Flow pattern analysis of right ventricular outflow tract in repaired tetralogy of Fallot through 4D flow MRI.

Cardiac magnetic resonance imaging (CMR) often shows discrepancies between right ventricular outflow tract (RVOT) flow and left ventricular outflow tract flow in patients with late-stage repaired tetralogy of Fallot (rTOF), leading to potential errors in pulmonary regurgitation fraction (PRF) assessment. This study aimed to identify the conditions under which RVOT flow can be acutely evaluated using four-dimensional (4D) flow CMR. Twenty-seven consecutive patients with rTOF underwent both two-dimensional phase-contrast (2D PC) and 4D flow CMR between 2016 and 2018, excluding those with peripheral pulmonary artery stenosis, RVOT conduit replacement, unknown surgical method, and an aortic valve regurgitation greater than 20%. Seven healthy controls also underwent only 4D Flow CMR. All healthy controls and fifteen patients with rTOF showed laminar RVOT flow, while seven patients exhibited helical, and four patients exhibited vortical RVOT flow in 4D flow CMR visualization. Flow-volume concordance between the pulmonary artery and aortic flow was significantly lower in patients with rTOF and PRF > 40% in 2D PC CMR. This concordance rate in the suprapulmonary valve was high in both the TOF and control groups, comparing at five RVOT locations in 4D flow CMR. Regarding RVOT flow regurgitation in 4D flow, the whole bulk evaluation exhibited greater variation depending on the flow type compared to the whole pixel-wise evaluation. The study confirmed the flow volume at the upper section of the pulmonary valve as the most accurate correlate of aortic flow volume. Furthermore, the 4D flow CMR using the pixel-wise method demonstrated superior accuracy compared to the traditional bulk flow method.

Unique Pulmonary Hypertensive Vascular Diseases Associated with Heart and Lung Developmental Defects.

Although pediatric pulmonary hypertension (PH) shares features and mechanisms with adult PH, there are also some significant differences between the two conditions. Segmental PH is a unique pediatric subtype of PH with unclear and/or multifactorial pathophysiological mechanisms, and is often associated with complex congenital heart disease (CHD), pulmonary atresia with ventricular septal defect, and aortopulmonary collateral arteries. Some cases of complex CHD, associated with a single ventricle after Fontan operation, show pathological changes in the small peripheral pulmonary arteries and pulmonary vascular resistance similar to those observed in pulmonary arterial hypertension (PAH). This condition is termed as the pediatric pulmonary hypertensive vascular disease (PPHVD). Recent advances in genetics have identified the genes responsible for PAH associated with developmental defects of the heart and lungs, such as TBX4 and SOX17. Targeted therapies for PAH have been developed; however, their effects on PH associated with developmental heart and lung defects remain to be established. Real-world data analyses on the anatomy, pathophysiology, genetics, and molecular biology of unique PPHVD cases associated with developmental defects of the heart and lungs, using nationwide and/or international registries, should be conducted in order to improve the treatments and prognosis of patients with these types of pediatric PH.

Association Between Maternal Factors in Early Pregnancy and Congenital Heart Defects in Offspring: The Japan Environment and Children's Study.

Background Many prenatal factors are reported to be associated with congenital heart defects (CHD) in offspring. However, these associations have not been adequately examined using large-scale birth cohorts. Methods and Results We evaluated a data set of the Japan Environmental and Children's Study. The primary outcome was a diagnosis of CHD by age 2 years. We defined the following variables as exposures: maternal baseline characteristics, fertilization treatment, maternal history of diseases, socioeconomic status, maternal alcohol intake, smoking, tea consumption, maternal dietary intake, and maternal medications and supplements up to 12 weeks of gestation. We used multivariable logistic regression analysis to assess the associations between various exposures and CHD in offspring. A total of 91 664 singletons were included, among which 1264 (1.38%) had CHD. In multivariable analysis, vitamin A supplements (adjusted odds ratio [aOR], 5.78 [95% CI, 2.30-14.51]), maternal use of valproic acid (aOR, 4.86 [95% CI, 1.51-15.64]), maternal use of antihypertensive agents (aOR, 3.80 [95% CI, 1.74-8.29]), maternal age ≥40 years (aOR, 1.59 [95% CI, 1.14-2.20]), and high maternal hemoglobin concentration in the second trimester (aOR, 1.10 per g/dL [95% CI, 1.03-1.17]) were associated with CHD in offspring. Conclusions Using a Japanese large-scale birth cohort study, we found 6 maternal factors to be associated with CHD in offspring.

