Proteome Dynamics and Bioinformatics Reveal Major Alterations in the Turnover Rate of Functionally Related Cardiac and Plasma Proteins in a Dog Model of Congestive Heart Failure.

Protein pool turnover is a critically important cellular homeostatic component, yet it has been little explored in the context of heart failure (HF) pathophysiology. We used in vivo 2H labeling/proteome dynamics for the nonbiased discovery of turnover alterations involving functionally linked cardiac and plasma proteins in canine tachypacing-induced HF, an established preclinical model of dilated cardiomyopathy. Compared with controls, dogs with congestive HF displayed bidirectional turnover changes of 28 cardiac proteins, that is, a reduced half-life of several key enzymes involved in glycolysis, homocysteine metabolism and glycogenesis, and increased half-life of proteins involved in proteolysis. Changes in plasma proteins were more modest: only 5 proteins, involved in various functions including proteolysis inhibition, hemoglobin, calcium and ferric iron binding, displayed increased or decreased turnover rates. In other dogs undergoing cardiac tachypacing, we infused for 2 weeks the myokine Follistatin-like protein 1, known for its ameliorative effects on HF-induced alterations. Proteome dynamics proved very sensitive in detecting the partial or complete prevention, by Follistatin-like protein 1, of cardiac and plasma protein turnover alterations. In conclusion, our study unveiled, for the first time in a large mammal, numerous HF-related alterations that may serve as the basis for future mechanistic research and/or as conceptually new molecular markers.

Continuous cyclosporine a infusion in patients with severe Kawasaki disease.

BACKGROUND: The efficacy and safety of continuous intravenous infusion of cyclosporine A (CICsA) in patients with intravenous immunoglobulin-resistant Kawasaki disease are unclear. METHODS: Between 2010 and 2020, 83 patients with Kawasaki disease that was not responsive to intravenous immunoglobulin (total dose ≥ 4 g/kg) were enrolled. All patients were started on CICsA (3 mg/kg/day) and switched to oral cyclosporine A (CsA) (4-6 mg/kg/day). Treatment efficacy, occurrence of coronary artery lesions (CALs), and laboratory parameters were evaluated. Patients were divided into two groups according to CICsA response: the responder group (afebrile ≤24 h after CICsA without additional treatment) and the weak responder group (afebrile >24 h after CICsA requiring additional treatment). RESULTS: Fifty-five patients became afebrile within 24 and 74 h became afebrile in less than 72 h. Adverse events included hypertension in four and hyperkalemia in two patients. Thirty-nine patients were defined as responders and 44 patients as weak responders. There were no significant differences in CAL between the two groups. In weak responders, white blood cells, neutrophils, and C-reactive protein levels were higher, and albumin, immunoglobulin G, and CsA concentration were lower than in responders, indicating that weak responders had more severe inflammatory findings. However, there were no significant differences in CAL. Logistic regression analysis revealed that the response to treatment for CICsA was associated with immunoglobulin G levels at baseline and CsA concentrations the day after CICsA. CONCLUSION: Although CICsA required additional treatments in about half of the cases, a favorable clinical course was observed by using this strategy, especially for reducing CAL.

Acute Perimyocarditis in an Adolescent Japanese Male after a Booster Dose of the BNT162b2 COVID-19 Vaccine.

