Roles of Oxidative Injury and Nitric Oxide System Derangements in Kawasaki Disease Pathogenesis: A Systematic Review.

Kawasaki disease (KD) is an acute febrile vasculitis that occurs mostly in children younger than five years. KD involves multiple intricately connected inflammatory reactions activated by a cytokine cascade. Despite therapeutic advances, coronary artery damage may develop in some patients, who will be at risk of clinical cardiovascular events and even sudden death. The etiology of KD remains unclear; however, it may involve both genetic and environmental factors leading to aberrant inflammatory responses. Given the young age of onset, prenatal or perinatal exposure may be etiologically relevant. Multisystem inflammatory syndrome in children, a post-infectious hyper-inflammatory disorder associated with severe acute respiratory syndrome coronavirus 2, has features that overlap with those of KD. Available evidence indicates that vascular endothelial dysfunction is a critical step in the sequence of events leading to the development of cardiovascular lesions in KD. Oxidative stress and the dysregulation of the nitric oxide (NO) system contribute to the pathogenesis of inflammatory responses related to this disease. This review provides current evidence and concepts highlighting the adverse effects of oxidative injury and NO system derangements on the initiation and progression of KD and potential therapeutic strategies for cardiovascular pathologies in affected children.

Vascular occlusion with 0.035-inch hydrogel expandable coils in congenital heart diseases and vascular anomalies.

BACKGROUND: We present our experience with transcatheter vascular occlusion using 0.035-inch hydrogel expandable coils, which has been reported only in a few cases in the pediatric cardiology fields. METHODS: This study is a retrospective analysis of all patients who underwent transcatheter embolization with 0.035-inch hydrogel coils at the Department of Pediatrics, Okayama University Hospital, between October 2018 and September 2020. RESULTS: Twenty patients with a median age of 5.1 years (0.05-26.0 years) and a median weight of 13.8 kg (3.0-56.8 kg) were included. A total of fifty-four 0.035-inch hydrogel coils, including 35 Azur 35 and nineteen Azur CX 35 coils (Terumo, Tokyo, Japan), were successfully deployed in 22 target vessels. The target vessels consisted of 10 aortopulmonary collaterals, 8 veno-venous collaterals, and 4 pulmonary arteriovenous malformations. We achieved technical success in all the target vessels. In total, the mean target vessel diameter was 4.4 mm, the mean number of 0.035-inch hydrogel coils was 2.5 per vessel. The mean device to vessel ratio was 1.6 for the anchor coil and 1.2 for the additional coil. Post-implantation angiograms revealed that the primary occlusion rate was 18/22 (82%). There were no periprocedural complications. CONCLUSIONS: The 0.035-inch hydrogel expandable coils are effective and safe in patients with congenital heart disease and vascular anomalies. These occlusion devices could be valuable options for interventional pediatric cardiologists.

Stepwise Treatment for Heterotaxy Syndrome and Functional Single Ventricle Complicated by Infra-Cardiac Total Anomalous Pulmonary Venous Connection with Ductus Venosus Stent Placement and Subsequent Occlusion.

Even today, when the surgical outcome of congenital heart disease in the neonatal period has improved, the prognosis for heterotaxy syndrome and functional single ventricle complicated with total anomalous pulmonary venous connection (TAPVC), especially the infra-cardiac type, is catastrophic. We describe a strategy that combines percutaneous ductus venosus (DV) stent placement and occlusion after TAPVC repair to ensure survival from initial surgery to bidirectional cavopulmonary shunt (BCPS) procedure and facilitate subsequent treatment. Three consecutive patients with heterotaxy syndrome and functional single ventricle complicated by infra-cardiac TAPVC treated with our own strategy were retrospectively studied. In two infants, DV stent placement was performed on the day of birth. In one case at 11 days of age. The risk of pulmonary vein obstruction was reduced, and on-pump surgery, including TAPVC repair, was performed on a standby basis. Since the rapid increase in hepatic enzymes occurred on postoperative day 0 to 1 in all cases, percutaneous stent occlusion was performed until postoperative day 3. The procedure improved liver function. One patient died due to severe atrioventricular valve regurgitation, one case underwent BCPS, and one patient was waiting to undergo. DV stent placement can avoid TAPVC repair in the early neonatal period. After TAPVC repair, the portosystemic shunt remained, resulting in hepatic dysfunction, but this could be improved by stent and vertical vein occlusion. A series of stepwise treatments can be useful to help such critically ill infants survive the high-risk neonatal period and achieve good BCPS circulation.

