Calcification of the aortic valve (CAVDS) is a major cause of aortic stenosis (AS) leading to loss of valve function which requires the substitution by surgical aortic valve replacement (SAVR) or ...transcatheter aortic valve intervention (TAVI). These procedures are associated with high post-intervention mortality, then the corresponding risk assessment is relevant from a clinical standpoint. This study compares the traditional Cox Proportional Hazard (CPH) against Machine Learning (ML) based methods, such as Deep Learning Survival (DeepSurv) and Random Survival Forest (RSF), to identify variables able to estimate the risk of death one year after the intervention, in patients undergoing either to SAVR or TAVI. We found that with all three approaches the combination of six variables, named albumin, age, BMI, glucose, hypertension, and clonal hemopoiesis of indeterminate potential (CHIP), allows for predicting mortality with a c-index of approximately
. Importantly, we found that the ML models have a better prediction capability, making them as effective for statistical analysis in medicine as most state-of-the-art approaches, with the additional advantage that they may expose non-linear relationships. This study aims to improve the early identification of patients at higher risk of death, who could then benefit from a more appropriate therapeutic intervention.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Calcific aortic stenosis is a disorder that impacts the physiology of heart valves. Fibrocalcific events progress in conjunction with thickening of the valve leaflets. Over the years, these events ...promote stenosis and obstruction of blood flow. Known and common risk factors are congenital defects, aging and metabolic syndromes linked to high plasma levels of lipoproteins. Inflammation and oxidative stress are the main molecular mediators of the evolution of aortic stenosis in patients and these mediators regulate both the degradation and remodeling processes. Mitochondrial dysfunction and dysregulation of autophagy also contribute to the disease. A better understanding of these cellular impairments might help to develop new ways to treat patients since, at the moment, there is no effective medical treatment to diminish neither the advancement of valve stenosis nor the left ventricular function impairments, and the current approaches are surgical treatment or transcatheter aortic valve replacement with prosthesis.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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.
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•G87E of ATP synthase subunit c is harmful under stressful conditions in humans•G87E increases PTPC opening•G87E worsens hypoxia/reoxygenation damage in STEMI patients•PTPC opening is positively related to reperfusion injury in STEMI patients
Studies in humans about the deleterious effects of PTPC opening in ischemia/reperfusion should be improved. Here, Morciano et al. identify a naturally occurring mutation in the subunit c that exacerbates the hypoxia/reoxygenation damage in human cardiomyocytes. Moreover, they report the correlation between PTPC opening and reperfusion injury in STEMI patients.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Background: Nowadays, one of the main goals of aortic valve surgery is to reduce the biological impact, mortality, and complications. It is well-known that long operative times in terms of the ...extracorporeal circulation, but above all, of the aortic cross-clamp time (ACC), represent a risk factor for mortality in patients undergoing cardiac surgery. In order to shorten the aortic cross-clamp time, many technological improvements, such as sutureless prostheses, have been introduced, but their actual effectiveness has not been proven yet. The aim of this study was to assess the 30-day outcomes of patients undergoing aortic valve replacement surgery, focusing on the ACC length. Methods: All 3139 patients undergoing aortic valve replacement between January 2013 and July 2022 at our institution were enrolled. The data were retrospectively collected and the baseline characteristics and intraoperative variables were recorded. In order to adjust the results according to the differences in the baseline characteristics, propensity score matching was performed and four groups of 351 patients were obtained based on the first, second, third, and fourth quartile of the ACC time. Results: The patient population included 132 redo surgeries (9.4%) and 61 cases of active endocarditis (4.3%), with an overall median EuroSCORE II of 1.8 (IQR 1.2–3.1). An increase across the groups was observed in terms of the acute kidney failure (p < 0.001) incidence, the number of blood transfusions (p = 0.022), prolonged hospital stays (p < 0.001), the and respiratory failure (p < 0.001) incidence. A p of < 0.1 was found for the 30-day mortality (p = 0.079). The predictors of an early 30-day mortality were standard full sternotomy (OR 2.48, 95% CI 1.14–5.40, p = 0.022), EuroSCORE II (OR 1.10, 95% CI 1.05–1.16, p < 0.001), and a trend for a longer ACC time (Q4 vs. Q1: OR 2.62, 95% CI 0.89–7.68, p = 0.080). Conclusions: Shortening the operative times resulted in marked improvements of the patients’ outcomes. The combined use of minimally invasive approaches and sutureless aortic valve prostheses allows for a lower 30-day events rate. New technologies should be assessed to obtain the best results with the least risk.
