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Background/Aims: MicroRNA-9 (miR-9) is involved in inflammatory reaction in atherosclerosis; however, its function and regulatory mechanisms remain unclear. We aimed to uncover the exact roles of miR-9 and downstream signaling pathways using in vitro human atherosclerosis models. Methods: We used oxidized low-density lipoprotein (oxLDL)-stimulated human THP-1 derived macrophages, oxLDL-stimulated human primary peripheral blood monocytes and lipopolysaccharides (LPS) or Alum-stimulated human THP-1 derived macrophages as in vitro atherosclerosis inflammation models. Transient transfection of over-expression vectors, small interference RNAs (siRNAs) or antisense oligonucleotides was used to regulate intracellular protein or miR-9 levels. Cell responses and signal transduction were detected by multiple assays including Western blotting, enzyme-linked immunosorbent assay (ELISA) and luciferase reporter assay. Results: MiR-9 inhibited while anti-miR-9 antisense oligonucleotides induced interleukin-1 beta (IL-1β) and NLRP3 inflammasome activation in all in vitro models. Janus kinase 1 (JAK1) and matrix metalloproteinase 13 (MMP-13) were identified as the target genes of miR-9. In oxLDL-stimulated human THP-1 derived macrophages, knockdown of JAK1 by siRNA blocked the phosphorylation of signal transducer and activator of transcription 1 (STAT1) and mimicked the effects of miR-9. In the same model, JAK1 knockdown blocked the phosphorylation of NF-κB p65 in the nuclei and the phosphorylation of NF-κB IκBα in the cytoplasm. Conclusions: Our study demonstrated that miR-9 could inhibit activation of the NLRP3 inflammasome and attenuate atherosclerosis-related inflammation, likely through the JAK1/STAT1 signaling pathway. Therefore, miR-9 may serve as a potential therapeutic target for atherosclerosis.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduce incidence of cardiovascular events in type 2 diabetes (T2D) patients. Yet, the impact of GLP-1RAs on coronary lesion progression and cardiovascular outcomes after coronary stent implantation remains unclear. We aimed to investigate the effects of GLP-1RAs on coronary lesion progression and major adverse cardiovascular events (MACEs) after percutaneous coronary intervention (PCI). This prospective cohort study enrolled 1664 patients with T2D who underwent PCI from January 2020 to March 2024. Matched GLP-1RAs-treated and non-treated cohorts were formed using the propensity score matching method. The primary endpoint was the incidence of MACEs (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, hospitalization for heart failure). Secondary endpoints included in-stent restenosis and non-target lesion progression. Two 131-patient cohorts with balanced baseline characteristics were formed by propensity score matching. During the median follow-up period of 20 months (ranging from 6 to 48 months), the incidence of MACEs was significantly lower in the GLP-1RA group (7.63%)compared to the control group (19.85%) (HR 0.444; 95%CI, 0.215–0.918; P  = 0.024). During a median follow-up period of 12 months, 79.39% (104/131) of patients in the control group and 82.44% (108/131) of patients in the GLP-1RA group successfully underwent coronary angiography follow-up. The incidence of in-stent restenosis was 2.78% (3/108) in the GLP-1RA group and 11.54% (12/104) in the control group ( P  = 0.028). Non-target lesion progression was found in 10.19% (11/108) patient of the GLP-1RA group and 22.12% (23/104) in the control group ( P  = 0.037). Notable disparities were observed between the two groups regarding improvements of BMI, SBP, HbA1c, LDL-C, CRP. GLP-1RAs significantly reduced the incidence of MACEs and coronary lesion progression in patients with T2D after coronary stent implantation. These findings suggest that GLP-1RAs may have beneficial effects on cardiovascular outcomes and coronary artery disease progression in this population.

