Frequency of prothrombin time-international normalized ratio monitoring and the long-term prognosis in patients with mechanical valve replacement.

BACKGROUND: The study aimed to assess the correlation between the monitoring frequency of PT-INR and the long-term prognosis in patients with mechanical heart valve (MHV) replacement after discharge. METHODS: This single-center, observational study enrolled patients who underwent MHV replacement and discharged from June 2015 to May 2018. Patients or their corresponding family members were followed with a telephone questionnaire survey in July-October 2020. Based on monitoring intervals, patients were divided into frequent monitoring (FM) group (≤ 1 month) and less frequent monitoring (LFM) group (> 1 month). The primary endpoint was the composite of thromboembolic event, major bleeding or all-cause death. The secondary endpoints were thromboembolic event, major bleeding or all-cause death, respectively. RESULTS: A total of 188 patients were included in the final analysis. The median follow-up duration was 3.6 years (Interquartile range: 2.6 to 4.4 years). 104 (55.3%) patients and 84 (44.7%) patients were classified into the FM group and the LFM group, respectively. The FM group had a significantly lower incidence of the primary endpoint than the LFM group (3.74 vs. 1.16 per 100 patient-years, adjusted HR: 3.31 [95% CI 1.05-10.42, P = 0.041]). Secondary analysis revealed that the risk of thromboembolic events and all-cause death were also reduced in the FM group. CONCLUSIONS: The management of warfarin treatment in patients after MHV replacement remains challenging. Patients with less frequent monitoring of PT-INR might have worse clinical prognosis than those with frequent PT-INR monitoring.

Transcription factor Sp2 promotes TGFB-mediated interstitial cell osteogenic differentiation in bicuspid aortic valves through a SMAD-dependent pathway.

Calcification of the bicuspid aortic valve (BAV) involves differential expression of various RNA genes, which is achieved through complex regulatory networks that are controlled in part by transcription factors and microRNAs. We previously found that miR-195-5p regulates the osteogenic differentiation of valvular interstitial cells (VICs) by targeting the TGF-ß pathway. However, the transcriptional regulation of miR-195-5p in calcified BAV patients is not yet clear. In this study, stenotic aortic valve tissues from patients with BAVs and tricuspid aortic valves (TAVs) were collected. Candidate transcription factors of miR-195-5p were predicted by bioinformatics analysis and tested in diseased valves and in male porcine VICs. SP2 gene expression and the corresponding protein levels in BAV were significantly lower than those in TAV, and a low SP2 expression level environment in VICs resulted in remarkable increases in RNA expression levels of RUNX2, BMP2, collagen 1, MMP2, and MMP9 and the corresponding proteins. ChIP assays revealed that SP2 directly bound to the transcription promoter region of miR-195-5p. Cotransfection of SP2 shRNA and a miR-195-5p mimic in porcine VICs demonstrated that SP2 repressed SMAD7 expression via miR-195-5p, while knockdown of SP2 increased the mRNA expression of SMAD7 and the corresponding protein and attenuated Smad 2/3 expression. Immunofluorescence staining of diseased valves confirmed that the functional proteins of osteogenesis differentiation, including RUNX2, BMP2, collagen 1, and osteocalcin, were overexpressed in BAVs. In Conclusion, the transcription factor Sp2 is expressed at low levels in VICs from BAV patients, which has a negative impact on miR-195-5p expression by binding its promoter region and partially promotes calcification through a SMAD-dependent pathway.

Nesfatin-1 mitigates calcific aortic valve disease via suppressing ferroptosis mediated by GSH/GPX4 and ZIP8/SOD2 axes.

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.

Operative Mortality After Type A Aortic Dissection Surgery: Differences Based on Sex and Age.

Background: There is controversy regarding sex differences in short-term mortality in acute type A aortic dissection (ATAAD). Objectives: This study aimed to investigate the impact of sex differences on 30-day operative mortality after ATAAD surgery and to determine if other covariates modify the association. Methods: Consecutive patients (N = 5670) with surgically repaired ATAAD were identified from the multicenter China 5A study. The primary outcome was operative mortality. The age dependency was modeled using a cubic spline curve. Results: There were 1,503 females (26.5%) and 4,167 males (73.5%). Females were older and had a lower percentage of comorbidities compared with males. Females had higher mortality compared to males (10.2% vs 8.2%, P = 0.019); however, there was no difference after propensity analyses (adjusted OR: 1.334 [95% CI: 0.918-1.938]). There was an interaction with sex and age (P interaction = 0.035): older age was associated with higher odds of operative mortality among females (OR: 1.045 [95% CI: 1.029-1.061]) compared with males (OR: 1.025 [95% CI: 1.016-1.035]). The risk of mortality for males and females appears to diverge at 55 years of age (P interaction = 0.019): females under 55 years of age had similar odds to males (OR: 0.852 [95% CI: 0.603-1.205]) but higher odds when over 55 years (OR: 1.420 [95% CI: 1.096-1.839]) compared to males. Conclusions: Under the age of 55 years, females have similar odds of operative mortality compared with males; however, over the age of 55 years females have higher odds than males. Understanding differences in risk allows for individualized treatment strategies. (Additive Anti-inflammatory Action for Aortopathy & Arteriopathy; NCT04398992).

