Nonischemic Donor Heart Preservation: New Milestone in Heart Transplantation History.

Heart transplantation is considered the gold standard for the treatment of advanced end-stage heart failure. However, standard donors after brain death are decreasing, whereas patients on the heart transplant waitlist are constantly rising. The introduction of the ex vivo machine perfusion device has been a turning point; in fact, these systems are able to significantly reduce ischemic times and have a potential effect on ischemia-related damage reduction. From a clinical standpoint, these machines show emerging results in terms of heart donor pool expansion, making marginal donors and donor grafts after circulatory death suitable for donation. This article aims to review mechanisms and preclinical and clinical outcomes of currently available ex vivo perfusion systems, and to explore the future fields of application of these technologies.

Tergitol Based Decellularization Protocol Improves the Prerequisites for Pulmonary Xenografts: Characterization and Biocompatibility Assessment.

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.

Anticoagulation alone as an effective and safe antithrombotic therapy in LVAD: When less is more.

To evaluate the safety and effectiveness of anticoagulation alone in HeartMate3 patients. According to antithrombotic regimen, patients were divided into 2 groups: Group-1(warfarin+aspirin) and Group-2(warfarin). A comparison of hemocompatibility-related adverse events (HRAEs), hemocompatibility score (HCS), and hemocoagulative laboratory markers, both qualitative and quantitative, between the 2 groups were performed. Fifty patients were enrolled, 28 (56%) in Group-1 and 22 in Group-2 (44%), without statistical differences at baseline. Median time of follow-up was 590 days (IQR: 410.25-1007.50). Eighteen HRAEs (36.0%) occurred: 17 in Group-1 (34%) and 1 in Group-2 (2%) (P < 0.001). The net HCS for Group-1 versus Group-2 was 24 points and 1 point (OR 12.116[2.034-233.226], P = 0.023), respectively. Hemocoagulative values turned into the normality and remained stable during follow-up, without differences between groups, except for ASPI-test (P = 0.003). HeartMate3 showed a high hemocompatibility independently from antithrombotic therapy. Aspirin avoidance resulted a safe and effective strategy since it reduced hemorrhagic events, without increasing thrombotic risk.

Small intestinal submucosa-derived extracellular matrix as a heterotopic scaffold for cardiovascular applications.

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.

Temperature-Related Effects of Myocardial Protection Strategies in Swine Hearts after Prolonged Warm Ischemia.

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.

A New Decellularization Protocol of Porcine Aortic Valves Using Tergitol to Characterize the Scaffold with the Biocompatibility Profile Using Human Bone Marrow Mesenchymal Stem Cells.

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.

Antiphospholipid antibody syndrome and LVAD: What are the chances? A case report and literature review.

Left-ventricular-assist-device (LVAD) implantation in patients with antiphospholipid-syndrome (APS) is considered a high-risk procedure and its indication still represents an open challenge. Herein, we report a 63-year-old man with APS and end-stage heart failure, for whom a HeartMate3-LVAD and a continuous rheologic profile monitoring with a multiparametric assessment resulted the optimal therapeutic strategy.

Porcelain aorta: A surgical dilemma in orthotopic heart transplantation.

BACKGROUND: Circumferential calcification of the ascending aorta, known as porcelain aorta, in a patient candidate to a heart transplant, requires technically demanding and high-risk procedural adjustments. AIMS: This case report showed successful replacement of ascending aorta due to extensive calcification at time of heart transplantation. MATERIALS AND METHODS: In the operating theatre, after median sternotomy, cardiopulmonary bypass (CPB) was achieved via the right femoral artery and vein. Due to the impossibility of replacing the ascending aorta using safe aortic cross-clamping, a moderate hypothermia was established, and circulatory arrest was realized. According to Kazui protocol for selective anterograde cerebral perfusion via anonymous trunk and left carotid artery, ascending aorta was replaced with vascular prosthesis. RESULTS: Thanks to accurate pre-surgical planning, which included hypothermic circulatory arrest, ascending aorta replacement, before orthotopic heart implantation, we were able to perform the procedure successfully and prevent neurological events. DISCUSSION: Although different reports showed the feasibility of heart transplant combined to aortic replacement for aneurysmatic pathology, few cases were described for porcelain aorta, due to technically demanding procedure and prohibitive aortic cross-clamping. To avoid vascular embolization, dissection and mural laceration, aortic cross-clamping is not recommended. We performed aortic replacement at first, to reduce allograft ischemia. CONCLUSION: The use of hypothermic circulatory arrest technique with selective cerebral perfusion for aortic replacement, followed by vascular graft clamping to favour cardiac allograft implantation, could be considered a winning combination to guarantee procedural success and to reduce perioperative complications.

Valve-shaped thrombus underneath an aortic bioprosthesis.

We describe massive thrombus formation completely occluding an aortic bioprosthesis in a patient with venoarterial extracorporeal membrane oxygenation and apical venting. The thrombus was surgically removed and the patient recovered with no complications. Timely identification and immediate surgical removal of thrombi may allow patient recovery with no severe complications.

