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Objective: Transapical off-pump beating-heart neochord implantation (NC) has shown encouraging early results in patients with degenerative mitral regurgitation. The aim of this study was to evaluate clinical and echocardiographic 5-year outcomes of patients who underwent NC., Methods: All patients who underwent NC at our institution from November 2013 to March 2016 were included. Indications were severe symptomatic degenerative mitral regurgitation due to leaflet prolapse/flail. Patients were classified as having favorable anatomy (FA) and unfavorable anatomy (UA) on the basis of the extent and severity of mitral valve disease. All patients underwent clinical and echocardiographic follow-up at 1, 3, 6, and 12 months, and annually thereafter. Data were prospectively collected and retrospectively analyzed. Outcomes were on the basis of the Mitral Valve Academic Research Consortium guidelines., Results: One hundred consecutive patients were included in the analysis (FA: 81%; UA: 19%). Median age was 66 years (interquartile range, 58-76) and median European System for Cardiac Operative Risk Evaluation (EuroSCORE) II was 1.4% (interquartile range, 0.7-2.3). Technical and procedural success were 98% and 94%, respectively. Thirty-day mortality was 2%. Device success was 94%, 92%, and 78%, at 30 days, 1-year, and 5 years, respectively. Patient success at 1 year was 92%. Median follow-up was 5.1 years. At 5 years, overall survival was 83% with no difference between FA and UA patients. Cumulative incidence of severe mitral regurgitation recurrence at 5 years was 14% (95% CI, 6.5%-22.8%) in FA patients and 63% (95% CI, 39.7%-86.2%) in UA patients, respectively (P < .001). Patients with FA compared with UA had a lower incidence of reintervention (14.7% vs 43.4%; P < .001)., Conclusions: Transapical off-pump beating heart NC might represent an acceptable option in patients with degenerative mitral valve disease and FA., (Copyright © 2022 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Objectives: MicroRNAs (miRs) are non-translated RNA sequences that elicit negative control over protein expression. The adipose tissue (AT) is considered the major producer of miRs and inflammatory interleukin 6 (IL-6). This study aims to investigate the relationship between production of IL-6 and miRs in AT., Methods: IL-6 gene expression was analysed in RNA extracts from subcutaneous AT of 75 patients with rheumatoid arthritis (RA), with qPCR. Genome-wide profile of human miRs (2565 miRs, 96.6%) was analysed in 35 AT samples on 3D microarray. The miR-processing proteins Dicer, Drosha and DGCR8 were analysed with qPCR. In silico prediction of protein targets for the differentially expressed (DE) miRs (p<0.05; log2FC >±0.5) was conducted by DIANA software. Seven AT samples were stimulated in vitro with IL-6 or IL-6+IL-6R antibody tocilizumab and analysed for the miR processing proteins., Results: We identified 30 DE miRs between AT with high and low IL-6 mRNA, of which 26 miRs were inversely related with IL-6 levels. DE miRs were predicted to interfere in oestrogen (p=0.001), FoxO (p=0.006) and insulin (p=0.03) signalling pathways. High expression of IL-6 in AT was associated with significantly higher expression of Dicer (p=0.04) and Drosha (p=0.04), while inhibition of IL-6 signalling with tocilizumab decreased the levels of total miRs processing enzymes (p=0.003)., Conclusions: IL-6 mRNA production in AT has a negative effect on the miRs expression profile and it increases miR-production capacity.

