Yoshiki Sawa - Academia.edu (original) (raw)

Papers by Yoshiki Sawa

Circulation journal, Nov 25, 2022

on behalf of the Japanese HeartMateII Investigators Background: The objective of this study is to... more on behalf of the Japanese HeartMateII Investigators Background: The objective of this study is to investigate the effect of preoperative diabetes on all-cause mortality and major postoperative complications among patients with continuous-flow left ventricular assist device (LVAD) by using data from a national database. Methods and Results: The 545 study patients who underwent primary HeartMateII implantation between 2013 and 2019 were divided into 2 groups according to their diabetes mellitus (DM) status; patients with DM (n=116) and patients without DM (n=429). First, the on-device survival and incidence of adverse events were evaluated. Second, after adjusting for patients' backgrounds, the change of laboratory data in the 2 groups were compared. Overall, on-device survival at 1, 2, and 3 years was almost equivalent between the 2 groups; it was 95%, 94%, and 91% in patients without DM, and 93%, 91%m and 91% in patients with DM (P=0.468) The incidence of adverse events was similar between 2 groups of patients, except for driveline exit site infection in the adjusted cohort. Cox proportional hazards regression analysis revealed younger age (HR: 0.98 (95% confidence interval (CI): 0.97-0.99, P=0.001) and presence of DM (HR: 1.83 (95% CI: 1.14-2.88), P=0.016) as significant predictors of driveline infection. Laboratory findings revealed no differences between groups throughout the periods. Conclusions: The clinical results after LVAD implantation in DM patients were comparable with those in non-DM patients, except for the driveline exit site infection.

Medicina, 2020

Background: Left ventricular assist device (LVAD) therapy has improved the clinical outcomes in a... more Background: Left ventricular assist device (LVAD) therapy has improved the clinical outcomes in advanced heart failure patients, however, this may differ between countries. We aimed to compare outcomes between Japanese and US LVAD cohorts. Methods: For 416 consecutive LVAD patients who received HeartMate II LVAD implantation and completed a one-year follow-up, age-matched Japanese patients (the Japanese registry for mechanically assisted circulatory support (J-MACS) group) and the US patients were compared for their clinical outcomes. Results: 154 J-MACS patients and 77 US patients were compared. Survival, free from hemocompatibility-related adverse events (HRAEs) in the J-MACS was statistically comparable with the US (75% vs. 63%, p = 0.79). J-MACS had more disabling strokes than the US (0.221 vs. 0.052/patient-year, p = 0.005), whereas there was less nonsurgical bleeding (0.045 vs. 0.117/patient-year, p = 0.024). The net hemocompatibility score was statistically comparable between...

Journal of Artificial Organs, 2020

The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation, 2018

The Jarvik 2000 ventricular assist device features a miniaturized intraventricular pump and an in... more The Jarvik 2000 ventricular assist device features a miniaturized intraventricular pump and an intermittent low-speed function that facilitates aortic valve opening. Despite its long history, little is known about the Jarvik device with regard to post-implantation outcomes. Prospectively collected data from 13 participating hospitals were extracted from the Japanese Registry for Mechanically Assisted Circulatory Support database to analyze mortality, morbidity and de-novo aortic regurgitation. Data on 83 patients who underwent implantation of the Jarvik 2000 were reviewed. Median support duration was 191 (maximum 758) days. All recipients underwent implantation as a bridge to transplantation. Overall survival proportions at 1 and 2 years were 85.0% and 79.3%, respectively. Nine patients were in INTERMACS Level 1, and 28 patients were on mechanical circulatory support at the time of implantation. Causes of death included stroke, infection and device malfunction. Three patients had th...

Tissue Engineering Part A, 2015

Introduction: Bone marrow-derived autologous human mesenchymal stem cells (MSCs) are one of the m... more Introduction: Bone marrow-derived autologous human mesenchymal stem cells (MSCs) are one of the most promising cell sources for cell therapy to treat heart failure. The cell sheet technique has allowed transplantation of a large number of cells and enhanced the efficacy of cell therapy. We hypothesized that the transplantation of MSC sheets may be a feasible, safe, and effective treatment for ischemic cardiomyopathy (ICM). Methods and Results: Human MSCs acquired from bone marrow were positive for CD73, CD90, and CD105 and negative for CD11b and CD45 by flow cytometry. Ten MSC sheets were created from a total cell number of 1 • 10 8 MSCs using temperature-responsive culture dishes. These were successfully transplanted over the infarct myocardium of porcine ICM models induced by placing an ameroid constrictor on the left anterior descending coronary artery without any procedural-related complications (MSC group = 6: sheet transplantation; sham group = 6, oral intake of tacrolimus in both groups). Premature ventricular contractions were rarely detected by Holter electrocardiogram (ECG) in the MSC group in the first week after transplantation. On echocardiography, the cardiac performance of the MSC group was significantly better than that of the sham group at 8 weeks after transplantation. On histological examination 8 weeks after transplantation, left ventricular (LV) remodeling was significantly attenuated compared with the sham group (cardiomyocyte size and interstitial fibrosis were measured). Immunohistochemistry of the von Willebrand factor showed that the vascular density in the infarct border area was significantly greater in the MSC group than the sham group. Expression of angiogenesis-related factors in the infarct border area of the MSC group was significantly greater than that of the sham group, as measured by real-time polymerase chain reaction. Conclusions: Bone marrow-derived MSC sheets improved cardiac function and attenuated LV remodeling in ICM without major complications, indicating that this strategy would be applicable in clinical settings.

