Efficacy and Tolerability of Ivabradine for Cardiomyopathy in Patients with Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is an intractable X-linked myopathy caused by dystrophin gene mutations. Patients with DMD suffer from progressive muscle weakness, inevitable cardiomyopathy, increased heart rate (HR), and decreased blood pressure (BP). The aim of this study was to clarify the efficacy and tolerability of ivabradine treatment for DMD cardiomyopathy.A retrospective analysis was performed in 11 patients with DMD, who received ivabradine treatment for more than 1 year. Clinical results were analyzed before (baseline), 6 months after, and 12 months after the ivabradine administration.The initial ivabradine dose was 2.0 ± 1.2 mg/day and the final dose was 5.6 ± 4.0 mg/day. The baseline BP was 95/64 mmHg. A non-significant BP decrease to 90/57 mmHg was observed at 1 month but it recovered to 97/62 mmHg at 12 months after ivabradine administration. The baseline HR was 93 ± 6 bpm and it decreased to 74 ± 12 bpm at 6 months (P = 0.011), and to 77 ± 10 bpm at 12 months (P = 0.008). A linear correlation (y = 2.2x + 5.1) was also observed between the ivabradine dose (x mg/day) and HR decrease (y bpm). The baseline LVEF was 38 ± 12% and it significantly increased to 42 ± 9% at 6 months (P = 0.011) and to 41 ± 11% at 12 months (P = 0.038). Only 1 patient with the lowest BMI of 11.0 kg/m2 and BP of 79/58 mmHg discontinued ivabradine treatment at 6 months, while 1-year administration was well-tolerated in the other 10 patients.Ivabradine decreased HR and increased LVEF without lowering BP, suggesting it can be a treatment option for DMD cardiomyopathy.

A Noonan-like pediatric patient with a de novo CBL pathogenic variant and an RNF213 polymorphism p.R4810K presenting with cardiopulmonary arrest due to left main coronary artery ostial atresia.

Left main coronary artery ostial atresia (LMCAOA) is an extremely rare condition. Here, we report the case of a 14-year-old boy with Noonan syndrome-like disorder in whom LMCAOA was detected following cardiopulmonary arrest. The patient had been diagnosed with Noonan syndrome-like disorder with a pathogenic splice site variant of CBL c.1228-2 A > G. He suddenly collapsed when he was running. After administering two electric shocks using an automated external defibrillator, the patient's heartbeat resumed. Cardiac catheterization confirmed the diagnosis of LMCAOA. Left main coronary artery angioplasty was performed. The patient was discharged without neurological sequelae. Brain magnetic resonance imaging revealed asymptomatic Moyamoya disease. In addition, RNF213 c.14429 G > A p.R4810K was identified. There are no reports on congenital coronary malformations of compound variations of RNF213 and CBL. In contrast, the RNF213 p.R4810K polymorphism has been established as a risk factor for angina pectoris and myocardial infarction in adults, and several congenital coronary malformations due to genetic abnormalities within the RAS/MAPK signaling pathway have been reported. This report aims to highlight the risk of sudden death in patients with RASopathy and RNF213 p.R4810K polymorphism and emphasize the significance of actively searching for coronary artery morphological abnormalities in these patients.

Predictors of long-term mortality among perioperative survivors of Fontan operation.

