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Objective: In patients with ischemic cardiomyopathy, coronary artery bypass grafting ensures better survival than medical therapy. However, the long-term clinical impact of complete revascularization remains unclear. This observational study aimed to evaluate the effects of complete revascularization on long-term survival and left ventricular functional recovery in patients with ischemic cardiomyopathy undergoing coronary artery bypass grafting. Methods: We retrospectively reviewed outcomes of 498 patients with ischemic cardiomyopathy who underwent complete (n = 386) or incomplete (n = 112) myocardial revascularization between 1993 and 2015. The baseline characteristics were adjusted using inverse probability of treatment weighting to reduce the impact of treatment bias and potential confounding. The mean follow-up duration was 77.2 ± 42.8 months in survivors. Results: The overall 5-year survival rate (complete revascularization, 72.5% vs incomplete revascularization, 57.9%, P = .03) and freedom from all-cause death and/or readmission due to heart failure (54.5% vs 40.1%, P = .007) were significantly greater in patients with complete revascularization than those with incomplete revascularization. After adjustments using inverse probability of treatment weighting, the complete revascularization group demonstrated a lower risk of all-cause death (hazard ratio, 0.61; 95% confidence interval, 0.43-0.86; P = .005) and composite adverse events (hazard ratio, 0.59; 95% confidence interval, 0.44-0.79; P

Objectives: The study objectives were to determine the incidence, predictors, and clinical impact of ventricular arrhythmias after coronary artery bypass grafting and to evaluate the impact of implantable cardioverter defibrillators on the survival of patients with ventricular arrhythmias. Methods: We enrolled 498 patients with a left ventricular ejection fraction of 40% or less who underwent coronary artery bypass grafting between 1993 and 2015. Clinical follow-up was completed in 94.0% of patients, with a median follow-up of 58.4 months. Results: Overall, 212 patients (43%) died, mainly of heart failure (n = 54, 10.8%) or sudden cardiac death (n = 40, 8.0%). The sudden cardiac death rate was highest during the first 6 months, with a monthly rate of 0.37%. Overall, 99 patients (20%) developed postoperative ventricular arrhythmias, and implantable cardioverter defibrillator was implanted in 55 patients. Previous ventricular arrhythmias (hazard ratio, 3.22; 95% confidence interval, 1.98-5.24; P

Background In patients with cardiogenic shock (CS), acute myocardial infarction (AMI) is the most common cause, and a percutaneous microaxial ventricular assist device (Impella, Abiomed, Danvers, MA) is a choice for temporary mechanical circulatory support. However, data are limited on complications and outcomes of Impella treatment in patients with CS with and without AMI. Methods and Results Using nationwide prospective registry data in Japan, we included a total of 2047 patients with CS in whom the Impella devices were successfully placed between February 2020 and December 2021. Patients were divided into 2 groups according to the primary indication for the Impella use: AMI versus non‐AMI. The primary end point was a composite of in‐hospital all‐cause death and major complications. Of the 2047 patients, the Impella was indicated for AMI in 1337 (65.3%). In the group without AMI, myocarditis was the leading cause of CS. Patients with AMI‐CS were older and more likely to have cardiovascular risk factors than those with non‐AMI‐CS. The rates of in‐hospital mortality (46.0% versus 43.9%, P=0.38) and major complications (35.2% versus 34.7%, P=0.85) were similar between the 2 groups. Overall, multivariable analysis identified older age, higher body mass index, previous transient ischemic attack or stroke, out‐of‐hospital cardiac arrest, and the Impella 5.0 as factors significantly associated with the primary end point. Conclusions The use of Impella in patients with and without AMI was related to similar clinical outcomes with high mortality and complication rates. Further studies are needed to identify patients who may benefit from the Impella devices in CS. Registration URL: https://www.umin.ac.jp/english. Identifier: UMIN000033603.

For ischemic cardiomyopathy (ICM) with limited therapeutic options, the induction of arteriogenesis has the potential to improve cardiac function through major restoration of blood flow. We hypothesized that transplantation of a Notch signaling-modified mesenchymal stem cell (SB623 cell) patch would induce angiogenesis and arteriogenesis in ischemic lesions, leading to improvement of left ventricular (LV) function in a rat ICM model. Two weeks after the induction of ischemia, SB623 cell patch transplantation into ICM rats (SB group, n = 10) or a sham operation (no-treatment group, n = 10) was performed. The LV ejection fraction was significantly improved at 6 weeks after SB623 cell patch transplantation ( P < 0.001). Histological findings revealed that the number of von Willebrand factor (vWF)-positive capillary vessels ( P < 0.01) and alpha smooth muscle actin (αSMA)- and vWF-positive arterioles with a diameter greater than 20 µm ( P = 0.002) was significantly increased in the SB group, suggesting the induction of angiogenesis and arteriogenesis. Moreover, rat cardiomyocytes treated with SB623 cell patch transplantation showed upregulation of ephrin-B2 ( P = 0.03) and EphB4 ( P = 0.01) gene expression, indicating arteriogenesis induction. In conclusion, SB623 cell patch transplantation improved LV function by inducing angiogenesis and arteriogenesis in a rat ICM model.

