Bilateral coronary ostial atresia in a patient with pulmonary atresia and ventricular septal defect.

This is a case of a female infant with bilateral coronary ostial atresia associated with pulmonary atresia and ventricular septal defect. She developed coronary ischemia at 1-month of age, when she underwent an aortopulmonary shunt and an aorta-right ventricle shunt. The double-orifice tricuspid valve was separating the right ventricle from the left ventricle. She required extracorporeal cardiopulmonary support because of ventricular dysfunction and mitral regurgitation. Although she was temporarily weaned off the support after mitral valvuloplasty, she died from multiple organ failure. To the best of our knowledge, bilateral coronary ostial atresia associated with pulmonary atresia with ventricular septal defect has not been reported previously.

[Mitral and Aortic Valve Replacement and Tricuspid Valve Repair in a Patient with Metal Allergy].

We report a 63-year-old woman came to our hospital with exertional dyspnea, palpitations, and abdominal distention. Echocardiography showed mitral, aortic, and tricuspid valve insufficiency, for which surgery was indicated. Twenty-six years ago, during dental therapy, she was diagnosed with metal allergy. A patch test demonstrated allergic reactions to manganese, chromium, and zinc. The patient underwent mitral and aortic valve replacement with the On-X prosthetic heart valve, which is primarily made of titanium and devoid of the allergens. She also underwent tricuspid valve repair with a Contour 3D annuloplasty ring, which is made of titanium alloy. She manifested no allergic symptoms three years after surgery. This case elucidates the importance of history taking regarding metal allergy and identification of allergens by patch testing in patients undergoing cardiac surgery involving metal device implantation.

Influence of Percutaneous Occlusion of Atrial Septal Defect on Left Atrial Function Evaluated Using 2D Speckle Tracking Echocardiography.

Percutaneous occlusion of atrial septal defect (ASD) has recently become a standard therapeutic strategy, but little is known about left atrial (LA) function thereafter. The present study aimed to determine LA function in 43 children with ASD and 13 controls based on LA strain measured by two-dimensional echocardiographic speckle tracking (2DE-ST). Among these children, 12 underwent surgery (ASD-S), 31 had device closure (ASD-D), and 13 were included as controls. LA strain was significantly decreased after ASD-D but was not significantly altered after ASD-S, indicating that percutaneous occlusion of an ASD might decrease LA function. Furthermore, the size of the ASD device negatively correlated with LA strain. These results imply that ASD occlusion devices negatively influence LA function and might be important when decided therapeutic strategies for ASD. LA strain measured by 2DE-ST should become a good indicator of LA function after ASD treatment in children.

ENDOSOMAL RAB EFFECTOR WITH PX-DOMAIN, an Interacting Partner of RAB5 GTPases, Regulates Membrane Trafficking to Protein Storage Vacuoles in Arabidopsis.

RAB5 GTPases act as molecular switches that regulate various endosomal functions in animal cells, including homotypic fusion of early endosomes, endosomal motility, endosomal signaling, and subcompartmentalization of the endosomal membrane. RAB5 proteins fulfill these diverse functions through interactions with downstream effector molecules. Two canonical RAB5 members, ARA7 and RAB HOMOLOG1 (RHA1), are encoded in the Arabidopsis thaliana genome. ARA7 and RHA1 play crucial roles in endocytic and vacuolar trafficking pathways. Plant RAB5 GTPases function via interactions with effector molecules, whose identities and functions are currently unclear. In this study, we searched for canonical RAB5 effector molecules of Arabidopsis and identified a candidate, which we called ENDOSOMAL RAB EFFECTOR WITH PX-DOMAIN (EREX). The intimate genetic interaction between EREX and RAB5 members, the results from subcellular colocalization experiments, and the direct interaction observed in an in vitro pull-down assay strongly suggest that EREX is a genuine effector of canonical RAB5s in Arabidopsis. We further found that close homologs of EREX play partially redundant functions with EREX in the transport of seed storage proteins. Our results indicate that canonical plant RAB5s acquired distinct effector molecules from those of non-plant systems to fulfill their functions.

[Midterm Outcomes and Therapeutic Effects of Total Cavopulmonary Connection (TCPC) Conversion].

