Carbonylation of Runx2 at K176 by 4-Hydroxynonenal Accelerates Vascular Calcification.

BACKGROUND: Vascular calcification, which is characterized by calcium deposition in arterial walls and the osteochondrogenic differentiation of vascular smooth muscle cells, is an actively regulated process that involves complex mechanisms. Vascular calcification is associated with increased cardiovascular adverse events. The role of 4-hydroxynonenal (4-HNE), which is the most abundant stable product of lipid peroxidation, in vascular calcification has been poorly investigated. METHODS: Serum was collected from patients with chronic kidney disease and controls, and the levels of 4-HNE and 8-iso-prostaglandin F2α were measured. Sections of coronary atherosclerotic plaques from donors were immunostained to analyze calcium deposition and 4-HNE. A total of 658 patients with coronary artery disease who received coronary computed tomography angiography were recruited to analyze the relationship between coronary calcification and the rs671 mutation in aldehyde dehydrogenase 2 (ALDH2). ALDH2 knockout (ALDH2-/-) mice, smooth muscle cell-specific ALDH2 knockout mice, ALDH2 transgenic mice, and their controls were used to establish vascular calcification models. Primary mouse aortic smooth muscle cells and human aortic smooth muscle cells were exposed to medium containing ß-glycerophosphate and CaCl2 to investigate cell calcification and the underlying molecular mechanisms. RESULTS: Elevated 4-HNE levels were observed in the serum of patients with chronic kidney disease and model mice and were detected in calcified artery sections by immunostaining. ALDH2 knockout or smooth muscle cell-specific ALDH2 knockout accelerated the development of vascular calcification in model mice, whereas overexpression or activation prevented mouse vascular calcification and the osteochondrogenic differentiation of vascular smooth muscle cells. In patients with coronary artery disease, patients with ALDH2 rs671 gene mutation developed more severe coronary calcification. 4-HNE promoted calcification of both mouse aortic smooth muscle cells and human aortic smooth muscle cells and their osteochondrogenic differentiation in vitro. 4-HNE increased the level of Runx2 (runt-related transcription factor-2), and the effect of 4-HNE on promoting vascular smooth muscle cell calcification was ablated when Runx2 was knocked down. Mutation of Runx2 at lysine 176 reduced its carbonylation and eliminated the 4-HNE-induced upregulation of Runx2. CONCLUSIONS: Our results suggest that 4-HNE increases Runx2 stabilization by directly carbonylating its K176 site and promotes vascular calcification. ALDH2 might be a potential target for the treatment of vascular calcification.

The role of periostin in cardiac fibrosis.

Cardiac fibrosis, which is the buildup of proteins in the connective tissues of the heart, can lead to end-stage extracellular matrix (ECM) remodeling and ultimately heart failure. Cardiac remodeling involves changes in gene expression in cardiac cells and ECM, which significantly leads to the morbidity and mortality in heart failure. However, despite extensive research, the elusive intricacies underlying cardiac fibrosis remain unidentified. Periostin, an extracellular matrix (ECM) protein of the fasciclin superfamily, acts as a scaffold for building complex architectures in the ECM, which improves intermolecular interactions and augments the mechanical properties of connective tissues. Recent research has shown that periostin not only contributes to normal ECM homeostasis in a healthy heart but also serves as a potent inducible regulator of cellular reorganization in cardiac fibrosis. Here, we reviewed the constitutive domain of periostin and its interaction with other ECM proteins. We have also discussed the critical pathophysiological functions of periostin in cardiac remodeling mechanisms, including two distinct yet potentially intertwined mechanisms. Furthermore, we will focus on the intrinsic complexities within periostin research, particularly surrounding the contentious issues observed in experimental findings.

Performance of CT-based deep learning in diagnostic assessment of suspicious lateral lymph nodes in papillary thyroid cancer: a prospective diagnostic study.

