Cardiovascular Therapeutics最新文献

Oxidative stress and endothelial dysfunction are critical drivers of atherosclerosis, but the mechanisms regulating oxidative stress under disturbed flow conditions remain incompletely understood. The ubiquitin–proteasome system, particularly E3 ubiquitin ligases, may play a pivotal role in modulating these processes. FBXO38, an E3 ligase involved in proteasomal degradation, has been implicated in various physiological pathways, but its role in regulating oxidative stress in endothelial cells is unknown. We hypothesized that FBXO38 mitigates endothelial damage induced by low oscillatory shear stress (LOSS) by promoting the ubiquitin–proteasome–dependent degradation of Nox1, a major source of reactive oxygen species (ROS). Using an in vitro LOSS model in human umbilical vein endothelial cells (HUVECs) and an in vivo mouse partial carotid ligation model, we assessed the expression of FBXO38 and Nox1 through quantitative PCR, western blotting, immunofluorescence, and immunohistochemistry. LOSS significantly reduced FBXO38 protein expression (by ~60%, p < 0.0001 at 24 h), leading to increased Nox1 protein levels (approximately two-fold, p < 0.001) and apoptosis. FBXO38 overexpression markedly attenuated Nox1 accumulation (~50% reduction, p < 0.05), reduced ROS production, and improved cell viability under LOSS conditions, whereas FBXO38 knockdown exacerbated these effects. Moreover, FBXO38 directly interacted with Nox1, suggesting a ubiquitin-dependent degradation mechanism. Our results reveal that FBXO38 regulates endothelial oxidative stress by controlling Nox1 stability under disturbed shear stress conditions. Although FBXO38 emerges as a promising candidate for therapeutic targeting, further studies are necessary to validate its potential in preclinical and clinical settings.

Background: Distinguishing between myocarditis (MC) and acute myocardial infarction (AMI) in the early stages is crucial due to their similar symptoms yet vastly different treatment protocols. This study seeks to utilize metabolomics techniques to differentiate between MC and AMI.

Methods: Plasma samples from 15 patients with MC and 12 patients with AMI were collected. Metabolic profiles of plasma from the two groups of patients were obtained using ultra-high performance liquid chromatography–mass spectrometry (UHPLC-MS), identifying metabolites with significant differences.

Results: We identified 30 significantly different metabolites in both diseases. In patients with MC, 17 metabolites were upregulated, including 5-hydroxy-L-tryptophan and LysoPC (18:2(9Z,12Z)), while 13 metabolites were downregulated, such as 11-cis-retinol, L-glutamate, and hydroxynicotinic acid. KEGG enrichment analysis revealed that the altered metabolites were enriched in tryptophan metabolism, linoleic acid metabolism, primary bile acid biosynthesis, nitrogen metabolism, and retinol metabolism. Biomarker analysis via receiver-operating characteristic curves highlighted 11-cis-retinol as the predominant biomarker, with an AUC value of 0.917.

Conclusions: In conclusion, patients experiencing AMI and MC undergo significant metabolic reprogramming. Metabolites exhibiting abnormal expression in peripheral blood hold diagnostic value for distinguishing between AMI and MC in clinical settings. 11-cis-retinol proved to be the pivotal biomarker for AMI, potentially aiding in the development of a robust predictive model for distinguishing between MC and AMI in clinical settings.

Background: Left atrial appendage closure (LAAC) prevents arterial thromboembolic events (ATEs) in nonvalvular atrial fibrillation (AF). Spontaneous echo contrast (SEC) is an independent risk factor for left atrial appendage (LAA) thrombosis; however, there is little knowledge about the relationship between preoperative SEC and the increased risk of device-related thrombosis (DRT) or ATEs in patients with AF who have undergone LAAC.

Methods: This retrospective study focused on patients with nonvalvular AF who successfully underwent LAAC surgery. Transesophageal echocardiography (TEE) was used to assess preoperative LAA status. SEC in LAA Grades 0–2 was defined as LAASEC−, and Grades 3–4 or previously diagnosed LAA thrombus formation as LAASEC+.

