Search

Abstract Background To evaluate the clinical outcomes and the validity of the in situ needle fenestration (ISNF) technique during thoracic endovascular aortic repair (TEVAR) for patients with aortic arch conditions. Methods A total of 115 patients with aortic arch conditions treated with ISNF during TEVAR between January 2018 and December 2021 were incorporated. Results The median age of the patients was 62.0 years, and 10.4% (12/115) were female. The median follow-up time was 31.0 months. A total of 175 supra-arch branches were reconstructed. A single branch was fenestrated in 80 patients, while the left subclavian artery (LSA) and left common carotid artery (LCCA) were fenestrated simultaneously in 11 patients, and all supra-arch branches were fenestrated in 24 patients. The rate of technical success was 100%, 30-day mortality was 3.5% (4/115), overall mortality was 8.7% (10/115), and aortic-related mortality was 2.6% (3/115). Aortic-related reintervention was required in 7.8% (9/115) of patients. Among the major postoperative complications, four patients developed retrograde type A dissection requiring emergent open surgery, three patients had cerebrovascular accidents, and one patient had an endoleak. No occlusions or stenoses of the main or branch aortic stents were observed. Conclusions The mid-term results of the ISNF technique during TEVAR for aortic arch conditions were within the acceptable range; however, further follow-up results are needed and long-term stability and durability needs to be assessed. Related fenestration devices also require further development.

Abstract The serum uric acid to serum creatinine ratio (SUA/sCr) is a standardized index of renal function. More importance was attached to the significance of this ratio in the progression of hypertension. While the association between the prognosis of hypertension and SUA/sCr is unknown. Therefore, we aimed to prospectively examine the associations of serum uric acid to serum creatinine ratio and all-cause and CVD mortality in adults with hypertension. Participants with hypertension from NHANES 1999–2018 (n = 15,269) were included. They were stratified by 1 increment of SUA/sCr ratio and categorized into 6 groups as ≤ 4, > 4 to 5, > 5 to 6, > 6 to 7, > 7 to 8, and > 8. The reason for categorization in 6 groups was to analyze the influence of different ratios on outcomes accurately and provide more precise guidance. The sample size is large enough that even if divided into 6 groups, it does not affect the statistical power. The primary outcomes were all-cause and CVD mortality. Weighted multivariable Cox proportional hazards regression models were used to estimate hazard ratio (HRs) of mortality. Restricted cubic spline regression models were utilized to examine dose–response associations between the serum uric acid to serum creatinine ratio and all-cause and CVD mortality. Relatively comprehensive stratified analyses were conducted to confirm the accuracy and stability of the results. There were 15,269 total participants, 49.4% of whom were men, with an average age of 56.6 years. Weighted multivariable Cox proportional hazards regression models demonstrated participants in the lowest group (≤ 4) had the HRs (95% CIs) of 1.43 (1.18, 1.73) for all-cause mortality and 2.8 (1.92, 4.10) for CVD mortality when compared to the reference group. Participants in the highest group (> 8) had the HRs (95% CIs) of 0.47 (0.25, 0.89) for CVD mortality when compared to the reference group. There were progressively lower risks for all-cause and CVD mortality with the SUA/sCr ratio increased (both P trend

Endothelial-to-mesenchymal transition (EndMT) is a key driver of atherosclerosis. Aerobic glycolysis is increased in the endothelium of atheroprone areas, accompanied by elevated lactate levels. Histone lactylation, mediated by lactate, can regulate gene expression and participate in disease regulation. However, whether histone lactylation is involved in atherosclerosis remains unknown. Here, we report that lipid peroxidation could lead to EndMT-induced atherosclerosis by increasing lactate-dependent histone H3 lysine 18 lactylation (H3K18la) in vitro and in vivo, as well as in atherosclerotic patients’ arteries. Mechanistically, the histone chaperone ASF1A was first identified as a cofactor of P300, which precisely regulated the enrichment of H3K18la at the promoter of SNAI1, thereby activating SNAI1 transcription and promoting EndMT. We found that deletion of ASF1A inhibited EndMT and improved endothelial dysfunction. Functional analysis based on ApoeKOAsf1aECKO mice in the atherosclerosis model confirmed the involvement of H3K18la in atherosclerosis and found that endothelium-specific ASF1A deficiency inhibited EndMT and alleviated atherosclerosis development. Inhibition of glycolysis by pharmacologic inhibition and advanced PROTAC attenuated H3K18la, SNAI1 transcription, and EndMT-induced atherosclerosis. This study illustrates precise crosstalk between metabolism and epigenetics via H3K18la by the P300/ASF1A molecular complex during EndMT-induced atherogenesis, which provides emerging therapies for atherosclerosis.

