Dataset Information

Congenital heart disease-associated pulmonary dysplasia and its underlying mechanisms.

ABSTRACT: Clinical observation indicates that exercise capacity, an important determinant of survival in patients with congenital heart disease (CHD), is most decreased in children with reduced pulmonary blood flow (RPF). However, the underlying mechanism remains unclear. Here, we obtained human RPF lung samples from children with tetralogy of Fallot as well as piglet and rat RPF lung samples from animals with pulmonary artery banding surgery. We observed impaired alveolarization and vascularization, the main characteristics of pulmonary dysplasia, in the lungs of RPF infants, piglets, and rats. RPF caused smaller lungs, cyanosis, and body weight loss in neonatal rats and reduced the number of alveolar type 2 cells. RNA sequencing demonstrated that RPF induced the downregulation of metabolism and migration, a key biological process of late alveolar development, and the upregulation of immune response, which was confirmed by flow cytometry and cytokine detection. In addition, the immunosuppressant cyclosporine A rescued pulmonary dysplasia and increased the expression of the Wnt signaling pathway, which is the driver of postnatal lung development. We concluded that RPF results in pulmonary dysplasia, which may account for the reduced exercise capacity of patients with CHD with RPF. The underlying mechanism is associated with immune response activation, and immunosuppressants have a therapeutic effect in CHD-associated pulmonary dysplasia.

SUBMITTER: Li DB

PROVIDER: S-EPMC9925164 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Congenital heart disease-associated pulmonary dysplasia and its underlying mechanisms.

Li De-Bao DB Xu Xiu-Xia XX Hu Yu-Qing YQ Cui Qing Q Xiao Ying-Ying YY Sun Si-Juan SJ Chen Li-Jun LJ Ye Lin-Cai LC Sun Qi Q

American journal of physiology. Lung cellular and molecular physiology 20221206 2

Clinical observation indicates that exercise capacity, an important determinant of survival in patients with congenital heart disease (CHD), is most decreased in children with reduced pulmonary blood flow (RPF). However, the underlying mechanism remains unclear. Here, we obtained human RPF lung samples from children with tetralogy of Fallot as well as piglet and rat RPF lung samples from animals with pulmonary artery banding surgery. We observed impaired alveolarization and vascularization, the ...[more]

PMID: 36472329

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Project description:ObjectivesThe purposes of this study were to determine why chronic obstructive pulmonary disease (COPD) is associated with heart failure (HF). Specific objectives included whether COPD is associated with myocardial fibrosis, whether myocardial fibrosis is associated with hospitalization for HF and death in COPD, and whether COPD and smoking are associated with myocardial inflammation.BackgroundCOPD is associated with HF independent of shared risk factors. The underlying pathophysiological mechanism is unknown.MethodsA prospective, multicenter, longitudinal cohort study of 572 patients undergoing cardiac magnetic resonance (CMR), including 450 patients with COPD and 122 age- and sex-matched patients with a median: 726 days (interquartile range: 492 to 1,160 days) follow-up. Multivariate analysis was used to examine the relationship between COPD and myocardial fibrosis, measured using cardiac magnetic resonance (CMR). Cox regression analysis was used to examine the relationship between myocardial fibrosis and outcomes; the primary endpoint was composite of hospitalizations for HF or all-cause mortality; secondary endpoints included hospitalizations for HF and all-cause mortality. Fifteen patients with COPD, 15 current smokers, and 15 healthy volunteers underwent evaluation for myocardial inflammation, including ultrasmall superparamagnetic particles of iron oxide CMR.ResultsCOPD was independently associated with myocardial fibrosis (p < 0.001). Myocardial fibrosis was independently associated with the primary outcome (hazard ratio [HR]: 1.14; 95% confidence interval [CI]: 1.08 to 1.20; p < 0.001), hospitalization for HF (HR: 1.25 [95% CI: 1.14 to 1.36]); p < 0.001), and all-cause mortality. Myocardial fibrosis was associated with outcome measurements more strongly than any other variable. Acute and stable COPD were associated with myocardial inflammation.ConclusionsThe associations between COPD, myocardial inflammation and myocardial fibrosis, and the independent prognostic value of myocardial fibrosis elucidate a potential pathophysiological link between COPD and HF.

Project description:With improved survival rates among congenital heart disease (CHD) patients, pulmonary arterial hypertension (PAH) linked to CHD becomes more prevalent in both children and adults. PAH remains a significant contributor to morbidity and mortality in this population. Although genome-wide association studies (GWAS) have identified potential genetic variants with PAH risk and prognosis, the identification of circulating biomarkers with causal roles in CHD-PAH remains unclear. We employed the summary data-based Mendelian randomization (SMR) method, integrating expression profile data from the Gene Expression Omnibus (GEO) database related to CHD-PAH. This approach aimed to pinpoint genes causally associated with risk of CHD-PAH. We used a two-sample Mendelian randomization (MR) approach to efficiently screen for circulating proteins affecting CHD-PAH, leveraging publicly available genetic data from the UK biobank Pharma Proteomics Project (UKB-PPP) (54,219 UKB participants). Genetic determinants (cis-SNPs) of circulating proteins were used as instruments, and MR analyses assessed the influence of these proteins on CHD-PAH susceptibility in the largest PAH GWAS (2085 cases and 9659 controls). We conducted colocalization analyses to ensure shared genetic signals between circulating proteins and PAH and performed immune cell infiltration analysis to understand immune regulatory mechanisms in CHD-PAH. We found that a 1 SD increase in circulating S100 calcium binding protein A3 (S100A3) levels correlated with a reduced PAH risk (OR: 0.073, 95% CI: 0.020-0.267; p = 0.00799). Sensitivity analyses including various cis-SNPs, provided consistent estimates for S100A3 (inverse variance weighted (IVW) OR: 0.085, 95% CI: 0.032-0.225; p = 7.5 × 10-7 and MR-Egger OR: 0.212, 95% CI: 0.013-3.376; p = 0.387). Colocalization analyses confirmed a shared genetic signal for S100A3 and PAH, with a posterior probability of 99.9%. Transcriptomic investigations further highlighted S100A3's protective role in CHD-PAH. Our study using SMR and GEO data identified S100A3 as a gene associated with a reduced risk of PAH in CHD patients. Elevated circulating levels of S100A3 were linked to a reduced PAH risk, and transcriptomic evidence further supported its protective function in CHD-PAH.

Dataset Information

Congenital heart disease-associated pulmonary dysplasia and its underlying mechanisms.

Publications

Congenital heart disease-associated pulmonary dysplasia and its underlying mechanisms.

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