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Nurse practitioner (NP) is widely known to be an essential position of medical team in the United States, but has not yet been established as an official qualification in Japan. NP in Japan (NP-J) is accepted instead of NP, but they are not the same. We summarized the actual activities of NP-J at our hospital and had an insight into the roles of NP-J in a university hospital and the problems of introduction of NP in the future. The benefits of working as a NP-J at a university hospital are the safe acquisition of procedures at an educational institution and the involvement of various departments. In the future, the education of NP-J in a university hospital may lead to the training of NP-J working in public and private hospitals. The problem of introduction of NP in the future is the legislation. The importance of task shifting and education of NP-J in a university hospital may lead to the spread of NP in the future in Japan.

As long-term surgical outcome of congenital heart disease has continued to improve, most pediatric patients with congenital heart disease are able to reach adulthood. However, adult congenital heart disease (ACHD) patients have increased risk of arrhythmia, valvular diseases, infectious endocarditis, and heart failure. The end-stage ACHD patients with advanced heart failure may require mechanical circulatory support to improve the heart failure symptoms or to recover from circulatory collapse, and may eventually aim to heart transplant or destination therapy. In general, long-term mechanical support for dilated cardiomyopathy or ischemic cardiomyopathy has been achieved with left ventricular assist device with excellent survival outcomes and improved quality of life. However, the ventricular assist device for end-stage ACHD patients can be challenging due to patient-specific anatomical feature, multiple histories of surgical and catheter-based interventions and possible multiple end-organ dysfunctions, and offered less frequently compared to non-ACHD patients. The Interagency Registry for Mechanically Assisted Circulatory Support data published recently showed that ACHD patients receiving long-term mechanical circulatory support consisted1 % of all registrants and had higher mortality after mechanical support than non-ACHD patients. However, the ACHD patients supported with left ventricular assist device had similar survival with non-ACHD patients and a large proportion of the mortality difference between ACHD and non-ACHD patients seemed to result from operative and perioperative factors. Therefore, the ventricular assist device therapy can be an excellent treatment for selected ACHD patients. In this paper, we describe the current status of ventricular assist device support for end-stage ACHD patients and consideration to the future.

Heart transplantation improves quality of life and survival in patients with advanced heart failure. However, the shortage of available heart donors and technological advances for left ventricular assist devices (LVAD) have led to longer waiting times for transplantation, and long-term use of LVAD may increase the medical complexity of subsequent transplantation. We present the case of a 35-year-old man who underwent heart transplantation after being supported by an LVAD for 1490 days (∼4 years). He was sensitized with kidney dysfunction and recurrent infections, including candidemia, at the time of transplantation. He underwent a successful heart transplantation with pretransplant plasma exchange, intravenous immunoglobulin administration, early initiation of everolimus, and prompt management of infections.

Tokyo Women's Medical University has a long history with leading development in the field of cardiovascular surgery in Japan, including ventricular assist device (VAD) and heart transplantation (HT). Our institute has performed implantable VAD implantation in 73 patients with refractory heart failure as a bridge to transplantation. The long-term survival rate of that showed 94%, 85%, and 61% in 1, 3, and 5 years, respectively. In addition, orthotopic HT has been provided for 38 patients, with survival after both 10 and 20 years shown to be 85%. In this era of destination therapy, it is considered that VAD and HT treatments will become standardized options for heart failure cases even in Japan. To achieve this target, we re-organized our heart team named "BIND" in 2018, providing a more seamless multidisciplinary approach. We believe that these actions can contribute to the development of HT in our country.

Purpose Immunosuppressant and steroid are inevitable for graft survival after renal transplantation, and their usage is known to be a risk factor for mortality and morbidity after cardiac surgery. We evaluated the long-term clinical outcomes in patients who underwent cardiac surgery after renal transplantation. Methods We retrospectively reviewed 23 patients who underwent cardiac surgery after renal transplantation with maintained grafts at the time of the cardiac surgery in our institution between June 2000 and June 2018 (19 males, 4 females; mean age, 55 (38-81) years). Results The interval from renal transplantation to cardiac surgery was 80.0 ± 84.6 (0.25-298) months. The mean follow-up period after cardiac surgery was 78.3 (range: 1-216) months. Cumulative survival rates at 1, 5, 7, and 10 years were 95.7%, 95.7%, 87.7%, and 68.2%, respectively. Renal graft survival rates at 1 and 5 years were 86.1% and 79.9%, respectively. Conclusions This retrospective review suggests that cardiac surgery in kidney transplant patients can result in good survival rates. Thanks to dedicated postoperative and long-term management, approximately 80% of the renal grafts still maintained their function 5 years after cardiac surgery.