Heart failure reviews, Jan 24, 2015

Cardiac failure is a major cause of mortality and morbidity worldwide, since the standard treatme... more Cardiac failure is a major cause of mortality and morbidity worldwide, since the standard treatment for cardiac failure in the clinical practice is chiefly to focus on removal of insults against the heart or minimisation of additional factors to exacerbate cardiac failure, but not on regeneration of the damaged cardiac tissue. A synthetic prostacyclin agonist, ONO-1301, has been developed as a long-acting drug for acute and chronic pathologies related to regional ischaemia, inflammation and/or interstitial fibrosis by pre-clinical studies. In addition, poly-lactic co-glycolic acid-polymerised form of ONO-1301, ONO-1301SR, was generated to achieve a further sustained release of this drug into the targeted region. This unique reagent has been shown to act on fibroblasts, vascular smooth muscle cells and endothelial cells in the tissue via the prostaglandin IP receptor to exert paracrinal release of multiple protective factors, such as hepatocyte growth factor, vascular endothelial gro...

BioMed research international, 2013

Heart failure is a life-threatening disorder worldwide and many papers reported about myocardial ... more Heart failure is a life-threatening disorder worldwide and many papers reported about myocardial regeneration through surgical method induced by LVAD, cellular cardiomyoplasty (cell injection), tissue cardiomyoplasty (bioengineered cardiac graft implantation), in situ engineering (scaffold implantation), and LV restrictive devices. Some of these innovated technologies have been introduced to clinical settings. Especially, cell sheet technology has been developed and has already been introduced to clinical situation. As the first step in development of cell sheet, neonatal cardiomyocyte sheets were established and these sheets showed electrical and histological homogeneous heart-like tissue with contractile ability in vitro and worked as functional heart muscle which has electrical communication with recipient myocardium in small animal heart failure model. Next, as a preclinical study, noncontractile myoblast sheets have been established and these sheets have proved to secrete multi...

Circulation Journal, 2012

Background: This report details experience of the conversion of the Toyobo left ventricular assis... more Background: This report details experience of the conversion of the Toyobo left ventricular assist device (LVAD; Nipro, Osaka, Japan) to the DuraHeart LVAD (TerumoHeart, Ann Arbor, MI, USA) in patients awaiting heart transplantation. Methods and Results: Eight patients (4 male, 4 female) with Toyobo paracorporeal LVAD underwent conversion to the third-generation centrifugal (DuraHeart) LVAD. The apical cuff of the Toyobo was not exchanged because the size was the same as that of the DuraHeart. All conversion operations were performed safely, but 3 patients who had infection of the Toyobo LVAD cannulation site prior to conversion suffered later pocket infections and 1 patient died because of sepsis. One patient underwent heart transplantation and 6 of 8 patients were awaiting heart transplantation at home. Conclusions: Conversions from the Toyobo LVAD to the DuraHeart LVAD were performed safely. Considering that implantable LVADs provide superior long-term survival and quality of life, conversion is a reasonable decision for Toyobo LVAD users in whom there are no infections.

Circulation, 2011

Background— We assessed changes in left ventricular (LV) volume and function and in regional myoc... more Background— We assessed changes in left ventricular (LV) volume and function and in regional myocardial wall stress in noninfarcted segments after restrictive mitral annuloplasty (RMA) with or without surgical ventricular restoration (SVR). Methods and Results— Thirty-nine patients with ischemic cardiomyopathy (ejection fraction ≤0.35) and severe mitral regurgitation (≥3) were studied before and 2.8 months after surgery with cine-angiographic multidetector computed tomography (cine-MDCT). Eighteen underwent RMA alone (RMA group) and 21 underwent RMA and SVR (RMA+SVR group). In addition to measuring conventional parameters (LV end-diastolic volume index [LVEDVI], LV end-systolic volume index [LVESVI], and LV ejection fraction), we evaluated the regional circumferential end-systolic wall stress and mean circumferential fiber shortening in both the basal and mid-LV regions using 3-dimensional cine-MDCT images. LV end-diastolic and end-systolic volume indexes were significantly greater ...

Cardiovascular Research, 2006

Objectives: Cell therapy is a promising strategy for ischemic cardiomyopathy. However, the direct... more Objectives: Cell therapy is a promising strategy for ischemic cardiomyopathy. However, the direct injection method has limitations for generalized cell delivery, especially in dilated cardiomyopathy (DCM). We hypothesized that a sheet-shaped myoblast graft would be superior to direct injection for improving cardiac performance in DCM. Methods: Male 27-week-old BIO TO-2 (DCM) hamsters that showed moderate cardiac remodeling were used as recipients. Myoblasts isolated from BIO F1B hamsters were cultured on dishes coated with poly(N-isopropylacrylamide), a temperature-responsive polymer, and spontaneously detached as a sheet-shaped graft at 20-C without enzymatic treatment. Three different therapies were conducted: (1) sheetshaped myoblast graft implantation (S group, n = 29); (2) myoblast injection (M group, n = 28); and (3) sham operation (C group, n = 28). In the S group, two sheet-shaped myoblast grafts were implanted on the left ventricle (LV) wall, and in the M group, myoblasts were injected into the right ventricle (RV) and LV walls. Results: After the sheet-shaped myoblast grafts were implanted, echocardiography demonstrated that the dilated LV dimension was significantly reduced, whereas the hearts in other groups showed a progression of LV dilation. The fractional shortening in the M and C groups decreased significantly while that in the S group was maintained at the preoperative level for 3 months after the operation. Histological examination demonstrated that in the S group, the LV wall thickness was increased, with viable myoblasts, and myocardial fibrosis was decreased compared with the other groups. Immunohistochemical staining demonstrated alpha-sarcoglycan and beta-sarcoglycan expression on the basement membrane of the cardiomyocytes in the S group but not in the other groups. The life expectancy was significantly prolonged in the S group. Conclusion: Sheet-shaped myoblast graft implantation improved cardiac performance and prolonged life expectancy, associated with a reduction in myocardial fibrosis and reorganization of the cytoskeletal proteins in DCM hamsters. Thus, sheet-shaped autologous myoblast graft implantation may induce restoration of the heart in DCM.

