone marrow markedly increased the SP fraction, whereas there was no effect on bone marrow from Bcrp[sup -/-] mice. These data suggest that Akt signaling modulates the SP cell phenotype by regulating the expression of Bcrp1. [ABSTRACT FROM AUTHOR]

Abstract: We describe as case of a 70-year-old man who underwent a percutaneous coronary intervention with stenting, for a severe stenosis complicated by a coronary aneurysm just distal to the stenotic site. Notably, coronary angiogram showed an immediate and progressive reduction in the size of coronary aneurysm. Curved planar reconstruction images of the enhanced CT showed no thrombus and no dissection of the coronary aneurysm. We speculate that coronary stenting might decrease the velocity of coronary flow through the stenosis. Consequently, stenting might attenuate the hydrodynamic wall stress on the aneurysm, and, in addtion, improve the degradation of the extracellular matrix structure through the regulation of matrix metalloproteinases. Regression of coronary aneurysm after stenting requires further investigations, because stenting may become a potential means for treating post-stenotic aneurysms. [Copyright &y& Elsevier]