Anomalous left coronary artery arising from the noncoronary cusp (LCANCC) is a rare congenital disorder. We herein describe a 17-year-old female patient with sudden cardiac arrest followed by refractory cardiogenic shock. LCANCC-induced acute myocardial infarction with left main coronary artery involvement was subsequently diagnosed, and the patient required a durable left ventricular assist device.

Acute aortic dissection with coronary malperfusion is a life‐threatening disease, resulting in demanding postoperative management. We report a successful insertion of percutaneous heart pump Impella through the intact true lumen in a patient with residual aortic dissection after the graft replacement. Careful evaluation of the access site and the Impella size selection is required., Percutaneous heart pump Impella could be inserted through the true lumen in patients with type A aortic dissection after the ascending and total aortic arch graft replacement.

A dual left anterior descending artery with an anomalous origin of the left coronary artery from the pulmonary artery is an extremely rare coronary artery anomaly, with only one case known previously reported. However, that study presented coronary anatomical findings with images and little is known regarding patient outcome following surgical management for this unique condition. We present here the first case report of an affected patient, who underwent off-pump coronary artery bypass grafting and ligation of the coronary anomaly, as well as postoperative course details.

Mesenchymal stromal/stem cell (MSC)-based therapy is a promising approach for the treatment of heart failure. However, current MSC-delivery methods result in poor donor cell engraftment, limiting the therapeutic efficacy. To address this issue, we introduce here a novel technique, epicardial placement of bi-layered, adhesive dressings incorporating MSCs (MSC-dressing), which can be easily fabricated from a fibrin sealant film and MSC suspension at the site of treatment. The inner layer of the MSC dressing, an MSC-fibrin complex, promptly and firmly adheres to the heart surface without sutures or extra glues. We revealed that fibrin improves the potential of integrated MSCs through amplifying their tissue-repair abilities and activating the Akt/PI3K self-protection pathway. Outer collagen-sheets protect the MSC-fibrin complex from abrasion by surrounding tissues and also facilitates easy handling. As such, the MSC-dressing technique not only improves initial retention and subsequent maintenance of donor MSCs but also augment MSC's reparative functions. As a result, this technique results in enhanced cardiac function recovery with improved myocardial tissue repair in a rat ischemic cardiomyopathy model, compared to the current method. Dose-dependent therapeutic effects by this therapy is also exhibited. This user-friendly, highly-effective bioengineering technique will contribute to future success of MSC-based therapy.

Objectives: Stroke is a substantial complication of left ventricular assist device (LVAD) implantation. The relationship between stroke and the anatomical position of the inflow cannula of patients who underwent LVAD implantation was investigated. Methods: We enrolled 15 patients with advanced-stage heart failure who underwent implantation of continuous-flow-LVAD. Data of patients who suffered a stroke within 6 months after LVAD implantation were retrospectively compared to those who remained free of stroke. The distance between the inflow duct and left ventricular (LV) septum (duct-sep distance) and its ratio to LV diastolic diameter (LVDd) were measured from echocardiography at 1 month after LVAD implantation. Receiver operating characteristic curves for the endpoint of stroke using the duct-sep distance to LVDd ratio was created and the cut-off value was calculated. The incidence of stroke during the 6 months after LVAD implantation according to this ratio was estimated using the Kaplan-Meier method. Results: At 1 month after LVAD implantation, there were no significant differences in baseline characteristics and echocardiography parameters between the stroke and stroke-free groups. Receiver operating characteristic curve analysis for the endpoint of stroke using the duct-sep distance to LVDd ratio revealed 0.217 as a cut-off value (sensitivity: 80%, specificity: 80%, area under the curve: 0.72). Stroke was more frequent in patients with a duct-sep distance to LVDd ratio ⩾0.217 at 1 month than in those with a lower ratio. Conclusion: The duct-sep distance to LVDd ratio was associated with the occurrence of stroke, suggesting that inflow cannula position influences the incidence of stroke.