Outcomes of Right Ventricular Outflow Tract Reconstruction in Children: Retrospective Comparison Between Bovine Jugular Vein and Expanded Polytetrafluoroethylene Conduits.

Bovine jugular vein (BJV) and expanded polytetrafluoroethylene (ePTFE) conduits have been described as alternatives to the homograft for right ventricular outflow tract (RVOT) reconstruction. This study compared RVOT reconstructions using BJV and ePTFE conduits performed in a single institution. The valve functions and outcomes of patients aged < 18 years who underwent primary RVOT reconstruction with a BJV or ePTFE conduit between 2013 and 2017 were retrospectively investigated. 44 patients (20 and 24 with BJV and ePTFE conduits, respectively) met the inclusion criteria. The mean follow-up time was 4.5 ± 1.5 years. No significant differences in peak RVOT velocity (1.8 ± 0.9 m/s vs 2.1 ± 0.9 m/s, P = 0.27), branch pulmonary stenosis (P = 0.50), or pulmonary regurgitation (P = 0.44) were found between the BJV and ePTFE conduit groups, respectively. Aneurysmal dilatation of the conduit was observed in 25.0% of the patients in the BJV conduit group but not in the ePTFE conduit group (P = 0.011). All the cases with aneurysmal dilatation of the BJV conduit were complicated with branch pulmonary stenosis up to 3.0 m/s (P = 0.004). No conduit infections occurred during the follow-up period, and no significant difference in conduit replacement (20.0% vs 8.3%, P = 0.43) was found between the BJV and ePTFE conduit groups, respectively. The outcomes of the RVOT reconstructions with BJV and ePTFE conduits were clinically satisfactory. Aneurysmal dilatation was found in the BJV conduit cases, with branch pulmonary stenosis as the risk factor.

Cardiosphere-derived exosomal microRNAs for myocardial repair in pediatric dilated cardiomyopathy.

Although cardiosphere-derived cells (CDCs) improve cardiac function and outcomes in patients with single ventricle physiology, little is known about their safety and therapeutic benefit in children with dilated cardiomyopathy (DCM). We aimed to determine the safety and efficacy of CDCs in a porcine model of DCM and translate the preclinical results into this patient population. A swine model of DCM using intracoronary injection of microspheres created cardiac dysfunction. Forty pigs were randomized as preclinical validation of the delivery method and CDC doses, and CDC-secreted exosome (CDCex)-mediated cardiac repair was analyzed. A phase 1 safety cohort enrolled five pediatric patients with DCM and reduced ejection fraction to receive CDC infusion. The primary endpoint was to assess safety, and the secondary outcome measure was change in cardiac function. Improved cardiac function and reduced myocardial fibrosis were noted in animals treated with CDCs compared with placebo. These functional benefits were mediated via CDCex that were highly enriched with proangiogenic and cardioprotective microRNAs (miRNAs), whereas isolated CDCex did not recapitulate these reparative effects. One-year follow-up of safety lead-in stage was completed with favorable profile and preliminary efficacy outcomes. Increased CDCex-derived miR-146a-5p expression was associated with the reduction in myocardial fibrosis via suppression of proinflammatory cytokines and transcripts. Collectively, intracoronary CDC administration is safe and improves cardiac function through CDCex in a porcine model of DCM. The safety lead-in results in patients provide a translational framework for further studies of randomized trials and CDCex-derived miRNAs as potential paracrine mediators underlying this therapeutic strategy.

Clinical outcomes after the endovascular treatments of pulmonary vein stenosis in patients with congenital heart disease.

