Calmodulinopathy in Japanese Children　- Their Cardiac Phenotypes Are Severe and Show Early Onset in Fetal Life and Infancy.

BACKGROUND: Cardiac calmodulinopathy, characterized by a life-threatening arrhythmia and sudden death in the young, is extremely rare and caused by genes encoding calmodulin, namely calmodulin 1 (CALM1), CALM2, and CALM3.Methods and Results: We screened 195 symptomatic children (age 0-12 years) who were suspected of inherited arrhythmias for 48 candidate genes, using a next-generation sequencer. Ten probands were identified as carrying variants in any of CALM1-3 (5%; median age 5 years), who were initially diagnosed with long QT syndrome (LQTS; n=5), catecholaminergic polymorphic ventricular tachycardia (CPVT; n=3), and overlap syndrome (n=2). Two probands harbored a CALM1 variant and 8 probands harbored 6 CALM2 variants. There were 4 clinical phenotypes: (1) documented lethal arrhythmic events (LAEs): 4 carriers of N98S in CALM1 or CALM2; (2) suspected LAEs: CALM2 p.D96G and D132G carriers experienced syncope and transient cardiopulmonary arrest under emotional stimulation; (3) critical cardiac complication: CALM2 p.D96V and p.E141K carriers showed severe cardiac dysfunction with QTc prolongation; and (4) neurological and developmental disorders: 2 carriers of CALM2 p.E46K showed cardiac phenotypes of CPVT. Beta-blocker therapy was effective in all cases except cardiac dysfunction, especially in combination with flecainide (CPVT-like phenotype) and mexiletine (LQTS-like). CONCLUSIONS: Calmodulinopathy patients presented severe cardiac features, and their onset of LAEs was earlier in life, requiring diagnosis and treatment at the earliest age possible.

Changes in bone turnover markers after discontinuing long-term glucocorticoid administration in children with idiopathic nephrotic syndrome: a multicenter retrospective observational study.

BACKGROUND: Glucocorticoids affect bone turnover. Little is known about how bone turnover changes when glucocorticoids are discontinued following long-term administration. METHODS: This retrospective observational study was conducted on the relationship between discontinuation of long-term administration of glucocorticoid and bone turnover markers (BTMs) in patients with childhood-onset idiopathic nephrotic syndrome. Serum bone alkaline phosphatase (BAP), intact procollagen type 1 N-terminal propeptide (P1NP), and tartrate-resistant acid phosphatase-5b (TRACP-5b) were evaluated as BTMs. RESULTS: Thirty-eight pairs of BTMs at glucocorticoid administration and after discontinuation were analyzed in 29 patients. The median age at baseline was 12.4 (interquartile range, 9.0-14.5) years, and the median time from the onset of nephrotic syndrome was 5.9 (3.3-9.7) years. The mean period from prednisolone discontinuation to the measurement of BTMs after glucocorticoid discontinuation was 3.5 ± 1.0 months. Changes in BTMs after glucocorticoid discontinuation were modest when the daily prednisolone dose was < 0.25 mg/kg/day (ln BAP standard deviation [SD] score, p = 0.19; log intact P1NP SD score, p = 0.70; TRACP-5b, p = 0.95). When the daily prednisolone dose was ≥ 0.25 mg/kg/day, all BTMs increased significantly after glucocorticoid discontinuation (ln BAP SD score, p < 0.01; log intact P1NP SD score, p < 0.01; TRACP-5b, p < 0.01). CONCLUSIONS: Decreased BTMs can rise within a few months of discontinuing long-term glucocorticoid administration. When the administered glucocorticoid dose is low, changes in BTMs may be small. A higher resolution version of the Graphical abstract is available as Supplementary information.

The effect of rituximab on the quality of life of children with refractory nephrotic syndrome.