Although mesenchymal stem cell transplantation has been successful in the treatment of ischemic cardiomyopathy, the underlying mechanisms remain unclear. Herein, we investigated whether mitochondrial transfer could explain the success of cell therapy in ischemic cardiomyopathy. Mitochondrial transfer in co-cultures of human adipose-derived mesenchymal stem cells and rat cardiomyocytes maintained under hypoxic conditions was examined. Functional recovery was monitored in a rat model of myocardial infarction following human adipose-derived mesenchymal stem cell transplantation. We observed mitochondrial transfer in vitro , which required the formation of cell-to-cell contacts and synergistically enhanced energy metabolism. Rat cardiomyocytes exhibited mitochondrial transfer 3 days following human adipose-derived mesenchymal stem cell transplantation to the ischemic heart surface post-myocardial infarction. We detected donor mitochondrial DNA in the recipient myocardium concomitant with a significant improvement in cardiac function. Mitochondrial transfer is vital for successful cell transplantation therapies and improves treatment outcomes in ischemic cardiomyopathy.

Introduction: Idiopathic dilated cardiomyopathy (DCM) is associated with abnormalities in cytoskeletal proteins, mitochondrial ATP transporter, microvasculature, and fibrosis. Mesenchymal stem cells (MSCs) can ameliorate distressed mitochondrial and structural proteins, as well as fibrosis, via the paracrine effect of cytokines. This study aimed to investigate whether the transplantation of adipose tissue-derived MSCs (ADSCs) reverses histological and functional abnormalities in the distressed myocardium of DCM-like hamsters by modulating the expression of adenine nucleotide translocase 1 (ANT-1). Methods: Eighteen weeks after birth, ADSCs were implanted onto the cardiac surface of δ-sarcoglycan (SG)-deficient hamsters or sham surgery was performed. Results: Left ventricular ejection fraction and end-systolic diameter were maintained in ADSC-treated animals for four weeks, ATP concentration was considerably elevated in the cardiomyocytes of these animals, and ANT-1 expression was significantly upregulated as well. The expression of extracellular matrix and myocardial cytoskeletal proteins, such as collagen, SG, and α-dystroglycan, did not differ between groups. However, significant improvements in myosin and Smad4 expression, cardiomyocyte hypertrophy, and capillary density occurred in the ADSC-treated group. Conclusions: We demonstrated that ADSCs might maintain cardiac function in the DCM hamster model by enhancing ATP concentration, as well as mitochondrial transporter and myosin expression, indicating their potential for DCM treatment.

Abstract Background Although detachment of the implanted valve prosthesis was a well-known complication in patients with Behçet’s disease, complete detachment of an aortic bileaflet valve prosthesis has never been reported. Case presentation An 18-year-old boy with Behçet’s disease (HLA-A26 positive) who had previously undergone aortic valve replacement with an 18-mm ATS-Advanced Performance (ATS-AP) valve (ATS Medical, Inc., Minneapolis, MN) at the age of 12 years, presented sudden-onset general fatigue and was emergently transferred to the regional hospital. Chest X-ray showed displacement of the implanted mechanical valve. An echocardiogram revealed mobile valve prosthesis and severe aortic regurgitation. Just before leaving for our hospital for surgical treatment, a completely detached valve prosthesis was floating in the ascending aorta. On arrival, the valve prosthesis was stuck to the transverse arch. Emergent removal of the previous mechanical valve from the aortic arch and redo aortic valve replacement with a 24-mm ATS-AP valve were performed under total circulatory arrest. Infectious endocarditis was denied by histopathological examination. The patient was back to the intensive care unit with extracorporeal membrane oxygenation support, which was successfully decannulated 5 days later. Conclusions This was the first report of a patient with Behçet’s disease who encountered a complete detachment of implanted aortic valve prosthesis. The patient could be rescued by emergent surgery.

Abstract Background We present three cases of severe peripartum cardiomyopathy (PPCM) that required mechanical circulatory supports. Case presentation Case 1: A 33-year-old woman developed acute heart failure (AHF) after normal spontaneous delivery. Intra-aortic balloon pump (IABP) was inserted on postpartum day (PD) 10 with a peripartum cardiomyopathy (PPCM), which was withdrawn on PD 30 after medical treatment including anti-prolactin drugs. Case 2: A 44-year-old woman developed AHF 1 month after vaginal delivery. IABP or extra-corporeal membrane oxygenation (ECMO) was not effective and a biventricular assist device was inserted. It was withdrawn on PD 85 after improvement of left ventricular ejection fraction (LVEF). Case3: A 37-year-old woman was transferred with a diagnosis of PPCM. Cardiac function unimproved by IABP or ECMO, and a left ventricular assist device was implanted. It was withdrawn on PD 386 after recovery of LVEF. Conclusion All the cases with PPCM recovered after mechanical circulatory supports and resumed social lives.