Mesenchymal stromal cell (MSC) transplantation has been investigated as an advanced treatment of heart failure; however, further improvement of the therapeutic efficacy and mechanistic understanding are needed. Our previous study has reported that epicardial placement of fibrin sealant films incorporating rat amniotic membrane-derived (AM)-MSCs (MSC-dressings) could address limitations of traditional transplantation methods. To progress this finding toward clinical translation, this current study aimed to examine the efficacy of MSC-dressings using human AM-MSCs (hAM-MSCs) and the underpinning mechanism for myocardial repair. Echocardiography demonstrated that cardiac function and structure were improved in a rat ischemic cardiomyopathy model after hAM-MSC-dressing therapy. hAM-MSCs survived well in the rat heart, enhanced myocardial expression of reparative genes, and attenuated adverse remodeling. Copy number analysis by qPCR revealed that upregulated reparative genes originated from endogenous rat cells rather than hAM-MSCs. These results suggest hAM-MSC-dressing therapy stimulates a secondary release of paracrine factors from endogenous cells improving myocardial repair ("secondary paracrine effect"), and cardiac M2-like macrophages were identified as a potential cell source of repair. We demonstrated hAM-MSCs increased M2-like macrophages through not only enhancing M2 polarization but also augmenting their proliferation and migration capabilities via PGE2, CCL2, and TGF-β1, resulting in enhanced cardiac function after injury.

Left ventricular assist devices (LVAD) are widely applied for patients with severe heart failure as a bridge to heart transplantation as well as destination therapy. Patients with implanted LVAD have an increased risk of cerebral thrombosis and computed tomographic perfusion (CTP) has the potential to be performed for early diagnosis and treatment of acute ischemic stroke (AIS), including interventional thrombectomy. Here, we report our series of CTP examination in patients having suspected AIS after LVAD implantation. We retrospectively investigated 33 contrast-enhanced CTPs from January 2017 to December 2018 which were performed in 12 cases of patients because of possible neurological findings leading to suspected AIS during LVAD circulatory support who did not have definite ischemic findings nor intracerebral hemorrhage on non-contrast computed tomography. AIS with perfusion disturbance area was diagnosed in 11 (33.3%) out of a total of 33 CTPs in 4 (33.3%) out of 12 patients. Endovascular thrombectomy (EVT) was successfully performed in this research study four times for three patients. CTP was able to detect and determine the indication for EVT without serious complications. CTP could potentially be the first-choice assessment for early diagnosis of AIS with recoverable ischemic penumbra in patients with LVAD implantation.

Introduction Patients with physiologically repaired corrected transposition of the great arteries (cTGA) have morphological right ventricle (RV) as systemic ventricle. They may develop systemic RV failure in long-term and subsequently require heart transplantation with or without ventricular assist device (VAD) placement. However, VAD placement for systemic RV carries technical challenges, including trabeculated and diverse shapes of RV, close proximity to tricuspid valve and various apex positions. Case Report A case was 38-year-old female with cTGA and pulmonary stenosis. She had surgical history of physiological repair and redo pulmonary artery plasty at 10 and 19 years of age, respectively. She had history of heart failure symptoms with systemic RV dysfunction since 27 years of age. She was re-admitted for recurrent heart failure and listed for heart transplantation at 37 year of age. Her cardiac position was mesocardia and systemic RV was longitudinally elongated with severely dilated left atrium. The aorta was left anterior to the pulmonary trunk. Therefore, the standard VAD placement from cardiac apex may cause interference of sternal closure by pump body, inflow obstruction due to close proximity to the tricuspid valve, and difficult anastomosis to the short anterior ascending aorta. In contrast, the vertical VAD placement from diaphragmatic surface towards the aortic valve seemed to resolve these challenges. At the operation, a cardiopulmonary bypass was established through femoral cannulation. Under transesophageal echocardiogram guidance, the optimal inflow cannulation site was decided. After aortic cross-clamp, the systemic RV trabeculation was resected and the 3rd generation VAD pump was placed vertically from RV diaphragmatic surface. The outflow graft was laid along left side of the heart and anastomosed to left lateral ascending aorta. Postoperatively, the VAD flow had been stable with no evidence of sucking or thrombus formation. She was discharged and currently waiting for heart transplantation. Summary It is important to determine VAD placement technique with thorough understanding of unique characteristics of cTGA. Vertical VAD placement to systemic RV and anastomosis of outflow cannula to the left side of the aorta can be a good option for patients with systemic RV failure with mesocardia.

Nutcracker syndrome (NCS) is known as a status of compression of the left renal vein (LRV) between the abdominal aorta and superior mesenteric artery (SMA). We here report a case of NCS in Marfan patients with type B aortic dissection who presented with sudden gross hematuria. Computed tomography revealed the compression of the LRV sandwiched between the SMA and the dilated dissecting abdominal aorta. The compression was released after surgical intervention and the hematuria was promptly recovered. This report highlights that NCS should be considered as a differential diagnosis of unexplained hematuria in patients with the chronic dissecting aorta.

