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Transplantation studies in mice and rats have shown that human embryonic-stem-cell-derived cardiomyocytes (hESC-CMs) can improve the function of infarcted hearts (1-3), but two critical issues related to their electrophysiological behaviour [...]

To realize the high-voltage vacuum circuit breaker, we investigated the voltage-distribution ratio after current interruption at the double-break vacuum circuit breaker. We used the spiral CuCr (20%) electrodes and the axial magnetic-field CuCr (50%) electrodes as the experimental electrodes. At the double-break vacuum circuit breaker, where two vacuum interruptions that had the same and different characteristics of the electrode structure and contact materials were connected in series, there was a bias in the voltage-distribution ratio of each vacuum interrupter after current interruption. This seems to be because there was difference in the postarc current that passed through each vacuum interrupter after current interruption. Index Terms--AC circuit breakers, capacitance, interrupts, voltage breakdown.

Author(s): Yuji Shiba (corresponding author) [1, 2]; Toshihito Gomibuchi [3]; Tatsuichiro Seto [3]; Yuko Wada [3]; Hajime Ichimura [3]; Yuki Tanaka [3]; Tatsuki Ogasawara [3]; Kenji Okada [3]; Naoko Shiba [...]

KY02111 is a widely used small molecule that boosts cardiomyogenesis of the mesoderm cells derived from pluripotent stem cells, yet its molecular mechanism of action remains elusive. The present study resolves the initially perplexing effects of KY02111 on Wnt signaling and subsequently identifies squalene synthase (SQS) as a molecular target of KY02111 and its optimized version, KY‐I. By disrupting the interaction of SQS with cardiac ER‐membrane protein TMEM43, KY02111 impairs TGFβ signaling, but not Wnt signaling, and thereby recapitulates the clinical mutation of TMEM43 that causes arrhythmogenic right ventricular cardiomyopathy (ARVC), an inherited heart disease that involves a substitution of myocardium with fatty tissue. These findings reveal a heretofore undescribed role of SQS in TGFβ signaling and cardiomyogenesis. KY02111 may find its use in ARVC modeling as well as serve as a chemical tool for studying TGFβ/SMAD signaling. [ABSTRACT FROM AUTHOR]

• Pluripotent stem cell-derived cardiomyocytes (PSC-CMs) have beneficial effects for heart function after transplantation. • PSC-CMs have immature phenotypes as compared with adult CMs. • Engrafted PSC-CMs cause ventricular arrhythmias by serving as an ectopic pacemaker. Pluripotent stem cells (PSCs), which include embryonic and induced pluripotent stem cells (ESCs and iPSCs, respectively), have great potential in regenerative medicine for heart diseases due to their virtually unlimited cardiogenic capacity. Many preclinical studies have described the functional benefits after transplantation of PSC-derived cardiomyocytes (PSC-CMs). However, transient ventricular arrhythmias were detected after injection into non-human primates and swine ischemic hearts; as engrafted PSC-CMs form an electrical coupling between host and graft, the immature characteristics of PSC-CMs may serve as an ectopic pacemaker. We are entering a critical time in the development of novel therapies using PSC-CMs, with the recent first clinical trial using human iPSC-CMs (hiPSC-CMs) being launched in Japan. In this review, we summarize the updated knowledge, perspectives, and limitations of PSC-CMs for heart regeneration. [ABSTRACT FROM AUTHOR]

A major hurdle in stem cell therapy is the tumorigenic risk of residual undifferentiated stem cells. This report describes the design and evaluation of synthetic hybrid molecules that efficiently reduce the number of human induced pluripotent stem cells (hiPSCs) in cell mixtures. The design takes advantage of Kyoto probe 1 (KP-1), a fluorescent chemical probe for hiPSCs, and clinically used anticancer drugs. Among the KP-1-drug conjugates we synthesized, we found an exceptionally selective, chemically tractable molecule that induced the death of hiPSCs. Mechanistic analysis suggested that the high selectivity originates from the synergistic combination of transporter-mediated efflux and the cytotoxicity mode of action. The present study offers a chemical and mechanistic rationale for designing selective, safe, and simple reagents for the preparation of non-tumorigenic clinical samples. [ABSTRACT FROM AUTHOR]