Objective: We investigated whether or not a history of multiple percutaneous coronary interventions (PCIs) is associated with clinical outcomes after surgery for ischemic mitral regurgitation. Methods: A total of 309 patients with chronic ischemic mitral regurgitation and left ventricular ejection fraction ≤40% who underwent restrictive mitral annuloplasty were classified as follows: patients with no or 1 previous PCI (nonmultiple PCI group [n = 211]) and patients with 2 or more previous PCIs (multiple PCIs group [n = 98]). Mean follow-up duration was 53 ± 40 months. Results: Before surgery, there were no intergroup differences in patient demographic characteristics except for lower estimated glomerular filtration rate in patients with multiple PCIs. These patients underwent concomitant coronary artery bypass grafting less frequently with a lower number of distal anastomoses (P

Duct-dependent systemic circulation is accompanied by a right-to-left ductal shunt, at least during systole. Although observations of paradoxical continuous left-to-right shunts in duct-dependent systemic circulation have been reported, the mechanism remains unclear. We report a continuous left-to-right ductal shunt throughout the cardiac cycle during the initial recovery phase from circulatory collapse and right ventricular (RV) dysfunction due to ductal closure in an infant with hypoplastic left heart and severe aortic coarctation. Further recovery improved his RV function and changed the ductal flow from continuous left-to-right to bidirectional, which is usually seen in duct-dependent systemic circulation. Marked RV dysfunction may contribute to the continuous left-to-right ductal shunt. A continuous left-to-right ductal shunt should not be used to rule out duct-dependent systemic circulation.

Despite major therapeutic advances, heart failure, as a non-communicable disease, remains a life-threatening disorder, with 26 million patients worldwide, causing more deaths than cancer. Therefore, novel strategies for the treatment of heart failure continue to be an important clinical need. Based on preclinical studies, allogenic human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) patches have been proposed as a potential therapeutic candidate for heart failure. We report the implantation of allogeneic hiPSC-CM patches in a patient with ischemic cardiomyopathy (ClinicalTrials.gov, #jRCT2053190081). The patches were produced under clinical-grade conditions and displayed cardiogenic phenotypes and safety in vivo (severe immunodeficient mice) without any genetic mutations in cancer-related genes. The patches were then implanted via thoracotomy into the left ventricle epicardium of the patient under immunosuppressive agents. Positron emission tomography and computed tomography confirmed the potential efficacy and did not detect tumorigenesis in either the heart or other organs. The clinical symptoms improved 6 months after surgery, without any major adverse events, suggesting that the patches were well-tolerated. Furthermore, changes in the wall motion in the transplanted site were recovered, suggesting a favorable prognosis and the potential tolerance to exercise. This study is the first report of a successful transplant of hiPSC-CMs for severe ischemic cardiomyopathy.

Coronary artery aneurysm and pseudoaneurysm are rare and mainly result from atherosclerosis. We present a successfully treated case of a giant right coronary artery aneurysm and pseudoaneurysm with a coronary artery fistula, which might have developed after cardiac surgery for a right ventricular tumor 35 years earlier. (Level of Difficulty: Advanced.)

Abstract Background In this study, we evaluated the prevalence of tricuspid regurgitation (TR) worsening in patients with left ventricular assist devices (LVADs) and its impact on late right ventricular (RV) failure. Methods We enrolled 147 patients of the 184 patients who underwent continuous-flow LVAD implantations from 2005 to March 2018. The prevalence of postoperative TR worsening and late RV failure were retrospectively evaluated. Results Concomitant tricuspid annuloplasty (TAP) was performed in 28 of 41 patients (68%) with preoperative TR greater than or equal to moderate (TR group) and in 23 of 106 patients (22%) with preoperative TR less than or equal to mild (non-TR group). Regarding the TR-free rates, despite receiving or not receiving concomitant TAP, there was no significant difference between the 2 groups (TR group: p = 0.37; non-TR group: p = 0.42). Of the 9 patients with postoperative TR greater than or equal to moderate, late RV failure developed in 3 patients, with TR worsening after RV failure in each case. During follow-up, 16 patients (11%) had late RV failure. As for the late RV failure-free rates, despite receiving or not receiving concomitant TAP, there was no significant difference between the 2 groups (TR group: p = 0.37; non-TR group: p = 0.96). Conclusions TR prognosis was preferable regardless of a patient receiving concomitant TAP; however, the presence of postoperative TR seemed to unrelated to late RV failure. Prophylactic TAP might not be necessary to prevent late RV failure.

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

Abstract Aims This study aimed to assess the value of the hepatocyte growth factor (HGF) as an independent predictor of a Fontan circulation failure. Methods and results This retrospective case–control study included 34 consecutive patients (19 men and 15 women) who underwent a post‐operative cardiac catheterization after a Fontan operation at the Saitama Medical University International Medical Center between April 2017 and December 2019. We divided the patients into two groups according to the HGF level: HGF 0.405 ng/mL could detect the need for a catheter intervention with 75.0% sensitivity and 83.3% specificity. A multivariable regression analysis showed that an elevated HGF was an independent predictor of an elevated CVP (β‐coefficient 21.2, SE 5.5, P = 0.0005) and decreased SvO2 (β‐coefficient −92.9, SE 12.4, P

