Objectives The inflammatory cascade and cell death post-myocardial ischemia reperfusion (MI/R) are very complex. Despite the understanding that macrophage inflammation has a pivotal role in the pathophysiology of MI/R, the contribution of macrophage inflammatory signals in tailoring the function of vascular endothelium remains unknown. Materials and methods In the present study, we analyzed the effects of NEDD4 on the NLRP3 inflammasome activation-mediated pyroptosis in vitro after an acute pro-inflammatory stimulus and in vivo in a MI/R mouse model. TTC and Evan’s blue dye, Thioflavin S, immunohistochemistry staining, and ELISA were performed in wild-type and NEDD4 deficiency mice. THP-1 cells were transfected with si-NEDD4 or si-SF3A2. HEK293T cells were transfected with NEDD4 or SF3A2 overexpression plasmid. ELISA analyzed the inflammatory cytokines in the cell supernatant. The levels of NEDD4, SF3A2, and NLRP3/GSDMD pathway were determined by Western blot. Protein interactions were evaluated by immunoprecipitation. The protein colocalization in cells was monitored using a fluorescence microscope. Results NEDD4 inhibited NLRP3 inflammasome activation and pyroptosis in THP-1 cells treated with lipopolysaccharide (LPS) and nigericin (Nig). Mechanistically, NEDD4 maintained the stability of NLRP3 through direct interaction with the SF3A2, whereas the latter association with NLRP3 indirectly interacted with NEDD4 promoting proteasomal degradation of NLRP3. Deletion of NLRP3 expression further inhibited the caspase cascade to induce pyroptosis. Interestingly, inhibiting NLRP3 inflammasome activation in THP-1 cells could prevent cardiac microvascular endothelial cells (CMECs) injury. In addition, NEDD4 deficiency decreased animal survival and increased myocardial infarct size, no-reflow area, and promoted macrophages infiltration post-MI/R. Conclusions NEDD4 could be a potential therapeutic target in microvascular injury following myocardial reperfusion.

ObjectivesLittle is known about the clinical prognosis of gasdermin D (GSDMD) in patients with ST-elevation myocardial infarction (STEMI). The purpose of this study was to investigate the association of GSDMD with microvascular injury, infarction size (IS), left ventricular ejection fraction (LVEF), and major adverse cardiac events (MACEs), in STEMI patients with primary percutaneous coronary intervention (pPCI).MethodsWe retrospectively analyzed 120 prospectively enrolled STEMI patients (median age 53 years, 80% men) treated with pPCI between 2020 and 2021 who underwent serum GSDMD assessment and cardiac magnetic resonance (CMR) within 48 h post-reperfusion; CMR was also performed at one year follow-up.ResultsMicrovascular obstruction was observed in 37 patients (31%). GSDMD concentrations ≧ median (13 ng/L) in patients were associated with a higher risk of microvascular obstruction and IMH (46% vs. 19%, P = 0.003; 31% vs. 13%, P = 0.02, respectively), as well as with a lower LVEF both in the acute phase after infarction (35% vs. 54%, P < 0.001) and in the chronic phase (42% vs. 56%, P < 0.001), larger IS in the acute (32% vs. 15%, P < 0.001) and in the chronic phases (26% vs. 11%, P < 0.001), and larger left ventricular volumes (119 ± 20 vs. 98 ± 14, P = 0.003) by CMR. Univariable and multivariable Cox regression analysis results showed that patients with GSDMD concentrations ≧ median (13 ng/L) had a higher incidence of MACE (P < 0.05).ConclusionsHigh GSDMD concentrations in STEMI patients are associated with microvascular injury (including MVO and IMH), which is a powerful MACE predictor. Nevertheless, the therapeutic implications of this relation need further research.

BackgroundThe strategy of ablation index (AI)-guided high-power ablation seems to be a novel strategy for performing pulmonary vein isolation (PVI). An AI-guided high-power ablation strategy was used in this study to determine whether superior vena cava isolation (SVCI) after PVI was feasible and safe for patients with AF.MethodsData from 53 patients with AF were collected. Mapping and ablation of SVC were performed. The applied power was set at 45 W and the procedure was guided by AI. The SVC was divided into six segments in a cranial view. The RF applications and AI values in different segments were compared and analyzed. Using receiver operating characteristic (ROC) analysis, the diagnostic accuracy of AI value for predicting segment block was evaluated.ResultsElectrical SVCIs were successfully achieved in all patients. SVCI was performed by segment ablation in most cases, with RF applications in different segments. The mean AI value in non-lateral walls was higher than that of the lateral wall (392 ± 28 vs. 371 ± 37, P < 0.001). Acutely blocked sites had significantly larger AI values compared with no-blocked sites (390 ± 30 vs. 343 ± 23, P < 0.001). The optimal AI cut-off value for non-lateral segments was 379 (sensitivity: 75.9%, specificity: 100%) and for lateral segments was 345 (sensitivity: 82.3%, specificity: 100%).ConclusionThe AI values were predictive of the acute conduction block of SVCI. With AI values of 345 and 379, respectively, conduction block was achieved in the lateral walls at a lower level than in the non-lateral walls.

Background: Ethanol infusion of the vein of Marshall (EI-VOM) has been widely used to facilitate mitral isthmus (MI) ablation. According to the literature, the success rate of achieving a bidirectional conduction block across the MI ranges from 51% to 96%, and there is no standardized strategy or method for other cardiac electrophysiologists. Objectives: This study aimed to introduce and evaluate a novel ablation method of MI. Methods: Consecutive patients with persistent atrial fibrillation (PeAF) that underwent catheter ablation were included. The MI ablation procedure followed a stepwise approach. In step 1, Ethanol infusion of the vein of Marshall (EI-VOM) was performed; in step 2, a "V-shape" endocardial linear ablation connecting the left inferior pulmonary vein (LIPV) to mitral annulus (MA) was performed; in step 3, earliest activation sites(EASs) near the ablation line were identified using activation mapping and reinforced ablation was performed; in step 4, precise epicardial ablation was performed, with the catheter introduced into the coronary sinus(CS) to aim at key ablation targets (KATs). Results: 135 patients with PeAF underwent catheter ablation. Finally, 119 of them were included in the stepwise ablation method. Bidirectional conduction blocks were achieved in 117 patients (98.3%). The block rates of every step were 0%, 58.0%, 44.0%, and 92.9%, and the cumulative block rates for the four steps were 0%, 58.0%, 76.5%, and 98.3%, respectively. No patient suffered from fatal complications. Conclusions: Our novel stepwise catheter ablation method for MI demonstrated a high bidirectional block rate with high reproducibility.