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Transcatheter mitral valve repair with the MitraClip system has been established in selected high-risk patients. The MitraClip procedure results in a relatively large iatrogenic atrial septal defect (iASD). This study aimed to investigate the prevalence and clinical course of iASD requiring transcatheter closure following the MitraClip procedure.Methods and Results: This study was conducted at all 59 institutions that perform transcatheter mitral valve repair with the MitraClip system in Japan. The data of patients on whom transcatheter iASD closure was performed were collected. Of the 2,722 patients who underwent the MitraClip procedure, 30 (1%) required transcatheter iASD closure. The maximum iASD size was 9±4 mm (range, 3-18 mm). The common clinical course of transcatheter iASD closure was hypoxemia with right-to-left shunt or right-sided heart failure with left-to-right shunt. Of the 30 patients, 22 (73%) required transcatheter closure within 24 h following the MitraClip procedure, including 12 with hypoxemia and 5 with right-sided heart failure complicated with cardiogenic shock. Of the 5 patients, 2 required mechanical circulatory support devices. Twenty-one patients immediately underwent transcatheter iASD closure, and hemodynamic deteriorations were resolved; however, 1 patient died without having undergone transcatheter closure.Transcatheter iASD closure was required in 1% of patients who underwent the MitraClip procedure. Many of these patients immediately underwent transcatheter iASD closure because of hypoxemia with right-to-left shunt or right-sided heart failure with left-to-right shunt.

Objectives: The aim of this study is to establish a guidance for device retrieval based on comprehensive bench tests. Background: Device embolisation remains a major complication in transcatheter closure of atrial septal defect and patent ductus arteriosus. Although percutaneous retrieval is feasible in the majority of cases, surgical retrieval may be required in complicated circumstances. However, the methods of transcatheter device retrieval have not been completely established. Methods: Bench tests of device retrieval were performed to verify the appropriate retrieval method according to device type/size. The devices used for testing were Amplatzer Septal Occluder (Abbott, Chicago, IL, United States of America), Figulla Flex II (Occlutech GmbH, Jena, Germany), Amplatzer Duct Occluder-I (Abbott), Amplatzer Duct Occluder-II (Abbott), and Amplatzer Vascular Plug-II (Abbott). The retrieval equipment constituted diagnostic catheters (multipurpose catheter and right Judkins catheter, 4-Fr or 5-Fr, Gadelius Medical, Tokyo, Japan), delivery sheath and cables for each device, Amplatz goose neck snares (Medtronic, Minneapolis, MN, United States of America), OSYPKA CATCHER (Osypka ag, Rheinfelden-Herten, Germany), and OSYPKA LASSOS (Osypka). We investigated the retrieval equipment and sheath sizes required for a successful retrieval procedure for variously sized devices. Results: For patent ductus arteriosus devices, the type of snare and the snaring position are considered important. For atrial septal defect devices, simple snare capture or a double-snare technique with a sufficiently large sheath is effective. Special care should be taken when using the OSYPKA CATCHER for device retrieval. Conclusions: The results of this study may assist in the selection of both capture devices and a retrieval sheath or a catheter for complete retrieval.

The emergence of human induced pluripotent stem cells (hiPSCs) has revealed the potential for curing end-stage heart failure. Indeed, transplantation of hiPSC-derived cardiomyocytes (hiPSC-CMs) may have applications as a replacement for heart transplantation and conventional regenerative therapies. However, there are several challenges that still must be overcome for clinical applications, including large-scale production of hiPSCs and hiPSC-CMs, elimination of residual hiPSCs, purification of hiPSC-CMs, maturation of hiPSC-CMs, efficient engraftment of transplanted hiPSC-CMs, development of an injection device, and avoidance of post-transplant arrhythmia and immunological rejection. Thus, we developed several technologies based on understanding of the metabolic profiles of hiPSCs and hiPSC derivatives. In this review, we outline how to overcome these hurdles to realize the transplantation of hiPSC-CMs in patients with heart failure and introduce cutting-edge findings and perspectives for future regenerative therapy.

In patients with atrial septal defect (ASD), atrial left-to-right shunting causes left atrial (LA) remodeling and dysfunction, leading to atrial fibrillation (AF). In adults with ASD and concomitant AF, LA function should be evaluated after ASD closure plus AF radiofrequency catheter ablation (RFCA).This multicenter retrospective cohort study included patients who underwent transcatheter ASD closure at one of the four leading hospitals. Patients with a history of AF also underwent preceding RFCA. The association between AF history and LA ejection fraction (EF) (indicating LA global function) at 6-12 months following ASD closure was evaluated. To account for differences in baseline characteristics between patients with and without a history of AF, we conducted the following statistical methods: (1) multivariate regression analysis in the prepropensity score (PS)-matched cohort and (2) univariate comparisons in the PS-matched cohort.Overall, this study included 231 patients (30 with AF history, 201 without). Multiple regression analysis showed that AF history was independently associated with impaired LAEF (β = -10.425, P0.001, model created prior to propensity matching). A one-to-one PS matching (25 pairs) showed that the LAEF at 6-12 months following ASD closure was significantly impaired in patients with ASD and AF history compared to that in patients without history of AF (median LAEF, 37.5% (interquartile range [IQR] 29.4%-48.5%) versus 52.3 [IQR 50.0%-56.6%]; P0.001).LA function was impaired in patients with ASD and a history of AF at 6-12 months after successful transcatheter ASD closure and on maintenance of sinus rhythm by RFCA.