Recent evidence indicates that reactive oxygen species play an important causative role in the onset and progression of valvular diseases. Here, we analyzed the oxidative modifications of albumin ...(HSA) occurring on Cysteine 34 and the antioxidant capacity of the serum in 44 patients with severe aortic stenosis (36 patients underwent aortic valve replacement and 8 underwent a second aortic valve substitution due to a degenerated bioprosthetic valve), and in 10 healthy donors (controls). Before surgical intervention, patients showed an increase in the oxidized form of albumin (HSA-Cys), a decrease in the native reduced form (HSA-SH), and a significant reduction in serum free sulfhydryl groups and in the total serum antioxidant activity. Patients undergoing a second valve replacement showed levels of HSA-Cys, free sulfhydryl groups, and total antioxidant activity similar to those of controls. In vitro incubation of whole blood with aspirin (ASA) significantly increased the free sulfhydryl groups, suggesting that the in vivo treatment with ASA may contribute to reducing oxidative stress. We also found that N-acetylcysteine and its amide derivative were able to regenerate HSA-SH. In conclusion, the systemic oxidative stress reflected by high levels of HSA-Cys is increased in patients with aortic valve stenosis. Thiol-disulfide breaking agents regenerate HSA-SH, thus paving the way to the use these compounds to mitigate the oxidative stress occurring in the disease.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
This study provides early results of re-operations after the prior surgical treatment of acute type A aortic dissection (AAD) and identifies risk factors for mortality. Between May 2003 and January ...2014, 117 aortic re-operations after an initial operation for AAD (a mean time from the first procedure was 3.98 years, with a range of 0.1–20.87 years) were performed in 110 patients (a mean age of 59.8 ± 12.6 years) in seven European institutions. The re-operation was indicated due to a proximal aortic pathology in ninety cases: twenty aortic root aneurysms, seventeen root re-dissections, twenty-seven aortic valve insufficiencies and twenty-six proximal anastomotic pseudoaneurysms. In fifty-eight cases, repetitive surgical treatment was subscripted because of distal aortic pathology: eighteen arch re-dissections, fifteen arch dilation and twenty-five anastomotic pseudoaneurysms. Surgical procedures comprised a total of seventy-one isolated proximals, thirty-one isolated distals and fifteen combined interventions. In-hospital mortality was 19.6 % (twenty-three patients); 11.1 % in patients with elective/urgent indication and 66.6 % in emergency cases. Mortality rates for isolated proximal, distal and combined operations regardless of the emergency setting were 14.1 % (10 pts.), 25.8 % (8 pts.) and 33.3 % (5 pts.), respectively. The causes of death were cardiac in eight, neurological in three, MOF in five, sepsis in two, bleeding in three and lung failure in two patients. A multivariate logistic regression analysis revealed that risk factors for mortality included previous distal procedure (
p
= 0.04), new distal procedure (
p
= 0.018) and emergency operation (
p
< 0.001). New proximal procedures were not found to be risk factors for early mortality (
p
= 0.15). This multicenter experience shows that the outcome of REAAD is highly dependent on the localization and extension of aortic pathology and the need for emergency treatment. Surgery in an emergency setting and distal re-do operations after previous AAD remain a surgical challenge, while proximal aortic re-operations show a lower mortality rate. Foresighted decision-making is needed in cases of AAD repair, as the results are essential preconditions for further surgical interventions.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background: The Ozaki procedure is an innovative surgical technique aiming at reconstructing aortic valves with human autologous pericardium. Even if this procedure is widely used, a comprehensive ...biological characterization of the glutaraldehyde (GA)-fixed pericardial tissue is still missing. Methods: Morphological analysis was performed to assess the general organization of pericardium subjected to the Ozaki procedure (post-Ozaki) in comparison to native tissue (pre-Ozaki). The effect of GA treatment on cell viability and nuclear morphology was then investigated in whole biopsies and a cytotoxicity assay was executed to assess the biocompatibility of pericardium. Finally, human umbilical vein endothelial cells were seeded on post-Ozaki samples to evaluate the influence of GA in modulating the endothelialization ability in vitro and the production of pro-inflammatory mediators. Results: The Ozaki procedure alters the arrangement of collagen and elastic fibers in the extracellular matrix and results in a significant reduction in cell viability compared to native tissue. GA treatment, however, is not cytotoxic to murine fibroblasts as compared to a commercially available bovine pericardium membrane. In addition, in in vitro experiments of endothelial cell adhesion, no difference in the inflammatory mediators with respect to the commercial patch was found. Conclusions: The Ozaki procedure, despite alteration of ECM organization and cell devitalization, allows for the establishment of a noncytotoxic environment in which endothelial cell repopulation occurs.
Background: The benefits of mitral repair versus replacement for endocarditis are inconclusive. This study compares outcomes of patients with infective endocarditis undergoing mitral valve repair ...versus replacement and investigates the impact of microbial etiology. Methods: All 251 patients undergoing mitral valve surgery for active endocarditis between 2010 and 2023 were enrolled, 180 (71.7%) replacement and 71 (28.3%) repair. To adjust for imbalances, inverse probability of treatment weighting was applied and 187 patients were obtained. Results: The analysis between groups, following the application of inverse probability of treatment weighting, showed no statistically significant differences across all considered outcomes. Early and late death was observed respectively in 6 (8.5%) and 11 (15.5%) patients in the repair group versus 24 (13.3%) and 45 (25.0%) in the replacement group without statistical significance (p = 0.221 and p = 0.446). Relapse occurred in six patients (8.5%) in the repair group after a median time of 4.0 months and in six (3.3%) in the replacement after 6.9 months (p = 0.071). Conclusions: Surgical strategy in mitral endocarditis has no effect on major postoperative complications, mortality, or medium/long-term survival. Staphylococcus aureus and Coagulase-negative Staphylococci represent a risk for early mortality and relapse. However, mitral valve repair for endocarditis can be pursued when it ensures the complete eradication of all infected tissue, particularly in cases caused by Streptococcus infection, in young patients, and after a minimum of 18 days of antibiotic therapy.
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