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Background: Patienets with congenital diaphragmatic hernia comorbidity with congenital heart disease have a more severe prognosis than those with either condition alone. Here we report the clinical outcomes of congenital diaphragmatic hernia patients with congenital heart disease who have either two ventricles or a functional single ventricle. Methods: The subjects included 17 congenital diaphragmatic hernia patients with congenital heart disease who were treated at Osaka Women’s and Children’s Hospital. The severity of congenital diaphragmatic hernia was assessed by the observed-expected lung-to-head ratio. We assessed the details of clinical course in the patients. Results: A total of 238 patients with congenital diaphragmatic hernia were born between 1981 and 2021 at our hospital. Of these, a total of 21 patients (8.8 %) had congenital heart disease and seventeen patients were evaluated for the study. Fourteen patients had two ventricles and three patients had single ventricle. Of seventeen patients, eight patients were alive and nine patients were dead. There was no significant difference in congenital diaphragmatic hernia severity between the alive and dead patients. The patients who survived had two ventricles and received definitive heart repair operations. Although two patients with a functional single ventricle had mild congenital diaphragmatic hernia severity, they were managed using mechanical ventilation management. All of the patients with a functional single ventricle could not undergo Glenn or Fontan operation, and died. Conclusion: Long-term survival may be expected in the patients with two ventricles. Patients with a functional single ventricle might not survive for a long time if they required ventilation due to the respiratory dysfunction.

Fibroblast-to-myofibroblast transition (FMT) is the primary inducer of cardiac fibrosis. ONO-1301, a synthetic prostacyclin agonist, reportedly promotes tissue fibrosis repair by enhancing anti-fibrotic cytokine production. We hypothesized that ONO-1301 attenuates pressure-overloaded cardiac fibrosis by modulating FMT and generated a pressure-overloaded murine model via transverse aortic constriction (TAC) to evaluate the in vivo effects of ONO-1301. Cardiac fibrosis, left ventricular dilatation, and systolic dysfunction were established 4 weeks after TAC; however, ONO-1301 treatment initiated 2 weeks after TAC significantly attenuated those effects. Furthermore, ONO-1301 treatment significantly upregulated expression levels of cardioprotective cytokines such as vascular endothelial growth factor and hepatocyte growth factor in TAC hearts, whereas FMT-related factors, including transforming growth factor (TGF)-β1 and connective tissue growth factor, were significantly downregulated. The number of α-smooth muscle actin (α-SMA)- and vimentin-positive cells, representing fibroblast-originated cells transitioned into myofibroblasts, was significantly reduced in ONO-1301-treated TAC hearts. We isolated cardiac fibroblasts (CFs) from the left ventricles of adult male mice and assessed the effects of ONO-1301 on CFs stimulated by TGF-β. Results showed that ONO-1301 co-incubation significantly suppressed TGF-β-induced α-SMA expression and collagen synthesis, and significantly inhibited TGF-β-induced CF proliferation and migration. Our findings suggest that ONO-1301 ameliorates pressure overloaded cardiac fibrosis by inhibiting TGF-β-induced FMT., Graphical Abstract, ONO-1301SR, a sustained-release drug-delivery system of a synthetic prostacyclin agonist, attenuates pressure overload-induced cardiac fibrosis by inhibiting TGF-β-induced fibroblast-to-myofibroblast transition in addition to enhancing the production of protective cytokines, such as hepatic growth factor (HGF), vascular endothelial growth factor (VEGF), and stromal cell-derived factor 1 (SDF-1).

OBJECTIVES This study aimed to identify the histological characteristics associated with bridge to recovery using Berlin Heart EXCOR® (BHE) in paediatric patients METHODS Of the 10 consecutive patients RESULTS The degree of myocardial fibrosis was significantly lower, and the capillary vascular density was significantly higher in the recovery group than in the non-recovery group [16% (standard deviation 5.9%) vs 28% (5.9%), P = 0.021, and 65 (11) vs 43 (18) units/high-power field, P = 0.037, respectively]. The changes during 3 months after BHE implantation in LV diastolic dimension (z-score) and ejection fraction were significantly greater in the recovery group than in the non-recovery group [−9.6 (3.5) vs −3.6 (4.5), P = 0.045, and 36% (13%) vs 13% (13%), P = 0.032, respectively]. CONCLUSIONS In paediatric patients

