Background Socioeconomic status ( SES ) is associated with health‐related quality of life ( HRQOL ) for children with critical congenital heart disease; however, literature from newly industrialized countries is scarce. Methods and Results This cross‐sectional study included 2037 surviving patients operated on for critical congenital heart disease at a tertiary hospital in China between May 2012 and December 2015. All eligible patients were aged 2 to 12 years. HRQOL was measured by the Pediatric Quality of Life Inventory 4.0 generic and 3.0 cardiac modules. Family SES was assessed by a composite of household income in the past year and occupation and education level of each parent in the family. Mean scores of major domains in HRQOL were significantly lower in the low‐ SES group than in the medium‐ and high‐ SES groups (total generic scores: 71.2±7.9 versus 75.0±8.0 and 76.0±7.9, respectively [ P <0.001]; psychosocial functioning: 70.8±9.0 versus 74.4±8.4 and 75.3±8.4 [ P <0.001]; physical functioning: 71.6±10.4 versus 76.0±9.7 and 77.1±9.4 [ P <0.001]; heart symptoms: 71.9±11.6 versus 75.7±11.0 and 76.8±10.3 [ P <0.001]; cognitive problems: 65.4±11.1 versus 69.4±12.1 and 74.6±13.6 [ P <0.001]). After adjustment for other clinical and demographic variables in the multivariable linear regression model, family SES significantly affected all dimensions of HRQOL except for treatment barriers, treatment anxiety, physical appearance and communication. Conclusions Family SES is an important factor associated with HRQOL in patients with critical congenital heart disease. Further targeted interventions to improve HRQOL that consider the family and environmental issues confronted by those who are economically disadvantaged might help these patients have better outcomes.

Objective— Pulmonary arterial hypertension is characterized by progressive pulmonary vascular remodeling and persistently elevated mean pulmonary artery pressures and pulmonary vascular resistance. We aimed to investigate whether transthoracic pulmonary artery denervation (TPADN) attenuated pulmonary artery (PA) remodeling, improved right ventricular (RV) function, and affected underlying mechanisms. We also explored the distributions of sympathetic nerves (SNs) around human PAs for clinical translation. Approach and Results— We identified numerous SNs in adipose and connective tissues around the main PA trunks and bifurcations in male Sprague Dawley rats, which were verified in samples from human heart transplant patients. Pulmonary arterial hypertensive rats were randomized into TPADN and sham groups. In the TPADN group, SNs around the PA trunk and bifurcation were completely and accurately removed under direct visualization. The sham group underwent thoracotomy. Hemodynamics, RV function, and pathological changes in PA and RV tissues were measured via right heart catheterization, cardiac magnetic resonance imaging, and pathological staining, respectively. Compared with the sham group, the TPADN group had lower mean pulmonary arterial pressures, less PA and RV remodeling, and improved RV function. Furthermore, TPADN inhibited neurohormonal overactivation of the sympathetic nervous system and renin-angiotensin-aldosterone system and regulated abnormal expressions and signaling of neurohormone receptors in local tissues. Conclusions— There are numerous SNs around the rat and human main PA trunks and bifurcations. TPADN completely and accurately removed the main SNs around PAs and attenuated pulmonary arterial hypertensive progression by inhibiting excessive activation of the sympathetic nervous system and renin-angiotensin-aldosterone system neurohormone-receptor axes.

Background: Cyanotic congenital heart disease (CCHD) is a complex pathophysiological condition involving systemic chronic hypoxia (CH). Some CCHD patients are unoperated due to various reasons and remain chronically hypoxic throughout their lives, which heightens the risk of heart failure as they age. Hypoxia activates cellular metabolic adaptation to balance energy demands by accumulating hypoxia-inducible factor 1-α (HIF-1α). This study aims to determine the effect of CH on cardiac metabolism and function in CCHD patients and its association with age. The role of HIF-1α in this process was investigated and potential therapeutic targets were explored. Methods: CCHD patients ( n = 25) were evaluated for cardiac metabolism and function using positron-emission tomography/computed tomography and magnetic resonance imaging. Heart tissue samples were subjected to metabolomic and protein analyses. CH rodent models were generated to enable continuous observation of changes in cardiac metabolism and function. The role of HIF-1α in cardiac metabolic adaptation to CH was investigated using genetically modified animals and isotope-labeled metabolomic-pathway tracing studies. Results: Prepubertal CCHD patients had glucose-dominant cardiac metabolism and normal cardiac function. By comparison, among patients who had entered puberty, the levels of myocardial glucose uptake and glycolytic intermediates were significantly decreased, but fatty acids were significantly increased, along with decreased left-ventricular ejection fraction. These clinical phenotypes were replicated in CH rodent models. In CCHD patients and animals exposed to CH, myocardial HIF-1α was upregulated prior to puberty, but was significantly downregulated during puberty. In cardiomyocyte-specific Hif-1α -knockout mice, CH failed to initiate the switch of myocardial substrates from fatty acids to glucose, thereby inhibiting ATP production and impairing cardiac function. Increased insulin resistance (IR) during puberty suppressed myocardial HIF-1α and was responsible for cardiac metabolic maladaptation in animals exposed to CH. Pioglitazone significantly reduced myocardial IR, restored glucose metabolism, and improved cardiac function in pubertal CH animals. Conclusions: In CCHD patients, maladaptation of cardiac metabolism occurred during puberty, along with impaired cardiac function. HIF-1α was identified as the key regulator of cardiac metabolic adaptation in animals exposed to CH, and pubertal IR could suppress its expression. Pioglitazone administration during puberty might help improve cardiac function in CCHD patients.

Background The early life gut microbiome is crucial in maintaining host metabolic and immune homeostasis. Though neonates with critical congenital heart disease (CCHD) are at substantial risks of malnutrition and immune imbalance, the microbial links to CCHD pathophysiology remain poorly understood. In this study, we aimed to investigate the gut microbiome in neonates with CCHD in association with metabolomic traits. Moreover, we explored the clinical implications of the host-microbe interactions in CCHD. Methods Deep metagenomic sequencing and metabolomic profiling of paired fecal samples from 45 neonates with CCHD and 50 healthy controls were performed. The characteristics of gut microbiome were investigated in three dimensions (microbial abundance, functionality, and genetic variation). An in-depth analysis of gut virome was conducted to elucidate the ecological interaction between gut viral and bacterial communities. Correlations between multilevel microbial features and fecal metabolites were determined using integrated association analysis. Finally, we conducted a subgroup analysis to examine whether the interactions between gut microbiota and metabolites could mediate inflammatory responses and poor surgical prognosis. Results Gut microbiota dysbiosis was observed in neonates with CCHD, characterized by the depletion of Bifidobacterium and overgrowth of Enterococcus, which was highly correlated with metabolomic perturbations. Genetic variations of Bifidobacterium and Enterococcus orchestrate the metabolomic perturbations in CCHD. A temperate core virome represented by Siphoviridae was identified to be implicated in shaping the gut bacterial composition by modifying microbial adaptation. The overgrowth of Enterococcus was correlated with systemic inflammation and poor surgical prognosis in subgroup analysis. Mediation analysis indicated that the overgrowth of Enterococcus could mediate gut barrier impairment and inflammatory responses in CCHD. Conclusions We demonstrate for the first time that an aberrant gut microbiome associated with metabolomic perturbations is implicated in immune imbalance and adverse clinical outcomes in neonates with CCHD. Our data support the importance of reconstituting optimal gut microbiome in maintaining host metabolic and immunological homeostasis in CCHD.