Outcomes of surgical resection for pulmonary metastasis from pancreatic cancer.

PURPOSE: As the number of long-term survivors of pancreatic cancer is expected to increase thanks to recent advances in multidisciplinary treatment and earlier diagnoses of pancreatic cancer, we are likely to encounter more cases of postoperative pulmonary nodules. We analyzed the clinical course and prognosis of resection of pulmonary metastases from pancreatic cancer to clarify the prognostic implication of pulmonary metastasectomy for pancreatic cancer. METHOD: We retrospectively analyzed 35 patients who underwent resection of lung metastases after pancreatic cancer surgery. Short- and long-term outcomes and factors associated with the prognosis were analyzed. RESULTS: The observation period was 20 (range, 1-101) months, with 3- and 5-year survival rates of 88.3% and 64.5% from pancreatectomy and 44.1% and 28.3% from lung resection, respectively. A univariate analysis revealed that a period from pancreatic cancer resection to pulmonary nodule shadow detection of < 15 months was associated with a significantly lower overall survival from pancreatic resection than a longer period. Conversely, histological type, stage, size of lung metastases, and resection technique were not associated with the overall survival. CONCLUSION: A long-term prognosis may be expected in some cases with a disease-free interval of ≥ 15 months. Our findings suggest that the disease-free interval may influence the prognosis.

A genetic and developmental biological approach for a family with complex congenital heart diseases-evidence of digenic inheritance.

Objective: Congenital heart disease (CHD) is caused by cardiovascular developmental defects and has a global prevalence of ∼1%. The etiology of CHD is multifactorial and remains generally unknown, despite advances in analytical techniques based on next-generation sequencing (NGS). The aim of our study was to elucidate the multi-genetic origin and pathogenesis of an intriguing familial case with complex CHD. Methods: We performed an original trio-based gene panel analysis using NGS of the family, including two siblings with CHD of single ventricular phenotype, and their unaffected parents. The pathogenicity of the detected rare variants was investigated in silico, and the functional effects of the variants were confirmed in vitro using luciferase assays. The combinatorial effect of gene alterations of the putative responsible genes was tested in vivo using genetically engineered mutant mice. Results: NGS-based gene panel analyses revealed two heterozygous rare variants in NODAL and in TBX20 common to the siblings and to just one of parents. Both variants were suspected pathogenic in silico, and decreased transcriptional activities of downstream signaling pathways were observed in vitro. The analyses of Nodal and Tbx20 double mutant mice demonstrated that Nodal+/-Tbx20-/- embryos showed more severe defects than Nodal+/+Tbx20-/- embryos during early heart development. The expression of Pitx2, a known downstream target of Nodal, was downregulated in Tbx20-/- mutants. Conclusions: Two rare variants on NODAL and TBX20 genes detected in this family were considered to be loss-of-function mutations. Our results suggest that NODAL and TBX20 may be complementary for the cardiac development, and a combinatorial loss-of-function of NODAL and TBX20 could be implicated in digenic inherence as the etiology of complex CHD associated with single ventricle defects in this family.

Left bronchial compression after an arterial switch operation with the LeCompte maneuver for transposition of the great arteries: A case report and literature review.

Left bronchial compression is a rarely reported, postoperative complication of the arterial switch operation with the LeCompte maneuver for transposition of the great arteries. Postoperative neopulmonary root dilatation and the anterior-posterior, anatomical relationship of the great vessels may cause this condition. Hypoxic pulmonary vasoconstriction may mask the condition even if the left bronchus has been severely obstructed. The apparent inconsistency between the abnormally decreased pulmonary blood flow and the absence of any irregularities in the vascular structure that might account for it suggested hypoxic pulmonary vasoconstriction to be the cause. We present herein a case of left bronchial compression presenting malacia after an arterial switch operation with the LeCompte maneuver and also present a review of seven, other, reported cases. Learning objectives: Left bronchial compression is a rare complication of the arterial switch operation with the LeCompte maneuver for transposition of the great arteries and is possibly caused by root dilatation and the anatomical relationship of the great vessels. Hypoxic pulmonary vasoconstriction may mask the condition.

Analysis of Coronary Arterial Aneurysm Regression in Patients With Kawasaki Disease by Aneurysm Severity: Factors Associated With Regression.