Perimyocarditis is a rare and serious cardiac complication following COVID-19 vaccination. Young males are most at risk after the second dose. With the introduction of the booster (third) dose, some reports have focused on the risk of perimyocarditis after a booster dose. However, no currently available report in Japan has comprehensively described this phenomenon. A healthy 14-year-old Japanese male, who had completed a two-dose primary series of the BNT162b2 (Pfizer-BioNTech) vaccine six months prior, developed fever and chest pain within 24 hours after a homologous booster dose. He was transferred to our institute because of worsening chest pain. A multiplex PCR test showed no evidence of active viral infections, including SARS-CoV-2. Electrocardiography revealed ST-segment elevation in almost all leads, suggesting pericarditis. Echocardiography showed normal systolic function. Laboratory data demonstrated C-reactive protein levels of 8.8 mg/dL and elevated cardiac damage markers (troponin T, 1.9 ng/mL; creatine phosphokinase, 1527 U/L; MB isoenzyme, 120 U/L), suggesting myocarditis. He was diagnosed with perimyocarditis associated with the booster dose, which was confirmed by cardiac magnetic resonance imaging four days after initial symptoms. Chest pain improved spontaneously along with a resolution of electrocardiographic findings and laboratory data within several days. He was discharged eight days after admission. Perimyocarditis is less frequent after a booster dose than after primary doses. In this case, the patient with booster-dose-associated perimyocarditis showed favorable clinical course without severe sequelae. The patient's clinical course was consistent with findings on previous large-scale reports on primary-dose-associated perimyocarditis and case series on booster-dose-associated perimyocarditis.

An Adolescent Patient with Sick Sinus Syndrome Complicated by Hypothyroidism Carrying an SCN5A Variant.

Previous studies have reported that hypothyroidism can lead to sick sinus syndrome (SSS) or other rhythm disturbances. Variants in the alpha subunit of the cardiac sodium channel (SCN5A) are known to be among the genetic causes of SSS. We encountered an adolescent patient with SSS and hypothyroidism who also harbored an SCN5A variant. The patient was a 13-year-old girl who was referred to our hospital because of bradycardia identified during a school electrocardiography screening. Clinical examination revealed severe hypothyroidism due to Hashimoto thyroiditis and SSS. After levothyroxine supplementation, her symptoms of hypothyroidism improved; however, the SSS did not. Genetic testing revealed a heterozygous variant (c.1066 G>A, p.Asp356Asn) in SCN5A. This is the first report of the coexistence of SSS due to an SCN5A variant and severe hypothyroidism in an adolescent patient. While patients with SCN5A variants exhibit phenotypic heterogeneity due to the presence of various modifiers, the presence of severe hypothyroidism may affect the development of SSS. This case highlights the importance of genetic analysis, including testing for SCN5A variants, in patients with hypothyroidism complicated by SSS or cardiac conduction disorders.

Percutaneous Atrial Septal Defect Closure in Adult Ebstein's Anomaly with Exertional Hypoxemia.

In Ebstein's anomaly, percutaneous atrial septal defect (ASD) closure for the treatment of hypoxemia due to a right-to-left interatrial shunt remains controversial. We report the case of a 40-year-old woman with Ebstein's anomaly who developed cyanosis and shortness of breath on exercise. Her symptoms improved after percutaneous ASD closure and her clinical course has been good during follow-up. The balloon ASD occlusion test, combined with dobutamine stimulation before the procedure, is useful to confirm treatment indication. A prior electrophysiological evaluation is also important because Ebstein's anomaly is often complicated by atrioventricular recurrent tachycardia.

Class I Histone Deacetylase Inhibition for the Treatment of Sustained Atrial Fibrillation.

Current therapies are less effective for treating sustained/permanent versus paroxysmal atrial fibrillation (AF). We and others have previously shown that histone deacetylase (HDAC) inhibition reverses structural and electrical atrial remodeling in mice with inducible, paroxysmal-like AF. Here, we hypothesize an important, specific role for class I HDACs in determining structural atrial alterations during sustained AF. The class I HDAC inhibitor N-acetyldinaline [4-(acetylamino)-N-(2-amino-phenyl) benzamide] (CI-994) was administered for 2 weeks (1 mg/kg/day) to Hopx transgenic mice with atrial remodeling and inducible AF and to dogs with atrial tachypacing-induced sustained AF. Class I HDAC inhibition prevented atrial fibrosis and arrhythmia inducibility in mice. Dogs were divided into three groups: 1) sinus rhythm, 2) sustained AF plus vehicle, and 3) sustained AF plus CI-994. In group 3, the time in AF over 2 weeks was reduced by 30% compared with group 2, along with attenuated atrial fibrosis and intra-atrial adipocyte infiltration. Moreover, group 2 dogs had higher atrial and serum inflammatory cytokines, adipokines, and atrial immune cells and adipocytes compared with groups 1 and 3. On the other hand, groups 2 and 3 displayed similar left atrial size, ventricular function, and mitral regurgitation. Importantly, the same histologic alterations found in dogs with sustained AF and reversed by CI-994 were also present in atrial tissue from transplanted patients with chronic AF. This is the first evidence that, in sustained AF, class I HDAC inhibition can reduce the total time of fibrillation, atrial fibrosis, intra-atrial adipocytes, and immune cell infiltration without significant effects on cardiac function.

