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1.
Artigo em Inglês | MEDLINE | ID: mdl-34524630

RESUMO

OBJECTIVE: To verify the amount of radiation exposure to the eye of operators during endocardiovascular surgery (ECVS) in hybrid operating room (HOR), which increases the risk of cataracts in surgeons. METHODS: Fifty cases of ECVS (including 36 transcatheter aortic valve implantation and 14 thoracic endovascular repair) using the transfemoral approach performed from February 2020 to July 2020 were included. A measurement device was attached to the left side of the head of the operators and their assistants to measure the cumulative dose (CD) of intraoperative radiation exposure. The subjects were divided into the control group (Group C, n = 26), received conventional protection using the protective curtain in HOR and the protected group (Group R, n = 24), received conventional protection and protection sheet. The normalized CD by dose area product (CD/DAP) was evaluated. RESULTS: The CD/DAP of the surgeons was significantly decreased in Group R, averaging at 5.97 µSV/Gy cm2 in Group C group and 4.40 µSV/Gy cm2 in Group R (p < 0.01). Moreover, CD/DAP of the assistant was significantly reduced in the Group R, with an average of 1.87 µSV/Gy cm2 in the Group C and 1.01 µSV/Gy cm2 in Group R (p < 0.01). CONCLUSIONS: The radiation exposure to the surgeon's eye could be significantly reduced by protection sheet.

2.
J Artif Organs ; 2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34581883

RESUMO

Women with implantable left-ventricular assist devices (LVADs) experience gynecological bleeding (GYN-bleeding). However, a few studies have investigated female-specific problems. Therefore, this study aimed to identify the risk factors for adverse GYN-bleeding after LVAD implantation. We retrospectively analyzed 59 women (mean age: 41 ± 15 years) with long-term implantable LVAD support (≥ 6 months) at our institution between 2005 and 2018. The history of GYN-bleeding before implantation was defined as abnormal utero-ovarian bleeding, excessive menstruation, uterine fibroids, and endometrial lesions. GYN-bleeding after implantation was defined as a requirement of emergency outpatient visits and/or hospitalization, blood transfusions, hormonal therapy, and/or surgery. Additionally, risk factors for GYN-bleeding were identified using the Cox regression model. Twenty-four GYN-bleeding cases were seen in 15 patients (two times: five patients, three times: two patients, 0.18 events per patient-year). The 1- and 2-year GYN-bleeding-free rates were 84% and 73%, respectively. Twelve patients (17 events) required RBC ≥ 4 units, and five patients (7 events) required FFP ≥ 4 units. Seven patients required pseudomenopausal treatment after blood transfusion, and four patients required surgical treatment. Fifteen patients with GYN-bleeding after implantation were significantly younger than the remaining 44 patients without GYN-bleeding (34 ± 12 years vs. 43 ± 16 years, P = 0.02). Multivariable risk analysis showed a history of GYN-bleeding before implantation was a significant risk factor (hazard ratio 3.7 [1.2-10.6], P = 0.004). Patients with a history of GYN-bleeding before LVAD implantation have a high risk of developing GYN-bleeding after implantation. We should identify the high-risk population and prepare for the management of GYN-bleeding.

3.
Ann Thorac Surg ; 2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34534528

RESUMO

BACKGROUND: This study aimed to clarify the incidence and determinants of postoperative adverse events in patients with ischemic cardiomyopathy who achieved long-term durable mitral valve repair. METHODS: Between 1999 and 2015, 166 patients with chronic ischemic mitral regurgitation (MR) and left ventricular (LV) ejection fraction ≤40% underwent restrictive mitral annuloplasty. During follow-up (65±34 months), echocardiographic assessments were performed 809 times (mean, 4.9±2.4 times) and 20 patients who had developed postoperative recurrent MR (≥moderate) were excluded. Finally, 146 patients (68±9 years) whose MR was well controlled over time were included. RESULTS: A total of 61 mortalities and/or 27 readmissions for heart failure were observed in 76 patients (52%). Among hospital survivors, age (adjusted hazard ratio: 1.05; P=0.001), and estimated glomerular filtration rate (adjusted hazard ratio: 0.61; P=0.001) were identified as independent predictors of long-term mortality and/or readmission for heart failure. The degree of LV function recovery after surgery was comparable between patients with and without adverse events. However, the former group showed greater values for systolic pulmonary artery pressure, tricuspid regurgitation severity, inferior vena cava dimension, and plasma brain natriuretic peptide level throughout the follow-up period (group effect p<0.05 for all). CONCLUSIONS: Approximately 50% of patients died or were hospitalized for heart failure even in the absence of recurrent mitral regurgitation during the 5-year follow-up, indicating that durable mitral repair does not always lead to favorable clinical outcomes. The adverse events might be related to volume overload secondary to impaired renal function and less favorable pulmonary hemodynamics.

