Endothelial Dysfunction in Patients with Severe Mitral Regurgitation

Mitral valve prolapse (MVP) is the most common cause of severe mitral regurgitation. It has been reported that MVP patients-candidates for mitral valve repair (MVRep)-showed an alteration in the antioxidant defense systems as well as in the L-arginine metabolic pathway. In this study, we investigate if oxidative stress and endothelial dysfunction are an MVP consequence or driving factors. Forty-five patients undergoing MVRep were evaluated before and 6 months post surgery and compared to 29 controls. Oxidized (GSSG) and reduced (GSH) forms of glutathione, and L-arginine metabolic pathway were analyzed using liquid chromatography-tandem mass spectrometry methods while osteoprotegerin (OPG) through the ELISA kit and circulating endothelial microparticles (EMP) by flow cytometry. Six-month post surgery, in MVP patients, the GSSG/GSH ratio decreased while symmetric and asymmetric dimethylarginines levels remained comparable to the baseline. Conversely, OPG levels significantly increased when compared to their baseline. Finally, pre-MVRep EMP levels were significantly higher in patients than in controls and did not change post surgery. Overall, these results highlight that MVRep completely restores the increased oxidative stress levels, as evidenced in MVP patients. Conversely, no amelioration of endothelial dysfunction was evidenced after surgery. Thus, therapies aimed to restore a proper endothelial function before and after surgical repair could benefit MVP patients

Corrigendum to “Identification of Patients Affected by Mitral Valve Prolapse with Severe Regurgitation: A Multivariable Regression Model”

In the article titled "Identification of Patients Affected by Mitral Valve Prolapse with Severe Regurgitation: A Multivariable Regression Model" [1], references [2, 3] should have been included as references 24 and 25 in the original article. Accordingly, in the introduction section, the text reading "Echocardiographically, MVP is defined as a single or bileaflet prolapse, at least 2mm beyond the long-axis annular plane, while the assessment of valve regurgitation takes into account the effective regurgitant orifice area (EROA) [2]" should be changed to "Echocardiographically, MVP is defined as a single or bileaflet prolapse, at least 2 mm beyond the long-axis annular plane, while the assessment of the severity of MR relies on several parameters according to the current recommendations [24, 25]." Additionally, the Acknowledgments section should be updated as follows: "The authors thank the entire Cardiac Surgery Unit at Centro Cardiologico Monzino for the clinical data and blood collection. The authors also would like to thank Dr. Paola Gripari for patient evaluation and critical review. This work was supported by the Fondazione Gigi e Pupa FerrariONLUS and the Italian Ministry of Health [RC2015-BIO30-2613051 to Centro CardiologicoMonzino].

Identification of patients affected by mitral valve prolapse with severe regurgitation : A multivariable regression model

Background. Mitral valve prolapse (MVP) is the most common cause of severe mitral regurgitation. Besides echocardiography, up to now there are no reliable biomarkers available for the identification of this pathology. We aim to generate a predictive model, based on circulating biomarkers, able to identify MVP patients with the highest accuracy. Methods. We analysed 43 patients who underwent mitral valve repair due to MVP and compared to 29 matched controls. We assessed the oxidative stress status measuring the oxidized and the reduced form of glutathione by liquid chromatography-tandem mass spectrometry method. Osteoprotegerin (OPG) plasma levels were measured by an enzyme-linked immunosorbent assay. The combination of these biochemical variables was used to implement several logistic regression models. Results. Oxidative stress levels and OPG concentrations were significantly higher in patients compared to control subjects (0.116\ub10.007 versus 0.053\ub10.013 and 1748\ub1100.2 versus 1109\ub145.3 pg/mL, respectively; p<0.0001). The best regression model was able to correctly classify 62 samples out of 72 with accuracy in terms of area under the curve of 0.92. Conclusions. To the best of our knowledge, this is the first study to show a strong association between OPG and oxidative stress status in patients affected by MVP with severe regurgitation

PCSK9 expression is regulated by pro-inflammatory cytokines and adipokines in HEPG2 cells