Introduction: Nowadays micro-invasive-procedures (off-pump, beating-heart) for mitral valve repair (MVRe) are abruptly expanding with the potential to be adopted as a valuable alternative to surgery. In the present manuscript, the authors review the available technologies intended to treat mitral regurgitation (MR) through transapical approach, including annuloplasty and chordal-repair options., Annuloplasty: To date, Valcare Amend is the only transapical MV ring to have been implanted in patients. The device allows for stabilization of the annulus through a complete semirigid d-shaped ring. The first-in-human successful procedure was performed in 2016 by our Group and subsequent clinical experience included a total of 14 implanted patients. Currently, the technology is under clinical trial evaluation to validate the efficacy and safety profile of the device., Chordal Repair: Beating-heart chordal implantation via transapical approach is a current feasible, safe and reproducible option. Neochord DS1000 is the most widely used technology in the field, with a solid procedural experience and good results in well-selected patients. Its clinical use has been validated in Europe since 2012, while it is still under clinical investigation in the United States. Harpoon MVRe system is a novel technology, recently CE-mark approved for clinical use., Discussion and Conclusions: Transapical micro-invasive technologies are current viable therapies to treat MR in selected patients. Although there are still several limitations that preclude an extensive use of such procedures, their results are promising in well-selected patients. Embracing transcatheter MVRe therapies should guide the cardiac surgeon through the new revolution of micro-invasive MV tailored repair., (© 2021 The Authors. Journal of Cardiac Surgery published by Wiley Periodicals LLC.)

Objectives: The goal of this multicentre retrospective study was to compare long-term clinical and haemodynamic outcomes of the Carpentier-Edwards Magna Ease (CEME) bioprosthesis by patient age., Methods: We included consecutive patients who underwent isolated and combined surgical aortic valve replacement (AVR) with CEME valve between January 2008 and March 2020 at 4 cardiac surgery centres in Italy. Survival distribution was evaluated at follow-up according to age and surgery type (combined or isolated AVR), together with freedom from structural valve deterioration (SVD), reoperation and combined events, i.e. SVD, reoperation, endocarditis and thromboembolic events., Results: A total of 1027 isolated and 1121 combined AVR were included; 776 patients were younger than 65 years whereas 1372 were 65 years or older. The 30-day Valve-Academic-Research-Consortium mortality was 2% (<65 years) and 6% (≥ 65 years) (P < 0.001), whereas it was 3% for isolated AVR and 7% for combined AVR (P < 0.001). The 12-year survival was 81% for those younger than 65 years vs 45% for those equal to or older than 65 years (P < 0.001), whereas they were 61% vs 49% for isolated and combined AVR (P = 0.10). The 12-year freedom from combined events, excluding death, was 79% for those younger than 65 years vs 87% for those equal to or older than (P = 0.51), whereas they were 83% for isolated and 86% for combined AVR (P = 0.10). The 12-year freedom from SVD was 93% and 93% in patients younger than 65 and those equal to or older than 65 years (P = 0.63), and the results were comparable even in cases with isolated and combined AVR (92% vs 94%, P = 0.21). A multivariable Cox analysis including gender, presence of patient-prosthesis mismatch, isolated AVR and age showed that only the age was an independent risk factor for the incidence of SVD (P = 0.029)., Conclusions: Outcomes from this large multicentre analysis demonstrated that a CEME bioprosthesis provides good clinical results and long-term durability even in patients younger than 65 years. Furthermore, the hazard for SVD has been shown to be lower for older age., Clinical Trial Registration Number: 105n/AO/21., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background and Aim of the Study: Micro-invasive cardiac surgery identifies procedures performed off-pump, on beating heart. Aim of this single-center retrospective study was to assess early outcomes of a totally micro-invasive strategy (percutaneous coronary intervention-PCI-followed by transapical off-pump NeoChord mitral repair) in patients with concomitant coronary artery disease (CAD) and degenerative mitral regurgitation (MR)., Methods: We analyzed early and 1-year follow-up data of patients who underwent a NeoChord procedure between November 2013 and May 2020, and preceded by PCI. Outcomes were defined according to Mitral Valve Academic Research Consortium (MVARC) definitions., Results: Among 220 patients who underwent NeoChord repair in the study period, 17 (7.7%) underwent PCI previously. CAD was an accidental finding during preoperative mitral evaluation in nine patients (52.9%; Group 1; with PCI occurring 2 months before NeoChord, interquartile range [IQR] = 1.0-2.7), while it was part of the past medical history in the remaining eight patients (47.1%; Group 2; with PCI occurring 30 months before NeoChord, IQR = 24.5-64.0). Twelve patients (70.6%) presented single-vessel disease, two patients (11.8%) triple-vessel disease. No surgical revisions for bleeding were required after NeoChord. At 1-year follow-up (n = 16), all patients were alive and did not experience major adverse events except for one reoperation due to late NeoChord failure. None required additional PCI., Conclusion: In our experience, PCI before NeoChord seems safe and effective, and performing PCI before NeoChord might not affect outcomes. A totally micro-invasive strategy in selected patients suffering from MR and CAD should be considered as a reasonable alternative to conventional surgery., (© 2021 The Authors. Journal of Cardiac Surgery published by Wiley Periodicals LLC.)