Summary: Macrophage activation is a hallmark of atherosclerosis, accompanied by a switch in core metabolism from oxidative phosphorylation to glycolysis. The crosstalk between metabolic rewiring and histone modifications in macrophages is worthy of further investigation. Here, we find that lactate efflux-associated monocarboxylate transporter 4 (MCT4)-mediated histone lactylation is closely related to atherosclerosis. Histone H3 lysine 18 lactylation dependent on MCT4 deficiency activated the transcription of anti-inflammatory genes and tricarboxylic acid cycle genes, resulting in the initiation of local repair and homeostasis. Strikingly, histone lactylation is characteristically involved in the stage-specific local repair process during M1 to M2 transformation, whereas histone methylation and acetylation are not. Gene manipulation and protein hydrolysis-targeted chimerism technology are used to confirm that MCT4 deficiency favors ameliorating atherosclerosis. Therefore, our study shows that macrophage MCT4 deficiency, which links metabolic rewiring and histone modifications, plays a key role in training macrophages to become repair and homeostasis phenotypes.

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

Abstract 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.

AbstractObjectives To ascertain if postoperative thrombocytopenia following open aortic surgery with a median sternotomy can predict early- and intermediate-term morbidity and mortality.Methods From January 2018 to December 2022, a comparison was made between patients who had and didn’t have postoperative thrombocytopenia (defined as a nadir < 75 × 103/μL after 72 h of open aortic surgery with median sternotomy). Intermediate-term mortality during follow-up was the main result, with cerebrovascular accident and acute renal injury requiring dialysis as secondary events. Inverse probability treatment weighting (IPTW) was used to account for selection bias between groups. The Kaplan-Meier method with the log-rank test was used to assess intermediate-term survivals following IPTW modification. To identify the nonlinear link between platelet nadir and mortality probability, a generalized additive mix model was applied. To help increase power in testing for the overall effect of platelet nadir on outcomes in the generalized additive mix model, the hazard ratios and 95% CIs for each subgroup and their interactions were examined.Results The study included 457 patients, 347 male (75.9%), with mean age of 54 ± 12 years. The last follow-up was done on April 14th, 2023 and the median follow-up time was 16 (6-31) months. Following IPTW, patient characteristics were balanced among cohorts. Platelet nadir was found to be significantly inversely related to early-term mortality (IPTW-adjusted hazard ratio = 0.968 (0.960, 0.977), p

ABSTRACTMarfan syndrome (MFS) is an autosomal dominant connective tissue disorder caused by mutation in fibrillin-1 (FBN1). However, the molecular mechanism underlying MFS remains poorly understood. The study aimed to explore how the L-type calcium channel (CaV1.2) modulates disease progression of MFS and to identify a potential effective target for attenuating MFS. KEGG enrichment analysis showed that the calcium signaling pathway gene set was significantly enriched. We demonstrated that FBN1 deficiency exhibited inhibition on both the expression of Cav1.2 and proliferation of vascular smooth muscle cells (VSMCs). Then, we examined whether FBN1 mediates Cav1.2 via regulating TGF-β1. Higher levels of TGF-β1 were observed in the serum and aortic tissues from patients with MFS. TGF-β1 modulated Cav1.2 expression in a concentration-dependent manner. We evaluated the role of Cav1.2 in MFS by small interfering RNA and Cav1.2 agonist Bay K8644. The effect of Cav1.2 on cell proliferation was dependent on c-Fos activity. These results demonstrated FBN1 deficiency decreased the expression levels of Cav1.2 via regulation of TGF-β1, and downregulation of Cav1.2 inhibited cell proliferation of human aortic smooth muscle cells (HASMCs) in MFS patients. These findings suggest that Cav1.2 may be an appealing therapeutic target for MFS.