Abstract Aims In patients with ischaemic mitral regurgitation (MR), the impact of mitral valve surgery with concomitant coronary artery bypass grafting (CABG) on post‐operative survival and left ventricular (LV) reverse remodelling remains unknown. Therefore, we investigated these outcomes following restrictive mitral annuloplasty (RMA) with and without CABG in those patients. Methods and results This study included 309 patients with chronic MR and ischaemic cardiomyopathy for whom concomitant CABG was indicated (n = 225) or not indicated (n = 84) with RMA. The primary endpoint was all cause mortality during the follow‐up, and the secondary endpoint was defined as the composite of mortality and re‐admission for heart failure. Linear mixed model was used to analyse serial echocardiographic changes in LV function. To reduce the impact of treatment bias and potential confounding in the direct comparisons between patients who underwent RMA with and those who underwent it without CABG, we established weighted Cox proportional‐hazards regression models with inverse‐probability‐of‐treatment weighting. Pre‐operatively, there were no intergroup differences in age (RMA with CABG, 67 ± 9 vs. RMA without CABG, 68 ± 11, P = 0.409) and logistic EuroSCORE II (16 ± 14 vs. 15 ± 15%, P = 0.496). The 30‐day mortalities were 2.7% and 3.6%, respectively (P = 0.67). During follow‐up with a mean duration of 72 ± 37 months (range, 5.6–179), there were 157 deaths and 105 re‐admissions for heart failure. Overall 1‐year and 5‐year survival rates were 83 ± 2% and 58 ± 3%, respectively. Patients who did not receive CABG with RMA had a significantly lower 5‐year survival rate (45% vs. 63%, P = 0.049) and freedom from adverse events defined as mortality and/or admission for heart failure (19% vs. 43%, P

Abstract Background Persistent left superior vena cava is a not uncommon congenital vascular abnormality. We report a case of heart transplantation with reconstruction of persistent left superior vena cava using a prosthetic vascular graft. Case presentation A 20-year-old man with idiopathic dilated cardiomyopathy and persistent left superior vena cava underwent orthotopic heart transplantation 2 years and 3 months after left ventricular assist device implantation. Because the persistent left superior vena cava had a larger diameter than the right superior vena cava, the transected persistent left superior vena cava was reconstructed with a prosthetic vascular graft anastomosed to the free wall of the right atrium. Postoperative enhanced computed tomography revealed good patency of the graft. The patient’s postoperative course has been uneventful during 2 years of follow-up, despite the risk of complications. Conclusions Reconstruction of a persistent left superior vena cava with a prosthetic vascular graft may be one option at the time of heart transplantation.

The loss of functional cells through immunological rejection after transplantation reduces the efficacy of regenerative therapies for cardiac failure that use allogeneic induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Recently, mixed-chimera mice with donor-specific immunotolerance have been established using the RGI-2001 (liposomal formulation of α-galactosyl ceramide) ligand, which activates invariant natural killer T (iNKT) cells. The present study aimed to investigate whether mixed chimerism, established using RGI-2001, prolongs graft survival in allogeneic iPSC-CM transplantation. Mixed-chimera mice were established via combinatorial treatment with RGI-2001 and anti-CD154 antibodies in an irradiated murine bone marrow transplant model. Luciferase-expressing allogeneic iPSC-CMs were transplanted into mixed-chimera and untreated mice, followed by in vivo imaging. RGI-2001 enhanced iNKT cell activation in mice, and mixed chimerism was successfully established. In vivo imaging revealed that while the allografts were completely obliterated within 2 weeks when transplanted to untreated mice, their survivals were not affected in the mixed-chimera mice. Furthermore, numerous CD3+ cells infiltrated allografts in untreated mice, but fewer CD3+ cells were present in mixed-chimera mice. We conclude that mixed-chimera mice established using RGI-2001 showed prolonged graft survival after allogeneic iPSC-CM transplantation. This donor-specific immunotolerance might increase the efficacy of regenerative therapies for heart failure with allogeneic iPSC-CMs.

Background Clinical effectiveness of autologous skeletal cell‐patch implantation for nonischemic dilated cardiomyopathy has not been clearly elucidated in clinical settings. This clinical study aimed to determine the feasibility, safety, therapeutic efficacy, and the predictor of responders of this treatment in patients with nonischemic dilated cardiomyopathy. Methods and Results Twenty‐four nonischemic dilated cardiomyopathy patients with left ventricular ejection fraction

Abstract Background The efficacy of cell transplantation in heart failure is reportedly modest, but adjuvant drugs combined with cell therapy may improve this efficacy. Peroxisome proliferator-activated receptor (PPAR)γ, one of the hypoglycemic medicine for diabetes mellitus, reportedly enhances cytokine production in adipose tissue-derived regenerative cells (ADRCs). We hypothesized that combined administration of PPARγ agonists and ADRCs may enhance the paracrine effects of adiponectin (APN), leading to functional recovery in a chronic myocardial infarction (MI) model. Methods ADRCs were isolated from adipose tissues of adult rats by gradient centrifugation and embedded in bio-compatible fibrin-glue to produce ADRCs grafts. In the in vitro study, the ADRCs grafts released APN, which was significantly enhanced by the PPARγ agonist (PGZ, pioglitazone). Transplantation of ADRCs grafts (group A), ADRCs mixed with PGZ (group AP), APN knockdown-ADRCs (group Si) or PGZ (group P) onto the epicardium or a sham operation (group C) was performed (n = 10–20 per group). Results The AP group showed significant improvement in ejection fraction compared to that in the other groups. In the AP group, a significantly larger number of M2-polarized macrophages was detected and existed for a significantly longer duration in the infarct area. Furthermore, comparing Si group and P group, western blotting of T-cadherin revealed that exogenous APN and local expression of T-cadherin were essential to this histological change and recovery of cardiac function. Conclusions Combined administration of PPARγ agonist and ADRSCs activated M2-polarized macrophages with enhancement of APN paracrine effects and lead to better cardiac function in a rat infarction model.

