Gene correction and overexpression of TNNI3 improve impaired relaxation in engineered heart tissue model of pediatric restrictive cardiomyopathy.

Research on cardiomyopathy models using engineered heart tissue (EHT) created from disease-specific induced pluripotent stem cells (iPSCs) is advancing rapidly. However, the study of restrictive cardiomyopathy (RCM), a rare and intractable cardiomyopathy, remains at the experimental stage because there is currently no established method to replicate the hallmark phenotype of RCM, particularly diastolic dysfunction, in vitro. In this study, we generated iPSCs from a patient with early childhood-onset RCM harboring the TNNI3 R170W mutation (R170W-iPSCs). The properties of R170W-iPSC-derived cardiomyocytes (CMs) and EHTs were evaluated and compared with an isogenic iPSC line in which the mutation was corrected. Our results indicated altered calcium kinetics in R170W-iPSC-CMs, including prolonged tau, and an increased ratio of relaxation force to contractile force in R170W-EHTs. These properties were reversed in the isogenic line, suggesting that our model recapitulates impaired relaxation of RCM, i.e., diastolic dysfunction in clinical practice. Furthermore, overexpression of wild-type TNNI3 in R170W-iPSC-CMs and -EHTs effectively rescued impaired relaxation. These results highlight the potential efficacy of EHT, a modality that can accurately recapitulate diastolic dysfunction in vitro, to elucidate the pathophysiology of RCM, as well as the possible benefits of gene therapies for patients with RCM.

Left ventricular assist device temporary explantation as a strategy for infection control in a pediatric patient.

We report a case of temporary Berlin Heart EXCOR® explantation in a pediatric patient with idiopathic dilated cardiomyopathy who suffered an uncontrollable inflow cannulation site infection while on bridge-to-transplantation. Despite failure to thrive and catheter-related infections, once free of the device, the patient was cured of infection using systemic antibiotics and surgical debridement. The patient underwent EXCOR® reimplantation after four months, and is awaiting heart transplantation in stable condition. A life-threatening ventricular assist device-related infection may require device explantation under conditions that may not fulfill conventional explantation criteria despite risks. Temporary explantation can be an effective strategy if isolated systolic dysfunction is managed carefully.

Fontan operation for tricuspid atresia with absent pulmonary valve: a case series.

Combined tricuspid atresia and absent pulmonary valve with dysplasia of the right ventricular myocardium is a very rare congenital heart anomaly with a poor prognosis. We present three cases of this rare disease that reached the Fontan operation without prior surgical intervention of the right ventricle or pulmonary artery; no right ventriclar dilation was detected. All patients had uneventful post-operative courses.

Surgical treatment of isolated unilateral absence of pulmonary artery with pulmonary hypertension.

A one-and-a-half-month-old patient with isolated unilateral absence of the right proximal pulmonary artery with prominent left pulmonary hypertension was diagnosed using CT. Medication therapy was initiated first. Left pulmonary artery pressure decreased after the initiation of medication therapy, and single-stage reconstruction of the right pulmonary artery was performed. The patient is asymptomatic 14 months postoperatively.

Antibiotic Prophylaxis for Open Chest Management After Pediatric Cardiac Surgery.