Background Chronic kidney disease (CKD) is an evolving paradigm for the risk assessment of cardiovascular diseases. We hypothesized that an advanced stage of CKD may predict the presence of peripheral arterial disease (PAD). Methods Screening for PAD by an ankle-brachial pressure index (ABI) ≤0.9 was conducted in a consecutive series of 583 subjects (mean age 68.1 ± 12.9 years, 411 men). Levels of estimated glomerular filtration rate (eGFR) and factors associated with the presence of PAD were examined. Results Sixty patients (10.3%) had PAD and 192 patients (32.9%) had eGFR <60 mL/min/1.73 m 2 among all subjects. In patients with an advanced stage of CKD (stage ≥3, equivalent to eGFR <60 mL/min/1.73 m 2 ), high prevalence of PAD (17.2%) and lower ABI levels (1.04 ± 0.18) were observed. Univariate analyses revealed that PAD was associated with an advanced stage of CKD [odds ratio (OR) 1.850, 95% confidence interval (CI) 1.322–2.588, p < 0.001], as well as age, male gender, systolic blood pressure, and hemoglobin A1c. Multivariate logistic regression analyses revealed that PAD was independently predicted by the CKD stages (OR 1.498, 95% CI 1.011–2.220, p = 0.044, adjusted for covariates). Conclusions An advanced stage of CKD is independently and significantly associated with the presence of PAD. Targeted screening with ABI measurement can be beneficial in patients with CKD. [ABSTRACT FROM AUTHOR]

A 15-year-old asymptomatic male patient presented with an electrocardiographic abnormality and left ventricular (LV) dysfunction (left ventricle ejection fraction of 40%) in a physical examination performed 2 years previously. LV dysfunction did not improve despite optimal medical therapy for dilated cardiomyopathy. Twelve-lead electrocardiography revealed a normal PR interval (138 ms) with a small delta-like wave in V2, but not a typical diagnostic wave that could be diagnosed as Wolff–Parkinson–White (WPW) syndrome by an electrocardiogram auto-analysis. Transthoracic echocardiography showed a remarkable asynchronous septal motion. An electrophysiological study was performed to exclude WPW syndrome. An accessory pathway (AP) was revealed on the lateral wall of the right ventricle, and radiofrequency catheter ablation was successfully performed to disconnect the AP. Thereafter, the dyssynchrony disappeared, and LV function improved. The intrinsic atrioventricular nodal conduction was very slow (A-H, 237 ms). The results of electrocardiogram auto-analysis could not be used to confirm the diagnosis of WPW syndrome because of the atypical delta wave. Conduction via the right lateral AP caused electrical dyssynchrony in the LV. This case suggests that atypical delta waves should be evaluated without depending on electrocardiographic auto-analyses in patients with LV dysfunction accompanied by dyssynchrony. [ABSTRACT FROM AUTHOR]

Objective: Importance of fatty acid components and imbalances has emerged in coronary heart disease. In this study, we analyzed fatty acids and ankle-brachial index (ABI) in a Japanese cohort. Methods: Peripheral arterial disease (PAD) was diagnosed in 101 patients by ABI ≤0.90 and/or by angiography. Traditional cardiovascular risk factors and components of serum fatty acids were examined in all patients (mean age 73.2±0.9 years; 81 males), and compared with those in 373 age- and sex-matched control subjects with no evidence of PAD. Results: The presence of PAD (mean ABI: 0.71±0.02) was independently associated with low levels of gamma-linolenic acid (GLA) (OR: 0.90; 95% CI: 0.85–0.96; P = 0.002), eicosapentaenoic acid∶arachidonic acid (EPA∶AA) ratio (OR: 0.38; 95% CI: 0.17–0.86; P = 0.021), and estimated glomerular filtration rate (OR: 0.97; 95% CI: 0.96–0.98; P<0.0001), and with a high hemoglobin A1c level (OR: 1.34; 95% CI: 1.06–1.69; P = 0.013). Individuals with lower levels of GLA (≤7.95 µg/mL) and a lower EPA∶AA ratio (≤0.55) had the lowest ABI (0.96±0.02, N = 90), while the highest ABI (1.12±0.01, N = 78) was observed in individuals with higher values of both GLA and EPA∶AA ratio (P<0.0001). Conclusion: A low level of GLA and a low EPA∶AA ratio are independently associated with the presence of PAD. Specific fatty acid abnormalities and imbalances could lead to new strategies for risk stratification and prevention in PAD patients. [ABSTRACT FROM AUTHOR]

