Aims: Mitochondrial homeostasis is essential for maintaining redox balance. Besides canonical autophagy, Rab9-dependent alternative autophagy is a crucial mechanism in metabolic cardiomyopathy. Here, we aim to investigate the role of alternative mitophagy and Beclin 1 haploinsufficiency (Beclin 1(+/-)) in high-fat diet (HFD)-induced metabolic cardiomyopathy. Results: Twenty-four-week HFD impaired glucose tolerance and cardiomyocyte contraction in wild-type mice, both of which were rescued in Beclin 1(+/-) mice. Beclin 1 haploinsufficiency had little effect on the conventional autophagy mediators (ATG5, LC3 II/LC3 I) but further upregulated Rab9 expression, a marker of alternative autophagy, in response to HFD challenge. Furthermore, either the inhibition of alternative autophagy or Beclin 1 haploinsufficiency abolished palmitic acid (PA)-induced cardiomyocyte contractile anomalies. In vitro, PA overactivated mitophagy, resulting in decreased mitochondrial content in H9C2 cells. These aberrations were alleviated in cells deficient in alternative autophagy but not in cells deficient in conventional autophagy. Mechanistically, HFD promoted reactive oxygen species (ROS) production, activated Rab9-dependent alternative mitophagy, and inhibited mitochondrial biosynthesis. Beclin 1(+/-) rescued HFD-induced ROS overflow, mitochondrial biogenesis impairment, and prevented Rab9 translocation from the cytoplasm to the mitochondria, thereby inhibiting Rab9-mediated mitophagy overactivation. Innovation: For the first time, this study suggests that prolonged alternative mitophagy exacerbates chronic HFD-induced cardiac dysfunction and supports the protective role of Beclin 1 haploinsufficiency in metabolic cardiomyopathy. This provides additional evidence for a target-based pharmacological intervention. Conclusion: Beclin 1 haploinsufficiency protects against HFD-induced cardiac dysfunction by inhibiting Rab9-dependent alternative mitophagy and ROS production, while promoting mitochondrial biogenesis. Modulating Beclin 1 expression holds promise in preventing chronic HFD-related cardiomyopathy.

BackgroundThe timing of central venous pressure (CVP) measurement may play a crucial role in heart failure management, yet no studies have explored this aspect.MethodsClinical information pertaining to patients in critical condition with a diagnosis of heart failure was retrieved from the MIMIC-IV database. The association between initial measurements of central venous pressure (CVP) and the incidence of mortality from all causes was analyzed using the Cox proportional hazards approach. Subgroup analysis and propensity score matching were conducted for sensitivity analyses.ResultsThis study included 11,241 participants (median age, 75 years; 44.70 % female). Utilizing restricted cubic spline and Kaplan–Meier survival analyses, it was determined that prognostic outcomes were better when CVP was measured within the initial 5-h window. Multivariate-adjusted 1-year (HR: 0.69; 95 % CI: 0.61–0.77), 90-day (HR: 0.70; 95 % CI: 0.62–0.80), and 30-day (HR: 0.67; 95 % CI: 0.57–0.78) all-cause mortalities were significantly lower in patients with early CVP measurement, which was proved robustly in subgroup analysis. Subsequent to the application of propensity score matching, a cohort of 1536 matched pairs was established, with the observed mortality rates continuing to be significantly lower among participants who underwent early CVP assessment.ConclusionsEarly CVP measurement (within 5 h) demonstrated an independent correlation with a decrease in both immediate and extended all-cause mortality rates among patients in critical condition suffering from heart failure.

Pulmonary arterial hypertension (PAH) is a progressive cardiopulmonary disease with unclear underlying molecular mechanisms and limited therapeutic options. This study aimed to explore the role of core fucosylation and the only glycosyltransferase FUT8 in PAH. We observed increased core fucosylation in a monocrotaline (MCT)-induced PAH rat model and isolated rat pulmonary artery smooth muscle cells (PASMCs) treated with platelet-derived growth factor-BB (PDGF-BB). We found that 2-fluorofucose (2FF), a drug used to inhibit core fucosylation, improved hemodynamics and pulmonary vascular remodeling in MCT-induced PAH rats. In vitro, 2FF effectively restrains the proliferation, migration, and phenotypic switching of PASMCs and promotes apoptosis. Compared with controls, serum FUT8 concentration in PAH patients and MCT-induced rats was significantly elevated. FUT8 expression appeared increased in the lung tissues of PAH rats, and the co-localization of FUT8 with α-SMA was also observed. SiRNA was used to knockdown FUT8 in PASMCs (siFUT8). After effectively silencing FUT8 expression, phenotypic changes induced in PASMCs by PDGF-BB stimulation were alleviated. FUT8 activated the AKT pathway, while the admission of AKT activator SC79 could partially counteract the negative effect of siFUT8 on the proliferation, apoptotic resistance, and phenotypic switching of PASMCs, which may be involved in the core fucosylation of vascular endothelial growth factor receptor (VEGFR). Our research confirmed the critical role of FUT8 and its mediated core fucosylation in pulmonary vascular remodeling in PAH, providing a potential novel therapeutic target for PAH.