4.
Biochem Biophys Res Commun ; 574: 91-96, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34450429

RESUMO

A major concern in the clinical application of induced pluripotent stem cells (iPSCs) is the prevention of tumorigenesis after implantation. Stem cells with high proliferative and differentiation potential are sensitive to radiation. Therefore, we hypothesized that irradiation may selectively eliminate residual undifferentiated human iPSCs (hiPSCs) in a cell population containing differentiated cardiomyocytes derived from hiPSCs (hiPSCs-CMs) and thus reduce tumorigenicity in vivo. hiPSC-CMs were irradiated with X-rays, after which the cell proliferation, apoptosis, morphology, and gene expression were analyzed. The gene expression of Lin28A, Nanog, Oct3/4, and SRY-box 2 was significantly lower in the irradiation group than in the control group. Irradiated hiPSC-CMs showed no change in proliferation potency and morphology compared to untreated hiPSC-CMs. Furthermore, irradiation did not induce apoptosis of differentiated cardiomyocytes. No significant difference in the gene expression of cardiac-specific markers, including α-myosin heavy chain, cardiac troponin T, and NK2 Homeobox 5, was observed between the groups. Tumorigenicity tests using NOG mice showed less frequent tumor formation in the irradiation group than in the control group. Irradiation of hiPSC-CMs significantly reduced the number of undifferentiated hiPSC and the tumor formation, while minimizing any adverse effects on hiPSC-CMs, thereby enabling safe hiPSC-based treatment.

5.
Artigo em Inglês | MEDLINE | ID: mdl-34246489

RESUMO

BACKGROUND: In patients with ischemic mitral regurgitation (MR) undergoing restrictive mitral annuloplasty (RMA), the ratio of left ventricular (LV) end-systolic dimension (LVESD) to mitral valve (MV) ring size (ie, LV-MV ring mismatch) is associated with postoperative recurrent MR. However, the impact of LV-MV ring mismatch on postoperative recurrent MR, LV function recovery, and long-term survival in patients with nonischemic dilated cardiomyopathy (DCM) remains unknown. METHODS: Sixty-six patients with nonischemic DCM (mean LVESD, 62 mm) underwent RMA (mean ring size, 26 mm) between 2003 and 2014. Recurrent MR was defined as MR grade ≥2+ at a 6-month echocardiographic evaluation. RESULTS: At the 6-month follow-up, 23 patients (35%) had developed recurrent MR. In univariable logistic regression analysis, larger LVESD (P = .012) and LVESD/ring size ratio (P = .008) were associated with recurrent MR. In multivariable models adjusted for age, sex, baseline LV ejection fraction, and severe MR, only LVESD/ring size ratio (odds ratio, 4.65; 95% confidence interval, 1.04-25.0; P = .048) remained significantly associated with MR recurrence. Receiver operating characteristic curve analysis demonstrated an optimal cutoff value for the LVESD/ring size ratio of 2.42. Patients with an LVESD/ring size ratio >2.42 (n = 30; mismatch) had a lower 5-year cumulative survival rate compared with those with an LVESD/ring size ratio ≤2.42 (n = 36; nonmismatch) (52% vs 71%; P = .045). Postoperatively, LV dimensions were significantly reduced in both groups; however, improvements in LVEF were only modest in the mismatched group (P = .091). CONCLUSIONS: LV-MV ring size mismatch was associated with an increased risk of recurrent MR in our series. This finding may aid the formulation of surgical strategies for patients with nonischemic DCM.

