BACKGROUND:The relationship between low-density lipoprotein cholesterol (LDL-C) levels and bleeding risk during antiplatelet therapy post-percutaneous coronary intervention (PCI) is uncertain, and the effect of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) on bleeding risk is unknown. METHODS:This retrospective cohort study analyzed data from 85,464 PCI patients on oral antiplatelet therapy across 82 Tianjin hospitals from 2017 to 2023, using 1:1 PSM. The primary outcome was Bleeding Academic Research Consortium (BARC) type 3 or 5 bleeding within one year. Kaplan-Meier survival curves and Cox regression models were employed to assess the association between PCSK9i and clinical outcomes, with Win-ratio analysis used for composite endpoints. RESULTS:Among 85,464 patients (64 % male), 1979 (2.32 %) received PCSK9i were followed for one year. After PSM, a balanced cohort of 1951 patients in both the PCSK9i and control groups was established. Multivariate cox regression analysis revealed that patients on PCSK9i had significantly reduced risks of NACE (aHR: 0.674, 95 %CI: 0.528-0.859, P = 0.001), MACCE (aHR: 0.674, 95 %CI: 0.524-0.866, P = 0.002), all-cause death (aHR: 0.501, 95 %CI: 0.275-0.915, P = 0.025), and revascularization (aHR: 0.604, 95 %CI: 0.419-0.872, P = 0.007) at one year. No significant differences were found in other endpoints. The hierarchical outcome significantly favored PCSK9i (matched win ratio 0.634, 95 % CI: 0.584-0.689, P < 0.001). CONCLUSIONS:PCSK9i therapy did not increase bleeding risk and was associated with lower risks of adverse outcomes compared to the control group.

Septic cardiomyopathy is a secondary myocardial injury caused by sepsis. N6-methyl-adenosine (m6A) modification is involved in the pathological progression of septic cardiomyopathy; however, the pathological mechanism remains unclear. In this study, we identified the overall m6A modification pattern in septic myocardial injury and determined its potential interactions with differentially expressed genes (DEGs). A sepsis mouse model exhibiting septic symptoms and myocardial tissue damage was induced by lipopolysaccharide (LPS). LPS-induced septic myocardial tissues and control myocardial tissues were subjected to methylated RNA immunoprecipitation sequencing and RNA sequencing to screen for differentially expressed m6A peaks and DEGs. We identified 859 significantly m6A-modified genes in septic myocardial tissues, including 432 upregulated and 427 downregulated genes. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed to explore the biological importance of differentially expressed m6A methylated genes and DEGs. Differentially expressed m6A methylated genes were enriched in immune- and inflammation-related pathways. Conjoint analysis revealed co-expression of differentially expressed m6A genes and DEGs, including genes that were upregulated or downregulated and those showing opposite trends. High expression of m6A-related genes (WTAP and IGF2BP2), interleukin-17, and interleukin-17 pathway-related genes (MAPK11 and TRAF3IP2) was verified using reverse transcription-quantitative PCR. We confirmed the presence of m6A modification of the transcriptome and m6A-mediated gene expression in septic myocardial tissues.

