NLRP3 Inflammasome Activation Through Heart-Brain Interaction Initiates Cardiac Inflammation and Hypertrophy During Pressure Overload.

BACKGROUND: Mechanical stress on the heart, such as high blood pressure, initiates inflammation and causes hypertrophic heart disease. However, the regulatory mechanism of inflammation and its role in the stressed heart remain unclear. IL-1ß (interleukin-1ß) is a proinflammatory cytokine that causes cardiac hypertrophy and heart failure. Here, we show that neural signals activate the NLRP3 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing 3) inflammasome for IL-1ß production to induce adaptive hypertrophy in the stressed heart. METHODS: C57BL/6 mice, knockout mouse strains for NLRP3 and P2RX7 (P2X purinoceptor 7), and adrenergic neuron-specific knockout mice for SLC17A9, a secretory vesicle protein responsible for the storage and release of ATP, were used for analysis. Pressure overload was induced by transverse aortic constriction. Various animal models were used, including pharmacological treatment with apyrase, lipopolysaccharide, 2'(3')-O-(4-benzoylbenzoyl)-ATP, MCC950, anti-IL-1ß antibodies, clonidine, pseudoephedrine, isoproterenol, and bisoprolol, left stellate ganglionectomy, and ablation of cardiac afferent nerves with capsaicin. Cardiac function and morphology, gene expression, myocardial IL-1ß and caspase-1 activity, and extracellular ATP level were assessed. In vitro experiments were performed using primary cardiomyocytes and fibroblasts from rat neonates and human microvascular endothelial cell line. Cell surface area and proliferation were assessed. RESULTS: Genetic disruption of NLRP3 resulted in significant loss of IL-1ß production, cardiac hypertrophy, and contractile function during pressure overload. A bone marrow transplantation experiment revealed an essential role of NLRP3 in cardiac nonimmune cells in myocardial IL-1ß production and cardiac phenotype. Pharmacological depletion of extracellular ATP or genetic disruption of the P2X7 receptor suppressed myocardial NLRP3 inflammasome activity during pressure overload, indicating an important role of ATP/P2X7 axis in cardiac inflammation and hypertrophy. Extracellular ATP induced hypertrophic changes of cardiac cells in an NLRP3- and IL-1ß-dependent manner in vitro. Manipulation of the sympathetic nervous system suggested sympathetic efferent nerves as the main source of extracellular ATP. Depletion of ATP release from sympathetic efferent nerves, ablation of cardiac afferent nerves, or a lipophilic ß-blocker reduced cardiac extracellular ATP level, and inhibited NLRP3 inflammasome activation, IL-1ß production, and adaptive cardiac hypertrophy during pressure overload. CONCLUSIONS: Cardiac inflammation and hypertrophy are regulated by heart-brain interaction. Controlling neural signals might be important for the treatment of hypertensive heart disease.

Quantitative Evaluation of Right Ventricular Workload Based on the Stroke Work Index in Patients after Right Ventricular Outflow Tract Reconstruction.

The evaluation of right ventricular workload is sometimes complicated in patients after right ventricular outflow tract reconstruction (RVOTR) because both stenotic and regurgitation lesions are involved. In this study, we modified the right ventricular stroke work index (RVSWI) and evaluated the relationship between the modified RVSWI (mRVSWI) and patient prognosis after RVOTR.We enrolled 69 patients who underwent RVOTR (the RVOTR group), including those who needed early reoperation (early reoperation subgroup) and those who did not (follow-up subgroup), and 13 age-matched control participants (control group). Based on the catheterization results 1 year after RVOTR, we compared the mRVSWI between these groups. Additionally, we evaluated the influence of the mRVSWI on the reoperation avoidance rate and survival.The mRVSWI in the RVOTR group was significantly greater than that in the control group (17.7 ± 8.6 vs. 11.0 ± 2.7 g·m/m2, p = 0.008). The mRVSWI in the early reoperation subgroup was significantly greater than that in the follow-up subgroup (32.5 ± 11.1 vs. 15.8 ± 6.0 g·m/m2, p < 0.0001). In the follow-up subgroup, patients with an mRVSWI higher than the upper limit of normal (16.4 g·m/m2) had a greater rate of reoperation than did the other patients (p = 0.0013). One patient died suddenly, and her mRVSWI was consistently high throughout her life.We established the mRVSWI as an index that integrates the pressure and volume load on the right ventricle. Our results indicate the utility of the mRVSWI for predicting patient prognosis after RVOTR.