The systemic benefits of anti-inflammatory pharmacotherapy vary across cardiovascular diseases in clinical practice. We aimed to evaluate the application of artificial intelligence to acute type A aortic dissection (ATAAD) patients to determine the optimal target population who would benefit from urinary trypsin inhibitor use (ulinastatin). Patient characteristics at admission in the Chinese multicenter 5A study database (2016–2022) were used to develop an inflammatory risk model to predict multiple organ dysfunction syndrome (MODS). The population (5,126 patients from 15 hospitals) was divided into a 60% sample for model derivation, with the remaining 40% used for model validation. Next, we trained an extreme gradient-boosting algorithm (XGBoost) to develop a parsimonious patient-level inflammatory risk model for predicting MODS. Finally, a top-six-feature tool consisting of estimated glomerular filtration rate, leukocyte count, platelet count, De Ritis ratio, hemoglobin, and albumin was built and showed adequate predictive performance regarding its discrimination, calibration, and clinical utility in derivation and validation cohorts. By individual risk probability and treatment effect, our analysis identified individuals with differential benefit from ulinastatin use (risk ratio [RR] for MODS of RR 0.802 [95% confidence interval (CI) 0.656, 0.981] for the predicted risk of 23.5%–41.6%; RR 1.196 [0.698–2.049] for the predicted risk of 41.6%). By using artificial intelligence to define an individual’s benefit based on the risk probability and treatment effect prediction, we found that individual differences in risk probability likely have important effects on ulinastatin treatment and outcome, which highlights the need for individualizing the selection of optimal anti-inflammatory treatment goals for ATAAD patients.

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

Abstract Purpose The present study evaluated the efficacy of C-reactive protein (CRP) and D-dimer and the combination of them as prognostic indicators for patients with acute type A aortic dissection (ATAAD). Methods This is a retrospective cohort study. From January 2019 to December 2021, patients with ATAAD admitted to the emergency medicine center of our hospital within 24 h after symptoms (chest pain, back pain, abdominal pain and so on) onset were enrolled in our study. Serum concentration of CRP and D-dimer were measured during hospitalization. Logistic regression was used to evaluate the association between these two biomarkers and in-hospital adverse outcomes (IAO) by adjusting confounding factors. Predictive efficacy was assessed by area under the curve (AUC) of receiver operating characteristic curve. Results A total of 199 patients with ATAAD were finally enrolled. They were categorized as Non-IAO group (n = 146) and IAO group (n = 53) according to postoperative outcomes. After controlling for potentially confounding variables, we found categorized variables that admission CRP > 54.28 mg/L, admission D-dimer > 8.45 mg/L and peak D-dimer > 24.89 mg/L were independent predictors of in-hospital adverse outcomes. Multiple Logistic regression analysis revealed that the odd ratios were 2.9 for admission D-dimer > 8.45 [95% Confidence Interval (CI) 1.11–7.5, p = 0.03], 4.9 for admission CRP > 54.28 (95% CI 1.6–14.9, p = 0.005) and 5.7 for peak D-dimer > 24.89 (95% CI 2.49–13, p 8.45 mg/L, peak D-dimer > 24.89 mg/L and admission CRP > 54.28 mg/L are independent predictors of in-hospital adverse outcomes in patients with ATAAD. Combination of these three markers will improve the predictive efficacy.

Background: The study was aimed at investigating the mathematical relationship between the aortic valve and aortic root through CTA imaging-based reconstruction. Methods: We selected 121 healthy participants and analyzed the measurements of aortic root dimensions, including the sinotubular junction (SJT), ventriculo-arterial junction (VAJ), maximum sinus diameter (SD), sinus height (SH), effective height (eH) and coaptation height (cH). We also reconstructed 3-D aortic valve cusps using CTA imaging to calculate the aortic cusp surface areas. Data were collected to analyze the ratios and the correlation between aortic valve and aortic root dimensions. Results: Among healthy participants, the STJ was approximately 10% larger than the VAJ, and the SD was 1.375 times larger than the VAJ. The average eH and cH were 8.94 mm and 3.62 mm, respectively. The aortic cusp surface areas were larger in men than women. Regardless of sex, the non-coronary cusp was found to be largest, and was followed by the right coronary cusp and the left coronary cusp. Although the aortic root dimensions were also significantly larger in in men than women, the STJ to VAJ, SD to VAJ, and SH to VAJ ratios did not significantly differ by sex. The mathematical relationship between the aortic cusp surface areas and VAJ orifice area was calculated as aortic cusp surface areas Conclusions: The aortic root has specific geometric ratios. The mathematical relationship between the aortic valve and aortic root might be used to guide aortic valve repair.