Circulation, Nov 10, 2015

Introduction: We recently reported a multi-center, single-arm, phase II study that evaluated the ... more Introduction: We recently reported a multi-center, single-arm, phase II study that evaluated the efficacy and safety of autologous skeletal myoblast sheet (TCD-51073) transplantation. The advantage of this procedure over a control group has not yet been analyzed. Hypothesis: TCD-51073 has better clinical outcome compared with background-matched control group. Methods: Seven patients with advanced heart failure due to ischemic etiology (TCD-51073 group, New York Heart Association [NYHA] class III; left ventricular ejection fraction (LVEF) <35%) refractory to optimal medical and coronary revascularization therapy, received TCD-51073 at 3 study centers between 2012 and 2013 with a 2-year follow-up period. As previously reported, 112 patients received cardiac resynchronization therapy (CRT) with follow-up at the University of Tokyo Hospital between 2007 and 2014. Results: Of them, 21 patients were selected for the control group by propensity score matching. No significant difference in baseline variables between the groups was observed. LVEF and NYHA class improved significantly in the TCD-51073 group during the 6-month study period (p<0.05). During the 2-year follow-up, 7 patients (33%) in the CRT group and no patient in the TCD-51073 group died due to cardiac disease or received VAD implantation (p=0.128 by the log-rank test). Conclusions: Transplantation of TCD-51073 is clinically advantageous in facilitating LV reverse remodeling, improving HF symptoms, and preventing cardiac death in patients with ischemic etiology when compared to background-matched patients receiving CRT.

Interactive cardiovascular and thoracic surgery, Jan 18, 2018

We previously reported that cell sheet transplantation combined with an omentopexy (OP) procedure... more We previously reported that cell sheet transplantation combined with an omentopexy (OP) procedure is more effective for repairing heart damage when compared with cell sheet transplantation alone. However, a simultaneous (conventional) laparotomy as part of the OP may adversely affect the general condition of critically ill heart failure patients who would otherwise benefit from cell sheet transplantation, which is a paradox to be reconciled before this treatment can be applied in a clinical setting. We devised a novel endoscopic approach termed 'transphrenic peritoneoscopy' (TPP) for minimal access to abdominal organs from the thoracic cavity. Herein, we evaluated the feasibility and safety of TPP with an OP in a porcine myocardial infarction model. Myocardial infarction was induced in 4 mini pigs by placing an ameroid constrictor around the left anterior descending artery. One month later, a left thoracotomy was performed in 2 randomly selected mini pigs, and a laparoscopic...

Circulation Journal, 2017

Japanese patients underwent continuous-flow LVAD implantation for endstage heart failure. All pat... more Japanese patients underwent continuous-flow LVAD implantation for endstage heart failure. All patients and family members provided informed consent to participate in related clinical studies. Follow-up data were collected for 0-4.84 years [mean, 1.70±1.12 years; median, 1.54 years; interquartile range (IQR), 0.70-2.62 years)]. All follow-up examinations were completed by April 30, 2017. Devices and Surgical Procedures The type of LVAD utilized was decided at the preoperative conference, though available devices have changed over time in Japan. Briefly,

PloS one, 2017

It has been shown that the size of myocardial infarction in rats created by coronary ligation tec... more It has been shown that the size of myocardial infarction in rats created by coronary ligation technique is not uniform, varying from 4% to 65%. We hypothesized that infarct size variability induced by coronary artery ligation might be caused by coronary artery branching pattern. Coronary artery angiography was performed in 50 normal Lewis rats and in chronic myocardial infarction models in which coronary artery was ligated immediately below the left atrial appendage or 2mm distal to the left atrial appendage (n = 25 for each), followed by histological analysis. Unlike the human, the rats had a single major septal artery arising from the proximal part of the left coronary artery (n = 30) or right coronary artery (n = 20). There were three branching patterns of left circumflex artery (LCX): 33 (66%) had LCX branching peripherally from a long left main coronary artery (LMCA), while the remainder 17 (34%) had the LCX branching from the proximal part of the septal artery or a short LMCA....

PloS one, 2017

The sympathetic nervous system is critical in maintaining the normal physiological function of th... more The sympathetic nervous system is critical in maintaining the normal physiological function of the heart. Its dysfunction in pathological states may exacerbate the substrate for arrhythmias. Obviously, knowledge of its three-dimensional (3D) structure is important, however, it has been revealed by conventional methods only to a limited extent. In this study, a new method of tissue clearance in combination with immunostaining unravels the 3D structure of the sympathetic cardiac network as well as its changes after myocardial infarction. Hearts isolated from adult male mice were optically cleared using the CUBIC-perfusion protocol. After making the hearts transparent, sympathetic nerves and coronary vessels were immunofluorescently labeled, and then images were acquired. The spatial distribution of sympathetic nerves was visualized not only along the epicardial surface, but also transmurally. They were distributed over the epicardial surface and penetrated into the myocardium to twist...

