Increased serum activin A level in congenital heart disease-associated pulmonary artery hypertension: A comparative study from the COHARD-PH registry.

Activin A, a member of TGF-ß superfamily, has been implicated in the pathogenesis of pulmonary artery hypertension (PAH). PAH due to congenital heart disease (CHD-PAH) is a major problem in developing countries. Activin A may have a role in PAH development and progression among uncorrected CHD. In this comparative study, serum activin A level was significantly increased in subjects with uncorrected CHD without the presence of PH and were more significantly risen in CHD-PAH, as compared to control. The utilization of serum activin A measurement seems promising to identify uncorrected CHD patients with PAH development and progression.

The screening of congenital heart disease by cardiac auscultation and 12-lead electrocardiogram among Indonesian elementary school students.

BACKGROUND: Screening for congenital heart disease (CHD) in school students is well-established in high-income countries; however, data from low-to-middle-income countries including Indonesia are limited. AIM: This study aimed to evaluate CHD screening methods by cardiac auscultation and 12-lead electrocardiogram to obtain the prevalence of CHD, confirmed by transthoracic echocardiography, among Indonesian school students. METHODS: We conducted a screening programme in elementary school students in the Province of Special Region of Yogyakarta, Indonesia. The CHD screening was integrated into the annual health screening. The trained general practitioners and nurses participated in the screening. The primary screening was by cardiac auscultation and 12-lead electrocardiogram. The secondary screening was by transthoracic echocardiography performed on school students with abnormal findings in the primary screening. RESULTS: A total of 6116 school students were screened within a 2-year period. As many as 329 (5.38%) school students were detected with abnormalities. Of those, 278 students (84.49%) had an abnormal electrocardiogram, 45 students (13.68%) had heart murmurs, and 6 students (1.82%) had both abnormalities. The primary screening programme was successfully implemented. The secondary screening was accomplished for 260 school students, and 18 students (6.9%) had heart abnormalities with 7 (2.7%) who were confirmed with septal defects and 11 (4.2%) had valve abnormalities. The overall prevalence was 0.29% (18 out of 6116). CONCLUSIONS: The primary screening by cardiac auscultation and 12-lead electrocardiogram was feasible and yielded 5.38% of elementary school students who were suspected with CHD. The secondary screening resulted in 6.9% confirmed cardiac abnormalities. The cardiac abnormality prevalence was 0.29%.

Serum soluble suppression of tumorigenicity-2 level associates with severity of pulmonary hypertension associated with uncorrected atrial septal defect.

Uncorrected atrial septal defect undergoes right ventricle chronic volume overload which may lead to pulmonary hypertension and Eisenmenger Syndrome. The soluble suppression of tumorigenicity-2 is a left ventricle strain biomarker; however, its role in right ventricle strain is unclear. This study aimed to investigate the implication of serum soluble suppression of tumorigenicity-2 in adult uncorrected atrial septal defect. This was a cross-sectional study. We enrolled 81 adult uncorrected secundum atrial septal defect patients. Clinical and hemodynamic data were collected. Serum samples were withdrawn from the pulmonary artery during right heart catheterization. Serum soluble suppression of tumorigenicity-2 and NT-proBNP levels were measured. Subjects were divided into three groups based on clinical and hemodynamic severity. The correlation of soluble suppression of tumorigenicity-2 with patients' data and comparison among groups were analyzed. A p value <0.05 was considered statistically significant. Results showed that, there were significant correlations between serum soluble suppression of tumorigenicity-2 and mean pulmonary artery pressure (r = 0.203, p = 0.035) and right ventricle end-diastolic diameter (r = 0.203, p <0.05). Median serum soluble suppression of tumorigenicity-2 level was incrementally increased from group I (atrial septal defect and no-pulmonary hypertension), group II (left-to-right atrial septal defect and pulmonary hypertension), to group III (Eisenmenger Syndrome): (17.4 ng/mL, 21.8 ng/mL, and 29.4 ng/mL, respectively). A post-hoc analysis showed that serum soluble suppression of tumorigenicity-2 level was significantly different between groups I and III (p = 0.01). Serum N terminal pro brain natriuretic peptide (NT-proBNP) level was consistently associated with worse clinical and hemodynamic parameters. No correlation was found between serum soluble suppression of tumorigenicity-2 and NT-proBNP level. In conclusion, serum soluble suppression of tumorigenicity-2 level had significant positive correlation with mean pulmonary artery pressure and right ventricle end-diastolic diameter in uncorrected secundum atrial septal defect patients. Higher serum soluble suppression of tumorigenicity-2 level was associated with the presence of pulmonary hypertension and Eisenmenger Syndrome in uncorrected secundum atrial septal defect patients.

