[Show abstract][Hide abstract] ABSTRACT: We treated a 77-year-old patient with secondary abdominal compartment syndrome that caused failure to maintain cardiopulmonary bypass while undergoing elective minimally invasive right mini-thoracotomy mitral valve and tricuspid valve repair procedures. During the operation, a decompression laparotomy was needed to relieve elevated intraabdominal pressure that caused instability of the cardiopulmonary bypass. Due to poor oxygenation and the long cardiopulmonary bypass time, the patient required peripheral extracorporeal membrane oxygenation before recovery. We alert surgeons to this rare complication that can occur even in patients undergoing minimally invasive surgery with a right mini-thoracotomy.
[Show abstract][Hide abstract] ABSTRACT: Objectives:
In recent years, supra-aortic rerouting and thoracic endovascular aortic repair (TEVAR) for treating aortic arch pathology have emerged as a less invasive option for high-risk patients. This study aimed to assess our strategy for preventing stroke and improving late outcomes after supra-aortic rerouting and TEVAR.
Between July 2008 and July 2015, we performed 280 cases of TEVAR for arch pathologies, using manufactured stent grafts. This study reviewed 101 patients who underwent supra-aortic rerouting and TEVAR for degenerative distal arch aneurysms (80 men, mean age 73.1 years, Zone 1/Zone 2 = 48/53). Since 2011, we have routinely used the brain protection method, which comprises blocking native forward flow from the left common carotid artery (LCA) and left subclavian artery (LSA) for zone 1 cases and the LSA for zone 2 cases before TEVAR.
The mean operation time was 178 ± 65 min. The stroke and 30-day death rates were 3 and 1%, respectively. Before the brain protection method was introduced, the perioperative risk factor for stroke was atheroma Grade ≥III (P = 0.035). Proximal landing zone (P = 0.58) and LSA sacrifice (P = 1.00) were not risk factors for stroke. No strokes occurred after using the brain protection method (before protection: 6% and after protection: 0%). Regarding late results, the rate of freedom from aorta-related death at 1 and 4 years was 97 and 95%, respectively. The rate of freedom from aortic events at 1 and 4 years was 91 and 86%, respectively. During follow-up, no type Ia endoleak developed and one type A dissection was observed.
Our strategy for supra-aortic rerouting and TEVAR showed satisfactory early and late results. The chief risk factor for perioperative stroke was atheroma, and blocking native forward flow from the LCA and the LSA prior to the TEVAR procedure helped prevent stroke.
No preview · Article · Feb 2016 · European journal of cardio-thoracic surgery: official journal of the European Association for Cardio-thoracic Surgery
[Show abstract][Hide abstract] ABSTRACT: Background:
Accurate prediction of both mortality and morbidity is of significant importance, but it is challenging in patients with severe heart failure. It is especially difficult to detect the optimal time for implanting mechanical circulatory support devices in such patients. We aimed to analyze the morphometric ultrastructure of nuclear chromatin in cardiomyocytes by developing an original clinical histopathological method. Using this method, we developed a biomarker to predict poor outcome in patients with dilated cardiomyopathy (DCM).
Methods and results:
As a part of their diagnostic evaluation, 171 patients underwent endomyocardial biopsy (EMB). Of these, 63 patients diagnosed with DCM were included in this study. We used electron microscopic imaging of cardiomyocyte nuclei and an automated image analysis software program to assess whether it was possible to detect discontinuity of the nuclear periphery. Twelve months after EMB, all patients with a discontinuous nuclear periphery (Group A, n = 11) died from heart failure or underwent left ventricular assist device (VAD) implantation. In contrast, in patients with a continuous nuclear periphery (Group N, n = 52) only 7 patients (13%) underwent VAD implantation and there were no deaths (p<0.01). We then evaluated chromatin particle density (Nuc-CS) and chromatin thickness in the nuclear periphery (Per-CS) in Group N patients; these new parameters were able to identify patients with poor prognosis.
We developed novel morphometric methods based on cardiomyocyte nuclear chromatin that may provide pivotal information for early prediction of poor prognosis in patients with DCM.
[Show abstract][Hide abstract] ABSTRACT: Statement of significance:
In vitro fabrication of vascularized three-dimensional (3D) human cardiomyocyte (CM) tissues derived from human induced pluripotent stem cells (iPSCs) has attracted much attention owing to their requirement of much amount of nutrition and oxygen, but not yet published. In this manuscript, we report construction of vascularized 3D-iPSC-CM tissues by a newly-discovered filtration-Layer-by-Layer (LbL) technique. The filtration-LbL fabricates nanometer-sized fibronectin and gelatin (FN-G) films onto iPSC-CM surfaces. The FN-G nanofilms induce cell-cell interactions via integrin molecules on cell surfaces, leading to construction of 3D-tissues. The constructed vascularized 3D-iPSC-CM tissues would be a promising tool for tissue regeneration and drug development. We believe that this manuscript has a strong impact and offers important suggestions to researchers concerned with biomaterials and tissue engineering.
