Complicaciones y descargas inapropiadas tras el implante de un desfibrilador subcutáneo en pacientes pediátricos / Complications and inappropriate shocks in pediatric patients receiving a subcutaneous implantable cardioverter defibrilator

Introducción y objetivos: La experiencia con el desfibrilador automático implantable subcutáneo (DAI-SC) en pacientes pediátricos aún es reducida. El objetivo de este estudio es determinar la incidencia de complicaciones en pacientes pediátricos de nuestro centro en función del tipo de DAI y del tamaño del paciente.MétodosSe incluyó a pacientes menores de 18 años que recibieron un DAI-SC desde 2016 y pacientes contemporáneos (desde 2014) que recibieron un DAI transvenoso (DAI-TV). El evento principal fue el combinado de complicaciones y descargas inapropiadas.ResultadosSe implantó un DAI-SC a 26 pacientes (edad, 14 [intervalo, 5-17] años; índice de masa corporal [IMC], 20,2). De ellos, 23 (88%) fueron implantes intermusculares y el resto, en subserrato, 24 (92%) con 2 incisiones. Se programaron 2 zonas en todos los pacientes: condicional a 230 (220-230) lpm y de choque a 250 lpm. El grupo de DAI-TV incluyó a 19 pacientes (edad, 11 [5-16] años; IMC, 19,2; el 79% monocamerales). La supervivencia libre del evento principal a 5 años fue el 80% de los pacientes con DAI-SC y el 63% del grupo con DAI-TV (p=0,54); la de descargas inapropiadas fue similar (el 85 frente al 89%; p=0,86), mientras que la de complicaciones fue mayor en el grupo de DAI-SC (el 96 frente al 57%; cloglog p=0.016). En el grupo de DAI-SC no hubo fallo de la terapia ni mayores complicaciones con un IMC ≤ 20.ConclusionesCon las técnicas de implante y programación actuales, el DAI-SC es eficaz y seguro en pacientes pediátricos, con similares descargas inapropiadas y menos complicaciones a corto y medio plazo que el DAI-TV. (AU)

Introduction and objectives: There is limited evidence regarding the use of subcutaneous implantable cardioverter-defibrillators (S-ICD) in pediatric patients. The aim of this study was to determine the incidence of complications in these patients at our center, according to the type of ICD and patient size.MethodsWe included all patients aged<18 years who received an S-ICD since 2016 at our center. As a control group, we also included contemporary patients (since 2014) who received a transvenous ICD (TV-ICD). The primary endpoint was a composite of complications and inappropriate shocks.ResultsA total of 26 patients received an S-ICD (median age, 14 [5-17] years; body mass index [BMI], 20.2 kg/m2). Implantation was intermuscular in 23 patients (88%) and subserratus in the remainder. Two incisions were used in 24 patients (92%). In all patients, 2 zones were programmed: a conditional zone set at 230 (220-230) bpm, and a shock zone set at 250 bpm. Nineteen patients received a TV-ICD (median age, 11 [range, 5-16] years; BMI, 19.2 kg/m2, 79% single-chamber). Survival free from the primary endpoint at 5 years was 80% in the S-ICD group and 63% in the TV-ICD group (P=.54). Survival free from inappropriate shocks was similar (85% vs 89%, P=.86), while survival free from complications was higher in the S-ICD group (96% vs 57%, cloglogP=.016). There were no therapy failures in the S-ICD group, and no increased complication rates were observed in patients with BMI ≤ 20 kg/m2.ConclusionsWith contemporary implantation techniques and programming, S-ICD is a safe and effective therapy in pediatric patients. The number of inappropriate shocks is similar to TV-ICD, with fewer short- and mid-term complications. (AU)

Left axillary approach for pulmonary valve replacement.