Results: A total of 519 AF patients (432 in LAASEC− group and 87 in LAASEC+ group) who underwent LAAC were included. At the 1-year follow-up, there was no significant difference in the incidence of DRT (2.5 vs. 3.8%, p = 0.636), ATEs (0.5 vs. 0%, p = 0.525), and all-cause mortality (2.1% vs. 2.3%, p = 0.899) between the LAASEC− group and the LAASEC+ group. However, the LAASEC+ group had higher proportions of cauliflower-type LAA and ≥ 3 lobes.

Conclusions: The difference in preoperative LAA thrombosis or LAASEC was not related to the incidence of DRT or ATEs in AF patients within 1 year after LAAC.

Introduction: Recent clinical practice guidelines do not recommend routine P2Y₁₂ inhibitor pretreatment for patients with non-ST-elevation acute coronary syndromes (NSTE-ACS) treated with an early invasive strategy based upon clinical trial data suggesting no improvement in clinical outcomes and increased risk of bleeding. A subset of patients with NSTE-ACS who receive pretreatment and subsequently require coronary artery bypass graft (CABG) surgery may require lengthy P2Y₁₂ inhibitor washout to reduce periprocedural bleeding risk, potentially prolonging hospitalization and increasing costs. We sought to study the association of P2Y₁₂ inhibitor pretreatment on value-based outcomes including length of stay, cost, and discharge destination.

Methods: We conducted a retrospective cohort study of patients presenting with NSTE-ACS who underwent CABG at a tertiary academic medical center between 2019 and 2021. We assessed the frequency of P2Y₁₂ inhibitor pretreatment over the study period and compared risk-adjusted length of stay, cost of hospitalization, and discharge destination among patients who did or did not receive pretreatment.

Results: One hundred eighty-eight patients met inclusion criteria, and 77% received pretreatment. The rate of pretreatment decreased significantly over the study period (p < 0.001). Pretreatment was associated with longer preoperative length of stay (4.2 ± 1.6 vs. 3.4 ± 2.5 days, p = 0.019), with no significant difference in postoperative or total length of stay. There was no difference in cost of hospitalization or likelihood of discharge to home following CABG.

Conclusion: Among patients presenting with NSTE-ACS who underwent inpatient CABG, P2Y₁₂ inhibitor pretreatment was associated with longer preoperative length of stay, but no difference in total length of stay, cost of hospitalization, or discharge destination in this observational, single-center study.

Objective: Calcific aortic valve disease (CAVD) is a progressive cardiovascular condition driven by the osteogenic differentiation of valve interstitial cells (VICs), with no effective drug therapies currently available. Hence, our objective is to investigate the impact of thrombospondin-1 (TSP-1) silencing on CAVD progression.

Methods: In vitro experiments were employed using human primary VICs with TSP-1 knockdown, cultured in osteogenic induction medium, and followed by analyses including western blot, alkaline phosphatase staining, alizarin red staining, immunofluorescence, and flow cytometry. In vivo experiments used two murine models of CAVD to determine the role of TSP-1 silencing on aortic valve calcification.

Results: We observed that silencing of TSP-1 reduced the osteogenic differentiation of VICs. Subsequent experiments demonstrated that TSP-1 knockdown suppressed nuclear factor-κB (NF-κB)–mediated inflammation during osteoblastic differentiation of VICs. Consistent findings were also observed in two murine models of CAVD.

Conclusions: The present study has shown that TSP-1 silencing could mitigate the development of CAVD by inhibiting NF-κB-mediated inflammation. We propose that targeting TSP-1-mediated NF-κB pathway could provide a potential therapeutic method for treating CAVD.