The Journal of thoracic and cardiovascular surgery, Jan 24, 2017

The angiogenic potential of endothelial progenitor cells (EPCs) may be limited by the absence of ... more The angiogenic potential of endothelial progenitor cells (EPCs) may be limited by the absence of their natural biologic foundation, namely smooth muscle pericytes. We hypothesized that joint delivery of EPCs and smooth muscle cells (SMCs) in a novel, totally bone marrow-derived cell sheet will mimic the native architecture of a mature blood vessel and act as an angiogenic construct to limit post infarction ventricular remodeling. Primary EPCs and mesenchymal stem cells were isolated from bone marrow of Wistar rats. Mesenchymal stem cells were transdifferentiated into SMCs by culture on fibronectin-coated culture dishes. Confluent SMCs topped with confluent EPCs were detached from an Upcell dish to create a SMC-EPC bi-level cell sheet. A rodent model of ischemic cardiomyopathy was then created by ligating the left anterior descending artery. Rats were randomized into 3 groups: cell sheet transplantation (n = 9), no treatment (n = 12), or sham surgery control (n = 7). Four weeks posti...

Circulation journal : official journal of the Japanese Circulation Society, Jan 16, 2017

Coronary artery bypass grafting (CABG) reduces functional mitral regurgitation (MR) associated wi... more Coronary artery bypass grafting (CABG) reduces functional mitral regurgitation (MR) associated with ischemic heart disease, although the predictive factors or mechanisms of reversibility of functional MR after CABG are not fully understood.We investigated whether mitral valve structure is associated with the outcome of functional MR after CABG.Methods and Results:From a consecutive series of 98 patients with mild-moderate functional MR preoperatively who underwent isolated CABG, we enrolled 66 patients who were followed up for >1 year postoperatively using echocardiography. The degree of MR was reduced in 34 patients (52%) postoperatively, in association with a lower rate of in-hospital treatment for cardiac failure in the long term, compared with the 32 patients (48%) with residual MR postoperatively. The patients with reduced MR postoperatively had longer estimated coaptation length and more anteriorly or centrally directed MR jets than those without reduced MR. On statistical ...

PLOS ONE, 2016

Allogeneic transplantation (Tx) of induced pluripotent stem cells (iPSCs) is a promising tissue r... more Allogeneic transplantation (Tx) of induced pluripotent stem cells (iPSCs) is a promising tissue regeneration therapy. However, this inevitably induces macrophage-mediated immune response against the graft, limiting its therapeutic efficacy. Monitoring the magnitude of the immune response using imaging tools would be useful for prolonging graft survival and increasing the therapy longevity. Minimally invasive quantitative detection of activated macrophages by medical imaging technologies such as positron emission tomography (PET) imaging targets translocator protein (TSPO), which is highly expressed on mitochondrial membrane, especially in activated macrophage. N,N-diethyl-2-[4-(2-fluoroethoxy) phenyl]-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-acetamide (DPA-714) is known as a TSPO ligand used in clinical settings. We herein hypothesized that immune rejection of the transplanted iPSC-derived cardiomyocytes (iPSC-CMs) of allogeneic origin may be quantitated using 18

Heart, lung & circulation, Jan 7, 2015

It is well-documented that persistent myocardial hypertrophy in patients with aortic stenosis is ... more It is well-documented that persistent myocardial hypertrophy in patients with aortic stenosis is related to suboptimal postoperative outcomes after aortic valve replacement. Although diabetes is known to potentially exacerbate myocardial hypertrophy, it has yet to be examined if it affects postoperative left ventricular mass regression (LVMR). A single-centre, retrospective analysis was performed on 183 consecutive patients who underwent either surgical or transcatheter aortic valve replacement between 2010 and May 2013. Patient demographics, postoperative outcomes and echocardiographic data were obtained preoperatively and a year after surgery. There were 42 diabetic and 141 non-diabetic patients. Preoperative characteristics of diabetic patients were statistically similar to those of non-diabetic patients, except for higher prevalence of hyperlipidaemia (p <0.001) and history of cerebrovascular disorder (p=0.046) in diabetic patients. Median value of postoperative LVMR of all p...

Journal of artificial organs : the official journal of the Japanese Society for Artificial Organs, Jan 13, 2015

We recently reported a multi-center, single-arm, phase II study that evaluated the efficacy and s... more We recently reported a multi-center, single-arm, phase II study that evaluated the efficacy and safety of autologous skeletal myoblast sheet (TCD-51073) transplantation. The advantage of this procedure over a control group has not yet been analyzed. Seven patients with advanced heart failure due to ischemic etiology (TCD-51073 group, New York Heart Association (NYHA) class III; left ventricular ejection fraction (LVEF) <35 %) refractory to optimal medical and coronary revascularization therapy, received TCD-51073 at 3 study centers between 2012 and 2013 with a 2-year follow-up period. As previously reported, 112 patients received cardiac resynchronization therapy (CRT) with follow-up at the University of Tokyo Hospital between 2007 and 2014. Of them, 21 patients were selected for the control group by propensity score matching. No significant difference in baseline variables between the groups was observed. LVEF and NYHA class improved significantly in the TCD-51073 group during t...