A 14-year-old girl was scheduled for pulmonary valve replacement. A computed tomography scan showed an enlarged cardiac silhouette with an aneurysmal pulmonary artery. A less-invasive approach through the left axilla with peripheral cannulation was selected. The patient was draped in the decubitus position, with a roll under the left shoulder and the left arm over the head. The anatomical landmarks were the left nipple and the tip of the scapula. A 5-cm vertical incision in the mid-axillary line was performed, and the thorax was entered through the fourth intercostal space. Peripheral cannulation for cardiopulmonary bypass was achieved by a right groin dissection. Partial bypass was instituted and, on an unloaded heart, the ascending aorta plus the right appendage and the pulmonary artery were further cannulated. With the heart beating, the pulmonary artery was opened, and a 25-mm biological Carpentier Perimount-Magna valve was chosen. A second stitch was used to close the arteriotomy with large bites in a double row to reduce the perimeter of the trunk. Cardiopulmonary bypass was discontinued (after 64 minutes), and the cannulas were removed sequentially. Echocardiography showed a good result, with proper valve function and a reduced pulmonary artery. The patient was discharged on postoperative day 12 on antiplatelet therapy.

Complications and inappropriate shocks in pediatric patients receiving a subcutaneous implantable cardioverter defibrilator.

INTRODUCTION AND OBJECTIVES: There is limited evidence regarding the use of subcutaneous implantable cardioverter-defibrillators (S-ICD) in pediatric patients. The aim of this study was to determine the incidence of complications in these patients at our center, according to the type of ICD and patient size. METHODS: We included all patients aged<18 years who received an S-ICD since 2016 at our center. As a control group, we also included contemporary patients (since 2014) who received a transvenous ICD (TV-ICD). The primary endpoint was a composite of complications and inappropriate shocks. RESULTS: A total of 26 patients received an S-ICD (median age, 14 [5-17] years; body mass index [BMI], 20.2 kg/m2). Implantation was intermuscular in 23 patients (88%) and subserratus in the remainder. Two incisions were used in 24 patients (92%). In all patients, 2 zones were programmed: a conditional zone set at 230 (220-230) bpm, and a shock zone set at 250 bpm. Nineteen patients received a TV-ICD (median age, 11 [range, 5-16] years; BMI, 19.2 kg/m2, 79% single-chamber). Survival free from the primary endpoint at 5 years was 80% in the S-ICD group and 63% in the TV-ICD group (P=.54). Survival free from inappropriate shocks was similar (85% vs 89%, P=.86), while survival free from complications was higher in the S-ICD group (96% vs 57%, cloglog P=.016). There were no therapy failures in the S-ICD group, and no increased complication rates were observed in patients with BMI ≤20 kg/m2. CONCLUSIONS: With contemporary implantation techniques and programming, S-ICD is a safe and effective therapy in pediatric patients. The number of inappropriate shocks is similar to TV-ICD, with fewer short- and mid-term complications.

A Novel GMP Protocol to Produce High-Quality Treg Cells From the Pediatric Thymic Tissue to Be Employed as Cellular Therapy.

Due to their suppressive capacity, the adoptive transfer of regulatory T cells (Treg) has acquired a growing interest in controlling exacerbated inflammatory responses. Limited Treg recovery and reduced quality remain the main obstacles in most current protocols where differentiated Treg are obtained from adult peripheral blood. An alternate Treg source is umbilical cord blood, a promising source of Treg cells due to the higher frequency of naïve Treg and lower frequency of memory T cells present in the fetus' blood. However, the Treg number isolated from cord blood remains limiting. Human thymuses routinely discarded during pediatric cardiac surgeries to access the retrosternal operative field has been recently proposed as a novel source of Treg for cellular therapy. This strategy overcomes the main limitations of current Treg sources, allowing the obtention of very high numbers of undifferentiated Treg. We have developed a novel good manufacturing practice (GMP) protocol to obtain large Treg amounts, with very high purity and suppressive capacity, from the pediatric thymus (named hereafter thyTreg). The total amount of thyTreg obtained at the end of the procedure, after a short-term culture of 7 days, reach an average of 1,757 x106 (range 50 x 106 - 13,649 x 106) cells from a single thymus. The thyTreg product obtained with our protocol shows very high viability (mean 93.25%; range 83.35% - 97.97%), very high purity (mean 92.89%; range 70.10% - 98.41% of CD25+FOXP3+ cells), stability under proinflammatory conditions and a very high suppressive capacity (inhibiting in more than 75% the proliferation of activated CD4+ and CD8+ T cells in vitro at a thyTreg:responder cells ratio of 1:1). Our thyTreg product has been approved by the Spanish Drug Agency (AEMPS) to be administered as cell therapy. We are recruiting patients in the first-in-human phase I/II clinical trial worldwide that evaluates the safety, feasibility, and efficacy of autologous thyTreg administration in children undergoing heart transplantation (NCT04924491). The high quality and amount of thyTreg and the differential features of the final product obtained with our protocol allow preparing hundreds of doses from a single thymus with improved therapeutic properties, which can be cryopreserved and could open the possibility of an "off-the-shelf" allogeneic use in another individual.