BACKGROUND: Pulmonary vein stenosis (PVS) is a condition with challenging treatment and leads to severe cardiac failure and pulmonary hypertension. Despite aggressive surgical or catheter-based intervention, the prognosis of PVS is unsatisfactory. This study aimed to assess the prognosis and to establish appropriate treatment strategies. METHODS: We retrospectively reviewed endovascular treatments for PVS (2001-2017) from the clinical database at the Okayama University Hospital. RESULTS: A total of 24 patients underwent PVS associated with total anomalous pulmonary venous connection and 7 patients underwent isolated congenital PVS. In total, 53 stenotic pulmonary veins were subjected to endovascular treatments; 40 of them were stented by hybrid (29) and percutaneous procedures (11) (bare-metal stent, n = 34; drug-eluting stent, n = 9). Stent size of hybrid stenting was larger than percutaneous stenting. Median follow-up duration from the onset of PVS was 24 months (4-134 months). Survival rate was 71 and 49% at 1 and 5 years, respectively. There was no statistically significant difference between stent placement and survival; however, patients who underwent bare-metal stent implantation had statistically better survival than those who underwent drug-eluting stent implantation or balloon angioplasty. Early onset of stenosis, timing of stenting, and small vessel diameter of pulmonary vein before stenting were considered as risk factors for in-stent restenosis. Freedom from re-intervention was 50 and 26% at 1 and 2 years. CONCLUSIONS: To improve survival and stent patency, implantation of large stent is important. However, re-intervention after stenting is also significant to obtain good outcome.

Balloon atrial septostomy in hypoplastic left heart syndrome with restrictive atrial septum.

BACKGROUND: Rashkind balloon atrial septostomy (BAS) can be challenging in infants with hypoplastic left heart syndrome (HLHS) and small atrial septal defect (ASD). METHODS: We retrospectively reviewed all infants with HLHS who underwent surgery and BAS between January 2006 and December 2015. The infants were divided into three groups: no BAS; catheter BAS; and open AS. Infants who underwent catheter BAS were divided into two groups based on atrial septal anatomy: standard and complex. RESULTS: Of the 70 patients, 57 (81%) underwent Glenn surgery. Subsequently, a significant difference in survival was observed: 86% (44/51), 91% (10/11), and 25% (2/8) in the no BAS, catheter BAS, and open AS groups, respectively (P = 0.0002). No significant difference was seen between the no BAS and the catheter BAS groups (P = 1.0). In the 56 patients who underwent catheterization after surgery, no intergroup differences in mean pulmonary artery pressure, pulmonary vascular resistance, or pulmonary artery index were found. We classified catheter BAS into standard (n = 5) and complex (n = 5) based on ASD location, and septum thickness. All patients in the standard group underwent complete Rashkind BAS, but in the complex group, only one patient underwent complete Rashkind BAS, with the remaining requiring initial static BAS (P = 0.048). Following septostomy, ASD size, ASD flow, and percutaneous oxygen saturation (SpO2 ) were not significantly different between the two groups. CONCLUSIONS: Catheter BAS is effective in infants with HLHS and a restrictive atrial septum. Infants with standard or complex atrial septum can achieve equivalent outcomes despite more patients often requiring static BAS.

Transcoronary cell infusion with the stop-flow technique in children with single-ventricle physiology.

BACKGROUND: Almost all reports on cardiac regeneration therapy have referred to adults, and only a few have focused on transcoronary infusion of cardiac progenitor cells using the stop-flow technique in children. METHODS: Intracoronary autologous cardiosphere-derived cell (CDC) transfer was conducted at Okayama University as a phase 1 clinical trial for seven patients with hypoplastic left heart syndrome between January 2011 and December 2012, and as a phase 2 clinical trial for 34 patients with single-ventricle physiology between July 2013 and March 2015. RESULTS: A total of 41 patients with single-ventricle physiology underwent transcoronary infusion of CDC with the stop-flow technique. The median age was 33 months (range, 5-70 months) and the median weight was 10.1 kg (range, 4.1-16.0 kg). Transient adverse events occurred during the procedure, including ST-segment elevation or depression, hypotension, bradycardia, and coronary artery vasospasm. All patients completely recovered. There were no major procedure-related adverse events. In this study, transcoronary infusion of CDC using the stop-flow technique was successfully completed in all patients. CONCLUSION: Transcoronary infusion of CDC using the stop-flow technique in children is a feasible and safe procedure.

Intracoronary Cardiac Progenitor Cells in Single Ventricle Physiology: The PERSEUS (Cardiac Progenitor Cell Infusion to Treat Univentricular Heart Disease) Randomized Phase 2 Trial.