Circulation journal, Nov 25, 2022

on behalf of the Japanese HeartMateII Investigators Background: The objective of this study is to... more on behalf of the Japanese HeartMateII Investigators Background: The objective of this study is to investigate the effect of preoperative diabetes on all-cause mortality and major postoperative complications among patients with continuous-flow left ventricular assist device (LVAD) by using data from a national database. Methods and Results: The 545 study patients who underwent primary HeartMateII implantation between 2013 and 2019 were divided into 2 groups according to their diabetes mellitus (DM) status; patients with DM (n=116) and patients without DM (n=429). First, the on-device survival and incidence of adverse events were evaluated. Second, after adjusting for patients' backgrounds, the change of laboratory data in the 2 groups were compared. Overall, on-device survival at 1, 2, and 3 years was almost equivalent between the 2 groups; it was 95%, 94%, and 91% in patients without DM, and 93%, 91%m and 91% in patients with DM (P=0.468) The incidence of adverse events was similar between 2 groups of patients, except for driveline exit site infection in the adjusted cohort. Cox proportional hazards regression analysis revealed younger age (HR: 0.98 (95% confidence interval (CI): 0.97-0.99, P=0.001) and presence of DM (HR: 1.83 (95% CI: 1.14-2.88), P=0.016) as significant predictors of driveline infection. Laboratory findings revealed no differences between groups throughout the periods. Conclusions: The clinical results after LVAD implantation in DM patients were comparable with those in non-DM patients, except for the driveline exit site infection.

Medicina, 2020

Background: Left ventricular assist device (LVAD) therapy has improved the clinical outcomes in a... more Background: Left ventricular assist device (LVAD) therapy has improved the clinical outcomes in advanced heart failure patients, however, this may differ between countries. We aimed to compare outcomes between Japanese and US LVAD cohorts. Methods: For 416 consecutive LVAD patients who received HeartMate II LVAD implantation and completed a one-year follow-up, age-matched Japanese patients (the Japanese registry for mechanically assisted circulatory support (J-MACS) group) and the US patients were compared for their clinical outcomes. Results: 154 J-MACS patients and 77 US patients were compared. Survival, free from hemocompatibility-related adverse events (HRAEs) in the J-MACS was statistically comparable with the US (75% vs. 63%, p = 0.79). J-MACS had more disabling strokes than the US (0.221 vs. 0.052/patient-year, p = 0.005), whereas there was less nonsurgical bleeding (0.045 vs. 0.117/patient-year, p = 0.024). The net hemocompatibility score was statistically comparable between...

Journal of Artificial Organs, 2020

The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation, 2018

The Jarvik 2000 ventricular assist device features a miniaturized intraventricular pump and an in... more The Jarvik 2000 ventricular assist device features a miniaturized intraventricular pump and an intermittent low-speed function that facilitates aortic valve opening. Despite its long history, little is known about the Jarvik device with regard to post-implantation outcomes. Prospectively collected data from 13 participating hospitals were extracted from the Japanese Registry for Mechanically Assisted Circulatory Support database to analyze mortality, morbidity and de-novo aortic regurgitation. Data on 83 patients who underwent implantation of the Jarvik 2000 were reviewed. Median support duration was 191 (maximum 758) days. All recipients underwent implantation as a bridge to transplantation. Overall survival proportions at 1 and 2 years were 85.0% and 79.3%, respectively. Nine patients were in INTERMACS Level 1, and 28 patients were on mechanical circulatory support at the time of implantation. Causes of death included stroke, infection and device malfunction. Three patients had th...

Tissue Engineering Part A, 2015

Introduction: Bone marrow-derived autologous human mesenchymal stem cells (MSCs) are one of the m... more Introduction: Bone marrow-derived autologous human mesenchymal stem cells (MSCs) are one of the most promising cell sources for cell therapy to treat heart failure. The cell sheet technique has allowed transplantation of a large number of cells and enhanced the efficacy of cell therapy. We hypothesized that the transplantation of MSC sheets may be a feasible, safe, and effective treatment for ischemic cardiomyopathy (ICM). Methods and Results: Human MSCs acquired from bone marrow were positive for CD73, CD90, and CD105 and negative for CD11b and CD45 by flow cytometry. Ten MSC sheets were created from a total cell number of 1 • 10 8 MSCs using temperature-responsive culture dishes. These were successfully transplanted over the infarct myocardium of porcine ICM models induced by placing an ameroid constrictor on the left anterior descending coronary artery without any procedural-related complications (MSC group = 6: sheet transplantation; sham group = 6, oral intake of tacrolimus in both groups). Premature ventricular contractions were rarely detected by Holter electrocardiogram (ECG) in the MSC group in the first week after transplantation. On echocardiography, the cardiac performance of the MSC group was significantly better than that of the sham group at 8 weeks after transplantation. On histological examination 8 weeks after transplantation, left ventricular (LV) remodeling was significantly attenuated compared with the sham group (cardiomyocyte size and interstitial fibrosis were measured). Immunohistochemistry of the von Willebrand factor showed that the vascular density in the infarct border area was significantly greater in the MSC group than the sham group. Expression of angiogenesis-related factors in the infarct border area of the MSC group was significantly greater than that of the sham group, as measured by real-time polymerase chain reaction. Conclusions: Bone marrow-derived MSC sheets improved cardiac function and attenuated LV remodeling in ICM without major complications, indicating that this strategy would be applicable in clinical settings.