No preview · Article · Jan 2016 · Acta biomaterialia
[Show abstract][Hide abstract] ABSTRACT: We describe four cases of the patients with ST-elevation myocardial infarction (STEMI) that were treated with interleukin-11 (IL-11), a cardioprotective cytokine. Recombinant human IL-11 (rhIL-11), was intravenously administered to two cases at low dose (6 µg/kg) and to two at high dose (25 µg/kg). The cytokine administration started just after the coronary occlusion was confirmed by coronary angiography (CAG), taking 3 h. Following CAG, percutaneous coronary intervention (PCI) was performed as a standard therapy. No serious adverse drug reactions were observed. All the cases left the hospital without the symptom of heart failure. We discuss the possibility of the clinical use of rhIL-11 as an adjunct therapy to PCI for the STEMI patients.
No preview · Article · Jan 2016 · Heart and Vessels
[Show abstract][Hide abstract] ABSTRACT: Advanced cardiac failure is a progressive intractable disease and is the main cause of mortality and morbidity worldwide. Since this pathology is represented by a definite decrease in cardiomyocyte number, supplementation of functional cardiomyocytes into the heart would hypothetically be an ideal therapeutic option. Recently, unlimited in vitro production of human functional cardiomyocytes was established by using induced pluripotent stem cell (iPSC) technology, which avoids the use of human embryos. A number of basic studies including ours have shown that transplantation of iPSC-derived cardiomyocytes (iPSC-CMs) into the damaged heart leads to recovery of cardiac function, thereby establishing "proof-of-concept" of this iPSC-transplantation therapy. However, considering clinical application of this therapy, its feasibility, safety, and therapeutic efficacy need to be further investigated in the pre-clinical stage. This review summarizes up-to-date important topics related to safety and efficacy of iPSC-CMs transplantation therapy for cardiac disease and discusses the prospects for this treatment in clinical studies.
No preview · Article · Jan 2016 · Current Gene Therapy
[Show abstract][Hide abstract] ABSTRACT: Transplantation of induced pluripotent stem cell-derived cardiac tissue constructs is a promising regenerative treatment for cardiac failure: however, its tumourigenic potential is concerning. We hypothesised that the tumourigenic potential may be eliminated by the host immune response after allogeneic cell transplantation. Scaffold-free iPSC-derived cardaic tissue sheets of C57BL/6 mouse origin were transplanted into the cardiac surface of syngeneic C57BL/6 mice and allogeneic BALB/c mice with or without tacrolimus injection. Syngeneic mice and tacrolimus-injected immunosuppressed allogeneic mice formed teratocarcinomas with identical phenotypes, characteristic, and time courses, as assessed by imaging tools including 18F-fluorodeoxyglucose-positron emission tomography. In contrast, temporarily immunosuppressed allogeneic mice, following cessation of tacrolimus injection displayed diminished progression of the teratocarcinoma, accompanied by an accumulation of CD4/CD8-positive T cells, and finally achieved complete elimination of the teratocarcinoma. Our results indicated that malignant teratocarcinomas arising from induced pluripotent stem cell-derived cardiac tissue constructs provoked T cell-related host immune rejection to arrest tumour growth in murine allogeneic transplantation models.
Full-text · Article · Jan 2016 · Scientific Reports
[Show abstract][Hide abstract] ABSTRACT: To develop a nanoscaled coating material for medical devices possessing weak antibacterial activity, dispersible and crystalline fluorinated hydroxyapatite (F-HAp) nanoparticles were prepared using anti-sintering agent to avoid calcination-induced sintering. The product was identical to fluoroapatite, as determined by X-ray diffraction and Fourier transform infrared spectroscopy. The primary particles generally showed rod-shape morphology with a length of 367 ± 67 nm and a width of 223 ± 21 nm measured by scanning electron microscopy (SEM). The dispersed average particle size (313 ± 51 nm) in ethanol analyzed by dynamic light scattering was almost the same as that obtained from the SEM images. In the evaluation of solubility in acidic aqueous solution, F-HAp and original HAp nanoparticles started to dissolve at around pH 3.4 and 4.2, respectively. Thus, the stability of F-HAp in a living body increased compared to original HAp. The antibacterial activity of F-HAp nanoparticles was higher than that of fluoride in NaF alone or the original HAp nanoparticles. However, it was estimated that the effect of F-HAp was much lower compared with that of silver, one of the popular antibacterial materials. Thus, the dispersed F-HAp nanoparticles possessing weak antimicrobial activity can be useful without severe damage to living tissue.