Background: Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) were recently shown to be capable of electromechanical integration following direct injection into intact or recently injured guinea pig hearts, and hESC-CM transplantation in recently injured hearts correlated with improvements in contractile function and a reduction in the incidence of arrhythmias. The present study was aimed at determining the ability of hESC-CMs to integrate and modulate electrical stability following transplantation in a chronic model of cardiac injury.Methods and Results: At 28 days following cardiac cryoinjury, guinea pigs underwent intracardiac injection of hESC-CMs, noncardiac hESC derivatives (non-CMs), or vehicle. Histology confirmed partial remuscularization of the infarct zone in hESC-CM recipients while non-CM recipients showed heterogeneous xenografts. The 3 experimental groups showed no significant difference in the left ventricular dimensions or fractional shortening by echocardiography or in the incidence of spontaneous arrhythmias by telemetric monitoring. Although recipients of hESC-CMs and vehicle showed a similar incidence of arrhythmias induced by programmed electrical stimulation at 4 weeks posttransplantation, non-CM recipients proved to be highly inducible, with a ∼3-fold greater incidence of induced arrhythmias. In parallel studies, we investigated the ability of hESC-CMs to couple with host myocardium in chronically injured hearts by the intravital imaging of hESC-CM grafts that stably expressed a fluorescent reporter of graft activation, the genetically encoded calcium sensor GCaMP3. In this work, we found that only ∼38% (5 of 13) of recipients of GCaMP3+ hESC-CMs showed fluorescent transients that were coupled to the host electrocardiogram.Conclusions: Human embryonic stem cell-derived cardiomyocytes engraft in chronically injured hearts without increasing the incidence of arrhythmias, but their electromechanical integration is more limited than previously reported following their transplantation in a subacute injury model. Moreover, non-CM grafts may promote arrhythmias under certain conditions, a finding that underscores the need for input preparations of high cardiac purity. [ABSTRACT FROM AUTHOR]

Background: Hyaluronan (HA) is a primary component of the extracellular matrix of cells, and it is involved in the pathogenesis of atherosclerosis. The purpose of this study was to investigate the role of HA in neointimal formation after vascular injury and determine its tissue-specific role in vascular smooth muscle cells (VSMCs) by using a cre-lox conditional transgenic (cTg) strategy. Methods and Results: HA was found to be expressed in neointimal lesions in humans with atherosclerosis and after wire-mediated vascular injury in mice. Inhibition of HA synthesis using 4-methylumbelliferone markedly inhibited neointimal formation after injury. In vitro experiments revealed that low-molecular-weight HA (LMW-HA) induced VSMC activation, including migration, proliferation, and production of inflammatory cytokines, and reactive oxygen species (ROS). The migration and proliferation of VSMCs were mediated by the CD44/RhoA and CD44/ERK1/2 pathways, respectively. Because HA synthase 2 (HAS2) is predominantly expressed in injured arteries, we generated cTg mice that overexpress the murine HAS2 gene specifically in VSMCs (cHAS2/CreSM22α mice) and showed that HA overexpression markedly enhanced neointimal formation after cuff-mediated vascular injury. Further, HA-overexpressing VSMCs isolated from cHAS2/CreSM22α mice showed augmented migration, proliferation, and production of inflammatory cytokines and ROS. Conclusion: VSMC-derived HA promotes neointimal formation after vascular injury, and HA may be a potential therapeutic target for cardiovascular disease. [ABSTRACT FROM AUTHOR]

Global warming caused by such gases as CO is a subject of great concern. Automobile emissions are an especially great problem in this respect. Therefore, hybrid cars are being widely developed and used. Because hybrid cars use electric power and gasoline, their emissions of CO are reduced. The electric motor of a hybrid car is driven by a battery, which has large capacity. Therefore, relays must interrupt a high DC current on switching between the electric motor and the gasoline engine, and hydrogen gas-filled relays are used for the purpose. In interruption tests in which we investigated the basic characteristics of hydrogen gas, the DC current did not reach a current-zero point. Thus, the current must be coerced to zero by using a high arc voltage. The loss coefficient and arc voltages of hydrogen are high, and we therefore performed interruption tests using a high arc voltage. Interruption tests and dielectric breakdowns test of air, pure hydrogen, and a hydrogen-nitrogen mixture indicated that an 80%-20% H-N mixture is the most effective. © 2010 Wiley Periodicals, Inc. Electr Eng Jpn, 174(2): 9-17, 2011; Published online in Wiley Online Library (). DOI 10.1002/eej.21042 [ABSTRACT FROM AUTHOR]