Medical, welfare, and educational challenges and psychological distress in parents caring for an individual with 22q11.2 deletion syndrome: A cross-sectional survey in Japan.

Parents of children with 22q11.2 deletion syndrome (22q11DS) experience distress not only due to multimorbidity in the patients, but also due to professionals' lack of understanding about 22q11DS and insufficient support systems. This study investigated relationships between medical, welfare, and educational challenges and parental psychological distress. A cross-sectional survey was conducted on primary caregivers of children with 22q11DS. Participants included 125 parents (114 mothers, 91.2%; average age = 44.3 years) who reported their challenges, psychological distress, and child's comorbidities of 22q11DS. Results showed that the difficulty in going to multiple medical institutions (ß = 0.181, p < 0.05) and lack of understanding by welfare staff and insufficient welfare support systems for 22q11DS (ß = 0.220-0.316, all p < 0.05) were associated with parental psychological distress, even after adjusting for child's comorbidities. In the subsample of parents whose child attended an educational institution, inadequate management in classroom and mismatch between service and users in educational settings were associated with psychological distress (ß = 0.222-0.296, all p < 0.05). This study reveals the importance of assessing not only severity of comorbidities in 22q11DS, but also the medical, welfare, and educational challenges for parental mental health.

Development and validation of a Japanese version of the TRANSITION-Q.

BACKGROUND: The evaluation of transition readiness is indispensable for long-term follow-ups of adolescent patients with childhood-onset chronic diseases (CCD). We developed a Japanese version of the TRANSITION-Q (TRANSITION-Q-J) and used it to assess Japanese patients with CCD. METHODS: The TRANSITION-Q-J was developed through forward and backward translations followed by cognitive interviews with five adolescent patients. The field test was conducted with 125 adolescent patients, and a retest was conducted with 113 adolescent patients. RESULTS: Confirmatory factor analysis supported the two-factor analysis model including F1 (communication and self-management) and F2 (examination behavior). Sufficient internal consistency and test-retest reliability were demonstrated among the total 14 items, F1, and F2 (Cronbach's α > 0.80, intraclass correlation coefficient > 0.85). Convergent and discriminant validity for the 14 items and F1 were acceptable; however, F2 did not correlate significantly with the Rosenberg Self-Esteem Scale and Independent Consciousness Scale. Regarding known-groups validity, the older group had a significantly higher mean TRANSITION-Q-J score (50.05) than the younger group (43.28; P = 0.04). The same results were found for both F1 and F2. CONCLUSIONS: The TRANSITION-Q-J for adolescent patients with CCD was developed and its reliability and validity were verified. This scale is easy to administer. In addition to being a tool for transition period support, it could be used to verify effective factors and in program outcome evaluation, including intervention studies.

Poor Myocardial Compaction in a Patient with Recessive MYL2 Myopathy.

Recessive mutations in the Myosin regulatory light chain 2 (MYL2) gene are the cause of an infantile-onset myopathy, associated with fatal myocardial disease of variable macromorphology. We here present the first Japanese family affected with recessive MYL2 myopathy. Affected siblings manifested typical features and the proband's autopsy findings were compatible with the diagnosis of noncompaction cardiomyopathy. The rapidly progressive clinical course of this recessive MYL2 cardiomyopathy highlights the crucial role of c-terminal tails in MYL2 protein in maintaining cardiac morphology and function.

Nonosmotic secretion of arginine vasopressin and salt loss in hyponatremia in Kawasaki disease.