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-β 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-β 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-β/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.

Background: Mechanical prostheses and bioprosthetic prostheses have their own advantages and disadvantages. Mechanical ones are recommended for younger patients (70 years old). There is still debate regarding which kind of prosthesis is better for middle-aged patients (50 to 70 years old) receiving aortic valve replacement (AVR). To solve this problem, we conducted this meta-analysis. Given that only one randomized controlled trial (RCT) study was included, we conducted a subgroup analysis of RCT and propensity score matching (PSM) retrospective studies to reduce the bias. Methods: We systematically searched articles related to clinical outcomes of mechanical and bioprosthetic prostheses in middle-aged patients receiving AVR in the PubMed, Cochrane Library, and China National Knowledge Infrastructure (CNKI) databases. The published date was up to 1 October 2022. Studies were excluded if not only middle-aged patients were included, or if they lacked direct comparisons between mechanical and bioprosthetic prostheses. Results: In total, 22 studies with 32,298 patients were included in the final analysis. The results show that patients aged between 50 and 70 receiving AVR with mechanical prostheses achieved better long-term survival and fewer reoperations and valve-related events but suffered more with bleeding events. No significant difference could be found in terms of early mortality and long-term cardiac death. The same results could be observed in the subgroup analysis of RCT and PSM retrospective studies. Conclusion: Both mechanical and bioprosthetic prostheses are beneficial to middle-aged patients undertaking AVR procedures. However, mechanical prostheses show better clinical outcomes in long-term survival and comorbidities. Individual recommendation is still necessary.

Abstract Aortic valve calcification develops in patients with chronic kidney disease who have calcium and phosphate metabolic disorders and poor prognoses. There is no effective treatment except valve replacement. However, metabolic disorders put patients at high risk for surgery. Increased acetylation of histones 3 and 4 is present in interstitial cells from human calcific aortic valves, but whether it is involved in aortic valve calcification has not been studied. In this study, we found that treating cultured porcine aortic valve interstitial cells with a high-calcium/high-phosphate medium induced calcium deposition, apoptosis, and expression of osteogenic marker genes, producing a phenotype resembling valve calcification in vivo. These phenotypic changes were attenuated by the histone acetyltransferase inhibitor C646. C646 treatment increased the levels of class I histone deacetylase members and decreased the acetylation of histones 3 and 4 induced by the high-calcium/high-phosphate treatment. Conversely, the histone deacetylase inhibitor suberoylanilide hydroxamic acid promoted valve interstitial cell calcification. In a mouse model of aortic valve calcification induced by adenine and vitamin D treatment, the levels of acetylated histones 3 and 4 were increased in the calcified aortic valves. Treatment of the models with C646 attenuated aortic valve calcification by restoring the levels of acetylated histones 3 and 4. These observations suggest that increased acetylation of histones 3 and 4 is part of the pathogenesis of aortic valve calcification associated with calcium and phosphate metabolic disorders. Targeting acetylated histones 3 and 4 may be a potential therapy for inoperable aortic valve calcification in chronic kidney disease patients.

Background: Bicuspid aortic valve is a heritable heart valve disease with characteristic early onset of valve calcification and stenosis with rapid progression compared with tricuspid aortic valve. Strong evidence indicates that many miRNAs and their target genes are involved in the development of BAV calcification. This study was designed to investigate miR-15a and Smad7 expressions in BAV and their mechanism of regulating calcification. Methods: Immunohistochemistry and western blotting were used to explore the expression levels of Smad7 and Runx2 in human aortic valve tissue. The expression of miR-15a, Smad7 and Runx2 were detected by RT-PCR. The relationship between miR-15a and Smad7 was assessed by dual-luciferase assay. MiR-15a was overexpressed in cultured porcine valve interstitial cells (PVICs) and the variations of Smad7 and Runx2 mRNA were evaluated by RT-PCR, as well as the changes of Smad7 and Runx2 protein. Alizarin reds staining was used to verify the calcification inhibition effect of miR-15a in cultured PVICs under calcification induction. Results: Compared with calcified TAV, remarkable higher expression of Smad7 and Runx2 were found in calcified BAV, significantly lower expressions of miR-15a and higher expressions of Smad7 and Runx2 mRNA, along with negative correlation between expressions of miR-15a and mRNA level of Smad7. MiR-15a-overexpressed PVICs shown upregulation of miR-15a, downregulation of Smad7 and Runx2 expression. PVICs under calcification induction shown significantly reduced calcification in miR-15a-overexpressed group. Conclusions: The lower miR-15a expression in BAV results in the high expression of Smad7, thereby reducing antagonism of Smad2/3–Smad4 complex to runx2 and promoting the progress of BAV calcification.

