Comparison of microRNA expressions for the identification of chemical hazards in in vivo and in vitro hepatic injury models.

Biofluid-based biomarkers provide an efficient tool for hazard identification of chemicals. Here, we explored the potential of microRNAs (miRNAs) as biomarkers for hepatotoxicity of chemicals by linking in vitro to in vivo animal models. A search of the literature identified candidate circulating miRNA biomarkers of chemical-induced hepatotoxicity. The expression of candidate miRNAs (miR-122, miR-151a, miR-192, miR-193a, miR-194, miR-21, miR-29c), was determined by real-time reverse transcription-polymerase chain reaction in in vivo acute liver injury induced by acetaminophen, and then were further compared with those of in vitro cell assays. Candidate miRNAs, except miR-29c, were significantly or biologically upregulated by acetaminophen, at a dose that caused acute liver injury as confirmed by hepatocellular necrosis. Except miR-122 and miR-193a, other miRNAs elevated in in vivo models were confirmed by in vitro models using HepG2 cells, whereas they failed by in vitro models using human primary hepatocytes. These findings indicate that certain miRNAs may still have the potential of toxicological biomarkers in linking in vitro to in vivo hepatotoxicity.

Evaluation of commissural malalignment of aortic-pulmonary sinus using cardiac CT for arterial switch operation: comparison with transthoracic echocardiography.

BACKGROUND: There are limited data regarding the influence of commissural malalignment of the aortic-pulmonary sinus on the arterial switch operation. OBJECTIVE: To compare diagnostic accuracy between cardiac CT and echocardiography for evaluating commissural malalignment of aortic-pulmonary sinus in children with complete transposition of the great arteries and to seek potential clinical implication of commissural malalignment on the arterial switch operation. MATERIALS AND METHODS: In 37 patients (35 boys; median age: 8 days, range: 3-80 days) with complete transposition of the great arteries who had tricuspid semilunar valves and underwent an arterial switch operation, the degree of the commissural rotation of the aortic-pulmonary sinus was assessed on cardiac CT (n=37) and echocardiography (n=35). With surgical finding as a reference, cardiac CT was compared with echocardiography in identifying commissural malalignment in 35 patients. The influence of the height difference between the semilunar valves measured by cardiac CT on the identification of commissural malalignment with cardiac CT and echocardiography was evaluated. The impact of commissural malalignment on coronary transfer techniques was evaluated. RESULTS: In operative findings, the commissures of the semilunar valves were aligned in 24 patients and malaligned in 13. With surgical findings as a reference, cardiac CT showed higher, but not statistically significant (P>0.05), sensitivity (91.7% vs. 75.0%), specificity (87.0% vs. 78.3%) and accuracy (88.6% vs. 77.1%) for the diagnosis of the malalignment than echocardiography. The measured height difference between the semilunar valves did not affect the identification of the malalignment with cardiac CT and echocardiography. The surgical malalignment group showed a higher requirement of modified coronary transfer techniques than the surgical aligned group (11/13 vs. 11/24, P=0.03). CONCLUSION: Cardiac CT and echocardiography appear useful for evaluating commissural malalignment of the semilunar valves in patients with complete transposition of the great arteries frequently requiring modified coronary transfer techniques at during an arterial switch operation.

Individual Pulmonary Veins Outgrow Somatic Growth After Primary Sutureless Repair for Total Anomalous Pulmonary Venous Drainage.