Abstract: Objective: Neointimal formation following percutaneous coronary intervention (PCI), termed restenosis, limits therapeutic revascularization. Since reendothelialization is one of the determinant factors for the development of neointimal formation, we examined the effects of granulocyte colony-stimulating factor (G-CSF) on reendothelialization and neointimal formation after vascular injury in mice. Methods and results: Wire-mediated vascular injury was produced in the femoral artery of C57BL/6 mice. G-CSF pretreatment significantly accelerated reendothelialization and decreased neointimal formation following vascular injury; however, this inhibitory effect of G-CSF was diminished when G-CSF was started following the injury. Flow cytometry analysis revealed that G-CSF treatment increased the number of endothelial progenitor cells (EPCs: CD34+/Flk-1+) in the peripheral circulation. Vascular injury was also produced in 2 types of mice whose bone marrow was replaced with that of enhanced green fluorescent protein- and Tie2/LacZ-transgenic mice. In the reendothelialized artery of these mice, few bone marrow-derived EPCs were detected. Furthermore, G-CSF treatment reduced the serum level of interleukin (IL)-6. Conclusion: G-CSF treatment accelerated reendothelialization and decreased neointimal formation following vascular injury, although there was little contribution of bone marrow-derived EPCs to the reendothelialization of the artery. These results suggest that G-CSF pretreatment has a therapeutic potential for prevention of restenosis following PCI. [Copyright &y& Elsevier]

Human iPS cell (iPSC)-derived cardiomyocytes (CMs) hold promise for drug discovery for heart diseases and cardiac toxicity tests. To utilize human iPSC-derived CMs, the establishment of three-dimensional (3D) heart tissues from iPSC-derived CMs and other heart cells, and a sensitive bioassay system to depict physiological heart function are anticipated. We have developed a heart-on-a-chip microdevice (HMD) as a novel system consisting of dynamic culture-based 3D cardiac microtissues derived from human iPSCs and microelectromechanical system (MEMS)-based microfluidic chips. The HMDs could visualize the kinetics of cardiac microtissue pulsations by monitoring particle displacement, which enabled us to quantify the physiological parameters, including fluidic output, pressure, and force. The HMDs demonstrated a strong correlation between particle displacement and the frequency of external electrical stimulation. The transition patterns were validated by a previously reported versatile video-based system to evaluate contractile function. The patterns are also consistent with oscillations of intracellular calcium ion concentration of CMs, which is a fundamental biological component of CM contraction. The HMDs showed a pharmacological response to isoproterenol, a β-adrenoceptor agonist, that resulted in a strong correlation between beating rate and particle displacement. Thus, we have validated the basic performance of HMDs as a resource for human iPSC-based pharmacological investigations. [ABSTRACT FROM AUTHOR]

Purpose of Review: Cardiovascular disease is the leading cause of mortality worldwide. Pluripotent stem cell-derived cardiomyocytes (PSC-CMs) have great potential to treat heart disease, owing to their capacity of engraftment and remuscularization in the host heart after transplantation. In the current review, we provide an overview of PSC-CMs for clinical transplantation. Recent Findings: Studies have shown that PSC-CMs can survive, engraft, and form gap junctions after transplantation, with functional benefit. Engrafted PSC-CMs matured gradually in host hearts. Only in a large animal model, transient ventricular arrhythmias were detected, mainly because of the ectopic pacing from the grafted PSC-CMs. Although intense immunosuppression is unavoidable in xenotransplantation, immunosuppression remains necessary for MHC-matched allogenic non-human primate PSC-CMs transplantation. Summary: This review offers insights on how PSC-CMs contribute to functional benefit after transplantation to injured non-human primate hearts. We believe that PSC-CM transplantation represents a potentially novel treatment for ischemic heart diseases, provided that several technological and biological limitations can be overcome. [ABSTRACT FROM AUTHOR]