BackgroundPulmonary arterial hypertension (PAH) associated with connective tissue disease (CTD) belongs to Group 1 pulmonary hypertension. Pulmonary veno-occlusive disease (PVOD), which is characterized by venous system aberrations, has been previously reported in CTD-PAH; however, it has rarely been observed in Sjogren's syndrome (SS).Case presentationOur 28-year-old female patient was admitted to the hospital with recurrent shortness of breath even after minimal physical activity. Her chest high-resolution CT scan demonstrated pulmonary artery dilatation and bilateral ground-glass nodules. A subsequent right heart catheterization confirmed pulmonary hypertension because her mean pulmonary arterial pressure was 62 mmHg. Our inquisitive genomic assessment identified a novel EIF2AK4 mutation at c.1021 C > T (p. Gln341*), the dominant causal gene of PVOD. Histological examination demonstrated stenosis and occlusions in the pulmonary veins. Because she presented with features such as dry eyes and Raynaud's phenomenon, we performed a biopsy on the labial salivary gland, which confirmed SS. Her treatment regimen included PAH-targeted therapies (tadalafil and macitentan) in combination with hydroxychloroquine. Although she was hospitalized several times due to acute exacerbation of PAH, her disease progression was under control, and she did not demonstrate any signs of pulmonary edema even after a three-year treatment period.ConclusionHere, we report the case of an SS-PAH patient with PVOD who carried a novel biallelic EIF2AK4 mutation, and PAH-targeted therapies were well tolerated by our patient.

AbstractBackground Systemic immune-inflammation index (SII) is a novel inflammatory-related biomarker, and we aim to explore whether it can predict the poor prognosis of patients with aortic stenosis (AS). Methods The detailed data of patients with AS were extracted from the MIMIC-IV database. Restricted cubic spline (RCS) and COX regression analyses were used to reveal the potential association between SII and all-cause mortalities. Propensity score matching (PSM), inverse probability of treatment weighting (IPTW), and subgroup analyses were conducted to validate our findings. Receiver operating characteristic (ROC) analysis was performed to assess the performance of SII prognostic model. Results 839 patients were included in the study cohort. RCS analysis elucidated that the death risk of patients was gradually elevated with the increase of SII. Multivariate-adjusted 30-day (HR: 2.130; 95% CI: 1.167–3.885), 90-day (HR:1.644; 95% CI: 1.059–2.552) and 1-year (HR: 1.634; 95% CI: 1.136–2.350) all-cause mortalities were significantly higher in patients with high SII, which remained robust after PSM, IPTW, and subgroup analyses. The area under the ROC curve of SII (AUC: 0.727; 95% CI: 0.683–0.771) was superior to that of SOFA (AUC: 0.577; 95% CI: 0.525–0.629) and SAPSII (AUC: 0.681; 95% CI: 0.638–0.724) scores. Conclusion For patients with AS, SII was an independent predictor of elevated short-and long-term all-cause mortalities, with good predictive capability.

BackgroundCardiac arrest (CA) can activate blood coagulation. This study aimed to explore the potential prognostic value of prothrombin time–international normalized ratio (INR) in post-CA patients.MethodsThe clinical data of eligible subjects diagnosed with CA was extracted from the MIMIC-IV database as the training cohort. Restricted cubic spline (RCS), Kaplan–Meier (K-M) survival curve, and Cox regression analyses were conducted to elucidate the association between the INR and all-cause mortality of post-CA patients. Subgroup analysis, propensity score matching (PSM), and inverse probability of treatment (IPTW) were also conducted to improve stability and reliability. Data of the validation cohort were collected from the eICU database, and logistic-regression analyses were performed to verify the findings of the training cohort.ResultsA total of 1,324 subjects were included in the training cohort. A linear correlation existed between INR and the risk of all-cause death of post-CA patients, as shown in RCS analysis, with a hazard ratio (HR) >1 when INR exceeded 1.2. K-M survival curve preliminarily indicated that subjects with INR ≥ 1.2 presented lower survival rate and shorter survival time, and the high level of INR was independently associated with 30-day, 90-day, 1-year, and in-hospital mortalities, with multivariate-adjusted HR of 1.44 (1.20, 1.73), 1.46 (1.23, 1.74), 1.44 (1.23, 1.69), and 1.37 (1.14, 1.64), respectively. These findings were consistent and robust across the subgroup analysis, PSM and IPTW analyses, and validation cohort.ConclusionsWe systematically and comprehensively demonstrated that elevated INR was associated with increased short- and long-term all-cause mortality of post-CA patients. Therefore, elevated INR may be a promising biomarker with prognosis significance.