BACKGROUND: The precise mechanism of hyponatremia in Kawasaki disease (KD) remains elusive because assessment of volume status based on serial changes in body weight is lacking in previous reports. METHODS: Seventeen patients who were diagnosed with KD and hyponatremia (serum sodium levels <135 mmol/L) were analyzed. Volume status was assessed based on serial changes in body weight. Plasma arginine vasopressin (ADH), urine electrolytes, and serum cytokine levels were measured on diagnosis of hyponatremia. An increase in body weight by >3% was defined as hypervolemia and a decrease in body weight by >3% was defined as hypovolemia. RESULTS: The volume status was hypervolemic in three patients (18%), euvolemic in 14 (82%), and hypovolemic in none (0%). Five (29%) patients were diagnosed with "syndrome of inappropriate secretion of antidiuretic hormone" (SIADH) and no patients were diagnosed with hypotonic dehydration. The contribution of decreased total exchangeable cations (salt loss) to hyponatremia (5.9% [interquartile range, 4.3%, 6.7%]) was significantly larger than that of increased total body water (-0.7% [-1.8%, 3.1%]) (P = 0.004). Serum interleukin-6 levels were elevated in all of the nine patients who were evaluated. Among the 12 (71%) patients who did not meet the criteria of SIADH and hypotonic dehydration, plasma ADH levels were inappropriately high in ten patients. These patients were also characterized by euvolemic or hypervolemic hyponatremia and salt loss, which might be compatible with a diagnosis of SIADH. CONCLUSIONS: Our study shows that hyponatremia in KD is euvolemic or hypervolemic and is associated with nonosmotic secretion of ADH and salt loss in the majority of patients.

Identification of liver fibrosis using the hepatic vein waveform in patients with Fontan circulation.

AIM: Liver fibrosis caused by congestive hepatopathy has emerged as an important complication after Fontan procedure. We evaluated the utility of the hepatic vein (HV) waveform using Doppler ultrasound for identification of liver fibrosis in Fontan patients. METHODS: We investigated the HV waveforms in 41 Fontan patients and assessed correlations with clinical parameters, liver fibrosis markers, and hemodynamic data. RESULTS: Based on our preliminary analysis of 64 adult patients with chronic liver disease who underwent liver biopsy, we classified HV waveforms into five types with reference to the degree of flattening (from type 1, normal triphasic waveform; to type 5, a monophasic waveform indicating cirrhosis), and confirmed a significant correlation between waveform pattern and fibrosis stage. Notably, we detected HV waveforms in all of the Fontan patients and classified them into five types. The HV waveform pattern positively correlated with γ-glutamyl transferase and hyaluronic acid levels, and negatively correlated with albumin level and platelet count, but did not correlate with central venous pressure or brain natriuretic peptide level, suggesting that HV waveform could reflect pathophysiological changes in the liver without being affected by hepatic congestion. The highest area under the receiver operating characteristic curve of the HV waveform for detecting advanced liver fibrosis, as defined by ultrasonic findings and clinical features, was 0.829 (81.8% sensitivity, 73.3% specificity), which was higher than that of other non-invasive fibrosis markers. CONCLUSIONS: Hepatic vein waveforms change in accordance with liver fibrosis progression in Fontan patients, and can be a useful indicator of liver fibrosis after the Fontan procedure.

Cardiac Rhythm Disturbances in Heterotaxy Syndrome.

OBJECTIVE: Heterotaxy syndrome is associated with complex cardiac malformations and cardiac conduction system abnormalities. Those with right atrial isomerism (RAI) have dual sinus nodes and dual atrioventricular nodes predisposing them to supraventricular tachycardia (SVT). Those with left atrial isomerism (LAI) lack a normal sinus node and are at risk of sinus node dysfunction (SND) and atrioventricular block (AV block). We report the occurrence and risk factors associated with arrhythmias in heterotaxy syndrome. METHODS: A retrospective review of all heterotaxy syndrome patients born and treated at our institution between 2000 and 2014 was performed. RESULTS: A total of 40 patients were identified; 16/40 (40%) with LAI and 24/40 (60%) with RAI. There were 12 deaths during follow-up [LAI 3/16 (19%), RAI 9/24 (38%); p = 0.30]. Twenty-one patients had arrhythmias during a mean follow-up period of 5.4 years; 14/16 (87%) in LAI and 7/24 (29%) in RAI (p < 0.001). Freedom from arrhythmia at 1,3,5 years of age was 75.0%, 37.9%, 22.7% in LAI, and 83.3%, 77.5%, 69.6% in RAI, respectively(p = 0.00261). LAI had a three-fold increase in developing arrhythmias. Left atrial isomerism was the only factor identified to be associated with arrhythmia occurrence. CONCLUSIONS: Arrhythmias were commonly seen in heterotaxy syndrome particularly in left isomerism with more than half of the patients having arrhythmias by 3 years of age. Atrial situs was the only risk factor identified to be associated with arrhythmias, and close follow-up is warranted in these patients.