OBJECTIVES Atrial function in Fontan patients is unknown. Our goal was to report the relationship of atrial function with the cardiac index and atrial function and clinical outcome through longer follow-up periods. METHODS Twelve patients were followed up for over 20 years after their first Fontan operation. Atrial function, including the expansion index, atrial ejection fraction, passive ejection fraction and active ejection fraction, was examined using cardiac computed tomography. The relationship of atrial function with the cardiac index and failing Fontan patients was analysed. RESULTS Twelve Fontan patients were included. The median follow-up period after the first Fontan operation was 27 (range, 21-33) years, and the median age of those examined was 33.5 (range, 24-60) years. There were 6 male patients (50%). The cardiac index showed a significant positive correlation with the expansion index (P = 0.02), the atrial ejection fraction (P = 0.035), and the active ejection fraction (P = 0.013). The expansion index (39.2 ± 19.6 vs 64.1 ± 3.9), atrial ejection fraction (26.6 ± 10.9 vs 39.0 ± 1.5%), booster pump (15.6 ± 9.0 vs 31.3 ± 3.5) and cardiac index (2.1 ± 0.3 vs 2.5 ± 0.2 L/min/m2) were significantly lower in patients with a history of arrhythmia than in patients without a history of arrhythmia (P CONCLUSIONS Patients with atrial arrhythmia and signs of Fontan failure have lower atrial function than those without.

Background There are few reports of the outcomes of standardized surgical management addressing the etiologic and morphologic aspects of mitral valve malformation according to Carpentier's classification. This study aimed to evaluate the long-term outcomes of mitral valve repair in children according to Carpentier's classification. Methods Patients who underwent mitral valve repair at our institution between 2000 and 2021 were retrospectively reviewed. Preoperative data, surgical techniques, and outcomes were analyzed according to Carpentier's classification. The proportion of patients free of mitral valve replacement and reoperation was estimated using Kaplan-Meier analysis. Results Twenty-three patients (median operative age, four months) were followed up for 10 (range, 2-21) years. Preoperative mitral regurgitation was severe in 12 patients and moderate in 11 patients. Eight, five, seven, and three patients had Carpentier's type 1, 2, 3, and 4 lesions, respectively. Ventricular septal defect (N = 9) and double outlet of the great arteries from the right ventricle (N = 3) were the most commonly associated cardiac malformations. There were no cases of operative mortality or deaths during the follow-up. The overall five-year rate of freedom from mitral valve replacement was 91%, whereas the five-year rates of freedom from reoperation were 74%, 80%, 71%, and 67% in type 1, 2, 3, and 4 lesions, respectively. Postoperative mitral regurgitation at the last follow-up was moderate in three patients and less than mild in 20 patients. Conclusions Current surgical management of congenital mitral regurgitation is generally considered adequate; however, more complicated cases required a combination of various surgical techniques.

In children with dilated cardiomyopathy, heart transplantation is the last treatment option. However, new regenerative treatments, such as cell therapy, have attracted scientific attention. We have previously demonstrated the efficacy of autologous skeletal myoblast sheet implantation for treatment of ischemic and dilated cardiomyopathy in adults. Because of the mechanism underlying this cell therapy, a similar effectiveness is expected for patients with pediatric dilated cardiomyopathy. Herein, we describe the case of a child with dilated cardiomyopathy who underwent an autologous skeletal myoblast sheet implantation, which proved to be safe, and led to sustained maintenance and improvements in cardiac function and clinical status.

Berlin Heart EXCOR® (BHE) ventricular assist device (VAD) (Berlin Heart, Berlin Heart AG, Berlin, Germany) implantation is prevalent in patients with severe heart failure. However, clinical outcomes of pediatric patients on long-term BHE support remain mainly unknown. This study aimed to report our clinical experience with long-term support of pediatric patients with severe heart failure supported by BHE VAD. Clinical outcomes of 11 patients (median age 8.4 months; two male), who underwent LVAD implantation of the Berlin Heart EXCO® (BHE) VAD (Berlin Heart, Berlin Heart AG, Berlin, Germany) between 2013 and 2017 at our institution were reviewed. The median support period was 312 (range 45-661) days and five patients were supported for more than 1 year. The longest support duration was 661 days. No mortality occurred, and six patients were successfully bridged to heart transplantation, while three patients were successfully weaned off the device. Two patients are currently on BHE support while they await heart transplantation. Four patients had cerebral bleeding or infarction, but only one case of persistent neurological deficit occurred. No fatal device-related infection occurred during LVAD support. BHE VAD can provide long-term support for pediatric patients with severe heart failure with acceptable mortality and morbidity rates with long-term support.

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.