Background Coronary arterial aneurysms (CAAs) associated with Kawasaki disease (KD) significantly affect prognosis. However, the clinical course of CAAs and factors associated with CAA regression have not been well analyzed. Methods and Results The cohort of the Z-Score 2nd Project Stage study, a multicenter, retrospective, cohort study involving 44 institutions in Japan including 1006 patients with KD, was examined. CAAs were classified by the z score of their internal diameter in the acute phase: small (z<5), medium (5≤z<10), and large (z≥10). The lower limit of small CAA was based on the Japanese Ministry of Health, Labour and Welfare criteria. In the right coronary artery, the CAA regression rates 10 years after diagnosis were 95.5% for small, 83.2% for medium, and 36.3% for large. In the proximal left anterior descending artery, the regression rates 10 years after diagnosis were 95.3% for small, 80.1% for medium, and 28.8% for large. Cox regression analysis showed that diagnosis under the age of 1 year and onset of KD in 2010 to 2012 for the right coronary artery and the left anterior descending artery, and female for the right coronary artery were significantly associated with a high regression rate, whereas large CAAs for the right coronary artery and the left anterior descending artery were significantly associated with a low regression rate. Conclusions The current study, the largest Japanese study of its kind, found that small aneurysm, recent onset, and diagnosis under the age of 1 year predict regression, and that even giant aneurysms could regress. These data may contribute to long-term management of coronary aneurysms. Registration URL: https://www.umin.ac.jp/ctr/; Unique identifier: UMIN000010606.

Efficacy of SubcutAneous implantable cardioVErter-defibrillators in ≤18 year-old CHILDREN: SAVE-CHILDREN registry.

BACKGROUND: In adult patients, subcutaneous implantable cardioverter defibrillators (S-ICDs) have been reported to be non-inferior to transvenous ICDs with respect to the incidence of device-related complications and inappropriate shocks. Only a few reports have investigated the efficacy of S-ICDs in the pediatric field. This study aimed to investigate the utility and safety of S-ICDs in patients ≤18 years old. METHODS: This study was a multicenter, observational, retrospective study on S-ICD implantations. Patients <18 years old who underwent S-ICD implantations were enrolled. The detailed data on the device implantations and eligibility tests, incidence of appropriate- and inappropriate shocks, and follow-up data were assessed. RESULTS: A total of 62 patients were enrolled from 30 centers. The patients ranged in age from 3 to 18 (median 14 years old [IQR 11.0-16.0 years]). During a median follow up of 27 months (13.3-35.8), a total of 16 patients (26.2%) received appropriate shocks and 13 (21.3%) received inappropriate shocks. The common causes of the inappropriate shocks were sinus tachycardia (n = 4, 30.8%) and T-wave oversensing (n = 4, 30.8%). In spite of the physical growth, the number of suitable sensing vectors did not change during the follow up. No one had any lead fractures or device infections in the chronic phase. CONCLUSIONS: Our study suggested that S-ICDs can prevent sudden cardiac death in the pediatric population with a low incidence of lead complications or device infections. The number of suitable sensing vectors did not change during the patients' growth.

Exercise Stress Electrocardiography Using the Two-Minute Jump Test in Children.

Although the treadmill and cycle ergometer are commonly used for exercise stress electrocardiography (ECG) testing, they are often difficult to perform with children. We herein evaluated the utility and safety of the 2-minute jump test (2MJT) as a simple, alternative exercise test. One hundred patients, including 60 male patients, with an average age at study commencement of 10.7±3.5 years (mean±standard deviation) and with no exercise restriction who underwent a cardiac check-up between November 2020 and March 2022 at the study center were included. After recording their resting ECG, they jumped for 2 minutes during ECG recording, and the change in heart rate (HR), ECG findings, and occurrence of adverse events were investigated. As a result, patients jumped 185±60 times in two minutes, and their HR increased from 76±13 beats/min at rest to 172±18 beats/min at peak during the test. Ninety (90%) patients attained the ideal target HR of > 150 beats/minute. During the recovery period after loading, five patients had abnormal ECG findings (ventricular extrasystoles, second-degree atrioventricular block, and atrial extrasystoles in two, two, and one patient, respectively) but completely resolved spontaneously within three minutes. Our findings suggested that the 2MJT is a useful and safe exercise test capable of inducing sufficient increase in HR in a short time in children.

Intramural aortic course in anomalous origin of single coronary artery from the right pulmonary artery: A case report and review of the literature.