Adiposity is strongly associated with cardiovascular (CV) morbidity. Uncoupling protein 1 (UCP1) increases energy expenditure in adipocytes and may counteract adiposity. Our objective was to investigate a connection between UCP1 expression and cardiovascular health in patients with rheumatoid arthritis (RA) in a longitudinal observational study. Transcription of UCP1 was measured by qPCR in the subcutaneous adipose tissue of 125 female RA patients and analyzed with respect to clinical parameters and the estimated CV risk. Development of new CV events and diabetes mellitus was followed for five years. Transcription of UCP1 was identified in 89 (71%) patients. UCP1 positive patients had often active RA disease ( p = 0.017), high serum levels of IL6 ( p = 0.0025) and were frequently overweight ( p = 0.015). IL-6 hi BMI hi patients and patients treated with IL6 receptor inhibitor tocilizumab had significantly higher levels of UCP1 compared to other RA patients ( p < 0.0001, p = 0.032, respectively). Both UCP1 hi groups displayed unfavorable metabolic profiles with high plasma glucose levels and high triglyceride-to-HDL ratios, which indicated insulin resistance. Prospective follow-up revealed no significant difference in the incidence of new CV and metabolic events in the UCP1 hi groups and remaining RA patients. The study shows that high transcription of UCP1 in adipose tissue is related to IL6-driven processes and reflects primarily metabolic CV risk in female RA patients.

Background: Cardiovascular disease (CVD) causes premature mortality in rheumatoid arthritis (RA). Levels of soluble (s)RAGE change with aging, hypertension and hypercholesterolemia. We assessed whether sRAGE was associated with increased risk of CVD in RA patients. Methods: Serum sRAGE was measured in 184 female RA patients and analyzed with respect to CVD risk estimated by the Framingham algorithm (eCVR), metabolic profile and inflammation. Levels of sRAGE in 13 patients with known cardio-metabolic morbidity defined the cut-off for low sRAGE. Prospective 5-year follow-up of new CV and metabolic events was completed. Results: Low sRAGE was significantly associated with previous history and with new imminent cardiometabolic events in the prospective follow-up of RA patients. In both cases, low sRAGE reflected higher estimation of CVR in those patients. Low sRAGE was attributed to adverse metabolic parameters including high fasting plasma glucose and body fat content rather than inflammation. The association of sRAGE and poor metabolic profile was prominent in patients younger than 50 years. Conclusions: This study points at low sRAGE as a marker of metabolic failure developed during chronic inflammation. It highlights the importance for monitoring metabolic health in female RA patients for timely prevention of CVD. Trial registration: ClinicalTrials.gov with ID NCT03449589. Registered 28, February 2018., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Nadali, Lyngfelt, Erlandsson, Silfverswärd, Andersson, Bokarewa and Pullerits.)