The authors have withdrawn their manuscript because they decided to modify their analysis because of how the imaging devices are employed in the real-world practice in Japan. Instead of simply comparing ICE vs. TEE patients, they decided that 3-way comparison comparing patients that underwent ASD closure with ICE alone vs. TEE alone vs Both Modalities is more practical and send clinically useful messages to the practicing physicians. Since it is highly likely that the above analysis will alter subsequent conclusions, the authors decided to withdraw the present version of their manuscript. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

The heart is electrically and mechanically controlled by the autonomic nervous system, which consists of both the sympathetic and parasympathetic systems. It has been considered that the sympathetic and parasympathetic nerves regulate the cardiomyocytes’ performance independently; however, recent molecular biology approaches have provided a new concept to our understanding of the mechanisms controlling the diseased heart through the plasticity of the autonomic nervous system. Studies have found that cardiac sympathetic nerve fibers in hypertrophic ventricles strongly express an immature neuron marker and simultaneously cause deterioration of neuronal cellular function. This phenomenon was explained by the rejuvenation of cardiac sympathetic nerves. Moreover, heart failure and myocardial infarction have been shown to cause cholinergic trans-differentiation of cardiac sympathetic nerve fibers via gp130-signaling cytokines secreted from the failing myocardium, affecting cardiac performance and prognosis. This phenomenon is thought to be one of the adaptations that prevent the progression of heart disease. Recently, the concept of using device-based neuromodulation therapies to attenuate sympathetic activity and increase parasympathetic (vagal) activity to treat cardiovascular disease, including heart failure, was developed. Although several promising preclinical and pilot clinical studies using these strategies have been conducted, the results of clinical efficacy vary. In this review, we summarize the current literature on the plasticity of cardiac sympathetic nerves and propose potential new therapeutic targets for heart disease.

Although the association between cardiac dysfunction and subarachnoid hemorrhage (SAH) has been recognized, its precise underlying mechanism remains unknown. Furthermore, no suitable animal models are available to study this association. Here, we established an appropriate animal model of SAH-induced cardiac dysfunction and elucidated its mechanism. In this rat model, contrast-enhanced computed tomography of the brain confirmed successful induction of SAH. Electrocardiography detected abnormalities in 55% of the experimental animals, while echocardiography indicated cardiac dysfunction in 30% of them. Further evaluation of left ventriculography confirmed cardiac dysfunction, which was transient and recovered over time. Additionally, in this SAH model, the expression of the acute phase reaction protein, proto-oncogene c-Fos increased in the paraventricular hypothalamic nucleus (PVN), the sympathetic nerve center of the brain. Polymerase chain reaction analysis revealed that the SAH model with cardiac dysfunction had higher levels of the macrophage-associated chemokine (C-X-C motif) ligand 1 (CXCL-1) and chemokine (C-C motif) ligand 2 (CCL-2) than the SAH model without cardiac dysfunction. Our results suggested that SAH caused inflammation and macrophage activation in the PVN, leading to sympathetic hyperexcitability that might cause cardiac dysfunction directly and indirectly. This animal model may represent a powerful tool to investigate the mechanisms of the brain-heart pathway.

One of the mechanisms of severe dysphagia due to lateral medullary syndrome may be a reversed pressure gradient caused by incoordination of pharyngeal contractility and UES opening during swallowing.

Visual Abstract, Highlights • hiPSCs are differentiated into CMs with large-scale 2-dimensional culture system, and refined by metabolic purification. • hiPSC-derived CMs are developed into CSs in special microwell plates. • Intramyocardial transplantation of CSs and GH improves cardiac function in small and large animal models. • Engraftment of CMs and angiogenesis are mechanisms for improvement of cardiac function. • Intramyocardial transplantation of CSs with a transplant injection device is a safe, effective, and feasible strategy for the treatment of HF., Summary The severe shortage of donor hearts hampered the cardiac transplantation to patients with advanced heart failure. Therefore, cardiac regenerative therapies are eagerly awaited as a substitution. Human induced pluripotent stem cells (hiPSCs) are realistic cell source for regenerative cardiomyocytes. The hiPSC-derived cardiomyocytes are highly expected to help the recovery of heart. Avoidance of teratoma formation and large-scale culture of cardiomyocytes are definitely necessary for clinical setting. The combination of pure cardiac spheroids and gelatin hydrogel succeeded to recover reduced ejection fraction. The feasible transplantation strategy including transplantation device for regenerative cardiomyocytes are established in this study.