AIMS: The criteria for 'good' Fontan haemodynamics have been poorly defined in relation to long-term outcomes. The aim of this study was to identify the risk factors for mortality among haemodynamic parameters obtained early after the Fontan operation. METHODS AND RESULTS: Clinical data of all perioperative survivors of the Fontan operation performed before 2011, from nine institutions, were collected through a retrospective chart review. In total, 1260 patients were included. The median age at the time of Fontan operation was 3.6 years. Post-operative cardiac catheterization was conducted in 1117 patients at a median period of 1.0 years after the operation. During the median follow-up period of 10.2 years, 107 patients died. The mortality rates at 10, 20, and 25 years after the operation were 5%, 12%, and 22%, respectively. On multivariable analysis, older age at the time of the operation {≥15 years, hazard ratio (HR) [95% confidence interval (CI)]: 3.2 (1.7-5.9)} and haemodynamic parameters obtained at post-operative catheterization, such as low ejection fraction [<30%, HR (95% CI): 7.5 (3.2-18)], low systemic oxygen saturation [<80%, HR (95% CI): 3.8 (1.6-9.1)], high central venous pressure [≥16 mmHg, HR (95% CI): 2.3 (1.3-3.9)], and low mean systemic arterial pressure [<60 mmHg, HR (95% CI): 3.0 (1.4-6.2)] were identified as independent predictors of mortality. The predictive model based on these parameters had a c-index of 0.75 at 10 years. CONCLUSIONS: Haemodynamic parameters obtained at a median period of 1.0 years, post-operatively, can accurately identify patients with a high mortality risk, who may need intensive management to improve long-term outcomes.

Atypical sites of twin atrioventricular nodes in a rare form of univentricular heart.

Twin atrioventricular nodes (AVNs) associated with complex tachycardias has been described in a heart with discordant atrioventricular (AV) connection. The present case had twin AVNs (approximately 3 o'clock and 8 o'clock position) of sole AV annulus with absent right AV connection. It is a first report demonstrated the twin AVNs identified at atypical sites associated with a univentricular heart with single inlet connection.

Risk factors for hospitalisation due to respiratory syncytial virus infection in children receiving prophylactic palivizumab.

Respiratory syncytial virus (RSV) is a common pathogen that causes extremely severe respiratory symptoms in the first few weeks and months of life. In infants with cardiopulmonary diseases, RSV infections have a significant clinical impact. Palivizumab, a humanised monoclonal antibody for RSV, has been shown to significantly reduce the rate of hospitalisation of high-risk infants diagnosed with RSV. However, we have experienced a significant number of RSV infections in our institution that required hospitalisation or intensive care, despite the administration of palivizumab. This study aimed to analyse the risk factors associated with severe RSV despite the use of palivizumab. We retrospectively reviewed the medical records of 688 patients who visited or were admitted to our hospital and received palivizumab. Thirty-seven (5.4%) patients required hospitalisation for RSV, despite receiving palivizumab. In addition, 31 of these patients (83.8%) required hospitalisation out of season for palivizumab injection. Preterm birth (≤ 28-week gestation), bronchopulmonary dysplasia (BPD), and trisomy 21 were risk factors for RSV-related hospitalisation in infected patients, despite receiving palivizumab. Furthermore, subgroup analysis of 69 patients with RSV revealed that hemodynamically significant congenital heart disease (CHD) was also a risk factor for RSV-related hospitalisation.Conclusion: Preterm birth (≤ 28 weeks of gestation), BPD, trisomy 21, hemodynamically significant CHD, and CHD requiring surgery or cardiac catheterisation/intervention during infancy could be considered when determining whether year-round administration of palivizumab is appropriate. What is Known: • Respiratory syncytial virus causes severe respiratory symptoms in infants, particularly those with cardiopulmonary diseases. • The use of palivizumab has reduced the rate of hospitalisation of infants diagnosed with RSV. Despite this, the rate of hospitalisation is still high. What is New: • We identified that preterm birth (≤ 28-week gestation), bronchopulmonary dysplasia, trisomy 21, and hemodynamically significant congenital heart disease were risk factors for RSV-related hospitalisation, even after receiving palivizumab treatment. • High-risk infants should be closely monitored and the prolonged use of palivizumab should be considered.

Perioperative junctional ectopic tachycardia associated with congenital heart disease: risk factors and appropriate interventions.