Aim: Clinical, genetic and experimental evidence indicates that proprotein convertase subtilisin/kexin 9 (PCSK9) may be either a cause or an effect of metabolic syndrome (MetS). We have recently demonstrated that PCSK9 is regulated by pro-inflammatory cytokine TNF-\u3b1 in a SOCS3-dependent manner (Ruscica et al., JBC, 2016). Thus, the present work aimed to further extend this observation and studied the possible molecular mechanisms linking the effects of cytokines (TNF-\u3b1) and adipokines (leptin and resistin) on de novo lipogenesis and PCSK9 expression. Methods: Human hepatocellular liver carcinoma cell line (HepG2) and HepG2 overexpressing PCSK9 (HepG2PCSK9) were used as in vitro tools. qPCR, Western blot, ELISA and luciferase reporter assays, together with siRNA directed to STAT3 and SOCS3, were used. Results: HepG2 expresses leptin (ObRl), resistin (Adenylyl cyclase-associated protein 1, CAP1), and adiponectin (AdipoR2) receptors. Notably, HepG2PCSK9 expresses higher levels of ObRl and AdipoR2. Twenty-four h treatment of HepG2 with TNF-\u3b1 (10 ng/mL), leptin (200 ng/mL) and resistin (50 ng/mL) induced the expression of both PCSK9 (2.3-, 2.0- and 3.5-fold, respectively) and the suppressor of JAK/STAT pathway, SOCS3 (3-, 1.8- and 1.9-fold, respectively). TNF-\u3b1 and leptin increased the secreting PCSK9 (+15% and +20%, respectively) but only leptin stimulated (+46%) PCSK9 promoter activity (+20%). TNF-\u3b1, leptin and resistin induced the gene expression of apoB, sterol regulatory element-binding protein 1 (SREBP1), stearoyl-CoA desaturase-1 (SCD-1), fatty acid synthase (FAS) and microsomal triglyceride transfer protein (MTP). The TNF-\u3b1 mediated effects were inhibited by transfection with siRNA anti-STAT3, suggesting the involvement of the JAK/STAT pathway. Conclusions: Pro-inflammatory cytokines and adipokines up-regulate PCSK9 expression and the key genes involved in the de novo lipogenesis. Future analyses will investigate the potential role of JAK/STAT/SOCS3 pathways in mediating these effects

Pre- and post-transplant minimal residual disease predicts relapse occurrence in children with acute lymphoblastic leukaemia

Relapse remains the leading cause of treatment failure in children with acute lymphoblastic leukaemia (ALL) undergoing allogeneic haematopoietic stem cell transplantation (HSCT). We retrospectively investigated the prognostic role of minimal residual disease (MRD) before and after HSCT in 119 children transplanted in complete remission (CR). MRD was measured by polymerase chain reaction in bone marrow samples collected pre-HSCT and during the first and third trimesters after HSCT (post-HSCT1 and post-HSCT3). The overall event-free survival (EFS) was 50%. The cumulative incidence of relapse and non-relapse mortality was 41% and 9%. Any degree of detectable pre-HSCT MRD was associated with poor outcome: EFS was 39% and 18% in patients with MRD positivity &lt;1&nbsp;×&nbsp;10−3 and ≥1&nbsp;×&nbsp;10−3, respectively, versus 73% in MRD-negative patients (P&nbsp;&lt;&nbsp;0·001). This effect was maintained in different disease remissions, but low-level MRD had a very strong negative impact only in patients transplanted in second or further CR. Also, MRD after HSCT enabled patients to be stratified, with increasing MRD between post-HSCT1 and post-HSCT3 clearly defining cohorts with a different outcome. MRD is an important prognostic factor both before and after transplantation. Given that MRD persistence after HSCT is associated with dismal outcome, these patients could benefit from early discontinuation of immunosuppression, or pre-emptive immuno-therapy

Impact of Valve Morphology on the Prevalence of Coronary Artery Disease : A Systematic Review and Meta-Analysis

Background-Literature studies suggested a lower prevalence of coronary artery disease (CAD) in bicuspid aortic valve (BAV) than in tricuspid aortic valve (TAV) patients. However, this finding has been challenged. We performed a meta-analysis to assess whether aortic valve morphology has a different association with CAD, concomitant coronary artery bypass grafting (CABG), and postoperative mortality. Methods and Results-Detailed search was conducted according to the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guideline to identify all patients with BAV or TAV and presence of CAD, concomitant myocardial surgical revascularization, and the postoperative mortality. Thirty-one studies on 3017 BAV and 4586 TAV patients undergoing aortic valve surgery were included. BAV patients showed a lower prevalence of CAD (odds ratio [OR]: 0.33; 95% CI: 0.17, 0.65), concomitant CABG (OR, 0.45; 95% CI: 0.35, 0.59), and postoperative mortality (OR, 0.62; 95% CI: 0.40, 0.97) than TAV. However, BAV subjects were significantly younger than TAV (mean difference: -7.29; 95% CI: -11.17, -3.41) were more frequently males (OR, 1.61; 95% CI: 1.33, 1.94) and exhibited a lower prevalence of hypertension (OR, 0.58; 95% CI: 0.39, 0.87) and diabetes (OR, 0.71; 95% CI: 0.54, 0.93). Interestingly, a metaregression analysis showed that younger age and lower prevalence of diabetes were associated with lower prevalence of CAD (Z value: -3.03; P=0.002 and Z value: -3.10; P=0.002, respectively) and CABG (Z value: -2.69; P=0.007 and Z value: -3.36; P=0.001, respectively) documented in BAV patients. Conclusions-Analysis of raw data suggested an association of aortic valve morphology with prevalence of CAD, concomitant CABG, and postoperative mortality. Interestingly, the differences in age and diabetes have a profound impact on prevalence of CAD between BAV and TAV. In conclusion, our meta-analysis suggests that the presence of CAD is independent of aortic valve morphology