RATIONALE: Patients with single ventricle physiology are at high risk of mortality resulting from ventricular dysfunction. The preliminary results of the phase 1 trial showed that cardiosphere-derived cells (CDCs) may be effective against congenital heart failure. OBJECTIVE: To determine whether intracoronary delivery of autologous CDCs improves cardiac function in patients with single ventricle physiology. METHODS AND RESULTS: We conducted a phase 2 randomized controlled study to assign in a 1:1 ratio 41 patients who had single ventricle physiology undergoing stage 2 or 3 palliation to receive intracoronary infusion of CDCs 4 to 9 weeks after surgery or staged reconstruction alone (study A). The primary outcome measure was to assess improvement in cardiac function at 3-month follow-up. Four months after palliation, controls had an alternative option to receive late CDC infusion on request (study B). Secondary outcomes included ventricular function, heart failure status, somatic growth, and health-related quality of life after a 12-month observation. At 3 months, the absolute changes in ventricular function were significantly greater in the CDC-treated group than in the controls (+6.4% [SD, 5.5] versus +1.3% [SD, 3.7]; P=0.003). In study B, a late CDC infusion in 17 controls increased the ventricular function at 3 months compared with that at baseline (38.8% [SD, 7.7] versus 34.8% [SD, 7.4]; P<0.0001). At 1 year, overall CDC infusion was associated with improved ventricular function (41.4% [SD, 6.6] versus 35.0% [SD, 8.2]; P<0.0001) and volumes (P<0.001), somatic growth (P<0.0001) with increased trophic factors production, such as insulin-like growth factor-1 and hepatocyte growth factor, and quality of life, along with a reduced heart failure status (P<0.0001) and cardiac fibrosis (P=0.014) relative to baseline. CONCLUSIONS: Intracoronary infusion of CDCs after staged palliation favorably affected cardiac function by reverse remodeling in patients with single ventricle physiology. This impact may improve heart failure status, somatic growth, and quality of life in patients and reduce parenting stress for their families. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01829750.

A staged decompression of right ventricle allows growth of right ventricle and subsequent biventricular repair in patients with pulmonary atresia and intact ventricular septum.

OBJECTIVES: To achieve the growth of right-sided heart structures, our choice of the first palliation for patients with pulmonary atresia and intact ventricular septum (PA-IVS) includes a modified Blalock-Taussig shunt (BTS) with pulmonary valvotomy. We sought to analyse the impact of the first palliation on the growth of right-sided heart structures and factors associated with a choice of definitive surgical procedure. METHODS: Fifty patients with PA-IVS who underwent a staged surgical approach from 1991 to 2012 were retrospectively reviewed. RESULTS: Right ventricular (RV)-coronary artery fistulas were seen in 42% of patients at the time of birth. All 50 patients had a modified BTS with pulmonary valvotomy. Six patients died after the first palliation or inter-stage. Thirty patients achieved a biventricular repair (BVR group), 6 patients had a 1 + 1/2 ventricular repair (1 + 1/2V group) and 5 patients had a Fontan completion (Fontan group). After modified BTS with pulmonary valvotomy, tricuspid valve z-score did not increase in any of the group (BVR: pre -2.79 vs post -2.24, 1 + 1/2V: pre -5.25 vs post -6.69, Fontan: pre -6.82 vs post -7.94). Normalized RV end-diastolic volume increased only in BVR group after modified BTS with pulmonary valvotomy (BVR: pre 32% vs post 64%, 1 + 1/2V: pre 43% vs post 42%, Fontan: pre 29% vs post 32%). Major RV-coronary artery fistula was a strong factor with proceeding single-ventricle palliation [BVR: 4/30 (13%) patients, 1 + 1/2V: 1/6 (17%) and Fontan: 4/5 (80%)]. CONCLUSIONS: Tricuspid valve growth was not obtained by modified BTS with pulmonary valvotomy; therefore, tricuspid valve size at birth appeared to be a predictor for achieving BVR. Proportionate RV growth was seen only in patients who achieved BVR. However, RV growth was not seen in patients having 1 + 1/2 ventricular repair. Major RV-coronary artery fistula was a strong predictor for proceeding single-ventricle palliation.

Intracoronary autologous cardiac progenitor cell transfer in patients with hypoplastic left heart syndrome: the TICAP prospective phase 1 controlled trial.