Patient Palatal lift prostheses (PLPs) are used for dysarthria caused by velopharyngeal incompetence (VPI) and improving hypernasal speech. In this case, we used a PLP with a flexible lift (f-PLP) in a patient with dysphagia associated with VPI due to right-sided cranial nerve injuries after a skull base surgery. We examined its efficacy in swallowing biomechanics and swallowing function using high-resolution manometry (HRM) and videofluoroscopic examination of swallowing (VF). The patient felt that it was easier to swallow with f-PLP. Furthermore, VF indicated that the pharyngeal residue with f-PLP was less than without it. HRM showed that velopharyngeal pressure and intrabolus pressure (IBP) with f-PLP were higher than those without it. Additionally, the upper esophageal sphincter (UES) relaxation time and UES nadir pressure on the patient's healthy left side compared to the right side improved with f-PLP. Discussion We discovered two clinical outcomes. First, the f-PLP ensured velopharyngeal closure and an increase in the hypopharyngeal IBP, which potentially improved the UES opening on the healthy side. Second, the f-PLP improved pharyngeal clearance, and the patient felt that it was easier to swallow with the f-PLP. This implies that an f-PLP potentially exhibits a positive effect on swallowing. Conclusions In this case, the f-PLP contributed to improving the pharyngeal passage of a bolus. We suggest that f-PLPs can be used for patients with dysarthria and those with dysphagia with VPI.

Detail morphological evaluation for ASD is essential to achieve successful transcatheter closure. Three-dimensional transesophageal echocardiography (3D-TEE) is emerging, but few studies have comprehensively verified the usefulness of 3D-TEE. We divided 329 patients who underwent transcatheter ASD closure at our university hospital into 157 in the Conventional group evaluated with 2-dimensional transesophageal echocardiography and balloon sizing (BS), and 172 in the 3D-TEE group evaluated with 3D-TEE additionally. We assessed usefulness of 3D-TEE and consider appropriate device selection procedure. Overall, the percentage with re-sizing of device tended to be lower in the 3D-TEE group than in the Conventional group (10.1% vs 6.0%, p = 0.187). Among preprocedural modalities, the device size was mainly decided based on the BS diameter. A logistic regression analysis demonstrated that large atrial septum aneurysms (ASA) were associated with a ≥ 2 mm discrepancy of the BS diameter from the preprocedural 3D-TEE diameter (p

The number of patients with heart failure (HF) is increasing with aging in our society worldwide. Patients with HF who are resistant to medication and device therapy are candidates for heart transplantation (HT). However, the shortage of donor hearts is a serious issue. As an alternative to HT, cardiac regenerative therapy using human pluripotent stem cells (hPSCs), such as human embryonic stem cells and induced pluripotent stem cells, is expected to be realized. Differentiation of hPSCs into cardiomyocytes (CMs) is facilitated by mimicking normal heart development. To prevent tumorigenesis after transplantation, it is important to eliminate non-CMs, including residual hPSCs, and select only CMs. Among many CM selection systems, metabolic selection based on the differences in metabolism between CMs and non-CMs is favorable in terms of cost and efficacy. Large-scale culture systems have been developed because a large number of hPSC-derived CMs (hPSC-CMs) are required for transplantation in clinical settings. In large animal models, hPSC-CMs transplanted into the myocardium improved cardiac function in a myocardial infarction model. Although post-transplantation arrhythmia and immune rejection remain problems, their mechanisms and solutions are under investigation. In this manner, the problems of cardiac regenerative therapy are being solved individually. Thus, cardiac regenerative therapy with hPSC-CMs is expected to become a safe and effective treatment for HF in the near future. In this review, we describe previous studies related to hPSC-CMs and discuss the future perspectives of cardiac regenerative therapy using hPSC-CMs.

ObjectiveTherapeutic strategies for atrial septal defect (ASD) with severe pulmonary arterial hypertension (PAH) are controversial. This study aimed to evaluate the efficacy of PAH-specific medications and subsequent transcatheter closure (ie, treat-and-repair strategy) on clinical outcomes.MethodsWe enrolled 42 patients who were referred to 13 institutions for consideration of ASD closure with concomitant PAH and underwent the treat-and-repair strategy. The endpoint was cardiovascular death or hospitalisation due to heart failure or exacerbated PAH.ResultsAt baseline prior to PAH-specific medications, pulmonary to systemic blood flow ratio (Qp:Qs), pulmonary vascular resistance (PVR), and mean pulmonary artery pressure (PAP) were 1.9±0.8, 6.9±3.2 Wood units and 45±15 mm Hg. Qp:Qs was increased to 2.4±1.2, and PVR and mean PAP were decreased to 4.0±1.5 Wood units and 35±9 mm Hg at the time of transcatheter ASD closure after PAH-specific medications. Transcatheter ASD closure was performed without any complications. During a median follow-up period of 33 months (1–126 months) after transcatheter ASD closure, one older patient died and one patient was hospitalised due to heart failure, but the other patients survived with an improvement in WHO functional class. PAP was further decreased after transcatheter ASD closure.ConclusionsThe treat-and-repair strategy results in low complication and mortality rates with a reduction in PAP in selected patients with ASD complicated with PAH who have a favourable response of medical therapy.