Vildagliptin, a DPP-4 Inhibitor, Attenuates Endothelial Dysfunction and Atherogenesis in Nondiabetic Apolipoprotein E-Deficient Mice.

Dipeptidyl peptidase-4 (DPP-4) inhibitors are novel antidiabetic agents with possible vascular protection effects. Endothelial dysfunction is an initiation step in atherogenesis. The purpose of this study was to investigate whether vildagliptin (Vilda) attenuates the development of endothelial dysfunction and atherosclerotic lesions in nondiabetic apolipoprotein E-deficient (ApoE-/-) mice. Eight-week-old nondiabetic ApoE-/- mice fed a Western-type diet received Vilda (50 mg/kg/day) for 20 weeks or 8 weeks. After 20 weeks of treatment, Vilda administration reduced atherogenesis in the aortic arch as determined by en face Sudan IV staining compared with the vehicle group (P < 0.05). Vilda also reduced lipid accumulation (P < 0.05) and vascular cell adhesion molecule-1 (VCAM-1) expression (P < 0.05) and tended to decrease macrophage infiltration (P = 0.05) into atherosclerotic plaques compared with vehicle. After 8 weeks of treatment, endothelium-dependent vascular reactivity was examined. Vilda administration significantly attenuated the impairment of endothelial function in nondiabetic ApoE-/- mice compared with the vehicle group (P < 0.05). Vilda treatment did not alter metabolic parameters, including blood glucose level, in both study protocols. To investigate the mechanism, aortic segments obtained from wild-type mice were incubated with exendin-4 (Ex-4), a glucagon-like peptide-1 (GLP-1) analog, in the presence or absence of lipopolysaccharide (LPS). Ex-4 attenuated the impairment of endothelium-dependent vasodilation induced by LPS (P < 0.01). Furthermore, Ex-4 promoted phosphorylation of eNOS at Ser1177 which was decreased by LPS in human umbilical endothelial cells (P < 0.05). Vilda inhibited the development of endothelial dysfunction and prevented atherogenesis in nondiabetic ApoE-/- mice. Our results suggested that GLP-1-dependent amelioration of endothelial dysfunction is associated with the atheroprotective effects of Vilda.

Direct hyperbilirubinemia in infants with congenital heart disease.

BACKGROUND: The association between congenital heart disease (CHD) and infantile cholestasis, a key finding for the diagnosis of biliary atresia (BA), has not been previously investigated. The aim of this study was therefore to investigate the characteristics of direct hyperbilirubinemia (D-HB) in infants with CHD. METHODS: All neonates admitted to the present hospital and diagnosed with CHD in 2015 and 2016 were included. D-HB (direct bilirubin ≥ 2.0 mg/dL) at ≤60 days of age and other clinical parameters were retrospectively reviewed. Statistical analysis according to presence of D-HB was performed using chi-squared test or Wilcoxon rank sum test. RESULTS: Seventy-six patients (M:F, 36:40) were included in this study. CHD consisted of ventricular septal defect in 17, patent ductus arteriosus in 10, and other in 49. Thirteen patients (17.1%) had D-HB at ≤60 days of age. Resolution of D-HB (DB < 2.0 mg/dL) occurred in 10 of the 13 patients during the hospital stay, and this occurred in ≤7 days in eight of the 10 patients. Sex, gestational age, birthweight, chromosomal anomalies, need for Fontan operation for CHD repair, and/or cardiac operation were not associated with D-HB at ≤60 days of age. CONCLUSION: While D-HB was frequently observed in infants with CHD, the majority of D-HB cases resolved spontaneously in ≤1 week. Neonatal clinical parameters or CHD status was not predictive of D-HB. D-HB lasting >1 week in infants with CHD should be evaluated for the cause.

Effect of i.v. immunoglobulin in the first 4 days of illness in Kawasaki disease.