Markers of subclinical atherosclerosis in patients with aortic valve sclerosis : A meta-analysis of literature studies

Objective: Growing evidence suggested an association between aortic valve sclerosis (AVSc) and cardiovascular (CV) events. However, little is known about the association of AVSc with major markers of subclinical atherosclerosis. We performed a meta-analysis of literature studies to address this issue. Approach and Results: Studies on the relationship between AVSc and common carotid artery intima-media thickness (IMT), prevalence of carotid plaques (CPs), flow-mediated dilation (FMD), aortic pulse wave velocity (PWV) and augmentation index (AIx) were systematically searched in electronic databases. Thirteen studies enrolling 1086 AVSc patients and 2124 controls were included. Compared to controls, AVSc patients showed higher IMT (MD: 0.32 mm; 95%CI: 0.07, 0.58; p=0.014), and higher prevalence of CPs (OR: 4.06; 95%CI: 2.38, 6.93; p<0.001). Moreover, lower FMD (MD: -4.48%; 95%CI: -7.23, -1.74; p=0.001) and higher PWV (MD: 0.96%; 95%CI: 0.11, 1.81; p=0.027) were found in AVSc subjects than in controls, with no differences in AIx (MD: 0.76%; 95%CI: -0.97, 2.49; p=0.389). In Meta-regression analyses body mass index and triglycerides levels have an impact on the difference in IMT between cases and controls, while male gender and smoking habit were associated with the difference in the prevalence of CPs between the two groups. Conclusion: AVSc is significantly associated with altered markers of subclinical atherosclerosis, thus supporting the concept that AVSc and atherosclerosis share common etiopathological mechanism and/or risk factors. On this basis, an echocardiogram carried out to assess the state of the aortic valve would be desirable whenever an altered subclinical marker of atherosclerosis is found

Aortic valve sclerosis adds to prediction of short-term mortality in patients with documented coronary atherosclerosis

Aims: Aortic valve sclerosis (AVSc), a non-uniform thickening of leaflets with an unrestricted opening, is characterized by inflammation, lipoprotein deposition, and matrix degradation. In the general population, AVSc predicts long-term cardiovascular mortality (+50%) even after adjustment for vascular risk factors and clinical atherosclerosis. We have hypothesized that AVSc is a risk-multiplier able to predict even short-term mortality. To address this issue, we retrospectively analyzed 90-day mortality of all patients who underwent isolated coronary artery bypass grafting (CABG) at Centro Cardiologico Monzino over a ten-year period (2006\u20132016). Methods: We analyzed 2246 patients and 90-day all-cause mortality was 1.5% (31 deaths). We selected only patients deceased from cardiac causes (n = 29) and compared to alive patients (n = 2215). A cardiologist classified the aortic valve as no-AVSc (n = 1352) or AVSc (n = 892). Cox linear regression and integrated discrimination improvement (IDI) analyses were used to evaluate AVSc in predicting 90-day mortality. Results: AVSc 90-day survival (97.6%) was lower than in no-AVSc (99.4%; p &lt; 0.0001) with a hazard ratio (HR) of 4.0 (95%CI: 1.78, 9.05; p &lt; 0.0001). The HR for AVSc, adjusted for propensity score, was 2.7 (95%CI: 1.17, 6.23; p = 0.02) and IDI statistics confirmed that AVSc significantly adds (p &lt; 0.001) to the identification of high-risk patients than EuroSCORE II alone. Conclusion: Our data supports the hypothesis that a risk stratification strategy based on AVSc, added to ESII, may allow better recognition of patients at high-risk of short-term mortality after isolated surgical myocardial revascularization. Results from this study warrant further confirmation

Standardized next-generation sequencing of immunoglobulin and T-cell receptor gene recombinations for MRD marker identification in acute lymphoblastic leukaemia; a EuroClonality-NGS validation study

Amplicon-based next-generation sequencing (NGS) of immunoglobulin (IG) and T-cell receptor (TR) gene rearrangements for clonality assessment, marker identification and quantification of minimal residual disease (MRD) in lymphoid neoplasms has been the focus of intense research, development and application. However, standardization and validation in a scientifically controlled multicentre setting is still lacking. Therefore, IG/TR assay development and design, including bioinformatics, was performed within the EuroClonality-NGS working group and validated for MRD marker identification in acute lymphoblastic leukaemia (ALL). Five EuroMRD ALL reference laboratories performed IG/TR NGS in 50 diagnostic ALL samples, and compared results with those generated through routine IG/TR Sanger sequencing. A central polytarget quality control (cPT-QC) was used to monitor primer performance, and a central in-tube quality control (cIT-QC) wa

Re: development of a next-generation tissue valve using a glutaraldehyde-fixed porcine aortic valve treated with decellularization, &#945;-galactosidase, space filler, organic solvent and detoxification

Comment on: Development of a next-generation tissue valve using a glutaraldehyde-fixed porcine aortic valve treated with decellularization, \u3b1-galactosidase, space filler, organic solvent and detoxification. [Eur J Cardiothorac Surg. 2015