Validation of a novel staging classification system based on the extent of cardiac damage among Chinese patients after transcatheter aortic valve replacement: A single-center retrospective study.

OBJECTIVES: We aimed to validate a novel staging system for aortic stenosis (AS) in a Chinese patient cohort undergoing transcatheter aortic valve replacement (TAVR), and to compare this classification system to the traditional Society of Thoracic Surgeons (STS) score for TAVR risk stratification. BACKGROUND: A novel staging system for AS based on the extent of cardiac damage upon echocardiography was recently proposed. METHODS: Patients were prospectively enrolled into the Transcatheter Aortic Valve Replacement Single Center Registry in Chinese Population and analyzed retrospectively following additional exclusion criteria. On the basis of echocardiographic findings of cardiac damage, patients were classified into five stages (0-4). RESULTS: A total of 427 patients were included in the current analysis. Forty-eight deaths occurred during a median follow-up of 730 days following TAVR. The staging system showed a statistically significant association between cardiac damage and all-cause mortality; advanced stages were associated with higher mortality. In a multivariate-adjusted Cox proportional hazards regression model, stage and STS scores served as risk factors for 2-year mortality. Each increment in the staging class was associated with an increased risk of mortality (hazard ratio, 1.275; 95% confidence interval [CI], 1.052-1.545). Receiver operating characteristic (ROC) curves were plotted for stage (area under the curve, 0.644; 95% CI, 0.562-0.725) and STS score (0.661; 0.573-0.749), and with no statistically significant differences between ROC curves (p = 0.920). CONCLUSIONS: We validated a novel staging system as a key risk factor for 2-year mortality in a Chinese TAVR patient cohort. Efficacy for risk stratification was comparable to the STS score.

Soluble receptor for advanced glycation end-products promotes angiogenesis through activation of STAT3 in myocardial ischemia/reperfusion injury.

Soluble receptor for advanced glycation end-products (sRAGE), which exerts cardioprotective effect through inhibiting cardiomyocyte apoptosis and autophagy during ischemia/reperfusion (I/R) injury, is also known to enhance angiogenesis in post-ischemic reperfusion injury-critical limb ischemia (PIRI-CLI) mice. However, whether sRAGE protects the heart from myocardial I/R injury via promoting angiogenesis remains unclear. Myocardial model of I/R injury was conducted by left anterior descending (LAD) ligation for 30 min and reperfusion for 2 weeks in C57BL/6 mice. And I/R injury in cardiac microvascular endothelial cells (CMECs) was duplicated by oxygen and glucose deprivation. The results showed that I/R-induced cardiac dysfunction, inflammation and myocardial fibrosis were all reversed by sRAGE. CD31 immunohistochemistry staining showed that sRAGE increased the density of vessels after I/R injury. The results from cultured CMECs showed that sRAGE inhibited apoptosis and increased proliferation, migration, angiogenesis after exposure to I/R. These effects were dependent on signal transducer and activator of transcription 3 (STAT3) pathway. Together, the present study demonstrated that activation of STAT3 contributed to the protective effects of sRAGE on myocardial I/R injury via promoting angiogenesis.

Interferon-γ mediates the protective effects of soluble receptor for advanced glycation end-product in myocardial ischemia/reperfusion.

The ubiquitin-proteasome system (UPS) is essential for protein degradation and plays critical roles in myocardial ischemia/reperfusion (MI/R) injuries. Previous studies have demonstrated that the soluble receptor for advanced glycation end-product (sRAGE) inhibited MI/R-induced apoptosis by upregulating proteasome subunits. However, the mechanism remains unknown. An MI/R model was established by left anterior descending (LAD) coronary artery ligation in mice. Recombinant sRAGE protein or saline was injected intramyocardially with or without neutralizing interferon-γ (IFN-γ) antibody injected intraperitoneally before ligation. In cardiomyocytes, ischemia was simulated with "ischemia buffer" and sRAGE was overexpressed by adenovirus. Adenovirus expressing the interference RNA of ß5i was used to knockdown ß5i in cardiomyocytes. IFN-γ was induced by sRAGE both in sham and MI/R mice. Blockade of IFN-γ using IFN-γ antibody abolished the rescue effects of sRAGE for cardiac dysfunction, infarct size and apoptosis provoked by MI/R. Blockade of IFN-γ reversed the upregulation of ß1i and ß5i expression induced by sRAGE during MI/R in heart, accompanied by decreasing chymotrypsin-like proteasome activity. In addition, IFN-γ antibody abolished the suppressing effect of sRAGE on MI/R-induced p38 and c-Jun N-terminal kinase (JNK) activation, as well as p53 expression, both in vivo and in vitro. However, knockdown of ß5i abolished the antiapoptosis effect of sRAGE during hypoxia/reoxygenation (H/R) in vitro, accompanied by decreased degradation of p53. Our data suggest a novel mechanism for sRAGE in preventing MI/R-induced apoptosis in heart: sRAGE inhibits MI/R-induced apoptosis in cardiomyocytes by degrading p53 by ß5i subunit that is increased via upregulation of IFN-γ.