OBJECTIVES: Although open chest management optimizes hemodynamics after cardiac surgery, it increases postoperative infections and leads to increased mortality. Despite the importance of antibiotic prophylaxis during open chest management, no specific recommendations exist. We aimed to compare the occurrence rates of bloodstream infection and surgical site infection between the different prophylactic antibiotic regimens for open chest management after pediatric cardiac surgery. DESIGN: Retrospective, single-center, observational study. SETTING: PICU at a tertiary children's hospital. PATIENTS: Consecutive patients younger than or equal to 18 years old with open chest management after cardiac surgery followed by delayed sternal closure, between January 2012 and June 2018. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We compared the composite occurrence rate of postoperative bloodstream infection and surgical site infection within 30 days after cardiac surgery between three prophylactic antibiotic regimens: 1) cefazolin, 2) cefazolin + vancomycin, and 3) vancomycin + meropenem. In 63 pediatric cardiac surgeries with open chest management, 17 bloodstream infections, and 12 surgical site infections were identified postoperatively. The composite occurrence rates of bloodstream infection and surgical site infection were 10 of 15 (67%), 10 of 19 (53%), and nine of 29 (31%) in the cefazolin, cefazolin + vancomycin, and vancomycin + meropenem regimens, respectively (p = 0.07). After adjusting for age, open chest management duration, extracorporeal membrane oxygenation use, and nasal methicillin-resistant Staphylococcus aureus colonization in multivariable analysis, there was no significant difference between the cefazolin and the cefazolin + vancomycin regimens (p = 0.19), while the vancomycin + meropenem regimen had a lower occurrence rate of bloodstream infection and surgical site infection than the cefazolin regimen (odds ratio, 0.0885; 95% CI, 0.0176-0.446; p = 0.003). CONCLUSIONS: In this study, a lower occurrence rate of postoperative bloodstream infection and surgical site infection was observed among patients with broad-spectrum antibiotic regimen after pediatric cardiac surgery with open chest management. Further studies, ideally randomized controlled studies investigating the efficacy of broad-spectrum antibiotics and their complications, are warranted before routine implementation of broad-spectrum prophylactic antibiotic regimen.

Hepatic vein redirection to improve pulmonary arteriovenous malformations after Fontan completion in patients with absence of inferior vena cava and hemiazygos continuation.

Pulmonary arteriovenous malformation is an important complication after Fontan completion in patients with univentricular circulation. Lack of hepatic venous flow in a pulmonary artery has been identified as a cause of pulmonary arteriovenous malformation. We report our experience with a case of redirection of the hepatic vein to the hemiazygos vein using a conduit via left thoracotomy and median sternotomy for the correction of unequal distribution of hepatic venous flow in the pulmonary arteries. The pulmonary arteriovenous malformation improved, leading to increased arterial saturation levels.

Post-Extubation Inhaled Nitric Oxide Therapy via High-Flow Nasal Cannula After Fontan Procedure.

In 2014, our hospital introduced inhaled nitric oxide (iNO) therapy combined with high-flow nasal cannula (HFNC) oxygen therapy after extubation following the Fontan procedure in patients with unstable hemodynamics. We report the benefits of HFNC-iNO therapy in these patients. This was a single-center, retrospective review of 38 patients who underwent the Fontan procedure between January 2010 and June 2016, and required iNO therapy before extubation. The patients were divided into two groups: patients in Epoch 1 (n = 24) were treated between January 2010 and December 2013, receiving only iNO therapy; patients in Epoch 2 (n = 14) were treated between January 2014 and June 2016, receiving iNO therapy and additional HFNC-iNO therapy after extubation. There were no significant differences between Epoch 1 and 2 regarding preoperative cardiac function, age at surgery, body weight, initial diagnosis (hypoplastic left heart syndrome, 4 vs. 2; total anomalous pulmonary venous return, 5 vs. 4; heterotaxy, 7 vs. 8), intraoperative fluid balance, or central venous pressure upon admission to the intensive care unit. Epoch 2 had a significantly shorter duration of postoperative intubation [7.2 (3.7-49) vs. 3.5 (3.0-4.6) hours, p = 0.033], pleural drainage [23 (13-34) vs. 9.5 (8.3-18) days, p = 0.007], and postoperative hospitalization [36 (29-49) vs. 27 (22-36) days, p = 0.017]. Two patients in Epoch 1 (8.3%), but none in Epoch 2, required re-intubation. Our results suggest that HFNC-iNO therapy reduces the duration of postoperative intubation, pleural drainage, and hospitalization.

The usefulness of staged extra-anatomic bypass for coarctation of the aorta with arch hypoplasia, from premature neonate to adult.

