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Background: Heart failure is a growing epidemic, and a typical aspect of heart failure pathophysiology is altered calcium transients. Normal cardiac calcium transients are initiated by Cav1.2 channels at cardiac T tubules. Bridging integrator 1 (BIN1) is a membrane scaffolding protein that causes Cav1.2 to traffic to T tubules in healthy hearts. The mechanisms of Cav1.2 trafficking in heart failure are not known.Objective: To study BIN1 expression and its effect on Cav1.2 trafficking in failing hearts.Methods: Intact myocardium and freshly isolated cardiomyocytes from nonfailing and end-stage failing human hearts were used to study BIN1 expression and Cav1.2 localization. To confirm Cav1.2 surface expression dependence on BIN1, patch-clamp recordings were performed of Cav1.2 current in cell lines with and without trafficking-competent BIN1. Also, in adult mouse cardiomyocytes, surface Cav1.2 and calcium transients were studied after small hairpin RNA-mediated knockdown of BIN1. For a functional readout in intact heart, calcium transients and cardiac contractility were analyzed in a zebrafish model with morpholino-mediated knockdown of BIN1.Results: BIN1 expression is significantly decreased in failing cardiomyocytes at both mRNA (30% down) and protein (36% down) levels. Peripheral Cav1.2 is reduced to 42% by imaging, and a biochemical T-tubule fraction of Cav1.2 is reduced to 68%. The total calcium current is reduced to 41% in a cell line expressing a nontrafficking BIN1 mutant. In mouse cardiomyocytes, BIN1 knockdown decreases surface Cav1.2 and impairs calcium transients. In zebrafish hearts, BIN1 knockdown causes a 75% reduction in calcium transients and severe ventricular contractile dysfunction.Conclusions: The data indicate that BIN1 is significantly reduced in human heart failure, and this reduction impairs Cav1.2 trafficking, calcium transients, and contractility. [ABSTRACT FROM AUTHOR]

Rationale: In 2005, lung allocation for transplantation in the United States changed from a system based on waiting time to a system based on the Lung Allocation Score (LAS).Objectives: To study the effect of the LAS on lung transplantation for idiopathic pulmonary arterial hypertension (IPAH) compared with other major diagnoses.Methods: We studied 7,952 adults listed for lung transplantation between 2002 and 2008. Analyses were restricted to patients with IPAH, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF). Transplantation, waiting list mortality, and post-transplant mortality were compared between diagnoses for patients listed before and after implementation of the LAS.Measurements and Main Results: The likelihood of transplantation from the waiting list increased for all diagnoses after implementation of the LAS. Waiting list mortality decreased for every diagnosis, except for IPAH, which remained unchanged. Implementation of the LAS was not associated with changes in post-transplant mortality for any diagnosis. Under the LAS system, patients with IPAH were less likely to be transplanted than patients with IPF (hazard ratio [HR], 0.53; P < 0.001) or CF (HR, 0.49; P < 0.001) and at greater risk of death on the waiting list than patients with COPD (HR, 3.09; P < 0.001) or CF (HR, 1.83; P = 0.025) after adjustment for demographics and transplant type. Post-transplant mortality for IPAH was not statistically different from that of other diagnoses.Conclusions: Implementation of the LAS has improved the likelihood of lung transplantation for listed patients with IPAH, but mortality on the waiting list remains high compared with other major diagnoses. [ABSTRACT FROM AUTHOR]

Background: Pulmonary hypertension in children often progresses despite optimal therapy. This document provides an evidence-based clinical practice guideline for the management of children with progressive pulmonary hypertension despite optimal therapy., Methods: A multidisciplinary panel identified pertinent questions regarding the management of children with pulmonary hypertension that has progressed despite optimal therapy, conducted systematic reviews of the relevant literature, and applied the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach to develop clinical recommendations., Results: After reviewing the research evidence, the panel considered the balance of desirable (benefits) and undesirable (harms and burdens) effects of the interventions in each proposed question. Valuation of our main outcomes was also considered, along with resources required, equity, acceptability, and feasibility. Recommendations were developed for or against interventional strategies specific to children with pulmonary hypertension that has progressed despite optimal therapy., Conclusions: Although there is a growing population of children with pulmonary hypertension, there is a striking lack of empirical evidence regarding management of those whose disease has progressed despite optimal pharmacotherapy. The panel formulated and provided the rationale for clinical recommendations for or against interventional strategies based on this limited empirical evidence, coupled with expert opinion, to aid clinicians in the management of these complex pediatric patients. In addition, we identified important areas for future research.