Preoperatively determining the intramural aortic course in a case of anomalous origin of single coronary artery from the right pulmonary artery is important for planning surgery, such as the unroofing technique. A thin wall separating the ascending aorta from the common coronary artery on transthoracic echocardiography and a crescent-shaped cross-section of the common coronary artery on computed tomography demonstrate an intramural aortic course of the common coronary artery. We present herein a case of anomalous origin of single coronary artery from the right pulmonary artery with an intramural aortic course and review eight other reported cases. .

Synthetic dimension band structures on a Si CMOS photonic platform.

Synthetic dimensions, which simulate spatial coordinates using nonspatial degrees of freedom, are drawing interest in topological science and other fields for modeling higher-dimensional phenomena on simple structures. We present the first realization of a synthetic frequency dimension on a silicon ring resonator integrated photonic device fabricated using a CMOS process. We confirm that its coupled modes correspond to a one-dimensional tight-binding model through acquisition of up to 280-GHz bandwidth optical frequency comb-like spectra and by measuring synthetic band structures. Furthermore, we realized two types of gauge potentials along the frequency dimension and probed their effects through the associated band structures. An electric field analog was produced via modulation detuning, whereas effective magnetic fields were induced using synchronized nearest- and second nearest-neighbor couplings. Creation of coupled mode lattices and two effective forces on a monolithic Si CMOS device represents a key step toward wider adoption of topological principles.

Quantification of monoacylglycerol lipase and its occupancy by an exogenous ligand in rhesus monkey brains using [18F]T-401 and PET.

Monoacylglycerol lipase (MAGL) is a cytosolic serine hydrolase that cleaves monoacylglycerols into fatty acids and is a potential target for the novel treatment of CNS disorders related to the endocannabinoid system and neuroinflammation. We have developed [18F]T-401 as a selective Positron emission tomography (PET) imaging agent for MAGL. In this study, we determined an analytical method to quantify MAGL availability and its occupancy by an exogenous inhibitor in rhesus monkey brains using [18F]T-401-PET. In rhesus monkeys, regional time-activity curves were described well when using an extended 2-tissue compartment model that accommodated the formation of a radiometabolite in the brain. This model yielded reliable estimates of the total distribution volume (VT), and the rank order of VT was consistent with known regional activity of MAGL enzyme in primates. The pretreatment of monkeys with JW642 resulted in a dose-dependent reduction of [18F]T-401 retentions in the brain, and VT. Lassen's graphical analysis indicated a VND of 0.69 mL/cm3 and a plasma JW642 concentration of 126 ng/mL for inhibiting the specific binding by 50%. [18F]T-401 and the method established can be used for quantification of MAGL in healthy brain and in disease conditions, and is suitable for evaluations of target engagement at cerebral MAGL.

Comparison of 3-D mandibular surfaces generated by MRI and CT.

OBJECTIVE: The purpose of this study was to evaluate the errors of three-dimensional mandibular surfaces generated using magnetic resonance imaging (MRI) when computed tomography (CT) was set as the gold standard. SETTINGS AND SAMPLE POPULATION: Seven patients with orthognathic deformities who had undergone CT and MRI scans were included in the study. MATERIALS AND METHODS: Mandibular surfaces were generated on each CT and MR image by the surface-rendering method. Intra-individual reliability between CT and MRI was statistically tested by the confidence limits of agreement (LOA) for systematic error, 95% confidence interval minimal detectable change (MDC95 ) for random error and intra-class correlation coefficient (ICC). RESULTS: The average total error was 1.6 mm. The greatest MDC95 was observed in the coronoid region in all directions. The other regions showed MDC95 values of < 1.8 mm (transvers direction), 3.5 mm (vertical direction) and 1.7 mm (antero-posterior direction). ICCs showed 'almost perfect' agreement with respect to all regions. CONCLUSION: Random errors were quantified for 3-D rendering of the mandible from MRI data. Although the coronoid region showed the greatest errors, the other regions of the mandibular surfaces generated using MRI were able to be evaluated.

MRS-measured glutamate versus GABA reflects excitatory versus inhibitory neural activities in awake mice.