Heart failure reviews, Jan 24, 2015

Cardiac failure is a major cause of mortality and morbidity worldwide, since the standard treatme... more Cardiac failure is a major cause of mortality and morbidity worldwide, since the standard treatment for cardiac failure in the clinical practice is chiefly to focus on removal of insults against the heart or minimisation of additional factors to exacerbate cardiac failure, but not on regeneration of the damaged cardiac tissue. A synthetic prostacyclin agonist, ONO-1301, has been developed as a long-acting drug for acute and chronic pathologies related to regional ischaemia, inflammation and/or interstitial fibrosis by pre-clinical studies. In addition, poly-lactic co-glycolic acid-polymerised form of ONO-1301, ONO-1301SR, was generated to achieve a further sustained release of this drug into the targeted region. This unique reagent has been shown to act on fibroblasts, vascular smooth muscle cells and endothelial cells in the tissue via the prostaglandin IP receptor to exert paracrinal release of multiple protective factors, such as hepatocyte growth factor, vascular endothelial gro...

BioMed research international, 2013

Heart failure is a life-threatening disorder worldwide and many papers reported about myocardial ... more Heart failure is a life-threatening disorder worldwide and many papers reported about myocardial regeneration through surgical method induced by LVAD, cellular cardiomyoplasty (cell injection), tissue cardiomyoplasty (bioengineered cardiac graft implantation), in situ engineering (scaffold implantation), and LV restrictive devices. Some of these innovated technologies have been introduced to clinical settings. Especially, cell sheet technology has been developed and has already been introduced to clinical situation. As the first step in development of cell sheet, neonatal cardiomyocyte sheets were established and these sheets showed electrical and histological homogeneous heart-like tissue with contractile ability in vitro and worked as functional heart muscle which has electrical communication with recipient myocardium in small animal heart failure model. Next, as a preclinical study, noncontractile myoblast sheets have been established and these sheets have proved to secrete multi...

Circulation Journal, 2012

Background: This report details experience of the conversion of the Toyobo left ventricular assis... more Background: This report details experience of the conversion of the Toyobo left ventricular assist device (LVAD; Nipro, Osaka, Japan) to the DuraHeart LVAD (TerumoHeart, Ann Arbor, MI, USA) in patients awaiting heart transplantation. Methods and Results: Eight patients (4 male, 4 female) with Toyobo paracorporeal LVAD underwent conversion to the third-generation centrifugal (DuraHeart) LVAD. The apical cuff of the Toyobo was not exchanged because the size was the same as that of the DuraHeart. All conversion operations were performed safely, but 3 patients who had infection of the Toyobo LVAD cannulation site prior to conversion suffered later pocket infections and 1 patient died because of sepsis. One patient underwent heart transplantation and 6 of 8 patients were awaiting heart transplantation at home. Conclusions: Conversions from the Toyobo LVAD to the DuraHeart LVAD were performed safely. Considering that implantable LVADs provide superior long-term survival and quality of life, conversion is a reasonable decision for Toyobo LVAD users in whom there are no infections.

Circulation, 2011

Background— We assessed changes in left ventricular (LV) volume and function and in regional myoc... more Background— We assessed changes in left ventricular (LV) volume and function and in regional myocardial wall stress in noninfarcted segments after restrictive mitral annuloplasty (RMA) with or without surgical ventricular restoration (SVR). Methods and Results— Thirty-nine patients with ischemic cardiomyopathy (ejection fraction ≤0.35) and severe mitral regurgitation (≥3) were studied before and 2.8 months after surgery with cine-angiographic multidetector computed tomography (cine-MDCT). Eighteen underwent RMA alone (RMA group) and 21 underwent RMA and SVR (RMA+SVR group). In addition to measuring conventional parameters (LV end-diastolic volume index [LVEDVI], LV end-systolic volume index [LVESVI], and LV ejection fraction), we evaluated the regional circumferential end-systolic wall stress and mean circumferential fiber shortening in both the basal and mid-LV regions using 3-dimensional cine-MDCT images. LV end-diastolic and end-systolic volume indexes were significantly greater ...

Cardiovascular Research, 2006

Objectives: Cell therapy is a promising strategy for ischemic cardiomyopathy. However, the direct... more Objectives: Cell therapy is a promising strategy for ischemic cardiomyopathy. However, the direct injection method has limitations for generalized cell delivery, especially in dilated cardiomyopathy (DCM). We hypothesized that a sheet-shaped myoblast graft would be superior to direct injection for improving cardiac performance in DCM. Methods: Male 27-week-old BIO TO-2 (DCM) hamsters that showed moderate cardiac remodeling were used as recipients. Myoblasts isolated from BIO F1B hamsters were cultured on dishes coated with poly(N-isopropylacrylamide), a temperature-responsive polymer, and spontaneously detached as a sheet-shaped graft at 20-C without enzymatic treatment. Three different therapies were conducted: (1) sheetshaped myoblast graft implantation (S group, n = 29); (2) myoblast injection (M group, n = 28); and (3) sham operation (C group, n = 28). In the S group, two sheet-shaped myoblast grafts were implanted on the left ventricle (LV) wall, and in the M group, myoblasts were injected into the right ventricle (RV) and LV walls. Results: After the sheet-shaped myoblast grafts were implanted, echocardiography demonstrated that the dilated LV dimension was significantly reduced, whereas the hearts in other groups showed a progression of LV dilation. The fractional shortening in the M and C groups decreased significantly while that in the S group was maintained at the preoperative level for 3 months after the operation. Histological examination demonstrated that in the S group, the LV wall thickness was increased, with viable myoblasts, and myocardial fibrosis was decreased compared with the other groups. Immunohistochemical staining demonstrated alpha-sarcoglycan and beta-sarcoglycan expression on the basement membrane of the cardiomyocytes in the S group but not in the other groups. The life expectancy was significantly prolonged in the S group. Conclusion: Sheet-shaped myoblast graft implantation improved cardiac performance and prolonged life expectancy, associated with a reduction in myocardial fibrosis and reorganization of the cytoskeletal proteins in DCM hamsters. Thus, sheet-shaped autologous myoblast graft implantation may induce restoration of the heart in DCM.