Background: Extracorporeal membrane oxygenation (ECMO) use in peripartum patients is rare, and there is a gap in the literature on the outcomes and guidance on using ECMO in peripartum patients. This study describes ECMO strategies our institution uses for peripartum patients and reports outcomes of ECMO use in peripartum patients with respiratory and/or cardiac failure., Methods: A case series of all peripartum patients, defined as pregnant or up to 6 weeks after delivery of an infant >20 weeks gestation, from 2018 to 2023 from a single center requiring ECMO support. Patients were included if ECMO was initiated in the setting of cardiac, pulmonary, or combined failure. Patient demographics, operative details, ECMO data, and adverse outcomes for maternal, fetus, and neonates were all collected., Results: Eighteen patients met the inclusion criteria. The cohort had a mean maternal age of 30.7 years old and was racially diverse. A majority of this cohort tested positive for COVID-19 ( n  = 10, 55%). ECMO was a bridge to recovery for all patients, of whom 14 (78%) were discharged out of the hospital alive. No patients received transplantation or a durable mechanical device. The most common complications were infection (25%) and postpartum hemorrhage (22%)., Conclusions: ECMO use in peripartum patients in a single tertiary center was associated with a high survival rate. Furthermore, a strong multidisciplinary team, careful reevaluation of clinical trajectory, and consideration of complications and risks associated with using ECMO in peripartum patients are possible frameworks to use when challenged with critically ill peripartum patients.

Lung transplantation is a definitive therapy for many end-stage lung pathologies. Extracorporeal membrane oxygenation (ECMO) is increasingly being used as a bridge to lung transplantation (BTT). HLA sensitization is a major barrier to lung transplantation. The development of HLA sensitization while undergoing ECMO support as a BTT has recently been reported in a 2-patient series., Methods: We performed a retrospective analysis of patients undergoing ECMO as a BTT at a single large academic medical center from January 2016 to April 2022. The study was approved by the institutional review board. We selected patients who had undergone ECMO support for at least 7 d with either negative HLA before cannulation or initial negative HLA on ECMO (3 patients)., Results: We identified 27 patients bridged to lung transplantation with available HLA data. Of this group, 8 patients (29.6%) developed significant HLA sensitization (>10%). We did not identify any factors predisposing to sensitization, including infection episodes or blood product transfusion. Sensitized patients demonstrated a trend toward an increased primary graft dysfunction rate, a need for posttransplant ECMO support, and a decreased 1-y survival; however, these did not meet statistical significance., Conclusions: Our study is the largest series today describing the association between HLA sensitization and ECMO therapy. We suggest that interaction between the immune system and ECMO circuit contributes to allosensitization pretransplant, similar to that occurring with ventricular assist device. Further work is needed to better characterize the incidence of HLA sensitization in a multicenter cohort and to identify potentially modifiable factors associated with HLA sensitization., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2023 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Initial experience with lung transplant of COVID-19-positive donors was marked by disappointing results, including a reported case of mortality through donor to recipient transmission of infection. However, since that time a number of improvements in preventative and therapeutic measures against COVID-19 have been developed. We present the case of a 51-year-old woman with scleroderma-associated interstitial lung disease who was awaiting lung transplant. A potential donor with excellent lung physiology was located; however, initial testing on bronchoalveolar lavage (BAL) was positive for COVID-19. The donor had tested positive 2 weeks prior and had symptomatically recovered. Our patient had been fully vaccinated but not seroconverted. Given the history of a donor with recovering COVID infection and a fully immunized recipient, our multidisciplinary team elected to proceed with the transplant. The patient successfully underwent bilateral lung transplant with standard induction immunosuppression. Bebtelovimab was given post-transplant day 1 because the recipient remained seronegative to COVID-19. Serial bronchoalveolar lavages post transplant have been negative for COVID-19. The patient has done well after transplant. She was seen in the clinic 2 months post transplant and is ambulatory without supplemental oxygen requirements. To our knowledge, this represents the first reported successful case of lung transplant with a donor positive for COVID-19 on lower respiratory tract sampling., (Published by Elsevier Inc.)