Indications of sutureless repair (SR) for pulmonary vein anomalies have evolved from re-operational SR for pulmonary vein stenosis after the repair of total anomalous pulmonary venous drainage (TAPVD) to primary SR for TAPVD associated with right atrial isomerism or isolated TAPVD with small individual pulmonary veins (IPVs) and an unfavorable pulmonary vein anatomy. We sought to determine whether small IPVs outgrow somatic growth after primary SR. Between 2004 and 2013, 21 children underwent primary SR for TAPVD: 13 with a functionally single ventricle, 11 with right atrial isomerism, six with isolated TAPVD, and 13 with a pulmonary venous obstruction. TAPVD types were supracardiac in nine, infracardiac in 10, and mixed in two. Utilizing cardiac computed tomography (CT), the maximal diameter of each IPV was measured, and pulmonary vein index (PVI, summation of cross-sectional areas of all four IPVs divided by body surface area) was calculated. There were five early deaths after SR. Among survivors, 10 had both preoperative and postoperative cardiac CT at a 3.6-month median interval. On postoperative cardiac CT, IPVs were patent in all patients except one who developed a left lower pulmonary vein obstruction. There was a 71 ± 48 % postoperative increase in the actual diameter of all four IPVs, and PVI increased significantly from 215 ± 55 to 402 ± 117 mm(2)/m(2) (P value = 0.005). IPVs outgrew somatic growth after primary SR of TAPVD. Primary SR may be a useful measure in TAPVD patients whose IPVs are small.

Malignant peripheral nerve sheath tumor arising from the left ventricle.

We report a case of a 32-year-old female who underwent complete excision of a malignant left ventricular peripheral nerve sheath tumor. Malignant peripheral nerve sheath tumors in the mediastinum, including the pericardium, are rare. This case report describes a malignant peripheral nerve sheath tumor arising from the left ventricular origin for which complete excision was possible.

Effect of Pulmonary Valve Replacement in the Repaired Tetralogy of Fallot Patients with Trans-annular Incision: More than 20 Years of Follow-up.

BACKGROUND AND OBJECTIVES: We reviewed the long-term outcomes after tetralogy of Fallot (TOF) repair with trans-annular incision; and evaluated the effectiveness of pulmonary valve replacement (PVR) on outcomes. METHODS: This was a retrospective review of clinical outcomes of 180 of 196 TOF patients who underwent total correction with trans-annular incision from 1991 to 1997 (PVR group: 81; non-PVR group: 99). RESULTS: The median age of the patients was 14.0 months (interquartile range [IQR], 10.7-19.8 months) at TOF repair. Ten in-hospital deaths (5.1%) occurred. During the follow-up, 81 patients underwent PVR at the median age of 13.5 years (IQR, 11.2-17.1 years). The patients in PVR group showed better outcomes than non-PVR group in overall survival rate (100% in PVR vs. 88.7% in non-PVR, p=0.007), in all adverse events (arrhythmia, neurologic complications, 95.5% in PVR vs. 74.6% in non-PVR, p=0.024) at 20 years. Age at TOF repair younger than 1 year (hazard ratio [HR], 2.265; p=0.01) and previous shunt history (HR, 2.195; p=0.008) were predictive for requiring PVR. During follow-up, 10 late deaths (5 sudden deaths) occurred in the non-PVR group, mainly due to ventricular arrhythmia and right ventricular failure; there was 1 late death (not a sudden death) in the PVR group. CONCLUSIONS: Long-term survival after repair of TOF with trans-annular incision were acceptable. However, arrhythmias were frequently observed during 20 years of follow-up. The patient age <1 year at the time of TOF repair and shunt implantation prior to TOF repair were predictive factors for requiring PVR.

Long-term durability of bioprosthetic valves in pulmonary position: Pericardial versus porcine valves.