Circulation, Nov 10, 2015

Introduction: We recently reported a multi-center, single-arm, phase II study that evaluated the ... more Introduction: We recently reported a multi-center, single-arm, phase II study that evaluated the efficacy and safety of autologous skeletal myoblast sheet (TCD-51073) transplantation. The advantage of this procedure over a control group has not yet been analyzed. Hypothesis: TCD-51073 has better clinical outcome compared with background-matched control group. Methods: Seven patients with advanced heart failure due to ischemic etiology (TCD-51073 group, New York Heart Association [NYHA] class III; left ventricular ejection fraction (LVEF) &amp;lt;35%) refractory to optimal medical and coronary revascularization therapy, received TCD-51073 at 3 study centers between 2012 and 2013 with a 2-year follow-up period. As previously reported, 112 patients received cardiac resynchronization therapy (CRT) with follow-up at the University of Tokyo Hospital between 2007 and 2014. Results: Of them, 21 patients were selected for the control group by propensity score matching. No significant difference in baseline variables between the groups was observed. LVEF and NYHA class improved significantly in the TCD-51073 group during the 6-month study period (p&amp;lt;0.05). During the 2-year follow-up, 7 patients (33%) in the CRT group and no patient in the TCD-51073 group died due to cardiac disease or received VAD implantation (p=0.128 by the log-rank test). Conclusions: Transplantation of TCD-51073 is clinically advantageous in facilitating LV reverse remodeling, improving HF symptoms, and preventing cardiac death in patients with ischemic etiology when compared to background-matched patients receiving CRT.

Interactive cardiovascular and thoracic surgery, Jan 18, 2018

We previously reported that cell sheet transplantation combined with an omentopexy (OP) procedure... more We previously reported that cell sheet transplantation combined with an omentopexy (OP) procedure is more effective for repairing heart damage when compared with cell sheet transplantation alone. However, a simultaneous (conventional) laparotomy as part of the OP may adversely affect the general condition of critically ill heart failure patients who would otherwise benefit from cell sheet transplantation, which is a paradox to be reconciled before this treatment can be applied in a clinical setting. We devised a novel endoscopic approach termed 'transphrenic peritoneoscopy' (TPP) for minimal access to abdominal organs from the thoracic cavity. Herein, we evaluated the feasibility and safety of TPP with an OP in a porcine myocardial infarction model. Myocardial infarction was induced in 4 mini pigs by placing an ameroid constrictor around the left anterior descending artery. One month later, a left thoracotomy was performed in 2 randomly selected mini pigs, and a laparoscopic...

Circulation Journal, 2017

Japanese patients underwent continuous-flow LVAD implantation for endstage heart failure. All pat... more Japanese patients underwent continuous-flow LVAD implantation for endstage heart failure. All patients and family members provided informed consent to participate in related clinical studies. Follow-up data were collected for 0-4.84 years [mean, 1.70±1.12 years; median, 1.54 years; interquartile range (IQR), 0.70-2.62 years)]. All follow-up examinations were completed by April 30, 2017. Devices and Surgical Procedures The type of LVAD utilized was decided at the preoperative conference, though available devices have changed over time in Japan. Briefly,

PloS one, 2017

It has been shown that the size of myocardial infarction in rats created by coronary ligation tec... more It has been shown that the size of myocardial infarction in rats created by coronary ligation technique is not uniform, varying from 4% to 65%. We hypothesized that infarct size variability induced by coronary artery ligation might be caused by coronary artery branching pattern. Coronary artery angiography was performed in 50 normal Lewis rats and in chronic myocardial infarction models in which coronary artery was ligated immediately below the left atrial appendage or 2mm distal to the left atrial appendage (n = 25 for each), followed by histological analysis. Unlike the human, the rats had a single major septal artery arising from the proximal part of the left coronary artery (n = 30) or right coronary artery (n = 20). There were three branching patterns of left circumflex artery (LCX): 33 (66%) had LCX branching peripherally from a long left main coronary artery (LMCA), while the remainder 17 (34%) had the LCX branching from the proximal part of the septal artery or a short LMCA....

PloS one, 2017

The sympathetic nervous system is critical in maintaining the normal physiological function of th... more The sympathetic nervous system is critical in maintaining the normal physiological function of the heart. Its dysfunction in pathological states may exacerbate the substrate for arrhythmias. Obviously, knowledge of its three-dimensional (3D) structure is important, however, it has been revealed by conventional methods only to a limited extent. In this study, a new method of tissue clearance in combination with immunostaining unravels the 3D structure of the sympathetic cardiac network as well as its changes after myocardial infarction. Hearts isolated from adult male mice were optically cleared using the CUBIC-perfusion protocol. After making the hearts transparent, sympathetic nerves and coronary vessels were immunofluorescently labeled, and then images were acquired. The spatial distribution of sympathetic nerves was visualized not only along the epicardial surface, but also transmurally. They were distributed over the epicardial surface and penetrated into the myocardium to twist...