Herein, we tested the hypothesis that low molecular weight hyaluronan (LMW-HA) inhibits lung epithelial ions transport in-vivo, ex-vivo, and in-vitro by activating the calcium-sensing receptor (CaSR). Twenty-four hours post intranasal instillation of 50-150 µg/ml LMW-HA to C57BL/6 mice, there was a 75% inhibition of alveolar fluid clearance (AFC), a threefold increase in the epithelial lining fluid (ELF) depth, and a 20% increase in lung wet/dry (W/D) ratio. Incubation of human and mouse precision cut lung slices with 150 µg/ml LMW-HA reduced the activity and the open probability (P o ) of epithelial sodium channel (ENaC) in alveolar epithelial type 2 (ATII) cells, and in mouse tracheal epithelial cells (MTEC) monolayers as early as 4 h. The Cl - current through cystic fibrosis transmembrane conductance regulator (CFTR) and the activity of Na,K-ATPase were both inhibited by more than 66% at 24 h. The inhibitory effects of LMW-HA on ion channels were reversed by 1 µM NPS-2143, or 150 µg/ml high molecular weight hyaluronan (HMW-HA). In HEK-293 cells expressing the calcium-sensitive Cl - channel TMEM16-A, CaSR was required for the activation of the Cl - current by LMW-HA. This is the first demonstration of lung ions and water transport inhibition by LMW-HA, and its mediation through the activation of CaSR., Competing Interests: Declaration of Competing Interest The authors have declared that no conflict of interest exists., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Pregnancy after cardiac transplantation poses immense challenges. Maternal risks include hypertensive disorders of pregnancy, rejection, and failure of the cardiac allograft that may lead to death. Fetal risks include potential teratogenic effects of immunosuppression and prematurity. Because of the high-risk nature of pregnancy in a heart transplant patient, management of reproductive health after cardiac transplantation should include preconception counseling to all women in the reproductive age group before and after cardiac transplantation. Reliable contraception is vital as nearly half of the pregnancies in this population are unintended. Despite the associated risks, successful pregnancies after cardiac transplantation have been reported. A multidisciplinary approach proposed in this review is essential for successful outcomes. A checklist for providers to guide management is provided.

Aims: Persistent mitral valve regurgitation (MR) after continuous flow left ventricular assist device implantation (cfLVAD) is associated with pulmonary hypertension and right ventricular failure with variable effects on survival across published studies. The aim of this study is to determine the incidence and predictors of persistent MR at 6-month follow-up after cfLVAD implantation and its impact on survival, haemodynamics, right ventricular function, and morbidity., Methods and Results: We performed a retrospective review of all adult cfLVAD recipients from January 2012 to June 2017 at a single tertiary university hospital with follow-up until April 2019. Primary outcome was to compare survival between patients with no-to-mild compared with persistent moderate-to-severe MR at 6 months. Secondary outcomes included right heart failure (RHF), length of stay, re-hospitalizations, and composite of death, transplant, and pump exchange during the length of follow-up. Final analytic sample was 111 patients. The incidence of persistent moderate or severe MR at 6 months was 26%. Significant predictors of persistent MR at 6 months were left atrium dimension and volume. The group with persistent moderate-to-severe MR at 6 months had higher incidence of RHF at 6 months (45% vs. 25%, P = 0.04). There was no difference in survival at 1 year between the groups (no-to-mild MR 85.5%, moderate-to-severe MR 87.9%, Wilcoxon P-value = 0.63). There was no difference in re-hospitalizations, length of stay, composite of death, transplant, or pump exchange during the length of follow-up between the comparison groups., Conclusions: Persistent moderate-to-severe MR after cfLVAD implantation is present in one fourth of patients and is associated with increased incidence of RHF, higher mean pulmonary pressure, and pulmonary capillary wedge pressure with no effect on 1 year survival. Increased left atrium size was associated with persistent moderate-to-severe MR at 6 months., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