To assess if magnetic resonance spectroscopy (MRS)-measured Glutamate (Glu) and GABA reflect excitatory and inhibitory neural activities, respectively, we conducted MRS measurements along with two-photon mesoscopic imaging of calcium signals in excitatory and inhibitory neurons of living, unanesthetized mice. For monitoring stimulus-driven activations of a brain region, MRS signals and mesoscopic neural activities were measured during two consecutive sessions of 15-min prolonged sensory stimulations. In the first session, putative excitatory neuronal activities were increased, while inhibitory neuronal activities remained at the baseline level. In the second half, while excitatory neuronal activities remained elevated, inhibitory neuronal activities were significantly enhanced. We assessed regional neurochemical statuses by measuring MRS signals, which were overall in accordance with the neural activities, and neuronal activities and neurochemical statuses in a mouse model of Dravet syndrome under resting condition. Mesoscopic assessments showed that activities of inhibitory neurons in the cortex were diminished relative to wild-type mice in contrast to spared activities of excitatory neurons. Consistent with these observations, the Dravet model exhibited lower concentrations of GABA than wild-type controls. Collectively, the current investigations demonstrate that MRS-measured Glu and GABA can reflect spontaneous and stimulated activities of neurons producing and releasing these neurotransmitters in an awake condition.

Echocardiographic Left Ventricular Z-Score Utility in Predicting Pulmonary-Systemic Flow Ratio in Children With Ventricular Septal Defect or Patent Ductus Arteriosus.

BACKGROUND: The correlation between the Z-score of the left ventricular (LV) diameter and the LV volume-overload due to pulmonary over-circulation in children with ventricular septal defect (VSD) or patent ductus arteriosus (PDA) remains unclear.Methods and Results:The present, retrospective study enrolled 70 children (aged 0.3-16.8 years; 33 males, 37 females) with a diagnosis of isolated VSD and/or PDA who underwent cardiac catheterization (CC) between 2015 and 2019. Patients with chromosomal/genetic anomalies, growth disorder, right-ventricular enlargement or other conditions causing LV enlargement were excluded. Echocardiographic parameters were retrospectively evaluated from the medical records, converted to a Z-score, then compared with CC data. The pulmonary-systemic flow ratio on CC (cQp/Qs) correlated significantly with the Z-score of both the LV end-diastolic diameter (Zd) (r=0.698, P<0.0001) and LV end-systolic diameter (r=0.593, P<0.0001). Regression analysis and curve-fitting were used to predict the cQp/Qs based on the Zd, and a significant regression equation was found on cubic regression (R2of 0.524, P<0.0001) showing a strong correlation with the cQp/Qs (r=0.724, P<0.0001). CONCLUSIONS: The Z-score of the LV diameter can be a useful, non-invasive marker for evaluating LV volume overload and determining the surgical indications in children with VSD or PDA because of its strong correlation with the cQp/Qs.

Neurodegenerative processes accelerated by protein malnutrition and decelerated by essential amino acids in a tauopathy mouse model.

Protein malnutrition is epidemiologically suggested as a potential risk factor for senile dementia, although molecular mechanisms linking dietary proteins and amino acids to neurodegeneration remain unknown. Here, we show that a low-protein diet resulted in down-regulated expression of synaptic components and a modest acceleration of brain atrophy in mice modeling neurodegenerative tauopathies. Notably, these abnormal phenotypes were robustly rescued by the administration of seven selected essential amino acids. The up-regulation of inflammation-associated gene expression and progressive brain atrophy in the tauopathy model were profoundly suppressed by treatment with these essential amino acids without modifications of tau depositions. Moreover, the levels of kynurenine, an initiator of a pathway inducing neuroinflammatory gliosis and neurotoxicity in the brain, were lowered by treatment through inhibition of kynurenine uptake in the brain. Our findings highlight the importance of specific amino acids as systemic mediators of brain homeostasis against neurodegenerative processes.

A genetically targeted reporter for PET imaging of deep neuronal circuits in mammalian brains.

Positron emission tomography (PET) allows biomolecular tracking but PET monitoring of brain networks has been hampered by a lack of suitable reporters. Here, we take advantage of bacterial dihydrofolate reductase, ecDHFR, and its unique antagonist, TMP, to facilitate in vivo imaging in the brain. Peripheral administration of radiofluorinated and fluorescent TMP analogs enabled PET and intravital microscopy, respectively, of neuronal ecDHFR expression in mice. This technique can be used to the visualize neuronal circuit activity elicited by chemogenetic manipulation in the mouse hippocampus. Notably, ecDHFR-PET allows mapping of neuronal projections in non-human primate brains, demonstrating the applicability of ecDHFR-based tracking technologies for network monitoring. Finally, we demonstrate the utility of TMP analogs for PET studies of turnover and self-assembly of proteins tagged with ecDHFR mutants. These results establish opportunities for a broad spectrum of previously unattainable PET analyses of mammalian brain circuits at the molecular level.