6.
Methods Mol Biol ; 2320: 23-27, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34302644

RESUMO

Regenerative medicine using human-induced pluripotent stem cells (hiPSCs) is a promising approach to treat heart failure. However, a large number of cells are required to achieve the desired therapeutic effect. The stirring-type suspension culture method allows a large-scale production of hiPSC-derived cardiomyocytes (more than 1 × 108 cells/100 mL), leading to a stable cell supply. Here, we describe a method to scale-up hiPSC-derived cardiomyocyte production with a high differentiation efficiency.


Assuntos
Diferenciação Celular/fisiologia , Células-Tronco Pluripotentes Induzidas/citologia , Miócitos Cardíacos/citologia , Animais , Técnicas de Cultura de Células/métodos , Células Cultivadas , Humanos , Camundongos
7.
Methods Mol Biol ; 2320: 29-33, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34302645

RESUMO

The human adult heart consists of approximately four billion cardiomyocytes, which do not possess self-renewal abilities. Severe myocardial infarction and dilated cardiomyopathy result in the loss of more than a billion cardiomyocytes. Induced pluripotent stem cells (iPSCs) can differentiate into various types of cells. Due to this ability, these cells could potentially serve as a new resource for cell therapy. Many studies have utilized cardiomyocytes derived from iPSCs for myocardial regeneration therapy. To obtain large number of cardiomyocytes for transplantation, we need to develop effective methods that would allow us to dissociate multiple cardiomyocyte aggregates simultaneously. Here, we describe a method to efficiently dissociate large number of iPSC-derived cardiomyocyte aggregates.


Assuntos
Células-Tronco Pluripotentes Induzidas/citologia , Miócitos Cardíacos/citologia , Diferenciação Celular/fisiologia , Células Cultivadas , Humanos , Infarto do Miocárdio/terapia
8.
Methods Mol Biol ; 2320: 65-73, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34302648

RESUMO

In this chapter, we introduce the method for fabricating thick and anisotropic cardiac tissue for heart regeneration. Aligned and biodegradable nanofiber can be prepared by electrospinning Food and Drug Administration-approved poly (lactic-co-glycolic acid) on a rotating drum. After the nanofibers are transferred on to a polydimethylsiloxane frame, the cardiomyocytes could be plated on the nanofiber to form thick and anisotropic cardiac tissue rapidly. Cardiac tissue-like construct could be easily created by one-step method, and transplanted onto the hearts of myocardium infarction models and lead to their functional recovery.


Assuntos
Infarto do Miocárdio/terapia , Miócitos Cardíacos/citologia , Nanofibras/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Animais , Anisotropia , Células Cultivadas , Masculino , Miocárdio/citologia , Ratos , Ratos Nus , Engenharia Tecidual/métodos , Tecidos Suporte/química
9.
Methods Mol Biol ; 2320: 75-79, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34302649

RESUMO

Myocardial tissues in vivo are complex three-dimensional structures. Significant efforts are currently focused on developing functionally and structurally similar tissues in vitro to transplant them for regenerative therapy and to evaluate pharmacological agents. We describe a method for constructing three-dimensional multilayered cardiac tissues by coating cells with extracellular matrix components (ECM).


Assuntos
Miócitos Cardíacos/citologia , Células Cultivadas , Matriz Extracelular/fisiologia , Humanos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Miocárdio/citologia , Medicina Regenerativa/métodos , Engenharia Tecidual/métodos
10.
Methods Mol Biol ; 2320: 235-245, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34302662

RESUMO

Cardiomyocytes differentiated from human induced pluripotent stem cells (hiPSCs) are powerful tools for elucidating the pathology behind inherited cardiomyopathies. Genome editing technologies enable targeted genome replacement and the generation of isogenic hiPSCs, allowing investigators to precisely determine the roles of identified mutations. Here, we describe a protocol to obtain isogenic hiPSCs with the corrected allele via homology-directed repair (HDR) using CRISPR/Cas9 genome editing under feeder-free conditions. Seeding hiPSCs in a 24-well plate and conducting the initial evaluation using direct genomic sequencing after 1 week is cost- and time-effective. Following optimization of the protocol, sequence confirmation of the corrected HDR clone is completed within 21 days.