Mechanism of aortic root dilation and cardiovascular function in tetralogy of Fallot.

The aortic root dilation in tetralogy of Fallot (TOF) is a long-term clinical problem, because a severely dilated aorta can lead to aortic regurgitation, dissection, or rupture, which can be fatal, necessitating surgical intervention. The details of the mechanism of aortic root dilation, however, are unclear. We have shown that aortic stiffness is increased in patients with repaired TOF, and may mirror the histological abnormality of elastic fiber disruption and matrix expansion. This aortic stiffness is related closely to the aortic dilation, indicating that aortic stiffness may be a predictor of outcome of aortic dilation. Furthermore, the aortic volume overload is a very important determinant of aortic diameter in TOF patients before corrective surgery. In addition, a chromosomal abnormality and the transforming growth factor-ß signaling pathway, a major contributor to aortic dilation in Marfan syndrome, also affect this mechanism. In this way, aortic dilation in TOF patients is suggested to be a multifactorial disorder. The aim of this review was therefore to clarify the mechanism of aortic dilation in TOF, focusing on recent research findings. Studies linking histopathology, mechanical properties, molecular/cellular physiology, and clinical manifestations of aortic dilation facilitate appropriate treatment intervention and improvement of long-term prognosis of TOF.

Progressive aortic dilation and aortic stiffness in children with repaired tetralogy of Fallot.

Progressive aortic dilation occurs in patients with tetralogy of Fallot (TOF), possibly due to abnormal histopathology of the aortic media that weakens the aortic wall. This medial histopathology may be reflected as aortic stiffness, which in turn may predict progressive aortic dilation. To test this theory, we studied the relationship between aortic wall stiffness, measured by pulse wave velocity (PWV), and subsequent aortic dilation in 32 consecutive patients with repaired TOF. The ascending aortic diameter (AOD) was obtained by two-dimensional transthoracic echocardiography performed at baseline and at the follow-up examination, 7.6 ± 2.0 years after baseline. TOF patients exhibited significantly greater AODs than normal reference values, at baseline (19.8 ± 5.0 vs 14.3 ± 3.1 mm; P = 0.0001) and at the follow-up examination (25.9 ± 3.8 vs 18.1 ± 2.4 mm; P = 0.0001). The observed change in AOD during the follow-up period (0.83 ± 0.43 mm/year) was significantly larger than the change that would be expected by the patient's growth (0.50 ± 0.25 mm/year; P = 0.0001). The PWV at baseline correlated positively with both AOD at follow-up (P = 0.0018) and the annual rate of aortic dilation (P = 0.0007). On multivariate regression analysis, PWV remained a significant and independent predictor of subsequent aortic dilation. These results suggest a causative role for aortic stiffening in the progressive aortic dilation noted in TOF, indicating that incorporating aortic stiffness as well as aortic diameter in the assessment of TOF aortopathy may help better define the need for, and the timing of, medical intervention.

Fontan completion following flow adjustable bilateral pulmonary artery banding.

We have performed bilateral pulmonary artery banding operations combined with planned percutaneous balloon dilatation at banding sites for patients with hypoplastic left heart syndrome and related anomalies. Here, we report a case of Fontan completion in a patient who underwent aortic arch repair and a bidirectional Glenn procedure following flowadjustable bilateral pulmonary artery banding. The patient had a double-inlet left ventricle, a hypoplastic right ventricle, a hypoplastic aortic arch, and coarctation of the aorta. She underwent banding at 9 days of age and balloon dilatation at 2 months. The Damus-Kaye-Stansel anastomosis, aortic arch repair, and bidirectional Glenn procedure were performed at 5 months of age, and the extracardiac Fontan procedure was performed at 1.5 years.