Summary Human pluripotent stem cells (hPSCs) have a unique metabolic signature for maintenance of pluripotency, self-renewal, and survival. Although hPSCs could be potentially used in regenerative medicine, the prohibitive cost associated with large-scale cell culture presents a major barrier to the clinical application of hPSC. Moreover, without a fully characterized metabolic signature, hPSC culture conditions are not optimized. Here, we performed detailed amino acid profiling and found that tryptophan (TRP) plays a key role in the proliferation with maintenance of pluripotency. In addition, metabolome analyses revealed that intra- and extracellular kynurenine (KYN) is decreased under TRP-supplemented conditions, whereas N-formylkynurenine (NFK), the upstream metabolite of KYN, is increased thereby contributing to proliferation promotion. Taken together, we demonstrate that TRP is indispensable for survival and proliferation of hPSCs. A deeper understanding of TRP metabolism will enable cost-effective large-scale production of hPSCs, leading to advances in regenerative medicine., Graphical Abstract, Highlights • TRP is the only AA that enables enhanced hPSC proliferation by supplementation • hPSCs proliferate with pluripotency after long-term culture in TRP supplementation • The proliferative properties of hPSCs are independent of AhR signaling • TRP-derived NFK contributes to enhanced hPSC proliferation, Cell Biology; Metabolomics; Stem Cell Research

New-onset atrial tachyarrhythmia (ATA) often develops after atrial septal defect (ASD) closure. Its development raises some potential concerns such as stroke and bleeding complications caused by anticoagulant therapy and limited access to the left atrium for catheter ablation. Although it is essential to identify the risk factors of new-onset ATA, few studies have examined these factors. This study investigated unknown risk factors for the development of new-onset ATA after transcatheter ASD closure in patients without a history of ATA.A total of 238 patients without a history of ATA, aged ≥18 years and who underwent transcatheter ASD closure at the current hospital were reviewed. Patient characteristics were compared between the groups with and without new-onset ATA. The factors associated with new-onset ATA were examined using univariate and multivariable analyses.Thirteen (13) (5.5%) patients experienced ATA during follow-up (mean, 21±14 months). Compared with patients without new-onset ATA, patients with new-onset ATA were older (48±18 vs 66±11 years; p0.001) and had high brain natriuretic peptide (BNP) levels (36±36 vs 177±306 pg/mL; p0.001). On multivariable analysis, BNP ≥40 pg/mL before ASD closure was associated with new-onset ATA after adjusting for age (OR, 4.91; 95% CI, 1.22-19.8; p=0.025).Patients with BNP levels40 pg/mL before transcatheter ASD closure may have a higher risk of developing new-onset ATA.

Detail morphological evaluation for ASD is essential to achieve successful transcatheter closure. Three-dimensional transesophageal echocardiography (3D-TEE) is emerging, but few studies have comprehensively verified the usefulness of 3D-TEE. We divided 329 patients who underwent transcatheter ASD closure at our university hospital into 157 in the Conventional group evaluated with 2-dimensional transesophageal echocardiography and balloon sizing (BS), and 172 in the 3D-TEE group evaluated with 3D-TEE additionally. We assessed usefulness of 3D-TEE and consider appropriate device selection procedure. Overall, the percentage with re-sizing of device tended to be lower in the 3D-TEE group than in the Conventional group (10.1% vs 6.0%, p = 0.187). Among preprocedural modalities, the device size was mainly decided based on the BS diameter. A logistic regression analysis demonstrated that large atrial septum aneurysms (ASA) were associated with a ≥ 2 mm discrepancy of the BS diameter from the preprocedural 3D-TEE diameter (p 0.05). Compared to the Amplatzer Septal Occluder, the differences in device size and the preprocedural ASD measurement were greater when using the Occlutech Figulla Flex II Occluder (FFII). Particularly, among the patients implanted with FFIIs, the discrepancies of the device size from the 3D-TEE measurement were greater in patients with large ASA than those with small ASA. Preprocedural 3D-TEE is useful to select the appropriate device size. Particularly, it is necessary to select a much larger device than that derived from the preprocedural 3D-TEE measurement when using FFII in patients with a septal aneurysm.

Background: Associated laryngeal paralysis (ALP) is defined as vagus nerve impairment combined with other lower cranial nerve paralysis. Traumatic ALP is reported infrequently. Case: A 72-year-old man was injured on the back of the head when a large tree fell on him; he was admitted to a general hospital, where he was diagnosed with brain concussion and Guillain-Barre syndrome (GBS). The patient developed aspiration pneumonia due to severe dysphagia. Although he underwent treatment and rehabilitation for 6 months, some disabilities persisted, and a percutaneous endoscopic gastrostomy tube was placed. Six months after the accident, the patient was transferred to our rehabilitation hospital. Videoendoscopic examination and videofluoroscopy revealed persistent upper esophageal sphincter (UES) opening, left dominant bilateral IX and X nerve paralysis, and left XII nerve paralysis; moreover, these examinations showed that the swallowing reflex was absent, although a bolus could pass through the UES. We suspected that the patient’s condition was not GBS and performed head computed tomography and magnetic resonance imaging; these revealed a bone fracture at the skull base. Consequently, the patient’s diagnosis was changed to bilateral ALP. He received swallowing rehabilitation for 2 months and could orally consume alternative nutrition. Finally, the patient was able to eat orally texture-modified foods (Food Intake LEVEL Scale level 8). Discussion: While post-trauma dysphagia due to bilateral ALP might be severe, patients can regain the ability to eat orally if clinicians understand the etiology of dysphagia and provide appropriate swallowing rehabilitation techniques, including patient position adjustment while eating and selection of food textures.

