Identification of Prostaglandin I2 Synthase Rare Variants in Patients With Williams Syndrome and Severe Peripheral Pulmonary Stenosis.

BACKGROUND: Peripheral pulmonary stenosis (PPS) is a condition characterized by the narrowing of the pulmonary arteries, which impairs blood flow to the lung. The mechanisms underlying PPS pathogenesis remain unclear. Thus, the aim of this study was to investigate the genetic background of patients with severe PPS to elucidate the pathogenesis of this condition. METHODS AND RESULTS: We performed genetic testing and functional analyses on a pediatric patient with PPS and Williams syndrome (WS), followed by genetic testing on 12 patients with WS and mild-to-severe PPS, 50 patients with WS but not PPS, and 21 patients with severe PPS but not WS. Whole-exome sequencing identified a rare PTGIS nonsense variant (p.E314X) in a patient with WS and severe PPS. Prostaglandin I2 synthase (PTGIS) expression was significantly downregulated and cell proliferation and migration rates were significantly increased in cells transfected with the PTGIS p.E314X variant-encoding construct when compared with that in cells transfected with the wild-type PTGIS-encoding construct. p.E314X reduced the tube formation ability in human pulmonary artery endothelial cells and caspase 3/7 activity in both human pulmonary artery endothelial cells and human pulmonary artery smooth muscle cells. Compared with healthy controls, patients with PPS exhibited downregulated pulmonary artery endothelial prostaglandin I2 synthase levels and urinary prostaglandin I metabolite levels. We identified another PTGIS rare splice-site variant (c.1358+2T>C) in another pediatric patient with WS and severe PPS. CONCLUSIONS: In total, 2 rare nonsense/splice-site PTGIS variants were identified in 2 pediatric patients with WS and severe PPS. PTGIS variants may be involved in PPS pathogenesis, and PTGIS represents an effective therapeutic target.

Pernicious Anemia in an Adult with Trisomy 21.

Pernicious anemia is an autoimmune disease caused by the malabsorption of vitamin B12. It usually appears in the elderly. People with trisomy 21 are susceptible to autoimmune diseases. This susceptibility is thought to be due to altered expression of the AIRE gene, which is located in the 21q22.3 region. Although pernicious anemia is not common in people with trisomy 21, AIRE is pointed out as a susceptibility gene of pernicious anemia in a genome-wide association study. Here, we report a man with trisomy 21, who suffered from the pernicious anemia. When he was in his 30 s, he visited our hospital because of diarrhea and poor oral intake. He showed thrombocytopenic purpura-like features, and was diagnosed as pernicious anemia. After supplementation of vitamin B12, he recovered from the illness. The reason for his early onset may be because of trisomy 21. Altered expression of AIRE might trigger the disease.

A Cardiac Arrest Case due to Left Coronary Artery Compression in Congenital Heart Disease-Associated Pulmonary Arterial Hypertension.

We report the case of an adult who had a cardiac arrest in the setting of pulmonary hypertension and a previously repaired intermediate atrioventricular septal defect, with left main coronary trunk stenosis due to dilatation of the main pulmonary artery. In patients with pulmonary hypertension exhibiting anginal symptoms, it is advisable to perform chest contrast computed tomography to confirm the pulmonary artery diameter and the presence of coronary artery compression. In addition, our case highlights the importance of early collaboration among specialists during the transition from adolescence to adulthood.

Nous décrivons le cas d'un adulte ayant subi un arrêt cardiaque alors qu'il présentait une hypertension pulmonaire et qu'il avait déjà subi la réparation d'une communication septale auriculoventriculaire intermédiaire, avec sténose de l'artère coronaire gauche principale causée par la dilatation de l'artère pulmonaire principale. Chez les patients atteints d'hypertension pulmonaire qui présentent des symptômes angineux, il est recommandé d'effectuer une tomodensitométrie thoracique avec produit de contraste pour confirmer le diamètre de l'artère pulmonaire et la présence d'une compression de l'artère coronaire. Notre cas souligne également l'importance d'établir sans tarder une collaboration entre spécialistes lors de la transition entre l'adolescence et l'âge adulte.

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.

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.

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.