Valve-in-valve/valve-in-ring transcatheter mitral valve implantation vs. redo surgical mitral valve replacement for patients with failed bioprosthetic valves or annuloplasty rings: A systematic review and meta-analysis.

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.

BMAL1 Promotes Valvular Interstitial Cells' Osteogenic Differentiation through NF-κ B/AKT/MAPK Pathway.

OBJECTIVES: Calcific aortic valve disease (CAVD) is most common in the aging population and is without effective medical treatments. Brain and muscle ARNT-like 1 (BMAL1) is related to calcification. It has unique tissue-specific characteristics and plays different roles in different tissues' calcification processes. The purpose of the present study is to explore the role of BMAL1 in CAVD. METHODS: The protein levels of BMAL1 in normal and calcified human aortic valves and valvular interstitial cells (VICs) isolated from normal and calcified human aortic valves were checked. HVICs were cultured in osteogenic medium as an in vitro model, and BMAL1 expression and location were detected. TGF-ß and RhoA/ROCK inhibitors and RhoA-siRNA were applied to detect the mechanism underlying the source of BMAL1 during HVICs' osteogenic differentiation. ChIP was applied to check whether BMAL1 could directly interact with the runx2 primer CPG region, and the expression of key proteins involved in the TNF signaling pathway and NF-κ B pathway was tested after silencing BMAL1. RESULTS: In this study, we found that BMAL1 expression was elevated in calcified human aortic valves and VICs isolated from calcified human aortic valves. Osteogenic medium could promote BMAL1 expression in HVICs and the knockdown of BMAL1 induced the inhibition of HVICs' osteogenic differentiation. Furthermore, the osteogenic medium promoting BMAL1 expression could be blocked by TGF-ß and RhoA/ROCK inhibitors and RhoA-siRNA. Meanwhile, BMAL1 could not bind with the runx2 primer CPG region directly, but knockdown of BMAL1 led to decreased levels of P-AKT, P-IκBα, P-p65 and P-JNK. CONCLUSIONS: Osteogenic medium could promote BMAL1 expression in HVICs through the TGF-ß/RhoA/ROCK pathway. BMAL1 could not act as a transcription factor, but functioned through the NF-κ B/AKT/MAPK pathway to regulate the osteogenic differentiation of HVICs.

Thoracoscopic ablation delays progression from paroxysmal to persistent atrial fibrillation.

OBJECTIVE: The study objective was to determine whether mini-invasive transthoracoscopic atrial fibrillation ablation can delay the progression of atrial fibrillation from paroxysmal to persistent. METHODS: Patients aged 18 to 80 years with paroxysmal nonvalvular atrial fibrillation and a history of stroke or systemic thromboembolism were consecutively enrolled from September 2014 to June 2019. In the treatment group, patients underwent transthoracoscopic atrial fibrillation ablation plus left atrial appendage excision (atrial fibrillation ablation plus left atrial appendage excision group). Patients unwilling to receive surgical intervention were treated with antiarrhythmic drugs and oral anticoagulants and recruited as a control group (atrial fibrillation plus antiarrhythmic drugs group). The primary end point was the progression of atrial fibrillation from paroxysmal to persistent. RESULTS: This study included 49 patients in the atrial fibrillation plus antiarrhythmic drugs group (29 men) and 77 patients in the atrial fibrillation ablation plus left atrial appendage excision group (48 men). In the atrial fibrillation ablation plus left atrial appendage excision group, after a median follow-up of 951 days (interquartile range, 529-1366 days), 8 patients (10.4%) progressed to persistent atrial fibrillation. In the atrial fibrillation plus antiarrhythmic drugs group, after a median follow-up of 835 days (interquartile range, 548-1214 days), 14 patients (28.6%) progressed to persistent atrial fibrillation. The atrial fibrillation ablation plus left atrial appendage excision group had a significantly lower incidence of atrial fibrillation progression than the atrial fibrillation plus antiarrhythmic drugs group during follow-up (3.9 vs 12.3 per 100 person-years, log-rank 8.6, P = .003). CONCLUSIONS: Patients with paroxysmal nonvalvular atrial fibrillation who chose to undergo transthoracoscopic atrial fibrillation ablation had a lower incidence of progression to persistent atrial fibrillation than patients who chose conservative therapy. This strategy might be especially suitable for patients with paroxysmal nonvalvular atrial fibrillation at high risk of stroke and high risk of bleeding.