BACKGROUND: Preoperative evaluation of the metastasis status of lateral lymph nodes (LNs) in papillary thyroid cancer is challenging. Strategies for using deep learning to diagnosis of lateral LN metastasis require additional development and testing. This study aimed to build a deep learning-based model to distinguish benign lateral LNs from metastatic lateral LNs in papillary thyroid cancer and test the model's diagnostic performance in a real-world clinical setting. METHODS: This was a prospective diagnostic study. An ensemble model integrating a three-dimensional residual network algorithm with clinical risk factors available before surgery was developed based on computed tomography images of lateral LNs in an internal dataset and validated in two external datasets. The diagnostic performance of the ensemble model was tested and compared with the results of fine-needle aspiration (FNA) (used as the standard reference method) and the diagnoses made by two senior radiologists in 113 suspicious lateral LNs in patients enrolled prospectively. RESULTS: The area under the receiver operating characteristic curve of the ensemble model for diagnosing suspicious lateral LNs was 0.829 (95% CI: 0.732-0.927). The sensitivity and specificity of the ensemble model were 0.839 (95% CI: 0.762-0.916) and 0.769 (95% CI: 0.607-0.931), respectively. The diagnostic accuracy of the ensemble model was 82.3%. With FNA results as the criterion standard, the ensemble model had excellent diagnostic performance ( P =0.115), similar to that of the two senior radiologists ( P =1.000 and P =0.392, respectively). CONCLUSION: A three-dimensional residual network-based ensemble model was successfully developed for the diagnostic assessment of suspicious lateral LNs and achieved diagnostic performance similar to that of FNA and senior radiologists. The model appears promising for clinical application.

Efficacy and safety of intracoronary versus intravenous tirofiban in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention: A meta-analysis of randomized controlled trials.

Background: Effective antiplatelet therapy is critical for patients with ST-segment elevation myocardial infarction (STEMI) and receiving primary percutaneous coronary interventions (PPCI). Intracoronary (IC) and intravenous (IV) administration of tirofiban are commonly used during the procedure of PPCI. However, which is the better administration route of tirofiban have not been fully evaluated. Methods: A comprehensive literature search of RCTs that comparing IC with IV tirofiban in STEMI patients undergoing PPCI was conducted, which were published as of May 7, 2022, in PubMed, Embase, Cochrane Library, Web of Science, Scopus and ClinicalTrials.gov. The primary efficacy endpoint was 30-day major adverse cardiovascular events (MACE) and the primary safety endpoint was in-hospital bleeding events. Results: This meta-analysis included 9 trials involving 1177 patients. IC tirofiban significantly reduced the incidence of 30-day MACE (RR 0.65, 95% CI: 0.44 to 0.95, P = 0.028) and improved the rate of the thrombolysis in myocardial infarction (TIMI) grade 3 flow in high-dose (25 µg/kg) group (RR = 1.13, 95% CI: 0.99-1.30, P = 0.001), in-hospital (WMD 2.03, 95% CI: 1.03 to 3.02, P < 0.001), and 6-month left ventricular injection fraction (LVEF) (WMD 6.01, 95% CI: 5.02 to 6.99, P < 0.001) compared with IV. There was no significant difference in the incidences of in-hospital bleeding events (RR 0.96, 95% CI: 0.67 to 1.38, P = 0.82) and thrombocytopenia (RR 0.63, 95% CI: 0.26 to 1.57, P = 0.32) between the two groups. Conclusions: IC tirofiban significantly improved the incidence of TIMI 3 in the high-dose group, in-hospital and 6-month LVEF, and reduced the 30-day MACE incidence without increasing the risk of bleeding compared with IV.

The role of aldehyde dehydrogenase 2 in cardiovascular disease.

Aldehyde dehydrogenase 2 (ALDH2) is a mitochondrial enzyme involved in the detoxification of alcohol-derived acetaldehyde and endogenous aldehydes. The inactivating ALDH2 rs671 polymorphism, present in up to 8% of the global population and in up to 50% of the East Asian population, is associated with increased risk of cardiovascular conditions such as coronary artery disease, alcohol-induced cardiac dysfunction, pulmonary arterial hypertension, heart failure and drug-induced cardiotoxicity. Although numerous studies have attributed an accumulation of aldehydes (secondary to alcohol consumption, ischaemia or elevated oxidative stress) to an increased risk of cardiovascular disease (CVD), this accumulation alone does not explain the emerging protective role of ALDH2 rs671 against ageing-related cardiac dysfunction and the development of aortic aneurysm or dissection. ALDH2 can also modulate risk factors associated with atherosclerosis, such as cholesterol biosynthesis and HDL biogenesis in hepatocytes and foam cell formation and efferocytosis in macrophages, via non-enzymatic pathways. In this Review, we summarize the basic biology and the clinical relevance of the enzymatic and non-enzymatic, tissue-specific roles of ALDH2 in CVD, and discuss the future directions in the research and development of therapeutic strategies targeting ALDH2. A thorough understanding of the complex roles of ALDH2 in CVD will improve the diagnosis, management and prognosis of patients with CVD who harbour the ALDH2 rs671 polymorphism.