CXC chemokine ligand 16 (CXCL16) expression is often observed in studies related to atherosclerosis (AS). However, the process by which CXCL16 promotes AS is still unknown. CXCL16 has the potential to be a therapeutic target for atherosclerotic disease, and we studied whether CXCL16 expression in carotid atherosclerotic plaques is correlated with plaque stability. The results revealed that the expression level of CXCL16 in unstable plaques was greater than that in stable plaques (p < 0.05). In an in vitro model, CXCL16 promoted the expression of interleukin-17A (IL-17A) and transforming growth factor-β (TGF-β) and the release of STAT3/NF-κB pathway-associated proteins by regulating the expression of IL-17A, TGF-β, and CXCL16. In conclusion, there is a positive feedback regulatory pathway between inflammatory factors and CXCL16 during the progression of carotid AS. Inflammatory factors and CXCL16 promote each other’s expression and activate the STAT3/NF-κB pathway to promote carotid AS. CXCL16 is highly expressed in carotid atherosclerotic plaques, affecting plaque stability and further leading to the development of AS-related diseases such as ischaemic stroke. Thus, we hypothesise that CXCL16 is a potential therapeutic target for treating AS and AS-related diseases.

Introduction: This study investigated the effect of vitamin D3 injection combined with high-intensity interval training on cell signaling pathways involved in excessive autophagy, specifically the mTOR (mechanistic target of rapamycin)–Beclin-1–Fyco-1 (FYVE and coiled-coil domain-containing protein 1)–cathepsin D pathway, in the heart tissue of Type 2 diabetes–induced rats.

Method: In this experimental study, 32 male Wistar rats were fed a high-fat diet for 6 weeks to induce Type 2 diabetes, followed by a single subcutaneous injection of 35 mg/kg streptozotocin (STZ). The rats were then randomly assigned to one of four groups: (1) diabetes control (DC), (2) diabetes + HIIT (DT), (3) diabetes + vitamin D3 (DV), and (4) diabetes + HIIT + vitamin D3 (DTV). HIIT sessions were conducted for 8 weeks, five times per week, at an intensity of 85%–95% of maximum running speed (V_max), while vitamin D3 was administered weekly via subcutaneous injection at a dose of 10,000 IU/kg. Twenty-four hours after the intervention period, heart and left ventricular tissues were collected for analysis of the levels of autophagy signaling proteins mTOR, phosphorylated mechanistic target of rapamycin (pmTOR), Beclin-1, Fyco-1, and cathepsin D.

Results: Two-way ANOVA revealed that Type 2 diabetes significantly increased the levels of Beclin-1, Fyco-1, and cathepsin D (p < 0.001) while significantly reducing the levels of mTOR and pmTOR (p < 0.001). HIIT, vitamin D3 injection, and their combined treatment significantly decreased the levels of Beclin-1, Fyco-1, and cathepsin D and increased the levels of mTOR and pmTOR compared to the diabetes control group (p < 0.001).

Conclusion: Type 2 diabetes increases autophagy in the left ventricle, marked by altered levels of key autophagy proteins. HIIT and vitamin D3 injections mitigate these effects by enhancing mTOR signaling and reducing excessive autophagy. These interventions show promise as nonpharmacological strategies to improve cardiac health in Type 2 diabetes and could be incorporated into clinical and rehabilitation programs.

Coronary artery disease (CAD) is a complex condition influenced by genetic factors, lifestyle, and other risk factors that contribute to increased mortality. This study is aimed at evaluating the diagnostic potential of genes associated with cuproptosis, ferroptosis, and pyroptosis (CFP) using network modularization and machine learning methods. CAD-related datasets GSE42148, GSE20680, and GSE20681 were sourced from the GEO database, and genes related to CFP genes were gathered from MsigDB and FerrDb datasets and literature. To identify diagnostic genes linked to these pathways, weighted gene coexpression network analysis (WGCNA) was used to isolate CAD-related modules. The diagnostic accuracy of key genes in these modules was then assessed using LASSO, SVM, and random forest models. Immunity and drug sensitivity correlation analyses were subsequently performed to investigate possible underlying mechanisms. The function of a potential gene, STK17B, was analyzed through western blot and transwell assays. Two CAD-related modules with strong correlations were identified and validated. The SVM model outperformed LASSO and random forest models, demonstrating superior discriminative power (AUC = 0.997 in the blue module and AUC = 1.000 in the turquoise module), with nine key genes identified: CTDSP2, DHRS7, NLRP1, MARCKS, PELI1, RILPL2, JUNB, STK17B, and SLC40A1. Knockdown of STK17B inhibited cell migration and invasion in human umbilical vein endothelial cells. In summary, our findings suggest that CFP genes hold potential as diagnostic biomarkers and therapeutic targets, with STK17B playing a role in CAD progression.

