Jun Xie

Background: Long-term outcomes differ substantially among patients with chronic total occlusion (CTO), and risk assessment remains challenging. Lipoprotein(a) [Lp(a)] and hyperuricemia are both associated with cardiovascular risk, but the prognostic significance of their coexistence in this population is uncertain. Methods: We retrospectively studied 391 patients with angiographically confirmed CTO. Patients were classified into four groups according to baseline Lp(a) and uric acid (UA) levels: neither elevated, elevated lipoprotein(a) only, hyperuricemia only, and both elevated. The primary outcome was major adverse cardiovascular and cerebrovascular events (MACCEs), defined as the first occurrence of all-cause death, non-fatal myocardial infarction, target vessel revascularization, or stroke. Cox regression was used to assess long-term associations, while additive and multiplicative interactions were examined. Incremental prognostic value was evaluated using model discrimination, reclassification, calibration, and bootstrap internal validation. Results: During a median follow-up of 73 months, event rates were 12.21%, 29.89%, 28.57%, and 66.27% across the four groups, respectively (P<0.001). Patients with both elevated lipoprotein(a) and hyperuricemia had the highest event risk compared with those with neither factor elevated (adjusted hazard ratio [aHR] 11.46, 95% confidence interval [CI] 6.44–20.41; P<0.001). In a sensitivity analysis restricted to all-cause death, non-fatal myocardial infarction, or stroke, the association remained significant (aHR 4.23, 95% CI 2.13–8.39; P<0.001). A positive additive interaction was observed, whereas the multiplicative interaction was not significant. The apparent C-indices were 0.691 and 0.828 for the Base and Expanded models, respectively; after bootstrap optimism correction, the corresponding C-indices were 0.634 and 0.791. Conclusions: Concurrent elevation of Lp(a) and UA was associated with higher long-term cardiovascular risk in patients with CTO and may provide prognostic information beyond either marker considered alone. These findings require external validation before the proposed dual-biomarker classification can be applied clinically.

Background: Intravascular lithotripsy (IVL) is an emerging technique for the treatment of severely calcified coronary lesions, yet head-to-head evidence comparing its prognostic value against standard rotational atherectomy (RA) in real-world practice, particularly in patients with tortuous or angulated coronary anatomy, remains lacking. Methods: This retrospective observational cohort study included 247 patients with severely calcified coronary lesions and concomitant tortuous or angulated anatomy who underwent percutaneous coronary intervention between January 2023 and March 2025, comprising 137 patients treated with RA and 110 treated with IVL. The primary endpoint was one-year composite major adverse cardiovascular events (MACE), encompassing all-cause mortality, target vessel revascularization, heart failure rehospitalization, in-stent restenosis, and stroke. Three complementary analytical strategies of escalating robustness, multivariable logistic regression, inverse probability of treatment weighting (IPTW) using a gradient boosted model (GBM), and doubly robust estimation, were employed to estimate the treatment effect of IVL vs. RA. Covariate balance was assessed using standardized mean differences (SMD ≤ 0.10). Results: Baseline characteristics were broadly comparable between groups, with significant differences observed only in LDL-C, total cholesterol, and HDL-C (all P < 0.05). After IPTW, all 20 covariates achieved SMD ≤ 0.10. IPTW analysis demonstrated a significant 52% reduction in the odds of MACE with IVL (OR 0.48, 95% CI 0.25–0.90; P < 0.05), with directionally consistent estimates from multivariable logistic regression (OR 0.49, 0.18–1.23; P = 0.14) and doubly robust estimation (OR 0.48, 0.18–1.25; P = 0.13). Among secondary outcomes, one-year heart failure rehospitalization was significantly lower with IVL (OR 0.22, 95% CI 0.03–0.78; P = 0.03); no significant differences were observed for mortality, target vessel revascularization, stroke, or in-stent restenosis. Conclusions: In this retrospective cohort of patients with severely calcified coronary lesions, all of whom had concomitant tortuous or angulated anatomy, IVL was associated with a lower risk of one-year MACE compared with RA, an effect driven primarily by a reduction in heart failure rehospitalisation. The consistency across three analytical models suggests robustness of this finding, although confirmation in adequately powered randomised controlled trials is warranted.

Background and Aims: Deep vein thrombosis (DVT) remains a major health burden with incompletely understood mechanisms and limited therapeutic options. This study aims to investigate the role of key molecules in DVT and to explore the feasibility of treatment strategies based on this mechanism. Methods: Plasma proteomic profiling (LC-MS/MS) was performed on DVT patients and healthy controls, identifying syndecan-4 (SDC4) as a differentially expressed protein. Functional investigations utilized SDC4 knockout mice, endothelial cell (EC)-specific lineage tracing models, and single-cell RNA sequencing to assess endothelial-to-mesenchymal transition (EndMT) during DVT progression. In vitro EndMT models were established in human umbilical vein endothelial cells. Protein interactions were confirmed by co-immunoprecipitation. Piezo1 was pharmacologically inhibited in vivo, and network pharmacology was used to seek a potential therapeutic agent. Results: SDC4 levels were elevated in DVT patients. SDC4 deficiency exacerbated thrombus formation and promoted EndMT, as evidenced by reduced EC markers and increased mesenchymal markers. Single-cell sequencing revealed a specific EC subpopulation (C1) driving EndMT, with Piezo1 identified as a downstream mediator of SDC4. Co-IP confirmed direct SDC4–Piezo1 interaction. Piezo1 upregulation activated the PI3K/Akt pathway, Piezo1 knockdown attenuated EndMT and reduced thrombus burden. Quercetin directly bound Piezo1, reduced its expression in a dose-dependent manner, and significantly decreased thrombus size in DVT mice. Conclusions: SDC4 shedding exacerbates DVT by promoting Piezo1-dependent EndMT via PI3K/Akt signalling. Quercetin shows therapeutic potential as a Piezo1 inhibitor.