Severe pulmonary hypertension and reduced right ventricle systolic function associated with maternal mortality in pregnant uncorrected congenital heart diseases.

BACKGROUND: Pregnant uncorrected congenital heart disease patients, especially those who already developed pulmonary hypertension, have increased risk for maternal mortality. The pulmonary hypertension severity and right ventricle function may be associated with higher maternal mortality. The study aimed to investigate the mortality rate of pregnant uncorrected congenital heart disease and the impact of pulmonary hypertension severity on mortality. METHODS: This is the sub study of COngenital HeARt Disease in adult and Pulmonary Hypertension Registry. The data of pregnant uncorrected congenital heart disease patients were analyzed from registry database. The maternal mortality was recorded. The data of demography, clinics, obstetrics, and transthoracic echocardiography were collected. The factors that influenced maternal mortality were analyzed. A statistical significance was determined when p value < 0.05. RESULTS: From 2012 until 2017, there were 78 pregnant congenital heart disease patients. Of them, 56 patients were eligible for analyses. The majority of congenital heart disease was atrial septal defect (91.1%). The maternal mortality rate was 10.7% (6 of 56). Pulmonary hypertension occurred in 48 patients, therefore the maternal mortality rate among congenital heart disease-pulmonary hypertension with majority of atrial septal defect was 12.5% (6 of 48). Among nonsurvivors, 100% suffered from severe pulmonary hypertension as compared to survivors (56.0%), p = 0.041. Most nonsurvivors were Eisenmenger syndrome (83.3%), significantly higher compared to survivors (22.0%), p = 0.006. Nonsurvivors had significantly worsened WHO functional class, reduced right ventricle systolic function, and right heart failure. The modes of maternal death were severe oxygen desaturation (66.7%) and respiratory failure and sepsis (33.3%). Most of the maternal deaths occurred within 24 h postpartum period. CONCLUSION: Maternal mortality rate among pregnant uncorrected congenital heart disease with majority of atrial septal defect was 10.7% and among congenital heart disease-pulmonary hypertension with majority of atrial septal defect was 12.5%. Factors related with maternal mortality were severe pulmonary hypertension, Eisenmenger syndrome, and reduced right ventricle systolic function.

Circulating soluble CD40 ligand mediates the interaction between neutrophils and platelets in acute coronary syndrome.

Following plaque rupture, activated platelet will induce subsequent inflammatory process including neutrophil recruitment. In vitro study demonstrated an interaction between neutrophils and platelets via a mechanism involving CD40-CD40 ligand. However, whether this mechanism exists in the clinical setting remains unknown. Fifty-four patients with acute myocardial infarction (AMI) and 25 with unstable angina of pain onset of < or = 24 h were enrolled consecutively. Acute myocardial infarction was diagnosed from three diagnostic criteria, i.e., anginal pain, electrocardiogram ST-T changes, and cardiac enzyme elevation. Unstable angina was diagnosed in patients without elevated cardiac enzymes. Peripheral venous blood was drawn at admission for routine blood count and soluble CD40 ligand (sCD40L) measurement. Neutrophil count was determined by an automated blood cell counter. Circulating sCD40L was measured using a standard enzyme-linked immunosorbent assay. Neutrophil count was significantly higher in AMI as compared with unstable angina (P < 0.001), whereas circulating sCD40L did not significantly differ. Despite marked elevation, no correlation was observed between neutrophil count and circulating sCD40L in AMI. Interestingly, we observed a strong and positive significant correlation between neutrophil count and circulating sCD40L level (r = 0.607, P = 0.002) in unstable angina. Circulating sCD40L is associated with neutrophil count and may mediate interaction between neutrophils and platelets in acute coronary syndrome, particularly in unstable angina.