Background: Cardiovascular adverse events represent critical complications of antineoplastic therapy with profound implications for cancer survivorship and treatment outcomes. Despite the clinical significance, comprehensive pharmacovigilance data characterizing distinctive cardiotoxicity profiles across modern cancer therapeutics remain limited. Objectives: This investigation systematically analyzes cardiotoxicity patterns associated with antineoplastic agents using the FDA Adverse Event Reporting System (FAERS) database to inform evidence-based cardiovascular monitoring strategies. Design: A retrospective pharmacovigilance study utilizing disproportionality analysis and time-to-onset evaluation. Methods: We conducted a comprehensive analysis of FAERS data spanning 2004–2024, employing validated disproportionality metrics including reporting odds ratio (ROR) and proportional reporting ratio (PRR) to detect significant drug-event associations. Advanced time-to-onset analysis revealed temporal patterns of cardiotoxicity development across therapeutic classes. Statistical significance was defined as ROR >1 with 95% confidence intervals excluding 1.0, and PRR >2 with chi-square >4. Results: Analysis of 18,289,374 reports identified 51,402 cases of antineoplastic-related cardiovascular toxicity, demonstrating distinct class-specific patterns. Anthracyclines exhibited profound associations with structural cardiac damage (doxorubicin-cardiomyopathy: ROR = 20.64, 95% CI: 19.87–21.45). Immune checkpoint inhibitors demonstrated unprecedented immune-mediated cardiac inflammation (pembrolizumab-myocarditis: ROR = 245.36, 95% CI: 218.42–275.88). Fluoropyrimidines showed distinctive vasospastic effects (5-fluorouracil-Prinzmetal angina: ROR = 18.27, 95% CI: 14.72–22.69). Critical temporal patterns emerged: fluoropyrimidines caused early-onset cardiotoxicity (median: 11 days, IQR: 4–28), anthracyclines showed intermediate onset (doxorubicin median: 64 days, IQR: 21–156; epirubicin median: 72 days, IQR: 28–168), while mitoxantrone demonstrated delayed effects (median: 457 days, IQR: 182–891). Cardiogenic shock emerged as the most lethal manifestation with a 43.08% mortality rate (95% CI: 40.12–46.14). Conclusion: This landmark pharmacovigilance study reveals previously uncharacterized temporal and mechanistic patterns of antineoplastic cardiotoxicity, providing an essential evidence-based framework for cardiovascular monitoring strategies. The findings highlight critical intervention windows: immediate monitoring for fluoropyrimidines, intermediate surveillance for anthracyclines (2–6 months), and extended follow-up for agents like mitoxantrone (>12 months). These insights support the development of risk-stratified cardio-oncology protocols tailored to specific therapeutic classes. Plain language summary Heart problems from cancer drugs: a large-scale safety study using FDA reports Cancer treatments can sometimes cause serious heart problems, but doctors need better information about which drugs cause which heart issues and when they occur. This study looked at over 18 million safety reports sent to the FDA between 2004 and 2024 to understand patterns of heart problems caused by cancer drugs. The researchers found more than 51,000 reports of heart problems linked to cancer medications. Different types of cancer drugs caused different heart problems at different times: • Anthracyclines (like doxorubicin) - older chemotherapy drugs that can permanently damage the heart muscle, typically causing problems after 2-5 months of treatment • Immune checkpoint inhibitors (like pembrolizumab) - newer immunotherapy drugs that can cause dangerous heart inflammation, often within the first few weeks • Fluoropyrimidines (like 5-fluorouracil) - drugs that can cause heart artery spasms, usually within the first 1-4 weeks • Mitoxantrone - a drug that can cause heart problems much later, often after more than a year The study found that cardiogenic shock (when the heart can’t pump enough blood) was the most dangerous heart problem, with nearly half of patients dying from it. These findings help doctors know when to watch patients most carefully for heart problems. For example, patients getting fluoropyrimidines need immediate heart monitoring, while those getting anthracyclines need regular heart checks for several months, and patients on mitoxantrone need long-term follow-up for over a year.

Our study was aimed to investigate the effects of lgals3a (Gal-3 encoding gene) on the development of zebrafish embryo and its underlying mechanisms. Morpholino (MO) technology was used to inhibit the expression of zebrafish lgals3a, and the effect of lgals3a gene knockdown on zebrafish embryo development and the number of monocyte macrophages was observed. Effect of lgals3a-e3i3-MO on apoptosis of zebrafish was detected by acridine orange staining. In addition, the mRNA expression levels of Wnt/β-catenin signaling pathway-related genes were detected by RT-qPCR. Compared with control-MO group, the zebrafish embryos injected with lgals3a-e3i3-MO had obvious defects in the head, eyes, and tail, and pericardial edema. Lgals3a-e3i3-MO significantly reduced the number of mononuclear macrophages in zebrafish embryos compared with the control-MO group. The results of acridine orange staining showed that compared with the control-MO group, lgals3a-e3i3-MO promoted cardiomyocyte apoptosis in zebrafish. Furthermore, lgals3a-e3i3-MO significantly up-regulated the expression of dkk1b, wnt9a, lrp5, fzd7a, β-catenin, Gsk-3β, mycn, myca in the Wnt/β-catenin pathway, and decreased the expression of lef1. These results indicate that lgals3a-e3i3-MO inhibits zebrafish embryo development, reduces the number of mononuclear macrophages, activates Wnt/β-catenin signaling pathway and promotes cardiomyocyte apoptosis.