The Journal of thoracic and cardiovascular surgery, Jan 24, 2017

The angiogenic potential of endothelial progenitor cells (EPCs) may be limited by the absence of ... more The angiogenic potential of endothelial progenitor cells (EPCs) may be limited by the absence of their natural biologic foundation, namely smooth muscle pericytes. We hypothesized that joint delivery of EPCs and smooth muscle cells (SMCs) in a novel, totally bone marrow-derived cell sheet will mimic the native architecture of a mature blood vessel and act as an angiogenic construct to limit post infarction ventricular remodeling. Primary EPCs and mesenchymal stem cells were isolated from bone marrow of Wistar rats. Mesenchymal stem cells were transdifferentiated into SMCs by culture on fibronectin-coated culture dishes. Confluent SMCs topped with confluent EPCs were detached from an Upcell dish to create a SMC-EPC bi-level cell sheet. A rodent model of ischemic cardiomyopathy was then created by ligating the left anterior descending artery. Rats were randomized into 3 groups: cell sheet transplantation (n = 9), no treatment (n = 12), or sham surgery control (n = 7). Four weeks posti...

Circulation journal : official journal of the Japanese Circulation Society, Jan 16, 2017

Coronary artery bypass grafting (CABG) reduces functional mitral regurgitation (MR) associated wi... more Coronary artery bypass grafting (CABG) reduces functional mitral regurgitation (MR) associated with ischemic heart disease, although the predictive factors or mechanisms of reversibility of functional MR after CABG are not fully understood.We investigated whether mitral valve structure is associated with the outcome of functional MR after CABG.Methods and Results:From a consecutive series of 98 patients with mild-moderate functional MR preoperatively who underwent isolated CABG, we enrolled 66 patients who were followed up for >1 year postoperatively using echocardiography. The degree of MR was reduced in 34 patients (52%) postoperatively, in association with a lower rate of in-hospital treatment for cardiac failure in the long term, compared with the 32 patients (48%) with residual MR postoperatively. The patients with reduced MR postoperatively had longer estimated coaptation length and more anteriorly or centrally directed MR jets than those without reduced MR. On statistical ...

PLOS ONE, 2016

Allogeneic transplantation (Tx) of induced pluripotent stem cells (iPSCs) is a promising tissue r... more Allogeneic transplantation (Tx) of induced pluripotent stem cells (iPSCs) is a promising tissue regeneration therapy. However, this inevitably induces macrophage-mediated immune response against the graft, limiting its therapeutic efficacy. Monitoring the magnitude of the immune response using imaging tools would be useful for prolonging graft survival and increasing the therapy longevity. Minimally invasive quantitative detection of activated macrophages by medical imaging technologies such as positron emission tomography (PET) imaging targets translocator protein (TSPO), which is highly expressed on mitochondrial membrane, especially in activated macrophage. N,N-diethyl-2-[4-(2-fluoroethoxy) phenyl]-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-acetamide (DPA-714) is known as a TSPO ligand used in clinical settings. We herein hypothesized that immune rejection of the transplanted iPSC-derived cardiomyocytes (iPSC-CMs) of allogeneic origin may be quantitated using 18

Heart, lung & circulation, Jan 7, 2015

It is well-documented that persistent myocardial hypertrophy in patients with aortic stenosis is ... more It is well-documented that persistent myocardial hypertrophy in patients with aortic stenosis is related to suboptimal postoperative outcomes after aortic valve replacement. Although diabetes is known to potentially exacerbate myocardial hypertrophy, it has yet to be examined if it affects postoperative left ventricular mass regression (LVMR). A single-centre, retrospective analysis was performed on 183 consecutive patients who underwent either surgical or transcatheter aortic valve replacement between 2010 and May 2013. Patient demographics, postoperative outcomes and echocardiographic data were obtained preoperatively and a year after surgery. There were 42 diabetic and 141 non-diabetic patients. Preoperative characteristics of diabetic patients were statistically similar to those of non-diabetic patients, except for higher prevalence of hyperlipidaemia (p <0.001) and history of cerebrovascular disorder (p=0.046) in diabetic patients. Median value of postoperative LVMR of all p...

Journal of artificial organs : the official journal of the Japanese Society for Artificial Organs, Jan 13, 2015

We recently reported a multi-center, single-arm, phase II study that evaluated the efficacy and s... more We recently reported a multi-center, single-arm, phase II study that evaluated the efficacy and safety of autologous skeletal myoblast sheet (TCD-51073) transplantation. The advantage of this procedure over a control group has not yet been analyzed. Seven patients with advanced heart failure due to ischemic etiology (TCD-51073 group, New York Heart Association (NYHA) class III; left ventricular ejection fraction (LVEF) <35 %) refractory to optimal medical and coronary revascularization therapy, received TCD-51073 at 3 study centers between 2012 and 2013 with a 2-year follow-up period. As previously reported, 112 patients received cardiac resynchronization therapy (CRT) with follow-up at the University of Tokyo Hospital between 2007 and 2014. Of them, 21 patients were selected for the control group by propensity score matching. No significant difference in baseline variables between the groups was observed. LVEF and NYHA class improved significantly in the TCD-51073 group during t...