Short-term efficacy of angiotensin receptor-neprilysin inhibitor treatment in patients with ST-segment elevation myocardial infarction with reduced ejection fraction after primary percutaneous coronary intervention: a propensity score matching study.

BACKGROUND: Acute myocardial infarction (AMI) causes a series of pathophysiological changes, including myocardial necrosis, myocardial edema, and microvascular damage. These changes eventually lead to severe cardiovascular events, such as ventricular remodeling, heart failure, and papillary dysfunction. Impaired cardiac function after ST-segment elevation myocardial infarction (STEMI) often manifests as a decrease in left ventricular ejection fraction (LVEF). Clinical trials have shown that angiotensin receptor-neprilysin inhibitor (ARNI) treatment has the potential to improve LVEF in patients with STEMI after primary percutaneous coronary intervention (PPCI). OBJECTIVE: The purpose of this study was to evaluate the short-term efficacy of ARNI versus angiotensin-converting enzyme inhibitor (ACEI) treatment in patients with STEMI who exhibit reduced LVEF after PPCI. METHODS: A total of 169 patients with STEMI exhibiting post-PPCI LVEF below 50% who were orally treated with ARNI between December 2017 and August 2020 were selected as the experimental group. A total of 136 patients with STEMI exhibiting post-PPCI LVEF below 50% who were orally treated with an ACEI between January 2016 and August 2020 were selected as the control group. LVEF was measured using cardiac ultrasonography during hospitalization and 3 months after discharge. Linear and logistic regression analyses were performed to compare patient demographics and hospitalization variables to evaluate the risk factors for change and rate of improvement in LVEF. Propensity score matching (PSM) was used to account for confounding factors. RESULTS: After PSM, the study cohort consisted of 81 patients in the ARNI group and 123 in the ACEI group. After an average follow-up period of 3 months, no significant difference was noted in the LVEF improvement rate between the experimental and control groups (P = 0.475, 95% CI: -0.062 to 0.134). Multivariate logistic regression analysis also indicated no significant correlation between the change in LVEF and oral ARNI treatment in patients with STEMI exhibiting reduced LVEF after PPCI (P > 0.05). CONCLUSION: The short-term effect of ARNI treatment on the cardiac function of patients with STEMI and reduced LVEF after PPCI is not superior to that of ACEI treatment.

Timing of angiography and outcomes in patients with non-ST-segment elevation myocardial infarction: Insights from the evaluation and management of patients with acute chest pain in China registry.

Objective: Although an invasive strategy has been recommended within 24 h for patients with non-ST-segment elevation myocardial infarction (NSTEMI), the optimal timing of the invasive strategy remains controversial. We sought to investigate the association between the different timings of invasive strategies and clinical outcomes in patients with NSTEMI. Materials and methods: Patients admitted with NSTEMI from the Evaluation and Management of Patients with Acute ChesT pain in China (EMPACT) registry between January 2016 and September 2017 were included. The primary outcomes were major adverse cardiac events (MACEs) within 30 days. Multivariable logistic regression was performed to assess independent risk factors for MACEs. Results: A total of 969 patients with NSTEMI from the EMPACT Registry were eligible for this study. Coronary angiography (CAG) was performed in 501 patients [<24 h, n = 150 (15.5%); ≥ 24 h, n = 351 (36.2%)]. The rate of MACEs at 30 days in all patients was 9.2%, including 54 (5.6%) deaths. Patients who underwent CAG had a lower rate of MACEs and mortality than those who did not receive CAG (MACEs: 5.6% vs. 13.0%, P < 0.001; mortality: 1.6% vs. 9.8%, P < 0.001). Nonetheless, no statistically significant difference was found in the rates of MACEs and mortality between the early (< 24 h) and delayed (≥ 24 h) CAG groups. Older age (OR: 1.036, 95% CI: 1.007, 1.065, P = 0.014), and acute heart failure (OR: 2.431, 95% CI: 1.244, 4.749, P = 0.009) increased the risk of MACEs and protective factors were underwent CAG (OR: 0.427, 95% CI: 0.219, 0.832, P = 0.012) or PCI (OR: 0.376, 95% CI: 0.163, 0.868, P = 0.022). In the multilevel logistic regression, older age (OR: 0.944, 95% CI: 0.932, 0.957, P < 0.001), cardiogenic shock (OR: 0.233, 95% CI: 0.079, 0.629, P = 0.009), pulmonary moist rales (OR: 0.368, 95% CI: 0.197, 0.686, P = 0.002), and prior chronic kidney disease (OR: 0.070, 95% CI: 0.018, 0.273, P < 0.001) was negatively associated with CAG. Conclusion: This real-world cohort study of NSTEMI patients confirmed that the early invasive strategy did not reduce the incidence of MACEs and mortality within 30 days compared with the delayed invasive strategy in NSTEMI patients.