Total cavopulmonary connection (TCPC) conversion prevents late complications after the atrio-pulmonary-Fontan procedure. However, the outcomes and effects of TCPC conversion are not fully known. We performed TCPC conversion in 31 patients (2004~2017). Concomitantly, we performed anti-arrhythmia surgery in 28 patients( 90%), atrioventricular valve surgery in 4, and pacemaker implantation in 2. There were no perioperative deaths, but one late death occurred due to protein-losing gastroenteropathy. Five-year survival was 96.8%. Eleven patients were readmitted for various reasons, including arrhythmia in 7 and heart failure in 1. The 5-year cardiac event-free rate was 67.7%. The cardiac index was significantly improved:1.58 l/min/m2 before to 3.57 l/min/m2 after surgery ( p=0.0075). Surgical and midterm outcomes of TCPC conversion were favorable. In the perioperative and late periods, therapeutic intervention was usually for atrial arrhythmia. This study demonstrated that TCPC conversion is an effective therapeutic procedure.

[Mid-aortic Syndrome Requiring Surgical Intervention during Infancy;Report of a Case].

Mid-aortic syndrome (MAS) is a very rare disease characterized by stenosis from the distal of the thoracic aorta to the abdominal aorta, in many case it is found as a result of hypertension and the like, and it needs surgical intervention in early childhood to adolescence. Here, we report a case of MAS which recognized prominent left ventricular myocardial hypertrophy from the early stage and needed surgical intervention in the infancy. We selected patch angioplasty using expanded polytetrafluoro ethylene( ePTFE) graft, and after surgery pressure gradient was disappeared.

[Association of lung volume with shunt size in Starnes' procedure in neonates with severe Ebstein's anomaly].

Our modification of Starnes' procedure reduces right ventricular volume using only "suture plication" to improve surgical outcomes. However, shunt size in the procedure varies widely between patients. As this may be related to small lung volume, we estimated lung volume in each patient using computed tomography (CT).Since 2007, we have performed Starnes' procedure in 4 patients. Preoperative cardiothoracic ratio was 89±4.5%. Age and body weight at operation were 4.3±2.6 days and 2.6±0.2 kg, respectively. Anatomic slices 3 mm thick were acquired in transverse planes by CT. Total lung volume was calculated by accumulating those slices. Total lung volume and lung volume/body weight were 97.2±34.1 ml, 36.8±11.5 ml/kg, respectively. In one patient, a 3 mm prosthetic graft was needed to place a clip to regulate blood flow. Another patient required an additional shunt. The patient with the smallest lung volume required treatment with an extracorporeal lung-assistance device. Chest X-rays of neonates with severe Ebstein's anomaly usually show a "wall-to-wall" heart. However, lung volume varies widely between patients. Estimation of lung volume using CT is useful. In patients with smaller lung volume, a larger shunt than usual may be required to obtain the necessary pulmonary blood flow.

An adult case of giant congenital left atrial wall aneurysm.

Congenital left atrial wall aneurysm is a rare disorder that occurs in a wide range of age groups from infancy to adulthood. Here, we present a case of a congenital left atrial wall aneurysm that was detected in a 19-year-old man who was surgically treated. Although the patient was asymptomatic without any pre-existing conditions, chest radiography performed as part of a routine health examination detected abnormalities in the heart. Contrast-enhanced computed tomography revealed a giant aneurysm measuring 72 mm × 56 mm that extended from the posteroinferior wall of the left atrium to the posterior surface of the left ventricle. Transthoracic echocardiography revealed mild mitral regurgitation. The patient was diagnosed as having a congenital left atrial wall aneurysm associated with mild mitral regurgitation. The aneurysm was resected through median sternotomy under cardiopulmonary bypass with cardioplegic arrest. During surgery, no structural abnormalities were noted in the mitral valve. After surgery, the patient was discharged without complications. Neither recurrence of the aneurysm nor exacerbation of mitral regurgitation was observed at 1 year postoperatively. Learning objective: A congenital left atrial wall aneurysm is a rare disorder. Rupture of the aneurysm is rare. However, when they are left untreated, there are concerns regarding arrhythmias, heart failure, and systemic embolism. Thus, surgical treatment is recommended. Aneurysms are resected under cardiopulmonary bypass. In cases of aneurysms complicated by moderate or severer mitral regurgitation, mitral valve repair is necessary. The prognosis following surgical treatment is favorable.