BACKGROUND: Rituximab (RTX) is an effective treatment for maintaining remission in patients with nephrotic syndrome (NS), but there are few reports on the effect of RTX treatment on quality of life (QOL). The purpose of this study was to examine the effect of periodically repeated RTX treatment from the perspective of QOL. METHODS: We systematically assessed the QOL of pediatric patients with refractory NS and parents' perceptions of their children's QOL through a 2 year RTX treatment protocol. Pediatric patients from Hokkaido University Hospital with refractory NS who met our specific criteria were enrolled between January 2015 and December 2015. The RTX infusion was performed 4 times at 6-month intervals, followed by mizoribine administration with early discontinuation of calcineurin inhibitors. Quality of life scores were measured by the Pediatric Quality of Life Inventory version 4.0 (PedsQL) at each RTX administration and evaluated 2 years later. RESULTS: Twenty-two patients were analyzed. The patients' QOL and their parents' perceptions of their QOL improved over our 2 year treatment protocol. Nevertheless, the parents' scores were lower than the patients' scores on all scales, with slower improvement. CONCLUSIONS: Our treatment protocol showed a significant improvement of QOL in patients with refractory NS. Although the risk of the RTX treatment should be considered, the treatment is useful for patients with refractory NS.

A case report: Twin sisters with restrictive cardiomyopathy associated with rare mutations in the cardiac troponin I gene.

Restrictive cardiomyopathy (RCM) is a rare cardiomyopathy in children, and its prognosis until now, has been poor. Recently some sarcomeric mutations have been reported as disease-causing genes of RCM. However, the genotype-phenotype correlation is not fully understood. Additionally, prognostic factors including sudden death in patients with RCM have not been elucidated. We report our experience in treating twin sisters with RCM or hypertrophic cardiomyopathy with RCM phenotype, both carriers of the same mutation in TNNI3, which encodes one of the major sarcomeric proteins in myofibrils. They were both diagnosed with RCM by cardiac catheterization at the age of 11 years. Despite appropriate follow-up and medical treatment, one died suddenly at the age of 11 years and the other also died at the age of 15 years due to heart failure while awaiting heart transplantation. In addition to our cases, other reports of younger fatal cases with RCM carrying TNNI3 mutations may suggest it as one of the prognostic factors. Genetic diagnosis is important in the clinical diagnosis, management, and treatment of cardiomyopathy. .

Efficacy of perampanel for epileptic seizures and daily behavior in a patient with Leigh syndrome: A case report.

BACKGROUND: Leigh syndrome (LS) is a mitochondrial disorder that shows abnormal basal ganglia lesion and psychomotor regression. Although vitamins have been used for LS, we have not found any effective drug. CASE PRESENTATION: A 26-year-old man who showed psychomotor delay and short stature at the age of 1 year was diagnosed with LS according to the results of cerebrospinal fluid and high signal intensity in the bilateral striatum on T2-weighted magnetic resonance imaging. He demonstrated psychomotor delay and breathing disorders, but the progression was very slow. His symptoms suddenly worsened at the age of 24 years after acute epididymitis. He showed epileptic seizures simultaneously and his activities of daily living (ADL) significantly worsened. Several antiepileptic drugs were ineffective, but his seizures were suppressed by a low dose of perampanel and his ADL improved. CONCLUSION AND DISCUSSION: Our case showed that low-dose perampanel could be a drug for epileptic seizures and improvement of ADL in patients with LS.

Periodically repeated rituximab administrations in children with refractory nephrotic syndrome: 2-year multicenter observational study.

BACKGROUND: Rituximab (RTX) is effective in maintaining remission in patients with nephrotic syndrome (NS), but a standard protocol of RTX administration has not been established. METHODS: This study was a 2-year multicenter observational study, in which consistent treatments and evaluations were performed. We enrolled pediatric patients with refractory NS between January 2015 and December 2015. RTX infusion was performed four times at 6-month intervals, followed by mizoribine pulse therapy with early discontinuation of calcineurin inhibitor (CNI). Primary endpoints were the relapse-free survival rate and the number of relapses after RTX administration. Secondary endpoints were changes in side effects associated with long-term steroid administration. RESULTS: Twenty-two patients were analyzed. The relapse-free survival rate at 1 year and 2 years was 50 and 46%, respectively. Twenty-one patients accomplished our protocol and the frequency of relapse was reduced under the discontinuation of CNI. Although two patients were diagnosed with frequent relapse and/or steroid dependency during the observation period, the frequency of relapse decreased with each rituximab dose. Statistically significant improvements in all steroid complications were observed in the final examination, but no significant improvements were observed from 1 to 2 years after RTX administration. One patient had agranulocytosis, and three patients showed electrocardiographic abnormalities. CONCLUSIONS: Our protocol was useful and safe for refractory NS. However, RTX administration four times might have been excessive in patients who had no relapse by 1 year after the initial RTX administration. Further investigation of the most appropriate method of RTX administration is required.