Various surgical techniques have been developed for coarctation of the aorta. However, coarctation repair in neonates with arch hypoplasia remains challenging. We herein report a case in which a premature neonate under 1500 g with coarctation of the aorta and arch hypoplasia underwent an extra-anatomical bypass at 18 days old. A second extra-anatomical bypass was performed at 3 years of age, and a third extra-anatomic bypass for recurrent coarctation was performed in adulthood. By increasing the size of the graft as the patient grows, extra-anatomic bypass can be a useful surgical option for premature neonates with coarctation and arch hypoplasia.

Impaired Relaxation in Induced Pluripotent Stem Cell-Derived Cardiomyocytes with Pathogenic TNNI3 Mutation of Pediatric Restrictive Cardiomyopathy.

BACKGROUND: Restrictive cardiomyopathy (RCM) is characterized by impaired diastolic function with preserved ventricular contraction. Several pathogenic variants in sarcomere genes, including TNNI3, are reported to cause Ca2+ hypersensitivity in cardiomyocytes in overexpression models; however, the pathophysiology of induced pluripotent stem cell (iPSC)-derived cardiomyocytes specific to a patient with RCM remains unknown. METHODS AND RESULTS: We established an iPSC line from a pediatric patient with RCM and a heterozygous TNNI3 missense variant, c.508C>T (p.Arg170Trp; R170W). We conducted genome editing via CRISPR/Cas9 technology to establish an isogenic correction line harboring wild type TNNI3 as well as a homozygous TNNI3-R170W. iPSCs were then differentiated to cardiomyocytes to compare their cellular physiological, structural, and transcriptomic features. Cardiomyocytes differentiated from heterozygous and homozygous TNNI3-R170W iPSC lines demonstrated impaired diastolic function in cell motion analyses as compared with that in cardiomyocytes derived from isogenic-corrected iPSCs and 3 independent healthy iPSC lines. The intracellular Ca2+ oscillation and immunocytochemistry of troponin I were not significantly affected in RCM-cardiomyocytes with either heterozygous or homozygous TNNI3-R170W. Electron microscopy showed that the myofibril and mitochondrial structures appeared to be unaffected. RNA sequencing revealed that pathways associated with cardiac muscle development and contraction, extracellular matrix-receptor interaction, and transforming growth factor-ß were altered in RCM-iPSC-derived cardiomyocytes. CONCLUSIONS: Patient-specific iPSC-derived cardiomyocytes could effectively represent the diastolic dysfunction of RCM. Myofibril structures including troponin I remained unaffected in the monolayer culture system, although gene expression profiles associated with cardiac muscle functions were altered.

Novel surgical technique for anomalous origin of a left coronary artery from the right sinus of Valsalva with a single coronary orifice.

Anomalous origin of a left coronary artery from the right sinus of Valsalva with a single coronary orifice is a rare congenital anomaly, which has been associated with myocardial ischemia and sudden death. Surgical repair is recommended upon its detection. A 14-year-old boy was diagnosed with anomalous origin of a left coronary artery from the right sinus of valsalva with a single coronary orifice after a syncope attack. The patient underwent relocation of the left coronary orifice. The postoperative course was uneventful, with no ventricular arrhythmia or syncope. The patient did not develop cardiac ischemia or infarction on exercise Tc-99 m myocardial scintigraphy 8 months after the procedure.

Univentricular Conversion for Acquired Severe Right Ventricular Failure.

In a 14-year-old boy, prolonged right ventricular (RV) dysfunction due to postmyocarditis cardiomyopathy developed, whereas left ventricular function recovered with conservative treatment. On catheterization, the RV end-diastolic volume index was 184 mL/m2, and mean pulmonary artery pressure was 16 mm Hg. Despite one-and-a-half ventricle repair, RV dilation continued to worsen; therefore, 3 years after the operation, RV exclusion and extracardiac total cavopulmonary connection were performed. Postoperatively, left ventricular function was maintained, and no further RV dilation was observed. Univentricular conversion may be an effective procedure for the treatment of acquired severe isolated right-sided heart failure.