A patient with heart failure due to nonischemic cardiomyopathy presented as a transfer to our institution following peripheral (femoral) venoarterial (VA) extracorporeal membrane oxygenation (ECMO) placement. With peripheral VA ECMO cannulation, the patient continued to have unstable ventricular tachyarrhythmias. Echocardiography demonstrated left ventricular (LV) dilation and severe mitral regurgitation (MR) with clinical and chest X-ray evidence of pulmonary edema. To provide venous drainage and simultaneous decompression of the left atrium (LA) and thereby indirect LV venting, a single multistage venous cannula was placed across the inter-atrial septum (IAS) using the previously described left atrial venoarterial (LA-VA) ECMO cannulation technique. Two- and three-dimensional (3D) transesophageal echocardiography (TEE) demonstrated utility in guiding cannula placement into the appropriate position and providing real time assessment of ventricular decompression and MR severity. There was subsequent improvement in pulmonary edema. This case is thought to be the first demonstration of real time resolution of pulmonary venous flow reversal in a patient undergoing LA-VA ECMO cannulation. This demonstration offers important mechanistic insight into some of the potential benefits of such an approach., (© 2021 Wiley Periodicals LLC.)

Limited data exist regarding patients with continuous-flow left ventricular assist device (LVAD) support who require long-term inotropes. Our primary objective was to evaluate the clinical characteristics and all-cause mortality of LVAD recipients with prolonged inotrope use (PIU). Secondary endpoints were to compare predictors of PIU, mortality, risk of late re-initiation of inotropes, time to gastrointestinal bleed (GIB), infection, and arrhythmias. Retrospective cohort study was conducted on adult patients with primary continuous-flow LVADs implanted from January 2008 to February 2017 and the patients were followed up through February 2018. We defined PIU as ≥14 days of inotrope support. Kaplan-Meier method, competing risk models and Cox proportional hazard models were used. Final analytic sample was 203 patients, 58% required PIU, and 10% were discharged on inotropes. There was no difference in preimplant characteristics. One-year survival rate was 87% if no PIU required, 74% if PIU required, and 72% if discharged on inotropes. PIU was associated with longer length of stay and higher incidence of GIB. We found no association between PIU and late re-initiation of inotropes, infection or arrhythmias. Adjusted hazard risk of death was increased in patients with PIU (HR = 1.66, P = .046), older age (HR = 1.28, P = .031), and higher creatinine levels (HR = 1.60, P = .007). Prolonged inotrope use is frequently encountered following LVAD implantation and is associated with adverse prognosis but remains a therapeutic option. Inability to wean inotropes prior to hospital discharge is a marker of patients at particularly higher risk of mortality following LVAD implantation., (© 2020 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.)