An Overview of Golgi Membrane-Associated Degradation (GOMED) and Its Detection Methods.

Autophagy is a cellular mechanism that utilizes lysosomes to degrade its own components and is performed using Atg5 and other molecules originating from the endoplasmic reticulum membrane. On the other hand, we identified an alternative type of autophagy, namely, Golgi membrane-associated degradation (GOMED), which also utilizes lysosomes to degrade its own components, but does not use Atg5 originating from the Golgi membranes. The GOMED pathway involves Ulk1, Wipi3, Rab9, and other molecules, and plays crucial roles in a wide range of biological phenomena, such as the regulation of insulin secretion and neuronal maintenance. We here describe the overview of GOMED, methods to detect autophagy and GOMED, and to distinguish GOMED from autophagy.

Development of small fluorescent probes for the analysis of autophagy kinetics.

Autophagy is a dynamic process that degrades subcellular constituents, and its activity is measured by autophagic flux. The tandem proteins RFP-GFP-LC3 and GFP-LC3-RFP-LC3ΔG, which enable the visualization of autophagic vacuoles of different stages by differences in their fluorescent color, are useful tools to monitor autophagic flux, but they require plasmid transfection. In this study, we hence aimed to develop a new method to monitor autophagic flux using small cell-permeable fluorescent probes. We previously developed two green-fluorescent probes, DALGreen and DAPGreen, which detect autolysosomes and multistep autophagic vacuoles, respectively. We here developed a red-fluorescent autophagic probe, named DAPRed, which recognizes various autophagic vacuoles. By the combinatorial use of these green- and red-fluorescent probes, we were able to readily detect autophagic flux. Furthermore, these probes were useful not only for the visualization of canonical autophagy but also for alternative autophagy. DAPRed was also applicable for the detection of autophagy in living organisms.

Inhibition of Insulin Secretion Induces Golgi Morphological Changes.

Objectives: The role of autophagy in pancreatic ß cells has been reported, but the relationship between autophagy and insulin metabolism is complex and is not fully understood yet. Design: We here analyze the relationship between autophagy and insulin metabolism from a morphological aspect. Methods: We observe the morphological changes of ß cell-specific Atg7-deficient mice and Atg5-deficient MIN6 cells with electron microscopy. Results: We find that Atg7-deficient ß cells exhibit a marked expansion of the endoplasmic reticulum (ER). We also find that the inhibitory state of insulin secretion causes morphological changes in the Golgi, including ministacking and swelling. The same morphological alterations are observed when insulin secretion is suppressed in Atg5-deficient MIN6 cells. Conclusions: The defect of autophagy induces ER expansion, and inhibition of insulin secretion induces Golgi swelling, probably via ER stress and Golgi stress, respectively.

Involvement of casein kinase 1 epsilon/delta (Csnk1e/d) in the pathogenesis of familial Parkinson's disease caused by CHCHD2.

Parkinson's disease (PD) is a common neurodegenerative disorder that results from the loss of dopaminergic neurons. Mutations in coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) gene cause a familial form of PD with α-Synuclein aggregation, and we here identified the pathogenesis of the T61I mutation, the most common disease-causing mutation of CHCHD2. In Neuro2a cells, CHCHD2 is in mitochondria, whereas the T61I mutant (CHCHD2T61I ) is mislocalized in the cytosol. CHCHD2T61l then recruits casein kinase 1 epsilon/delta (Csnk1e/d), which phosphorylates neurofilament and α-Synuclein, forming cytosolic aggresomes. In vivo, both Chchd2T61I knock-in and transgenic mice display neurodegenerative phenotypes and aggresomes containing Chchd2T61I , Csnk1e/d, phospho-α-Synuclein, and phospho-neurofilament in their dopaminergic neurons. Similar aggresomes were observed in a postmortem PD patient brain and dopaminergic neurons generated from patient-derived iPS cells. Importantly, a Csnk1e/d inhibitor substantially suppressed the phosphorylation of neurofilament and α-Synuclein. The Csnk1e/d inhibitor also suppressed the cellular damage in CHCHD2T61I -expressing Neuro2a cells and dopaminergic neurons generated from patient-derived iPS cells and improved the neurodegenerative phenotypes of Chchd2T61I mutant mice. These results indicate that Csnk1e/d is involved in the pathogenesis of PD caused by the CHCHD2T61I mutation.