Background: Lipid profiles differ naturally between individuals and between populations. So far, the data relating to non-fasting lipid profiles has been derived predominantly from studies on Western population. The characteristics and clinical significance of non-fasting lipids in Chinese patients with coronary heart disease (CHD) in response to traditional Chinese diets remain poorly understood. Methods: A total of 1022 Chinese CHD patients with coronary artery luminal stenosis >40% as diagnosed by coronary artery angiography were enrolled in the study. All patients received standard treatment for CHD, including statins. They were divided into an intermediate stenosis group (luminal stenosis 40–70%, n = 486) or a severe stenosis group (luminal stenosis >70%, n = 536). Their blood lipid profiles were measured in the fasting state, and 4 hours after normal breakfast. All participants were followed up for five years. Major adverse cardiovascular events (MACE) including all-cause death, cardiac death, myocardial infarction, unscheduled coronary revascularization and stroke were recorded. Results: After normal breakfast intake, patients with intermediate or severe stenosis showed an apparent increase in the levels of triglyceride (TG), remnant cholesterol (RC) and Apo (apolipoprotein) A1 compared to the fasting state, but a significant reduction in the levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), Apo B and Apo E. In addition to the traditional risk factors (older age, male, diabetes and smoking) and coronary artery stenosis, the fasting levels of LDL-C and Apo B, as well as non-fasting levels of HDL-C and Apo A1, were identified as independent predictors of 5-year MACE occurrence by multivariate Cox proportional hazards analysis. Patients in the 1st tertile of the non-fasting HDL-C group (<0.86 mmol/L) showed a significantly higher risk of MACE than 3rd tertile (>1.07 mmol/L) (1st tertile: 2.786, 95% CI (confidence intervals) [1.808, 4.293], p < 0.001). Conclusions: This prospective observational study found that lipid profiles in either the fasting or non-fasting states were associated with the long-term risk of MACE in Chinese CHD patients. In addition to the fasting LDL-C level, a low non-fasting HDL-C level may also be an independent risk factors for cardiovascular events. Measurement of lipid profiles during the non-fasting state may be feasible for the management of CHD patients in routine clinical practice in China.

Hyperuricemia is associated with poor clinical outcomes in several cardiovascular diseases, including heart failure (HF). However, whether lowering serum uric acid (SUA) levels improves the prognosis of HF remains insufficiently studied. To evaluate whether urate-lowering therapy (ULT) with febuxostat confers clinical benefits in patients with HF and concomitant hyperuricemia. Prospective, observational cohort study. Patients with chronic HF and hyperuricemia were enrolled and assigned either to a febuxostat group or to a non-ULT group and were followed prospectively for 5 years. The primary endpoint was all-cause mortality or rehospitalization for HF. Among 2005 patients, those with higher SUA levels experienced more endpoint events. After propensity score matching, we found that febuxostat therapy significantly reduced the incidence of primary endpoints in patients with HF with preserved ejection fraction (HFpEF) [ = 0.012; hazard ratios (HR), 0.744; 95% confidence intervals (CI), 0.589-0.939], but not in those with HF with reduced ejection fraction (HFrEF) or mildly reduced ejection fraction (HFmrEF) ( = 0.234; HR, 0.894; 95% CI, 0.742-1.077). The benefits of febuxostat in HFpEF were most evident in patients within the highest tertiles of B-type natriuretic peptide (BNP) ( = 0.021; HR, 0.647; 95% CI, 0.436-0.960) and SUA ( = 0.025; HR, 0.651; 95% CI, 0.441-0.963). High SUA levels are associated with increased all-cause mortality and rehospitalization for HF. Febuxostat-mediated SUA reduction significantly improved clinical outcomes in patients with HFpEF, particularly those with elevated SUA and BNP levels.

