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Chronological age represents the main factor in donor selection criteria for organ transplantation, however aging is very heterogeneous. Defining the biological aging of individual organs may contribute to supporting this process. In this study we examined the biological age of the heart [right (RA)/left atrium (LA)] and peripheral blood leucocytes in the same subject, and compared these to assess whether blood mirrors cardiac biological aging. Biological aging was studied in 35 donors (0.4–72 years) by exploring mitotic and non-mitotic pathways, using telomere length (TL) and age-dependent methylation changes in certain CpG loci (DNAmAge). Heart non-mitotic DNAmAge was strongly younger than that of both blood (− 10 years, p  < 0.0001) and chronological age (− 12 years, p  < 0.0001). Instead, heart and blood mitotic age (TL) were similar, and there was no difference in DNAmAge and TL between RA and LA. DNAmAge negatively correlated with TL in heart and blood ( p  ≤ 0.01). Finally, blood and heart TL ( p  < 0.01) and DNAmAge ( p  < 0.0001) were correlated. Therefore, blood can be a proxy indicator of heart biological age. While future investigation on post-transplant graft performance in relation to biological aging is still needed, our study could contribute to opening up novel basic and clinical research platforms in the field of organ transplantation.

Background and Objectives: Prosthesis–patient mismatch (PPM) after surgical aortic valve replacement (SAVR) is associated with worse clinical outcomes and worse valve durability. The aim of this retrospective single-center study was to evaluate the consistency between predicted PPM (PPMp) and measured PPM (PPMm) after SAVR with three different bioprostheses. Materials and Methods: We analyzed data of all consecutive patients who underwent surgical aortic valve replacement with Magna Ease, Intuity, and Inspiris Resilia bioprostheses (Edwards Lifesciences, Irvine, CA, USA) at our institution. PPM was defined if EOAi ≤ 0.85 cm2/m2. PPMm was determined by institutional echo lab-measured EOAi on discharge-day echocardiogram. PPMp was assessed using reference values for each valve model and size indexed to BSA based on height, weight, prosthesis type, and size. For the overall population and for the three valve types we evaluated the sensitivity, specificity, positive predicted value, negative predicted value, and accuracy of PPMp. Furthermore, the consistency between PPMm and PPMp were evaluated according to prosthesis type, size, stent internal diameter (ID), and true ID. Results: A total of 1323 patients underwent SAVR; complete hemodynamic data were available for 872 patients, who represent the population of our study. Magna Ease, Intuity, and Inspiris Resilia were implanted in 446 (51.1%), 341 (39.1%), and 85 (9.7%) patients, respectively. In 635 out of 872 cases (72.8%), PPMp was consistent with PPMm (Magna Ease: 321/446, 72%; Inspiris Resilia: 58/85, 68.2%; Intuity: 256/341, 75%). Overall, the sensitivity, specificity, positive predicted value, negative predicted value, and accuracy of PPMp were 0.26, 0.83, 0.24, 0.84, and 0.73, respectively (Magna Ease: 0.21, 0.82, 0.3, 0.8, and 0.72; Inspiris Resilia: 0.11, 0.82, 0.14, 0.79, and 0.68; Intuity: 0.45, 0.78, 0.19, 0.93, and 0.75). Conclusions: The consistency between PPMp and PPMm was suboptimal. We did not observe differences between PPMp and PPMm among different valve types. Discordance between PPMp and PPMm was more evident in smaller valve sizes. When implanting small valves, the evaluation of PPMp should be used with caution to avoid unexpected PPMm.