Background: NSTEMI accounts for the majority of the in-hospital MI. However, whether differences exist between in-hospital NSTEMI patients referred to cardiology and those who are not remains unclear. Aims This study aims to compare the characteristics and prognosis of in-hospital NSTEMI patients referred to cardiology with those who are not. Methods: Data for this study were obtained from a retrospective cohort comprising patients from 72 hospitals between 2010 and 2023. Patients who developed NSTEMI during hospitalization were identified and classified into the referral and the non-referral group based on whether they were referred to cardiology. The primary endpoint was Major Adverse Cardiovascular and Cerebrovascular Events (MACCE), comprising cardiovascular death(CD), recurrent MI, stroke, and repeat revascularization at 1 year. The secondary endpoints were in-hospital all-cause mortality, 1-year all-cause mortality, CD, and Net Adverse Clinical Events (NACE), including CD, recurrent MI, BARC≥3 bleeding events, and repeat revascularization. Kaplan-Meier curves were used to depict survival between the two groups. A multivariable Cox regression model, adjusted for age, sex, Killip classification, and medical history, was utilized to analyze the association between referral and 1-year outcomes. Additionally, multivariate logistic regression analysis was employed to examine the factors related to in-hospital mortality. Results: The study included 6218 patients were in the non-referral group (mean age 73 years, 43.4% women) and 1260 in the cardiology referral group (mean age 70.8 years, 43.4% women). The non-referral group was less likely to take antiplatelet drugs, statins, or undergoing PCI (p<0.001). Multivariate logistic regression showed that cardiology referral was a significant factor affecting in-hospital mortality (OR: 0.405, 95%CI: 0.310-0.528). All the 1-year endpoints-free survival rates were better in the referral group than in the non-referral group (Log-rank p<0.001). Multivariate Cox regression analysis showed that referral were associated with a lower risk of 1-year MACCE (HR: 0.878, 95%CI: 0.801-0.964), NACE (HR: 0.882, 95%CI: 0.805-0.967), all-cause mortality (HR: 0.729, 95%CI: 0.658-0.808) and CD (HR: 0.743, 95%CI: 0.657-0.840). Conclusion: In-hospital NSTEMI patients referred to cardiology had better outcomes compared to those who were not, partly due to higher rates of revascularization and adherence to guideline-recommended medical therapy.

Aims: This study aimed to characterize circular RNA (circRNA) profiles associated with atrial fibrosis-related atrial fibrillation (AF) and reveal critical circRNAs for AF. Methods: Sprague Dawley rats were randomly divided into control and atrial fibrosis-related AF groups (n = 15 in each group). The rats in the atrial fibrosis-related AF group were induced by chronic intermittent hypoxia (CIH), and then confirmed by electrocardiograms, echocardiography, hematoxylin-eosin staining, Masson staining, immunohistochemistry assays and western blotting. After that, the atrial tissues were sent for circRNA sequencing, and the differentially expressed circRNAs were identified and validated by quantitative real-time polymerase chain reaction (qRT-PCR). Finally, a series of cell experiments were performed to explore the roles of two crucial circRNAs in rat atrial fibroblasts. Results: A CIH-induced AF model was successfully established in the rats. After sequencing, five upregulated and 11 downregulated circRNAs were identified in the CIH-induced AF group. These dysregulated circRNAs were primarily associated with "carbohydrate metabolism" and "cardiovascular diseases". Two circRNAs (circRNA_0263 and circRNA_1507) were predicted to regulate target gene expression by interacting with corresponding miRNAs, including rno-miR-29b-5p, rno-miR-29b-3p, rno-miR-496-5p, rno-miR-136-5p, and novel123-mature. Additionally, circRNA_0263 knockdown and circRNA_1507 overexpression inhibited the cell viability of fibroblasts, and downregulated the expression of fibrosis-related proteins. Conclusion: A series of circRNAs were identified as dysregulated in an AF rat model, and circRNA_0263 and circRNA_1507 might be crucial for atrial fibrosis-related AF development by competing with several miRNAs.

Background:Atrial fibrosis caused by long-term atrial fibrillation influences the outcomes of clinical treatment. An improved understanding of the mechanisms underlying atrial fibrillation may reveal new therapeutic targets. This study was conducted to analyze the changes in protein levels in the atrial tissue of a rat model of atrial fibrillation based on proteome sequencing. Methods:Sprague-Dawley rats were used to develop a model of atrial fibrillation induced by chronic intermittent hypoxia (CIH). Histopathological changes were detected using hematoxylin and eosin staining and Masson's staining, and immunohistochemistry and western blotting for the levels of fibrosis biomarkers. Atrial fibrosis tissue samples were also evaluated by proteome sequencing. Differentially expressed proteins (DEPs) between the CIH and control groups were evaluated in functional assay. The expression levels of several key proteins were validated using western blotting. Results:CIH resulted in atrial fibrosis and induced atrial fibrillation. We identified 145 DEPs between the CIH and control groups. These included Myh7, Myl2, Myl3, and Atpla3, which are involved in signaling pathways related to hypertrophic cardiomyopathy, glycerolipid metabolism, and cardiac muscle contraction. Western blotting revealed the upregulation of Myh7, Myl2, and Myl3 and the downregulation of Atpla3 in the CIH group compared with the control group. These results were consistent with the sequencing results. Conclusions:Myh7, Myl2, Myl3, and Atpla3 may play key roles in the progression of atrial fibrillation through their involvement in cardiovascular-disease-related signaling pathways.