Abstract Background Dilated cardiomyopathy (DCM) is a life-threatening heart muscle disease characterized by progressive heart failure, which often requires left ventricular assist device (LVAD) implantation or heart transplantation (HTx). A tissue engineering strategy using cell sheets for end-stage heart failure has emerged in recent years. Case presentation Here, we describe a 50-year-old DCM patient with severe symptoms of heart failure with severe mitral regurgitation (MR) who was not a candidate for LVAD or HTx. The patient underwent mitral valve replacement followed by the transplantation of autologous myoblast sheets. Conclusion The patient’s clinical symptoms improved with a preservation of cardiac performance, and he has survived for over 6 years since the combined surgery. This combined method was feasible and appeared to be effective, and thus represents a promising strategy for treating severe heart failure in end-stage DCM and as an alternative treatment for selected patients who are not candidates for LVAD or HTx.

Right ventricular dysfunction is a predictor for worse outcomes in patients with congenital heart disease. Myocardial ischemia is primarily associated with right ventricular dysfunction in patients with congenital heart disease and may be a therapeutic target for right ventricular dysfunction. Previously, autologous skeletal myoblast patch therapy showed an angiogenic effect for left ventricular dysfunction through cytokine paracrine effects; however, its efficacy in right ventricular dysfunction has not been evaluated. Thus, this study aimed to evaluate the angiogenic effect of autologous skeletal myoblast patch therapy and amelioration of metabolic and functional dysfunction, in a pressure-overloaded right heart porcine model. Pulmonary artery stenosis was induced by a vascular occluder in minipigs; after two months, autologous skeletal myoblast patch implantation on the right ventricular free wall was performed (n = 6). The control minipigs underwent a sham operation (n = 6). The autologous skeletal myoblast patch therapy alleviated right ventricular dilatation and ameliorated right ventricular systolic and diastolic dysfunction. 11C-acetate kinetic analysis using positron emission tomography showed improvement in myocardial oxidative metabolism and myocardial flow reserve after cell patch implantation. On histopathology, a higher capillary density and vascular maturity with reduction of myocardial ischemia were observed after patch implantation. Furthermore, analysis of mRNA expression revealed that the angiogenic markers were upregulated, and ischemic markers were downregulated after patch implantation. Thus, autologous skeletal myoblast patch therapy ameliorated metabolic and functional dysfunction in a pressure-overloaded right heart porcine model, by alleviating myocardial ischemia through angiogenesis.

Background Extracellular matrix, especially laminin‐221, may play crucial roles in viability and survival of human‐induced pluripotent stem cell‐derived cardiomyocytes (hiPS‐CMs) after in vivo transplant. Then, we hypothesized laminin‐221 may have an adjuvant effect on therapeutic efficacy by enhancing cell viability and survival after transplantation of 3‐dimensional engineered cardiac tissue (ECT) to a rat model of myocardial infarction. Methods and Results In vitro study indicates the impacts of laminin‐221 on hiPS‐CMs were analyzed on the basis of mechanical function, mitochondrial function, and tolerance to hypoxia. We constructed 3‐dimensional ECT containing hiPS‐CMs and fibrin gel conjugated with laminin‐221. Heart function and in vivo behavior were assessed after engraftment of 3‐dimensional ECT (laminin‐conjugated ECT, n=10; ECT, n=10; control, n=10) in a rat model of myocardial infarction. In vitro assessment indicated that laminin‐221 improves systolic velocity, diastolic velocity, and maximum capacity of oxidative metabolism of hiPS‐CMs. Cell viability and lactate dehydrogenase production revealed that laminin‐221 improved tolerance to hypoxia. Furthermore, analysis of mRNA expression revealed that antiapoptotic genes were upregulated in the laminin group under hypoxic conditions. Left ventricular ejection fraction of the laminin‐conjugated ECT group was significantly better than that of other groups 4 weeks after transplantation. Laminin‐conjugated ECT transplantation was associated with significant improvements in expression levels of rat vascular endothelial growth factor. In early assessments, cell survival was also improved in laminin‐conjugated ECTs compared with ECT transplantation without laminin‐221. Conclusions In vitro laminin‐221 enhanced mechanical and metabolic function of hiPS‐CMs and improved the therapeutic impact of 3‐dimensional ECT in a rat ischemic cardiomyopathy model. These findings suggest that adjuvant laminin‐221 may provide a clinical benefit to hiPS‐CM constructs.

Abstract Complete surgical resection of chronic expanding intrapericardial hematoma was often difficult because of the severe adhesion. Preoperative coil embolization of the feeding vessels can prevent recurrent expanding of the residual hematoma and would achieve good results.

We report the case of a patient with severely calcified constrictive pericarditis and liver cirrhosis who underwent successful off-pump radical pericardiectomy. The cardiac parameters significantly improved without severe complications. We demonstrate the usefulness of off-pump surgical treatment for constrictive pericarditis with liver cirrhosis. (Level of Difficulty: Intermediate.)

Abstract Transplant of human induced pluripotent stem cell derived cardiomyocytes (hiPS-CMs) cell-sheet is a promising approach for treating ischemic cardiomyopathy (ICM). However, poor blood supply to the transplanted cell-sheet is a concern related to the effectiveness and durability of the treatment. Herein, we hypothesized that the combined the omentum flap might enhance survival and the therapeutic effects of hiPS-CM cell-sheet transplant for ICM treatment. Treatment by Wnt signaling molecules in hiPS cells produced hiPS-CMs, which were magnetically labeled by superparamagnetic iron oxide (SPIO), followed by culture in the thermoresponsive dishes to generate hiPS-CMs cell-sheets. A porcine ICM model included 4 groups; sham operation, omentum flap only, cell-sheet only, or combination therapy. Ejection fraction (EF) was significantly greater in the cell-sheet only and combination group compared to the other groups during the follow-up period. At 3 months, the EF of the combination group was significantly greater than that of the cell-sheet only group. Consistently, the survival rate of the SPIO-labeled hiPS-CMs, as assessed by MRI, was significantly greater in the combination group than in the cell-sheet only group. This cell delivery system would be useful in optimizing the hiPS-CM cell-sheet transplant for treating severe heart failure.