Summary Cardiac regenerative therapies utilizing human induced pluripotent stem cells (hiPSCs) are hampered by ineffective large-scale culture. hiPSCs were cultured in multilayer culture plates (CPs) with active gas ventilation (AGV), resulting in stable proliferation and pluripotency. Seeding of 1 × 106 hiPSCs per layer yielded 7.2 × 108 hiPSCs in 4-layer CPs and 1.7 × 109 hiPSCs in 10-layer CPs with pluripotency. hiPSCs were sequentially differentiated into cardiomyocytes (CMs) in a two-dimensional (2D) differentiation protocol. The efficiency of cardiac differentiation using 10-layer CPs with AGV was 66%–87%. Approximately 6.2–7.0 × 108 cells (4-layer) and 1.5–2.8 × 109 cells (10-layer) were obtained with AGV. After metabolic purification with glucose- and glutamine-depleted and lactate-supplemented media, a massive amount of purified CMs was prepared. Here, we present a scalable 2D culture system using multilayer CPs with AGV for hiPSC-derived CMs, which will facilitate clinical applications for severe heart failure in the near future., Graphical Abstract, Highlights • Efficient mass production of hiPSCs by multilayer culture plates with AGV • Efficient mass production of hiPSC-CMs using a massive 2D culture system with AGV • Mass production of pure hiPSC-CMs via metabolic selection, In this article, Fujita and colleagues show that human induced pluripotent stem cells (hiPSCs) and hiPSC-derived cardiomyocytes (hiPSC-CMs) are stably and efficiently produced using multilayer culture plates with an active gas ventilation system because of stable CO2 and O2 concentration in culture media. Large numbers of obtained hiPSC-CMs are metabolically purified under glucose- and glutamine-depleted and lactate-supplemented conditions.

Sleep-disordered breathing (SDB) or short sleep duration and coronary artery disease (CAD) are related, yet, the prevalence of SDB and short sleep duration as well as their mechanism remain unknown. Enhanced vascular inflammation is also implicated as one of the pathophysiologic mechanisms in CAD. The aims of this study were to evaluate the prevalence of patients with SDB and short sleep duration, and to examine their relationship with serum C-reactive protein (CRP) level in CAD patients.We evaluated 161 CAD patients who underwent percutaneous coronary intervention, using nocturnal pulse oximetry, a non-invasive screening method for nocturnal intermittent hypoxia. Based on three percent oxygen desaturation index (3% ODI), the patients were divided into nocturnal intermittent hypoxia (3% ODI ≥ 15; n = 45) and control groups (3% ODI 15, n = 116). The nocturnal intermittent hypoxia group had higher body mass index and serum CRP level compared with the control group. Short sleep duration (6 h, n = 45) was also associated with increased CRP level compared with the control group (≥6 h, n = 116). In multiple regression analysis, nocturnal intermittent hypoxia (β = 0.332, 95% confidence interval [CI] 0.102-0.562, P = 0.005) and short sleep duration (β = 0.311, 95% CI 0.097-0.526, P = 0.005) were both independent determinants for log serum CRP level.Nocturnal intermittent hypoxia and short sleep duration were independently associated with elevated serum CRP level in CAD patients, suggesting that both SDB and sleep shortage are associated with enhanced inflammation in CAD patients. SDB and sleep duration may be important modifiable factors in the clinical management of patients with CAD.

BackgroundAtrial septal defect (ASD) and patent ductus arteriosus (PDA) are both common congenital heart diseases, but the combination of these two cardiac defects is extremely rare, and the therapeutic strategy is controversial.Case summaryWe treated an adult patient with combined ASD and PDA, and safely attained a successful outcome with two-stage transcatheter closure, which is PDA closure preceding ASD closure, to prevent serious complications.DiscussionTranscatheter closure of one of the defects is now widely accepted as an alternative to surgical closure. In addition, adults with both ASD and PDA are better suited for transcatheter closure than surgical closure. One of the reasons is the difficulty to ligate the ductus arteriosus of an adult patient due to its friability and calcification. Meanwhile, simultaneous combined transcatheter closure of ASD and PDA can result in serious complications, such as thrombocytopenia and haemolysis, whose mechanism is considered to be the destruction of platelets and red blood cells by the residual shunt through implanted devices. Additionally, antiplatelet therapy that prevents device-related thrombus formation after ASD closure can possibly exacerbate thrombocytopenia and haemolysis. Therefore, the staged strategy is reasonable from the perspectives of antiplatelet therapy and haemodynamic changes.