Preoperative Predictors of Late Aortic Expansion in Acute Type B Aortic Dissection Treated with TEVAR.

BACKGROUND: A patent false lumen (FL) in patients with thoracic endovascular aortic repair (TEVAR)-treated type B aortic dissection (TBAD) can cause a significant risk for late aortic expansion (LAE). We hypothesize that preoperative features can predict the occurrence of LAE. METHODS: Sufficient preoperative and postoperative follow-up clinical and imaging feature data for patients treated with TEVAR in the First Affiliated Hospital of Nanjing Medical University from January 2018 to December 2020 were collected. A univariate analysis and multivariable logistic regression analysis were used to find potential risk factors of LAE. RESULTS: Ninety-six patients were finally included in this study. The mean age was 54.5 ± 11.7 years and 85 (88.5%) were male. LAE occurred in 15 (15.6%) of 96 patients after TEVAR. Two preoperative factors showed strong associations with LAE according to the multivariable logistic regression analysis: preoperative partial thrombosis of the FL (OR = 10.989 [2.295-48.403]; p = 0.002) and the maximum descending aortic diameter (OR = 1.385 [1.100-1.743] per mm increase; p = 0.006). CONCLUSIONS: Preoperative partial thrombosis of the FL and an increase in the maximum aortic diameter are strongly associated with late aortic expansion. Additional interventions of the FL may help to improve the prognosis of patients with the high risk of late aortic expansion.

False lumen-dependent segmental arteries are associated with spinal cord injury in frozen elephant trunk procedure for acute type I aortic dissection.

Objective: To investigate the association between false lumen (FL) dependency of segmental arteries (SAs) at T9-L3 levels and the risk of spinal cord injury (SCI) following total arch replacement and frozen elephant trunk (FET) implantation in the setting of acute DeBakey type I aortic dissection (AAD). Methods: The study involved consecutive patients with AAD who underwent total arch replacement and FET implantation between 2020 and 2022. Primary outcome was postoperative SCI. The inverse probability of treatment weighting (IPTW) method was employed to minimize the impact of no-randomization bias. Antegrade placement of FET was followed by end-to-end anastomosis of a 4-branch arch graft at the proximal landing site of FET. Results: A total of 146 patients were included (age, 50.5 ± 11.7 years, 115 male), of whom 35 (24%) had SAs at T9-L3 levels completely dependent on FL (FL-dependency group). There was no significant difference in early (30-day or in-hospital) mortality rates between FL-dependency (14.3%) and FL-independency (18.0%) groups (P = .80), however, the rate of SCI was significantly higher in the FL-Dependency group (34.3% vs 2.7%, P < .001). After adjustments, FL dependency was associated with a significantly increased risk of SCI (odds ratio, 13.1; 95% confidence interval, 4.2-41.0; P < .001), whereas it was not significantly associated with risks of early mortality or other major complications (P = .16-.98). Conclusions: FL dependency of SAs at the T9-L3 levels was significantly associated with the development of SCI following FET implantation in AAD, warning against its uses on patients presenting with FL dependency of SAs at critical segments.

Upregulated microRNA­330­3p promotes calcification in the bicuspid aortic valve via targeting CREBBP.