No preview · Article · Dec 2015 · ASAIO journal (American Society for Artificial Internal Organs: 1992)
[Show abstract][Hide abstract] ABSTRACT: Purpose:
We assessed the effects of different types of prosthetic rings on mitral annular dynamics using real-time three-dimensional echocardiography (RT3DE).
RT3DE was performed in 44 patients, including patients undergoing mitral annuloplasty using the Cosgrove-Edwards flexible band (Group A, n = 10), the semi-rigid Sorin Memo 3D ring (Group B, n = 17), the semi-rigid Edwards Physio II ring (Group C, n = 7) and ten control subjects. Various annular diameters were measured throughout the cardiac cycle.
We observed flexible anterior annulus motion in all of the groups except Group C. A flexible posterior annulus was only observed in Group B and the Control group. The mitral annular area changed during the cardiac cycle by 8.4 ± 3.2, 6.3 ± 2.0, 3.2 ± 1.3, and 11.6 ± 5.0 % in Group A, Group B, Group C, and the Control group, respectively. The dynamic diastolic to systolic change in mitral annular diameters was lost in Group C, while it was maintained in Group A, and to a good degree in Group B. In comparison to the Control group, the mitral annulus shape was more ellipsoid in Group B and Group C, and more circular in Group A.
Although mitral regurgitation was well controlled by all of the types of rings that were utilized in the present study, we demonstrated that the annulus motion and annulus shape differed according to the type of prosthetic ring that was used, which might provide important information for the selection of an appropriate prosthetic ring.
[Show abstract][Hide abstract] ABSTRACT: Aims:
Leucine-richα2-glycoprotein (LRG) is considered as a biomarker of the clinical activities of chronic inflammatory diseases, includingheart failure. However, its pathophysiological roles in cardiac remodellingafter myocardial infarction (MI) remain to be clarified.In this study, we have addressed functional roles of LRG in cardiac remodellingafter MI.
Methods and results:
MI was generated by ligating the left coronary artery in mice.Real-time RT-PCR and immunoblot analyses revealed that the expressionsof LRG transcript and protein wereupregulated in post-infarct myocardium. LRG protein was produced by heart-infiltratingmyeloid cells, such as macrophages and neutrophils.To elucidate functional roles of LRG in cardiac remodelling,we generated MI in wild-type (WT) and LRG-deficient (LRG-/-) mice and found that LRGgene ablation aggravated myocardial fibrosis with cardiac dysfunction after MI.Immunohistochemical analyses with anti-CD31 antibody revealed that capillary density decreasedat border zone in LRG-/-micecompared with WT mice. Consistently, the expression of apelin receptor was reduced in LRG-/-mice, implyingthat the impaired angiogenic activity is associated with adverse cardiacremodellingin LRG-/-mice. Moreover, LRGgene ablation suppressed the activation ofsmad1/5/8, a pro-angiogenic signallingpathway. Finally, the transplantation of WT bone marrow cells into LRG-/-mice attenuated cardiac fibrosis with functional improvement after MI, accompanied by restoration of capillary densitycompared with the bone marrow transplantation from LRG-/-mice.
LRG, produced by heart-infiltratingmyeloid cells, suppresses adverse cardiac remodellingafter MI asa novel cardioprotective factor. LRG signallingcould beatherapeutic targetagainst cardiovascular diseases.
Preview · Article · Dec 2015 · Cardiovascular Research
[Show abstract][Hide abstract] ABSTRACT: Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene which encodes dystrophin protein. Dystrophin defect affects cardiac muscle as well as skeletal muscle. Cardiac dysfunction is observed in all patients with DMD over 18 years of age, but there is no curative treatment for DMD cardiomyopathy. To establish novel experimental platforms which reproduce the cardiac phenotype of DMD patients, here we established iPS cell lines from T lymphocytes donated from two DMD patients, with a protocol using Sendai virus vectors. We successfully conducted the differentiation of the DMD patient-specific iPS cells into beating cardiomyocytes. DMD patient-specific iPS cells and iPS cell-derived cardiomyocytes would be a useful in vitro experimental system with which to investigate DMD cardiomyopathy.