BACKGROUND:Early identification of modifiable risk factors is essential for the prevention of frailty. This study aimed to explore the causal relationships between a spectrum of genetically predicted risk factors and frailty. METHODS:Univariable and multivariable Mendelian randomisation (MR) analyses were performed to explore the relationships between 22 potential risk factors and frailty, using summary genome-wide association statistics. Frailty was accessed by the frailty index. RESULTS:Genetic liability to coronary artery disease (CAD), type 2 diabetes mellitus (T2DM), ischaemic stroke, atrial fibrillation and regular smoking history, as well as genetically predicted 1-SD increase in body mass index, systolic blood pressure, diastolic blood pressure, low-density lipoprotein cholesterol, triglycerides, alcohol intake frequency and sleeplessness were significantly associated with increased risk of frailty (all p<0.001). In addition, there was a significant inverse association between genetically predicted college or university degree with risk of frailty (beta -0.474; 95% CI (-0.561 to -0.388); p<0.001), and a suggestive inverse association between high-density lipoprotein cholesterol level with risk of frailty (beta -0.032; 95% CI (-0.055 to -0.010); p=0.004). However, no significant causal associations were observed between coffee consumption, tea consumption, serum level of total testosterone, oestradiol, 25-hydroxyvitamin D, C reactive protein or moderate to vigorous physical activity level with frailty (all p>0.05). Results of the reverse directional MR suggested bidirectional causal associations between T2DM and CAD with frailty. CONCLUSIONS:This study provided genetic evidence for the causal associations between several modifiable risk factors with lifetime frailty risk. A multidimensional approach targeting these factors may hold a promising prospect for prevention frailty.

OBJECTIVES A novel temperature-controlled intravascular radiofrequency balloon angioplasty (RFBA) technique was designed and developed for atherosclerosis (AS) management. METHODS After establishing an AS model based on a balloon denudation injury of the abdominal aorta and a high cholesterol diet in rabbits, 46 animals were randomly assigned to the RFBA group (n = 28) or the plain balloon angioplasty (PBA) group (n = 28). The groups were further subdivided based on post-treatment euthanasia times (1 hour, 7 days, 14 days, and 28 days). Histopathological changes were observed by hematoxylin and eosin and Masson's staining. Immunohistochemistry, western blotting, and real-time quantitative polymerase chain reaction were used to detect changes in pro-inflammatory, anti-inflammatory, and apoptotic factors; TGF-β/Smad-2 pathway protein Immune levels; and mRNA levels in tissues, respectively. RESULTS The vascular lumen area in the RFBA group was larger than that in the PBA group at the same time points, although the change in the vascular lumen area was not different between groups. The expression of Bax, TGF-β, Smad-2, and Caspase-3 in the RFBA group was significantly higher than that in the PBA group. The expression levels of Bcl-2 in the RFBA group were significantly lower than those in the PBA group. CONCLUSIONS At 28 days, RFBA dilated the atherosclerotic blood vessels and thickened the fibrous cap of atherosclerotic plaques to promote plaque stability. RFBA was also found to activate apoptotic factors and the TGF-/Smad-2 inflammatory pathway.

