[Background] We recently reported that mouse and human iPS cells could be generated from somatic ... more [Background] We recently reported that mouse and human iPS cells could be generated from somatic cells by gene transfer of Oct3/4, Sox2, c-Myc and Klf4. Although the morphology, growth characteristics and pluripotency of iPS cells are believed to be similar to those of ES cells, there are several versions such as Fbx-iPS, Nanog-iPS cells, and it remains unknown whether what type of iPS cell could be appropriate for the cardiovascular regeneration therapy. This study investigated the cardiomyocyte differentiation potential of mouse iPS cells, molecular characterization of iPS-induced cardiomyocytes, and the safety and feasibility of their transplantation into the heart. [Methods and Results] We used several lines of Fbx-iPS and Nanog-iPS cells and induced cardiomyocyte differentiation using the hanging drop culture method. Mouse ES cells were used as control. Both Fbx-iPS and Nanog-iPS cells could differentiate into cardiomyocytes, and the incidence of beating embryoid bodies was similar to that of ES cells. RT-PCR analyses and immunohistochemistry revealed that both iPS cells expressed all the cardiomyocyte marker genes including Nkx2.5, GATA4, MEF2C, myosin light chain-2v, α-myosin heavy chain, atrial natriuretic peptide, and α-sarcomeric actinin, and they showed normal structures. Electron microscopic study revealed that iPS cell derived cardiomyocytes had the typical morphological cardiomyocyte structure, which is difficult to distinguish from that of ES cell derived cells. Electrical physiological study showed that iPS cell derived cardiomyocytes had sinus node-like or fetal ventricular type action potentials. Purified iPS cell derived cardiomyocytes could be successfully transplanted into murine hearts and the engrafted cells survived and were integrated into host myocardium. Nanog-iPS cell derived cells showed no severe complication after transplantation, however Fbx-iPS cell derived cells showed teratoma in the host tissue. Fbx-iPS cells expressed extrinsic c-myc after differentiation. [Conclusions] The iPS cells proved to be an attractive cell source for the regeneration of cardiomyocytes, however safety and careful characterization is necessary before clinical application.
Although BTB/POZ family proteins play a critical role in the development of various organs, and a... more Although BTB/POZ family proteins play a critical role in the development of various organs, and are recently known as a substrate adaptor of CUL3 ubiquitin ligases, the involvement of these proteins in heart development remains unknown. We recently isolated the novel protein, RhoBTB3, an 83-kD protein which comprises an N-terminal Rho GTPase resembling domain and two tandem BTB domains. The purpose of this study was to investigate the molecular and functional characteristics of this protein in mice heart. [Methods and Results] RhoBTB3 was faintly expressed in the embryonic heart, but was strongly expressed in the adult heart. It was weakly expressed in adult brain and testis. RhoBTB3-GFP fusion protein cDNA was transfected into primary cultured rat cardiomyocytes using adenovirus. Fluorescence microscopy revealed that RhoBTB3 was located at the cytoplasm of living cardiomyocytes. HA-tagged RhoBTB3 and MYC-tagged CUL family proteins (1 – 5) were co-transfected into COS7 cells. RhoBTB...
Although extracorporeal life support (ECLS) is utilized for acute hemodynamic collapse, clinical ... more Although extracorporeal life support (ECLS) is utilized for acute hemodynamic collapse, clinical outcomes for such patients are uncertain. The present study examined 30-day clinical outcomes in patients treated with ECLS for acute hemodynamic collapse, and determined the factors associated with 30-day mortality in patients who required ECLS for cardiopulmonary arrest (CPA). A total of 200 patients, in whom emergency ECLS was utilized for acute hemodynamic collapse from 2006 to 2015, were analyzed retrospectively. The impact of CPA on all-cause 30-day death in the overall population was examined by multivariable logistic regression analysis; comparisons were made between 30-day survivors (n = 78) and non-survivors (n = 122). In addition, clinical factors associated with 30-day survival for patients in whom ECLS was utilized for CPA (n = 139) were examined. All-cause 30-day mortality in the overall study population was 61 % (122/200). CPA was the most common cause of ECLS requirement ...