BackgroundSystemic Immune-Inflammation Index (SII), known as an easy, economical and useful marker, correlates with the severity of inflammatory response. However, the usefulness of SII in necrotizing enterocolitis (NEC) remains unclear. Therefore, we evaluated the correlation of SII at NEC diagnosis and subsequent surgery.MethodsRetrospective review of 131 neonates with NEC in a tertiary-level pediatric referral hospital was conducted with assessments of demographic data, general blood examination results at NEC diagnosis, treatment strategies and clinical outcomes. The receiver operating characteristic (ROC) curve determined the optimal cut-off values of SII, platelet-to-lymphocyte ratio (PLR), and neutrophil-to-lymphocyte ratio. Univariate/multivariate logistic regression analysis and ROC curve were conducted to evaluate the predictive significance of SII in identifying the patients who eventually received surgery. Additionally, NEC-related deaths were assessed.ResultsOverall, 49 (37.4%) cases received surgical intervention and mortality was 12.3% (14/131). The area under ROC curve of SII at NEC diagnosis to predict subsequent surgery was 0.833 (optimal cut-off value: 235.85). The SII value in surgical intervention group was significantly higher than that in medical treatment group (332.92 ± 158.52 vs. 158.84 ± 106.82, P < 0.001). Independent influencing factors for surgical NEC were SII (95% confidence interval [CI]: 4.568∼36.449, odds ratio [OR]:12.904, P < 0.001) and PLR (95% CI: 1.071∼7.356, OR:2.807, P = 0.036). SII ≤ 235.85 could identify patients at high risk for surgery, with 87.76% sensitivity, 73.17% specificity, outperformed PLR. Furthermore, mortality was significantly higher in patients with SII ≤ 235.85 than those with SII > 235.85 (20.0% vs. 1.5%, P < 0.001).ConclusionSII and PLR at NEC diagnosis were independent influencing factors for subsequent surgery. SII ≤ 235.85 may be a useful predictive marker for the identification of surgical NEC and mortality.

Purpose It has been shown that abnormalities of coagulation and fibrinolysis system are involved in the pathogenesis of necrotizing enterocolitis (NEC), but not well studied challenge in the context of early detection of disease progression. The present study mainly explores the predictive significance of coagulation parameters at the time of NEC diagnosis in identifying the patients who eventually received surgery and/or NEC-related deaths. Methods The retrospective study of 114 neonates with NEC was conducted with assessments of demographic data, laboratory results at the time of NEC diagnosis, treatment methods and prognosis. According to treatment methods, patients were divided into surgical intervention group and medical treatment group. Predictive factors were put forward and determined by receiver operating characteristic (ROC) curve analysis. An analysis of the surgical intervention and prognosis was performed. Results Of 114 patients, 46 (40.4%) cases received surgical intervention and 14 (12.3%) deaths. prothrombin time (PT), PT international normalized ratio, activated partial thromboplastin time (APTT), fibrinogen and platelet count at the time of NEC diagnosis were independently associated with surgical NEC. The APTT could identify patients at high risk for surgical NEC, with 67.39% sensitivity, 86.76% specificity, better than that of other serological parameters. Coagulopathy was found in 38.6% of all patients. For surgical intervention, the area under the ROC curve (AUC) of coagulopathy was 0.869 (95% confidence interval [CI]: 0.794 ~ 0.944, P < 0.001), with 82.61% sensitivity and 91.18% specificity, outperformed APTT (95% CI: 0.236 ~ 0.173, P = 0.001). Furthermore, the AUC for coagulopathy to predict mortality was 0.809 (95% CI: 0.725 ~ 0.877, P < 0.001), with 92.86% sensitivity and 69.0% specificity. Conclusion Coagulation parameters at the time of NEC diagnosis were conducive to early prediction of surgical NEC and -related deaths, which should be closely monitored in neonates at high risk of NEC and validated as a clinical decision-making tool.

Purpose Coagulation disorder in congestive heart failure (CHF) has been well-documented. The prognostic value of a composite coagulation disorder score, which combines the absolute platelet count, international normalized ratio (INR), and activated partial thromboplastin time (APTT), has not been assessed in CHF. The present study endeavored to explore the association between the coagulation disorder score and adverse outcomes of critically ill patients with CHF. Methods Patients diagnosed with CHF in the Medical Information Mart for Intensive Care III (MIMIC-III) database were included in the present retrospective cohort study. The coagulation disorder score was calculated according to the abnormalities of the absolute platelet count, INR, and APTT within 24 h after intensive care unit admission. The primary outcomes were the short-term all-cause mortality, including 30-, 90-day and in-hospital mortalities. The Kaplan–Meier (K-M) survival curve and the Cox proportional hazard model were performed to assess the correlation between coagulation disorder score and outcome events. Results A total of 6,895 patients were enrolled in this study and divided into four groups according to the coagulation disorder score. K-M survival curve preliminarily indicated that subjects with higher coagulation disorder score presented lower survival rate and shorter survival time. After adjustment for potential confounders, the multivariate Cox analysis further illustrated that elevated coagulation disorder score as a quartile variable was significantly associated with increased all-cause mortality (quartile 4 vs. quartile 1, 30-day: HR [95% CI], 1.98 [1.50, 2.62], 90-day: HR [95% CI], 1.88 [1.49, 2.37], in-hospital: HR [95%CI], 1.93 [1.42, 2.61]). Conclusion In critically ill patients with CHF, ones with high coagulation disorder score tend to be worse clinical prognosis, which would be a promising biomarker and helpful for the management of CHF patients.