European Heart Journal最新文献

Background and aims: Atherosclerosis (AS), a chronic inflammatory disorder, persists as the predominant contributor to global cardiovascular morbidity and mortality. Macrophage-mediated inflammatory response plays a pivotal role in atherosclerotic lesion progression. This study investigates the functional significance and therapeutic potential of macrophage SH3 domain-binding kinase 2 (SBK2) in AS pathogenesis, with particular emphasis on its translational relevance.

Methods: Single-cell sequencing data of atherosclerotic plaques in mice fed with high-fat diet for different time periods were analysed. SBK2 expression levels were quantified in both human atherosclerotic lesions and murine arterial tissues. This study evaluated the impacts of SBK2 whole-body knockout, macrophage-specific knockout, and overexpression on murine AS progression. The molecular mechanisms were systematically investigated through integrated approaches including single-cell sequencing, co-immunoprecipitation assays, in vitro kinase activity assays, and mass spectrometry analysis. High-throughput screening of a small-molecule compound library identified potent SBK2 agonists.

Results: SBK2 expression was elevated in macrophages within advanced murine and human atherosclerotic plaques. Despite this upregulation, genetic ablation or macrophage-specific SBK2 deficiency exacerbated plaque formation and inflammatory responses, whereas macrophage-targeted SBK2 overexpression attenuated disease progression. This indicates that SBK2 induction represents a compensatory protective response within the atherosclerotic microenvironment. Mechanistic studies revealed that SBK2 phosphorylates NLRP3 at Ser161, triggering Tollip-dependent autophagic degradation of the inflammasome component and subsequent inflammasome inactivation. Pharmacological activation of SBK2 using rebaudioside N (RN) effectively suppressed NLRP3-mediated IL-1β/IL-18 secretion, reduced inflammatory responses, and diminished atherosclerotic burden. Notably, RN's therapeutic effects were completely abolished in SBK2-deficient models, validating its target specificity.

Conclusions: Macrophage SBK2 serves as an endogenous safeguard factor that suppresses atherosclerosis by phosphorylating NLRP3 to enable its selective autophagic degradation. SBK2 is identified as the sole known protein kinase capable of mediating the selective clearance of this inflammasome. Targeting the SBK2-NLRP3 axis with RN offers a precise therapeutic strategy to mitigate inflammatory cardiovascular risk. This study identifies SBK2 as a novel therapeutic target and highlights kinase-driven inflammasome resolution as a paradigm for AS management.

Background and aims: Despite current antithrombotic treatments, the recurrence of ischaemic events remains high in patients with diabetes mellitus (DM) or aspirin resistance after acute coronary syndrome (ACS). Whether twice-daily aspirin dosing reduces major adverse cardiovascular events (MACE) in this population remains unknown.

Methods: In this prospective multicentre, randomized trial, patients with ACS and DM or high-risk of aspirin resistance (HRAR) defined as: (i) an index event occurring while on aspirin; (ii) body mass index ≥27 kg/m2; or (iii) increased waist circumference were assigned to receive enteric-coated aspirin once daily (100 mg/day) or twice daily (100 mg morning and evening). The primary outcome was MACE, a composite of any death, myocardial infarction, stroke, urgent coronary revascularization, stent thrombosis, or acute arterial thrombotic event assessed using a time-to-first-event analysis. The main secondary outcome was major bleeding (Bleeding Academic Research Consortium type 3-5).

Results: In total, 2484 participants were enrolled (77.2% with DM, 55.5% with ST-elevation segment myocardial infarction). The median follow-up duration was 18 (interquartile range: 17.6-18.3) months. The primary outcome occurred in 95 of 1228 participants (7.7%) in the twice-daily aspirin group, and 110 of 1256 (8.8%) in the once-daily group (hazard ratio [HR] 0.90; 95% confidence interval [CI] 0.69-1.19; P = .42). Major bleeding rates were similar between the groups (1.9% vs 2.1%; HR 0.88; 95% CI 0.50-1.55).

Conclusions: In patients with ACS and DM or HRAR, twice-daily aspirin did not significantly reduce the risk of MACE compared to once-daily dosing. No significant difference was observed in major bleeding between groups.

Trial registration: NCT02520921/EUDRACT No: 2015-000947-18.

Background and aims: Cardiac remodelling following MI is intricately linked to macrophage polarization dynamics, yet the underlying mechanisms remain incompletely elucidated. In this study, circHIPK2, a novel circRNA, was identified as being upregulated in inflammatory cardiac macrophages following MI. Its expression correlated with post-MI inflammation dynamics, suggesting a regulatory role in macrophage polarization. It was hypothesized that circHIPK2 functions as a molecular switch of macrophage polarization during MI progression.