Collateral filling of chronic total occlusion (CTO) segments is considered to affect hemodynamic ... more Collateral filling of chronic total occlusion (CTO) segments is considered to affect hemodynamic stability in primary percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI) with CTO, however its value as a prognostic indicator for mortality is uncertain. The present study examined the relationship between collateral filling of CTO segments and short-term mortality in patients with STEMI with a comorbid CTO lesion. Among 829 STEMI patients who underwent primary PCI, 74 patients with CTO were identified. Collateral filling of their CTO segment was assessed by Rentrop grade (0; n=10, 1; n=13, 2; n=31, 3; n=20) in their initial angiogram and whether the origin of the feeding collateral donor artery was infarct-related artery (IRA) was evaluated using their final angiogram in primary PCI; IRA (n=26) and non-IRA group (n=48). The relationship between these classifications and 30-day all-cause mortality was examined retrospectively. The 30-day mortalities w...
Cardiovascular Intervention and Therapeutics, 2016
The aim of this study is to evaluate differences in stent endothelial coverage among the second g... more The aim of this study is to evaluate differences in stent endothelial coverage among the second generation of drug-eluting stents. Incomplete stent coverage is one of the major causes of late stent thrombosis. Rabbits fed a normal diet received an everolimus (Xience Prime; EES) and a zotarolimus-eluting stent (Resolute Integrity; R-ZES) in each iliac artery, followed by sacrifice at 14 and 28 days after stent implantation. In addition, a group of atherosclerotic rabbits similarly received EES and R-ZES, and were sacrificed at 28 days. The extent of stent endothelial coverage was assessed by scanning electron microscopy. To evaluate endothelial coverage after bifurcation stenting, rabbits received EES and R-ZES placed with culotte stenting at the iliac bifurcation, followed by sacrifice at 14 and 28 days. In rabbits fed a normal diet, the percent uncovered strut area 14 days after stent implantation was significantly higher in R-ZES than in EES (10.1% (IQR 9.8-15.5) vs. 3.0% (IQR 1.5-9.7), p = 0.03), whereas it was not significantly different at 28-days (3.9% (IQR 0.8-10.3) vs. 1.0% (IQR 0.0-2.8), p = 0.2). In rabbits with induced atheroma, R-ZES also showed less endothelial coverage 28 days after stent implantation (5.3% (IQR 2.2-9.9) vs. 1.1% (IQR 0-6.2), p = 0.03). In the culotte stenting model, the percent uncovered strut area of the proximal overlapped segment was significantly higher in R-ZES at 14 days (15.8% (IQR 14.3-17.7) vs. 8.8% (IQR 8.3-9.8), p = 0.03) and 28 days (9.9% (IQR 4.1-13.9) vs. 2.5% (IQR 1.6-6.7), p = 0.04) after stent implantation. The carina area also showed a better coverage in EES compared with R-ZES. EES showed a better stent endothelial coverage compared with R-ZES after stent implantation in the early phase in normals, in arteries with lipid rich plaque, and in bifurcation stented sites.
Journal of the American College of Cardiology, Jan 15, 2017
Transcatheter aortic valve replacement (TAVR) in patients with bicuspid aortic valve stenosis (AS... more Transcatheter aortic valve replacement (TAVR) in patients with bicuspid aortic valve stenosis (AS) is being increasingly performed. From the Bicuspid AS TAVR multicenter registry, the procedural and clinical outcomes in patients with bicuspid versus tricuspid AS were compared. Outcomes of 561 patients with bicuspid AS and 4,546 patients with tricuspid AS were compared after propensity-score matching assembling 546 pairs of patients with similar baseline characteristics. Procedural and clinical outcomes were recorded according to VARC-2 criteria. Compared to patients with tricuspid AS, patients with bicuspid AS had more frequent conversion to surgery (2.0% vs. 0.2%; p=0.006) and significantly lower device success rate (85.3% vs. 91.4%; p=0.002). Early generation devices (Sapien XT/CoreValve) were implanted in 320 patients with bicuspid and 321 patients with tricuspid AS whereas new generation devices (Sapien 3/Lotus/Evolut R) were implanted in 226 and 225 patients with bicuspid and t...