LincRNA-p21 Upregulates Nuclear Orphan Receptor Nr4a2 and Aggravates Myocardial Ischemia/Reperfusion Injury via Targeting MiR-466i-5p.

Myocardial ischemia/reperfusion (I/R) injury can bring about more cardiomyocyte death and aggravate cardiac dysfunction, but its pathogenesis remains unclear. This study aimed to investigate the role of long intergenic noncoding RNA-p21 (LincRNA-p21) in myocardial I/R injury and its underlying mechanism. Mice were subjected to myocardial I/R injury by ligation and release of the left anterior descending artery, and HL-1 cardiomyocytes were treated with hydrogen peroxide. Infarct area, cardiac function, and cardiomyocyte apoptosis were determined. Consequently, LincRNA-p21 was found to significantly be elevated both in the reperfused hearts and H2O2-treated cardiomyocytes. Moreover, genetic inhibition of LincRNA-p21 brought about reduced infarct area and improved cardiac function in mice subjected to myocardial I/R injury. LincRNA-p21 knockdown was also demonstrated to inhibit cardiomyocyte apoptosis both in vivo and in vitro. Notably, LincRNA-p21 silencing increased the expression of microRNA-466i-5p (miR-466i-5p) and suppressed the expression of nuclear receptor subfamily 4 group A member 2 (Nr4a2). Mechanically, LincRNA-p21 downregulated and directly interacted with miR-466i-5p, while application of miR-466i-5p inhibitor promoted cardiomyocyte apoptosis that was improved by LincRNA-p21 inhibition. Furthermore, Nr4a2 upregulation caused by LincRNA-p21 overexpression was partially reversed by miR-466i-5p mimics. Thus, LincRNA-p21 positively regulated the expression of Nr4a2, through sponging miR-466i-5p, promoting cardiomyocyte apoptosis in myocardial I/R injury. The current study revealed a novel LincRNA-p21/miR-466i-5p/Nr4a2 pathway for myocardial I/R injury, indicating that LincRNA-p21 may serve as a potential target for future therapy.

Activin receptor-like kinase 7 promotes apoptosis of vascular smooth muscle cells via activating Smad2/3 signaling in diabetic atherosclerosis.

Vascular smooth muscle cells (VSMCs) is a vital accelerator in the late phase of diabetic atherosclerosis, but the underlying mechanism remains unclear. The aim of our study was to investigate whether activin receptor-like kinase 7 (ALK7)-Smad2/3 pathway plays an important role in VSMC apoptosis of diabetic atherosclerosis. It was shown that ALK7 expression was obviously elevated in the aorta of ApoE-/- mice with type 2 diabetes mellitus. Inhibition of ALK7 expression significantly improved the stability of atherosclerotic plaques and reduced cell apoptosis. Further experiments showed that ALK7 knockdown stabilized atherosclerotic plaques by reducing VSMC apoptosis via activating Smad2/3. Our study uncovered the important role of ALK7-Smad2/3 signaling in VSMCs apoptosis, which might be a potential therapeutic target in diabetic atherosclerosis.

Clinical Outcomes Following Simple or Complex Stenting for Coronary Bifurcation Lesions: A Meta-Analysis.

Background: Stent placement remains a challenge for coronary bifurcation lesions. While both simple and complex stenting strategies are available, it is unclear which one results in better clinical outcomes. This meta-analysis aims to explore the long-term prognosis following treatment with the 2 stenting strategies. Method: Randomized controlled trials found from searches of the PubMed, EMBASE, and Cochrane Central Register of Controlled Trials were included in this meta-analysis. The complex stent placement strategy was identified as the control group, and the simple stent placement strategy was identified as the experimental group. Data were synthesized with a random effects model. The quality of the randomized controlled trials was assessed by Jadad scale scores. The clinical endpoints at 6 months, 1 year, and 5 years were analyzed. Results: A total of 11 randomized controlled trials met the inclusion criteria. A total of 2494 patients were included in this meta-analysis. The odds ratio [OR] of the major adverse cardiac events (MACEs) at 6 months was 0.85 (95% confidence interval [CI] 0.53-1.35; P = .49, I 2 = 0%). The OR of the MACEs at 1 year was 0.61 (95% CI 0.36-1.05; P = .08, I 2 = 0%). The OR of the MACEs at 5 years was 0.69 (95% CI 0.51-0.92; P = .01, I 2 = 0%). Compared with the complex strategy, the simple strategy was associated with a lower incidence of MACEs at 5 years. Conclusion: Compared to the complex stenting strategy, the simple stenting strategy can better reduce the occurrence of long-term MACEs for coronary bifurcation lesions.