Assuntos
Sistemas CRISPR-Cas , Edição de Genes/métodos , Genoma Humano , Células-Tronco Pluripotentes Induzidas/metabolismo , Miócitos Cardíacos/metabolismo , Diferenciação Celular , Células Clonais/citologia , Células Clonais/metabolismo , Eletroporação/métodos , Desenho de Equipamento , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Puromicina/farmacologia , Reparo de DNA por Recombinação
11.
J Am Heart Assoc ; 10(13): e008649, 2021 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-34212772

RESUMO

Background Clinical effectiveness of autologous skeletal cell-patch implantation for nonischemic dilated cardiomyopathy has not been clearly elucidated in clinical settings. This clinical study aimed to determine the feasibility, safety, therapeutic efficacy, and the predictor of responders of this treatment in patients with nonischemic dilated cardiomyopathy. Methods and Results Twenty-four nonischemic dilated cardiomyopathy patients with left ventricular ejection fraction <35% on optimal medical therapy were enrolled. Autologous cell patches were implanted over the surface of the left ventricle through left minithoracotomy without procedure-related complications and lethal arrhythmia. We identified 13 responders and 11 nonresponders using the combined indicator of a major cardiac adverse event and incidence of heart failure event. In the responders, symptoms, exercise capacity, and cardiac performance were improved postoperatively (New York Heart Association class II 7 [54%] and III 6 [46%] to New York Heart Association class II 12 [92%] and I 1 [8%], P<0.05, 6-minute walk test; 471 m [370-541 m] to 525 m [425-555 m], P<0.05, left ventricular stroke work index; 31.1 g·m2·beat [22.7-35.5 g·m2·beat] to 32.8 g·m2·beat [28-38.5 g·m2·beat], P=0.21). However, such improvement was not observed in the nonresponders. In responders, the actuarial survival rate was 90.9±8.7% at 5 years, which was superior to the estimated survival rate of 70.9±5.4% using the Seattle Heart Failure Model. However, they were similar in nonresponders (47.7±21.6% and 56.3±8.1%, respectively). Multivariate regression model with B-type natriuretic peptide, pulmonary capillary wedge pressure, and expression of histone H3K4me3 (H3 lysine 4 trimethylation) strongly predicted the responder of this treatment (B-type natriuretic peptide: odds ratio [OR], 0.96; pulmonary capillary wedge pressure: ​OR, 0.58; H3K4me3: OR, 1.35, receiver operating characteristic-area under the curve, 0.96, P<0.001). Conclusions This clinical trial demonstrated that autologous skeletal stem cell-patch implantation might promise functional recovery and good clinical outcome in selected patients with nonischemic dilated cardiomyopathy, in addition to safety and feasibility. Registration URL: http://www.umin.ac.jp/english/. Unique identifiers: UMIN000003273, UMIN0000012906 and UMIN000015892.

12.
Sci Rep ; 11(1): 14698, 2021 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-34282197

RESUMO

In contrast to hypertrophic cardiomyopathy, there has been reported no specific pattern of cardiomyocyte array in dilated cardiomyopathy (DCM), partially because lack of alignment assessment in a three-dimensional (3D) manner. Here we have established a novel method to evaluate cardiomyocyte alignment in 3D using intravital heart imaging and demonstrated homogeneous alignment in DCM mice. Whilst cardiomyocytes of control mice changed their alignment by every layer in 3D and position twistedly even in a single layer, termed myocyte twist, cardiomyocytes of DCM mice aligned homogeneously both in two-dimensional (2D) and in 3D and lost myocyte twist. Manipulation of cultured cardiomyocyte toward homogeneously aligned increased their contractility, suggesting that homogeneous alignment in DCM mice is due to a sort of alignment remodelling as a way to compensate cardiac dysfunction. Our findings provide the first intravital evidence of cardiomyocyte alignment and will bring new insights into understanding the mechanism of heart failure.