OBJECTIVES: The long-term durability of the 2 most commonly used types of bioprosthetic valves in the pulmonic position, the porcine and pericardial valves, is unclear. We compared the long-term durability of the pericardial (Carpentier-Edwards PERIMOUNT [CE]) and porcine (Hancock II) valves in the pulmonic position in patients with congenital cardiac anomalies. METHODS: We retrospectively reviewed the medical records of 258 cases (248 patients) of pulmonary valve implantation or replacement using CE (129 cases, group CE) or porcine (129 cases, group H) valves from 2 institutions between 2001 and 2009. RESULTS: The patients' age at pulmonary valve implantation was 14.9 ± 8.7 years. No significant differences in perioperative characteristics were observed between groups CE and H. Follow-up data were complete in 219 cases (84.9%) and the median follow-up duration was 10.5 (interquartile range, 8.4∼13.0) years. Ten mortalities (3.9%) occurred. Sixty-four patients underwent reoperation for pulmonary valve replacement due to prosthetic valve failure; 10 of these 64 patients underwent reoperation during the study period. Patients in group CE were significantly more likely to undergo reoperation (hazard ratio, 2.17; confidence interval, 1.26-3.72; P = .005) than patients in group H. Patients in group CE showed had a greater prosthetic valve dysfunction (moderate-to-severe pulmonary regurgitation or pulmonary stenosis with ≥3.5 m/s peak velocity through the prosthetic pulmonary valve) rate (hazard ratio, 1.83; confidence interval, 1.07-3.14; P = .027) than patients in group H. CONCLUSIONS: Compared with the pericardial valve, the porcine valve had long-term advantages in terms of reduced reoperation rate and prosthetic valve dysfunction in the pulmonic position in patients with congenital cardiac anomalies.

Identification of urinary microRNA biomarkers for in vivo gentamicin-induced nephrotoxicity models.

BACKGROUND: Although previous in vivo studies explored urinary microRNA (miRNA), there is no agreement on nephrotoxicity-specific miRNA biomarkers. OBJECTIVES: In this study, we assessed whether urinary miRNAs could be employed as biomarkers for nephrotoxicity. METHODS: For this, literature-based candidate miRNAs were identified by reviewing the previous studies. Female Sprague-Dawley rats received subcutaneous injections of a single dose or repeated doses (3 consecutive days) of gentamicin (GEN; 137 or 412 mg/kg). The expression of miRNAs was analyzed by real-time reverse transcription-polymerase chain reaction in 16 h pooled urine from GEN-treated rats. RESULTS: GEN-induced acute kidney injury was confirmed by the presence of tubular necrosis. We identified let-7g-5p, miR-21-3p, 26b-3p, 192-5p, and 378a-3p significantly upregulated in the urine of GEN-treated rats with the appearance of the necrosis in proximal tubules. Specifically, miR-26-3p, 192-5p, and 378a-3p with highly expressed levels in urine of rats with GEN-induced acute tubular injury were considered to have sensitivities comparable to clinical biomarkers, such as blood urea nitrogen, serum creatinine, and urinary kidney injury molecule protein. CONCLUSIONS: These results indicated the potential involvement of urinary miRNAs in chemical-induced nephrotoxicity, suggesting that certain miRNAs could serve as biomarkers for acute nephrotoxicity.

High-content analysis of in vitro hepatocyte injury induced by various hepatotoxicants.

In vitro prediction of hepatotoxicity can enhance the performance of non-clinical animal testing for identifying chemical hazards. In this study, we assessed high-content analysis (HCA) using multi-parameter cell-based assays as an in vitro hepatotoxicity testing model using various hepatotoxicants and human hepatocytes such as HepG2 cells and human primary hepatocytes (hPHs). Both hepatocyte types were exposed separately to multiple doses of ten hepatotoxicants associated with liver injury whose mechanisms of action have been described. HCA data were obtained using fluorescence probes for nuclear size (Hoechst), mitochondrial membrane potential (TMRM), cytosolic free calcium (Fluo-4AM), and lipid peroxidation (BODIPY). Cellular alterations were observed in response to all hepatotoxicants tested. The most sensitive parameter was TMRM, with high sensitivity at a low dose, next was BODIPY, followed by Fluo-4AM. HCA data from HepG2 cells and hPHs were generally concordant, although some inconsistencies were noted. Both hepatocyte types showed mild or severe mitochondrial impairment and lipid peroxidation in response to several hepatotoxicants. The results demonstrate that the application of HCA to in vitro hepatotoxicity testing enables more efficient hazard identification, and further, they suggest that certain parameters could serve as sensitive endpoints for predicting the hepatotoxic potential of chemical compounds.

Acetylcholinesterase activity in the brain of wild birds in Korea-2014 to 2016.

