Introduction: Cardiac immune-related adverse events (irAEs) from PD-1-targeting immune check-point inhibitors (ICIs) are an increasing concern due to their high mortality rate. Collagen plays a crucial role in maintaining cardiac structure, elasticity, and signal transduction; however, the effects and mechanisms of PD-1 inhibitor on cardiac collagen remodeling remain poorly understood.Methods: C57BL/6 mice were injected with anti-mouse PD-1 antibody to create a PD-1 inhibitor-treated model. Cardiac function was measured by echocardiography, and collagen distribution was analyzed with Masson’s trichrome staining and Sirius Red staining. Single-nucleus RNA sequencing was performed to examine the effects of PD-1 inhibition on gene expression in cardiac fibroblasts (CFs) and endothelial cells (ECs). EC-CF crosstalk was assessed using co-culture experiments and ELISA. ChIP assay was performed to analyze the regulation of TCF12 on TGF-β1 promoter. Western blot, qRT-PCR, and immunofluorescence staining were used to detect the expression of TCF12, TGF-β1, and endothelial-to-mesenchymal transition (EndMT) markers. Reactive oxygen species (ROS) levels were evaluated by DHE staining, MDA content, and SOD activity assays.Results: We report a newly discovered cardiotoxic effect of PD-1 inhibitor, which causes aberrant collagen distribution in the heart, marked by a decrease in interstitial collagen and an increase in perivascular collagen deposition. Mechanistically, PD-1 inhibitor does not directly affect CFs but instead impact them through EC-CF crosstalk. PD-1 inhibitor reduces TGF-β1 secretion in ECs by downregulating TCF12, which we identify as a transcriptional promoter of TGF-β1. This subsequently decreases CF activity, leading to reduced interstitial collagen deposition. Additionally, PD-1 inhibitor induces EndMT, increasing perivascular collagen deposition. The endothelial dysfunction induced by PD-1 inhibitor results from ROS accumulation in ECs. Inhibiting ROS with N-acetylcysteine (NAC) preserves normal collagen distribution and cardiac function in PD-1 inhibitor-treated mice by reversing TCF12 downregulation and EndMT in ECs.Conclusion: Our results suggest that PD-1 inhibitor causes ROS accumulation in cardiac ECs, leading to imbalanced collagen distribution (decrease in interstitial collagen and increase in perivascular collagen) in the heart by modulating TCF12/TGF-β1-mediated EC-CF crosstalk and EndMT. NAC supplementation could be an effective clinical strategy to mitigate PD-1 inhibitor-induced imbalanced collagen distribution and cardiac dysfunction.

Chronic alcohol intake contributes to high mortality rates due to ethanol-induced cardiac hypertrophy and contractile dysfunction, which are accompanied by increased oxidative stress and disrupted mitophagy. Alpha-lipoic acid (α-LA), a well-known antioxidant, has been shown to protect against cardiac hypertrophy and inflammation. However, little is known about its role and mechanism in the treatment of alcoholic cardiomyopathy. Here, we evaluated the role of α-LA in alcohol-induced cardiac damage by feeding mice a 4.8% (v/v) alcohol diet with or without α-LA for 6 w. Our results suggested that chronic alcohol consumption increased mortality, blood alcohol concentrations, and serum aldehyde levels, but a-LA attenuated the elevations in mortality and aldehydes. Chronic alcohol intake also induced cardiac dysfunction, including enlarged left ventricles, reduced left ventricular ejection fraction, enhanced cardiomyocyte size, and increased serum levels of brain natriuretic peptide, lactate dehydrogenase, and creatine kinase myocardial isoenzyme. Moreover, alcohol intake led to the accumulation of collagen fiber and mitochondrial dysfunction, the effects of which were alleviated by α-LA. In addition, α-LA intake also prevented the increase in reactive oxygen species production and the decrease in mitochondrial number that were observed after alcohol consumption. Chronic alcohol exposure activated PINK1/Parkin-mediated mitophagy. These effects were diminished by α-LA intake by the activation of aldehyde dehydrogenase 2. Our data indicated that α-LA helps protect cardiac cells against the effects of chronic alcohol intake, likely by inhibiting PINK1/Parkin-related mitophagy through the activation of aldehyde dehydrogenase 2.

Objectives Identifying high-risk paediatric patients with a poor prognosis and providing timely and adequate treatment are critical. This study aimed to evaluate the effects of different types of cardiac enzyme spectrum within 24 hours of admission on the short-term prognosis of patients in paediatric intensive care units. Design A retrospective study. Setting A single-centre, tertiary care hospital in China, with patient data from 2010 to 2018. Participants A total of 4343 critically ill children were enrolled. Intervention None. Primary and secondary outcome measures The main outcome measure was in-hospital mortality, which was defined as death from any cause during hospitalisation. The secondary outcome was 30-day mortality, intensive care unit (ICU) length of stay (LOS) and total LOS. Results Using the local polynomial regression fitting method, an approximately linear increase in in-hospital mortality was detected for creatine kinase (CK), creatine kinase MB (CK-MB), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH). Among the different types of cardiac enzyme spectrum, LDH had the highest area under the curve value (0.729), followed by AST (0.701), CK-MB (0.613) and CK (0.557). The Kaplan‒Meier analysis showed that the patients in the high LDH group had higher 30-day mortality. The multivariate logistic regression revealed that high LDH was independently associated with in-hospital mortality (OR 2.45, 95% CI 1.84 to 3.24). After propensity score matching (PSM) and sensitivity analysis, the results remained consistent. Conclusions LDH is a reliable outcome predictor in critically ill children, including those with various comorbidities.