Posttranslational modifications of platelet adhesion receptors.

Platelets play a key role in normal hemostasis, whereas pathological platelet adhesion is involved in various cardiovascular events. The underlying cause in cardiovascular events involves plaque rupture leading to subsequent platelet adhesion, activation, release, and eventual thrombosis. Traditional antithrombotic drugs often target the signal transduction process of platelet adhesion receptors by influencing the synthesis of some key molecules, and their effects are limited. Posttranslational modifications (PTMs) of platelet adhesion receptors increase the functional diversity of the receptors and affect platelet physiological and pathological processes. Antithrombotic drugs targeting PTMs of platelet adhesion receptors may represent a new therapeutic idea. In this review, various PTMs, including phosphorylation, glycosylation, ubiquitination, nitrosylation, methylation, lipidation, and proteolysis, of three platelet adhesion receptors, glycoprotein Ib-IX-V (GPIb-IX-V), glycoprotein VI (GPVI), and integrin αIIbß3, are reviewed. It is important to comprehensively understand the PTMs process of platelet adhesion receptors.

Hydrogen therapy after resuscitation improves myocardial injury involving inhibition of autophagy in an asphyxial rat model of cardiac arrest.

Hydrogen (H2) therapy is a therapeutic strategy using molecular H2. Due to its ability to regulate cell homeostasis, H2 therapy has exhibited marked therapeutic effects on a number of oxidative stress-associated diseases. The present study investigated the effectiveness of H2 therapy in protecting against myocardial injury in a rat model of asphyxial cardiac arrest and cardiopulmonary resuscitation. Rats underwent 10-min asphyxia-induced cardiac arrest (CA) and cardiopulmonary resuscitation (CPR), and were randomly divided into control and H2 therapy groups. After resuscitation, the H2 therapy group was administered room air mixed with 2% H2 gas for respiration. During CA/CPR, the arterial pressure and heart rate were measured every minute. Survival rate, cardiac function, myocardial injury biomarkers creatine kinase-MB and cardiac troponin-T, and histopathological changes were evaluated to determine the protective effects of H2 therapy in CA/CPR. Immunohistochemistry and western blot analysis were used to determine the expression levels of autophagy-associated proteins. In vitro, H9C2 cells were subjected to hypoxia/reoxygenation and H2-rich medium was used in H2 treatment groups. Western blotting and immunofluorescence were used to observe the expression levels of autophagy-associated proteins. Moreover, an adenovirus-monomeric red fluorescent protein-green fluorescent protein-LC3 construct was used to explore the dynamics of autophagy in the H9C2 cells. The results showed that H2 therapy significantly improved post-resuscitation survival and cardiac function. H2 therapy also improved mitochondrial mass and decreased autophagosome numbers in cardiomyocytes after resuscitation. The treatment inhibited autophagy activation, with lower expression levels of autophagy-associated proteins and decreased autophagosome formation in vivo and vitro. In conclusion, H2 gas inhalation after return of spontaneous circulation improved cardiac function via the inhibition of autophagy.

Adenosine Kinase Inhibition Prevents Severe Acute Pancreatitis via Suppressing Inflammation and Acinar Cell Necroptosis.