Introduction: Restrictive right ventricular physiology (r-RVP) is common in late after repair of tetralogy of Fallot (TOF) and reported to reflect diastolic dysfunction. Right ventricular (RV) diastolic dysfunction sometimes remains after pulmonary valve replacement (PVR) and is associated with arrhythmia. Pulmonary arterial end-diastolic forward flow (EDFF) is considered as a marker of r-RVP, and associated with RV volume, right atrial (RA) function, and the degree of pulmonary valve regurgitation (PR). The aim of this study is to evaluate the impact of EDFF before PVR on the clinical outcomes after PVR in patients with repaired TOF. Methods: This was a single-center, retrospective review of 46 patients who underwent PVR for moderate to severe PR between 2003 and 2019. Cases were examined EDFF before PVR and divided into two groups: with EDFF (EDFF+, n=23) and without EDFF (EDFF-, n=23). Patients with histories of atrial tachyarrhythmia underwent concomitant maze procedure. RV and RA volume were evaluated by magnetic resonance imaging. Post-PVR survival and the development of arrhythmia were assessed. Results: Age at PVR was 38±14 in EDFF+ and 35±10 years old in EDFF- (p=0.41), and the incidence of preoperative arrhythmia was not different (30% and 35%, p=1.0). RVESVI (102±24 and 86±26 ml/m 2 , p=0.048) and RAVI (84±19 and 70±20 ml/m 2 , p=0.025) before PVR, and RVEDVI (116±27 and 100±24 ml/m 2 , p=0.04) and RVESVI (71±23 and 55±16 ml/m 2 , p=0.01) at one year after PVR were greater in EDFF+. One patient in each group died due to non-cardiac disease. 5-year atrial tachyarrhythmia free rate was 62% in EDFF+ and 100% in EDFF- (Log-rank p=0.004). Multivariate Cox regression analysis revealed EDFF before PVR was a risk factor for atrial tachyarrhythmia after PVR (Hazard ratio 17 (95% CI, 2.2-406), p=0.025). Conclusions: EDFF before PVR was a significant risk factor for the development of postoperative atrial tachyarrhythmia. EDFF can complement the current indication for PVR.

OBJECTIVES The clinical significance of persistent end-diastolic forward flow (EDFF) after pulmonary valve replacement (PVR) remains unclear in patients with repaired tetralogy of Fallot. This study aimed to identify the characteristics of these patients and the impact of persistent EDFF on outcomes. METHODS Of 46 consecutive patients who underwent PVR for moderate to severe pulmonary regurgitation between 2003 and 2019, 23 (50%) did not show EDFF before PVR [group (−)]. In the remaining 23 patients with EDFF before PVR, EDFF was diminished after PVR in 13 (28%) [group (+, −)] and persisted in 10 (22%) [group (+, +)]. The following variables were compared between these 3 groups: (i) preoperative right ventricular (RV) and right atrial volumes measured by magnetic resonance imaging, haemodynamic parameters measured by cardiac catheterization and the degree of RV myocardial fibrosis measured by RV biopsy obtained at PVR and (ii) the post-PVR course, development of atrial arrhythmia and need for intervention. RESULTS A high RV end-diastolic pressure, a greater right atrial volume index and a greater RV end-systolic volume index before PVR and a high degree of RV fibrosis were significantly associated with persistent EDFF 1 year after PVR. Persistent EDFF was a significant risk factor for postoperative atrial tachyarrhythmia, and catheter ablation and pacemaker implantation were required more frequently in these patients. CONCLUSIONS Persistent EDFF after PVR could predict a worse prognosis, especially an increased risk of arrhythmia. Close follow-up is required in patients with persistent EDFF for early detection of arrhythmia and prompt reintervention if necessary. Clinical trial registration number Institutional review board of Osaka University Hospital, number 16105

Background Diaphragmatic hernia is a rare complication of ventricular assist device (VAD), mainly developing after explantation of the device. We herein report a case of diaphragmatic hernia that developed following the implantation of VAD. Case presentation A 4-month-old girl with a diagnosis of dilated cardiomyopathy underwent VAD implantation for a bridge to heart transplantation. Three months later, intermittent vomiting developed, and left-sided diaphragmatic hernia was confirmed on plain X-ray and computed tomography. Without any findings of ischemia, we performed elective thoracoscopic repair of the diaphragmatic hernia. In the right decubitus position, thoracoscopy revealed the small intestine to be herniated into the left thorax. After reduction of the herniated intestine, the defect of the diaphragm (3 × 2 cm in size) was directly closed with interrupted non-absorbable sutures. Her postoperative course was uneventful. Conclusion Thoracoscopic repair of diaphragmatic hernia associated with VAD implantation may be a safe approach.