Cardiomyocyte deoxyribonucleic acid damage and cardiac recovery in paediatric dilated cardiomyopathy.

OBJECTIVES: The goal of this study was to identify the clinical significance of the deoxyribonucleic acid (DNA) damage response marker, phosphorylated H2A histone variant X, on the bridge to recovery in low-weight paediatric patients with dilated cardiomyopathy (DCM) after having a Berlin Heart EXCOR implanted. METHODS: Consecutive paediatric patients with DCM who had an EXCOR implanted for DCM at our hospital between 2013 and 2021 were reviewed. Patients were classified into 2 groups according to the degree of DNA damage in the left ventricular cardiomyocytes-the low DNA damage group and the high DNA damage group-using the median value as the threshold. We examined and compared the preoperative factors and histologic findings associated with cardiac functional recovery following the explant procedure in the 2 groups. RESULTS: Competing outcome analysis of 18 patients (median body weight, 6.1 kg) showed that the incidence of an EXCOR explant was 40% at 1 year after the implant procedure. Serial echocardiography revealed significant left ventricular functional recovery in the low DNA damage group 3 months after the implant. The univariable Cox proportional hazards model revealed that the percentage of phosphorylated H2A histone variant X-positive cardiomyocytes was the significant factor associated with cardiac recovery and the EXCOR explant (hazard ratio, 0.16; 95% confidence interval, 0.027-0.51; P = 0.0096). CONCLUSIONS: The degree of DNA damage response to the EXCOR implant may aid in predicting the bridge to recovery with EXCOR among low-weight paediatric patients with DCM.

Risk factors for atrial arrhythmia recurrence after atrial arrhythmia surgery with pulmonary valve replacement.

Objectives: Atrial arrhythmias are a significant cause of late morbidity and mortality in patients after tetralogy of Fallot repair. However, reports on their recurrence following atrial arrhythmia surgery are limited. We aimed to identify the risk factors for atrial arrhythmia recurrence after pulmonary valve replacement (PVR) and arrhythmia surgery. Methods: We reviewed 74 patients with repaired tetralogy of Fallot who underwent PVR for pulmonary insufficiency at our hospital between 2003 and 2021. Twenty-two patients (mean age, 39 years) underwent PVR and atrial arrhythmia surgery. A modified Cox-maze III was performed in 6 patients with chronic atrial fibrillation, and a right-sided maze was performed in 12 with paroxysmal atrial fibrillation, 3 with atrial flutter, and 1 with atrial tachycardia. Atrial arrhythmia recurrence was defined as any documented sustained atrial tachyarrhythmia requiring intervention. The influence of preoperative parameters on recurrence was assessed with the Cox proportional-hazards model. Results: The median follow-up period was 9.2 years (interquartile range, 4.5-12.4). Cardiac death and redo-PVR due to prosthetic valve dysfunction were not observed. Eleven patients had atrial arrhythmia recurrence after discharge. Atrial arrhythmia recurrence-free rates were 68% at 5 years and 51% at 10 years after PVR and arrhythmia surgery. Multivariable analysis revealed that right atrial volume index (hazard ratio, 1.04; 95% confidence interval, 1.01-1.08, P = .009) was a significant risk factor for atrial arrhythmia recurrence after arrhythmia surgery and PVR. Conclusions: Preoperative right atrial volume index was associated with atrial arrhythmia recurrence, which may assist in planning the timing of atrial arrhythmia surgery and PVR.

Pseudoaneurysm after aortopulmonary window repair and bilateral lung transplantation for eisenmenger syndrome: a case report.