Endothelial cell-derived endothelin-1 promotes cardiac fibrosis in diabetic hearts through stimulation of endothelial-to-mesenchymal transition.

BACKGROUND: Persistently high plasma endothelin-1 (ET-1) levels in diabetic patients have been associated with the development of cardiac fibrosis, which results from the deposition of extracellular matrix and fibroblast recruitment from an as-yet unknown source. The underlying mechanism, however, remains elusive. Here, we hypothesize that ET-1 might contribute to the accumulation of cardiac fibroblasts through an endothelial-to-mesenchymal transition in diabetic hearts. METHODS AND RESULTS: We induced diabetes mellitus in vascular endothelial cell-specific ET-1 knockout [ET-1(f/f);Tie2-Cre (+)] mice and their wild-type littermates using the toxin streptozotocin. Gene expression and histological and functional parameters were examined at 8, 24, and 36 weeks after the induction of diabetes mellitus. Diabetes mellitus increased cardiac ET-1 expression in wild-type mice, leading to mitochondrial disruption and myofibril disarray through the generation of superoxide. Diabetic mice also showed impairment of cardiac microvascularization and a decrease in cardiac vascular endothelial growth factor expression. ET-1 further promotes cardiac fibrosis and heart failure through the accumulation of fibroblasts via endothelial-to-mesenchymal transition. All of these features were abolished in ET-1(f/f);Tie2-Cre (+) hearts. Targeted ET-1 gene silencing by small interfering RNA in cultured human endothelial cells ameliorated high glucose-induced phenotypic transition and acquisition of a fibroblast marker through the inhibition of transforming growth factor-beta signaling activation and preservation of the endothelial cell-to-cell contact regulator VE-cadherin. CONCLUSIONS: These results provide new insights suggesting that diabetes mellitus-induced cardiac fibrosis is associated with the emergence of fibroblasts from endothelial cells and that this endothelial-to-mesenchymal transition process is stimulated by ET-1. Targeting endothelial cell-derived ET-1 might be beneficial in the prevention of diabetic cardiomyopathy.

Vascular endothelial cell-derived endothelin-1 mediates vascular inflammation and neointima formation following blood flow cessation.

AIMS: Although endothelin-1 (ET-1) has been suggested to contribute to the pathogenesis of neointima formation and atherosclerosis, the individual roles of ET-1 derived from certain cell types in this disease remain unclear. In this study, we determined the role of vascular endothelial ET-1 on vascular inflammation and neointima formation using vascular endothelial ET-1-knockout [ET-1(f/f); Tie2-Cre (+)] mice. METHODS AND RESULTS: Intimal hyperplasia was induced by complete ligation of the left carotid artery in 12-week-old male ET-1(f/f);Tie2-Cre (+) mice (n = 35) and the wild-type (WT) littermates (n = 34). Following this intervention, neointima formation was reduced in ET-1(f/f);Tie2-Cre (+) mice compared with the WT mice, independent of the difference in blood pressure. This reduction was associated with a decrease in inflammatory cell recruitment to the vessel wall, which was accompanied by reduced expression levels of endothelial adhesion molecules as well as chemokines and a decrease in vascular smooth muscle cell proliferation. CONCLUSION: The results of our study provide direct evidence for the role of vascular endothelial ET-1 in mediating vascular inflammation and neointima formation following vascular injury in addition to promoting vasoconstriction and cell proliferation. Furthermore, this study suggests a strategy for the efficient design of ET receptor antagonists with targeted inhibition of ET-1 signalling in vascular endothelial cells.