The Donation-after-Circulatory-Death (DCD) heart transplantation program increases donor pool but resulting in more serious ischemic-related myocardial injury (IRI), leading to higher incidence of primary graft dysfunction (PGD). Ex-vivo machine perfusion (EVMP) for DCD heart is being considered a useful aid in improving grafts number and quality assessment, aiming to better outcomes. In this review we will analyze the role of EVMP techniques in the context of DCD with special attention to their clinical aims and results and future perspectives. A review of available clinical and pre-clinical studies involving EVMP with DCD donation model was performed. Thirty-four original articles about preclinical studies were found. First studies were designed to evaluate graft function in DCD hearts after EVMP, while recent research focus on possible therapies that could be associated with EVMP. Twenty-one original articles about clinical studies were found with the Organ-Care-System (TransMedics) as MP used. Outcomes, such as survival rates or rejection episodes, are comparable to outcomes from donation-after-brain-death. EVMP in the setting of DCD heart transplantation can be a valid tool for organ preservation and transport. The role of pre-clinical research will be crucial to reduce IRI, achieve organ reconditioning and reduce incidence of PGD.

Structural cardiac lesions are often surgically repaired using prosthetic patches, which can be biological or synthetic. In the current clinical scenario, biological patches derived from the decellularization of a xenogeneic scaffold are gaining more interest as they maintain the natural architecture of the extracellular matrix (ECM) after the removal of the native cells and remnants. Once implanted in the host, these patches can induce tissue regeneration and repair, encouraging angiogenesis, migration, proliferation, and host cell differentiation. Lastly, decellularized xenogeneic patches undergo cell repopulation, thus reducing host immuno-mediated response against the graft and preventing device failure. Porcine small intestinal submucosa (pSIS) showed such properties in alternative clinical scenarios. Specifically, the US FDA approved its use in humans for urogenital procedures such as hernia repair, cystoplasties, ureteral reconstructions, stress incontinence, Peyronie’s disease, penile chordee, and even urethral reconstruction for hypospadias and strictures. In addition, it has also been successfully used for skeletal muscle tissue reconstruction in young patients. However, for cardiovascular applications, the results are controversial. In this study, we aimed to validate our decellularization protocol for SIS, which is based on the use of Tergitol 15 S 9, by comparing it to our previous and efficient method (Triton X 100), which is not more available in the market. For both treatments, we evaluated the preservation of the ECM ultrastructure, biomechanical features, biocompatibility, and final bioinductive capabilities. The overall analysis shows that the SIS tissue is macroscopically distinguishable into two regions, one smooth and one wrinkle, equivalent to the ultrastructure and biochemical and proteomic profile. Furthermore, Tergitol 15 S 9 treatment does not modify tissue biomechanics, resulting in comparable to the native one and confirming the superior preservation of the collagen fibers. In summary, the present study showed that the SIS decellularized with Tergitol 15 S 9 guarantees higher performances, compared to the Triton X 100 method, in all the explored fields and for both SIS regions: smooth and wrinkle.

Cardiac implantable electronic devices manage arrhythmias but are limited by mechanical failures, infection risks, and poor long-term biocompatibility. Developing a biological alternative that restores intrinsic pacemaking remains a key clinical challenge. We developed cardiac scaffolds from porcine atrioventricular nodes using an optimized Tergitol-based decellularization protocol. Morphological, ultrastructural, proteomic, and mechanical analyses were conducted to assess ECM integrity and preservation of native architecture. The decellularization process effectively removed cellular and nuclear components while preserving three-dimensional structure, collagen content, and overall ECM organization. Analyses confirmed that key features essential for pacemaker tissue support were maintained. Our findings demonstrate that the scaffold retains native characteristics suitable for biologically inspired pacemaker applications. This work provides a foundation for ECM-derived hydrogel development, cytocompatibility testing, and integration with cardiomyocytes in next-generation tissue-engineered cardiac scaffolds.