The risk factors and the appropriate interventions for perioperative junctional ectopic tachycardia (JET) in congenital heart disease (CHD) surgery have not been sufficiently investigated despite the severity of this complication. This study aimed to examine the risk factors and interventions for perioperative JET. From 2013 to 2020, 1062 surgeries for CHD (median patient age: 4.3 years, range 0.0-53.0) with or without a cardiopulmonary bypass (CPB) were performed at Hokkaido University, Japan. We investigated the correlation between perioperative JET morbidity factors, such as age, genetic background, CPB/aortic cross-clamp (ACC) time, use of inotropes and dexmedetomidine, STAT score, and laboratory indices. The efficacy of JET therapies was also evaluated. Of the 1062 patients, 86 (8.1%) developed JET. The 30-day mortality was significantly high in JET groups (7% vs. 0.8%). The independent risk factors for JET included heterotaxy syndrome [odds ratio (OR) 4.83; 95% confidence interval (CI) 2.18-10.07], ACC time exceeding 90 min (OR 1.90; CI 1.27-2.39), and the use of 3 or more inotropes (OR 4.11; CI 3.02-5.60). The combination of anti-arrhythmic drugs and a temporary pacemaker was the most effective therapy for intractable JET. Perioperative JET after CHD surgery remains a common cause of mortality. Inotrope use was a risk factor for developing JET overall surgery risk. In short ACC surgeries, heterotaxy syndrome could increase the risk of JET, which could develop even without inotrope use in long ACC surgeries. It is crucial not to delay the treatment in cases with unstable hemodynamics caused by this arrhythmia. It is recommended to reduce numbers not dose of inotropes.

A geometrical pitfall of Area-Length method; -Is left ventricle volume evaluation of repaired Tetralogy of Fallot by angiocardiography accurate?

Biplane Area-Length (AL) method by left ventriculography (LVG) has been widely adopted as a standard method to estimate left ventricular volume. However, we have experienced difficulties in adopting the value by AL method for the children with Tetralogy of Fallot (TOF) due to the discrepancy among volumetric modalities. This study validated some limitations of AL method, considering the basic principles of its formulation. A single center retrospective cohort study was conducted for 1 year. The confirmed 22 cases with repaired TOF at our hospital were enrolled. The clinical characteristics, some cardiac MRI analyses, and all the cardiac catheterization studies were collected. Angiographic data were compared with historic cohorts of Kawasaki disease without any coronary artery lesions by using AL method. Cardiac MRI analyses of ten TOF patients were additionally available. LVG studies showed that the length of the long axis on anteroposterior view (AP) was not equal to that on lateral view (LT) due to anatomically apical elevation in TOF, followed by a significant difference found in the sagittal lengths of the LV long axis between AP and LT (P = 0.003). Because the difference critically affected the formula depending on biplane AL method, the calculated LVEDV of TOF group appeared overestimated, compared with the control group (TOF vs control group: 119.5% ± 6.3% vs 96.4 ± 3.5% of Normal, P = 0.006). Available cardiac MRI analyses of some patients in TOF group revealed 55% increase of LVEDV by AL method (angiocardiography 116 ± 7.0 vs CMR 75 ± 3.7 ml/m2, P = 0.0025). A pitfall exists when applying biplane AL method to measure LV volume especially for TOF patients, because the long axis on AP view is not always identical to that on LT view.

Challenges in the primary prevention of sudden cardiac death in hypertrophic cardiomyopathy in the young.

A case of hypertrophic cardiomyopathy in the transition from childhood to adulthood, which was low risk by the conventional risk assessment model, medium risk by the adult risk prediction model, and high risk by the paediatric risk prediction model, was inserted an implantable cardioverter-defibrillator. Three years post-implantation, the patient was resuscitated with an appropriate discharge of cardioverter-defibrillator.

Efficacy of cibenzoline for hypertrophic obstructive cardiomyopathy in paediatric patients with RAS/MAPK pathway syndromes.

RASopathies - caused by mutations in the RAS/MAPK signaling pathway - are frequently associated with cardiac diseases, such as hypertrophic obstructive cardiomyopathy. Although cibenzoline is useful for adult hypertrophic obstructive cardiomyopathy patients, little is known about its effect in children. Here, we report two paediatric cases of hypertrophic obstructive cardiomyopathy associated with RASopathies where the condition was improved by cibenzoline.