Arrhythmias and major adverse cardiac events remain significant complications following ST-segment elevation myocardial infarction (STEMI). Shenfu injection, a traditional Chinese medicine formulation, has shown cardioprotective effects in preclinical studies. This trial is aimed at investigating whether Shenfu injection as an adjunctive therapy to standard treatment could reduce arrhythmias and improve clinical outcomes in patients with STEMI undergoing percutaneous coronary intervention (PCI). A single-center, prospective, randomized, controlled trial was conducted at Shanghai Ninth People's Hospital among 245 patients with STEMI undergoing PCI. Participants were randomized to receive either standard therapy plus Shenfu injection (50 mL, administered intravenously twice daily for five consecutive days) ( = 123) or standard therapy alone ( = 122). The primary endpoint was the incidence of in-hospital arrhythmias. Secondary endpoints included major adverse cardiac events (MACEs) during the 12-month follow-up period and cardiac magnetic resonance imaging parameters. A total of 245 patients underwent randomization (123 assigned to Shenfu injection group and 122 assigned to control group). During hospitalization, patients assigned to Shenfu injection had a significantly lower incidence of arrhythmias compared with the control group (24.4% vs. 38.5%, = 0.017), with the most pronounced effect on frequent ventricular premature contractions (7.3% vs. 15.5%, = 0.042). After adjustment for key baseline covariates including age, coronary artery disease extent, myocardial injury markers (CK-MB max and TNI max), left ventricular ejection fraction, B-type natriuretic peptide, door-to-balloon time, hypertension, and diabetes mellitus, Shenfu injection remained independently associated with reduced risk of in-hospital arrhythmias (adjusted OR 0.454, 95% CI: 0.249-0.827, = 0.010). Cardiac magnetic resonance imaging performed in 174 patients revealed significantly smaller infarct size (16.1 ± 9.1 vs. 20.8 ± 13.1 g, = 0.007) and lower incidence of microvascular obstruction (45.0% vs. 65.0%, = 0.008) in the Shenfu group, with both parameters showing significant positive correlations with arrhythmia occurrence. During the 12-month follow-up, patients receiving Shenfu injection had a higher event-free rate from MACEs compared with the control group (12-month Kaplan-Meier event-free rate estimates, 84.6% vs. 73.0%, respectively; = 0.028). Treatment with Shenfu injection as an adjunctive therapy to standard treatment in patients with STEMI undergoing PCI significantly reduced in-hospital arrhythmias, infarct size, microvascular obstruction, and major adverse cardiac events during a 12-month follow-up period. The independent effect on arrhythmias after comprehensive statistical adjustment and the demonstrated correlation between reduced myocardial damage and arrhythmia prevention suggest the potential therapeutic value of Shenfu injection in improving both short-term and long-term outcomes in STEMI patients. Chinese Clinical Trial Registry Identifier: ChiCTR2200066918.

Background Myocardial ischaemia reperfusion injury (MIRI) is a difficult problem in clinical practice, and it may involve various microRNAs. This study investigated the role that endogenous microRNA-146a plays in myocardial ischaemia reperfusion and explored the possible target genes. Methods MIRI models were established in microRNA-146a deficient (KO) and wild type (WT) mice. MicroRNA-146a expression was evaluated in the myocardium of WT mice after reperfusion. The heart function, area of myocardium infarction and in situ apoptosis were compared between the KO and WT mice. Microarray was used to explore possible target genes of microRNA-146a, while qRT-PCR and dual luciferase reporter assays were used for verification. Western blotting was performed to detect the expression levels of the target gene and related signalling molecules. A rescue study was used for further testing. Results MicroRNA-146a was upregulated 1 h after reperfusion. MicroRNA-146a deficiency decreased heart function and increased myocardial infarction and apoptosis. Microarray detected 19 apoptosis genes upregulated in the KO mice compared with the WT mice. qRT-PCR and dual luciferase verified that Med1 was one target gene of microRNA-146a. TRAP220, encoded by Med1 in the KO mice, was upregulated, accompanied by an amplified ratio of Bax/Bcl2 and increased cleaved caspase-3. Inhibition of microRNA-146a in H9C2 cells caused increased TRAP220 expression and more apoptosis under the stimulus of hypoxia and re-oxygenation, while knockdown of the increased TRAP220 expression led to decreased cell apoptosis. Conclusions MicroRNA-146a exerts a protective effect against MIRI, which might be partially mediated by the target gene Med1 and related to the apoptosis signalling pathway.