Insufficient supply of cardiac grafts represents a severe obstacle in heart transplantation. Donation after circulatory death (DCD), in addition to conventional donation after brain death, is one promising option to overcome the organ shortage. However, DCD organs undergo an inevitably longer period of unprotected warm ischemia between circulatory arrest and graft procurement. In this scenario, we aim to improve heart preservation after a warm ischemic period of 20 min by testing different settings of myocardial protective strategies. Pig hearts were collected from a slaughterhouse and assigned to one of the five experimental groups: baseline (BL), cold cardioplegia (CC), cold cardioplegia + adenosine (CC-ADN), normothermic cardioplegia (NtC + CC) or normothermic cardioplegia + cold cardioplegia + adenosine (NtC-ADN + CC). After treatment, tissue biopsies were taken to assess mitochondrial morphology, antioxidant enzyme activity, lipid peroxidation and cytokine and chemokine expressions. NtC + CC treatment significantly prevented mitochondria swelling and mitochondrial cristae loss. Moreover, the antioxidant enzyme activity was lower in this group, as was lipid peroxidation, and the pro-inflammatory chemokine GM-CSF was diminished. Finally, we demonstrated that normothermic cardioplegia preserved mitochondria morphology, thus preventing oxidative stress and the subsequent inflammatory response. Therefore, normothermic cardioplegia is a better approach to preserve the heart after a warm ischemia period, with respect to cold cardioplegia, before transplantation.

Static cold storage (SCS) remains the gold standard for preserving donor hearts before transplantation but is associated with ischaemia, anaerobic metabolism, and organ injuries, leading to patient morbidity and mortality. We aimed to evaluate whether continuous, hypothermic oxygenated machine perfusion (HOPE) of the donor heart is safe and superior compared with SCS. We performed a multinational, multicentre, randomised, controlled, open-label clinical trial with a superiority design at 15 transplant centres across eight European countries. Adult candidates for heart transplantation were eligible and randomly assigned in a 1:1 ratio. Donor inclusion criteria were age 18–70 years with no previous sternotomy and donation after brain death. In the treatment group, the preservation protocol involved the use of a portable machine perfusion system ensuring HOPE of the resting donor heart. The donor hearts in the control group underwent ischaemic SCS according to standard practices. The primary outcome was time to first event of a composite of either cardiac-related death, moderate or severe primary graft dysfunction (PGD) of the left ventricle, PGD of the right ventricle, acute cellular rejection at least grade 2R, or graft failure (with use of mechanical circulatory support or re-transplantation) within 30 days after transplantation. We included all patients who were randomly assigned, fulfilled inclusion and exclusion criteria, and received a transplant in the primary analysis and all patients who were randomly assigned and received a transplant in the safety analyses. This trial was registered with ClicalTrials.gov (NCT03991923) and is ongoing. A total of 229 patients were enrolled between Nov 25, 2020, and May 19, 2023. The primary analysis population included 204 patients who received a transplant. There were no patients who received a transplant lost to follow-up. All 100 donor hearts preserved with HOPE were transplantable after perfusion. The primary endpoint was registered in 19 (19%) of 101 patients in the HOPE group and 31 (30%) of 103 patients in the SCS group, corresponding to a risk reduction of 44% (hazard ratio 0·56; 95% CI 0·32–0·99; log-rank test p=0·059). PGD was the primary outcome event in 11 (11%) patients in the HOPE group and 29 (28%) in the SCS group (risk ratio 0·39; 95% CI 0·20–0·73). In the HOPE group, 63 (65%) patients had a reported serious adverse event (158 events) versus 87 (70%; 222 events) in the SCS group. Major adverse cardiac transplant events were reported in 18 (18%) and 33 (32%) patients in the HOPE and SCS group (risk ratio 0·56; 95% CI 0·34–0·92). Although there was not a significant difference in the primary endpoint, the 44% risk reduction associated with HOPE was suggested to be a clinically meaningful benefit. Post-transplant complications, measured as major adverse cardiac transplant events, were reduced. Analysis of secondary outcomes suggested that HOPE was beneficial in reducing primary graft dysfunction. HOPE in donor heart preservation addresses the existing challenges associated with graft preservation and the increasing complexity of donors and heart transplantation recipients. Future investigation will help to further elucidate the benefit of HOPE. XVIVO Perfusion.