Aortic valve regurgitation (AR) is a critical complication during circulatory support with a left ventricular assist device (LVAD). The time-course of AR and related factors, including outflow graft anastomosis site design, were investigated. Twenty-three patients who had continuous-flow LVAD implantation and were supported for more than 6 months were investigated. AR grade (none, 0; trivial, 0.5; mild, 1; mild-moderate, 1.5; moderate, 2; moderate-severe, 2.5; severe, 3) and aortic valve opening were evaluated with echocardiography. Computed tomography was performed to all the patients postoperatively. The angle of the outflow graft to the aorta (O-A angle, parallel 0; tangent 90°, 0-180°), aortic diameter at the anastomosis site, sino-tubular junction (STJ) diameter, distance between the STJ and the anastomosis site, and distance between the anastomosis site and the brachiocephalic artery were measured. The patients' age was 38 ± 11 years. Support duration was 686 ± 354 days. Mean AR grade after continuous-flow LVAD implantation was increased to around mild and was maintained thereafter. No patient needed any intervention to the aortic valve. The aortic valves of 82.6% of patients were closed continuously. The O-A angle (83 ± 14) was positively correlated with maximum AR grade (p = 0.0095). The O-A angle was significantly smaller in patients with maximum AR grade of 1 or less (77 ± 9°) than in those with 1.5 or greater (94 ± 15°, p = 0.021). The other CT measurements had no correlation with AR grade. In conclusion, the O-A angle was correlated with AR grade progression. The O-A angle appears to be one of the important factors related to AR under continuous-flow LVAD support.

Purpose The methods for detection of post-transplant rejection, especially antibody-mediated rejection (AMR) have been developed for the past three decades and contributed the elucidation of the cardiac allograft vasculopathy (CAV) progression from AMR. However, variation in individual cases is found and it is important to a prediction of the clinical CAV extension to know how various technique is involved on a true clinic. The contribution of alloimmune factors has been increasingly recognized, and thus it is useful to evaluate antibody patterns to prevent CAV. Methods Subjects consisted of 43 patients (10 women; average age at heart transplantation (HTX), 26.1±17.5 years; observation period, 12.1±7.9 years after HTX) who underwent HTX at least 2 years earlier, as well as regular immunological testing, such as panel reactive antibody testing. Clinical data were retrospectively analyzed. Results (1) Twelve patients showed significant progression of CAV (more than ISHLT CAV2) during follow-up after transplantation, and eight patients demonstrated positive for HLA Class 1 or Class 2 antibodies. Five of these eight patients showed positive donor-specific antibodies and negative for Class 1 C1q antibodies, but four of these five showed positive for Class 2 C1q antibodies. These four patients demonstrated rapid progression of CAV. (2) Four of the 43 patients had a history of C4d-positive antibody-related rejection (AMR), and two of these four patients showed persistent positive Class 2 C1q antibodies. (3) Nine of 12 patients who showed significant progression of CAV demonstrated positive for Class 1 or Class 2 antibodies, or positive for Class 2 C1q antibodies, or had a history of AMR. Conclusion Alloimmune response is greatly involved in CAV progression, but a difference is found in the extension mechanism in individual cases. Regular immunological evaluations for not only HLA IgG antibodies but also C1q antibodies are useful to better characterize CAV progression.

