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Abstract Clonal hematopoiesis of indeterminate potential (CHIP) is characterized by the presence of clones of mutated blood cells without overt blood diseases. In the last few years, it has emerged that CHIP is associated with atherosclerosis and coronary calcification and that it is an independent determinant of cardiovascular mortality. Recently, CHIP has been found to occur frequently in patients with calcific aortic valve disease (CAVD) and it is associated with a poor prognosis after valve replacement. We assessed the frequency of CHIP by DNA sequencing in the blood cells of 168 CAVD patients undergoing surgical aortic valve replacement or transcatheter aortic valve implantation and investigated the effect of CHIP on 12 months survival. To investigate the pathological process of CAVD in CHIP carriers, we compared by RNA-Seq the aortic valve transcriptome of patients with or without CHIP and non-calcific controls. Transcriptomics data were validated by immunohistochemistry on formalin-embedded aortic valve samples. We confirm that CHIP is common in CAVD patients and that its presence is associated with higher mortality following valve replacement. Additionally, we show, for the first time, that CHIP is often accompanied by a broad cellular and humoral immune response in the explanted aortic valve. Our results suggest that an excessive inflammatory response in CHIP patients may be related to the onset and/or progression of CAVD and point to B cells as possible new effectors of CHIP-induced inflammation.

ABSTRACT: Objective: To evaluate the cost-effectiveness of dalbavancin compared with standard of care (SoC) treatment as daptomycin or teicoplanin in patients with sternal wound infections (SWI). Methods: Multicentre retrospective study of patients diagnosed with SWI from January 2016 to December 2019 at two cardiac surgery facilities treated with dalbavancin, teicoplanin or daptomycin. Patients with SWI treated with dalbavancin were compared with SoC to evaluate resolution of infection at 90 and 180 days from infection diagnosis, length of stay (LoS) and management costs. Results: 48 patients with SWI were enrolled, 25 (50%) male, median age 67 (60–73) years, Charlson index score 5 (4–7). Fifteen patients were treated with dalbavancin (31%) and 33 with SoC (69%): teicoplanin in 21 (63%), and daptomycin in 12 (37%). Staphylococcus species were the most frequent isolates (44, 92%), mostly (84%) resistant to methicillin. All patients were treated with surgical debridement followed by negative pressure wound therapy. Wound healing at day 90 and 180 was achieved in 46 (95.8%) and 34 (82.9%) of patients, respectively. A shorter length of hospitalization in patients treated with dalbavancin compared with SoC [12 (7–18) days vs 22 (12–36) days, p:0.009] was found. Treatment with dalbavancin resulted in total cost savings of €16 026 (95% CI 5976–26 076, P < 0.001). Savings were mainly related to the LoS that was significantly shorter in the dalbavancin group, generating significantly lower cost compared to SoC group. Conclusion: Dalbavancin treatment of sternal wound infections is effective and seems to reduce hospitalization length, leading to significantly lower costs.

Clinically significant tricuspid regurgitation (TR) is common and associated with excess mortality. At the same time right ventricular (RV) failure is a complex clinical syndrome that results from many causes, but is often associated with long-term prognosis. Whilst results of isolated tricuspid valve (TV) surgery are often unsatisfactory and limited by the prohibitive risk of most patients, the recent development of percutaneous recovery techniques has opened new scenarios. In consideration of the complexity of the mechanisms that lead to right heart failure and RV dysfunction it is important to understand the real advantages that percutaneous TV treatment can offer, more specifically the effect of TR reduction on RV remodeling in the setting of functional tricuspid regurgitation (fTR).

Abstract Although aortic valve replacement remains the gold standard treatment for aortic valve diseases like stenosis (AS) or insufficiency, new surgical methods have been developed with a focus in the reconstruction of the aortic valve rather than replacing it. The Ozaki procedure involves a tailored replacement of each individual valvular leaflet with glutaraldehyde-treated autologous pericardium and aims to reproduce the normal anatomy of the aortic valve. Cases of patients with unicuspid aortic valve treated with the Ozaki procedure are uncommon in the litrature and become even more rare when it comes to concomitant diseases like AS and ascending aorta aneurysm. We present the case of a 21-year-old, fit and asymptomatic male, with unicuspid aortic valve with severe stenosis and ascending aorta dilatation, surgically treated with tricuspidization of the aortic valve with glutaraldehyde-treated autologous pericardium and replacement of the ascending aorta with a straight synthetic graft. Postoperative studies showed a fully functional, neo-tailored tricuspid aortic valve with trivial regurgitation. The patient had an uncomplicated recovery, stayed in the intensive care unit for 2 days and was discharged on the 7th postoperative day.

Summary: Preclinical models of ischemia/reperfusion injury (RI) demonstrate the deleterious effects of permeability transition pore complex (PTPC) opening in the first minutes upon revascularization of the occluded vessel. The ATP synthase c subunit (Csub) influences PTPC activity in cells, thus impacting tissue injury. A conserved glycine-rich domain in Csub is classified as critical because, when mutated, it modifies ATP synthase properties, protein interaction with the mitochondrial calcium (Ca2+) uniporter complex, and the conductance of the PTPC. Here, we document the role of a naturally occurring mutation in the Csub-encoding ATP5G1 gene at the G87 position found in two ST-segment elevation myocardial infarction (STEMI) patients and how PTPC opening is related to RI in patients affected by the same disease. We report a link between the expression of ATP5G1G87E and the response to hypoxia/reoxygenation of human cardiomyocytes, which worsen when compared to those expressing the wild-type protein, and a positive correlation between PTPC and RI.