A case of neonatal fulminant myocarditis with dystrophic calcification: Usefulness of two-dimensional speckle-tracking echocardiography.

Dystrophic calcification is a rare but fatal complication associated with severe myocarditis. Detecting calcified lesions and evaluating ventricular function are essential for the management of myocarditis. We report a case of neonatal acute myocarditis with dystrophic calcification successfully assessed by two-dimensional speckle-tracking echocardiography. The calcification spontaneously resolved, and the recovery of myocardial function was evaluated by speckle-tracking echocardiography. Speckle-tracking echocardiography could be a useful method to evaluate regional ventricular dysfunction corresponding to dystrophic calcification as well as that caused by myocarditis and the follow-up because of its repeatability. Learning objective: 1) Dystrophic calcification can occur as a rare complication associated with severe myocarditis. 2) Dystrophic calcification can spontaneously resolve with the recovery of myocardial function. 3) Speckle-tracking echocardiography is a useful tool for the evaluation of the extent of and myocardial function in dystrophic calcification and the follow-up.

Efficacy of immunoglobulin plus prednisolone for prevention of coronary artery abnormalities in severe Kawasaki disease (RAISE study): a randomised, open-label, blinded-endpoints trial.

BACKGROUND: Evidence indicates that corticosteroid therapy might be beneficial for the primary treatment of severe Kawasaki disease. We assessed whether addition of prednisolone to intravenous immunoglobulin with aspirin would reduce the incidence of coronary artery abnormalities in patients with severe Kawasaki disease. METHODS: We did a multicentre, prospective, randomised, open-label, blinded-endpoints trial at 74 hospitals in Japan between Sept 29, 2008, and Dec 2, 2010. Patients with severe Kawasaki disease were randomly assigned by a minimisation method to receive either intravenous immunoglobulin (2 g/kg for 24 h and aspirin 30 mg/kg per day) or intravenous immunoglobulin plus prednisolone (the same intravenous immunoglobulin regimen as the intravenous immunoglobulin group plus prednisolone 2 mg/kg per day given over 15 days after concentrations of C-reactive protein normalised). Patients and treating physicians were unmasked to group allocation. The primary endpoint was incidence of coronary artery abnormalities during the study period. Analysis was by intention to treat. This trial is registered with the University Hospital Medical Information Network clinical trials registry, number UMIN000000940. FINDINGS: We randomly assigned 125 patients to the intravenous immunoglobulin plus prednisolone group and 123 to the intravenous immunoglobulin group. Incidence of coronary artery abnormalities was significantly lower in the intravenous immunoglobulin plus prednisolone group than in the intravenous immunoglobulin group during the study period (four patients [3%] vs 28 patients [23%]; risk difference 0·20, 95% CI 0·12-0·28, p<0·0001). Serious adverse events were similar between both groups: two patients had high total cholesterol and one neutropenia in the intravenous immunoglobulin plus prednisolone group, and one had high total cholesterol and another non-occlusive thrombus in the intravenous immunoglobulin group. INTERPRETATION: Addition of prednisolone to the standard regimen of intravenous immunoglobulin improves coronary artery outcomes in patients with severe Kawasaki disease in Japan. Further study of intensified primary treatment for this disease in a mixed ethnic population is warranted. FUNDING: Japanese Ministry of Health, Labour and Welfare.

Efficacy of intravenous immunoglobulin combined with prednisolone following resistance to initial intravenous immunoglobulin treatment of acute Kawasaki disease.