Methods: To test this hypothesis, circHIPK2 levels were modulated in vitro using siRNA and overexpression vectors. A murine MI model with macrophage-targeted inhibition of circHIPK2 through AAV9-mediated shRNA delivery was employed. Cardiac function was evaluated using echocardiography, histology, and PET imaging. An ex vivo co-culture platform incorporating living myocardial slices from heart failure patients and circHIPK2-modulated human iPSC-derived macrophages was established to explore a translational potential.

Results: CircHIPK2 interacts with its binding partner G3BP1 to promote stress granule formation in macrophages. This interaction initiates a downstream inflammatory cascade, highlighting its role in immune regulation. Inhibition of circHIPK2 suppressed inflammatory signalling and reduced pro-inflammatory cytokine secretion. In a mouse model of MI, macrophage-specific inhibition of circHIPK2 improved cardiac function, reshaped the inflammatory environment, and attenuated fibrosis progression. Silencing circHIPK2 in human macrophages demonstrated therapeutic potential in established heart failure, promoting beneficial cardiac healing.

Conclusions: Targeting circHIPK2 in macrophages may represent a promising therapeutic strategy for treating inflammatory cardiac conditions and heart failure, potentially leading to the development of RNA-based therapies targeting immune cells in MI treatment.

Background and aims: Catheter ablation is performed in patients with recurrent ventricular tachycardia (VT) but remains complex and limited to experienced centres. Ventricular tachycardia ablation guided by pre-procedural imaging was shown promising in non-randomized trials. InEurHeart aims to evaluate computed tomography (CT)-guided VT ablation vs conventional ablation in a multicentre randomized controlled trial.

Methods: In 14 European centres, 113 patients with prior myocardial infarction and clinically significant VT were randomly assigned to CT-guided (n = 57) or conventional (n = 56) VT ablation. The primary objective was to demonstrate reduced procedural duration when using CT guidance. Secondary endpoints included efficacy (incidence and burden of ventricular arrhythmia), safety, as well as composite endpoints.

Results: The primary endpoint showed a significant decrease in procedure time favouring CT-guided ablation: 149 ± 51 to 120 ± 50 min, -19% [95% confidence interval (CI) -32; -7]; P = .0027 in intention to treat, and 149 ± 51 to 107 ± 38 min, -28% (95% CI -40; -16); P < .0001 per protocol. Major adverse events occurred in two (3.5%) in the conventional group vs one (1.8%) in the CT-guided group [-1.8% (95% CI -7.9; 4.3)]. Ventricular tachycardia-free survival at 1 year was achieved in 37 (67.3%) patients for conventional vs 43 (76.8%) for CT-guided VT ablation [9.5% (95% CI -10.4; 29.4), P = NS]. Ventricular tachycardia burden was decreased by 90% in the CT-guided group.

Conclusions: In patients with ischaemic cardiomyopathy, CT-guided VT ablation reduces the procedure duration while maintaining a favourable efficacy and safety profile when compared with VT ablation without image integration.

Background and aims: The benefits of the Mediterranean diet (MedDiet) are well established. However, one component, wine, remains controversial. This study assessed the association between MedDiet (with or without wine consumption) and major cardiovascular disease (CVD) or all-cause mortality.

Methods: The PREDIMED trial included 7447 high-risk participants. Adherence to MedDiet was measured using a validated 14-item questionnaire, including one item on wine (cut-off: seven glasses/week). The CVD events were recorded over a 4.8-year follow-up, while all-cause mortality was tracked for 17 years. A younger Spanish cohort (the SUN project), including 23,133 participants followed up for 22 years, was also evaluated.

Results: In PREDIMED, compared with poor compliers with MedDiet (excluding wine), good compliers (excluding wine), had a multivariable-adjusted hazard ratio (HR) of 0.84 [95% confidence interval (CI) 0.61-1.15] for CVD. For good compliers with MedDiet (including wine), the HR for CVD was 0.55 (95% CI 0.36-0.83). For all-cause mortality, MedDiet compliers (excluding wine) had HR of 0.77 (95% CI 0.68-0.87), which was 0.67 (95% CI 0.57-0.78) for MedDiet compliers (including wine). In exploratory dose-response analyses, reduced risk for death was not present in PREDIMED participants who drank three or more glasses of wine/day. Additionally, analyses least vulnerable to threats of abstainer bias were not significant and neither were multiplicative interaction terms for the wine item in the questionnaire. In the SUN cohort, no significant associations were observed between MedDiet compliance, wine, and CVD. However, for all-cause mortality, the HR was 0.94 (95% CI 0.71-1.26) for MedDiet compliers (excluding wine) and 0.54 (95% CI 0.28-1.04) for MedDiet compliers (including wine). When pooling both cohorts, wine consumption within the MedDiet was associated with lower all-cause mortality (P = .01).

Conclusions: In PREDIMED, moderate wine consumption, as part of the MedDiet, appeared to be associated with lower mortality and CVD risk. Some non-significant associations and interactions advise caution in interpretation of these findings.