BACKGROUND: Aortopulmonary window (APW) is a rare congenital cardiac anomaly characterized by communication between the main pulmonary artery and ascending aorta. There are various surgical techniques, and the short- and long-term results are excellent if the surgical repair is performed early in life. To our knowledge, there have been no reports of pseudoaneurysm after APW repair. Herein, we present a case of a 30-year-old woman with an ascending aortic pseudoaneurysm found at the site of APW repair nine months after the APW repair and bilateral lung transplantation. CASE PRESENTATIONS: A 30-year-old woman presented with APW and Eisenmenger syndrome. The patient underwent APW repair and bilateral lung transplantation. We transected the communication between the aorta and pulmonary artery and closed the aortic side directly with strips of felts. Nine months after the surgery, the patient complained of chest pain. Cardiac computed tomography revealed an ascending aortic pseudoaneurysm at the anastomotic site. Emergent graft replacement of the ascending aorta was performed and the postoperative course was uneventful. CONCLUSIONS: We have presented a case of a pseudoaneurysm at the anastomotic site after APW repair and bilateral lung transplantation. The choice of surgical technique should be based on the patient's background requiring lung transplantation, and in these cases close postoperative follow-up is required.

Inferior-to-Superior Vena Cava Bypass for Baffle Stenosis After Atrial Switch.

An atrial switch operation was successfully performed in an 11-month-old patient with transposition of the great arteries. Good cardiac function was noted on regular follow-ups. A severe inferior vena cava baffle stenosis was detected after a ruptured hepatocellular carcinoma at the age of 39 years. Liver cirrhosis and hepatocellular carcinoma could have been associated with liver congestion resulting from the stenosis. After partial hepatectomy, inferior vena cava-to-superior vena cava bypass was performed without cardiopulmonary bypass. The patient's postoperative course was uneventful, liver enzyme levels decreased to normal limits, and distant recurrence of hepatocellular carcinoma has not been observed.

Successful bridge to transplantation with long-term support using Berlin heart EXCOR in a child with failing Fontan.

A 2-year-old girl underwent the Fontan operation for aortic valve stenosis, mitral valve stenosis, a hypo-plastic left ventricle, and a non-compacted right ventricle. The patient's cardiac function reduced gradually thereafter, mainly due to systemic ventricular dysfunction. A Berlin Heart EXCOR (BHE) ventricular assist device with a 10-mL pump was implanted at 4 years of age. After 465 days, BHE support without major complications, the patient underwent heart transplantation. A safe and long-term BHE support was achieved with proper case selection and repeated examinations.

Clinical significance of diastolic dysfunction on outcomes of pulmonary valve replacement for pulmonary insufficiency.

OBJECTIVES: According to the current guidelines of pulmonary valve replacement (PVR) for pulmonary insufficiency, the age at the time of PVR is becoming younger. However, recent studies have shown that the improvements in mortality have leveled off, making it important to suppress the cumulative lifetime risk of morbidity. In this study we aimed to identify the risk factors for morbidity late after PVR. METHODS: Sixty-three patients who underwent PVR for pulmonary insufficiency after intracardiac repair of tetralogy of Fallot or pulmonary atresia with ventricular septal defect at our hospital from 2003 to 2019 were included in this study. Morbidity of PVR included arrhythmia requiring treatment and hospitalization for heart failure. The influence of hemodynamic parameters before PVR was analyzed using the Cox proportional hazards model. RESULTS: The median postoperative follow-up period was 6.5 years. Cardiac death and redo PVR because of prosthetic valve dysfunction were not observed. Twenty-two patients suffered cardiovascular adverse events, including 16 supraventricular tachycardia, 3 sick sinus syndrome/atrioventricular block, 2 sustained ventricular tachycardia, and 1 heart failure hospitalization as first events. In the multivariable analysis, pulmonary end diastolic forward flow (hazard ratio [HR], 7.8; 95% CI, 2.6-23; P < .001), right atrial volume index (HR, 1.02; 95% CI, 1.01-1.04; P = .005), and right atrial pressure (HR, 1.2; 95% CI, 1.01-1.45; P = .042) were significant risk factors for adverse events late after PVR. CONCLUSIONS: End diastolic forward flow, large right atrial volume index, and high right atrial pressure before PVR, which are considered markers of diastolic dysfunction, were significant risk factors for cardiovascular adverse events after PVR.

Pulmonary venous obstruction after extracardiac total cavopulmonary connection in right atrial isomerism.