Immunogenicity of immature pluripotent stem cells is a topic of intense debate. Immunogenic antigens, which are specific in pluripotent states, have not been described previously. In this study, we identified glypican-3 (GPC3), a known carcinoembryonic antigen, as a pluripotent state-specific immunogenic antigen. Additionally, we validated the applicability of human leukocyte antigen (HLA)-class I-restricted GPC3-reactive cytotoxic T lymphocytes (CTLs) in the removal of undifferentiated pluripotent stem cells (PSCs) from human induced pluripotent stem cell (hiPSC)-derivatives. HiPSCs uniquely express GPC3 in pluripotent states and were rejected by GPC3-reactive CTLs, which were sensitized with HLA-class I-restricted GPC3 peptides. Furthermore, GPC3-reactive CTLs selectively removed undifferentiated PSCs from hiPSC-derivatives in vitro and inhibited tumor formation in vivo. Our results demonstrate that GPC3 works as a pluripotent state-specific immunogenic antigen in hiPSCs and is applicable to regenerative medicine as a method of removing undifferentiated PSCs, which are the main cause of tumor formation.

The nervous system and cardiovascular system develop in concert and are functionally interconnected in both health and disease. This white paper focuses on the cellular and molecular mechanisms that underlie neural-cardiac interactions during development, during normal physiological function in the mature system, and during pathological remodelling in cardiovascular disease. The content on each subject was contributed by experts, and we hope that this will provide a useful resource for newcomers to neurocardiology as well as aficionados.

Human pluripotent stem cells (hPSCs) are uniquely dependent on aerobic glycolysis to generate ATP. However, the importance of oxidative phosphorylation (OXPHOS) has not been elucidated. Detailed amino acid profiling has revealed that glutamine is indispensable for the survival of hPSCs. Under glucose- and glutamine-depleted conditions, hPSCs quickly died due to the loss of ATP. Metabolome analyses showed that hPSCs oxidized pyruvate poorly and that glutamine was the main energy source for OXPHOS. hPSCs were unable to utilize pyruvate-derived citrate due to negligible expression of aconitase 2 (ACO2) and isocitrate dehydrogenase 2/3 (IDH2/3) and high expression of ATP-citrate lyase. Cardiomyocytes with mature mitochondria were not able to survive without glucose and glutamine, although they were able to use lactate to synthesize pyruvate and glutamate. This distinguishing feature of hPSC metabolism allows preparation of clinical-grade cell sources free of undifferentiated hPSCs, which prevents tumor formation during stem cell therapy.

A 58-year-old woman visited the emergency room for faintness on exertion 1 month after treatment of an atrial septal defect (ASD) by transcatheter closure (Amplatzer septal occluder [ASO], St. Jude Medical, St. Paul, Minnesota). An electrocardiogram showed advanced atrioventricular (AV) block ([

BACKGROUND Induced pluripotent stem cell (iPSC)‒based regenerative therapy is a promising strategy for cardiovascular disease treatment ; however, the method is limited by the myocardial retention of grafted iPSCs. Thus, an injection protocol that efficiently introduces and retains human iPSC-derived cardiomyocytes (hiPSC-CMs) within the myocardium is urgently needed. The objective of the present study was to develop a method to improve the retention of hiPSCs in the myocardium for cardiac therapy. METHODS We efficiently produced hiPSC-CM spheroids in 3-dimensional (3D) culture using microwell plates, and developed an injection device for optimal 3D distribution of the spheroids in the myocardial layer. Device biocompatibility was assessed with purified hiPSC-CM spheroids. Device effectiveness was evaluated in 10- to 15-month-old farm pigs ( n = 15) and 5- to 24-month-old micro-minipigs (n = 20). The pigs were euthanized after injection, and tissues were harvested for retention and histologic analysis. RESULTS We demonstrated an injection device for direct intramyocardial transplantation of hiPSC-CM spheroids from large-scale culture. The device had no detrimental effects on cell viability , spheroid shape, or size. Direct epicardial injection of spheroids mixed with gelatin hydrogel into beating porcine hearts using this device resulted in better distribution and retention of transplanted spheroids in a layer within the myocardium than did conventional needle injection procedures. CONCLUSIONS The combination of the newly developed transplant device and spheroid formation promotes the retention of transplanted CMs. These findings support the clinical application of hiPSC-CM spheroid‒based cardiac regenerative therapy in patients with heart failure.

A 92-year-old woman with a history of patent ductus arteriosus (PDA) was referred to our hospital because of worsening dyspnea, with New York Heart Association classification IV. She had 3 admissions because of congestive heart failure within a year. A 12-lead ECG showed atrial fibrillation, and a chest radiograph showed severe pulmonary congestion and cardiomegaly (Figure [A]). The plasma B-type natriuretic peptide level was 4527.9 pg/mL. The echocardiogram showed a reduced ejection fraction of 39% and moderate to severe aortic valve stenosis (peak velocity=3.9 m/s; mean pressure gradient=29 mm Hg; aortic valve area=0.83 cm2). The reconstructed 3-dimensional computed tomography (CT; Ziostation2; Ziosoft Inc, Tokyo, Japan) revealed a 50-mm thoracic aortic aneurysm and a large PDA (Krichenko type A, 4.7 mm of the pulmonary artery side) with severe calcifications surrounding it (Figure B–D; Movies I and II in the Data Supplement). Because of her refractory heart failure despite treatment with intravenous furosemide and dobutamine, we decided to perform a transcatheter occlusion of PDA 8 days after her admission to the hospital. For the transcatheter occlusion procedure, we …