BACKGROUND: Although early treatment of Kawasaki disease (KD) with i.v. immunoglobulin (IVIG) is expected to prevent coronary artery abnormalities, the effectiveness of IVIG by day 4 of illness remains to be determined. METHODS: This was a multi-institutional, retrospective cohort study. Patients diagnosed with KD at ≤4 days of illness were divided into two groups: those who received initial IVIG before and on day 5 of illness. Baseline characteristics were adjusted using propensity scores. The primary endpoint was the need for additional treatment. RESULTS: Of 339 patients diagnosed with KD by day 4, 181 and 158 received IVIG before and on day 5 of illness, respectively. Patients in the early treatment group had more adverse prognostic factors: infancy, early onset of the principal symptoms, and abnormal laboratory data. We thus adjusted baseline characteristics before treatment decisions using propensity scores. Propensity score matching of the two groups yielded 100 observations. More patients required additional treatment in the matched early treatment group: 37% vs 24% (adjusted OR, 1.7; 95%CI: 1.06-2.8; P = 0.047). The difference was more pronounced for risk of relapse after initial resolution of fever: 14% vs 5.0% (adjusted OR, 3.2; 95%CI: 1.3-7.7; P = 0.02). The risk of coronary artery lesion did not differ significantly. CONCLUSIONS: IVIG treatment by day 4 of illness is associated with the requirement for additional treatment even after adjustment of baseline characteristics. Increased resistance to IVIG when given by day 4 should be considered in order to improve the treatment regimen for early-diagnosed KD.

A Qualitative Assessment of Adolescent Girls' Perception of Living with Congenital Heart Disease: Focusing on Future Pregnancies and Childbirth.

PURPOSE: Congenital heart disease (CHD) is the most common birth anomaly in Japan, occurring in approximately 10.6 of every 1,000 live births. Advancements in medical and surgical care have increased births by women diagnosed with CHD. The study's purpose was to examine the perceptions of pregnancy and childbirth among adolescent girls with CHD. DESIGN AND METHODS: Twelve semi-structured interviews were conducted, and the data were analyzed using a modified grounded-theory approach. RESULTS: Three categories and 16 subcategories were extracted. Adolescent girls with CHD reported feelings of distress and anxiety while struggling with their disease, and feared how their disease might negatively influence their future pregnancy. These concerns were related to a desire to become familiar with CHD. The girls also explored how their disease would be managed during pregnancy and childbirth. Overall, these perceptions were influenced by the girls' acceptance of their disease, and support from family, friends, and healthcare professionals. CONCLUSIONS: Healthcare professionals might assess adolescent girls' awareness of their disease before discussing pregnancy and childbirth risks. To encourage them to understand and cope with their disease, healthcare professionals might provide interventions tailored to the timing, stage, and degree of pregnancy and childbirth awareness. This could allow safer life planning, especially concerning pregnancy and childbirth decisions. PRACTICE IMPLICATIONS: To address adolescent girls' needs, healthcare professionals should continuously assess their awareness of pregnancy and childbirth as well as their psychological status, alongside CHD issues.

Fever pattern and C-reactive protein predict response to rescue therapy in Kawasaki disease.

BACKGROUND: Evidence to guide rescue therapy in refractory Kawasaki disease (KD) is lacking. The aim of this study was to determine the most important variables in predicting non-response to rescue therapy in refractory KD. METHODS: We retrospectively analyzed 171 patients diagnosed with refractory KD resistant to initial i.v. immunoglobulin (IVIG). Participants received rescue therapy consisting of IVIG monotherapy or IVIG plus prednisolone. Characteristics and laboratory variables were compared between rescue therapy non-responders and responders. Multivariate logistic regression analysis was performed to determine the independent predictors of non-response to rescue therapy. RESULTS: Among the 171 participants, 54 (31.6%) were non-responders to rescue therapy. On univariate analysis, fever pattern after initial IVIG, day of illness at rescue therapy, rescue therapy regimen and six laboratory variables (pre-IVIG sodium, C-reactive protein [CRP]; post-IVIG white blood cell count, platelet count, sodium, CRP) were useful in discriminating between non-responders and responders. These nine variables were included in multivariate logistic regression analysis. Persistent fever after initial IVIG (aOR, 2.39; 95%CI: 1.07-5.37) and post-IVIG CRP (aOR, 1.09; 95%CI: 1.02-1.17, per 1 mg/dL increase) were identified as independent predictors of non-response to rescue therapy. IVIG rescue monotherapy (aOR, 3.05; 95%CI: 1.05-8.84) also predicted non-response after adjusting for fever pattern and post-IVIG CRP. CONCLUSIONS: Persistent fever and elevated CRP after initial IVIG are predictive of non-response to rescue therapy for refractory KD. For patients at high risk of non-response, IVIG plus prednisolone, or even further intensified rescue therapy regimens may be preferable.