Background: Inflammatory disorder and acinar cell death contribute to the initiation and progression of severe acute pancreatitis (SAP). Adenosine kinase (ADK) has potential effects on both inflammation and cell death. However, the role of ADK in SAP remains to be explored. Methods: To establish an experimental SAP model, male C57BL/6 mice were intraperitoneally injected with cerulein (50 µg/kg, seven doses at hourly intervals) and LPS (10 mg/kg, at the last cerulein injection). For ADK inhibition, ABT702 (1.5 mg/kg) was intraperitoneally injected 1 h before cerulein treatment. The pancreas and serum were collected and analyzed to determine the severity of pancreatic injury and explore the potential pathophysiological mechanisms. Pancreatic acinar cells (AR42J) were used to explore the in vitro effects of ADK inhibition on cerulein-induced inflammation and necroptotic cell death. Results: ADK inhibition notably attenuated the severity of SAP, as indicated by the decreased serum amylase (7,416.76 ± 1,457.76 vs. 4,581.89 ± 1,175.04 U/L) and lipase (46.51 ± 11.50 vs. 32.94 ± 11.46 U/L) levels and fewer pancreatic histopathological alterations (histological scores: 6.433 ± 0.60 vs. 3.77 ± 0.70). MOMA-2 and CD11b staining confirmed that ADK inhibition prevented the infiltration of neutrophils and macrophages. The phosphorylation of nuclear factor-κB (NF-κB) was also reduced by ADK inhibition. ADK inhibition markedly limited the necrotic area of the pancreas and prevented the activation of the necroptotic signaling pathway. Endoplasmic reticulum (ER) stress was activated in the pancreas using the SAP model and cerulein-treated AR42J cells whereas ADK inhibition reversed the activation of ER stress both in vivo and in vitro. Moreover, the alleviating effects of ADK inhibition on ER stress, inflammation, and cell necroptosis were eliminated by the adenosine A2A receptor antagonist. Conclusion: ADK inhibition reduced inflammation and necroptotic acinar cell death in SAP via the adenosine A2A receptor/ER stress pathway, suggesting that ADK might be a potential therapeutic target for SAP.

Macrophage ALDH2 (Aldehyde Dehydrogenase 2) Stabilizing Rac2 Is Required for Efferocytosis Internalization and Reduction of Atherosclerosis Development.

BACKGROUND: Clinical studies show that the most common single-point mutation in humans, ALDH2 (aldehyde dehydrogenase 2) rs671 mutation, is a risk factor for the development and poor prognosis of atherosclerotic cardiovascular diseases, but the underlying mechanism remains unclear. Apoptotic cells are phagocytosed and eliminated by macrophage efferocytosis during atherosclerosis, and enhancement of arterial macrophage efferocytosis reduces atherosclerosis development. METHODS: Plaque areas, necrotic core size, apoptosis, and efferocytosis in aortic lesions were investigated in APOE-/- mice with bone marrow transplanted from APOE-/-ALDH2-/- and APOE-/- mice. RNA-seq, proteomics, and immunoprecipitation experiments were used to screen and validate signaling pathways affected by ALDH2. Efferocytosis and protein levels were verified in human macrophages from wild-type and rs671 mutation populations. RESULTS: We found that transplanting bone marrow from APOE-/-ALDH2-/- to APOE-/- mice significantly increased atherosclerosis plaques compared with transplanting bone marrow from APOE-/- to APOE-/- mice. In addition to defective efferocytosis in plaques of APOE-/- mice bone marrow transplanted from APOE-/-ALDH2-/- mice in vivo, macrophages from ALDH2-/- mice also showed significantly impaired efferocytotic activity in vitro. Subsequent RNA-seq, proteomics, and immunoprecipitation experiments showed that wild-type ALDH2 directly interacted with Rac2 and attenuated its degradation due to decreasing the K48-linked polyubiquitination of lysine 123 in Rac2, whereas the rs671 mutant markedly destabilized Rac2. Furthermore, Rac2 played a more crucial role than other Rho GTPases in the internalization process in which Rac2 was up-regulated, activated, and clustered into dots. Overexpression of wild-type ALDH2 in ALDH2-/- macrophages, rather than the rs671 mutant, rescued Rac2 degradation and defective efferocytosis. More importantly, ALDH2 rs671 in human macrophages dampened the apoptotic cells induced upregulation of Rac2 and subsequent efferocytosis. CONCLUSIONS: Our study has uncovered a pivotal role of the ALDH2-Rac2 axis in mediating efferocytosis during atherosclerosis, highlighting a potential therapeutic strategy in cardiovascular diseases, especially for ALDH2 rs671 mutation carriers.

Mortality in cardiogenic shock patients receiving mechanical circulatory support: a network meta-analysis.