RATIONALE: Hypoplastic left heart syndrome (HLHS) remains a lethal congenital cardiac defect. Recent studies have suggested that intracoronary administration of autologous cardiosphere-derived cells (CDCs) may improve ventricular function. OBJECTIVE: The aim of this study was to test whether intracoronary delivery of CDCs is feasible and safe in patients with hypoplastic left heart syndrome. METHODS AND RESULTS: Between January 5, 2011, and January 16, 2012, 14 patients (1.8±1.5 years) were prospectively assigned to receive intracoronary infusion of autologous CDCs 33.4±8.1 days after staged procedures (n=7), followed by 7 controls with standard palliation alone. The primary end point was to assess the safety, and the secondary end point included the preliminary efficacy to verify the right ventricular ejection fraction improvements between baseline and 3 months. Manufacturing and intracoronary delivery of CDCs were feasible, and no serious adverse events were reported within the 18-month follow-up. Patients treated with CDCs showed right ventricular ejection fraction improvement from baseline to 3-month follow-up (46.9%±4.6% to 52.1%±2.4%; P=0.008). Compared with controls at 18 months, cardiac MRI analysis of CDC-treated patients showed a higher right ventricular ejection fraction (31.5%±6.8% versus 40.4%±7.6%; P=0.049), improved somatic growth (P=0.0005), reduced heart failure status (P=0.003), and lower incidence of coil occlusion for collaterals (P=0.007). CONCLUSIONS: Intracoronary infusion of autologous CDCs seems to be feasible and safe in children with hypoplastic left heart syndrome after staged surgery. Large phase 2 trials are warranted to examine the potential effects of cardiac function improvements and the long-term benefits of clinical outcomes. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01273857.

Mutations of NOTCH3 in childhood pulmonary arterial hypertension.

Mutations of BMPR2 and other TGF-ß superfamily genes have been reported in pulmonary arterial hypertension (PAH). However, 60-90% of idiopathic PAH cases have no mutations in these genes. Recently, the expression of NOTCH3 was shown to be increased in the pulmonary artery smooth muscle cells of PAH patients. We sought to investigate NOTCH3 and its target genes in PAH patients and clarify the role of NOTCH3 signaling. We screened for mutations in NOTCH3, HES1, and HES5 in 41 PAH patients who had no mutations in BMPR2, ALK1, endoglin, SMAD1/4/8, BMPR1B, or Caveolin-1. Two novel missense mutations (c.2519 G>A p.G840E, c.2698 A>C p.T900P) in NOTCH3 were identified in two PAH patients. We performed functional analysis using stable cell lines expressing either wild-type or mutant NOTCH3. The protein-folding chaperone GRP78/BiP was colocalized with wild-type NOTCH3 in the endoplasmic reticulum, whereas the majority of GRP78/BiP was translocated into the nuclei of cells expressing mutant NOTCH3. Cell proliferation and viability were higher for cells expressing mutant NOTCH3 than for those expressing wild-type NOTCH3. We identified novel NOTCH3 mutations in PAH patients and revealed that these mutations were involved in cell proliferation and viability. NOTCH3 mutants induced an impairment in NOTCH3-HES5 signaling. The results may contribute to the elucidation of PAH pathogenesis.

Fluctuating liver functions in siblings with MPV17 mutations and possible improvement associated with dietary and pharmaceutical treatments targeting respiratory chain complex II.

BACKGROUND/AIMS: To describe the clinical and biological findings of two Japanese siblings with novel MPV17 gene mutations (c.451insC/c.509C > T) manifesting hepatic mitochondrial DNA depletion syndrome. METHODS: We observed these brothers and sought to determine the efficacy of treatment targeting respiratory chain complex II for the younger brother. RESULTS: A 3-month-old boy had presented with profound liver dysfunction, failure to thrive, and watery diarrhea. Although he was then placed on a carbohydrate-rich diet, his liver function thereafter fluctuated greatly in association with viral infections, and rapidly deteriorated to liver failure. He underwent liver transplantation at 17 months of age but died at 22 months of age. The younger brother, aged 47 months at the time of this writing, presented with liver dysfunction from 8 months of age. His transaminase levels also fluctuated considerably fluctuations in association with viral infections. At 31 months of age, treatment with succinate and ubiquinone was initiated together with a lipid-rich diet using ketone milk. Thereafter, his transaminase levels normalized and never fluctuated, and the liver histology improved. CONCLUSIONS: These cases suggested that the clinical courses of patients with MPV17 mutations are greatly influenced by viral infections and that dietary and pharmaceutical treatments targeting the mitochondrial respiratory chain complex II may be beneficial in the clinical management of MPV17 mutant patients.