A Case of Infantile Mitochondrial Cardiomyopathy Treated with a Combination of Low-Dose Propranolol and Cibenzoline for Left Ventricular Outflow Tract Stenosis.

Hypertrophic cardiomyopathy is a common cardiac complication in mitochondrial disorders, and the morbidity rate in neonatal cases is up to 40%. The mortality rate within 3 months for neonatal-onset mitochondrial cardiomyopathy is known to be high because there is currently no established treatment.We report the case of a male infant with neonatal-onset mitochondrial disorder presenting lactic acidosis and hypertrophic cardiomyopathy. Genetic analysis of the patient revealed recurrent m.13513G>A, p.Asp393Asn in mitochondrially encoded NADH dehydrogenase 5 gene (MT-ND5). Low-dose propranolol was initially administered for cardiomyopathy; however, he developed hypertrophic obstructive cardiomyopathy (HOCM) at 3 months of age. To reduce the risk of hypoglycemia associated with high-dose propranolol, cibenzoline, a class Ia antiarrhythmic drug, was added at a dose of 2.5 mg/kg/day and increased weekly to 7.5 mg/kg/day with monitoring of the blood concentration of cibenzoline. Left ventricular outflow tract stenosis (LVOTS) dramatically improved from 5.4 to 1.3 m/second in LVOTS peak velocity after 6 weeks, without notable adverse effects. The plasma N-terminal pro-brain natriuretic peptide level decreased from 65,854 to 10,044 pg/mL. Furthermore, myocardial hypertrophy also improved, as the left ventricular mass index decreased from 173.1 to 108.9 g/m2 after 3 months of the treatment.The administration of cibenzoline, in conjunction with low-dose propranolol, may serve an effective treatment for HOCM in infantile patients with mitochondrial disorders.

A rare case of multiple brain abscesses caused by apical periodontitis of deciduous teeth in congenital heart disease: a case report.

BACKGROUND: A brain abscess is a focal infection in which abscesses form in the brain. A brain abscess is a rare but fatal disease when rupture occurs into the ventricles. We report a case of multiple brain abscesses caused by a hematogenous infection from the apical periodontitis of deciduous teeth. CASE PRESENTATION: The patient was a 7-years and 8-months-old male with congenital heart disease. The patient sought medical attention due to fever and headache, for which he was started on three antibiotics with a diagnosis of multiple brain abscesses. Given that apical periodontitis of deciduous teeth was strongly suspected as the source of the brain abscess, the deciduous teeth were extracted. Immediately after deciduous teeth extraction, the patient's headache and neurological symptoms disappeared. CONCLUSIONS: After teeth extraction, a clear shrinkage of the brain abscess was observed, and the patient was discharged from the hospital.

Left ventricular inflow obstruction due to a coronary arteriovenous fistula: a paediatric case report.

BACKGROUND: We report a rare case of left ventricular inflow obstruction from a branch of the left circumflex coronary artery to the right atrium caused by a coronary arteriovenous fistula (CAVF) in a young Japanese male child. CASE PRESENTATION: The patient was diagnosed with CAVF following a heart murmur shortly after birth. The left-to-right shunt caused right ventricular volume overload and pulmonary congestion. An emergency surgical intervention was performed for the CAVF on day 6 after birth. However, by 5 years of age, his left ventricular inflow obstruction worsened. We found an abnormal blood vessel originating from the proximal part of a branch of the left circumflex coronary artery, circling the outside of the mitral valve annulus along the medial side of the coronary sinus. As the child gets older, the blood inflow into the left ventricle might get restricted further, resulting in left-sided heart failure. CONCLUSION: Our findings suggest that even after CAVF closure surgery, it is essential to monitor for complications caused by progressive dilatation of a persistent CAVF.

Fast pathway ablation unmasks nodoventricular fibers in a 15-year-old patient with supraventricular tachycardia.