Background: Double-lumen venovenous extracorporeal membrane oxygenation may be used as a bridge to lung transplantation. Predictors of outcome with this strategy have not been well described., Methods: All patients with irreversible lung disease who developed acute pulmonary failure and required double-lumen venovenous extracorporeal membrane oxygenation as a bridge to decision or lung transplant at our institution were included in this study. Survival of the extracorporeal membrane oxygenation patients was compared with listed patients who did not require extracorporeal membrane oxygenation with lung allocation score in the highest 10% for the same period., Results: Fifteen patients (46 ± 17 years old) received double-lumen venovenous extracorporeal membrane oxygenation cannula. Mean length of extracorporeal membrane oxygenation support was 18.2 (1-60) days. Of these, seven patients were bridged to lung transplant, six died on extracorporeal membrane oxygenation, and two weaned to recovery. Amount of red blood cell transfusion was significantly higher (3.3 vs 18.5 U, p = 0.003) and lowest oxygen saturation was significantly lower in non-survivors (84.5% vs 66.3%, p = 0.002). Of the seven patients who were already listed for lung transplant at the onset of extracorporeal membrane oxygenation, five were transplanted. Overall survival to hospital discharge was 60%. Survival of patients with lung allocation score in the highest 10% (average lung allocation score 83.4) in the same period was 80%., Conclusion: Double-lumen venovenous extracorporeal membrane oxygenation cannula is a feasible option to bridge patients to decision or lung transplantation. Blood transfusion requirement and low oxygen saturation are markers of poor prognosis. Listing status at the time of cannulation and ambulation during extracorporeal membrane oxygenation support may be important indicators of good outcome.

Background: Continuous-flow ventricular assist devices (CF-VADs) produce non-physiologic flow with diminished pulsatility, which is a major risk factor for development of adverse events, including gastrointestinal (GI) bleeding and arteriovenous malformations (AVMs). Introduction of artificial pulsatility by modulating CF-VAD flow has been suggested as a potential solution. However, the levels of pulsatility and frequency of CF-VAD modulation necessary to prevent adverse events are currently unknown and need to be evaluated., Methods: The purpose of this study was to use human aortic endothelial cells (HAECs) cultured within an endothelial cell culture model (ECCM) to: (i) identify and validate biomarkers to determine the effects of pulsatility; and (ii) conclude whether introduction of artificial pulsatility using flow-modulation approaches can mitigate changes in endothelial cells seen with diminished pulsatile flow. Nuclear factor erythroid 2-related factor 2 (Nrf-2)-regulated anti-oxidant genes and proteins and the endothelial nitric oxide synthase/endothelin-1 (eNOS/ET-1) signaling pathway are known to be differentially regulated in response to changes in pulsatility., Results: Comparison of HAECs cultured within the ECCM (normal pulsatile vs CF-VAD) with aortic wall samples from patients (normal pulsatile [n = 5] vs CF-VADs [n = 5]) confirmed that both the Nrf-2-activated anti-oxidant response and eNOS/ET-1 signaling pathways were differentially regulated in response to diminished pulsatility. Evaluation of 2 specific CF-VAD flow-modulation protocols to introduce artificial pulsatility, synchronous (SYN, 80 cycles/min, pulse pressure 20 mm Hg) and asynchronous (ASYN, 40 cycles/min, pulse pressure 45 mm Hg), suggested that both increased expression of Nrf-2-regulated anti-oxidant genes and proteins along with changes in levels of eNOS and ET-1 can potentially be minimized with ASYN and, to a lesser extent, with SYN., Conclusions: HAECs cultured within the ECCM can be used as an accurate model of large vessels in patients to identify biomarkers and select appropriate flow-modulation protocols. Pressure amplitude may have a greater effect in normalizing anti-oxidant response compared with frequency of modulation., (Copyright © 2018 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Delayed sternal closure (DSC) is occasionally adopted after implantation of left ventricular assist device (LVAD). Recent studies suggest that DSC be used for high risk group of patients with coagulopathy, hemodynamic instability or right ventricular failure. However, whether DSC is efficacious for bleeding complication or right ventricular failure is not known. This study is single center analysis of 52 patients, who underwent LVAD implantation. Of those 52 patients, 40 consecutive patients underwent DSC routinely. The sternum was left open with vacuum assist device after implantation of LVAD. Perioperative outcome of the patients who underwent routine DSC were compared with 12 patients who had immediate sternal closure (IC). Mean Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) level of IC group and DSC group were 2.7 and 2.6, respectively. Postoperative bleeding (643 vs. 1469 ml, p < 0.001), duration of inotropic support (109 vs. 172 h, p = 0.034), and time to extubation (26 vs. 52 h, p = 0.005) were significantly increased in DSC group. Length of ICU stay (14 vs. 15 days, p = 0.234) and hospital stay (28 vs. 20 days, p = 0.145) were similar. Incidence of right ventricular failure and tamponade were similar in the two groups. Routine DSC after implantation of an LVAD did not prove to be beneficial in reducing complications associated with coagulopathy and hemodynamic instability including cardiac tamponade or right ventricular failure. We suggest that DSC be selectively applied for patients undergoing LVAD implant.