Background Recent research has revealed that reparative (alternatively activated or M2-like) macrophages play an important role in post-myocardial infarction (MI) cardiac repair, proposing that augmentation of these cells will enhance recovery from MI. Transplantation of bone marrow mononuclear cells (BM-MNCs) is an emerging therapy for MI while its therapeutic efficacy in previous clinical trials is not satisfactory. Given that BM-MNCs are a natural source of macrophages, we hypothesized that induced differentiation/polarisation of BM-MNCs to reparative macrophages before transplantation may enhance the effect of BM-MNC transplantation. Purpose This study aimed to develop a robust in vitro protocol to produce reparative macrophages from BM-MNCs and to establish the pre-clinical proof of concept data for reparative macrophage transplantation for the treatment of MI. Methods and results Mouse BM-MNCs were treated with M-CSF plus IL-4, IL-10, TGF-β1 or combinations of these in vitro. The concomitant M-CSF+IL-4 protocol (both 20ng/ml) produced the highest rate (89.7±0.7%) and number (1.7-fold larger than the original cell number) of CD11b+F4/80+CD206+ macrophages. Expression and secretion of tissue repair-related factors of the produced cells, including IGF-1, TGF-β1, VEGF and IL1-ra, were more extensive compared to BM-MNCs. Then, 5x105 BM-MNC-derived reparative macrophages, 5x105 BM-MNCs, or saline only (control) were intramyocardially injected in a mouse MI model based on coronary artery ligation. At 4 weeks after treatment, echocardiography demonstrated that reparative macrophage transplantation markedly improved cardiac function (left ventricular ejection fraction; 57.2±1.6%, n=11) compared to both BM-MNC transplantation (48.4±1.3%, n=9) and control group (44.4±2.0%, n=9). Histological studies showed that infarct size was the smallest after reparative macrophage transplantation in association with the greatest tissue repair in the peri-infarct myocardium, including augmented microvascular formation, reduced cardiomyocyte hypertrophy and reduced pathological interstitial fibrosis. These were corresponded to amplified myocardial upregulation of tissue repair-related genes. Of note, survival of donor reparative macrophages in the heart post-transplantation was >10-fold greater compared to BM-MNCs. It was also found that reparative macrophage transplantation increased host-derived cardiac reparative macrophages. This might be a part of the mechanism by which reparative macrophage transplantation augmented myocardial repair, and our in vitro antibody neutralisation study indicated that TGF-β1 played a role in this donor macrophage-to-host macrophage pathway. Conclusion M-CSF+IL-4 treatment was effective in producing reparative macrophages from BM-MNCs in vitro. Addition of this pre-treatment improved the therapeutic effect of BM-MNC transplantation. Further pre-clinical and clinical development of this advanced cell therapy is warrantied. Acknowledgement/Funding British Heart Foundation (RG/15/3/31236); Heart Research UK (RG2618/12/13 and TRP06/15); St Barts Medical School London

Background: Reparative (alternatively activated or M2-like) macrophages play an important role in post-myocardial infarction (MI) cardiac repair. Transplantation of bone marrow mononuclear cells (BM-MNCs) is an emerging therapy for MI while its therapeutic efficacy in previous clinical trials is not satisfactory. We hypothesized that induced differentiation/polarisation of BM-MNCs to reparative macrophages before transplantation may enhance the effect of BM-MNC transplantation. Purpose: This study aimed to develop a robust in vitro protocol to produce reparative macrophages from BM-MNCs and to establish the pre-clinical proof of concept data for reparative macrophage transplantation for the treatment of MI. Methods & Results: Mouse BM-MNCs were treated with M-CSF plus IL-4, IL-10, TGF-β1 or combinations of these in vitro . The concomitant M-CSF+IL-4 protocol produced the highest rate and number of CD11b + F4/80 + CD206 + macrophages. Expression and secretion of tissue repair-related factors of the produced cells, including IGF-1, TGF-β1, VEGF and IL1-ra, were more extensive compared to BM-MNCs. Then, reparative macrophages, BM-MNCs or PBS only were intramyocardially injected in a mouse MI model. At 4 weeks after treatment, echocardiography demonstrated that reparative macrophage transplantation markedly improved cardiac function (left ventricular ejection fraction; 57.2±1.6%, n=11) compared to both BM-MNC transplantation (48.4±1.3%, n=9) and control group (44.4±2.0%, n=9). Histological studies showed that infarct size was the smallest after reparative macrophage transplantation in association with the greatest tissue repair in the peri-infarct myocardium, including augmented microvascular formation, reduced cardiomyocyte hypertrophy and reduced pathological interstitial fibrosis. It was also found that reparative macrophage transplantation increased host-derived reparative macrophages through TGF-β1 secretion. Conclusion: M-CSF+IL-4 treatment was effective in producing reparative macrophages from BM-MNCs in vitro . Addition of this pre-treatment improved the therapeutic effect of BM-MNC transplantation. Further pre-clinical and clinical development of this advanced cell therapy is warranted.