Long-term outcome of renal function in children after stem cell transplantation measured by estimated glomerular filtration rate.

BACKGROUND: Stem cell transplantation (SCT) outcomes have improved over the last three decades, with many patients being rescued with this treatment. However, improved outcomes have led to issues with long-term sequelae. One of these sequelae in children is renal dysfunction, an index of which is estimated using glomerular filtration rate (eGFR). PROCEDURE: We retrospectively analyzed eGFR in 83 pediatric patients who received SCT. Data from all patients extended up to 12 months or more post SCT. The median follow-up time was 127.7 months (range 12.0-268.8 months). RESULTS: Eighteen patients (21.7%) had low eGFR (<90 ml/min/1.73 m2 ) post SCT. Cumulative incidence of low eGFR was 25.8 ± 2.0%. Nine (10.6%) patients had a low eGFR pre-SCT. However, pre- and post-SCT incidence of low eGFR were not correlated. Meanwhile, only two patients (2.4%) exhibited severe renal dysfunction, with eGFRs < 60 ml/min/1.73 m2 . Independent risk factors for low eGFR were solid tumor and use of fludarabine. Moreover, age at SCT ≥ 7 years was also a long-term post-SCT risk factor for low eGFR in all patients. CONCLUSION: Independent post-SCT long-term risk factors for low eGFR in children were solid tumor and use of fludarabine. Moreover, age at SCT ≥ 7 years was a post-SCT long-term risk factor for low eGFR across all patients.

Clinical features of adult patients with Eisenmenger's syndrome in Japan and Korea.

BACKGROUND: There are few articles on mortality and morbidity of adult patients with Eisenmenger's syndrome (ES) in the current era when disease targeting therapy (DTT) has been available. METHODS AND RESULTS: 198 patients (a median age 35 years, 64% female) with ES who visited the 16 participating institutes in Japan and Korea from 1998 to 2009 were enrolled. Clinical data during adulthood were collected from each institutional chart and analyzed centrally. During a median follow-up of 8 years, 30 patients died including 14 sudden deaths. 89 patients took oral medication of DTT and clinical improvement was observed in 54 of them. However, survival rate in patients taking DTT was not different from those without (87% vs 84%, p=0.55). When the clinical data in between first and last clinic visits were compared in 85 patients, the patients with NYHA >/=III increased from 24% to 48% (p<0.001), SpO2 decreased from 89% to 85% (p=0.008) and hematocrit increased from 51.4% to 52.9% (p=0.04). Non-survivors had poorer NYHA function class, lower body weight (BW), lower body mass index (BMI), and higher serum level of Cr at the first visits than survivors. CONCLUSIONS: Long term survival and clinical status of adult patients with ES remains unsatisfactory even in the current era of DTT. Poor NYHA functional class, low BW, low BMI and high serum level of Cr were related to mortality. DTT therapy improved clinical status in many patients with Eisenmenger's syndrome, but no significant impact on survival could be shown.

The cause of B-type natriuretic peptide elevation and the dose-dependent effect of angiotensin-converting enzyme inhibitor on patients late after tetralogy of Fallot repair.