Transcatheter closure of an atrial septal defect (ASD) with the Amplatzer Septal Occluder (ASO) (St. Jude Medical, St. Paul, Minnesota) is a well-established treatment strategy. Although a majority of ASDs are easy to close percutaneously, large ASDs or those with deficient aortic/superior rims are

Background Percutaneous closure has replaced surgery for the majority of cases of secundum atrial septal defect (ASD). However, technological advances have made contemporary minimally invasive cardiac surgery (MICS) less invasive than conventional surgery. The aim of this study was to compare clinical outcomes of percutaneous closure of secundum ASD with those of contemporary MICS.Methods and Results:We conducted a single-center retrospective study of 354 patients with ASD treated either with the Amplatzer Septal Occluder (134 patients) or MICS (220 patients) between 2000 and 2013. Success rates and the incidence of complications were compared. The success rates were 98% for percutaneous closure and 100% for MICS. There were no deaths in either group. Major complications occurred in 2 patients (1.5%) who underwent percutaneous closure and in 8 patients (3.6%) treated with MICS (P=0.16). Minor complications occurred in 15 patients (11.2%) who underwent percutaneous closure and in 46 patients (20.9%) treated with MICS (P=0.02). On multivariate analysis, MICS (odds ratio [OR]: 2.91, 95% confidence interval [CI]: 1.46-5.81; P=0.002) and age >70 years (OR: 3.50, 95% CI: 1.40-8.75; P=0.008) were independent predictors of complications. Conclusions Percutaneous closure and MICS had high success rates without deaths. For ASD patients with a suitable anatomy, percutaneous closure can be considered as the first therapeutic option.

Restoration of cardiac function is the most desirable treatment of severe heart failure. However, effective regenerative therapy for the lost cardiomyocytes is currently an unmet medical need. Induced pluripotent stem cells (iPSCs) are the ideal cell source for regenerative cardiomyocytes, because they can be reprogrammed from patient cells, enabling autologous transplantation. However, the clinical application of iPSC-derived cardiomyocytes is hampered by several roadblocks. The quality of iPSCs must be guaranteed for clinical applications. Although the protocols to differentiate iPSCs to cardiomyocytes have been improved, it remains a substantial challenge to acquire a large amount of iPSC-derived cardiomyocytes. Mass floating cell culture is an effective system to solve this problem; however, the remaining undifferentiated stem cells are the critical issue. The most important step for clinical application is the purification of cardiomyocytes to avoid tumor formation after transplantation, and the quality of regenerative cardiomyocytes must also be controlled. The phenotype of cardiomyocytes is normally infant-type immediately after differentiation, comprising nodal, atrial, and ventricular cardiomyocytes. In addition, the transplantation strategies to support cell engraftment are essential for cell therapies. Co-transplantation with biodegradable materials such as fibrin, collagen, and gelatin may be helpful to improve graft survival. Acute and chronic immunological rejection should be well controlled with appropriate immunosuppressive therapies. Safety issues of transplanted cardiomyocytes, such as arrhythmia, teratoma formation, and side effects of immunosuppressive therapies, are also very important. These fundamental issues must be solved to move toward clinical application, with the ultimate goal of cardiac regenerative therapies with iPSCs.

Background— Magnetic resonance imaging (MRI) in the CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction (CADUCEUS) trial revealed that cardiosphere-derived cells (CDCs) decrease scar size and increase viable myocardium after myocardial infarction (MI), but MRI has not been validated as an index of regeneration after cell therapy. We tested the validity of contrast-enhanced MRI in quantifying scarred and viable myocardium after cell therapy in a porcine model of convalescent MI. Methods and Results— Yucatan minipigs underwent induction of MI and 2–3 weeks later were randomized to receive intracoronary infusion of 12.5×10 6 mismatched allogeneic CDCs or vehicle. Allogeneic CDCs induced mild local mononuclear infiltration but no systemic immunogenicity. MRI revealed that allogeneic CDCs attenuated remodeling, improved global and regional function, decreased scar size, and increased viable myocardium compared with placebo 2 months post-treatment. Extensive histological analysis validated quantitatively the MRI measurements of scar size, scar mass, and viable mass. CDCs neither altered gadolinium contrast myocardial kinetics nor induced changes in vascular density or architecture in viable and scarred myocardium. Histology demonstrated that CDCs lead to cardiomyocyte hyperplasia in the border zone, consistent with the observed stimulation of endogenous regenerative mechanisms (cardiomyocyte cycling, upregulation of endogenous progenitors, angiogenesis). Conclusions— Contrast-enhanced MRI accurately measures scarred and viable myocardium after cell therapy in a porcine model of convalescent MI. MRI represents a useful tool for assessing dynamic changes in the infarct and monitoring regenerative efficacy.

Transcatheter closure of secundum atrial septal defect (ASD) has been widely performed as a less invasive alternative to surgery with zero mortality so far in Japan. In the US and Europe, intracardiac echocardiography (ICE) has replaced transesophageal echocardiography (TEE) as a primary imaging tool during percutaneous ASD closure. However, the experience of ICE in ASD closure is limited in Japan. Consecutive 51 patients underwent percutaneous ASD closure with ICE guidance. Clinical results were compared to those of 41 patients who underwent ASD closure with TEE guidance. Pediatric patients and patients with multiple ASDs who were expected to need multiple devices were excluded. Success rate was similar in both groups (ICE 96.1 %, TEE 92.7 %). Catheterization laboratory time was significantly shortened with ICE than with TEE (131 vs. 155 min, p = 0.0003). There were no complications related to the use of ICE. ICE-guided ASD closure is feasible in most adult patients. ICE is superior to TEE in shortening catheterization laboratory time and eliminating general anesthesia, and can potentially replace TEE as the primary image guide during percutaneous ASD closure.