Background: Long-term survival of lung transplant recipients (LTRs) is limited by the occurrence of bronchiolitis obliterans syndrome (BOS). Recent evidence suggests a role for microbiome alterations in the occurrence of BOS, although the precise mechanisms are unclear. In this study we evaluated the relationship between the airway microbiome and distinct subsets of immunoregulatory myeloid-derived suppressor cells (MDSCs) in LTRs., Methods: Bronchoalveolar lavage (BAL) and simultaneous oral wash and nasal swab samples were collected from adult LTRs. Microbial genomic DNA was isolated, 16S rRNA genes amplified using V4 primers, and polymerase chain reaction (PCR) products sequenced and analyzed. BAL MDSC subsets were enumerated using flow cytometry., Results: The oral microbiome signature differs from that of the nasal, proximal and distal airway microbiomes, whereas the nasal microbiome is closer to the airway microbiome. Proximal and distal airway microbiome signatures of individual subjects are distinct. We identified phenotypic subsets of MDSCs in BAL, with a higher proportion of immunosuppressive MDSCs in the proximal airways, in contrast to a preponderance of pro-inflammatory MDSCs in distal airways. Relative abundance of distinct bacterial phyla in proximal and distal airways correlated with particular airway MDSCs. Expression of CCAAT/enhancer binding protein (C/EBP)-homologous protein (CHOP), an endoplasmic (ER) stress sensor, was increased in immunosuppressive MDSCs when compared with pro-inflammatory MDSCs., Conclusions: The nasal microbiome closely resembles the microbiome of the proximal and distal airways in LTRs. The association of distinct microbial communities with airway MDSCs suggests a functional relationship between the local microbiome and MDSC phenotype, which may contribute to the pathogenesis of BOS., (Copyright © 2017 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Fast relaxation of cross-bridge generated force in the myocardium facilitates efficient diastolic function. Recently published research studying mechanisms that modulate the relaxation rate has focused on molecular factors. Mechanical factors have received less attention since the 1980s when seminal work established the theory that reducing afterload accelerates the relaxation rate. Clinical trials using afterload reducing drugs, partially based on this theory, have thus far failed to improve outcomes for patients with diastolic dysfunction. Therefore, we reevaluated the protocols that suggest reducing afterload accelerates the relaxation rate and identified that myocardial relengthening was a potential confounding factor. We hypothesized that the speed of myocardial relengthening at end systole (end systolic strain rate), and not afterload, modulates relaxation rate and tested this hypothesis using electrically-stimulated trabeculae from mice, rats, and humans. We used load-clamp techniques to vary afterload and end systolic strain rate independently. Our data show that the rate of relaxation increases monotonically with end systolic strain rate but is not altered by afterload. Computer simulations mimic this behavior and suggest that fast relengthening quickens relaxation by accelerating the detachment of cross-bridges. The relationship between relaxation rate and strain rate is novel and upends the prevailing theory that afterload modifies relaxation. In conclusion, myocardial relaxation is mechanically modified by the rate of stretch at end systole. The rate of myocardial relengthening at end systole may be a new diagnostic indicator or target for treatment of diastolic dysfunction., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Patients with heart failure (HF) have diaphragm abnormalities that contribute to disease morbidity and mortality. Studies in animals suggest that reactive oxygen species (ROS) cause diaphragm abnormalities in HF. However, the effects of HF on ROS sources, antioxidant enzymes, and protein oxidation in the diaphragm of humans is unknown. NAD(P)H oxidase, especially the Nox2 isoform, is an important source of ROS in the diaphragm. Our main hypothesis was that diaphragm from patients with HF have heightened Nox2 expression and p47 phox phosphorylation (marker of enzyme activation) that is associated with elevated protein oxidation. We collected diaphragm biopsies from patients with HF and brain-dead organ donors (controls). Diaphragm mRNA levels of Nox2 subunits were increased 2.5-4.6-fold over controls ( p < 0.05). Patients also had increased protein levels of Nox2 subunits (p47 phox , p22 phox , and p67 phox ) and total p47 phox phosphorylation, while phospho-to-total p47 phox levels were unchanged. The antioxidant enzyme catalase was increased in patients, whereas glutathione peroxidase and superoxide dismutases were unchanged. Among markers of protein oxidation, carbonyls were increased by ~40% ( p < 0.05) and 4-hydroxynonenal and 3-nitrotyrosines were unchanged in patients with HF. Overall, our findings suggest that Nox2 is an important source of ROS in the diaphragm of patients with HF and increases in levels of antioxidant enzymes are not sufficient to maintain normal redox homeostasis. The net outcome is elevated diaphragm protein oxidation that has been shown to cause weakness in animals.