Patients after surgical repair of tetralogy of Fallot (TOF) may experience various complications that result in neurohormonal activation, including plasma B-type natriuretic peptide (BNP) elevation. Right ventricular (RV) dilation is a frequent complication, and few treatments are available. This study aimed to identify the factor or factors leading to BNP elevation and to clarify the effects of angiotensin-converting enzyme inhibitor (ACE-I) on changes in BNP levels in patients with repaired TOF. Plasma BNP levels and hemodynamic data derived from cardiac catheterization were analyzed. In addition, longitudinal BNP levels and ACE-I dosages were analyzed for patients administered ACE-I. For 31 patients with repaired TOF, who mainly had RV dilation, log BNP levels were significantly correlated with the RV end-diastolic volume index (P = 0.02) as well as ventricular volume and pressure (P < 0.01). For 11 patients medicated with ACE-I, BNP levels were significantly lower at the time of maximal ACE-I dosage than at the time of minimal dosage (P < 0.01). Furthermore, BNP levels decreased as the ACE-I dosage per body weight increased (P < 0.01). In conclusion, elevation of BNP in patients after TOF repair could reflect volume and pressure load in the RV end-diastolic phase, and ACE-I may reduce BNP levels in a dose-dependent manner.

Idiopathic reentrant right ventricular outflow tract tachycardia with presystolic potential of central pathway.

A 12-year-old girl with recurrent palpitation due to idiopathic ventricular tachycardia (VT) with a left bundle branch block configuration and inferior axis was referred to our hospital. During the VT, a spiky presystolic potential (SP) was recorded at the septum of right ventricular outflow tract (RVOT) just below pulmonary valve. The SP was entrained with a decremental property by pacing from right ventricular apex. Concealed entrainment was observed by pacing where the SP was recorded. Delivery of radiofrequency current targeting the SP abolished the VT. The SP with the decremental property could represent the central pathway of this idiopathic RVOT reentrant VT.

Aortic pressure wave reflection in children.

Aortic pressure wave reflection is one of the risk factors for developing cardiovascular disease in adults, and the degree of pressure wave reflection increases with aging. However, enhanced pressure wave reflection has also been reported in infants and children. The purpose of this study was to clarify pressure wave reflection during childhood and to determine the reference for the augmentation index, which is one of the most useful parameters used to represent the degree of aortic pressure wave reflection in children. This study enrolled 72 patients with normal aortic circulation. The aortic pressure waveform was recorded using a pressure sensor-mounted catheter, and the augmentation index was thus calculated. The augmentation index tended to decrease with increasing age until around 15 years of age and then increased thereafter. For children below 15 years of age, multiple regression analysis revealed a significant negative correlation between body height and augmentation index. In children, increases in aortic pressure wave reflection are probably attributable to changes in body height.

Efficacy of oral sildenafil in a beraprost-treated patient with severe pulmonary hypertension secondary to type I glycogen storage disease.

Pulmonary arterial hypertension (PAH) is a rare complication of glycogen storage disease (GSD), and several cases with a poor outcome have been reported. A 17-year-old boy, who was diagnosed with GSD at 1 year of age, complained of shortness of breath on exertion, and was diagnosed with PAH based on the echocardiographic findings. Beraprost sodium (BPS) was started, and his symptoms improved after 3 months of treatment. Eighteen months later, he experienced frequent episodes of syncope. Because increasing the dose of BPS was ineffective, he was admitted to hospital. The echocardiogram showed marked elevation of the right ventricular pressure and low cardiac output, and his symptoms deteriorated despite continuous infusion of olprinone hydrochloride. Because a single dose of sildenafil increased his cardiac output, treatment with 25 mg sildenafil twice daily was started. His symptoms gradually ameliorated, and 3 weeks later he left the hospital. Two months after starting sildenafil, the cardiac index and the serous B-type natriuretic peptide concentration had become normal. Sildenafil may be effective in patients with secondary PAH and in patients who have developed tolerance to BPS.

Aortic reservoir function after arterial switch operation in elementary school-aged children.