Gene expression profile in the early stage of angiotensin II-induced cardiac remodeling: a time series microarray study in a mouse model.

BACKGROUND/AIMS: Angiotensin II (Ang II) plays a critical role in the cardiac remodeling contributing to heart failure. However, the gene expression profiles induced by Ang II in the early stage of cardiac remodeling remain unknown. METHODS: Wild-type male mice (C57BL/6 background, 10-weeek-old) were infused with Ang II (1500 ng/kg/min) for 7 days. Blood pressure was measured. Cardiac function and remodeling were examined by echocardiography, H&E and Masson staining. The time series microarrays were then conducted to detected gene expression profiles. RESULTS: Microarray results identified that 1,489 genes were differentially expressed in the hearts at day 1, 3 and 7 of Ang II injection. These genes were further classified into 26 profiles by hierarchical cluster analysis. Of them, 4 profiles were significant (No. 19, 8, 21 and 22) and contained 904 genes. Gene Ontology showed that these genes mainly participate in metabolic process, oxidation-reduction process, extracellular matrix organization, apoptotic process, immune response, and others. Significant pathways included focal adhesion, ECM-receptor interaction, cytokine-cytokine receptor interaction, MAPK and insulin signaling pathways, which were known to play important roles in Ang II-induced cardiac remodeling. Moreover, gene co-expression networks analysis suggested that serine/cysteine peptidase inhibitor, member 1 (Serpine1, also known as PAI-1) localized in the core of the network. CONCLUSIONS: Our results indicate that many genes are mainly involved in metabolism, inflammation, cardiac fibrosis and hypertrophy. Serpine1 may play a central role in the development of Ang II-induced cardiac remodeling at the early stage.

The Predictors of Conduction Disturbances Following Transcatheter Aortic Valve Replacement in Patients With Bicuspid Aortic Valve: A Multicenter Study.

Objective: To evaluate the predictors of new-onset conduction disturbances in bicuspid aortic valve patients using self-expanding valve and identify modifiable technical factors. Background: New-onset conduction disturbances (NOCDs), including complete left bundle branch block and high-grade atrioventricular block, remain the most common complication after transcatheter aortic valve replacement (TAVR). Methods: A total of 209 consecutive bicuspid patients who underwent self-expanding TAVR in 5 centers in China were enrolled from February 2016 to September 2020. The optimal cut-offs in this study were generated from receiver operator characteristic curve analyses. The infra-annular and coronal membranous septum (MS) length was measured in preoperative computed tomography. MSID was calculated by subtracting implantation depth measure on postoperative computed tomography from infra-annular MS or coronal MS length. Results: Forty-two (20.1%) patients developed complete left bundle branch block and 21 (10.0%) patients developed high-grade atrioventricular block after TAVR, while 61 (29.2%) patients developed NOCDs. Coronal MS <4.9 mm (OR: 3.08, 95% CI: 1.63-5.82, p = 0.001) or infra-annular MS <3.7 mm (OR: 2.18, 95% CI: 1.04-4.56, p = 0.038) and left ventricular outflow tract perimeter <66.8 mm (OR: 4.95 95% CI: 1.59-15.45, p = 0.006) were powerful predictors of NOCDs. The multivariate model including age >73 years (OR: 2.26, 95% CI: 1.17-4.36, p = 0.015), Δcoronal MSID <1.8 mm (OR: 7.87, 95% CI: 2.84-21.77, p < 0.001) and prosthesis oversizing ratio on left ventricular outflow tract >3.2% (OR: 3.42, 95% CI: 1.74-6.72, p < 0.001) showed best predictive value of NOCDs, with c-statistic = 0.768 (95% CI: 0.699-0.837, p < 0.001). The incidence of NOCDs was much lower (7.5 vs. 55.2%, p < 0.001) in patients without Δcoronal MSID <1.8 mm and prosthesis oversizing ratio on left ventricular outflow tract >3.2% compared with patients who had these two risk factors. Conclusion: The risk of NOCDs in bicuspid aortic stenosis patients could be evaluated based on MS length and prosthesis oversizing ratio. Implantation depth guided by MS length and reducing the oversizing ratio might be a feasible strategy for heavily calcified bicuspid patients with short MS.