Abstract: Bone marrow- (BM-) derived cells can differentiate into smooth muscle-like cells (SMLC), resulting in vascular pathogenesis. However, the molecular mechanism of the differentiation remains unknown. We have recently reported that Notch signaling promotes while a Notch target HERP1 inhibit the differentiation of mesenchymal cells to SMC. During the differentiation of BM-derived mononuclear cells into smooth muscle α-actin (SMA)-positive cells, expression of Jagged1 and SMC-specific Notch3 was increased. Blocking Notch with γ-secretase inhibitor prevented the induction of SMA. Wire-mediated vascular injury was produced in femoral arteries in mice transplanted with green fluorescent protein (GFP)-positive cells. Many double-positive cells for GFP/Jagged1 or GFP/Notch3 were detected in the thickened neointima. In contrast, only a few SMA-positive cells were positive for GFP in neointima where HERP1, a suppressor for Notch, were abundantly expressed. In conclusion, Notch-HERP1 pathway plays an important role in differentiation of BM-derived mononuclear cells into SMLC. [Copyright &y& Elsevier]

Duchenne muscular dystrophy (DMD) is a devastating muscle disorder caused by frameshift mutations in the DMD gene. DMD involves cardiac muscle, and the presence of ventricular arrhythmias or congestive failure is critical for prognosis. Several novel therapeutic approaches are being evaluated in ongoing clinical trials. Among them, exon-skipping therapy to correct frameshift mutations with antisense oligonucleotides is promising; however, their therapeutic efficacies on cardiac muscle in vivo remain unknown. In this study, we established induced-pluripotent stem cells (iPSCs) from T cells from a DMD patient carrying a DMD -exon 46–55 deletion, differentiated the iPSCs into cardiomyocytes, and treated them with phosphorodiamidate morpholino oligomers. The efficiency of exon-45 skipping increased in a dose-dependent manner and enabled restoration of the DMD gene product, dystrophin. Further, Ca2+-imaging analysis showed a decreased number of arrhythmic cells and improved transient Ca2+ signaling after exon skipping. Thus, exon-45 skipping may be effective for cardiac involvement in DMD patients harboring the DMD -exon 46–55 deletion. • DMD causes muscle weakness, cardiomyopathy, and arrhythmia, which can be fatal. • DMD exon-45 skipping was performed with a PMO and iPSC-derived cardiomyocytes. • Exon-45 skipping restored dystrophin expression with the DMD exon-46–55 deletion. • The cardiomyocytes showed improved Ca2+ transients and decreased arrhythmia. • Exon-45 skipping may help treat DMD cardiac disorders, especially arrhythmia. [ABSTRACT FROM AUTHOR]

Matrix metalloprotease (MMP)-9 is an endopeptidase associated with the pathogenesis of Duchenne muscular dystrophy (DMD). The precise function of MMP-9 in DMD has not been elucidated to date. We investigated the effect of genetic ablation of MMP-9 in the mdx mouse model ( mdx / Mmp9 −/− ). At the early disease stage, the muscles of mdx / Mmp9 −/− mice showed reduced necrosis and neutrophil invasion, accompanied by down-regulation of chemokine MIP-2. In addition, muscle regeneration was enhanced, which coincided with increased macrophage infiltration and upregulation of MCP-1, and resulted in increased muscle strength. The mdx / Mmp9 −/− mice also displayed accelerated upregulation of osteopontin expression in skeletal muscle at the acute onset phase of dystrophy. However, at a later disease stage, the mice exhibited muscle growth impairment through altered expression of myogenic factors, and increased fibroadipose tissue. These results showed that MMP-9 might have multiple functions during disease progression. Therapy targeting MMP-9 may improve muscle pathology and function at the early disease stage, but continuous inhibition of this protein may result in the accumulation of fibroadipose tissues and reduced muscle strength at the late disease stage. [ABSTRACT FROM AUTHOR]

Abstract: Although we previously reported the development of cell-dense thickened cardiac tissue by repeated transplantation-based vascularization of neonatal rat cardiac cell sheets, the cell sources for human cardiac cells sheets and their functions have not been fully elucidated. In this study, we developed a bioreactor to expand and induce cardiac differentiation of human induced pluripotent stem cells (hiPSCs). Bioreactor culture for 14days produced around 8×107 cells/100ml vessel and about 80% of cells were positive for cardiac troponin T. After cardiac differentiation, cardiomyocytes were cultured on temperature-responsive culture dishes and showed spontaneous and synchronous beating, even after cell sheets were detached from culture dishes. Furthermore, extracellular action potential propagation was observed between cell sheets when two cardiac cell sheets were partially overlaid. These findings suggest that cardiac cell sheets formed by hiPSC-derived cardiomyocytes might have sufficient properties for the creation of thickened cardiac tissue. [Copyright &y& Elsevier]