Full-text · Article · Dec 2015 · International Heart Journal
[Show abstract][Hide abstract] ABSTRACT: As a series of endeavors to establish suitable measures for sound development of regenerative medicine using human stem cell-based products, we studied scientific principles, concepts, and basic technical elements for ensuring the quality and safety of therapeutic products derived from the processing of human embryonic stem cells (hESCs), taking into consideration scientific and technological advances, ethics, regulatory rationale, and international trends in human stem cell-derived products. This led to the development of Japanese official Notification No. 0907-6, “Guideline on Ensuring the Quality and Safety of Pharmaceuticals and Medical Devices Derived from the Processing of Human Embryonic Stem Cells,” issued by Pharmaceuticals and Food Safety Bureau, Ministry of Health, Labour and Welfare of Japan, on September 7, 2012. The present paper addresses various aspects of products derived from hESCs, in addition to similar points to consider that are described previously for allogeneic human stem cell-based products. Major additional points include 1) establishment of hESCs; 2) establishment of stable and well-characterized cell banks of hESCs and relevant intermediate cell products; 3) concerns about the presence of undifferentiated cells in final products, which may result in ectopic tissue formation and/or tumorigenesis; and 4) concerns about undesirable immunological reactions caused by the final products. The ultimate goal of this series of guidelines on regenerative medicine is to provide suitable medical opportunities as soon as possible to the patients with severe diseases that are difficult to treat with conventional modalities. If these guidelines are interpreted and employed in a flexible and meaningful way in this context, they should serve as a useful means to achieve their goals.
[Show abstract][Hide abstract] ABSTRACT: Background:
Improving both systolic and diastolic function may be the most important factor in treating heart failure. In this study, we hypothesized that cell-sheet transplantation could improve these function in the damaged heart.
We generated a dilated cardiomyopathy model in beagles by continuous ventricle pacing at 240 beats per minute. After 4 weeks, the beagles underwent skeletal myoblast cell sheet transplantation (SMCST) or a sham operation, and rapid ventricle pacing continued for an additional 4 weeks. Six of the e8 beagles treated by SMCST were still alive 4 weeks after the procedure. We evaluated SMCST's cardiotherapeutic effects by comparing beagles treated by SMCST with beagles that underwent a sham operation (control, n = 5).
Diastolic function, as well as systolic function improved significantly in the SMCST group as compared with the sham group (control vs SMCST group, median [interquartile range]: E/E', 16 [0.9] vs 11 [1.0]; P < 0.001; tau, 47 [6.0] vs 36 [4.4] ms: P = 0.005. Ejection fraction, 22 (6.0) versus 46 (7.5) %, P < 0.001; end-systolic elastance, 2.5 (0.4) versus 8.2 (3.5) mm Hg/ml, P = 0.001). Histological examination revealed that the volume of collagen I and the collagen I/III ratio in the myocardium were significantly higher in the control than that in the SMCST group (collagen I, 6.0 [0.8] vs 2.6 [1.3]; P = 0.006; collagen I/III ratio, 4.8 [1.7] vs 1.2 [0.4]; P = 0.010).
The potential of SMCST to ameliorate both systolic and diastolic performance was proven. The SMCST may be an alternative therapy of conventional medical treatment in the dilated cardiomyopathy heart.This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/3.0.
[Show abstract][Hide abstract] ABSTRACT: Human pluripotent stem cells (hPSCs), such as human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs), are leading candidate cells as raw materials for cell therapy products, because of their capacity for pluripotent differentiation and unlimited self-renewal. hPSC-derived products have already entered the scope of clinical application. However, the assessment and control of their tumorigenicity remains to be a critical challenge. Sensitive detection of the pluripotent cellular impurities is necessary for the safety and quality control of the hPSC-derived products. In the present study, we established a sensitive assay for detection of the residual undifferentiated hiPSCs in cardiomyocytes, using droplet digital PCR (ddPCR). The ddPCR method with a probe and primers for LIN28 significantly detected as low as 0.001% undifferentiated hiPSCs in primary cardiomyocytes, which is equivalent to the ratio of a single hiPSC to 1 × 105 cardiomyocytes. The ddPCR also showed that LIN28 expression is extremely low in human tissues including liver, heart, pancreas, kidney, spinal cord, corneal epithelium and lung. These results suggest that the ddPCR method targeting LIN28 transcripts is highly sensitive and useful for the quality assessment of various cell therapy products derived from hPSCs.
[Show abstract][Hide abstract] ABSTRACT: The Symposium of Regenerative Medicine for Patients, organized by the Japanese Society for Regenerative Medicine, was held on 28 September 2014 in Tokyo, Japan. The event provided an overview of the important areas of cell-based medicine, and highlighted the first-in-human clinical trial of induced pluripotent stem cell (iPSC)-derived products. Recent advances in regenerative medicine were also discussed, especially regarding the use of somatic cells such as chondrocytes, skeletal myocytes and cardiomyocytes under both the Act on the Safety of Regenerative Medicine, and the Pharmaceuticals, Medical Devices and Other Therapeutic Products Act.