Background/Aims: Aortic stenosis caused by leaflet calcification in the bicuspid aortic valve (BAV) is more accelerative than that in the tricuspid aortic valve (TAV). MicroRNA-195 (miR-195) is downregulated more in stenotic than in insufficient BAVs, but its expression in BAVs compared with TAVs is unclear. We aimed to investigate the roles of miR-195 and its calcification-related target SMAD7 in stenotic BAVs compared with those in TAVs. Methods: Twenty-one stenotic BAV and 29 TAV samples were collected from surgical patients and examined for the expression of miR-195 and SMAD7 by RT-PCR. The samples were also assessed by western blotting and immunohistochemistry for the functional protein alteration associated with calcification. Dual-luciferase assay was performed to determine the putative target of miR-195 before the effects of miR-195 expression on osteogenic progression was demonstrated in cultured porcine valve interstitial cells (VICs). Results: Compared with TAV, the expression of miR-195 was remarkably lower in the BAV leaflet with higher expression of SMAD7, which was then validated as a direct target of miR-195. Their negative correlation was then confirmed in cultured VICs. Under an osteogenic environment, the cellular calcification was promoted in miR-195-repressed VICs expressing higher BMP-2 and Runx2 and higher activity of MMP-2 compared with the controls. Finally, higher MMP-2 and MMP-9 expression and more collagen distribution were observed in BAV than TAV samples. Conclusions: miR-195 is downregulated more in stenotic BAV than TAV in this study. The downregulation of miR-195 is associated with valvular calcification via targeting SMAD7, which promotes the remodeling of the extracellular matrix.

The human induced pluripotent stem cell line HELPi001-A was derived from peripheral blood mononuclear cells (PBMC) of a 35-year-old female Beals syndrome patient carrying a heterozygous FBN2c.728 T > C mutation. HELPi001-A were positive for pluripotent stem cell markers, had a normal karyotype and the ability to differentiate into cells representing all three germ layers. The patient not only demonstrated typical characteristics of Beals syndrome such as joint contractures and crumpled ears, but also demonstrated aortic dissection. HELPi001-A could serve as a platform for exploring the pathogenesis of cardiovascular and connective tissue disorders related to FBN2 mutation.

Background Chronic intermittent hypoxia (CIH) is a distinct pathological mechanism of obstructive sleep apnea (OSA), which is recognized as an independent risk factor for cardiovascular diseases. The aims of this study were to ascertain whether CIH induces atrial fibrillation (AF), to determine whether cardiac sympathetic denervation (CSD) can prevent it and suppress blood pressure, and to explore the potential molecular mechanisms involved. Methods and Results Sixty Sprague‐Dawley male rats were randomly divided into 4 groups: sham, CSD, CIH, CIH+CSD. The rats were exposed either to CIH 8 hours daily or normoxia for 6 weeks. Cardiac pathology and structure were analyzed by hematoxylin and eosin staining and echocardiogram. ECG, blood pressure, body weight, and blood gas were recorded. Connexin 43 and tyrosine hydroxylase were detected by western blot, immunohistochemistry, and immunofluorescence. CIH induced atrial remodeling, and increased AF inducibility. CSD treatment reduced postapneic blood pressure rises and AF susceptibility, which could attenuate CIH‐associated structural atrial arrhythmogenic remodeling. In addition, CIH‐induced sympathetic nerve hyperinnervation and CSD treatment reduced sympathetic innervation, which may affect CIH‐induced AF‐associated sympathovagal imbalance. Connexin 43 was specifically downregulated in CIH, whereas CSD treatment increased its expression. Conclusions These results suggested CIH induces atrial remodeling, increases AF inducibility, results in sympathetic nerve hyperinnervation, and decreases connexin 43 expression, but CSD treatment reduces AF susceptibility, postapneic blood pressure increase, sympathetic innervation, and the alteration of Cx43, which may be a key point in the genesis of CIH‐induced AF.