Total anomalous pulmonary venous connection with ccTGA and VSD: Can pulmonary artery banding avert pulmonary venous obstruction?

We describe a rare case of infracardiac total anomalous pulmonary venous connection (TAPVC), associated with congenitally corrected transposition of the great arteries (ccTGA) and ventricular septal defect, in which the patient had undergone pulmonary artery banding (PAB) at 16 days of age. She began to have episodes of severe cyanosis while crying, 2 weeks after PAB. Cardiac catheterization at 34 days of age showed severe pulmonary hypertension and a transhepatic pressure gradient of 7 mmHg. The infant underwent TAPVC repair and conventional repair for ccTGA at 35 days of age. Although PAB might have the provisional effect of delaying the manifestation of pulmonary venous obstruction (PVO), it is unable to prevent the development of PVO due to the high resistance of the hepatic sinusoids. Signs of PVO should be closely monitored so that TAPVC can be repaired in a timely fashion.

Epicardial adipose tissue volume and adipocytokine imbalance are strongly linked to human coronary atherosclerosis.

OBJECTIVE: The impact of epicardial adipose tissue (EAT) over abdominal or overall adiposity on coronary artery disease (CAD) is currently unknown. We compared the association among EAT volume (EATV), cytokine/adipocytokine profiles in EAT and subcutaneous fat, and atherogenic CAD. APPROACH AND RESULTS: Paired samples were obtained from EAT and subcutaneous adipose tissue during elective cardiac surgery for CAD (n=50) or non-CAD (n=50). EATV was the sum of cross-sectional EAT areas, and visceral and subcutaneous fat areas were determined at the umbilicus level on computed tomography scans. CD68(+), CD11c(+), and CD206(+) cells were counted using immunohistochemical staining. Cytokine/adipocytokine expression was evaluated using quantitative real-time polymerase chain reaction. Multivariate analysis indicated that male sex, age, diabetes mellitus, high triglycerides, and low high-density lipoprotein cholesterol, and EATV index (EATV/body surface area, cm(3)/m(2)) were significant CAD predictors (corrected R(2)=0.401; P<0.001); visceral fat area, hypertension, smoking, low-density lipoprotein cholesterol (140 mg/dL [3.63 mmol/L]) or statin use were not predictors. The EATV index positively correlated with the CD68(+) and CD11c(+) cell numbers and nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3), interleukin-1ß, and interleukin-1R expression; and negatively correlated with adiponectin expression in EAT. A multivariate analysis model, including CD68(+) cells and interleukin-1ß, and adiponectin expression in EAT strongly predicted CAD (corrected R(2)=0.756; P<0.001). CONCLUSIONS: EATV and macrophage and cytokine/adipocytokine signals in EAT strongly correlated with CAD. Our findings suggest that EATV and adipocytokine imbalance are strongly linked to human coronary atherosclerosis.

Serum hyaluronic acid concentration in Fontan circulation: correlation with hepatic function and portal vein hemodynamics.

Although liver fibrosis causes significant morbidity in the late postoperative period of the Fontan procedure, the diagnostic value of hyaluronic acid (HA), a serum marker of liver fibrosis, has not been established in Fontan patients. The purpose of this study was to determine whether increased serum HA concentration in Fontan patients is associated with an increase in inspiratory-to-expiratory flow rate ratio (Qin/Qex) of the portal vein (PV), which is indicative of liver fibrosis. We retrospectively studied 28 consecutive patients with Fontan circulation who underwent cardiac catheterisation for various indications. The median age at examination was 5.5 years (range 2.2-5.6). The median HA concentration was 17.7 ng mL(-1) (range 10.0-82.1), which was used to divide our 28 patients into two groups. Patients in the high-HA group had significantly greater Qin/Qex of the PV than those in the low-HA group (1.25 ± 0.12 vs. 1.12 ± 0.11, p < 0.05). Platelet counts were significantly lower in the high-HA group (216 ± 74 vs. 294 ± 104 × 10(9) L(-1), p < 0.05). No significant difference was found in inferior vena caval pressure. In conclusion, increase of HA concentration in Fontan patients accompanies the change in PV hemodynamics peculiar to liver cirrhosis and might be an early indicator of liver fibrosis.

Prenatal aortic arch development in double aortic arch: Understanding postnatal closure of left aortic arch: A case report.