Soluble receptor for advanced glycation end-products enhanced the production of IFN-γ through the NF-κB pathway in macrophages recruited by ischemia/reperfusion.

The current study investigated the role of sRAGE in the production of IFN­Î³ in macrophages with I/R treatment. The number of macrophages in myocardial tissues treated with I/R with or without sRAGE was determined via immunohistochemical staining. Proliferative activity of macrophages was analyzed by a 5­BrdU incorporation assay. Differentiation of macrophages was detected via immunofluorescence staining of iNOS (M1 macrophage marker). IFN­Î³ production, due to sRAGE stimulation, in Raw 264.7 macrophages and the NF­κB signaling pathway were measured using western blotting. A ChIP assay was used to examine the interactions between NF­κB and the promoter of IFN­Î³. The results showed that the number of macrophages in I/R­treated myocardial tissues was increased following sRAGE infusion. Proliferation of macrophages was increased significantly in the presence of sRAGE; after I/R treatment, the cells preferred to differentiate into M1 macrophages. IFN­Î³ expression in Raw 264.7 macrophages was suppressed by an NF­κB inhibitor (Bay117082) but enhanced by sRAGE, with or without I/R treatment. Furthermore, sRAGE increased the phosphorylation of IκB, IKK and NF­κB, as well as the translocation of NF­κB into the nucleus of Raw 264.7 macrophages, with or without I/R treatment. ChIP results showed that sRAGE promoted NF­κB binding to the promoter of IFN­Î³ in Raw 264.7 macrophages. Therefore, the findings of the present study indicated that sRAGE protected the heart from I/R injuries, which might be mediated by promoting infiltration and the differentiation of macrophages into M1, which would then synthesize and secrete IFN­Î³ through activating the NF­κB signaling pathway.

Soluble receptor for advance glycation end-products inhibits ischemia/reperfusion-induced myocardial autophagy via the STAT3 pathway.

The pathogenesis of myocardial ischemia/reperfusion (I/R) is poorly understood, but recent evidence suggests that autophagy plays crucial roles in I/R injuries. Soluble receptor for advanced glycation end-products (sRAGE) exerts protective effects during I/R by decreasing cardiac apoptosis, which is mediated via increasing the ubiquitin proteasome system (UPS) and signal transducer and activator of transcription 3 (STAT3). The present study examined the effects and mechanisms of sRAGE on I/R-triggered cardiac autophagy. I/R was performed in mice or primary neonatal cardiomyocytes with or without sRAGE administration or overexpression. Cardiac function and infarct size were detected in mouse hearts. Apoptosis, autophagy and autophagy-related signaling pathways were detected in mouse hearts and cardiomyocytes. The results demonstrated that sRAGE significantly improved cardiac function and reduced infarct size during I/R in mice. sRAGE inhibited I/R-induced apoptosis, which correlated with a reduction in autophagy-associated proteins, including ATG7, Beclin-1 and microtubule-associated protein 1 light chain 3 (LC3). sRAGE reduced autophagosome formation during I/R in vivo and in vitro. sRAGE significantly activated STAT3, but not mammalian target of rapamycin (mTOR), during I/R in vivo and in vitro, and suppression of STAT3 abolished the sRAGE inhibition of autophagy during I/R in vitro. Activation of autophagy using ATG7 overexpression with an adenovirus significantly abolished the sRAGE-induced reduction of cardiac apoptosis during I/R. These results suggest that sRAGE inhibits I/R injuries in the heart via a decrease in autophagy, a process that is dependent on STAT3 activation.