Reparative macrophages play an important role in cardiac repair post-myocardial infarction (MI). Bone marrow mononuclear cells (BM-MNCs) have been investigated as a donor for cell therapy but with limited clinical success. These cells, however, may be utilized as a source for reparative macrophages. This translational study aimed to establish a robust in vitro protocol to produce functional reparative macrophages from BM-MNCs and to establish pre-clinical evidence of the efficacy of reparative macrophage transplantation for the treatment of MI. Mouse BM-MNCs were treated with M-CSF plus IL-4, IL-10, TGF-β1 or combinations of these in vitro. The concomitant administration of M-CSF and IL-4 produced the highest rate and largest number of CD11b+F4/80+CD206+ reparative macrophages. Expression and secretion of tissue repair-related factors including IGF-1, TGF-β1, VEGF and IL1-ra were remarkably enhanced in reparative macrophages compared to BM-MNCs. These cells were transplanted in a mouse MI model, resulting in evident improvement in cardiac function recovery, compared to BM-MNC transplantation. Histological studies showed that reparative macrophage transplantation enhanced myocardial tissue repair including augmented microvascular formation, reduced cardiomyocyte hypertrophy and attenuated interstitial fibrosis. Moreover, survival of reparative macrophages in the heart post-transplantation was increased compared to BM-MNCs. Reparative macrophage transplantation also increased host-derived reparative macrophages in part through TGF-β secretion. In conclusion, concomitant M-CSF + IL-4 treatment effectively produced reparative macrophages from BM-MNCs in vitro. Transplantation of produced reparative macrophage achieved a superior therapeutic efficacy, compared to BM-MNC transplantation, through the enhanced quantity and quality of donor cell engraftment. Further development of this advanced cell-based therapy is warranted. Electronic supplementary material The online version of this article (10.1007/s00395-019-0742-1) contains supplementary material, which is available to authorized users.

Purpose We previously reported experimental advantages of new titanium mesh wrapped inflow cannula for left ventricular assist device (LVAD) to avoid wedge thrombus formation. There was no thrombus formation in any of the explanted LVAD system and around the outside of the inflow cannula after 2 months from LVAD implantation in calves. We had applied this newly developed inflow cannula into the clinical arena with EVAHEART LVAD since 2013. We had clinically evaluated experience of this inflow cannula and showed the clear induction of autologous neointima avoiding wedge thrombus formation for over 5 years from LVAD implantation. Methods Retrospective data were analyzed from 19 patients who underwent EVAHEART LVAD implantation using newly inflow cannula as a bridge to transplant since September 2013 at Tokyo Women's Medical University. Results All patients achieved hospital discharge on LVAD support. 9 patients underwent heart transplantation and 3 of 9 patients were supported over 5 years (5.12-5.45 years) from LVAD implantation. Thromboembolic complications in these patients included 1 cerebral bleeding event, 1 cerebral infarction and 2 transit ischemic attack. In macroscopically findings were no thrombus formation around the inflow cannula. The titanium mesh was completely enveloped with white neointima tissue that appeared to have grown from the ventricular endocardium (Figure). Conclusion The titanium mesh inflow cannula induces autologous neointima avoiding wedge thrombus formation in clinical experience for over 5 years after LVAD implantation.

Transplantation of mesenchymal stromal cells (MSCs) is an emerging therapy for the treatment of heart failure. However, the delivery method of MSC is currently suboptimal. The use of self-assembling peptide hydrogels, including PuraMatrix® (PM; 3-D Matrix, Ltd), has been reported for clinical hemostasis and in research models. This study demonstrates the feasibility and efficacy of an advanced approach for MSC-therapy, that is coating of the epicardium with the instantly-produced PM hydrogel incorporating MSCs (epicardial PM-MSC therapy). We optimized the conditions/procedure to produce “instant” 2PM-MSC complexes. After spreading on the epicardium by easy pipetting, the PM-MSC complex promptly and stably adhere to the beating heart. Of note, this treatment achieved more extensive improvement of cardiac function, with greater initial retention and survival of donor MSCs, compared to intramyocardial MSC injection in rat heart failure models. This enhanced efficacy was underpinned by amplified myocardial upregulation of a group of tissue repair-related genes, which led to enhanced repair of the damaged myocardium, i.e. augmented microvascular formation and reduced interstitial fibrosis. These data suggest a potential for epicardial PM-MSC therapy to be a widely-adopted treatment of heart failure. This approach may also be useful for treating diseases in other organs than the heart.

The algorithm for the physiological control provided by left ventricular assist devices (LVADs) has been controversial. In particular, little is known about the physiological control algorithm (such as for achieving physiological circadian rhythms) in continuous-flow LVADs. To investigate the existence of circadian variation, we retrospectively evaluated the LVAD flow-correlated motor current of patients supported by continuous-flow LVADs. The motor current and the pump speed were collected from the external controller every 10 min after device implantation, and the data were divided for every 30-day period, which began on midnight on the first post-operative day. The subjects were 18 patients (mean age 37.7, mean body surface area 1.71 m(2) at the time of operation) with dilated cardiomyopathy or dilated phase of hypertrophic cardiomyopathy. As of August 1, 2013, the patients' median support duration was 889 days. The mean calculated dominant period of motor current variation was 24.0 h and the mean amplitude was 11.7 mA for the entire duration. The amplitude of the motor current circadian variation tended to be increased until around the fifth month. The motor current had a tendency to be relatively low during the night time and high during the day time. A significant difference was found between the night-time and day-time mean motor current for the entire duration (p 0.05). In conclusion, the circadian variation of the motor current could be observed over long term in patients with fixed rotation speed continuous-flow LVAD support.