Acetylcholinesterase (AChE) activity level can be used as a diagnostic marker for anticholinesterase pesticide poisoning. In this study, we aimed to establish a baseline level of normal brain AChE activity in wild birds. AChE activity was measured in the brains of 87dead wild birds (26 species). The level of AChE activity ranged from 6.40 to 15.9 µmol/min/g of brain tissue in normal wild birds. However, the brain tissue AChE activity level in wild birds exposed to organophosphate (OP) pesticide was 48.0%-96.3% of that in the normal birds. These results may serve as reference values to facilitate routine diagnosis and monitoring of OP-poisoned wild birds.

Reoperation for coronary artery stenosis after arterial switch operation.

OBJECTIVES: Coronary artery stenosis after an arterial switch operation (ASO) leads to subsequent reoperation. Therefore, we investigated the indications for reoperation and the results of reoperation to suggest methods to improve our management protocol for coronary artery stenosis after an ASO. METHODS: Between September 2003 and December 2016, 86 consecutive patients who underwent an ASO were included in the study. The indications for reoperation, reoperation techniques and postoperative results were investigated. RESULTS: There were 4 in-hospital deaths (4.7%). One late death occurred during the median follow-up period of 59.6 months. The 5-year overall survival rate was 94.2%. Seven reoperations were performed in 5 patients due to coronary artery stenosis. The indications for reoperation were severe coronary artery stenosis confirmed by computed tomography (CT) angiography or coronary angiography with or without symptoms. Patients with a coronary artery between the great arteries or a high take-off coronary artery frequently required reoperation due to coronary artery stenosis. None of the patients who underwent unroofing or cut-back angioplasty experienced complications during the median follow-up period of 52.0 months. However, 2 patients who underwent ostioplasty required an additional reoperation due to coronary artery restenosis. CONCLUSIONS: A standardized follow-up protocol including CT angiography or coronary angiography after the ASO is required to address coronary artery stenosis. Good reoperation results were observed using the unroofing and cut-back angioplasty techniques.

Development of a Pulmonary Arteriovenous Fistula after a Modified Glenn Shunt in Tetralogy of Fallot and Its Resolution after Shunt Takedown in a 57-Year-Old Patient.

Pulmonary arteriovenous fistula (PAVF) is a complication of the Glenn shunt. A 57-year-old tetralogy of Fallot (TOF) patient, who had undergone a Glenn shunt and TOF total correction, complained of dyspnea and cyanosis. PAVFs were present in the right lung, and right lung perfusion was nearly absent. After coil embolization, takedown of the Glenn shunt, and reconstruction of the right pulmonary artery, the patient's symptoms were relieved. Extrapulmonary radioisotope uptake caused by the PAVFs shown in lung perfusion scans decreased, and right lung perfusion increased gradually. Although the development and resolution of PAVFs after a Glenn shunt have been reported in the pediatric population, this may be the first report on this change in old age.

Biventricular Repair after Bilateral Pulmonary Artery Banding as a Rescue Procedure for a Neonate with Hypoplastic Left Heart Complex.

Hypoplastic left heart complex (HLHC) consists of less severe underdevelopment of the left ventricle without intrinsic left valvular stenosis, i.e., a subset of hypoplastic left heart syndrome (HLHS). HLHC patients may be able to undergo biventricular repair, while HLHS requires single ventricle palliation (or transplant). However, there is no consensus regarding the likelihood of favorable outcomes in neonates with HLHC selected to undergo this surgical approach. This case report describes a neonate with HLHC, co-arctation of the aorta (CoA), and patent ductus arteriosus (PDA) who was initially palliated using bilateral pulmonary artery banding due to unstable ductus-dependent circulation. A postoperative echocardiogram showed newly appearing CoA and progressively narrowing PDA, which resulted in the need for biventricular repair 21 days following the palliation surgery. The patient was discharged on postoperative day 13 without complications and is doing clinically well seven months after surgery.

Detachment of the tricuspid valve for ventricular septal defect closure in infants younger than 3 months.