The living, innovative, fully engineered, long-lasting and advanced bioreplacement research program: when Italian Regional Institutions support research.

Tweetable abstract Born with the aim of creating tissues and organs for transplant, the LIFELAB research program represents a unique reality in Italy. The program has gained promising results in the first phase, due to the synergy of 21 groups of researchers.

Totally peripheral approach for ICD lead vegetation removal in a GUCH patient.

AngioVac system (AngioDynamics) has already proved to be a useful tool in the treatment of thrombotic and endocarditic formations concerning the venous district. Herein, the AngioVac aspiration system combined with the bidirectional rotational Evolution mechanical sheath lead extraction was used for an effective and safety cardiac-device-related-infective-endocarditis removal in a grown-up congenital heart disease patient through a totally peripheral approach.

Myocardial oxygen consumption during histidine-tryptophan-ketoglutarate cardioplegia in young human hearts.

OBJECTIVES: Energy demand and supply need to be balanced to preserve myocardial function during paediatric cardiac surgery. After a latent aerobic period, cardiac cells try to maintain energy production by anaerobic metabolism and by extracting oxygen from the given cardioplegic solution. Myocardial oxygen consumption (MVO2) changes gradually during the administration of cardioplegia. METHODS: MVO2 was measured during cardioplegic perfusion in patients younger than 6 months of age (group N: neonates; group I: infants), with a body weight less than 10 kg. Histidine-tryptophan-ketoglutarate crystalloid solution was used for myocardial protection and was administered during a 5-min interval. To measure pO2 values during cardioplegic arrest, a sample of the cardioplegic fluid was taken from the inflow line before infusion. Three fluid samples were taken from the coronary venous effluent 1, 3 and 5 min after the onset of cardioplegia administration. MVO2 was calculated using the Fick principle. RESULTS: The mean age of group N was 0.2 ± 0.09 versus 4.5 ± 1.1 months in group I. The mean weight was 3.1 ± 0.2 versus 5.7 ± 1.6 kg, respectively. MVO2 decreased similarly in both groups (min 1: 0.16 ± 0.07 vs 0.36 ± 0.1 ml/min; min 3: 0.08 ± 0.04 vs 0.17 ± 0.09 ml/min; min 5: 0.05 ± 0.04 vs 0.07 ± 0.05 ml/min). CONCLUSIONS: We studied MVO2 alterations after aortic cross-clamping and during delivery of cardioplegia in neonates and infants undergoing cardiac surgery. Extended cardioplegic perfusion significantly reduces energy turnover in hearts because the balance procedures are both volume- and above all time-dependent. A reduction in MVO2 indicates the necessity of a prolonged cardioplegic perfusion time to achieve optimized myocardial protection.

From bench to bedside: Impact of left ventricular assist device outflow conduit anastomosis position on outcome.

Continuous flow left ventricular assist devices (LVADs) have become a valuable therapy for end-stage heart failure. In vitro research highlighted a role of outflow cannula position on the pattern of blood flow in the aorta. However, the clinical effects of the alterations of flow remain unclear. We investigate short- and long-term outcomes of patients implanted with Jarvik 2000 LVAD, according to the ascending (Group 1) versus descending (Group 2) outflow graft connection to the aorta in a multicenter study. From May 2008 to October 2014, 140 consecutive end-stage heart failure patients underwent Jarvik 2000 LVAD implantation in 17 Italian centers. According with a preliminary multivariate analysis, we selected the 90 patients implanted in the four high-volume centers to avoid bias (Group 1 n = 39, Group 2 n = 51). Among the groups, no differences were recorded in the hospital mortality and the main complications occurring after LVAD implantation were similar. In multivariable analysis, the ascending aorta outflow cannula position and higher creatinine at discharge were significant predictors for long-term survival. Postimplant hemolysis was more pronounced in descending aorta outflow graft anastomosis. Outflow graft anastomosis to the ascending aorta is associated with better long-term survival, independent of age and perfusion techniques, reflecting the previous in vitro results.

Biological versus mechanical aortic valve replacement in non-elderly patients: a single-centre analysis of clinical outcomes and quality of life.