13.
Stem Cell Res ; 54: 102420, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34126557

RESUMO

Drug efficacy assessment without using animals is important for development of cardiac fibrosis treatment. In this study, potential anti-fibrotic drugs were screened in a model of diseased myocardium using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) and non-CM in in vitro and in vivo heart failure models. Cardiomyogenic differentiation was induced in hiPSC to generate cardiac tissue, including both iPSC-CM and non-CM expressing fibroblast markers. Stimulation with TGF-ß significantly increased cardiac fibrotic extracellular matrix (ECM) gene expression, and decreased cardiac contractile/relaxation velocity. Anti-fibrotic HGF significantly decreased fibrotic changes induced by TGF-ß. A prostacyclin agonist, ONO-1301 (ONO), camostat mesilate (Cs), and pirfenidone (Pf) significantly decreased fibrotic ECM expression, and improved contraction/relaxation in the model stimulated with TGF-ß. Consistent with the in vitro assay, the administration of ONO, Cs, or Pf for 8 weeks in J2N-k hamsters preserved the left ventricular ejection fraction and decreased cardiac fibrosis compared with the controls. The in vitro model simulating fibrotic cardiac tissue showed precise screening of anti-fibrotic drugs which indicated the expected therapeutic response in an in vivo heart failure model, suggesting that the in vitro model presented in this study is a useful tool for the screening of anti-fibrotic drugs.


Assuntos
Células-Tronco Pluripotentes Induzidas , Animais , Avaliação Pré-Clínica de Medicamentos , Fibrose , Humanos , Miócitos Cardíacos/patologia , Volume Sistólico , Função Ventricular Esquerda
14.
J Heart Lung Transplant ; 40(8): 767-777, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34108109

RESUMO

BACKGROUND: Although induced pluripotent stem (iPS) cell-derived cardiac constructs may have a potential in cardiomyogenesis of a distressed myocardium, obtaining polarity in cardiac constructs, such as via myocyte alignment, may be crucial to achieve a maximum contractile force for better clinical outcomes. We herein hypothesized that transplantation of an aligned cardiac tissue derived from iPS cells has therapeutic effects in a porcine ischemic cardiomyopathy model as a preclinical trial. METHODS: Aligned cardiac tissues were developed by culturing high-purity iPS cell-derived cardiomyocytes in xeno-free conditions and transplanting them into infarct porcine hearts (iPS-CM group, n = 7; control, n = 6). Three months after treatment, therapeutic efficacy was evaluated functionally and histologically. RESULTS: In vitro assessment revealed that the aligned cardiac tissue containing high purity cardiomyocytes contracted homogeneously and had excellent mechanical properties. In the in vivo study, the left ventricular ejection fraction of the iPS-CM group was significantly greater than that of the control group, 3 months after transplantation (37.8% ± 2.3% vs 28.3% ± 2.5%, p < 0.05). Pathologically, attenuated interstitial fibrosis, attenuation of hypertrophied cardiomyocytes, and an increased capillary density were also prominent in the iPS-CM group. A limited amount of engraftment of the transplanted tissue maintaining tissue alignment was observed at 2 weeks after transplantation. CONCLUSIONS: The creation of large-scale functional aligned cardiac tissue was feasible, and the transplantation of the aligned tissue improved cardiac function with angiogenesis and antifibrotic effects in a porcine cardiomyopathy model.

15.
J Artif Organs ; 2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34160717

RESUMO

A major concern in the clinical application of cell therapy is the manufacturing cost of cell products, which mainly depends on quality control. The mycoplasma test, an important biological test in cell therapy, takes several weeks to detect a microorganism and is extremely expensive. Furthermore, the manual detection of mycoplasma from images requires high-level expertise. We hypothesized that a mycoplasma identification program using a convolutional neural network could reduce the test time and improve sensitivity. To this end, we developed a program comprising three parts (mycoplasma detection, prediction, and cell counting) that allows users to evaluate the sample and verify infected/non-infected cells identified by the program. In experiments conducted, stained DNA images of positive and negative control using mycoplasma-infected and non-infected Vero cells, respectively, were used as training data, and the program results were compared with those of conventional methods, such as manual counting based on visual observation. The minimum detectable mycoplasma contaminations for manual counting and the proposed program were 10 and 5 CFU (colony-forming unit), respectively, and the test time for manual counting was 20 times that for the proposed program. These results suggest that the proposed system can realize a low-cost and streamlined manufacturing process for cellular products in cell-based research and clinical applications.