The most common aortic valve diseases in adults are stenosis due to calcification and regurgitation. In pediatric patients, aortic pathologies are less common. When a native valve is surgically replaced by a prosthetic one, it is necessary to consider that the latter has a limited durability. In particular, current bioprosthetic valves have to be replaced after approximately 10 years; mechanical prostheses are more durable but require the administration of permanent anticoagulant therapy. With regard to pediatric patients, both mechanical and biological prosthetic valves have to be replaced due to their inability to follow patients’ growth. An alternative surgical substitute can be represented by the acellular porcine aortic valve that exhibits less immunogenic risk and a longer lifespan. In the present study, an efficient protocol for the removal of cells by using detergents, enzyme inhibitors, and hyper- and hypotonic shocks is reported. A new detergent (Tergitol) was applied to replace TX-100 with the aim to reduce toxicity and maximize ECM preservation. The structural integrity and efficient removal of cells and nuclear components were assessed by means of histology, immunofluorescence, and protein quantification; biomechanical properties were also checked by tensile tests. After decellularization, the acellular scaffold was sterilized with a standard protocol and repopulated with bone marrow mesenchymal stem cells to analyze its biocompatibility profile.

Right ventricle outflow tract obstruction (RVOTO) is a congenital pathological condition that contributes to about 15% of congenital heart diseases. In most cases, the replacement of the right ventricle outflow in pediatric age requires subsequent pulmonary valve replacement in adulthood. The aim of this study was to investigate the extracellular matrix scaffold obtained by decellularization of the porcine pulmonary valve using a new detergent (Tergitol) instead of Triton X-100. The decellularized scaffold was evaluated for the integrity of its extracellular matrix (ECM) structure by testing for its biochemical and mechanical properties, and the cytotoxicity/cytocompatibility of decellularized tissue was assessed using bone marrow-derived mesenchymal stem cells. We concluded that Tergitol could remove the nuclear material efficiently while preserving the structural proteins of the matrix, but without an efficient removal of the alpha-gal antigenic epitope. Therefore, Tergitol can be used as an alternative detergent to replace the Triton X-100.

Introduction and aims: Malnutrition is associated with increased morbidity and mortality in patients who undergo cardiac surgery. Nevertheless, objective assessment of malnourished patients undergoing heart transplantation (HT) is limited. We aimed to analyze the relationship between the malnutrition status and the early and late clinical outcomes of patients undergoing HT using a novel semi-quantitative tool. Methods: All patients aged ≥18 years who underwent HT between January 2015 and July 2020 in a single center were retrospectively evaluated and included in the study. The semi-quantitative Malnutrition Universal Screening Tool (MUST) score (already validated in heart failure) was calculated for each patient at the time of transplantation to assess their nutritional status. A propensity score weighting approach was performed to evaluate the association between the increase in MUST score and the risk of early complications and in-hospital mortality. A Cox regression analysis was performed to assess follow-up mortality. Results: A total of 168 HT patients (median age 58.4 years, IQR 49.5–65.2, men n = 128, 76%) were included within the study period. Their median preoperative BMI was 24.0 kg/m2 (IQR 21.2–27.9). Preoperative MUST scores of 0, 1, and ≥2 were found in 92 (55%), 24 (14%), and 52 (31%) patients, respectively. The median preoperative eGFR was 64.3 mL/min (IQR 49.0–83.2). An increase in MUST score (from 0 to 2) was not significantly related to major postoperative complications or in-hospital mortality. An analogous increase in MUST score was associated with increased follow-up mortality risk (hazard ratio 1.28, 95% CI 1.04–1.83, p = 0.024). Conclusions: Malnutrition assessed with the MUST score seems not to be associated with increased in-hospital mortality or major postoperative complications in patients who undergo HT, but according to our preliminary data it is related to patients’ long-term mortality.