OBJECTIVES: Although several previous studies have reported that a ventricular septal defect (VSD) can be closed safely through the detached tricuspid valve (TV) without impairing TV function, this has not been demonstrated for infants younger than 3 months. METHODS: We enrolled 296 infants younger than 3 months who underwent VSD closure through the right atrium between January 2004 and December 2013. In the study group of 49 patients (16.6%), the TV was detached for better exposure of the defect. RESULTS: The median age and weight were 63.5 days (14-90 days) and 4.4 kg (2.1-6.7 kg), without intergroup differences. Abnormal chordal attachment of the TV in preoperative echocardiography was associated with detachment of the TV during surgery (P = .001). Cardiopulmonary bypass (P = .001) and aortic crossclamp (P < .001) times were significantly longer in the study group. A permanent pacemaker was required for 2 patients in the control group. Follow-up echocardiography was available for 282 patients at a median of 21 months (1-108 months) after the operation. On final echocardiography, tricuspid regurgitation greater than grade 2 was observed in 1 patient in the study group and residual VSD existed in 4 patients (1 in the study group), without statistical significance. CONCLUSIONS: Detachment of the TV can be used safely for better exposure of the VSD without increased risk of tricuspid regurgitation in infants younger than 3 months. Preoperative echocardiography might be useful for predicting the possibility of detachment of the TV for enhancing exposure of the VSD.

Aortic Root Translocation with Arterial Switch for Transposition of the Great Arteries or Double Outlet Right Ventricle with Ventricular Septal Defect and Pulmonary Stenosis.

Double outlet right ventricle (DORV) and transposition of the great arteries (TGA) with ventricular septal defect (VSD) and pulmonary stenosis (PS) are complex heart diseases, the treatment of which remains a surgical challenge. The Rastelli procedure is still the most commonly performed treatment. Aortic root translocation including an arterial switch operation is advantageous anatomically since it has a lower possibility of conduit blockage and the left ventricle outflow tract remains straight. This study reports successful aortic root transpositions in two patients, one with DORV with VSD and PS and one with TGA with VSD and PS. Both patients were discharged without postoperative complications.

Anatomic variability of the thoracic duct in pediatric patients with complex congenital heart disease.

OBJECTIVE: Thoracic duct mass ligation (TDML) through a right thoracotomy (RT), regardless of the side of the pleural effusion, is a standard procedure for chylothorax that is refractory to medical treatment. This procedure may be unsuccessful in patients with complex congenital heart disease, which necessitates additional left thoracotomy (LT) for left periaortic mass ligation. We hypothesized that failure of the right-sided approach is attributable to the anatomic variation of the path of the thoracic duct. METHODS: Of the children who underwent surgery for congenital heart disease between 1992 and 2014, a total of 70 of 8880 (0.8%) underwent TDML by RT (n = 57) or LT (n = 13; LT after RT in 10, and primary LT in 3). RESULTS: Persistent chylothorax was successfully resolved in 65 patients (65 of 70; 93%) within 15 days (2-79 days) after the first or second TDML; 5 patients died with a chest-tube(s) in situ. After excluding mortality without chest-tube removal, we sought to identify the risk factor(s) necessitating LT in 65 patients (RT group: 54; LT group: 11). On logistic regression analysis, the LT group was more likely to have dextrocardia (odds ratio: 6.38; 95% confidence interval: 1.09-37.25; P = .04). The incidence of abnormal atrial situs, great arterial malposition, right descending thoracic aorta, and bilateral superior vena cavae were comparable in the 2 groups. CONCLUSIONS: The path of the thoracic duct may vary in pediatric patients with complex congenital heart disease. Left periaortic mass ligation should be considered in patients with chylothoraces that persist after the right-sided approach, especially in patients with dextrocardia.

Heart Transplantation in a Patient with Left Isomerism.