16.
Hum Mol Genet ; 30(15): 1384-1397, 2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-33949662

RESUMO

Desmoglein-2, encoded by DSG2, is one of the desmosome proteins that maintain the structural integrity of tissues, including heart. Genetic mutations in DSG2 cause arrhythmogenic cardiomyopathy, mainly in an autosomal dominant manner. Here, we identified a homozygous stop-gain mutations in DSG2 (c.C355T, p.R119X) that led to complete desmoglein-2 deficiency in a patient with severe biventricular heart failure. Histological analysis revealed abnormal deposition of desmosome proteins, disrupted intercalated disk structures in the myocardium. Induced pluripotent stem cells (iPSCs) were generated from the patient (R119X-iPSC), and the mutated DSG2 gene locus was heterozygously corrected to a normal allele via homology-directed repair (HDR-iPSC). Both isogenic iPSCs were differentiated into cardiomyocytes [induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs)]. Multielectrode array analysis detected abnormal excitation in R119X-iPSC-CMs but not in HDR-iPSC-CMs. Micro-force testing of three-dimensional self-organized tissue rings (SOTRs) revealed tissue fragility and a weak maximum force in SOTRs from R119X-iPSC-CMs. Notably, these phenotypes were significantly recovered in HDR-iPSC-CMs. Myocardial fiber structures in R119X-iPSC-CMs were severely aberrant, and electron microscopic analysis confirmed that desmosomes were disrupted in these cells. Unexpectedly, the absence of desmoglein-2 in R119X-iPSC-CMs led to decreased expression of desmocollin-2 but no other desmosome proteins. Adeno-associated virus-mediated replacement of DSG2 significantly recovered the contraction force in SOTRs generated from R119X-iPSC-CMs. Our findings confirm the presence of a desmoglein-2-deficient cardiomyopathy among clinically diagnosed dilated cardiomyopathies. Recapitulation and correction of the disease phenotype using iPSC-CMs provide evidence to support the development of precision medicine and the proof of concept for gene replacement therapy for this cardiomyopathy.

17.
Chem Commun (Camb) ; 57(42): 5131-5134, 2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-33988188

RESUMO

Controlled release of oxygen from myoglobin was achieved by modulating autoxidation of oxymyoglobin using ascorbic acid as a reductant by temperature variation. Long-term storage, prompt release and re-storage of oxygen were also available with this system. Furthermore, 20 nm thick nanofilms composed of oxymyoglobin and type I collagen containing ascorbic acid could successfully show autoxidation of oxymyoglobin in response to environmental temperature. The ultrathin nanofilms will be useful as oxygen-controlled releasable scaffolds for tissue engineering application.


Assuntos
Mioglobina/metabolismo , Nanoestruturas/química , Oxigênio/metabolismo , Ácido Ascórbico/química , Colágeno Tipo I/química , Colágeno Tipo I/metabolismo , Mioglobina/química , Oxirredução , Oxigênio/química , Técnicas de Microbalança de Cristal de Quartzo , Temperatura
18.
Sci Rep ; 11(1): 10351, 2021 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-33990626

RESUMO

Duchenne muscular dystrophy (DMD) is characterized by progressive muscle degeneration accompanied by dilated cardiomyopathy. Recently, abnormality of yes-associated protein (YAP) has been reported as the pathogenesis of muscle degeneration of DMD; however YAP activity remains unclear in dystrophic heart of DMD. Herein, we investigated YAP activity using disease-specific induced pluripotent stem cell (iPSC) derived cardiomyocytes (CMs) in DMD. DMD-iPSCs were generated from DMD patient with exon 48-54 deletion in DMD, and genome-edited (Ed)-DMD-iPSCs with in-frame (Ed-DMD-iPSCs) were created using CRISPR/Cas9. Nuclear translocation of YAP [nuclear (N)/cytoplasmic (C) ratio] was significantly lower in DMD-iPSC-CMs than in Ed-DMD-iPSC-CMs. In addition, Ki67 expression, indicating proliferative ability, was significantly lower in DMD-iPSC-CMs than Ed-DMD-iPSC-CMs. Therefore, immunofluorescent staining showed that actin stress fibers associated with YAP activity by mechanotransduction were disorganized in DMD-iPSC-CMs. Lysophosphatidic acid (LPA), a known lipid mediator on induction of actin polymerization, significantly increased YAP activity and actin dynamics in DMD-iPSC-CMs using live cell imaging. These results suggested that altered YAP activity due to impaired actin dynamics reduced proliferative ability in DMD-iPSC-CMs. Hence, decreased YAP activity in dystrophic heart may contribute to DMD-cardiomyopathy pathogenesis.