Neutrophil extracellular traps (NETs) constitute a vital antimicrobial defense mechanism of neutrophils, contributing to various physio-pathological processes; however, the role of plasma membrane asymmetry in this process remains unknown. Here we identify Xk-related protein 8 (XKR8), a plasma membrane phospholipid scramblase, as a pivotal regulator of NETs formation. Upon NETs induction, XKR8 is cleaved by caspase-3, thereby disrupting plasma membrane lipid asymmetry via phospholipid scrambling. Mutation of the caspase-3 cleavage site in XKR8 impairs NET formation. Inhibition of calcium signals before lipid scrambling abrogates NET formation, whereas blockade after scrambling does not. Cleaved XKR8 reorients plasma membrane lipids, altering membrane lipid tension and promoting Ca²⁺ signals through mechanosensitive channels. XKR8-deficient mice exhibit compromised NET formation and impaired control of Candida albicans pulmonary infection, showing that XKR8 is indispensable for neutrophil-driven immune responses in vivo. These findings define caspase-3–XKR8plasma membrane phospholipid scrambling as a central mechanism controlling NET formation and underscore its critical role in neutrophil-dependent antifungal immunity.

Acute myocardial infarction remains a leading threat to human health. Although advances in medical technology and the widespread adoption of emergency coronary interventions have significantly impr...

Epigenetic editing is a promising strategy for modifying gene expression while avoiding the permanent alterations and potential genotoxicity of genome-editing technologies. Here we designed optimized epigenetic regulators (EpiRegs) by testing combinations of transcription activator-like effector (TALE)-based and catalytically deactivated Cas9 (dCas9)-based epigenetic modification effectors and fusion protein structures. TALE-based EpiReg (EpiReg-T) achieved a final efficiency of 98% in mice, surpassing the initial dCas9-based efficiency of 64%. We demonstrated the approach in macaques by introducing DNA methylation and histone modifications to inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9) expression, thereby lowering low-density lipoprotein cholesterol levels. A single dose of EpiReg-T delivered with lipid nanoparticles achieved efficient (>90%) and long-lasting (343 days) silencing of PCSK9 in the liver. Integrative multiomic analyses revealed minimal off-target effects in EpiReg-T-treated monkeys, mice and human-derived cells. EpiReg can be redirected to other genes by reengineering the DNA-binding domain. Our findings represent a step toward the clinical application of epigenetic editing for the treatment of human diseases.

Excessive cardiac fibrosis is a key cause of heart failure and adverse ventricular remodeling after myocardial infarction. The abnormally activated fibroblasts after scar maturation are the chief culprit. Single-cell RNA sequencing of mouse cardiac interstitial cells after myocardial infarction depicts a late-activated fibroblast subpopulation F-Act and initially identifies its characteristic antigen CD248, which is also verified in human hearts. On this basis, we develop a CD248-targeted biotin-binding immune receptor T cell therapy against F-Act to correct cardiac repair disorders. In our study, the precise removal of F-Act after the scar matured effectively inhibits fibrotic expansion in the peri-infarct zone and improves cardiac function. This therapy provides an idea for the treatment of cardiac fibrosis and also promotes the application of engineered T cells to non-tumor diseases.

Small interfering RNA (siRNA) therapies hold great potential for treating myocardial ischemia-reperfusion injury (MIRI); while their practical application is limited by the low bioavailability, off-target effects, and poor therapeutic efficacy. Here, we present an innovative engineered neutrophil membrane-camouflaged nanocomplex for targeted siRNA delivery and effective MIRI therapy. A nanoparticle (NP)-based siRNA delivery system, namely MNM/siRNA NPs, is camouflaged with neutrophil membranes modified by hemagglutinin (HA) and integrins. Our comprehensive in vitro studies show that MNM/siRNA NPs effectively facilitate endosomal escape through HA, achieve excellent targeting via integrins, and significantly reduce integrin α9 expression. Furthermore, in MIRI mice, we identify integrin α9 as a potential target for MIRI therapy and demonstrate that MNM/siRNA NPs significantly decrease myocardial infarction area and improve cardiac function by reducing neutrophil recruitment, neutrophil extracellular trap (NET) and microthrombus formation. These findings highlight the engineered membrane-camouflaged NPs as a promising siRNA delivery platform, offering an effective treatment strategy for MIRI.