OBJECTIVES: To determine the most effective first-line rescue therapy for intravenous immunoglobulin (IVIG) nonresponders, using IVIG, prednisolone, or both, to prevent coronary artery abnormalities (CAAs). STUDY DESIGN: We retrospectively reviewed the clinical records of 359 consecutive patients with Kawasaki disease who failed to respond to initial IVIG. RESULTS: CAAs up to 1 month after treatment were less common in the IVIG+prednisolone group (15.9%) than in the IVIG group (28.7%, P = .005) and the prednisolone group (30.6%, P = .01). The IVIG+prednisolone group had significantly lower risks of failing to respond to first-line rescue therapy (aOR 0.16, 95% CI 0.09-0.31), CAAs up to 1 month (aOR 0.46, 95% CI 0.27-0.90), and CAAs at 1 month (aOR 0.40, 95% CI 0.18-0.91) than the IVIG group. In the prednisolone and IVIG+prednisolone groups, risk score, day of illness at first-line rescue therapy, prednisolone monotherapy, and resistance to first-line rescue therapy were independent risk factors for CAA. Sex and resistance to first-line rescue therapy were independent risk factors in the IVIG group. CONCLUSIONS: IVIG+prednisolone may be superior to IVIG or prednisolone as first-line rescue therapy in the treatment of IVIG nonresponders. To establish the efficacy of rescue therapy with IVIG+prednisolone following nonresponse to initial IVIG, a prospective randomized trial is warranted.

Noninvasive assessment of left ventricular contractility in pediatric patients using the maximum rate of pressure rise in peripheral arteries.

The maximum rate of left ventricular pressure rise (LV dp/dt(max)) is a good indicator of ventricular contractility. However, its measurement requires invasive cardiac catheterization. By applying the relationship between the ratio of aorta (Ao) dp/dt(max) to LV dp/dt(max) and the mean artery pressure (MAP), we tested the possible noninvasive estimation of LV dp/dt(max) by the maximum rate of pressure rise in peripheral arteries, as measured by tonometry. The study subjects were 31 children with cardiovascular disease. The LV and Ao pressures were measured during cardiac catheterization, with simultaneous recording of the brachial (BrA) or radial (RaA) artery pressure. The relationships between BrA dp/dt(max) and Ao dp/dt(max) and between RaA dp/dt(max) and Ao dp/dt(max) were determined (Ao dp/dt(max) = 0.299 × BrA dp/dt(max) + 210.6, n = 17, r = 0.78, SEE = 74.0, P = 0.0002, and Ao dp/dt(max) = 1.442 × RaA dp/dt(max) + 165.9, n = 14, r = 0.87, SEE = 66.1, P = 0.0001). Using these relationships and the equation Ao dp/dt(max)/LV dp/dt(max) = 0.694 - 4.00 × 10(-3) × MAP, LV dp/dt(max) was estimated from BrA dp/dt(max) or RaA dp/dt(max). The estimated LV dp/dt(max) correlated well with the measured LV dp/dt(max) independent of the site of measurement (y = 0.912 × x + 112.9, r = 0.91, P < 0.0001). Furthermore, there was excellent correlation between the measured and estimated LV dp/dt(max) after changes in contractility with dobutamine in 10 randomly selected patients (y = 0.86 × x + 34.2, r = 0.77, P = 0.01). It is possible to estimate LV dp/dt(max) noninvasively in children using tonometry. This procedure can be useful for bedside assessment of LV contractility and the clinical management of patients with cardiovascular disease.

Kawasaki Disease: Pathology, Risks, and Management.

Kawasaki disease (KD), first reported as an acute febrile mucocutaneous lymph node syndrome, is a self-limiting vasculitis of unknown etiology. The most important aspect of KD is the prevention of coronary artery lesion (CAL) because myocardial ischemia or infarction due to CAL might be lethal. In addition to the CAL, patients with KD develop systemic vasculitis, which indicates the presence of vascular endothelial damage. Studies assessing pulse wave velocity or percentage change in flow-mediated dilatation have shown that aortic stiffness is increased in patients with KD history. In contrast, the cardio-ankle vascular index, a novel parameter not affected by blood pressure, has not demonstrated increased aortic stiffness in patients with KD. Although many studies using various parameters have suggested a risk of atherosclerosis in patients with a history of KD, a few others have reported no significant differences between KD patients and controls. Therefore, it will be necessary to thoroughly understand the characteristics of each parameter, before evaluating the results of those studies, to understand systemic vascular dysfunction in these populations, and to manage their vascular health. Although it is controversial whether the risk of atherosclerosis in patients with KD is higher, those with CAL are thought to be at a high risk of atherosclerosis. Therefore, appropriate treatment to prevent CAL in the acute phase and subsequent regular follow-up is important. Here, we review the pathology, risk, and management of vascular disorders, especially systemic vascular disorders, in patients with KD history.