Plaque vulnerability and rupture rather than plaque size are the major cause of clinical events in patients with intermediate coronary lesions. Therefore, the present study was aimed to explore potential markers associated with plaque rupture in acute coronary syndrome (ACS) patients with intermediate coronary lesions. A total of 82 ACS patients presenting with only intermediate coronary lesions (40-70% stenosis demonstrated by quantitative coronary angiography) and no severe stenosis in other main coronary arteries [median age 63 years, 53 male and 29 female] were enrolled. Plaque morphology were assessed by optical coherence tomography (OCT). Hematological indices were assayed by automated hematological analyzer. Plaque rupture was identified in 14 patients by OCT. Neutrophil to lymphocyte ratio (NLR) in patients with plaque rupture ( = 14) was significantly higher than that in patients with non-plaque rupture ( = 68) [3.85 (3.28, 4.77) vs. 2.13 (1.40, 2.81), < 0.001]. Multivariate logistic regression analysis revealed that NLR was one of the independent risk factors for plaque rupture in intermediate coronary artery lesions (odds ratio 1.64, 95% confidence intervals 1.18-2.29, = 0.003). ROC curve analysis found a cutoff point of NLR > 2.94 for plaque rupture with 93.8% sensitivity and 77.9% specificity. NLR, an inflammatory biomarker, is closely associated with plaque rupture in intermediate coronary artery lesions. Monitoring NLR may be useful in risk stratification and management for intermediate coronary artery lesions.

Importance Lower extremity peripheral arterial disease (PAD) is a significant health concern among older adults globally, affecting both mortality and quality of life. Objective To evaluate the temporospatial trends and its risk factors in lower extremity PAD-related burden among adults aged 60 years and older from 1990 to 2021. Design, setting, and participants This repeated cross-sectional study utilized data from the Global Burden of Disease Study 2021, encompassing 204 countries and territories. The study population included adults aged 60 years and older. Exposure Lower extremity PAD among older adults from January 1990 to December 2021. Main outcomes and measures Primary outcomes included age-standardized prevalence rates (ASPR), mortality rates (ASMR), disability-adjusted life-years (DALYs), and average annual percentage changes (AAPCs). Trends were analyzed by age, sex, and sociodemographic index (SDI). Joinpoint regression analysis was used to identify significant trend changes. Results From 1990 to 2021, global trends showed decreases in lower extremity PAD-related prevalence, mortality, and DALYs. Significant geographical disparities were observed: high-SDI regions had the highest prevalence (11,171.66 per 100,000 in 2021) but showed declining trends (AAPC, -0.74; 95% CI, -0.80 to -0.68), while low-SDI regions had the lowest prevalence (4,842.40 per 100,000) but demonstrated increasing trends (AAPC, 0.22; 95% CI, 0.21 to 0.24). Regionally, although lower extremity PAD-related prevalence showed a decreasing trend in most regions from 1990 to 2021, there were still some regions with an increasing trend (North Africa and Middle East AAPC, 0.57; 95% CI, 0.55 to 0.59). Temporal analysis showed sex-specific divergent trends in recent years, with males exhibiting an upward trend since 2015 (APC, 0.15; 95% CI, 0.07 to 0.24), while females showed a slowed decline since 2014 (APC, -0.06; 95% CI, -0.12 to -0.01). Decomposition analysis identified population growth as the primary driver of PAD burden increase, with epidemiological changes showing contrasting effects across SDI regions. Among risk factors, high fasting glucose emerged as the leading contributor, while smoking’s contribution decreased. Conclusions and relevance This study revealed significant disparities in lower extremity PAD burden across different SDI levels and regions, with low-SDI countries facing an increasing burden. The contrasting trends between high- and low-SDI regions, coupled with varying risk factor patterns (particularly the rise in high fasting glucose and decline in smoking), suggest the need for targeted interventions in resource-limited settings to address this growing health challenge among older adults. Key points Question What are the trends in the burden of lower extremity PAD among older adults at the global, regional, and sociodemographic index subgroup levels from 1990 to 2021? Finding In this cross-sectional study among older adults, although lower extremity PAD prevalence (measured per 100000 population) decreased from 9525.09 to 8220.21 from 1990 to 2021, divergent trends were observed with high-SDI countries showing decline while low-SDI countries demonstrated increases. Population growth was the primary driver of PAD burden globally, while risk factor patterns varied significantly, with high fasting glucose emerging as the leading risk factor and smoking showing substantial decline. Meaning The lower extremity PAD burden among older adults shows significant disparities across SDI regions, highlighting the need to address healthcare inequities and strengthen preventive measures in low-SDI countries. The changing patterns of risk factors underscore the importance of targeted interventions and comprehensive disease management strategies across different socioeconomic settings.