Background/Aims: Abnormal expression of microRNA-124 (miR-124) was found in non-small cell lung cancer (NSCLC). However, the association between miR-124 and CDH2 has not been reported yet. This study aims to reveal the inhibiting effects of miR-124 on the expression of CDH2 in NSCLC. Methods: Quantitative real-time polymerase chain reaction was used to evaluate the expression of miR-124 and CDH2 in NSCLC tissues. Cell viability, apoptosis and invasion assays were carried out in NSCLC cell lines after transfection. The regulation mechanism was confirmed by luciferase report assay and western blot (WB). Results: Significantly decreased expression of miR-124 was found in NSCLC specimens and cell lines. Overexpression of miR-124 apparently suppressed the proliferation and invasion of NSCLC cell lines in vitro. Luciferase report assay and WB revealed that CDH2 was a target gene of miR-124. Furthermore, results of WB showed that epithelial-mesenchymal transition (EMT) could be inhibited by up-regulation of miR-124. Conclusions: Taken together, our findings present the first evidence that miR-124 could suppress the expression of CDH2 and regulate EMT, which might lead to a potential therapeutic strategy focusing on miR-124 and CDH2 for human lung cancer.

Background Marfan syndrome (MFS) is an inherited connective tissue disorder affecting the ocular, skeletal and cardiovascular systems. Previous studies of MFS have demonstrated the association between genetic defects and clinical manifestations. Our purpose was to investigate the role of novel genetic variants in determining MFS clinical phenotypes. Methods We sequenced the whole exome of 19 individuals derived from three Han Chinese families. The sequencing data were analyzed by a standard pipeline. Variants were further filtered against the public database and an in-house database. Then, we performed pedigree analysis under different inheritance patterns according to American College of Medical Genetics guidelines. Results were confirmed by Sanger sequencing. Results Two novel loss-of-function indels (c.5027_5028insTGTCCTCC, p.D1677Vfs*8; c.5856delG, p.S1953Lfs*27) and one nonsense variant (c.8034C>A, p.Y2678*) of FBN1 were identified in Family 1, Family 2 and Family 3, respectively. All affected members carried pathogenic mutations, whereas other unaffected family members or control individuals did not. These different kinds of loss of function (LOF) variants of FBN1 were located in the cbEGF region and a conserved domain across species and were not reported previously. Conclusions Our study extended and strengthened the vital role of FBN1 LOF mutations in the pathogenesis of MFS with an autosomal dominant inheritance pattern. We confirm that genetic testing by next-generation sequencing of blood DNA can be fundamental in helping clinicians conduct mutation-based pre- and postnatal screening, genetic diagnosis and clinical management for MFS.

Rheumatic heart disease is an autoimmune disease caused by group A streptococci infection and frequently affects the aortic valve. Sex differences are common in the disease progression, treatment, and outcome. However, little is known about the sex differences in the pathology of aortic valves in rheumatic heart disease.We studied the end-stage calcific aortic valves from male versus female patients to reveal the sex-dependent pathology differences and molecular changes associated with requiring valve replacement.Aortic valves from 39 patients with rheumatic heart disease (19 males and 20 females) were collected at the time of aortic valve replacement for comparative pathology, immunohistochemistry, and gene expression analyses. Clinical characteristics were also analyzed and compared between the two groups.Aortic valves from female patients exhibited increased expression of collagens, infiltration of monocytes/macrophages and neovascularization. Aortic valves from female patients also had increased expression of inflammatory genes involved in the NFKB pathway (phosphorylated NFKB p65 subunit, IL8, and NOS3) and Th1 cytokine genes (IFNA and IL12B). The severe valve pathology in female patients was correlated with a higher serum level of anti-streptolysin O antibodies.Inflammation is more prominent in aortic valves of female patients with rheumatic heart disease. This sex difference may contribute to the severe valve pathology and worse outcome of female patients.