Abstract Background Congenital left main coronary atresia is an extremely rare coronary anomaly. Long-term surgical outcomes and the optimal management strategies for recurrence of ischemia remain uncertain. Herein, we present a case involving successful redo coronary artery bypass grafting for unstable angina 27 years after the initial coronary artery bypass grafting for congenital left main coronary atresia. Case presentation A 33-year-old woman was referred to our department with unstable angina. At the age of 6, she had undergone coronary artery bypass grafting of the second diagonal branch using the left internal thoracic artery and the obtuse marginal branch using saphenous vein grafting for left main coronary atresia. Although a coronary angiogram showed a patent left internal thoracic artery graft to the second diagonal branch and a patent saphenous vein graft to the obtuse marginal branch, the left anterior descending artery was not being perfused by the grafts because of a disruption of blood flow to the left anterior descending artery from the left internal thoracic artery. Therefore, we performed a redo coronary artery bypass grafting using the in situ right internal thoracic artery to the first diagonal branch, which was to be connected to the left anterior descending artery, resulting in amelioration of the ischemia of the left anterior wall. The patient was discharged 10 days after the operation and has been in good health for over 3 years without recurrence of chest symptoms. Conclusions Coronary revascularization using a saphenous vein and left internal thoracic artery grafts is effective in achieving an adequate blood supply to the distal coronary arteries, and this effect can last for decades. However, careful follow-up is necessary because recurrent myocardial ischemia due to the development of a coronary artery occlusion may occur in adulthood.

Cardiac sarcoma treatment is challenging for surgeons because of frequent tumor recurrence and poor prognosis. In addition, optimal management of recurrences is not well established. The multi-targeted tyrosine kinase inhibitor, pazopanib, was recently approved for soft-tissue sarcoma. Herein, we present a case involving recurrent cardiac angiosarcoma where the patient survived for 2 years with complete remission of disease after repeated surgical resection and treatment with oral pazopanib. Based on our experience, aggressive surgical resection combined with pazopanib may be a valid treatment for recurrent cardiac angiosarcoma to improve patient survival.

Allogeneic transplantation of induced pluripotent stem cell (iPSC)-derived cardiomyocytes is apromising treatment for cardiac diseases, although immune rejection by the recipient poses a concern. In this study, we aimed to investigate whether concomitant transplantation of vasculogenically conditioned peripheral blood mononuclear cells, which are otherwise immunosuppressive, may enhance graft survival. Luciferase-transduced, iPSC-derived cardiomyocytes from C57BL/6 mice were transplanted to the dorsal subcutaneous space of syngeneic C57BL/6 mice (n = 19), allogeneic Balb/c mice treated with (n = 20) or without (n = 20) immunosuppressants, and those injected with vasculogenically conditioned peripheral blood mononuclear cells (n = 20). Although graft survival, assessed by bioluminescence, was comparable among the groups initially, it improved significantly at days 7 and 10 in allogeneic transplanted mice treated with vasculogenically conditioned peripheral blood mononuclear cells than in others (P < 0.01). Our results proved that cell-based immunosuppression may boost clinical outcomes from allogeneic cell therapy.

Induced pluripotent stem cells (iPSCs) can serve as a source of cardiomyocytes (CMs) to treat end-stage heart failure; however, transplantation of genetically dissimilar iPSCs even within species (allogeneic) can induce immune rejection. We hypothesized that this might be limited by matching the major histocompatibility complex (MHC) antigens between the donor and the recipient. We therefore transplanted fluorescence-labeled (GFP) iPSC-CMs donated from a macaque with homozygous MHC haplotypes into the subcutaneous tissue and hearts of macaques having heterozygous MHC haplotypes (MHC-matched; group I) or without identical MHC alleles (group II) in conjunction with immune suppression. Group I displayed a higher GFP intensity and less immune-cell infiltration in the graft than group II. However, MHC-matched transplantation with single or no immune-suppressive drugs still induced a substantial host immune response to the graft. Thus, the immunogenicity of allogeneic iPSC-CMs was reduced by MHC-matched transplantation although a requirement for appropriate immune suppression was retained for successful engraftment.