BACKGROUND: After the arterial switch procedure, decreased distensibility of the aortic root has been reported, which means impaired aortic reservoir function of the coronary circulation, but there have been no reports regarding the relationship of this issue to myocardial perfusion. Therefore, in the present study the aortic reservoir function and coronary supply-demand balance were examined in patients after undergoing the arterial switch operation (ASO) around the time of entering elementary school. METHODS AND RESULTS: Diastolic runoff (DR), which is the percentage of diastolic blood flow to total cardiac output, was measured as the index of aortic reservoir function. The subendocardial viability ratio was investigated as the index of coronary supply - demand balance. In the patient group, the aortic root was dilated (p<0.0001) and distensibility was impaired (p<0.0001) in comparison with an age-matched control group. However, there was no difference between the 2 groups in DR or subendocardial viability ratio. CONCLUSIONS: Coronary supply - demand balance was preserved in the pediatric ASO patients, despite the aortic root dysfunction. The preserved DR suggests that dilatation of the aorta compensates for aortic reservoir function. Because large artery dysfunction predicts future cardiovascular diseases, careful follow-up is crucial.

Pressure wave reflection after successful balloon dilatation of aortic coarctation.

After successful surgical repair in patients with aortic coarctation, the early onset of cardiovascular diseases is an important subsequent complication and one of the causes is the enhanced aortic pressure wave reflection. Balloon angioplasty has become established as an effective alternative to surgery, but there have been no reports regarding pressure wave reflection after balloon dilatation in patients with aortic coarctation. A 29-year-old patient with aortic coarctation was admitted for angioplasty, which was performed successfully. Six months later, catheter examination demonstrated enhanced aortic pressure wave reflection, although there was no pressure difference. After balloon dilatation patients with aortic coarctation may be also at high risk for future cardiovascular diseases.

Doxorubicin induces apoptosis by activation of caspase-3 in cultured cardiomyocytes in vitro and rat cardiac ventricles in vivo.

Doxorubicin (DOX) is widely used to treat patients suffering from cancer, but the usage for patients is limited because of the dose-dependent cardiotoxicity. We hypothesized that DOX induces apoptosis through caspase activation in cardiomyocytes, and we examined this hypothesis using both rat primary cultured cardiomyocytes and rat hearts from an animal model. Cardiomyocytes were treated with DOX for 24 h. The activity of caspase-3 was significantly increased by DOX treatment. In rats with DOX injected intravenously once a week for 5 weeks, left ventricular fractional shortening evaluated by echocardiography was significantly decreased at age 14 weeks, 2 weeks after the end of DOX-administration. At 16 weeks of age, endothelin-1 mRNA and atrial natriuretic peptide mRNA were also significantly increased, likewise, and TUNEL positive cells were significantly increased in the ventricles of DOX-treated rats. The activity of caspase-3 in the ventricles was also significantly increased compared to that of untreated rats at 16 weeks. However, the activity of caspase-8 and the expression level of Fas-ligand mRNA were comparable with those of the untreated rats. In conclusion, DOX induces apoptosis through the activation of caspase-3, suggesting that apoptosis has an important role in the progression of cardiomyopathy due to DOX.

[Predictors of hemodynamically successful left pulmonary artery stent implantation in patients after repair of tetralogy of Fallot].

OBJECTIVES: Left pulmonary artery stenosis is a well-known postoperative complication in patients with tetralogy of Fallot. Recently, balloon expandable intravascular stents have been widely used to relieve those lesions. However, the increase in left pulmonary blood flow is not adequate in some patients, although the vessels are suitably dilated. This study evaluated the predictors of hemodynamical improvement. METHODS: The study population consisted of nine patients with morphologically successful stent implantation for left pulmonary artery stenosis after repair of tetralogy of Fallot. Patients were divided into two groups. Four patients had hemodynamical improvement by stent implantation, with relative perfusion of the left lung of over 30% of total pulmonary perfusion. The other five patients had relative perfusion of the left lung of under 30% of total pulmonary perfusion after stent implantation. The timing of stent implantation and the morphological features of pulmonary artery were compared between the two groups. RESULTS: In hemodynamically improved patients, the stent implantation was performed earlier(6.1 +/- 3.5 vs 16.1 +/- 6.5 years old, p = 0.029), and the interval between surgical repair and stenting was shorter (3.7 +/- 2.7 vs 11.3 +/- 4.7 years, p = 0.025). There was no difference in the left pulmonary artery diameter after stenting, but the right pulmonary artery diameter was significantly smaller in hemodynamically improved patients (99.0 +/- 23.7 vs 135.0 +/- 15.1% normal, p = 0.027). CONCLUSIONS: Effective stent implantation for left pulmonary artery stenosis in patients with tetralogy of Fallot after repair must be performed before compensatory right pulmonary artery growth occurs.