Background: The NeoChord echo-guided transapical beating heart repair is a promising early-stage minimally invasive surgical procedure for degenerative mitral valve (MV) regurgitation (DMR) correction. The technique has been improved since its inception following procedure standardization, patient selection optimization, and learning curve stabilization. We hereby present the mid-term clinical results through three years of our large single center experience., Methods: All consecutive patients with severe symptomatic DMR due to prolapse or flail of one or both mitral leaflets that underwent the NeoChord procedure between November 2013 and June 2019 were included. Patients were categorized according to MV anatomy; Type A isolated central posterior leaflet prolapse and/or flail, Type B posterior multi-segment prolapse and/or flail, Type C anterior and/or bi-leaflet prolapse or flail, Type D paracommissural prolapse and/or flail and/or significant leaflet and/or annular calcifications. Patients underwent clinical and echocardiographic follow-up at one, three, six, twelve months and yearly thereafter. Clinical outcomes and the composite primary endpoint (patient success) were defined according to Mitral Valve Academic Research Consortium (MVARC) criteria. Mitral regurgitation (MR) severity was graded as absent, mild, moderate and severe according to American Society of Echocardiography (ASE) and European Society of Cardiology (ESC) guidelines., Results: Two hundred and three patients were included; median follow-up was 24 months [interquartile range (IQR), 9-36]. Median age was 64 years (IQR, 54-74 years), median Society of Thoracic Surgeons (STS) Predicted Risk of Mortality (PROM) was 0.60% (IQR, 0.32-1.44%). There were 106 Type A patients (52.2%), 68 Type B (33.5%), 16 Type C (7.9%), and 13 Type D (6.4%). Kaplan-Meier estimate of survival was 99.0%±0.7% at one and two years and 94.0%±2.9% at three years. At one-year follow-up patient success was 91.2%±2.0% and 111 patients (74%) presented a residual MR mild or less (1+). At three-year follow-up patient success was 81.2%±3.8% and 32 patients (64%) had a residual MR mild or less (1+). Patient success was significantly different according to anatomical type (P=0.001). Echocardiographic analysis showed a significant acute left ventricle and left atrial reverse remodeling that was maintained up to three years., Conclusions: The NeoChord echo-guided transapical beating heart repair procedure demonstrated good clinical outcomes and echocardiographic results up to three-year follow-up., Competing Interests: Conflicts of Interest: GG, AC received travel grants from NeoChord Inc. The other authors have no conflicts of interest to declare., (2021 Annals of Cardiothoracic Surgery. All rights reserved.)

Objectives: Few anecdotal cases have been reported in the literature regarding heart transplant recipients and infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We report our experience with 6 patients hospitalized in Northern Italy during the outbreak., Methods: Of the 396 living heart transplant recipients from 1985 to 2020 included in the study, 6 patients developed the novel 2019 coronavirus disease. Risk factors, last follow-up characteristics, onset presentation, in-hospital course of disease and blood examinations data were collected for these patients., Results: All patients were symptomatic and had positive results from a nasopharyngeal swab test for SARS-CoV-2. Of the 6 patients, 5 were hospitalized and 1 remained self-quarantined at home. Two patients died and 3 were discharged home. Two patients were admittted to the intensive care unit . Immunosuppressive therapy was modified with a median reduction comprising doses that were 50% cyclosporine and 50% mycophenolate. All patients received a medium-dose of corticosteroids as a bolus medication in addition to their therapy. All hospitalized patients received hydroxychloroquine; 2 patients received ritonavir/lopinavir. Broad-spectrum antibiotics for prophylaxis were administered to all. One patient had an ischaemic stroke and died of sepsis., Conclusions: In the absence of any strong evidence regarding the treatment of heart transplant recipients infected with SARS-CoV-2, we faced a new challenge in managing viral infection in an immunosuppressed population. Because immunomodulation interaction with the infection seems to be crucial for developing severe forms of the disease, we managed to reduce immunosuppressive therapy by adding medium doses of corticosteroids. Despite the limited number of affected patients, this report suggests that special considerations should be given to treating coronavirus disease in the heart transplant recipient population., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Transcatheter Mitral Valve Repair (TMVRe) technologies constitute a rapidly expanding field, and have the potential of being adopted as a valuable alternative to surgery in selected patients. TMVRe devices can be distinguished depending on the targeted part of the Mitral Valve (MV) apparatus. Standard classification includes leaflet repair, direct/indirect annuloplasty, chordal repair, and ventricular/chamber remodeling devices. We present the current device situation on chordal repair technologies. Nowadays, transapical off-pump beating heart chordal implantation procedure has become a safe and reproducible option for Degenerative Mitral Regurgitation (DMR). Besides the truly minimally-invasiveness of the procedure, another unique advantage offered by a beating-heart chordal implantation is the real-time assessment of chordal length adjustment during heart cycle with a normally filled left ventricle. Currently, one system is commercially available in Europe, the NeoChord DS 1000 (NeoChord, Inc., St. Louis Park, MN) and the Harpoon TDS-5 (Edwards Lifesciences, Irvine, CA) should become available soon. There is also a diffuse and strong interest to move from a transapical procedure toward a fully transcatheter (transfemoral and transeptal) procedure as shown by the increased number of preclinical programs under development. Interestingly, to achieve outcomes that equate to those of open surgery in DMR, transcatheter therapies will need to follow rigid indications due to strict patient selection criteria for each device, or adopt multiple techniques in a single repair procedure for complex MV disease. Continuous analysis of current clinical results together with future dedicated trial will be of extreme importance to foster the new and upcoming field of transcatheter MV therapy technology development.