Scarce data are available on the impact of age on transcatheter aortic valve implantation (TAVI) ... more Scarce data are available on the impact of age on transcatheter aortic valve implantation (TAVI) outcomes. We therefore, analyzed 1,845 consecutive patients from 9 Italian centers who underwent TAVI with the Corevalve Revalving System from September 2007 to March 2014; patients were dichotomized according to their age in the date of the procedure, as follows: 75 to 85 years old and >85 years old. End points were defined according to Valve Academic Research Consortium definitions. In-hospital, 30-day, and 1-year clinical and echocardiographic data were available for 100% of the patients included. Propensity matching was performed. Procedural success rates were high (>94%) and comparable between groups. Although worse baseline renal function was observed in the older group, the incidence of acute kidney injury after procedure was comparable (17.1% and 17.4%, respectively for the 75- to 85- and >85-year-old group, p = 0.877); importantly, >99% of acute kidney injury episode...
[Background] We recently reported that human induced pluripotent stem (iPS) cells can be induced ... more [Background] We recently reported that human induced pluripotent stem (iPS) cells can be induced to differentiate into cardiomyocytes, and characterized their phenotype. Future investigation of hum...
Cardiovascular intervention and therapeutics, Jan 28, 2016
The purpose of this study is to determine reduction of door-to-balloon (D2B) time using a single ... more The purpose of this study is to determine reduction of door-to-balloon (D2B) time using a single universal guiding catheter (Ikari-Left catheter) in transradial approach. In this procedure, we can skip a total of five steps compared with a conventional procedure (two catheter insertions, two catheter removals, and one catheter engagement). Reducing total ischemic time is important to achieving a better outcome in primary percutaneous coronary intervention (PCI) for ST segment elevation myocardial infarction (STEMI). We retrospectively compared 30 consecutive STEMI patients who underwent transradial primary PCI with a single guiding catheter (IL group) with 30 consecutive patients with conventional transradial primary PCI. Patients with cardiogenic shock, heart failure, or need for intra-aortic balloon pumping support before primary PCI were excluded. Baseline characteristics were not different between the two groups. The D2B time was significantly shorter in the IL group (55 ± 16 vs...
[Background] We recently reported that mouse and human iPS cells could be generated from somatic ... more [Background] We recently reported that mouse and human iPS cells could be generated from somatic cells by gene transfer of Oct3/4, Sox2, c-Myc and Klf4. Although the morphology, growth characteristics and pluripotency of iPS cells are believed to be similar to those of ES cells, there are several versions such as Fbx-iPS, Nanog-iPS cells, and it remains unknown whether what type of iPS cell could be appropriate for the cardiovascular regeneration therapy. This study investigated the cardiomyocyte differentiation potential of mouse iPS cells, molecular characterization of iPS-induced cardiomyocytes, and the safety and feasibility of their transplantation into the heart. [Methods and Results] We used several lines of Fbx-iPS and Nanog-iPS cells and induced cardiomyocyte differentiation using the hanging drop culture method. Mouse ES cells were used as control. Both Fbx-iPS and Nanog-iPS cells could differentiate into cardiomyocytes, and the incidence of beating embryoid bodies was similar to that of ES cells. RT-PCR analyses and immunohistochemistry revealed that both iPS cells expressed all the cardiomyocyte marker genes including Nkx2.5, GATA4, MEF2C, myosin light chain-2v, α-myosin heavy chain, atrial natriuretic peptide, and α-sarcomeric actinin, and they showed normal structures. Electron microscopic study revealed that iPS cell derived cardiomyocytes had the typical morphological cardiomyocyte structure, which is difficult to distinguish from that of ES cell derived cells. Electrical physiological study showed that iPS cell derived cardiomyocytes had sinus node-like or fetal ventricular type action potentials. Purified iPS cell derived cardiomyocytes could be successfully transplanted into murine hearts and the engrafted cells survived and were integrated into host myocardium. Nanog-iPS cell derived cells showed no severe complication after transplantation, however Fbx-iPS cell derived cells showed teratoma in the host tissue. Fbx-iPS cells expressed extrinsic c-myc after differentiation. [Conclusions] The iPS cells proved to be an attractive cell source for the regeneration of cardiomyocytes, however safety and careful characterization is necessary before clinical application.