We report the case of a 37-year-old man who suffered from biventricular failure due to left isomerism, inferior vena cava interruption with azygos vein continuation, bilateral superior vena cava, double outlet of right ventricle, complete atrioventricular septal defect, pulmonary stenosis, and isolated dextrocardia. Heart transplantation in patients with systemic venous anomalies often requires the correction and reconstruction of the upper & lower venous drainage. We present a case of heart transplantation in a patient with left isomerism, highlighting technical modifications to the procedure, including the unifocalization of the caval veins and reconstruction with patch augmentation.

Cardiac Resynchronization Therapy in Infant with Dilated Cardiomyopathy during Extracorporeal Membrane Oxygenator.

Although heart transplantation is a final therapeutic option in pediatric patients with dilated cardiomyopathy (DCMP), the shortage of pediatric heart donors is a major obstacle. In adults with DCMP characterized by cardiac dyssynchrony, cardiac resynchronization therapy (CRT) is known to be an effective treatment option. However, there is a lack of evidence on the effectiveness of CRT in infants with DCMP. Several studies have reported improvement in hemodynamics and cardiac performance following CRT in infants with DCMP. Here, we report CRT in an infant with DCMP during extracorporeal membrane oxygenation with 5 months of follow-up.

Translocation of the aortic arch with norwood procedure for hypoplastic left heart syndrome variant with circumflex retroesophageal aortic arch.

Retroesophageal aortic arch, in which the aortic arch crosses the midline behind the esophagus to the contralateral side, is a rare form of vascular anomaly. The complete form may cause symptoms by compressing the esophagus or the trachea and need a surgical intervention. We report a rare case of a hypoplastic left heart syndrome variant with the left retroesophageal circumflex aortic arch in which the left aortic arch, retroesophageal circumflex aorta, and the right descending aorta with the aberrant right subclavian artery encircle the esophagus completely, thus causing central bronchial compression. Bilateral pulmonary artery banding and subsequent modified Norwood procedure with extensive mobilization and creation of the neo-aorta were performed. As a result of the successful translocation of the aorta, the airway compression was relieved. The patient underwent the second-stage operation and is doing well currently.

Long term outcomes of aortic root replacement: 18 years' experience.

BACKGROUND: We reviewed the long-term outcomes of aortic root replacement at Asan Medical Center and investigated the predictors affecting mortality. MATERIALS AND METHODS: A retrospective analysis was performed on 225 consecutive adult patients undergoing aortic root replacement with mechanical conduits (n=169), porcine aortic root prosthesis (n=23), or aortic homografts (n=33) from January 1992 to September 2009. The median follow-up duration was 6.1 years (range, 0 to 18.0 years). RESULTS: The porcine root group was older than the other groups (freestyle 55.9±14.3 years vs. mechanical 46.3±14.6 years, homograft 48.1±14.7 years; p=0.02). The mechanical group had the highest incidence of the Marfan syndrome (mechanical 22%, freestyle 4%, homograft 3%; p=0.01). Surgery performed for infective endocarditis was more frequent in the homograft group (mechanical 10%, freestyle 10%, homograft 40%; p<0.001). The overall 30-day mortality was 5.3% (12/225). Actuarial survival rates in the mechanical, porcine root, and homograft groups were 79.4%, 81.5%, and 83.5% at 5 years and 67%, 61.9%, and 61.1% at 10 years, respectively (p=0.73). By multivariate analysis, preoperative diabetes mellitus, older age, and longer cardiopulmonary bypass time were independent predictors of mortality. Incidence of postoperative complications, including infective endocarditis and thromboembolism were comparable in all of the groups. CONCLUSION: Aortic root replacement can be safely performed with different types of prostheses as the outcome was not affected by the choice of prosthesis. Further studies are required to assess the long-term durability of biological prostheses.

Axillofemoral Bypass to Treat Severe Heart Failure Caused by Takayasu's Arteritis.

Takayasu's arteritis is an inflammatory vasculitis that primarily affects the aorta and its major branches. Involvement of the thoracic and abdominal aortas, although rare, causes marked hypertension and may lead to severe heart failure. We report the improvement of cardiac function after axillofemoral bypass grafting in a 59-year-old woman who had this condition.