A 45-year-old woman with repaired complex congenital heart disease, who underwent placement of Jarvik 2000, a ventricular assist device (VAD) for 4 years, experienced abdominal pain due to outflow graft compression caused by seroma formation between the outflow graft and ringed Gore-Tex graft. We exchanged the pump of Jarvik 2000 and punched several small holes in the new ringed Gore-Tex graft. Seroma formation between the two grafts should be considered as a cause of outflow graft obstruction in patients with the long-term support of VAD, and additional surgical interventions to the ringed Gore-Tex graft may prevent this complication.

Pure restrictive cardiomyopathy is a strong risk factor for poor outcomes in children with cardiomyopathy on ventricular assist devices. Owing to concomitant right heart failure, children with end-staged restrictive cardiomyopathy who are supported with a ventricular assist device often require a biventricular assist device, which is another risk factor for waitlist mortality in heart transplantation candidates. Herein, we report the case of a 3-year-old boy with pure restrictive cardiomyopathy who successfully underwent heart transplantation after 12 months of support with staged biventricular assist devices. Owing to the progression of diastolic dysfunction, the left ventricular assist device could not provide adequate circulation support. Despite the provision of biventricular assist device support, the patient required a complex management strategy that involved balancing the left and right ventricular assist device supports. We were able to stabilize the patient by careful synchronization of the supports and proceeded to heart transplantation. TRIAL REGISTRATION: Clinical Registration No.: Institutional Review Board of Osaka University Hospital, approval no. 16105.

OBJECTIVES Atrial arrhythmia and right ventricular (RV) diastolic dysfunction are associated with increased morbidity and mortality in patients with repaired tetralogy of Fallot (TOF). This study was performed to determine whether the preoperative right atrial (RA) volume can predict the development of atrial arrhythmia after pulmonary valve replacement (PVR) in patients with TOF. METHODS Forty-seven consecutive adult patients with repaired TOF underwent PVR from 2003 to 2018. Seventeen patients showed preoperative atrial arrhythmia and underwent the Maze procedure concomitantly. The preoperative RA volume was evaluated with computed tomography and image analysis software. RESULTS The median follow-up period after PVR was 6.8 years. Among 17 patients who underwent the Maze procedure, recurrent atrial arrhythmia developed in 8 patients. Among 30 patients without preoperative atrial arrhythmia, novel atrial arrhythmia developed in 2 patients. The RA volume index was a significant predictor according to the multivariate analysis (P = 0.003). The RA volume index showed a significant positive correlation with the RV end-diastolic pressure (P CONCLUSIONS The RA volume predicts the development of atrial arrhythmia after PVR in patients with repaired TOF. RA volume measurement is strongly recommended in the management of this patient population. Clinical trial registration number Institutional review board of Osaka University Hospital, number 16105.

Colorectal anastomotic leakage is one of the most feared and fatal complications of colorectal surgery. To date, no external coating material that can prevent anastomotic leakage has been developed. As myoblasts possess anti-inflammatory capacity and improve wound healing, we developed a multilayered human skeletal muscle myoblast (HSMM) sheet by periodic exposure to supraphysiological hydrostatic pressure during repeated cell seeding. We assessed whether the application of an HSMM sheet can promote the healing process after colonic anastomosis. Partial colectomy and insufficient suturing were employed to create a high-risk colo-colonic anastomosis model in 60 nude rats. Rats were divided into a control group ( n = 30) and an HSMM sheet group ( n = 30). Macroscopic findings, anastomotic bursting pressure, and histology at the colonic anastomotic site were evaluated on postoperative day (POD) 3, 5, 7, 14, and 28. The application of an HSMM sheet significantly suppressed abscess formation at the anastomotic site compared to the control group on POD3 and 5. The anastomotic bursting pressure in the HSMM sheet group was higher than that in the control group on POD3 and 5. Inflammatory cell infiltration in the HSMM sheet group was significantly suppressed compared to that in the control group throughout the time course. Collagen deposition in the HSMM sheet group on POD3 was significantly abundant compared to that in the control group. Regeneration of the mucosa at the colonic anastomotic site was promoted in the HSMM sheet group compared to that in the control group on POD14 and 28. Immunohistochemical analysis demonstrated that surviving cells in the HSMM sheet gradually decreased with postoperative time and none were detected on POD14. These results suggest that the application of a multilayered HSMM sheet may prevent postoperative colonic anastomotic leakage.