We described a 15-year-old boy who underwent the catheter ablation for the nodoventricular (NV) tachycardia that had difficulty in differentiation from atrioventricular nodal reentrant tachycardia with upper common pathway. The modification of the fast pathway revealed an anterograde conduction of the NV fiber. We successfully performed the catheter ablation targeting for the right ventricular insertion site of the NV fiber.

Successful surgical management of cyanotic congenital heart disease complicated by pulmonary aspergillosis.

Pulmonary aspergillosis associated with cyanotic congenital heart disease is a rare condition, which is known to have a poor prognosis. We report a case of a 21-year-old woman with truncus arteriosus and major aortopulmonary collateral arteries who underwent primary Rastelli procedure after thoracoscopic lobectomy for the management of progressive pulmonary aspergillosis.

Resveratrol-Encapsulated Mitochondria-Targeting Liposome Enhances Mitochondrial Respiratory Capacity in Myocardial Cells.

The development of drug delivery systems for use in the treatment of cardiovascular diseases is an area of great interest. We report herein on an evaluation of the therapeutic potential of a myocardial mitochondria-targeting liposome, a multifunctional envelope-type nano device for targeting pancreatic ß cells (ß-MEND) that was previously developed in our laboratory. Resveratrol (RES), a natural polyphenol compound that has a cardioprotective effect, was encapsulated in the ß-MEND (ß-MEND (RES)), and its efficacy was evaluated using rat myocardioblasts (H9c2 cells). The ß-MEND (RES) was readily taken up by H9c2 cells, as verified by fluorescence-activated cell sorter data, and was observed to be colocalized with intracellular mitochondria by confocal laser scanning microscopy. Myocardial mitochondrial function was evaluated by a Seahorse XF Analyzer and the results showed that the ß-MEND (RES) significantly activated cellular maximal respiratory capacity. In addition, the ß-MEND (RES) showed no cellular toxicity for H9c2 cells as evidenced by Premix WST-1 assays. This is the first report of the use of a myocardial mitochondria-targeting liposome encapsulating RES for activating mitochondrial function, which was clearly confirmed based on analyses using a Seahorse XF Analyzer.

Forns Index is a predictor of cardiopulmonary bypass time and outcomes in Fontan conversion.

Recent reports suggested that cardiopulmonary bypass (CPB) time is one of the risk factors for postoperative complications after Fontan conversion. Although Fontan conversion may be performed for the patients with hepatic fibrosis after initial Fontan procedure, there is no predictive indicator regarding the liver function associated with hemostasis which can affects CPB time. Thirty-one patients who underwent Fontan conversion using the same surgical procedure (extracardiac conduit conversion with right atrium exclusion) were enrolled. In multivariate analyses including age at Fontan conversion, interval from initial Fontan to conversion, hemodynamic data such as right atrial pressure, ventricular end-diastolic pressure, and cardiac index, hepatic data such as platelet count, prothrombin time international normalized ratios, serum total bilirubin, hyaluronic acid levels, five known indices for hepatic fibrosis (Forns Index, APRI, FIB4, FibroIndex, and MELD-XI), and liver stiffness measured by ultrasound elastography, only the Forns Index remained independently associated with the CPB time (P < 0.01) and blood transfusions (plasma transfusions and platelet concentrations: P < 0.01 for both). The cutoff level for Forns Index to predict the prolonged CPB time (exceeding 240 min) was 4.85 by receiver-operating characteristic curve (area under the curve 0.823, sensitivity 76.9%, and specificity 72.2%). Three patients with Forns Index > 7.0 had poor outcomes with long CPB time and massive blood transfusions in contrast with the other 28 patients. In conclusion, Forns Index could serve as a practical predictor of CPB time and is associated with blood transfusion volume in Fontan conversion.

Pulmonary vasodilators can lead to various complications in pulmonary "arterial" hypertension associated with congenital heart disease.