[Show abstract][Hide abstract] ABSTRACT: As a series of endeavors to establish suitable measures for sound development of regenerative medicine using human stem cell-based products, we studied scientific principles, concepts and basic technical elements for ensuring the quality and safety of therapeutic products derived from allogeneic human induced pluripotent stem cells (iPS cells) or iPS cell-like cells, taking into consideration scientific and technological advances, ethics, regulatory rationale, and international trends in human stem cell-derived products. This led to the development of Japanese official Notification No. 0907-5, “Guideline on Ensuring the Quality and Safety of Pharmaceuticals and Medical Devices Derived from the Processing of Allogeneic Human Induced Pluripotent Stem(-Like) Cells,” issued by Pharmaceuticals and Food Safety Bureau, Ministry of Health, Labour and Welfare of Japan, on September 7, 2012. The present paper addresses various aspects of products derived from allogeneic human iPS cells (or iPS cell-like cells), in addition to similar points to consider that are described previously for allogeneic human stem cell-based products. Major additional points include 1) possible existence of allogeneic human iPS cell-like cells that are different from iPS cells in specific biological features; 2) the use of allogeneic human iPS(-like) cells as appropriate starting materials for regenerative medicine, where necessary and significant; 3) establishment of an allogeneic human iPS(-like) cell line and its characterization; 4) establishment of well-characterized stable cell banks and relevant intermediate cell products, if necessary; 5) concerns about the presence of undifferentiated cells in final products; such cells may cause ectopic tissue formation and/or tumorigenesis; and 6) concerns about undesirable immunological reactions that may be caused by the final products. The ultimate goal of this guidance is to provide suitable medical opportunities as soon as possible to the patients with severe diseases that are difficult to treat with conventional modalities.
[Show abstract][Hide abstract] ABSTRACT: A 60-year old female was referred to our institution for surgical intervention to treat bilateral coronary artery fistulas
to the pulmonary artery (PA). Multidetector computed tomography (MDCT) imaging showed two tortuous vessels with multiple aneurysmal
dilatations originating from the right coronary artery and left anterior descending artery. Furthermore, oximetry revealed
an oxygen step-up of 10% between the PA and the right ventricle, consistent with an estimated left-to-right shunt of 47.1%,
indicating that the patient was a candidate for surgery. Under heart arrest, the main PA was longitudinally opened and a single
efferent hole sized 10 mm in diameter located in the anterior sinus of the pulmonary trunk was closed. Thereafter, the two
afferent vessels were individually ligated at their proximal origins. Postoperative MDCT demonstrated no evidence of abnormal
vessel communication between the coronary arteries and the PA, as well as relatively dilated native coronary arteries when
compared with the preoperative state. At the 6-month follow-up examination, the patient was asymptomatic and showed no complications.
Full-text · Article · Oct 2015 · European journal of cardio-thoracic surgery: official journal of the European Association for Cardio-thoracic Surgery
[Show abstract][Hide abstract] ABSTRACT: Background:
Although transcatheter aortic valve implantation (TAVI) is a new alternative treatment with acceptable midterm results for high surgical risk patients, at present performing the procedure in dialysis patients is not reimbursed in Japan.Methods and Results:The study group of 17 dialysis patients (mean age, 76.7±5.0 years) underwent TAVI with the SAPIEN/SAPIEN XT. EuroSCORE and STS score were 25.0±19.0% and 15.4±12.3%, respectively. Transiliofemoral and transapical approaches were performed in 7 (41.2%) and 10 patients (58.8%), respectively. ICU and hospital stays after TAVI were 1.8±1.6 and 12.9±12.7 days, respectively. Mean transvalvular gradients at discharge significantly decreased from 45.9±13.3 mmHg to 10.7±4.3 mmHg (P<0.0001) and effective orifice area significantly increased from 0.78±0.17 to 1.69±0.37 cm(2)(P<0.0001). Device success was 87.5%. One patient required a valve-in-valve procedure on 187-postoperative-day for an acute increase in paravalvular leakage caused by initial lower implantation of the device. The overall mortality at 1 year was 0% and clinical efficacies at 30 days, 6 months, and 1 year were 93.8%, 83.3%, and 69.2%, respectively.
Satisfactory early results were achieved with TAVI in Japanese dialysis patients with a high surgical risk, indicating it is a safe and effective alternative for the treatment of aortic valve stenosis in such patients.
Full-text · Article · Oct 2015 · Circulation Journal