Minimal access surgery for the repair of simple congenital heart defects: factors affecting hospital stay after surgery.

OBJECTIVE: We reviewed our experience of minimal access surgery to elucidate the efficacy and safety of this approach and determine the factors affecting hospital stay. METHODS: Seventy-seven patients (age, 11.8 +/- 11.0 years), with body weight of more than 10 kg, were operated using various forms of minimal access approach for repair of simple congenital heart defects [atrial septal defect (ASD) in 40, ventricular septal defect in 37]. These included lower partial sternotomy (n = 68) and mini-thoracotomy (n = 9, ASD only) with limited skin incision of 4-11 cm. The anesthetic protocol was modified to wean all patients from ventilator soon after operation. The protocol of discharge from hospital (critical pass) was 14 days in the early period (n = 30) and 10 days in the late period (n = 47). RESULTS: There were no hospital or late death, and no hospital re-admission. None of patients required blood transfusion. The endotracheal tube was extubated in the operating room in 48 cases (62%). Twenty-four patients (31%) failed to fulfill conditions of the critical pass. Univariate analysis of factors affecting unfavorably the critical pass demonstrated that the median approach, retention of pericardial effusion and social reasons were statistically significant, while an opened pleura and aortic cross-clamp time were marginally significant. Multivariate analysis indicated that the retention of pericardial effusion was the only significant factor that failed critical pass [p = 0.007, odds ratio (OR) 5.7, 95% confidence interval (CI) 1.61 -19.8]. In addition, a pericardio-pleural fenestration was the only significant factor that affected favorably the pericardial effusion (p = 0.035, OR 0.2, 95% CI 0.47-0.89) by multivariate analysis. CONCLUSIONS: Our experience demonstrated that minimal access surgery of the simple congenital heart defects provided excellent cosmetic results. Retention of pericardial effusion, possibly due to pericarditis, was a major risk factor of the prolonged hospital stay. The pericardio-pleural fenestration could reduce the risk of retention of effusion.

[Combination of oral endothelin-A receptor antagonist and oral prostacyclin analogue is superior to each drug alone in ameliorating pulmonary hypertension in rats].

OBJECTIVES: To investigate whether the combination of an oral endothelin (ET)-A receptor antagonist and an oral prostacyclin(PGI2) analogue is superior to the single use of each drug alone for treating pulmonary hypertension(PH). BACKGROUND: Treatment with intravenous PGI2 or an ET-A receptor antagonist was effective for PH; however, the effect of both administrations is unclear. METHODS: We administered the oral ET-A receptor antagonist TA-0201 and/or the oral PGI2 analogue beraprost sodium(BPS) to monocrotaline-induced PH rats for 19 days in the following groups: normal rats with vehicle treatment (Control group), PH rats with vehicle treatment (PH group), PH rats with TA-0201 treatment (PH + TA group), PH rats with BPS treatment (PH + BPS group), and PH rats with TA-0201 and BPS treatment (PH + TA + BPS group). RESULTS: Right ventricular systolic pressure and Pp/Ps were markedly higher in the PH group than in the Control group. The increased right ventricular systolic pressure and Pp/Ps were significantly and comparably depressed in the PH + TA group and PH + BPS group; it was more greatly depressed in the PH + TA + BPS group than in the groups with each drug alone. The indices of right ventricular hypertrophy showed the same tendency as the increase in right ventricular systolic pressure in the five groups. The expression of beta-myosin heavy chain mRNA in right ventricle was markedly augmented in the PH group; the enhancement was inhibited in the PH + TA + BPS group to the greatest degree. Medial wall thickness of the pulmonary artery was markedly increased in the PH group; the increase was depressed in PH + TA + BPS group. Combined treatment also ameliorated PH even if it started from the post-onset of PH. CONCLUSIONS: The combination of an oral ET-A receptor antagonist and an oral PGI2 analogue is superior to the single use of each drug alone in inhibiting the progression of PH.