OBJECTIVE: Mechanical circulatory support (MCS) devices are widely used for cardiogenic shock (CS). This network meta-analysis aims to evaluate which MCS strategy offers advantages. METHODS: A systemic search of PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials was performed. Studies included double-blind, randomized controlled, and observational trials, with 30-day follow-ups. Paired independent researchers conducted the screening, data extraction, quality assessment, and consistency and heterogeneity assessment. RESULTS: We included 39 studies (1 report). No significant difference in 30-day mortality was noted between venoarterial extracorporeal membrane oxygenation (VA-ECMO) and VA-ECMO plus Impella, Impella, and medical therapy. According to the surface under the cumulative ranking curve, the optimal ranking of the interventions was surgical venting plus VA-ECMO, medical therapy, VA-ECMO plus Impella, intra-aortic balloon pump (IABP), Impella, Tandem Heart, VA-ECMO, and Impella plus IABP. Regarding in-hospital mortality and 30-day mortality, the forest plot showed low heterogeneity. The results of the node-splitting approach showed that direct and indirect comparisons had a relatively high consistency. CONCLUSIONS: IABP more effectively reduce the incidence of 30-day mortality compared with VA-ECMO and Impella for the treatment of CS.

Short- and Long-Term Prognosis of Intravascular Ultrasound-Versus Angiography-Guided Percutaneous Coronary Intervention: A Meta-Analysis Involving 24,783 Patients.

BACKGROUND: Intravascular ultrasound (IVUS) guided percutaneous coronary intervention (PCI) has potential benefits. This meta-analysis aimed to explore whether IVUS-guided PCI had better short- and long-term prognoses than angiography-guided PCI. METHODS: We retrieved studies from PubMed, Embase, and Cochrane Library. Clinical trials including retrospective and randomized controlled trials (RCTs) that compared IVUS-guided PCI with angiography-guided PCI were included. The patients were followed up after operation at 30 days, 1 year, 2 years, and 3 years. The clinical outcomes were target lesion revascularization (TLR), target vessel revascularization (TVR), and MACEs, including stent thrombosis (ST), myocardial infarction (MI), cardiac death, and all-cause death. The study population included patients with MI, coronary bifurcation lesions, short or long lesions, and unprotected left main coronary artery stenosis (ULMCA). The quality of retrospective trials was evaluated using the Newcastle-Ottawa Scale, and the quality of randomized controlled trials was evaluated using the Jadad score. A total of 20 clinical trials met the criteria. Three trials were randomized controlled trials, while 17 were retrospective trials. RESULTS: A total of 24,783 patients were included. In observational trials, the OR of MACEs was 0.49 (95% CI: 0.38-0.62) in 30 days, 0.65 (95% CI: 0.58-0.73) in one year, 0.51 (95% CI: 0.36-0.71) in two years, and 0.45 (95% CI: 0.31-0.65) in three years. In patients with long coronary lesions, the OR of MACEs in 1 year was 0.64 (95% CI: 0.28-1.50). In patients with left main artery disease, the OR of MACEs in 3 years was 0.42 (95% CI: 0.26-0.67). Compared with angiography-guided PCI, IVUS-guided PCI was associated with a lower incidence of MACEs during the same following period. CONCLUSION: Compared with angiography-guided PCI, IVUS-guided PCI has better performance in reducing the occurrence of MACEs.

4-Hydroxy-2-Nonenal Promotes Cardiomyocyte Necroptosis via Stabilizing Receptor-Interacting Serine/Threonine-Protein Kinase 1.

Background: Necroptosis is a vital regulator of myocardial ischemia/reperfusion (MI/R) injury. Meanwhile, 4-hydroxy-2-nonenal (4-HNE) is abundantly increased during MI/R injury. However, whether 4-HNE induces cardiomyocyte necroptosis during MI/R remains unknown. Methods: To observe the relationship between 4-HNE and necroptosis during MI/R, C57BL/6 mice and aldehyde dehydrogenase 2-transgenic (ALDH2-Tg) mice were both exposed to left anterior descending artery ligation surgery to establish MI/R injury models. For further study, isolated mouse hearts and H9c2 cells were both treated with 4-HNE to elucidate the underlying mechanisms. Results: Necroptosis and 4-HNE were both upregulated in I/R-injured hearts. Cardiomyocyte necroptosis was significantly decreased in I/R-injured hearts from ALDH2-Tg mice as compared with that of wild-type mice. In vitro studies showed that necroptosis was enhanced by 4-HNE perfusion in a time- and concentration-dependent manner. Knockdown of receptor-interacting serine/threonine-protein kinase 1 (RIP1) using small interfering RNA (siRNA) prevented 4-HNE-induced cardiomyocyte necroptosis, manifesting that RIP1 played a key role in the upregulation of cell necroptosis by 4-HNE. Further studies found that 4-HNE reduced the protein degradation of RIP1 by preventing K48-polyubiquitination of RIP1. Conclusion: 4-HNE contributes to cardiomyocyte necroptosis by regulating ubiquitin-mediated proteasome degradation of RIP1.