The aim was to investigate the effect of balloon pulmonary angioplasty (BPA) on right ventricular (RV) function in chronic thromboembolic pulmonary hypertension. Twenty-six patients with chronic thromboembolic pulmonary hypertension were enrolled and were divided into 2 groups, group H with high (>30 mm Hg) mean pulmonary arterial pressure and group L with low (25 to 30 mm Hg) mean pulmonary arterial pressure. RV function was assessed using 2-dimensional speckle-tracking echocardiography as well as 3-dimensional echocardiography, and RV dyssynchrony was assessed by the RV strain curves. Exercise capacity was evaluated by the 6-minute walk distance. RV dilatation was significantly reduced after BPA. In group H, RV ejection fraction, RV free wall longitudinal strain and RV dyssynchrony were all impaired before BPA and were ameliorated after BPA. In group L, RV ejection fraction as well as RV dyssynchrony were impaired without the reduction of RV free wall longitudinal strain and were improved after BPA, indicating that RV dysfunction may be attributable to the RV dyssynchrony in group L. Furthermore, RV dyssynchrony at baseline was the only parameter that was correlated with improvement in the 6-minute walk distance after BPA. RV dyssynchrony may affect RV function and could be the useful parameter for clinical outcome after BPA.

Background Infusion of allogeneic cardiosphere‐derived cells (allo‐ CDC s) postreperfusion elicits cardioprotective cellular postconditioning in pigs with acute myocardial infarction. However, the long‐term effects of allo‐ CDC s have not been assessed. We performed a placebo‐controlled pivotal study for long‐term evaluation, as well as shorter‐term mechanistic studies. Methods and Results Minipigs underwent 1.5‐hour mid‐left anterior descending balloon occlusion followed by reperfusion and were randomized to receive intracoronary allo‐ CDC s or vehicle 30 minutes postreperfusion. Left ventriculography ( LVG ) demonstrated preserved ejection fraction ( EF ) and attenuation of LV remodeling in CDC ‐treated pigs. Pigs underwent cardiac magnetic resonance imaging ( MRI ) and LVG 1 hour and 8 weeks after therapy to evaluate efficacy. MRI showed improvement of EF and attenuation of LV remodeling immediately after allo‐ CDC infusion. In addition, allo‐ CDC s improved regional function and decreased hypertrophy 2 months post‐treatment. Histological analysis revealed increased myocardial salvage index, enhanced vascularity, sustained reductions in infarct size/area at risk and scar transmurality, and attenuation of collagen deposition in the infarct zone of allo‐ CDC ‐treated pigs at 2 months. Allo‐ CDC s did not evoke lymphohistiocytic infiltration or systemic humoral memory response. Short‐term experiments designed to probe mechanism revealed antiapoptotic effects of allo‐ CDC s on cardiomyocytes and increases in cytoprotective macrophages, but no increase in overall inflammatory cell infiltration 2 hours after cell therapy. Conclusions Allo‐ CDC infusion postreperfusion is safe, improves cardiac function, and attenuates scar size and remodeling. The favorable effects persist for at least 2 months after therapy. Thus, cellular postconditioning confers not only acute cardioprotection, but also lasting structural and functional benefits.

Single-vessel, intracoronary infusion of stem cells under stop-flow conditions has proven safe but achieves only limited myocardial coverage. Continuous flow intracoronary delivery to one or more coronary vessels may achieve broader coverage for treating cardiomyopathy, but has not been investigated. Using nonocclusive coronary guiding catheters, we infused allogeneic cardiosphere-derived cells (CDCs) either in a single vessel or sequentially in all three coronary arteries in porcine ischemic cardiomyopathy and used magnetic resonance imaging (MRI) to assess structural and physiological outcomes. Vehicle-infused animals served as controls. Single-vessel stop-flow and continuous-flow intracoronary infusion revealed equivalent effects on scar size and function. Sequential infusion into each of the three major coronary vessels under stop-flow or continuous-flow conditions revealed equal efficacy, but less elevation of necrotic biomarkers with continuous-flow delivery. In addition, multi-vessel delivery resulted in enhanced global and regional tissue function compared to a triple-vessel placebo-treated group. The functional benefits after global cell infusion were accompanied histologically by minimal inflammatory cellular infiltration, attenuated regional fibrosis and enhanced vessel density in the heart. Sequential multi-vessel non-occlusive delivery of CDCs is safe and provides enhanced preservation of left ventricular function and structure. The current findings provide preclinical validation of the delivery method currently undergoing clinical testing in the Dilated cardiomYopathy iNtervention With Allogeneic MyocardIally-regenerative Cells (DYNAMIC) trial of CDCs in heart failure patients.