Although BTB/POZ family proteins play a critical role in the development of various organs, and a... more Although BTB/POZ family proteins play a critical role in the development of various organs, and are recently known as a substrate adaptor of CUL3 ubiquitin ligases, the involvement of these proteins in heart development remains unknown. We recently isolated the novel protein, RhoBTB3, an 83-kD protein which comprises an N-terminal Rho GTPase resembling domain and two tandem BTB domains. The purpose of this study was to investigate the molecular and functional characteristics of this protein in mice heart. [Methods and Results] RhoBTB3 was faintly expressed in the embryonic heart, but was strongly expressed in the adult heart. It was weakly expressed in adult brain and testis. RhoBTB3-GFP fusion protein cDNA was transfected into primary cultured rat cardiomyocytes using adenovirus. Fluorescence microscopy revealed that RhoBTB3 was located at the cytoplasm of living cardiomyocytes. HA-tagged RhoBTB3 and MYC-tagged CUL family proteins (1 – 5) were co-transfected into COS7 cells. RhoBTB...
Although extracorporeal life support (ECLS) is utilized for acute hemodynamic collapse, clinical ... more Although extracorporeal life support (ECLS) is utilized for acute hemodynamic collapse, clinical outcomes for such patients are uncertain. The present study examined 30-day clinical outcomes in patients treated with ECLS for acute hemodynamic collapse, and determined the factors associated with 30-day mortality in patients who required ECLS for cardiopulmonary arrest (CPA). A total of 200 patients, in whom emergency ECLS was utilized for acute hemodynamic collapse from 2006 to 2015, were analyzed retrospectively. The impact of CPA on all-cause 30-day death in the overall population was examined by multivariable logistic regression analysis; comparisons were made between 30-day survivors (n = 78) and non-survivors (n = 122). In addition, clinical factors associated with 30-day survival for patients in whom ECLS was utilized for CPA (n = 139) were examined. All-cause 30-day mortality in the overall study population was 61 % (122/200). CPA was the most common cause of ECLS requirement ...
Collateral filling of chronic total occlusion (CTO) segments is considered to affect hemodynamic ... more Collateral filling of chronic total occlusion (CTO) segments is considered to affect hemodynamic stability in primary percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI) with CTO, however its value as a prognostic indicator for mortality is uncertain. The present study examined the relationship between collateral filling of CTO segments and short-term mortality in patients with STEMI with a comorbid CTO lesion. Among 829 STEMI patients who underwent primary PCI, 74 patients with CTO were identified. Collateral filling of their CTO segment was assessed by Rentrop grade (0; n=10, 1; n=13, 2; n=31, 3; n=20) in their initial angiogram and whether the origin of the feeding collateral donor artery was infarct-related artery (IRA) was evaluated using their final angiogram in primary PCI; IRA (n=26) and non-IRA group (n=48). The relationship between these classifications and 30-day all-cause mortality was examined retrospectively. The 30-day mortalities w...
Cardiovascular Intervention and Therapeutics, 2016
The aim of this study is to evaluate differences in stent endothelial coverage among the second g... more The aim of this study is to evaluate differences in stent endothelial coverage among the second generation of drug-eluting stents. Incomplete stent coverage is one of the major causes of late stent thrombosis. Rabbits fed a normal diet received an everolimus (Xience Prime; EES) and a zotarolimus-eluting stent (Resolute Integrity; R-ZES) in each iliac artery, followed by sacrifice at 14 and 28 days after stent implantation. In addition, a group of atherosclerotic rabbits similarly received EES and R-ZES, and were sacrificed at 28 days. The extent of stent endothelial coverage was assessed by scanning electron microscopy. To evaluate endothelial coverage after bifurcation stenting, rabbits received EES and R-ZES placed with culotte stenting at the iliac bifurcation, followed by sacrifice at 14 and 28 days. In rabbits fed a normal diet, the percent uncovered strut area 14 days after stent implantation was significantly higher in R-ZES than in EES (10.1% (IQR 9.8-15.5) vs. 3.0% (IQR 1.5-9.7), p = 0.03), whereas it was not significantly different at 28-days (3.9% (IQR 0.8-10.3) vs. 1.0% (IQR 0.0-2.8), p = 0.2). In rabbits with induced atheroma, R-ZES also showed less endothelial coverage 28 days after stent implantation (5.3% (IQR 2.2-9.9) vs. 1.1% (IQR 0-6.2), p = 0.03). In the culotte stenting model, the percent uncovered strut area of the proximal overlapped segment was significantly higher in R-ZES at 14 days (15.8% (IQR 14.3-17.7) vs. 8.8% (IQR 8.3-9.8), p = 0.03) and 28 days (9.9% (IQR 4.1-13.9) vs. 2.5% (IQR 1.6-6.7), p = 0.04) after stent implantation. The carina area also showed a better coverage in EES compared with R-ZES. EES showed a better stent endothelial coverage compared with R-ZES after stent implantation in the early phase in normals, in arteries with lipid rich plaque, and in bifurcation stented sites.