Inhibition of adenosine kinase attenuates myocardial ischaemia/reperfusion injury.

Increased adenosine helps limit infarct size in ischaemia/reperfusion-injured hearts. In cardiomyocytes, 90% of adenosine is catalysed by adenosine kinase (ADK) and ADK inhibition leads to higher concentrations of both intracellular adenosine and extracellular adenosine. However, the role of ADK inhibition in myocardial ischaemia/reperfusion (I/R) injury remains less obvious. We explored the role of ADK inhibition in myocardial I/R injury using mouse left anterior ligation model. To inhibit ADK, the inhibitor ABT-702 was intraperitoneally injected or AAV9 (adeno-associated virus)-ADK-shRNA was introduced via tail vein injection. H9c2 cells were exposed to hypoxia/reoxygenation (H/R) to elucidate the underlying mechanisms. ADK was transiently increased after myocardial I/R injury. Pharmacological or genetic ADK inhibition reduced infarct size, improved cardiac function and prevented cell apoptosis and necroptosis in I/R-injured mouse hearts. In vitro, ADK inhibition also prevented cell apoptosis and cell necroptosis in H/R-treated H9c2 cells. Cleaved caspase-9, cleaved caspase-8, cleaved caspase-3, MLKL and the phosphorylation of MLKL and CaMKII were decreased by ADK inhibition in reperfusion-injured cardiomyocytes. X-linked inhibitor of apoptosis protein (XIAP), which is phosphorylated and stabilized via the adenosine receptors A2B and A1/Akt pathways, should play a central role in the effects of ADK inhibition on cell apoptosis and necroptosis. These data suggest that ADK plays an important role in myocardial I/R injury by regulating cell apoptosis and necroptosis.

Late Stent Thrombosis After Drug-Coated Balloon Coronary Angioplasty for In-Stent Restenosis.

A 41-year-old woman with chest pain for 6 hours was admitted to our chest pain center, presenting with acute myocardial infarction. Coronary angiography showed acute total occlusion in the proximal left anterior descending artery due to late stent thrombosis. After thrombus aspiration and intracoronary administration of 0.5 mg tirofiban, repeated angiography showed that no obvious residual stenosis remained. The patient underwent drug-coated balloon angioplasty 69 days ago and was then administered dual antiplatelet treatment (aspirin and clopidogrel) uninterruptedly. Genetic testing found that both cytochrome P450 2C19 (CYP2C19) (G681A) and glycoprotein Ia (GPIa) (C807T, G873A) were hybrid mutant types, demonstrating that the patient was possibly resistant to clopidogrel and aspirin simultaneously. Thus, clopidogrel was replaced by ticagrelor and no more cardiovascular adverse events occurred during the 2-year follow-up.

Aldehyde dehydrogenase 2 protects against sympathetic excitation-induced cardiac fibrosis.

Sympathetic stimulated-cardiac fibrosis imposes great significance on both disease progression and survival in the pathogenesis of many cardiovascular diseases. However, there are few effective therapies targeting it clinically. The cardioprotective effect of aldehyde dehydrogenase 2 (ALDH2) has been explored in many pathological conditions, whether it can exert benefit effects on chronic sympathetic stimulus-induced cardiac fibrosis remains unclear. In this study, we determined to explore the role of ALDH2 on isoproterenol (ISO)-induced cardiac fibroblasts (CF) proliferation and cardiac fibrosis. It was found that ALDH2 enzymatic activity was impaired in ISO-induced HCF proliferation and Aldh2 deficiency promoted mouse CF proliferation. Alda-1, an ALDH2 activator, exerted obvious suppressive effect on ISO-induced HCF proliferation, together with the induction of cell cycle arrest at G0/G1 phase and decreased expression of cyclin E1 and cyclin-dependent kinase 2 (CDK2). Mechanistically, the inhibitory role of Alda-1 on HCF proliferation was achieved by decreasing mitochondrial reactive oxygen species (ROS) production, which was partially reversed by rotenone, an inducer of ROS. In addition, wild-type mice treated with Alda-1 manifested with reduced fibrosis and better cardiac function after ISO pump. In summary, Alda-1 alleviates sympathetic excitation-induced cardiac fibrosis via decreasing mitochondrial ROS accumulation, highlighting ALDH2 activity as a promising drug target of cardiac fibrosis.