Objective: We assessed what predicts nutritional adequacy at day 14 following implantation of left ventricular assist device (LVAD). Method: We retrospectively reviewed the cases of 97 adult patients who underwent LVAD implantation at our institution from June 2011 to June 2016. We divided the patients into two groups based on the administered enteral nutrition (EN) calories on post-operative day (POD) 14: the EN calories of group SEN (sufficient enteral nutrition) were >80% of their total target calories, or the EN calories of group IEN (insufficient enteral nutrition) were

Background Estimation of the predissected descending aortic diameter is important for deciding on the size of a stent graft in cases of acute aortic dissection. However, no equations for estimating this diameter have been previously reported. Methods and Results We developed and validated new equations by investigating computed tomography images that were scanned within 3 years before dissection and those that were scanned immediately after the onset of dissection. Among 1127 patients with acute aortic dissection (425 type A and 702 type B), 36 were matched for the study from October 2005 to March 2017 at 4 centers. New equations were developed in 17 patients and validated in 19 patients. We measured the predissected whole circumference length (CL) and postdissected whole CL, true lumen CL, the major diameter, and the minor diameter of the acutely dissected aorta, followed by calculation of (post‐trueCL+post‐wholeCL)/2 and (post–major diameter+post—minor diameter)/2. Six equations (linear function) and modified equations were derived from each of the above‐mentioned parameters. In the derivation sets, equations that used the parameter of (post‐trueCL+post‐wholeCL)/2 were strongly correlated with pre‐wholeCL (Y=0.9433x+5.0147; R2=0.9001) and showed significantly less bias compared with the other 5 equations (P

Restrictive cardiomyopathy (RCM) is a rare form of cardiomyopathy that is characterized by restrictive ventricular filling. Elevated filling pressure leads to pulmonary hypertension (PH), which often progresses to combined post- and pre-capillary PH (Cpc-PH) with increased diastolic pulmonary vascular pressure gradient (DPG) and pulmonary vascular resistance (PVR) caused by longstanding backward hemodynamic consequences of left heart disease (LHD) leading to morphological changes in the pulmonary vasculature. Patients with high PVR undergoing left ventricular assist device (LVAD) implantation are at increased risk of postoperative right-sided heart failure requiring concomitant implantation of a right ventricular assist device (RVAD). We report a case of RCM with severe Cpc-PH due to extremely elevated DPG and PVR. The patient presented recurrent syncope caused by severe PH. Right heart catheterization (RHC) revealed highly elevated DPG 30 mmHg and PVR 25.3 Wood units (WU) and subsequent significant reduction of right ventricular afterload during vasoreactivity testing with inhaled nitric oxide (NO) to DPG 5 mmHg and PVR 10.5 WU. During the administration of pulmonary vasodilators, pulmonary congestion worsened. Second RHC revealed elevated pulmonary arterial wedge pressure (PAWP) and modest decrease of pulmonary arterial pressure (PAP) 87 mmHg and PVR 9.6 WU. Therefore, an inotropic agent and systemic vasodilator were added for the treatment of left-sided heart failure. Targeting elevated filling pressures with both PAH-specific and heart failure treatment, a further decrease of right ventricular afterload with DPG of 5 mmHg and PVR of 3.8 WU was achieved. In a next step, LVAD was successfully implanted, without need for RVAD, as a bridge to transplantation. This is the first reported case of Cpc-PH that revealed the potential reversibility of extremely elevated DPG and PVR, and suggests the importance of preoperative RHC-guided optimized medical PAH-specific and heart failure treatment before LVAD implantation.

ObjectivesWe hypothesized that systemic administration of high-mobility group box 1 fragment attenuates the progression of myocardial fibrosis and cardiac dysfunction in a hamster model of dilated cardiomyopathy by recruiting bone marrow mesenchymal stem cells thus causing enhancement of a self-regeneration system.MethodsTwenty-week-old J2N-k hamsters, which are δ-sarcoglycan-deficient, were treated with systemic injection of high-mobility group box 1 fragment (HMGB1, n = 15) or phosphate buffered saline (control, n = 11). Echocardiography for left ventricular function, cardiac histology, and molecular biology were analyzed. The life-prolonging effect was assessed separately using the HMGB1 and control groups, in addition to a monthly HMGB1 group which received monthly systemic injections of high-mobility group box 1 fragment, 3 times (HMGB1, n = 11, control, n = 9, monthly HMGB1, n = 9).ResultsThe HMGB1 group showed improved left ventricular ejection fraction, reduced myocardial fibrosis, and increased capillary density. The number of platelet-derived growth factor receptor-alpha and CD106 positive mesenchymal stem cells detected in the myocardium was significantly increased, and intra-myocardial expression of tumor necrosis factor α stimulating gene 6, hepatic growth factor, and vascular endothelial growth factor were significantly upregulated after high-mobility group box 1 fragment administration. Improved survival was observed in the monthly HMGB1 group compared with the control group.ConclusionsSystemic high-mobility group box 1 fragment administration attenuates the progression of left ventricular remodeling in a hamster model of dilated cardiomyopathy by enhanced homing of bone marrow mesenchymal stem cells into damaged myocardium, suggesting that high-mobility group box 1 fragment could be a new treatment for dilated cardiomyopathy.