Purpose Numerous difficulties remain associated with pediatric heart transplantation. Therefore, the development of a ventricular assist device (VAD) specific to these cases is extremely important for therapeutic effectiveness. We present 5 cases of severe heart failure that were managed by ventricular assist device implantation, as a bridge to transplantation. Methods We examined the clinical course of 5 patients (4 boys, 1 girl; mean age, 10.6 ± 1.5 years; range, 8-12 years) who underwent implantation of a pneumatic extracorporeal ventricular assist device between February 2004 and May 2009. Four patients had dilated cardiomyopathy and one had corrected transposition of the great arteries. Results The mean period between onset of heart failure and ventricular assist device implantation was 594 ± 750 days (range, 94-1702 days), and the mean duration of ventricular assist support was 112 ± 98 days (range, 44-284 days). Four patients underwent heart transplantation overseas and one died of cerebral hemorrhage. Conclusions Careful management of pediatric VAD patients and development of a device designed specifically for pediatric patients are essential for improving clinical outcomes in the future.

Background Transplantation of allogeneic mesenchymal stromal cells ( MSC s) is a promising treatment for heart failure. We have shown that epicardial placement of cell sheets markedly increases donor cell survival and augments therapeutic effects compared with the current methods. Although immune rejection of intramyocardially injected allogeneic MSC s have been suggested, allogeneic MSC s transplanted on the heart surface (virtual space) may undergo different courses. This study aimed to elucidate immunologic response against epicardially placed allogeneic MSC s, rejection or acceptance of these cells, and their therapeutic effects for heart failure. Methods and Results At 4 weeks after coronary artery ligation, Lewis rats underwent epicardial placement of MSC sheets from syngeneic Lewis or allogeneic Fischer 344 rats or sham treatment. At days 3 and 10 after treatment, similar ratios (≈50% and 30%, respectively) of grafted MSC s survived on the heart surface in both MSC sheet groups. By day 28, survival of syngeneic MSC s was substantially reduced (8.9%); survival of allogeneic MSC s was more extensively reduced (0.2%), suggesting allorejection. Correspondingly, allogeneic MSC s were found to have evoked an immunologic response, albeit low level, as characterized by accumulation of CD 4 + T cells and upregulation of interleukin 6. Despite this alloimmune response, the allogeneic MSC sheet achieved myocardial upregulation of reparative factors, enhanced repair of the failing myocardium, and improved cardiac function to the equivalent degree observed for the syngeneic MSC sheet. Conclusions Allogeneic MSC s placed on the heart surface evoked an immunologic response; however, this allowed sufficient early phase donor cell survival to induce equivalent therapeutic benefits to syngeneic MSC s. Further development of this approach toward clinical application is warranted.

2001年9月より2004年12月の間に再生血管を用いて外科手術を行った44症例につき,その中期遠隔期の成績を検討した.ポリl乳酸(24例)またはポリグリコール酸(20例)を補強材とし,内外側にスポンジ状のポリカプロラクトンとポリ乳酸の共重合体を塗布したハイブリッドポリマーをパッチまたは導管として使用した.術当日にFicoll法により骨髄単核球細胞を分離し,ポリマー上に播種,移植した.再生血管を用いて,肺動脈形成または右室流出路形成術を16例に,フォンタン型手術を28例に行った.対象は,男性(児)19例,女性(児)25例で,手術時平均年齢は7.4±6.4歳,術後在院平均日数は42±23日であった.再手術時に再生血管を使用した例は18例で,うち14例が先行手術時に自己心膜やウシ心嚢膜パッチにより肺動脈形成術が行われており,4例がAPCフォンタン術,Bjork,Septationからの転換例であった.病院死亡は認められなかった.全症例の最終経過観察日ないしイベントまでの平均観察期間は3.0±1.3年であった.再生血管に関連しない心不全死を遠隔期に3例,脳出血死を1例認めた.再生血管に関連する再手術例は2例であった.再生血管に関連しない再手術1例,グラフトの閉塞1例,グラフトの狭窄などに対するPTA介入例5例を認めた.生分解性ポリマーと自己細胞による再生血管は,再手術時などに使用できる有用な代用生物(生体適合性)補填物である.内皮化など組織学的にも既存の人工物よりも有利であり,ワーファリンの回避や血栓の防止などに寄与すると考えられる.