19.
Am J Physiol Heart Circ Physiol ; 320(5): H2161-H2168, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33834869

RESUMO

Right ventricular failure (RVF) is a serious adverse event after left ventricular assist device (LVAD) implantation but difficult to be characterized. This study aimed to visualize the dynamic circulatory equilibrium of acute RVF after LVAD implantation using a new four-quadrant diagram constructed by 1) cardiac function with central venous pressure (CVP) and cardiac index (CI) axes, 2) arterial vascular resistance with CI and mean blood pressure (mBP) axes, 3) pressure-diuretic function with mBP and net urinary sodium output (net U-Na) axes, and 4) venous compliance with net U-Na and CVP axes. Twenty LVAD patients were stratified into two groups, group S (≤10 days) and group L (>10 days), according to duration of postoperative inotropic support. The preoperative equilibrium loops were small in both groups. In the early postoperative phase, the loop in group S became dramatically enlarged to the left and upward, indicating increased CVP and CI by LVAD support. In group L, however, augmentation of CI was smaller despite similarly increased CVP, and net U-Na was decreased despite increased mBP. In the late postoperative phase, the equilibrium loop in group L recovered as similar to that seen in group S. Thus, acute RVF, as shown in group L, was characterized by the shape of the loop constructed by marked increased CVP, a relatively small increase in CI, and concomitant impairment of pressure natriuresis. In conclusion, the novel four-quadrant presentation of systemic circulatory equilibrium provides clear visualization of RVF after LVAD implantation, thus serving as a useful guide for prompt and optimal management.NEW & NOTEWORTHY Systemic circulatory dynamics are regulated by various negative feedback systems, including cardiac, arterial, venous, and renal functions, as well as autonomic nervous systems. The present novel four-quadrant presentation of their functions allows clear visualization of dynamic organ-to-organ interactions that can lead to a new circulatory equilibrium after therapeutic intervention. This new system physiological framework can serve as a useful guide for prompt and optimal management of circulatory malfunction.


Assuntos
Insuficiência Cardíaca/diagnóstico por imagem , Coração Auxiliar , Hemodinâmica/fisiologia , Disfunção Ventricular Direita/diagnóstico por imagem , Adulto , Pressão Venosa Central/fisiologia , Ecocardiografia , Feminino , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Disfunção Ventricular Direita/fisiopatologia
20.
Sci Rep ; 11(1): 7292, 2021 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-33790393

RESUMO

Clinical outcomes of pulmonary arterial hypertension (PAH) may be improved using targeted delivery system. We investigated the efficacy of ONO1301 (prostacyclin agonist) nanospheres (ONONS) in Sugen5416/hypoxia rat models of PAH. The rats were injected with saline (control) or ONONS (n = 10, each) on days 21 and 28, respectively. Hepatocyte growth factor (HGF)-expressing fibroblasts and inflammatory cytokines were measured. Cardiac performance was assessed and targeted delivery was monitored in vivo, using Texas red-labeled nanoparticles. Compared with control, HGF-expressing fibroblasts and HGF expression levels were significantly higher in the ONONS group, while the levels of interleukin-6, interleukin-1ß, transforming growth factor-ß, and platelet-derived growth factor were lower. Histological assessment revealed significant amelioration of the percent medial wall thickness in pulmonary vasculature of rats in the ONONS group. Rats in the ONONS group showed decreased proliferating cell nuclear antigen-positive smooth muscle cells and improved right ventricle pressure/left ventricle pressure. No difference was seen in the accumulation of Texas red-labeled nanoparticles in the brain, heart, liver, and spleen between PAH and normal rats. However, a significant area of nanoparticles was detected in the lungs of PAH rats. ONONS effectively ameliorated PAH, with selective delivery to the damaged lung.


Assuntos
Anti-Hipertensivos/uso terapêutico , Hipertensão Pulmonar/tratamento farmacológico , Nanocápsulas/química , Piridinas/uso terapêutico , Animais , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/farmacologia , Células Cultivadas , Epoprostenol/agonistas , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fator de Crescimento de Hepatócito/genética , Fator de Crescimento de Hepatócito/metabolismo , Interleucinas/genética , Interleucinas/metabolismo , Masculino , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Fator de Crescimento Derivado de Plaquetas/genética , Fator de Crescimento Derivado de Plaquetas/metabolismo , Artéria Pulmonar/citologia , Piridinas/administração & dosagem , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo
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