BACKGROUND: Patients with functional single ventricle and right atrial isomerism (RAI) often have multiform cardiac pulmonary venous (PV) connection, which could be a risk factor for pulmonary venous obstruction (PVO) after extracardiac total cavopulmonary connection (EC-TCPC) owing to compression of the conduit. OBJECTIVE: To investigate the anatomical risk factors for PVO after EC-TCPC in RAI. METHODS: Twenty-nine patients with RAI without extracardiac total anomalous pulmonary venous connection were enrolled. No patients had PVO before EC-TCPC. A total of 14 and 15 patients had PV orifices ipsilateral and contralateral to the extracardiac conduit, respectively. The former 14 patients were assigned to two groups based on development of PVO after EC-TCPC (groups O and N). The pre- and post-operative cardiac morphologies and their relationship with the conduit were compared. RESULTS: After the EC-TCPC, the pressure gradients between the atrium and the PV were 5.0 ± 2.5 and 0.44 ± 0.2 mmHg in groups O and N, respectively (p < 0.01); however, the pressure gradients in the left and right PVs were not significantly different, suggesting stenosis of the common PV orifice. The ratio of the horizontal distance from the vertebrae to the PV orifice and to the lateral edge of the atrium was significantly higher (0.38 ± 0.2 vs. 0.17 ± 0.1; p = 0.04) and the orifice was smaller (8.9 ± 2.0 vs. 15 ± 4.7 mm; p < 0.01) in group O than in group N. CONCLUSION: In cases with ipsilateral locations of the conduit and PV orifice, small size and more lateral location of the PV orifice may be preoperative risk factors for development of PVO.

Bilateral Pulmonary Artery Banding in Ebstein's Anomaly With Circular Shunting.

We present a case of critical Ebstein's anomaly with circular shunting, diagnosed in utero. The fetal cardiothoracic area ratio was elevated; tricuspid regurgitation and pulmonary regurgitation worsened with fetal hydrops. At 35 weeks 6 days of gestation, elective caesarean section delivery was performed. Planned bilateral pulmonary artery banding and pulmonary trunk ligation were performed as a palliative operation 4 hours after birth, with the infant in a stable condition. At age 5 days, we performed the Starnes operation. The postoperative course was uneventful and a bidirectional Glenn operation was performed at age 4 months.

Left ventricular function after a Fontan operation in patients with pulmonary atresia with an intact ventricular septum.

OBJECTIVES: In patients with pulmonary atresia with an intact ventricular septum (PA/IVS), there are no reports about the impact of sinusoidal communication (SC) on left ventricular (LV) performance after a Fontan operation; therefore, the purpose of this study was to fill this gap in the literature. METHODS: We performed a single-centre, retrospective study of 46 patients with PA/IVS. Nineteen patients who underwent the Fontan procedure were enrolled and divided into 2 groups: those with SC (SC group) and those without SC (N group). The 2 groups were compared in terms of postoperative cardiac function. RESULTS: Thirteen patients were in the SC group (4 patients with right ventricle-dependent coronary circulation) and 6, in the N group. Although 2 of the patients with right ventricular (RV)-dependent coronary circulation showed focal asynergy of the LV wall, others showed no findings of myocardial infarction. The patients' preoperative age and age during the observation period after the Fontan operation did not differ. There was no difference in LV ejection fraction, cardiac index and RV and pulmonary artery pressure before and after the Fontan operation. Preoperative RV volume in the N group was greater than that in the SC group. Brain natriuretic peptide levels were higher in the SC group after the Fontan operation. On ventricular efficacy analysis, contractility was lower (1.8 ± 0.32 vs 2.5 ± 0.40 mmHg/ml/m2, P = 0.001) and ventricular efficacy was worse (1.0 ± 0.15 vs 0.86 ± 0.11, P = 0.046) in the SC group during the postoperative period. CONCLUSIONS: Compared to patients with PA/IVS without SC, patients with PA/IVS with SC had a low cardiac contractility and decreased cardiac output efficiency after the Fontan procedure.