Continuous Incisional Lidocaine in Pediatric Patients following Open Heart Surgery.

Continuous incisional lidocaine infusion has been proposed as an adjunctive therapy in the management of postoperative pain in adult patients. The aim of this study was to determine the efficacy and safety of a continuous subcutaneous lidocaine infusion in pediatric patients following open heart surgery. All patients receiving a subcutaneous lidocaine infusion in median sternotomy incisions after open heart surgery during 2 consecutive years were included in the study. A historical cohort of patients was used as a control group. Demographic variables (age, size, and surgical procedure), variables related to sedation and analgesia (COMFORT and analgesia scales, drug doses, and duration), and complications were registered. 106 patients in the lidocaine infusion group and 79 patients in the control group were included. Incisional analgesia was effective for the treatment of pain as it reduced the dose and duration of intravenous fentanyl (odds ratio (OR) 6.26, confidence interval (CI) 95%: 2.48-15.97, p = 0.001; OR 4.30, CI 95%: 2.09-8.84, p = 0.001, respectively). The reduction in fentanyl use was more important in children over two years of age. Adverse effects were seen in three children (2.8%): they all had decreased level of consciousness, and one of them presented seizures as well. Two of these three patients had lidocaine levels over 2 mcg/ml. A continuous lidocaine incisional infusion is effective for the treatment of pain after open heart surgery. This procedure reduced intravenous analgesic drug requirements in pediatric patients undergoing a median sternotomy incision. Although the incidence of secondary effects is low, monitoring of neurologic status and lidocaine blood levels are recommended in all patients.

A Neonatal ABO non-compatible heart transplant from a circulatory-determined death donor using NRP/Cold storage.

BACKGROUND: Donation after Circulatory death is gaining worldwide acceptance. Most protocols regard their first cases to be performed with donor and recipient in the same institution. Few records of children or distant procurement have been published. METHODS: Our institution was offered a heart from a 3-day-old, 3.4-kg child, blood group A, suffering irreversible encephalopathy. Parents accepted withdrawal of life-sustaining therapy and agreed to donation. The donor hospital was located 340 km away. Concomitantly, a 2-month-old, 3.1 kg, blood group type B and with non-compaction ventricles was awaiting for the heart transplant in our unit. RESULTS: Thirty-seven minutes after withdrawal of life-sustaining therapy, the heart arrested. Five minutes afterwards, a sternotomy was performed. The supra-aortic vessels were clamped altogether. Aorta and right appendage were cannulated and connected to heart-lung machine. The innominate artery above the clamp was severed. The heart resumed spontaneous rhythm in less than 1 min. Ventilation was restored and extracorporeal circulation was maintained for 32 min. Upon cardiologic arrest, the graft was harvested as routinely. The heart was cold-stored and transported by plane to our Hospital. An orthotopic bicaval transplant was performed. Overall cold ischaemia was 245 min. Ten weeks later, the child was discharged home in good condition. CONCLUSION: Donation in circulatory death could increase the pool in neonates. Extracorporeal circulation proves successful for procurement in neonates. Distant procurement plus cold storage for donation in circulatory death is feasible. Donation in circulatory death and ABO non-compatible strategies are complementary to each other.

Role of RIPK1 in SMAC mimetics-induced apoptosis in primary human HIV-infected macrophages.