Double aortic arch (DAA) is a rare congenital abnormality characterized by a vascular ring that often requires surgical intervention due to respiratory complications. The DAA and right aortic arch with mirror-image branches (RAA-MB) represent abnormalities in development of the aortic arch. However, prognosis differs significantly, as the DAA forms vascular rings, whereas the RAA-MB typically does not. Distinguishing between the conditions becomes particularly challenging in cases of DAA with closure of the posterior portion of the left aortic arch (LAA) because the postnatal manifestations closely resemble those of RAA-MB. Herein, we present a case of DAA in which longitudinal observation of the LAA and RAA diameters during pregnancy aimed in predicting postnatal closure of the LAA. A 37-year-old female with suspected DAA was referred to our hospital at 26 weeks of gestation. Initial measurements revealed comparable diameters for the LAA and RAA; however, the LAA diameter decreased to approximately half that of the RAA by term owing to growth restrictions. Postnatal contrast computed tomography confirmed the closure of the posterior portion of the LAA and RAA with Kommerell diverticulum. Our findings suggest that careful monitoring of DAA throughout fetal development, especially during the third trimester, may aid in predicting atretic changes in the nondominant arch after birth, allowing an easy distinction between the DAA and RAA-MB after birth.

Perivascular adipose tissue-secreted angiopoietin-like protein 2 (Angptl2) accelerates neointimal hyperplasia after endovascular injury.

Much attention is currently focused on the role of perivascular adipose tissue in development of cardiovascular disease (CVD). Some researchers view it as promoting CVD through secretion of cytokines and growth factors called adipokines, while recent reports reveal that perivascular adipose tissue can exert a protective effect on CVD development. Furthermore, adiponectin, an anti-inflammatory adipokine, reportedly suppresses neointimal hyperplasia after endovascular injury, whereas such vascular remodeling is enhanced by pro-inflammatory adipokines secreted by perivascular adipose, such as tumor necrosis factor-α (TNF-α). These findings suggest that extent of vascular remodeling, a pathological process associated with CVD development, depends on the balance between pro- and anti-inflammatory adipokines secreted from perivascular adipose tissue. We previously demonstrated that angiopoietin-like protein 2 (Angptl2), a pro-inflammatory factor secreted by adipose tissue, promotes adipose tissue inflammation and subsequent systemic insulin resistance in obesity. Here, we examined whether Angptl2 secreted by perivascular adipose tissue contributes to vascular remodeling after endovascular injury in studies of transgenic mice expressing Angptl2 in adipose tissue (aP2-Angptl2 transgenic mice) and Angptl2 knockout mice (Angptl2(-/-) mice). To assess the role of Angptl2 secreted by perivascular adipose tissue on vascular remodeling after endovascular injury, we performed adipose tissue transplantation experiments using these mice. Wild-type mice with perivascular adipose tissue derived from aP2-Angptl2 mice exhibited accelerated neointimal hyperplasia after endovascular injury compared to wild-type mice transplanted with wild-type tissue. Conversely, vascular inflammation and neointimal hyperplasia after endovascular injury were significantly attenuated in wild-type mice transplanted with Angptl2(-/-) mouse-derived perivascular adipose tissue compared to wild-type mice transplanted with wild-type tissue. RT-PCR analysis revealed that mouse Angptl2 expression in perivascular adipose tissue was significantly increased by aging, hypercholesterolemia, and endovascular injury, all risk factors for coronary heart disease (CHD). Immunohistochemical and RT-PCR analysis of tissues from patients with CHD and from non-CHD patients indicated that ANGPTL2 expression in epicardial adipose tissue was unchanged. Interestingly, that analysis also revealed a positive correlation in ANGPTL2 and ADIPONECTIN expression in epicardial adipose tissue of non-CHD patients, a correlation not seen in CHD patients. However, in epicardial adipose tissue from CHD patients, ANGPTL2 expression was positively correlated with that of TNF-α, a correlation was not seen in non-CHD patients. These findings suggest that pro-inflammatory adipokines cooperatively accelerate CHD development and that maintaining a balance between pro- and anti-inflammatory adipokines likely protects non-CHD patients from developing CHD. Overall, our studies demonstrate that perivascular adipose tissue-secreted Angptl2 accelerates vascular inflammation and the subsequent CVD development.