One key risk factor of aortic valve stenosis in clinical practice is bicuspid aortic valve (BAV). Increasing evidence indicates that numerous microRNAs (miRs/miRNAs) are involved in BAV calcification via their target genes. miR­330­3p was found to be involved in the deterioration of BAV calcification by miR profiling in human calcified BAV and tricuspid aortic valve (TAV) tissues in the present study and the underlying mechanism was investigated. RNA sequencing was performed on four BAV and four TAV tissues from patients with aortic stenosis before these leaflets were examined for the expression levels of miR­330­3p and CREB­binding protein (CREBBP) by reverse transcription­PCR. The alteration of functional factors associated with calcification was also assessed by Western blotting and immunohistochemistry in human aortic tissue samples. The putative target of miR­330­3p was detected by dual­luciferase assay in 293 cells. Furthermore, the influence of miR­330­3p expression on osteogenic progression was explored in cultured porcine valve interstitial cells (VICs). Rescue experiments of CRBBP were performed to confirm the influence of the miR­330­3p­CREBBP pathway in the calcification progress in porcine VICs. RNA sequencing indicated distinct expression of miR­330­3p in human BAV tissues compared with TAV, which was then confirmed by PCR. CREBBP expression levels in human BAV and TAV leaflets also demonstrated the opposite alterations. This negative correlation was then confirmed in cultured porcine VICs. Under an osteogenic environment, cellular calcification was promoted in miR­330­3p­overexpressed porcine VICs expressing higher bone morphogenetic protein 2, Runt­related transcription factor 2, matrix metalloproteinase (MMP)­2, MMP­9 and collagen I compared with controls. Rescue experiments further confirmed that miR­330­3p played its role via targeting CREBBP in porcine VICs. Collectively, miR­330­3p was upregulated in calcified BAV compared with TAV. The upregulation of miR­330­3p promotes the calcification progress partially via targeting CREBBP.

Rab7­mediated autophagy regulates phenotypic transformation and behavior of smooth muscle cells via the Ras/Raf/MEK/ERK signaling pathway in human aortic dissection.

Autophagy regulates the metabolism, survival and function of numerous types of cell, including cells that comprise the cardiovascular system. The dysfunction of autophagy has been demonstrated in atherosclerosis, restenotic lesions and hypertensive vessels. As a member of the Ras GTPase superfamily, Rab7 serves a significant role in the regulation of autophagy. The present study evaluated how Rab7 affects the proliferation and invasion, and phenotypic transformations of aortic dissection (AD) smooth muscle cells (SMCs) via autophagy. Rab7 was overexpressed in AD tissues and the percentage of synthetic human aortic SMCs (HASMCs) was higher in AD tissues compared with NAD tissues. Downregulation of Rab7 decreased cell growth, reduced the number of invasive cells and decreased the percentage cells in the G1 phase. Autophagy of HASMCs was inhibited following Rab7 knockdown. Inhibition of autophagy with 3­methyladenine or Rab7 knockdown suppressed the phenotypic conversion of contractile to synthetic HASMCs. The action of Rab7 may be mediated by inhibiting the Ras/Raf/mitogen­activated protein kinase (MAPK) kinase (MEK)/extracellular signal related kinase (ERK) signaling pathway. In conclusion, the results revealed that Rab7­mediated autophagy regulated the behavior of SMCs and the phenotypic transformations in AD via activation of the Ras/Raf/MEK/ERK signaling pathway. The findings of the present study may improve understanding of the role Rab7 in the molecular etiology of AD and suggests the application of Rab7 as a novel therapeutic target in the treatment of human AD.

Hybrid ablation versus transcatheter ablation for atrial fibrillation: A meta-analysis.

BACKGROUND: Despite the successful creation of complex lesion sets during hybrid ablation (HA), reoccurrence of atrial fibrillation (AF), and/or atrial arrhythmia and procedural complications still occur. The main objective of this study was to compare the efficacy and safety between HA and transcatheter ablation (TA). METHODS: We searched Pubmed, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) database up to October 2017. Studies that satisfied our predefined inclusion criteria were included. Of the 894 records, 4 studies encompassing 331 patients were included in our study. We assessed pooled data using random-effect or fixed-effect model. The main endpoint was freedom of atrial arrhythmia after follow-up duration, secondary results were procedure time and intraoperative and postoperative adverse events. Similarly, tertiary outcomes were endocardial time, fluoroscopy time, and postoperative hospitalization. RESULTS: Compared with TA, HA treatment through mini-thoracotomy access improved superiority in freedom of atrial arrhythmia after follow-up duration (odds ratio [OR] = 6.67, 95% confidence interval [CI]: 2.63-16.90), but HA increased the incidence of intraoperative and postoperative adverse events for AF patients (OR = 2.98, 95% CI: 1.30-6.83). HA through either mini-thoracotomy or transdiaphragmatic/subxiphoid access had longer procedure time and postoperative hospitalization than TA. However, endocardial time was shorter than TA. CONCLUSIONS: For AF patients, HA possessed of an overall superior outcome using mini-thoracotomy way to TA. Although HA had longer procedure time, it yielded a reduction in endocardial time. Meanwhile, we should pay attention to the significantly high risk of intraoperative and postoperative adverse events that the HA generated.