Macrophages serve as viral reservoirs due to their resistance to apoptosis and HIV-cytopathic effects. We have previously shown that inhibitor of apoptosis proteins (IAPs) confer resistance to HIV-Vpr-induced apoptosis in normal macrophages. Herein, we show that second mitochondrial activator of caspases (SMAC) mimetics (SM) induce apoptosis of monocyte-derived macrophages (MDMs) infected in vitro with a R5-tropic laboratory strain expressing heat stable antigen, chronically infected U1 cells, and ex-vivo derived MDMs from HIV-infected individuals. To understand the mechanism governing SM-induced cell death, we show that SM-induced cell death of primary HIV-infected macrophages was independent of the acquisition of M1 phenotype following HIV infection of macrophages. Instead, SM-induced cell death was found to be mediated by IAPs as downregulation of IAPs by siRNAs induced cell death of HIV-infected macrophages. Moreover, HIV infection caused receptor interacting protein kinase-1 (RIPK1) degradation which in concert with IAP1/2 downregulation following SM treatment may result in apoptosis of macrophages. Altogether, our results show that SM selectively induce apoptosis in primary human macrophages infected in vitro with HIV possibly through RIPK1. Moreover, modulation of the IAP pathways may be a potential strategy for selective killing of HIV-infected macrophages in vivo.

TLR-4 Agonist Induces IFN-γ Production Selectively in Proinflammatory Human M1 Macrophages through the PI3K-mTOR- and JNK-MAPK-Activated p70S6K Pathway.

IFN-γ, a proinflammatory cytokine produced primarily by T cells and NK cells, activates macrophages and engages mechanisms to control pathogens. Although there is evidence of IFN-γ production by murine macrophages, IFN-γ production by normal human macrophages and their subsets remains unknown. Herein, we show that human M1 macrophages generated by IFN-γ and IL-12- and IL-18-stimulated monocyte-derived macrophages (M0) produce significant levels of IFN-γ. Further stimulation of IL-12/IL-18-primed macrophages or M1 macrophages with agonists for TLR-2, TLR-3, or TLR-4 significantly enhanced IFN-γ production in contrast to the similarly stimulated M0, M2a, M2b, and M2c macrophages. Similarly, M1 macrophages generated from COVID-19-infected patients' macrophages produced IFN-γ that was enhanced following LPS stimulation. The inhibition of M1 differentiation by Jak inhibitors reversed LPS-induced IFN-γ production, suggesting that differentiation with IFN-γ plays a key role in IFN-γ induction. We subsequently investigated the signaling pathway(s) responsible for TLR-4-induced IFN-γ production in M1 macrophages. Our results show that TLR-4-induced IFN-γ production is regulated by the ribosomal protein S6 kinase (p70S6K) through the activation of PI3K, the mammalian target of rapamycin complex 1/2 (mTORC1/2), and the JNK MAPK pathways. These results suggest that M1-derived IFN-γ may play a key role in inflammation that may be augmented following bacterial/viral infections. Moreover, blocking the mTORC1/2, PI3K, and JNK MAPKs in macrophages may be of potential translational significance in preventing macrophage-mediated inflammatory diseases.

Hybrid Procedures. Opening Doors for Surgeon and Cardiologist Close Collaboration.

Background: Collaboration between cardiac surgeons and cardiologists can offer interventions that each specialist may not be able to offer on their own. This type of collaboration has been demonstrated with the hybrid Stage I in patients with hypoplastic heart syndrome. Since that time, a hybrid approach to cardiac interventions has been expanded to an incredible variety of potential indications. Methods: Seventy-one patients were scheduled for a hybrid procedure along 8 years. This was defined as close collaboration between surgeon and cardiologist working together in the same room, either cath-lab (27 patients) or theater (44 patients). Results: Six groups were arbitrarily defined. A: vascular cut-down in the cath-lab (27 neonates); B: bilateral banding (plus ductal stent) in hypoplastic left heart syndrome or alike (15 children); C: perventricular closure of muscular ventricular septal defect (10 cases); D: balloon/stenting of pulmonary branches along with major surgical procedure (12 kids); E: surgical implantation of Melody valve (six patients) and others (F, one case). Two complications were recorded: left ventricular free wall puncture and previous conduit tearing. Both drawbacks were successfully sort out under cardiopulmonary by-pass. Conclusion: Surgeon and cardiologist partnership can succeed where their isolated endeavors are not enough. Hybrid procedures keep on spreading, overcoming initial expectations. As a bridge to biventricular repair or transplant, bilateral banding plus ductal stent sounds interesting. Novel indications can be classified into different groups. Hybrid procedures are not complication-free.

