Our study indicates that the accumulation of 4-hydroxy-2-nonenal plays an important role in lung ischemia-reperfusion injury. Alda-1 pretreatment can attenuate lung ischemia-reperfusion injury, possibly through the activation of aldehyde dehydrogenase-2, which in turn removes 4-hydroxy-2-nonenal in human pulmonary alveolar epithelial cells. Alda-1 pretreatment has clinical implications to protect lungs during cardiopulmonary bypass.

Therapeutic hypothermia is commonly used during cardiopulmonary bypass (CPB) to protect the heart against myocardial injury in cardiac surgery. Patients who suffer from chronic hypoxia (CH), such as those with certain heart or lung conditions, are at high risk of severe myocardial injury after cardiac surgery, but the underlying mechanisms are unknown. This study tested whether CH attenuates hypothermic cardioprotection during CPB. Using a rat model of CPB, we found that hypothermic cardioprotection was impaired in CH rats but was preserved in normoxic rats. Cardiac proteomes showed that cold-inducible RNA binding protein (CIRBP) was significantly (P = 0.03) decreased in CH rats during CPB. Methylation analysis of neonatal rat cardiomyocytes under CH and myocardium specimens from patients with CH showed that CH induced hypermethylation of the Cirbp promoter region, resulting in its depression and failure to respond to cold stress. Cirbp-knockout rats showed attenuated hypothermic cardioprotection, whereas Cirbp-transgenic rats showed an enhanced response. Proteomics analysis revealed that the cardiac ubiquinone biosynthesis pathway was down-regulated during CPB in Cirbp-knockout rats, resulting in a significantly (P = 0.01) decreased concentration of ubiquinone (CoQ10). Consequently, cardiac oxidative stress was aggravated and adenosine 5′-triphosphate production was impaired, leading to increased myocardial injury during CPB. CoQ10-supplemented cardioplegic solution improved cardioprotection in rats exposed to CH, but its effect was limited in normoxic rats. Our study suggests that an individualized cardioprotection strategy should be used to fully compensate for the consequences of epigenetic modification of Cirbp in patients with CH who require therapeutic hypothermia.

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: Post-cardiac surgery patients exhibit a higher incidence of postoperative delirium (PD) compared to non-cardiac surgery patients. Patients with various cardiac diseases suffer from preoperative sleep disorder (SPD) induced by anxiety, depression, breathing disorder, or other factors. Objective: To examine the effect of sleep disorder on delirium in post-cardiac surgery patients. Methods: We prospectively selected 186 patients undergoing selective cardiac valve surgery. Preoperative sleep quality and cognitive function of all eligible participants were assessed through the Pittsburgh Sleep Quality Index (PSQI) and the Montreal Cognitive Assessment, respectively. The Confusion Assessment Method for Intensive Care Unit was used to assess PD from the first to seventh day postoperatively. Patients were divided into two groups according to the PD diagnosis: (1) No PD group and (2) the PD group. Results: Of 186 eligible patients, 29 (15.6%) were diagnosed with PD. A univariate analysis showed that gender (p = 0.040), age (p = 0.009), SPD (p = 0.008), intraoperative infusion volume (p = 0.034), postoperative intubation time (p = 0.001), and intensive care unit stay time (p = 0.009) were associated with PD. A multivariate logistic regression analysis demonstrated that age (odds ratio (OR): 1.106; p = 0.001) and SPD (OR: 3.223; p = 0.047) were independently associated with PD. A receiver operating characteristic curve demonstrated that preoperative PSQI was predictive of PD (area under curve: 0.706; 95% confidence interval: 0.595–0.816). A binomial logistic regression analysis showed that there was a significant association between preoperative 6 and 21 PSQI scores and PD incidence (p = 0.009). Conclusions: Preoperative SPD was significantly associated with PD and a main predictor of PD.