Congenital heart disease-associated pulmonary arterial hypertension (CHD-PAH) is one of the major complications in patients with CHD. A timely closure of the left-to-right shunt will generally result in the normalization of the pulmonary hemodynamics, but a few patients have severe prognosis in their early childhood. We hypothesized that wide-ranging pathological mechanism in PAH could elucidate the clinical state of severe CHD-PAH. Using electronic medical records, we retrospectively analyzed six infants with severe CHD-PAH who had treatment-resistant PH. All patients were born with congenital malformation syndrome. After starting on a pulmonary vasodilator, five of the six patients developed complications including pulmonary edema and interstitial lung disease (ILD), and four patients had alveolar hemorrhage. After steroid therapy, the clinical condition improved in four patients, but two patients died. The autopsy findings in one of the deceased patients indicated the presence of recurrent alveolar hemorrhage, pulmonary venous hypertension, ILD, and PAH. Based on the clinical course of these CHD-PAH in patients and the literature, CHD-PAH can occur with pulmonary vascular obstructive disease (PVOD)/pulmonary capillary hemangiomatosis (PCH), ILD, and/or alveolar hemorrhage. The severity of CHD-PAH may depend on a genetic disorder, respiratory infection, and upper airway stenosis. Additionally, pulmonary vasodilators may be involved in the development of PVOD/PCH and ILD. When patients with CHD-PAH show unexpected deterioration, clinicians should consider complications associated with PVOD/PCH and/or pulmonary disease. In addition, the choice of upfront combination therapy for pediatric patients with CHD-PAH should be selected carefully.

Retrograde sharp potential resembling the his-bundle electrogram: is this a case of atrioventricular re-entrant tachycardia involving twin atrioventricular nodes with the anterior node exhibiting only retrograde conduction?

A 2-year-old male with right isomerism was referred for supraventricular tachycardias. Atrial pacing study revealed that anterograde conduction was only through the posterior atrioventricular node. During the mapping of ventriculoatrial conduction, we identified a sharp potential resembling a His-bundle electrogram with a decremental property at the anterior wall of the common atrium. Catheter ablation for the potential eliminated the anterior ventriculoatrial conduction, thereby indicating retrograde activation of the possible anterior atrioventricular node.

Progressive left ventricular dysfunction and myocardial fibrosis in Duchenne and Becker muscular dystrophy: a longitudinal cardiovascular magnetic resonance study.

This study examined the progression of left ventricular dysfunction and myocardial fibrosis in patients with Duchenne muscular dystrophy (DMD) or Becker muscular dystrophy (BMD) to evaluate the effects of angiotensin-converting enzyme inhibitor (ACEI). Ninety-eight cardiovascular magnetic resonance (CMR) studies in 34 consecutive patients with DMD (n = 21) or BMD (n = 13) were retrospectively reviewed. Left ventricular ejection fraction (LVEF) and the extent of myocardial late gadolinium enhancement (LGE) were semiautomatically quantified. During the study period, five patients had already been treated with ACEI at the first CMR; five were started on ACEI at LVEF ≥ 55% and 10 at LVEF < 55%. All patients had hyperenhanced myocardium on LGE images at the first CMR (median extent, 3.3%; interquartile range 0.1-14.3%). A mixed-effects model for longitudinal data of each patient, adjusted for age, type of muscular dystrophy, steroid use, and ACEI use showed that higher age (ß = - 1.1%/year; 95% confidence interval [CI], - 1.8% to - 0.4%; p = 0.005) and no use of ACEI (ß = - 3.1%; 95% CI, - 5.4% to - 0.8%; p = 0.009) were significantly associated with a lower LVEF. When ACEI use was stratified by time of initiation (LVEF ≥ 55% vs. < 55%), only ACEI initiation at LVEF < 55% had a beneficial effect on LVEF at each imaging examination (ß = 3.7%; 95% CI, 0.9-6.4%; p = 0.010). ACEI use or the time of initiation of ACEI did not significantly affect age-related increase in LGE. ACEI attenuated the age-related decline in LVEF only in patients with DMD or BMD and reduced LVEF, suggesting that further investigation on prophylactic use of cardioprotective therapy in these patients is warranted.