Kazuhiko Ishimaru1), Kyoichi Nishigaki1), Tomomitsu Kanaya1), Kanta Araki1), Kae Nakamura2), Takeshi Sasaki2), Mitsuhiro Fujino2), Yasuhiro Hirano2), Yuki Kawasaki2), Eiji Ehara2), Syuichiro Yoshida3), Yoko Yoshida3), Tsugutoshi Suzuki3), and Yosuke Murakami2) 1) Department of Pediatric Cardiovascular Surgery, Osaka City General Hospital, Osaka, Japan 2) Department of Pediatric Cardiology, Osaka City General Hospital, Osaka, Japan 3) Department of Pediatric Electrophysiology, Osaka City General Hospital, Osaka, Japan

A 6-year-old boy with pulmonary regurgitation after complete repair of congenital heart disease underwent an alternative surgical repair for pulmonary valve replacement. Trileaflet pulmonary valve reconstruction using expanded polytetrafluoroethylene membrane is a clinically feasible technique for pulmonary regurgitation in such a young child in whom large-sized bioprosthetic valves cannot be implanted.

Background This study aimed to identify the prognostic value of the preoperative stroke volume ratio (right ventricular stroke volume/left ventricular stroke volume) for redilatation of the right ventricle after pulmonary valve replacement in patients with repaired tetralogy of Fallot. Methods From April 2004 to November 2013, 20 patients with repaired tetralogy of Fallot underwent pulmonary valve replacement for pulmonary valve regurgitation and right ventricular dilatation. Serial changes in ventricular volume were examined by cardiac magnetic resonance or computed tomography imaging. The redilatation ratio was calculated for right ventricular end-diastolic and end-systolic volume indices by dividing the increment in right ventricular volume from the first (median, 1.1 years) to the second (median, 3.2 years) evaluations after pulmonary valve replacement by the first evaluation. The relationships between the stroke volume ratio and redilatation ratio were assessed. The degree of right ventricular myocardial fibrosis was examined in 13 patients and compared with the stroke volume ratio. Results Right ventricular volume (redilatation) significantly increased from a median of 1.1 to 3.2 years after pulmonary valve replacement. Significant positive correlations were detected between the stroke volume ratio and redilatation ratio of the right ventricular end-diastolic ( r = 0.50. p = 0.02) and end-systolic volume indices ( r = 0.49, p = 0.03). The stroke volume ratio also showed a significant positive correlation with the degree of right ventricular myocardial fibrosis ( r = 0.73, p = 0.005). Conclusions The preoperative stroke volume ratio can predict redilatation of the right ventricle after pulmonary valve replacement and the degree of right ventricular myocardial fibrosis.

BACKGROUND Pulmonary valve replacement (PVR) is a common reoperation, typically required approximately 10 years following right ventricular outflow tract reconstruction and especially true in cases of tetralogy of Fallot. However, an improved prosthetic valve is required. METHODS AND RESULTS A fresh decellularized pulmonary allograft was used for PVR to correct pulmonary valve regurgitation in a 35-year-old man 33 years following tetralogy of Fallot repair. The postoperative course and short-term valve function were excellent. This is the first case of a decellularized pulmonary allograft in Japan. CONCLUSIONS Fresh decellularized pulmonary allografts have the potential to become a new source of material for PVR in patients who have undergone right ventricular outflow tract reconstruction.

An 8-year-old boy with hypertrophic nonobstructive cardiomyopathy with ventricular fibrillation underwent implantation of an implantable cardioverter defibrillator. The lead was inserted through a pursestring suture in the right atrial appendage, and the tip of coil was placed in the right ventricular apex under fluoroscopic guidance. Another defibrillation coil was placed in the back of the left atrium and left ventricle by the transverse sinus. The device wrapped in a monofilament mesh sheet was placed in the intraperitoneal space. This case utilized a new technique for an implantable cardioverter defibrillator implantation in a small child.

A 9-year-old patient with massive destruction of the mitral apparatus caused by active infective endocarditis underwent mitral valve plasty using a modified commissural autologous pericardial patch repair. This procedure is a clinically relevant and feasible technique for pediatric patients with active mitral valve endocarditis.

Loeys–Dietz syndrome (LDS) is a recognized connective tissue disorder characterized by progressive aortic aneurysm and dissection. Patients are at high risk of aortic dissection or rupture at an early age, but to our knowledge, surgery on the great arteries has never been attempted in the neonatal period. We report a case of LDS with dilated pulmonary arteries and an interrupted aortic arch complex in a neonate. We performed bilateral pulmonary artery banding, but 12 days after the procedure, the infant died of rupture of the distal portion of the banding sites following massive dilatation.