FLIP-based autophagy-detecting technique reveals closed autophagic compartments.

Autophagy results in the degradation of cytosolic components via two major membrane deformations. First, the isolation membrane sequesters components from the cytosol and forms autophagosomes, by which open structures become closed compartments. Second, the outer membrane of the autophagosomes fuses with lysosomes to degrade the inner membrane and its contents. The efficiency of the latter degradation process, namely autophagic flux, can be easily evaluated using lysosomal inhibitors, whereas the dynamics of the former process is difficult to analyze because of the challenges in identifying closed compartments of autophagy (autophagosomes and autolysosomes). To resolve this problem, we here developed a method to detect closed autophagic compartments by applying the FLIP technique, and named it FLIP-based Autophagy Detection (FLAD). This technique visualizes closed autophagic compartments and enables differentiation of open autophagic structures and closed autophagic compartments in live cells. In addition, FLAD analysis detects not only starvation-induced canonical autophagy but also genotoxic stress-induced alternative autophagy. By the combinational use of FLAD and LC3, we were able to distinguish the structures of canonical autophagy from those of alternative autophagy in a single cell.

Swiss-cheese ventricular septal defect closure by combination sandwich patch.

A 7-year-old boy with a history of neonatal pulmonary artery banding underwent almost complete closure of a sieve-like "Swiss-cheese" ventricular septal defect, using a combination sandwich patch technique through a right ventriculotomy. Although defects existed in the high-, mid-, and low-trabecular septa, a right ventriculotomy and division of the muscle trabeculations continuing the septal and moderator bands helped delineate the edges of the defects. Although patients with "Swiss-cheese" ventricular septal defects may be candidates for a Fontan operation conventionally, a combination patch technique could be considered the procedure of choice.

Long-term results of tricuspid reconstruction with pericardium in an infant.

We report the long-term clinical outcome of an 8-month-old infant who underwent tricuspid reconstruction using fresh autologous pericardium for severe tricuspid regurgitation due to defects in the leaflets of the tricuspid valve after ventricular septal defect closure and ablation. Ten years after surgery, the tricuspid function is good with mild regurgitation and mild stenosis. From the age of 8 months to 11 years, the patient's body weight and height increased fourfold and twofold, respectively. Thus, a fresh autologous pericardial patch could be the material of choice for tricuspid leaflet repair in pediatric patients.

Mid-term outcomes of Contegra implantation for the reconstruction of the right ventricular outflow tract to proximal branch pulmonary arteries: Japan multicentre study.

OBJECTIVES: To reveal the mid-term outcomes of Contegra implantation for the reconstruction of the right ventricular outflow tract to proximal branch pulmonary arteries in a multicentre study. METHODS: Between April 2013 and December 2019, 178 Contegra conduits were implanted at 5 Japanese institutes. The median age and body weight at operation were 16 months (25th-75th percentile: 8-32) and 8.3 kg (6.4-10.6). Sixteen patients were neonates (9.0%). Selected conduit sizes were 12 mm in 28 patients (15.7%), 14 mm in 67 patients (37.6%), 16 mm in 66 patients (37.1%), 18 mm in 5 patients (2.8%) and <12 mm in 12 patients (6.7%). Fifty-six grafts (31.4%) were ring supported. Proximal branch pulmonary arteries were concomitantly augmented in 85 patients (47.5%). Follow-up was completed in all patients and the median follow-up period was 3.1 years (1.3-5.1). RESULTS: The overall, conduit explantation-free and conduit infection-free survival rates at 5 years were 91.3%, 71.0% and 83.7%, respectively. Infection (P = 0.009) and common arterial trunk (P = 0.024) were risk factors for explantation. Conduit durability was shorter in smaller one (P < 0.001). Catheter interventions (for conduit to proximal branch pulmonary artery)-free survival rates at 5 years was 52.9%; however, need for catheter interventions was not a risk factor for conduit explantation. CONCLUSIONS: Mid-term outcomes of reconstruction of the right ventricular outflow tract to the proximal branch pulmonary arteries with Contegra were acceptable. The need for explantation over time was higher in smaller conduits. Conduit infection was a strong risk factor for conduit explantation. Frequently and repeated catheter interventions effectively extended the conduit durability.

