ABSTRACT
OBJECTIVE: Calcific aortic valve disease (CAVD) predominantly affects the elderly and currently lacks effective medical treatments. Nesfatin-1, a peptide derived from the cleavage of Nucleobindin 2, has been implicated in various calcification processes, both physiological and pathological. This study explores the impact of Nesfatin-1 on the transformation of aortic valve interstitial cells (AVICs) in CAVD. METHODS AND RESULTS: In vitro experiments showed that Nesfatin-1 treatment mitigated the osteogenic differentiation of AVICs. Corresponding in vivo studies demonstrated a deceleration in the progression of CAVD. RNA-sequencing of AVICs treated with and without Nesfatin-1 highlighted an enrichment of the Ferroptosis pathway among the top pathways identified by the Kyoto Encyclopedia of Genes and Genomes analysis. Further examination confirmed increased ferroptosis in both calcified valves and osteoblast-like AVICs, with a reduction in ferroptosis following Nesfatin-1 treatment. Within the Ferroptosis pathway, ZIP8 showed the most notable modulation by Nesfatin-1. Silencing ZIP8 in AVICs increased ferroptosis and osteogenic differentiation, decreased intracellular Mn2+ concentration, and reduced the expression and activity of superoxide dismutase (SOD2). Furthermore, the silencing of SOD2 exacerbated ferroptosis and osteogenic differentiation. Nesfatin-1 treatment was found to elevate the expression of glutathione peroxidase 4 (GPX4) and levels of glutathione (GSH), as confirmed by Western blotting and GSH concentration assays. CONCLUSION: In summary, Nesfatin-1 effectively inhibits the osteogenic differentiation of AVICs by attenuating ferroptosis, primarily through the GSH/GPX4 and ZIP8/SOD2 pathways.
Subject(s)
Aortic Valve Stenosis , Aortic Valve , Calcinosis , Ferroptosis , Nucleobindins , Phospholipid Hydroperoxide Glutathione Peroxidase , Superoxide Dismutase , Ferroptosis/genetics , Nucleobindins/metabolism , Nucleobindins/genetics , Animals , Aortic Valve/pathology , Aortic Valve/metabolism , Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism , Phospholipid Hydroperoxide Glutathione Peroxidase/genetics , Calcinosis/metabolism , Calcinosis/pathology , Calcinosis/genetics , Aortic Valve Stenosis/metabolism , Aortic Valve Stenosis/pathology , Aortic Valve Stenosis/genetics , Superoxide Dismutase/metabolism , Superoxide Dismutase/genetics , Humans , Cation Transport Proteins/metabolism , Cation Transport Proteins/genetics , Glutathione/metabolism , Male , Osteogenesis/drug effects , Osteogenesis/genetics , Mice , Rats , DNA-Binding Proteins/metabolism , DNA-Binding Proteins/genetics , Osteoblasts/metabolism , Osteoblasts/pathology , Osteoblasts/drug effects , Disease Models, Animal , Cell Differentiation , Calcium-Binding Proteins/metabolism , Calcium-Binding Proteins/geneticsABSTRACT
Background: Valve-in-valve (ViV)/valve-in-ring (ViR) transcatheter mitral valve implantation (TMVI) is a less invasive alternative to redo surgical mitral valve replacement (SMVR). To further verify its feasibility, we aimed to appraise early clinical outcomes after either ViV/ViR TMVI or redo SMVR for failed bioprosthetic valves or annuloplasty rings, as a comparison of long-term follow-up results are not available for these procedures. Methods: We systematically searched PubMed, Cochrane Controlled Trials Register, EMBASE, and Web of Science to identify studies that compared ViV/ViR TMVI and redo SMVR. Fixed- and random-effects meta-analyses were used to compare the early clinical results between these two groups. Results: A total of 3,890 studies published from 2015 to 2022 were searched, and ten articles comprising 7,643 patients (ViV/ViR TMVI, 1,719 patients; redo SMVR, 5,924 patients) were included. In this meta-analysis, ViV/ViR TMVI significantly improved in-hospital mortality (fixed-effects model: odds ratio [OR], 0.72; 95% confidence interval [CI], 0.57-0.92; P = 0.008) and for the matched populations (fixed-effects model: OR, 0.42; 95% CI, 0.29-0.61; P < 0.00001). ViV/ViR TMVI also outperformed redo SMVR in 30-day mortality and in rates of early postoperative complications. ViV/ViR TMVI resulted in less time spent in the ICU and hospital, whereas it showed no significant difference in one-year mortality. A lack of comparison of long-term clinical outcomes and postoperative echocardiographic results are important limitations of our results. Conclusions: ViV/ViR TMVI is a reliable alternative to redo SMVR for failed bioprosthetic valves or annuloplasty rings as a result of lower in-hospital mortality, higher 30-day survival, and lower early postoperative complication rates, although there is no significant difference in 1-year mortality.
ABSTRACT
Association of distinct inflammatory profiles with short-term mortality is little known in type A aortic dissection (TAAD). Latent class analysis was used to identify distinct inflammatory profiles based on leukocyte, neutrophils, monocyte, lymphocytes, platelet, fibrinogen, D-dimer, neutrophils-lymphocyte ratio, platelet-lymphocyte ratio, and lymphocyte-monocyte ratio. We identified 193 patients with median age of 56 (IQR 47-63) years and 146 males. Patients were divided as hyper-inflammatory profiles (84 [43.5%]) and hypo-inflammatory profiles (109 [56.5%]). Although baseline characteristics were not different, hyper-inflammatory patients had higher 6-month mortality (20 [23.8%] vs. 11 [10.1%]; P = 0.014) and 30-day mortality (18 [21.4%] vs. 9 [8.3%], P = 0.009) than hypo-inflammatory patients. After adjustment for potential confounders, hyper-inflammatory profiles remain associated with higher risk of 6-month mortality than hypo-inflammatory profiles (adjusted OR 2.427 [95%CI 1.154, 5.105], P = 0.019). Assessment of preoperative inflammatory profiles adds clarity regarding the extent of inflammatory response to TAAD aetiopathologies, highlighting individual anti-inflammatory pharmacotherapy for TAAD. ClinicalTrials.gov Identifier: NCT04398992.