Background: Which patients with coronary artery disease (CAD) should have oral nitrates on their discharge medication list after coronary angiography (CAG)? To assess the relationship between oral nitrates included in the discharge medication list and major adverse cardiovascular events (MACEs) among CAD patients, we designed this retrospective cohort study.Methods: A total of 2979 CAD patients hospitalised in the Department of Cardiology, Affiliated Hospital of Jining Medical University from May 2013 to October 2015 were enrolled, grouped according to whether oral nitrates were included at discharge after CAG, and followed up for MACEs for a mean of 4.42 years after discharge. The primary endpoint was MACEs. Multivariate Cox proportional hazards models were used to analyses potential confounding factors. Stratified analysis was used to observe the relationship between oral nitrates and MACEs by different covariates.Results: The median follow-up time was 4.61 years, and 296 (9.94%) patients experienced MACEs. Multivariate Cox proportional hazards model analysis showed no association between oral nitrates on the discharge medication list and the occurrence of MACEs among patients with CAD (p > 0.05) after adjusting for some covariates, such as SYNTAX score (hazard ratio (HR): 1.18, 95% confidence interval (CI): 0.90-1.55, p = 0.2420). Stratified analysis revealed a higher incidence of MACEs among hypertensive patients prescribed oral nitrates at discharge (HR: 1.67, 95% confidence CI: 1.13-2.46, p = 0.0046). However, prescribing nitrates at discharge for patients with low uric acid levels increased the incidence of MACEs, which showed a possible trend towards significance (HR: 1.44, 95% CI: 0.99-2.09, p = 0.0525)Conclusion: There was no association between oral nitrates included in the discharge medication list and the development of MACEs among patients with CAD after adjusting for some covariates, such as SYNTAX score. Oral nitrates after discharge for CAD patients combined with hypertension increased the occurrence of MACEs. Oral nitrates after discharge for CAD patients combined with low uric acid levels may increase theoccurrence of MACEs, and close monitoring for any adverse events is recommended.

Background: Obesity is an independent factor for cardiovascular diseases, impacting health across different age groups. cardiovascular magnetic resonance (CMR) imaging is considered the gold standard for noninvasive assessment of cardiovascular structure and function. We conducted a Mendelian randomization (MR) study to explore the associations between obesity-related traits and the clinical pre-phenotype of cardiac and aortic structure and function. Methods: Independent genetic variations significantly correlated with adult body mass index, adult waist-to-hip ratio, birth weight, child body mass index, and excess visceral fat were selected as instrumental variables. Eighty-two CMR imaging features were obtained from the UK Biobank Genome-Wide Association Study. These features served as clinical pre-phenotypes, providing early indications of the structure and function of the 4 cardiac chambers and 2 aortic slices. Preliminary analyses were conducted using MR and inverse variance-weighted methods. Causal directions were determined through Steiger filtering and testing, achieving confirmation. Sensitivity analyses were performed using weighted median, MR-Egger, and MR-PRESSO methods. Results: Adult BMI was positively correlated with left ventricular end-systolic volume, right ventricular end-diastolic volume, right ventricular end-systolic volume, and right ventricular volume per beat. The adult waist-to-hip ratio was inversely proportional to right atrial volume per beat, right atrial maximum volume, right atrial minimum volume, partial regional longitudinal strain, regional peak circumferential strain, and regional radial strain, and positively proportional to partial regional peak circumferential strain and partial end-diastolic local myocardial wall thickness characteristics. Birth weight was positively correlated with maximum right atrial volume, minimum right atrial volume, right atrial volume per beat, right ventricular end-diastolic volume, right ventricular output per beat, maximum area of the ascending aorta, minimum area of the ascending aorta, and negatively correlated with longitudinal strain in some regions. Body mass index in children is positively correlated with left ventricular end-diastolic volume, left ventricular end-systolic volume, left atrial volume per beat, right ventricular end-diastolic volume, and right ventricular volume per beat. Conclusion: This study suggests that obesity may lead to myocardial hypertrophy and dilation of the cardiac chambers and aorta, thereby exerting adverse effects on the cardiovascular system and increasing the susceptibility to HF.

Background: Acute myocardial infarction (AMI) is a critical and fatal cardiovascular condition. The role of cuproptosis as an emerging mechanism in the pathogenesis of AMI remains to be fully elucidated. Methods: Patient data were acquired from the Gene Expression Omnibus database. Differential expression analysis was performed on cuproptosis-related genes (CRGs). LASSO regression was employed to identify key CRGs and develop a diagnostic classification model for AMI. Weighted gene co-expression network analysis was performed to investigate key modules associated with the disease and its molecular classification. Subsequently, machine learning techniques were used to identify critical genes within these modules. The diagnostic efficacy of these genes for AMI was assessed using receiver operating characteristic analysis. The functions of the identified key genes were ultimately validated at the cellular level. Results: Six characteristic CRGs were selected via LASSO regression. The AMI diagnostic classification model based on these CRGs demonstrated superior performance. Patients were classified into two subtypes related to cuproptosis, revealing significant differences in enrichment pathways between these subtypes. SYTL3, SCML1, and PMAIP1 were identified as key genes for AMI, with area under the curves of 0.813, 0.795, and 0.873, respectively. Knocking down PMAIP1 expression reduced intracellular copper levels in hypoxia-induced HUVECs. Conclusions: This study clarifies the role of cuproptosis in AMI and highlights the potential involvement of PMAIP1, providing a theoretical basis for further investigation into cuproptosis in AMI.