心血管疾病(cardiovascular disease,CVD)是全世界死亡的主要原因.研究表明表观遗传修饰在CVD的进展中起着重要作用.在几种已知的RNA修饰中,N6-甲基腺苷(N6-methyladenosine,m6A)RNA甲基化修饰是研究最多的RNA表观转录组修饰,该过程是动态的、可逆的,在mRNA代谢和各种生物活动中起着至关重要的作用.在这篇综述中,我们描述了 m6A甲基化的作用机制,总结了 m6A甲基化在CVD中的作用,包括动脉粥样硬化、心肌梗死、心力衰竭和糖尿病相关CVD等.m6A甲基化及其调控因子有望成为CVD的治疗靶点.

BACKGROUND Cardiac fibrosis has gradually gained significance in the field of cardiovascular disease; however, its specific pathogenesis remains unclear. This study aims to establish the regulatory networks based on whole-transcriptome RNA sequencing analyses and reveal the underlying mechanisms of cardiac fibrosis. METHODS An experimental model of myocardial fibrosis was induced using the chronic intermittent hypoxia (CIH) method. Expression profiles of long non-coding RNA (lncRNA), microRNA (miRNA), and messenger RNA (mRNA) were acquired from right atrial tissue samples of rats. Differentially expressed RNAs (DERs) were identified, and functional enrichment analysis was performed. Moreover, a protein-protein interaction (PPI) network and competitive endogenous RNA (ceRNA) regulatory network that are related to cardiac fibrosis were constructed, and the relevant regulatory factors and functional pathways were identified. Finally, the crucial regulators were validated using qRT-PCR. RESULTS DERs, including 268 lncRNAs, 20 miRNAs, and 436 mRNAs, were screened. Further, 18 relevant biological processes, such as "chromosome segregation, " and 6 KEGG signaling pathways, such as "cell cycle, " were significantly enriched. The regulatory relationship of miRNA-mRNA-KEGG pathways showed eight overlapping disease pathways, including "pathways in cancer." In addition, crucial regulatory factors, such as Arnt2, WNT2B, GNG7, LOC100909750, Cyp1a1, E2F1, BIRC5, and LPAR4, were identified and verified to be closely related to cardiac fibrosis. CONCLUSION This study identified the crucial regulators and related functional pathways in cardiac fibrosis by integrating the whole transcriptome analysis in rats, which might provide novel insights into the pathogenesis of cardiac fibrosis.

Background and aims:The role of circular RNAs (circRNAs) in the pathophysiology of cardiovascular disease is gradually being elucidated; however, their roles in atrial fibrillation (AF)-related fibrosis are largely unknown. This study aimed to characterize the different circRNA profiles in the rapid-pacing atria of dogs and explore the mechanisms involved in atrial fibrosis. Methods:A rapid right atrial-pacing model was established using electrical stimulation from a pacemaker. After 14 days, atrial tissue was collected for circRNA sequencing analysis. In vitro fibrosis was established by stimulating canine atrial fibroblasts with angiotensin II (Ang II). The fibroblasts were transfected with siRNA and overexpressing plasmids to explore the effects of cfa-circ002203 on fibroblast proliferation, migration, differentiation, and the expression of fibrosis-related proteins. Results:In total, 146 differentially expressed circRNAs were screened, of which 106 were upregulated and 40 were downregulated. qRT-PCR analysis showed that cfa-circ002203 was upregulated in both in vivo and in vitro fibroblast fibrosis models. The upregulation of cfa-circ002203 enhanced proliferation and migration while weakening the apoptosis of fibroblasts. Western blotting showed that cfa-circ002203 overexpression increased the protein expression levels of fibrosis-related indicators (Col I, Col III, MMP2, MMP9, and α-SMA) and decreased the protein expression levels of pro-apoptotic factors (Bax and Caspase 3) in Ang II-induced fibroblast fibrosis. Conclusion:Cfa-circ002203 might serve as an active promoter of the proliferation, migration, and fibrosis of atrial fibroblasts and is involved in AF-induced fibroblast fibrosis.