Objectives: The aim of this study was to describe possible mechanisms of recurrent mitral regurgitation (MR) in patients who have been treated with the NeoChord procedure., Methods: Patients presenting with recurrent severe or moderate MR were categorized as Not Expected Surgical-Like Result (NESLR)-Redo and NESLR-MR2 [NESLR reintervention or moderate MR (2+), respectively]. NESLR patients were stratified by onset (intraoperative, perioperative 24 h-30 days, or early 30 days to follow-up), by MR jet direction (central or eccentric) and by jet orientation (anterior or posterior). Specific mechanisms of NESLR were analysed., Results: Fifty-two patients were identified with 13 (25%) categorized as NESLR-Redo, and 39 (75%) as NESLR-MR2. NESLR-Redo patient stratification included: intraoperative = 2 patients (1.2%), both eccentric anteriorly directed jets; perioperative = 7 patients (4.2%), all eccentric with 3 anteriorly and 4 posteriorly directed jets; and early = 4 patients (2.4%), 1 central, 3 eccentric, 2 posteriorly and 1 anteriorly directed jets. NESLR-MR2 patient stratification included: perioperative = 2 patients (5.1%), both eccentric, 1 anteriorly and 1 posteriorly directed jets; and early = 37 patients (94.9%), 4 central, 33 eccentric, 22 anteriorly and 11 posteriorly directed jets. Possible mechanisms of recurrent MR were identified as: patient selection (17.3%), technical issues (28.8%), progression of baseline disease (15.4%), left ventricle reverse remodelling (1.9%), excessive over-tensioning (35.8%) and PML curling (30.8%)., Conclusions: The mechanisms of recurrent MR after the NeoChord procedure can be determined. Understanding recurrent MR mechanisms has led to improvements in procedural standardization and ad hoc prevention strategies that have been widely adopted since our initial clinical experience., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Objectives: Since low insulin-like growth factor (IGF) 1 is often linked to inflammation, we analyze whether serum levels of IGF1 are associated with cardiovascular disease (CVD) in rheumatoid arthritis (RA) in a longitudinal observational study., Methods: A CVD risk was estimated (eCVR) in 184 female RA patients (mean age 52 years) and in 132 female patients after ischemic stroke (mean age 56 years) with no rheumatic disease, using the Framingham algorithm. The median level of IGF1 divided the cohorts in IGF1 high and IGF1 low groups. A 5-year prospective follow-up for new CVD events was completed in all RA patients. The Mantel-Cox analysis and event-free survival curves were prepared. Unsupervised clustering of proteins within the IGF1 signaling pathway was employed to identify their association with eCVR., Results: Low IGF1 resulted in a higher eCVR in RA patients (7.2% and 3.3%, p = 0.0063) and in stroke (9.3% and 7.1%, p = 0.033). RA had higher rate for new CVD events at prospective follow-up (OR 4.96, p = 0.028). Hypertension was the major risk factor associated with low IGF1 in RA and stroke. In hypertension, IGF1 was no longer responsible for intracellular activation and lost its correlation to IRS1/2 adaptor proteins. The clustering analysis confirmed that combination of low IGF1 and IRS1/2 with high IL6, insulin, and glucose predisposed to high eCVR and emphasized the functional role of serum IGF1., Conclusions: Low serum IGF1 precedes and predicts development of early CVD events in female RA patients. Hypertension and aberrant IGF1 receptor signaling are highlighted as the important contributors to IGF1-related CVD events.