Journal of the American College of Cardiology, Jan 15, 2017
Transcatheter aortic valve replacement (TAVR) in patients with bicuspid aortic valve stenosis (AS... more Transcatheter aortic valve replacement (TAVR) in patients with bicuspid aortic valve stenosis (AS) is being increasingly performed. From the Bicuspid AS TAVR multicenter registry, the procedural and clinical outcomes in patients with bicuspid versus tricuspid AS were compared. Outcomes of 561 patients with bicuspid AS and 4,546 patients with tricuspid AS were compared after propensity-score matching assembling 546 pairs of patients with similar baseline characteristics. Procedural and clinical outcomes were recorded according to VARC-2 criteria. Compared to patients with tricuspid AS, patients with bicuspid AS had more frequent conversion to surgery (2.0% vs. 0.2%; p=0.006) and significantly lower device success rate (85.3% vs. 91.4%; p=0.002). Early generation devices (Sapien XT/CoreValve) were implanted in 320 patients with bicuspid and 321 patients with tricuspid AS whereas new generation devices (Sapien 3/Lotus/Evolut R) were implanted in 226 and 225 patients with bicuspid and t...
Scarce data are available on the impact of age on transcatheter aortic valve implantation (TAVI) ... more Scarce data are available on the impact of age on transcatheter aortic valve implantation (TAVI) outcomes. We therefore, analyzed 1,845 consecutive patients from 9 Italian centers who underwent TAVI with the Corevalve Revalving System from September 2007 to March 2014; patients were dichotomized according to their age in the date of the procedure, as follows: 75 to 85 years old and >85 years old. End points were defined according to Valve Academic Research Consortium definitions. In-hospital, 30-day, and 1-year clinical and echocardiographic data were available for 100% of the patients included. Propensity matching was performed. Procedural success rates were high (>94%) and comparable between groups. Although worse baseline renal function was observed in the older group, the incidence of acute kidney injury after procedure was comparable (17.1% and 17.4%, respectively for the 75- to 85- and >85-year-old group, p = 0.877); importantly, >99% of acute kidney injury episode...
[Background] We recently reported that human induced pluripotent stem (iPS) cells can be induced ... more [Background] We recently reported that human induced pluripotent stem (iPS) cells can be induced to differentiate into cardiomyocytes, and characterized their phenotype. Future investigation of hum...
Cardiovascular intervention and therapeutics, Jan 28, 2016
The purpose of this study is to determine reduction of door-to-balloon (D2B) time using a single ... more The purpose of this study is to determine reduction of door-to-balloon (D2B) time using a single universal guiding catheter (Ikari-Left catheter) in transradial approach. In this procedure, we can skip a total of five steps compared with a conventional procedure (two catheter insertions, two catheter removals, and one catheter engagement). Reducing total ischemic time is important to achieving a better outcome in primary percutaneous coronary intervention (PCI) for ST segment elevation myocardial infarction (STEMI). We retrospectively compared 30 consecutive STEMI patients who underwent transradial primary PCI with a single guiding catheter (IL group) with 30 consecutive patients with conventional transradial primary PCI. Patients with cardiogenic shock, heart failure, or need for intra-aortic balloon pumping support before primary PCI were excluded. Baseline characteristics were not different between the two groups. The D2B time was significantly shorter in the IL group (55 ± 16 vs...
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