Objectives: Treatment of aortic valve stenosis is evolving, indications for transcatheter approach (TAVI) have increased but also surgical valve replacement has changed with the use of minimally invasive approaches. Comparisons between TAVI and surgery have rarely been done with minimally invasive techniques (mini-SAVR) in the surgical arm. Aim of the present study is to compare mini-SAVR and TAVI in a multicenter recent cohort. Methods: Evaluated were 2904 patients undergone mini-SAVR (2407) or TAVI (497) in 10 different centers in the period 2011–2016. The Heart Team approved treatment for complex cases. The primary outcome is the incidence of 30-day mortality following mini-SAVR and TAVI. Secondary outcomes are the occurrence of major complications following both procedures. Propensity matched comparisons was performed based on multivariable logistic regression model. Results: In the overall population TAVI patients had increased surgical risk (median EuroSCORE II 3.3% vs. 1.7%, p ≤ 0.001) and 30-day mortality was higher (1.5% and 2.8% in mini-SAVR and TAVI respectively, p = 0.048). Propensity score identified 386 patients per group with similar baseline profile (median EuroSCORE II ~3.0%). There was no difference in 30-day mortality (3.4% in mini-SAVR and 2.3% in TAVI; p = 0.396) and stroke, surgical patients had more blood transfusion, kidney dysfunction and required longer ICU and hospital length of stay while TAVI patients had more permanent pace maker insertion. Conclusions: Mini-SAVR and TAVI are both safe and effective to treat aortic stenosis in elderly patients with comorbidities. A joint evaluation by the heart-team is essential to direct patients to the proper approach. Keywords: Aortic valve, TAVI, Elderly patients, Outcomes

The amniotic membrane has long been applied for wound healing and treatment of ophthalmological disorders, even though the mechanisms underlying its actions remain to be clarified. Recently, cells derived from fetal membranes of human term placenta have raised strong interest in regenerative medicine for their stem cell potential and immunomodulatory features. Our study aimed to investigate the possible utility of amniotic membrane to limit postischemic cardiac injury. A fragment of human amniotic membrane was applied onto the left ventricle of rats that had undergone ischemia through left anterior descending coronary artery ligation. Echocardiographic assessment of morphological and functional cardiac parameters was then performed over a 3-month period. We demonstrated that application of an amniotic membrane fragment onto ischemic rat hearts could significantly reduce postischemic cardiac dysfunction. The amniotic membrane-treated rats showed higher preservation of cardiac dimensions and improved cardiac contractile function in terms of higher left ventricle ejection fraction, fractional shortening, and wall thickening. These improvements were apparent by day 7 after application of the amniotic membrane, persisted for at least 2 months, and occurred independently of cardiac injury severity. No engraftment of amniotic cells was detected into host cardiac tissues. Our results suggest that use of amniotic membrane may constitute a convenient vehicle for supplying cells that produce cardioprotective soluble factors, and reinforce the notion that this tissue constitutes a cell source with clinical potential that has yet to be completely revealed.

Cells derived from the amniotic membranes of human term placenta have drawn much interest for their characteristics of multipotency and low immunogenicity, supporting a variety of possible clinical applications in the field of cell transplantation and regenerative medicine. We have previously shown that cells derived from the mesenchymal region of human amnion (AMTC) can strongly inhibit T-lymphocyte proliferation. In this study, we demonstrate that AMTC can block differentiation and maturation of monocytes into dendritic cells (DC), preventing the expression of the DC marker CD1a and reducing the expression of HLA-DR, CD80, and CD83. The monocyte maturation block resulted in impaired allostimulatory ability of these cells on allogeneic T cells. In attempting to define the mechanisms responsible for these findings, we have observed that the presence of AMTC in differentiating DC cultures results in the arrest of the cells to the G 0 phase and abolishes the production of inflammatory cytokines such as TNF-α, CXCL10, CXCL9, and CCL5. Finally, we also demonstrate that the monocytic cells present in the amniotic mesenchymal region fail to differentiate toward the DC lineage. Taken together, our data suggest that the mechanisms by which AMTC exert immumodulatory effects do not only relate directly to T cells, but also include inhibition of the generation and maturation of antigen-presenting cells. In this context, AMTC represent a very attractive source of multipotent allogeneic cells that promise to be remarkably valuable for cell transplantation approaches, not only due to their low immunogenicity, but also because of the added potential of modulating immune responses, which could be fundamental both for controlling graft rejection after transplantation and also for controlling diseases characterized by inflammatory processes.

Fetal membranes (amnion and chorion) have recently raised significant attention as potential sources of stem cells. We have recently demonstrated that cells derived from human term placenta show stem cell phenotype, high plasticity, and display low immunogenicity both in vitro and in vivo. Moreover, placenta-derived cells, after xenotransplantation, are able to engraft in solid organs including the lung. On these bases, we studied the effects of fetal membrane-derived cells on a mouse model of bleomycin-induced lung fibrosis. Fetal membrane-derived cells were infused 15 min after intratracheal bleomycin instillation. Different delivery routes were used: intraperitoneal or intratracheal for both xenogeneic and allogeneic cells, and intravenous for allogeneic cells. The effects of the transplanted cells on bleomycin-induced inflammatory and fibrotic processes were then scored and compared between transplanted and control animals at different time points. By PCR and immunohistochemistry analyses, we demonstrated the presence of transplanted cells 3, 7, 9, and 14 days after transplantation. Concomitantly, we observed a clear decrease in neutrophil infiltration and a significant reduction in the severity of bleomycin-induced lung fibrosis in mice treated with placenta-derived cells, irrespective of the source (allogeneic or xenogeneic) or delivery route. Our findings constitute further evidence in support of the hypothesis that placenta-derived cells could be useful for clinical application, and warrant further studies toward the use of these cells for the repair of tissue damage associated with inflammatory and fibrotic degeneration.