OBJECTIVES: Ideal alternatives for replacing native arteries, which have biocompatibility such as growth potential, anti-thrombogenesis and durability, have yet to be discovered. We previously demonstrated the utility of tissue-engineered vascular autografts; however, the use of these autografts is limited to low-pressure conditions. The aim of this study was to create the tissue-engineered arterial patch (TEAP) that could be used in high-pressure systems, and to evaluate the maturation in this regenerative tissue. METHODS: We developed a new biodegradable polymer scaffold, which is composed of a co-polymer of epsilon-caprolactone and lactide acid [P(CL/LA)] and a poly-L-lactide acid (PLLA). To obtain mechanical strength, we modified PLLA that is degraded by hydrolysis for 1–2 years in contrast to polyglycolic acid in our low-pressure study previously. We implanted an oval-shaped patch (30 × 15 mm) of this polymer without cell seeding into the descending aorta of 12 dogs, and followed the animals for 1, 3 and 6 months (n= 4 in each group). The cell proliferation in the patch was evaluated with histological and immunohistochemical methods. Additionally, the expression of vascular endothelial growth factor (VEGF) and smooth muscle myosin heavy chain (smMHC) mRNA in the patches was determined with reverse transcriptase-polymerase chain reaction. RESULTS: Macroscopically, there was no incidence of rupture or aneurysmal formation on the patch. The luminal surface of the TEAP was covered with a single layer of endothelial cells stained with vWF immunohistochemically at 1 month after implantation. αSMA-positive cells that indicated smooth muscle cells and collagen fibres were observed in the patch and they increased over time. The VEGF mRNA expression in the patch at 1 month was significantly higher than that of native arterial tissue (1 month; 0.124 ± 0.017 ng/µl, native; 0.009 ± 0.003 ng/µl, P< 0.05). The smMHC mRNA expression gradually increased, and reached 60% of that of the native artery at 6 months (6 months: 0.351 ± 0.028 ng/µl, native: 0.540 ± 0.027 ng/µl). CONCLUSIONS: We demonstrated the maturation of endothelial and smooth muscle cells in TEAP, suggesting that this biodegradable polymer scaffold could be used as an alternative vascular material even in high-pressure systems.

We provided a left ventricular assist device (LVAD) for a 22-year-old man with congenital L-transposition of the great arteries after anatomic repair at the age of 7 years. He was hospitalized for progressive low-output syndrome caused by intractable biventricular failure. He received LVAD in his morphologic left ventricle with a concomitant pulmonary valve replacement. After the surgery, critical multiorgan failure with severe right heart failure occurred. It took three postoperative months to normalize all organ function following improvement of morphologic right ventricular function. He has remained stable with LVAD support for 1.5 years.

Background The EVAHEART left ventricular assist device was approved in 2010 by the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) for bridge to heart transplantation (BTT). However, its effectiveness has not been evaluated since approval. In this study we evaluated the EVAHEART device in a commercial setting in Japan. Methods Ninety-six consecutive patients enrolled in the Japanese Registry for Mechanically Assisted Circulatory Support (J-MACS), who were listed for transplant or likely to be listed and who received an EVAHEART device, were enrolled from 2011 to 2013 at 14 Japanese centers. Patients’ survival rates, adverse events and quality-of-life data were obtained from the J-MACS Registry. Results Patients’ median age was 43 years (85% male). The Interagency Registry for Mechanically Assisted Circulatory Support profiles revealed 12 patients in Level 1, 45 in Level 2, 37 in Level 3 and 1 in Level 4. The mean support duration was 384.7 days, with a cumulative duration of 101.2 years. The Kaplan–Meier survival rate during support was 93.4% at 6 months, 87.4% at 1 year and 87.4% at 2 years. Seventy-seven patients (80.2%) currently remain on support, 7 received a transplant and 10 died during support. Major adverse events included drive-line infection (14.6%) and neurologic events such as ischemic stroke (17.7%), hemorrhage (13.5%), transient ischemic attack (3.1%), pump thrombosis (1%) and hemolysis (1%). There was no gastrointestinal (GI) bleeding or right heart failure requiring right ventricular assist device (RVAD). There was no pump exchange due to mechanical failure. Conclusions The EVAHEART device provides safe, reliable and long-term circulatory support with improved survival in commercial settings of BTT in Japan, where the transplant waiting period is much longer. Incidences of GI bleeding, hemolysis, right ventricular failure, device thrombosis and mechanical failure were extremely rare in patients on EVAHEART devices.