Purpose: This study is aimed at identifying clinical and echocardiographic factors associated with all-cause mortality or heart transplantation (HTx) in young patients with dilated cardiomyopathy (DCM).

Methods: We conducted a retrospective analysis of hospitalized patients (aged 18–45 years) diagnosed with DCM between January 2012 and December 2022. All patients underwent a 2-year medical therapy for heart failure, followed by at least 1 year of follow-up. Clinical and echocardiographic data were collected at baseline and after the 2-year treatment period. Multivariate Cox proportional hazards regression with a backward stepwise method was used to identify risk factors for all-cause mortality or HTx.

Results: The study cohort comprised 67 patients. Over a median follow-up of 38 months (range 18–50), 15 patients died and 24 underwent HTx. Significant risk factors for all-cause mortality/HTx included smoking, digoxin use, elevated N-terminal pro-brain natriuretic peptide (NT-proBNP, ≥ 5678 pg/mL), higher C-reactive protein (CRP, ≥ 3.0 mg/L), higher uric acid (UA, ≥ 570 μmol/L), lower left ventricular ejection fraction (LVEF, ≤25%), and enlarged end-diastolic left ventricular diameter (LVD, ≥ 65 mm). Among these, elevated CRP (hazard ratio, HR = 6.727, p < 0.001) and enlarged LVD (HR = 3.038, p = 0.007) were the strongest independent risk factors, irrespective of other risk factors. Moreover, each 5 mm annual increase in end-systolic left atrial diameter (LAD, HR = 3.641, p < 0.001) and each unit annual increase in Ln(NT-proBNP) (HR = 4.069, p < 0.001) were the strongest predictors of all-cause mortality/HTx, even after accounting for the effects of body mass index, duration of treatment, and baseline CRP level.

Conclusions: Intensive monitoring and medical care may be beneficial for young adult DCM patients with defined risk factors such as smoking, elevated NT-proBNP and CRP, lower LVEF, and enlarged LV diameter. Our findings suggest that personalized intensive monitoring and medical care based on identified risk factors may improve outcomes in young adult DCM patients.

Background: With the progression of chronic kidney disease (CKD), we can often observe cardiac remodeling, fibrosis, and cardiac failure in patients. Cysteine-rich protein 61 (CCN1) is an extracellular matrix protein that plays a reuse role in cardiac remodeling. However, whether CCN1 participates in the crosslink between the heart and kidney in CKD and the potential mechanism remains unknown.

Methods: We constructed a mouse model of CKD by 5/6 nephrectomy (5/6 Nx). Hematoxylin–eosin staining (H&E), Masson’s trichrome staining, and Sirius red staining were used to observe cardiac morphology and fibrosis. H9c2 cells were treated with si-CCN1 or si-NC or mitogen-activated protein kinase (MAPK)–related inhibitors or agonist before being cultured with 5/6 Nx mouse serum. The relative protein level was detected by Western blotting.

Results: We observed that CCN1 expression was markedly enhanced in the serum and heart tissues, accompanied by disordered myocardial arrangement, obvious cardiac fibrosis, hypertrophy, and decreased cardiac systolic function reflected by echocardiography. The relative markers collagen 1 (COL-1), transforming growth factor-β (TGF-β), heavy-chain cardiac myosin (MyHC), and atrial natriuretic peptide (ANP) presented an increase in expression. In vivo and in vitro, after the knockdown of CCN1, the above results in the CKD group or CKD serum group were reversed; in addition, the MAPK signaling pathway was obviously activated due to 5/6 Nx, which was abolished by CCN1 inhibition. CCN1 silencing or MAPK pathway inhibition also decreased the expression of myocardial fibrosis and hypertrophy markers in H9c2 cells, while MAPK-related agonist partly reversed the effect of CCN1 inhibition.

Conclusion: Our in vivo and in vitro study showed that specific CCN1 deficiency markedly alleviated cardiac remodeling in 5/6 Nx mice through the inhibition of the MAPK pathway.