BackgroundThe prevalence of cerebral microbleeds (CMBs) in gradient echo T2*‐weighted brain MRI has a positive correlation with hemorrhagic stroke incidence. However, the prevalence of CMBs in patients with left ventricular assist devices (LVADs) has not been evaluated. We evaluated the prevalence of CMBs and the relationship with hemorrhagic stroke incidence in patients with LVADs. Method and ResultsWe analyzed results from brain MRI in prospective examinations of 35 consecutive patients who had undergone LVAD explantation for heart transplantation or recovery since 2011. The number and distribution of CMBs were counted, then the relationship between baseline characteristics and adverse events during LVAD support were analyzed. The mean age was 37.7±12.4 years and the mean LVAD duration was 2.43±1.08 years. Thirty‐four (97%) patients had at least one CMB. Nine (26%) developed hemorrhagic stroke during LVAD support, and patients with hemorrhagic stroke had a significantly greater number of CMBs compared with patients without hemorrhagic stroke (5 [interquartile range (IQR), 4–7] versus 9 [IQR, 5–23]; odds ratio 1.14 [95% Confidence Interval (CI), 1.02–1.32], P=0.05). There was no significant relationship between age, LVAD support duration, or systolic blood pressure during LVAD. However, patients who had at least one episode of bacteremia (9 [IQR, 4–16] versus 5 [IQR, 3–7], P=0.06) and pump pocket infection (14 [IQR, 4–27] versus 5 [IQR, 3–7], P=0.08) showed a trend toward a greater number of CMBs than patients without bacteremia. ConclusionsThirty‐four (97%) patients with continuous‐flow LVAD had at least one CMB, and the number of CMBs were more prevalent in patients with hemorrhagic stroke and in patients with LVAD‐related infection.

BackgroundWhen transplanted into failing heart, autologous somatic tissue–derived cells yield functional recovery via paracrine effects that enhance native regeneration. However, the therapeutic effects are modest. We developed a method in which scaffold‐free cell sheets are attached to the epicardial surface to maximize paracrine effects. This Phase I clinical trial tested whether transplanting autologous cell–sheets derived from skeletal muscle is feasible, safe, and effective for treating severe congestive heart failure. Methods and ResultsFifteen ischemic cardiomyopathy patients and 12 patients with dilated cardiomyopathy, who were in New York Heart Association functional class II or III and had been treated with the maximum medical and/or interventional therapies available, were enrolled. Scaffold‐free cell sheets of 3 to 9×108 cells derived from autologous muscle were transplanted over the LV free wall via left thoracotomy, without additional interventional treatments. There were no procedure‐related major complications during follow‐up. The majority of the ischemic cardiomyopathy patients showed marked symptomatic improvement in New York Heart Association classification (pre: 2.9±0.5 versus 6 months: 2.1±0.4, P

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. The rats with distal coronary ligation presented myocardial infarction localized to an anterior territory irrespective of LCX branching pattern. In the rats with proximal coronary ligation, 64% (n = 16) had broad myocardial infarction involving the anterior and lateral territories, while the remainder (36%, n = 9) had myocardial infarction localized to an anterior territory with the intact LCX arising proximally from a short LMCA. The interventricular septum was spared from infarction in all rats because of its anatomical location. Infarct size variations were caused not only by ligation site but also by varying LCX branching patterns. There are potential risks to create different sizes of myocardial infarction, particularly when targeting a broad range of myocardial infarction. The territory of the septal artery always appears to be spared from myocardial infarction induced by the coronary ligation technique.

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 18F-DPA-714-PET imaging study. iPSC-CM cell-sheets of C57BL/6 mice origin were transplanted on the surface of the left ventricle (LV) of C57BL/6 mice as a syngeneic cell-transplant model (syngeneic Tx group), or Balb/c mice as an allogeneic model (allogeneic Tx group). 18F-DPA-714-PET was used to determine the uptake ratio, calculated as the maximum standardized uptake value in the anterior and septal wall of the LV. The uptake ratio was significantly higher in the allogeneic Tx group than in the syngeneic group or the sham group at days 7 and day 10 after the cell transplantation. In addition, the immunochemistry showed significant presence of CD68 and CD3-positive cells at day 7 and 10 in the transplanted graft of the allogeneic Tx group. The expression of TSPO, CD68, IL-1 beta, and MCP-1 was significantly higher in the allogeneic Tx group than in the syngeneic Tx and the sham groups at day 7. The 18F-DPA-714-PET imaging study enabled quantitative visualization of the macrophages-mediated immune rejection of the allogeneic iPSC-cardiac. This imaging tool may enable the understanding and monitoring host-immune response of the host, allogeneic cell transplantation therapy.

Cell surface glycans vary widely, depending on cell properties. We hypothesized that glycan expression on induced pluripotent stem cells (iPSCs) might change during cardiomyogenic differentiation toward the myocardial phenotype. N-glycans were isolated from iPSCs, iPSC-derived cardiomyocytes (iPSC-CM), and original C57BL/6 mouse myocardium (Heart). Their structures were analyzed by a mapping technique based on HPLC elution times and MALDI-TOF/MS spectra. Sixty-eight different N-glycans were isolated; the structures of 60 of these N-glycans were identified. The quantity of high-mannose type (immature) N-glycans on the iPSCs decreased with cardiomyogenic differentiation, but did not reach the low levels observed in the heart. We observed a similar reduction in neutral N-glycans and an increase in fucosylated or sialyl N-glycans. Some structural differences were detected between iPSC-CM and Heart. No N-glycolyl neuraminic acid (NeuGc) structures were detected in iPSC-CM, whereas the heart contained numerous NeuGc structures, corresponding to the expression of cytidine monophosphate-N-acetylneuraminic acid hydroxylase. Furthermore, several glycans containing Galα1-6 Gal, rarely identified in the other cells, were detected in the iPSC-CM. The expression of N-glycan on murine iPSCs changed toward the myocardial phenotype during cardiomyogenic differentiation, leaving the structural differences of NeuGc content or Galα1-6 Gal structures. Further studies will be warranted to reveal the meaning of the difference of N-glycans between the iPSC-CM and the myocardium.