Successful Management in an Infant Patient of PHACE Syndrome with a Complicated Aortic Arch Anomaly.

PHACE syndrome is a congenital disorder often associated with a cervicofacial infantile hemangioma and complicated cardiovascular malformations. Patients with PHACE syndrome often have complex aortic arch anomalies, longer aortic stenosis or agenesis segments, and increased vascular tortuosity; therefore, perioperative management and surgical repair are challenging. We report a case of a female infant with PHACE syndrome and complex cardiovascular anomalies such as a double aortic arch associated with interruption of the left aortic arch, coarctation of the right aortic arch, patent ductus arteriosus, ventricular septal defect, and atrial septal defect. She was born at 36 weeks of gestation (birth weight, 2,150 g) and the diagnosis was confirmed by three-dimensional computed tomography. Because her patent ductus arteriosus did not close at first, her heart failure was managed preoperatively without prostaglandin E 1. We initially attempted to promote weight gain. Surgical planning and simulation were performed using the patient-specific three-dimensional cardiovascular model created from computed tomography data. She underwent a successful aortic arch reconstruction by an end-to-side anastomosis with anterior patch augmentation at the age of 56 days. Detailed planning and simulation before surgery were vital in achieving favorable outcomes. Careful management and surgical planning using a patient-specific three-dimensional model are vital, especially in patients with complex malformations, such as in our case.

Case Report: Anterior Scleritis Presenting as a Primary Ocular Manifestation in Multisystem Inflammatory Syndrome in Children With COVID-19.

Multisystem inflammatory syndrome in children (MIS-C) is a newly defined hyperinflammatory disease linked to antecedent coronavirus disease 2019. Patients with MIS-C present with various symptoms, and ocular findings such as mild bilateral conjunctivitis are relatively common. However, detailed descriptions of severe ocular reports associated with MIS-C are scarce in the current literature. Here we report a case of MIS-C in a Japanese boy, with severe eye manifestations in the form of anterior scleritis as the primary MIS-C symptom. Detailed ocular examinations by ophthalmologists may be key for clarifying the pathophysiology of MIS-C.

A case of congenital fiber-type disproportion syndrome presenting dilated cardiomyopathy with ACTA1 mutation.

BACKGROUND: Actin, alpha, skeletal muscle 1 (ACTA1) is one of the causative genes of nemaline myopathy (NM) and congenital fiber-type disproportion (CFTD). CFTD is characterized by type 1 fiber atrophy and distinguished from NM in the absence of rods. Eight patients with CFTD, including one patient with dilated cardiomyopathy (DCM), have previously been reported. Herein, we report the case of a 10-year-old boy presenting with CFTD and DCM. METHODS: We performed exome sequencing and analyzed the effect of Met327Lys mutations on cultured C2C12 muscle cells compared with that seen in the wild type (WT, ACTA1) and previously identified Asp294Val mutations associated with a severe phenotype of CFTD without cardiomyopathy. RESULTS: Exome sequencing revealed a de novo mutation, c.980 T > A, p.(Met327Lys), in ACTA1 (NM_001100.4). C2C12 cells transfected with the WT plasmid expressed ACTA1 in the nucleus and cytoplasm. Cells with the Asp294Val mutant showed needle-like structures in the cytoplasm, whereas the expression of the Met327Lys mutant resulted in few aggregations but many apoptotic cells. CONCLUSION: Apoptosis induced in Met327Lys-transfected muscle cells supports the pathogenicity of the mutation and can be implicated as one of the histopathological features associated with CFTD, as in NM.