Transapical off-pump mitral valve repair (MVr) with NeoChord implantation has become widely applied in Europe for patients presenting with severe mitral regurgitation due to leaflet prolapse or flail. The procedure is performed under real-time 2D- and 3D-transesophageal echocardiography (TEE) for both implantation and neochordae tension adjustment allowing real-time monitoring of hemodynamic recovery. Preoperative anatomic and echocardiographic selection criteria, procedure refinement, as well as innovative ex-vivo surgical simulator training have been developed and strategically employed in the past few years, to generate a robust precision-based procedural framework with significantly enhanced operator use, patient safety and clinical outcomes. The procedure has evolved into a reproducibly successful and safe approach, which complements existing surgical treatment strategies available to eligible patients with chronic severe degenerative mitral regurgitation., Competing Interests: Conflicts of Interest: A Colli, G Gerosa received travel grants from Neochord, Inc. D Adams is the Co-Principal Investigator of the Rechord Trial, which is supported by Neochord, Inc. The other authors have no conflicts of interest to declare.

Despite the predominance of female patients and uncommon obesity, rheumatoid arthritis (RA) is tightly connected to increased cardiovascular morbidity. The aim of this study was to investigate transcriptional activity in the subcutaneous white adipose tissue (WAT) with respect to this disproportionate cardiovascular risk (CVR) in RA. CVR was estimated in 182 female patients, using the modified Systematic Coronary Risk Evaluation scale, and identified 93 patients with increased CVR. The overall transcriptional activity in WAT was significantly higher in patients with CVR and was presented by higher serum levels of WAT products leptin, resistin and IL-6 (all, p < 0.001). CVR was associated with high WAT-specific transcription of the signal transducer and activator of transcription 3 ( STAT3 ) and the nuclear factor NF-kappa-B p65 subunit ( RELA ), and with high transcription of serine-threonine kinase B ( AKT1 ) in leukocytes. These findings suggest Interleukin 6 (IL-6) and leptin take part in WAT-specific activation of STAT3 . The binary logistic regression analysis confirmed an independent association of CVR with IL-6 in serum, and with STAT3 in WAT. The study shows an association of CVR with transcriptional activity in WAT in female RA patients. It also emphasizes the importance of STAT3 regulatory circuits for WAT-related CVR in RA., Competing Interests: The authors declare no conflict of interest.

Background: Signalling through insulin-like growth factor 1 receptor (IGF-1R) is essential for cell survival, but may turn pathogenic in uncontrolled tissue growth in tumours. In rheumatoid arthritis (RA), the IGF-1R signalling is activated and supports expansion of the inflamed synovia., Aim: In the present study, we assess if disruption of IGF-1R signalling resolves arthritis., Material and Methods: Clinical associations of IGF-1R expression in leukocytes of the peripheral blood were studied in 84 RA patients. Consequences of the IGF-1R signalling inhibition for arthritis were studied in mBSA immunised Balb/c mice treated with NT157 compound promoting degradation of insulin receptor substrates., Results: In RA patients, high expression of IGF-1R in leukocytes was associated with systemic inflammation as verified by higher expression of NF-kB, serum levels of IL6 and erythrocyte sedimentation rate, and higher pain perception. Additionally, phosphorylated IGF-1R and STAT3 enriched T cells infiltrate in RA synovia. Treatment with NT157 inhibited the phosphorylation of IGF-1R and STAT3 in synovia, and alleviated arthritis and joint damage in mice. It also reduced expression of IGF-1R and despaired ERK and Akt signalling in spleen T cells. This limited IL-6 production, changed RoRgt/FoxP3 balance and IL17 levels., Conclusion: IGF-1R signalling contributes to T cell dependent inflammation in arthritis. Inhibition of IGF-1R on the level of insulin receptor substrates alleviates arthritis by restricting IL6-dependent formation of Th17 cells and may open for new treatment strategies in RA., (Copyright © 2017 Elsevier B.V. All rights reserved.)

A rare case of intracerebral chondroma in a 45 years old man with a long history of headache and recent epilepsy is presented. Microscopic examination of the resected tumor revealed that it was chondroma.