Identification of novel genes involved in apoptosis of HIV-infected macrophages using unbiased genome-wide screening.

BACKGROUND: Macrophages, besides resting latently infected CD4+ T cells, constitute the predominant stable, major non-T cell HIV reservoirs. Therefore, it is essential to eliminate both latently infected CD4+ T cells and tissue macrophages to completely eradicate HIV in patients. Until now, most of the research focus is directed towards eliminating latently infected CD4+ T cells. However, few approaches have been directed at killing of HIV-infected macrophages either in vitro or in vivo. HIV infection dysregulates the expression of many host genes essential for the survival of infected cells. We postulated that exploiting this alteration may yield novel targets for the selective killing of infected macrophages. METHODS: We applied a pooled shRNA-based genome-wide approach by employing a lentivirus-based library of shRNAs to screen novel gene targets whose inhibition should selectively induce apoptosis in HIV-infected macrophages. Primary human MDMs were infected with HIV-eGFP and HIV-HSA viruses. Infected MDMs were transfected with siRNAs specific for the promising genes followed by analysis of apoptosis by flow cytometry using labelled Annexin-V in HIV-infected, HIV-exposed but uninfected bystander MDMs and uninfected MDMs. The results were analyzed using student's t-test from at least four independent experiments. RESULTS: We validated 28 top hits in two independent HIV infection models. This culminated in the identification of four target genes, Cox7a2, Znf484, Cstf2t, and Cdk2, whose loss-of-function induced apoptosis preferentially in HIV-infected macrophages. Silencing these single genes killed significantly higher number of HIV-HSA-infected MDMs compared to the HIV-HSA-exposed, uninfected bystander macrophages, indicating the specificity in the killing of HIV-infected macrophages. The mechanism governing Cox7a2-mediated apoptosis of HIV-infected macrophages revealed that targeting respiratory chain complex II and IV genes also selectively induced apoptosis of HIV-infected macrophages possibly through enhanced ROS production. CONCLUSIONS: We have identified above-mentioned novel genes and specifically the respiratory chain complex II and IV genes whose silencing may cause selective elimination of HIV-infected macrophages and eventually the HIV-macrophage reservoirs. The results highlight the potential of the identified genes as targets for eliminating HIV-infected macrophages in physiological environment as part of an HIV cure strategy.

Point-of-care manufacturing: a single university hospital's initial experience.

BACKGROUND: The integration of 3D printing technology in hospitals is evolving toward production models such as point-of-care manufacturing. This study aims to present the results of the integration of 3D printing technology in a manufacturing university hospital. METHODS: Observational, descriptive, retrospective, and monocentric study of 907 instances of 3D printing from November 2015 to March 2020. Variables such as product type, utility, time, or manufacturing materials were analyzed. RESULTS: Orthopedic Surgery and Traumatology, Oral and Maxillofacial Surgery, and Gynecology and Obstetrics are the medical specialties that have manufactured the largest number of processes. Working and printing time, as well as the amount of printing material, is different for different types of products and input data. The most common printing material was polylactic acid, although biocompatible resin was introduced to produce surgical guides. In addition, the hospital has worked on the co-design of custom-made implants with manufacturing companies and has also participated in tissue bio-printing projects. CONCLUSIONS: The integration of 3D printing in a university hospital allows identifying the conceptual evolution to "point-of-care manufacturing."

Ectopic FOXP3 Expression in Combination with TGF-ß1 and IL-2 Stimulation Generates Limited Suppressive Function in Human Primary Activated Thymocytes Ex Vivo.