The mid-term outcome of Fontan conversion compared with primary total cavopulmonary connection.

BACKGROUND: The indication of Fontan conversion (FC) from atriopulmonary connection (APC) to total cavopulmonary connection (TCPC) is unclear. We sought to analyze the mid-term outcome of prophylactic and therapeutic Fontan conversion compared with that of primary TCPC. METHODS: Patients with a univentricular heart who underwent cardiac catheterization at >18 years of age between July 2005 and July 2019 were included and divided into three groups: symptomatic APC patients who underwent therapeutic FC (t-FC, n = 13), asymptomatic APC patients after prophylactic FC (p-FC, n = 15), and patients who had primary TCPC procedure (pTCPC, n = 24). RESULTS: The mean last follow up was at the age of 32.0 ± 7.8, 26.8 ± 3.8, and 27.3 ± 7 years (p = 0.07) in t-FC, p-FC, and pTCPC, respectively. There was no late death. All of t-FC and 12 (80%) of p-FC cases underwent concomitant arrhythmic surgery. Consequently, five and four patients in t-FC and p-FC groups required pacemaker implantations mostly due to sinus node dysfunction. Thromboembolism was seen in 2 cases in both t-FC (15%) and p-FC (13%), and 1 case in pTCPC (4%) (p = 0.50). The last cardiac catheterization was performed at the age of 29.5 ± 8.5, 24.6 ± 3.8, and 26.3 ± 7.1 years (p = 0.11) in t-FC, p-FC, and pTCPC patients, respectively. There was no significant difference in central venous pressure, aortic pressure, and cardiac index among the three groups. There was no late supraventricular tachyarrhythmic event seen in t-FC and p-FC, whereas two patients in pTCPC had newly developed atrial flutter. CONCLUSIONS: FC is a safe and feasible procedure to bring APC patients back onto the same track of primary TCPC patients in terms of hemodynamics as well as arrhythmia. The antiarrhythmic procedure should be carefully chosen because sinus node dysfunction can frequently occur and FC itself would reduce the risk of arrhythmia.

Annuloplasty ring removal from patients with hemolysis after mitral valve repair.

We present a case of severe hemolysis following a mitral valve repair, which was successfully treated by removing the annuloplasty ring. The etiology of the hemolysis appeared to be a small regurgitant jet at the level of the annuloplasty ring.

Association Between Atg5-independent Alternative Autophagy and Neurodegenerative Diseases.

Autophagy is a cellular process that degrades intracellular components, including misfolded proteins and damaged organelles. Many neurodegenerative diseases are considered to progress via the accumulation of misfolded proteins and damaged organelles; therefore, autophagy functions in regulating disease severity. There are at least two types of autophagy (canonical autophagy and alternative autophagy), and canonical autophagy has been applied to therapeutic strategies against various types of neurodegenerative diseases. In contrast, the role of alternative autophagy has not yet been clarified, but it is speculated to be involved in the pathogenesis of various neurodegenerative diseases, including Alzheimer's disease.

Wipi3 is essential for alternative autophagy and its loss causes neurodegeneration.

Alternative autophagy is an Atg5/Atg7-independent type of autophagy that contributes to various physiological events. We here identify Wipi3 as a molecule essential for alternative autophagy, but which plays minor roles in canonical autophagy. Wipi3 binds to Golgi membranes and is required for the generation of isolation membranes. We establish neuron-specific Wipi3-deficient mice, which show behavioral defects, mainly as a result of cerebellar neuronal loss. The accumulation of iron and ceruloplasmin is also found in the neuronal cells. These abnormalities are suppressed by the expression of Dram1, which is another crucial molecule for alternative autophagy. Although Atg7-deficient mice show similar phenotypes to Wipi3-deficient mice, electron microscopic analysis shows that they have completely different subcellular morphologies, including the morphology of organelles. Furthermore, most Atg7/Wipi3 double-deficient mice are embryonic lethal, indicating that Wipi3 functions to maintain neuronal cells via mechanisms different from those of canonical autophagy.