OBJECTIVES: The aim of this study was to evaluate short- and long-term clinical outcomes, including the perceived health-related quality of life, in patients younger than 65 years having undergone aortic valve replacement either with biological or mechanical valve prostheses. METHODS: Between 2002 and 2013, 242 consecutive patients <65 years of age underwent isolated aortic valve replacement at our institution, either with biological (n = 134, 55.4%) or mechanical (n = 108, 44.6%) prostheses. Survival, health-related quality of life, short- and long-term clinical outcomes and echocardiographic data were analysed with a retrospective, single-centre study. Propensity matching was performed. RESULTS: No significant difference in survival was found between the 2 groups (mechanical versus biological: 100% vs 96.6% at 1 year, 98.2% vs 93.1% at 5 years and 92.3% vs 83.4% at 10 years after surgery, P = 0.091). For all the interviewed patients (n = 161, 66.5%), perceived quality of life at the latest follow-up was excellent. Need for reoperation was higher in the bioprosthetic group (8% vs 0%, P = 0.995), whereas the rate of major bleedings was higher in the mechanical valve group (3% vs 20%, P = 0.094). The mean and maximum transvalvular pressure gradients were 20.5 ± 9.7 and 37.4 ± 17.5 mmHg in the biological group and 14.8 ± 4.8 and 26.6 ± 9.2 mmHg in the mechanical group (P = 0.014). CONCLUSIONS: No significant differences were found between biological and mechanical valves in terms of patients' survival, clinical outcomes and quality of life. Mean and maximum transvalvular pressure gradients were significantly higher in the biological group. The majority of patients would opt for the same prosthesis type, if asked to choose again.

RegenHeart: A Time-Effective, Low-Concentration, Detergent-Based Method Aiming for Conservative Decellularization of the Whole Heart Organ.

Heart failure is the worst outcome of all cardiovascular diseases and still represents nowadays the leading cause of mortality with no effective clinical treatments, apart from organ transplantation with allogeneic or artificial substitutes. Although applied as the gold standard, allogeneic heart transplantation cannot be considered a permanent clinical answer because of several drawbacks, as the side effects of administered immunosuppressive therapies. For the increasing number of heart failure patients, a biological cardiac substitute based on a decellularized organ and autologous cells might be the lifelong, biocompatible solution free from the need for immunosuppression regimen. A novel decellularization method is here proposed and tested on rat hearts in order to reduce the concentration and incubation time with cytotoxic detergents needed to render acellular these organs. By protease inhibition, antioxidation, and excitation-contraction uncoupling in simultaneous perfusion/submersion modality, a strongly limited exposure to detergents was sufficient to generate very well-preserved acellular hearts with unaltered extracellular matrix macro- and microarchitecture, as well as bioactivity.

The biological age of the heart is consistently younger than chronological age.

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.

A Step-by-Step Problem-Solving Strategy in a Patient With Heart Failure and Cerebral Aneurysm.

Left ventricular assist device implantation is an established treatment for patients with end-stage heart failure. The HeartMate 3 (Abbott Laboratories, Abbott Park, IL) is a continuous-flow centrifugal pump, recently introduced in the clinic, that has shown greater hemocompatibility compared with similar devices of previous generations. Nevertheless, anticoagulation is still required after HeartMate 3 implant to avoid pump dysfunction. Hereafter, we describe the case of a patient candidate to left ventricular assist device implantation for end-stage heart failure presenting a concomitant cerebrovascular lesion, accidentally found during preoperative assessment, that would have contraindicated the procedure (for the prohibitive risk of cerebral hemorrhage), unless a step by step problem-solving approach was adopted.

HandS ECMO: Preliminary Experience With "Hub and Spoke" Model in Neonates With Meconium Aspiration Syndrome.

We aim to evaluate clinical outcomes of emergent extracorporeal membrane oxygenation (ECMO) implantation in newborns with life-threatening meconium aspiration syndrome (MAS) in peripheral hospitals with Hub and Spoke (HandS) setting. We retrospectively reviewed all neonates presenting with MAS, with no other comorbidities, treated with HandS ECMO, in peripheral hospitals. Team activation time (TAT) was described as the time from first alerting call to ECMO support initiation. From May 2014 to December 2016, 4 patients met our inclusion criteria. In addition, 2 cases occurred on the same day, requiring a second simultaneous HandS ECMO team activation. All patients were younger than 8 days of life (1, 1, 4, and 7), with a mean BSA 0.21 ± 0.03m2 , and TAT of 203, 265, 320, and 340 min. One patient presented ventricular fibrillation after priming administration. Veno-arterial ECMO was established in all patients after uneventful surgical neck vessels cannulation (right carotid artery and jugular vein). Mean time from skin incision to ECMO initiation was 19 ± 1.4 min. Mean length of ECMO support was 2.75 ± 1.3 days. All patients were weaned off support without complications. At a mean follow up of 20.5 ± 7.8 months, all patients are alive, with no medications, normal somatic growth, and neuropsychological development. MAS is a life-threatening condition that can be successfully managed with ECMO support. A highly trained multidisciplinary HandS ECMO team is crucial for the successful management of these severely ill newborns in peripheral hospitals.

Mitral Valve Repair and Anomalous Origin of Circumflex Artery: To Ring or Not to Ring.

We describe a case of an adult patient with mitral valve regurgitation and the anomalous origin and course of the left circumflex coronary artery. Use of a ringless procedure or a microinvasive approach, such as transapical neochordae implantation, would have possibly avoided a life-threatening post-operative complication. (Level of Difficulty: Advanced.).