Regulatory T cells (Tregs), which are characterized by the expression of the transcription factor forkhead box P3 (FOXP3), are the main immune cells that induce tolerance and are regulators of immune homeostasis. Natural Treg cells (nTregs), described as CD4+CD25+FOXP3+, are generated in the thymus via activation and cytokine signaling. Transforming growth factor beta type 1 (TGF-ß1) is pivotal to the generation of the nTreg lineage, its maintenance in the thymus, and to generating induced Treg cells (iTregs) in the periphery or in vitro arising from conventional T cells (Tconvs). Here, we tested whether TGF-ß1 treatment, associated with interleukin-2 (IL-2) and CD3/CD28 stimulation, could generate functional Treg-like cells from human thymocytes in vitro, as it does from Tconvs. Additionally, we genetically manipulated the cells for ectopic FOXP3 expression, along with the TGF-ß1 treatment. We demonstrated that TGF-ß1 and ectopic FOXP3, combined with IL-2 and through CD3/CD28 activation, transformed human thymocytes into cells that expressed high levels of Treg-associated markers. However, these cells also presented a lack of homogeneous suppressive function and an unstable proinflammatory cytokine profile. Therefore, thymocyte-derived cells, activated with the same stimuli as Tconvs, were not an appropriate alternative for inducing cells with a Treg-like phenotype and function.

Selective killing of human M1 macrophages by Smac mimetics alone and M2 macrophages by Smac mimetics and caspase inhibition.

The inflammatory and anti-inflammatory Mϕs have been implicated in many diseases including rheumatoid arthritis, multiple sclerosis, and leprosy. Recent studies suggest targeting Mϕ function and activation may represent a potential target to treat these diseases. Herein, we investigated the effect of second mitochondria-derived activator of caspases (SMAC) mimetics (SMs), the inhibitors of apoptosis (IAPs) proteins, on the killing of human pro- and anti-inflammatory Mϕ subsets. We have shown previously that human monocytes are highly susceptible whereas differentiated Mϕs (M0) are highly resistant to the cytocidal abilities of SMs. To determine whether human Mϕ subsets are resistant to the cytotoxic effects of SMs, we show that M1 Mϕs are highly susceptible to SM-induced cell death whereas M2a, M2b, and M2c differentiated subsets are resistant, with M2c being the most resistant. SM-induced cell death in M1 Mϕs was mediated by apoptosis as well as necroptosis, activated both extrinsic and intrinsic pathways of apoptosis, and was attributed to the IFN-γ-mediated differentiation. In contrast, M2c and M0 Mϕs experienced cell death through necroptosis following simultaneous blockage of the IAPs and the caspase pathways. Overall, the results suggest that survival of human Mϕs is critically linked to the activation of the IAPs pathways. Moreover, agents blocking the cellular IAP1/2 and/or caspases can be exploited therapeutically to address inflammation-related diseases.

Technical modifications for transplant in the failing Fontan.

INTRODUCTION: Heart transplant after Fontan completion poses a unique surgical challenge. Twenty patients are presented, stressing the technical hints performed in the five anastomoses to match the graft in the recipient. METHODS: Data are collected from 20 Fontan patients between 2013 and 2019. Age (13 years), weight (37 kg.), and time interval between Fontan and transplant (7 years) are presented as median. Extracardiac conduit (size 18/20) was implanted in 15 patients, whereas atrio-pulmonary connection was performed in 4 and lateral tunnel in 1. Six patients developed protein-losing enteropathy. Seventeen stents had been previously deployed. RESULTS: The five anastomoses underwent some changes. Left atrium once, aorta 9 times, superior vena cava 7 times, pulmonary branches 15 times, and inferior vena cava 12 times. Follow-up was complete for a median of 42 months (range 6-84). Two patients died. ECMO was needed in six cases for pulmonary hypertension. Four patients had collateral vessels occluded in the cath lab, and stents were placed in superior vena cava (1) and aorta (1) post-transplant. Protein-losing enteropathy was resolved in five patients. Interestingly, one patient was on a systemic assist device before transplant (Levitronix) and right assistance (ECMO) afterwards. CONCLUSIONS: Transplant in Fontan patients is actually challenging. Hints in every of the five proposed anastomoses must be anticipated, including stents removal. Extra tissue from the donor (innominate vein, aortic arch, and pericardium) is strongly advisable. ECMO for right ventricular dysfunction was needed in nearly one-third of the cases. Overall results can match other transplant cohorts.

Cirugía de raíz aórtica tras switch arterial / Aortic root surgery after arterial switch operation

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Cirugía sobre stents. Nuevos retos en cardiopatías congénitas / Surgery in patients with stents. New challenges in congenital heart disease

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