Purpose: Venovenous extracorporeal membrane oxygenation (VV ECMO) is an effective therapy in patients with acute lung injury and end-stage lung disease. Although immobility increases the risk of complications, ambulation of patients on VV ECMO is not the standard of care in many institutions. Staff concerns for patient safety remain a barrier to ambulation. In this case series, we present our experience utilizing a nurse-driven ambulatory VV ECMO process to safely rehabilitate patients., Methods: We retrospectively reviewed all VV ECMO cases at our institution between January 1, 2011, and November 1, 2013. Inclusion criteria for this study required patients to be cannulated in the right internal jugular vein and ambulated while on VV ECMO., Results: During the period from January 1, 2011, to November 1, 2013, 18 patients (mean age 49 ± 15 years, 12 male) were ambulated while on ECMO. Eight received a transplant and survived to discharge. Of the remaining patients, 4 were successfully weaned from VV ECMO and 6 died following decisions by the family to withdraw care. The mean duration of VV ECMO support was 18 ± 16 days with the maximum duration being 61 days. All patients received physical therapy, range of motion at the bedside, and ambulated in the hospital. There were no patient falls, decannulations, or any other complications related to ambulation., Conclusion: The adoption of a nurse-driven program to ambulate patients on VV ECMO is safe and may reduce other complications associated with immobility., (© 2016, NATCO.)

Background: Previous studies have demonstrated the safety of flexible bronchoscopy (FB) in mechanically ventilated subjects. However, the safety of FB in adult subjects receiving extracorporeal membrane oxygenation (ECMO) has not been described previously., Methods: A retrospective review was conducted of all adult subjects who underwent FB while receiving ECMO support at the University of Alabama at Birmingham Hospital from January 1, 2013, to December 31, 2014. Physiologic variables, pre- and post-FB ECMO, and ventilator settings were recorded., Results: 79 adult subjects underwent FB receiving ECMO with a total of 223 bronchoscopies. The most common indications for bronchoscopy included diagnostic evaluation of infection in subjects with pneumonia (29%) and clearance of excessive secretions (22%). In 70% of subjects, moderate or greater amounts of secretions were noted. FB yielded positive culture data in 37 subjects (47%), which resulted in a change to the antibiotic regimen in 14 subjects (38%) with positive culture data. No significant differences in mean PaO2 /FIO2 , mean ECMO flow, mean sweep gas, ventilator settings, or hemodynamic parameters (heart rate, oxygen saturation, and mean blood pressure) were noted before and after FB. Complications were mild and transient: blood-tinged secretions after FB in 21% cases, which resolved spontaneously, intraprocedural hypoxemia in 2.2% of cases, and dysrhythmia in <1% of cases. There were no episodes of ECMO cannula dislodgement or inadvertent extubation., Conclusions: FB can be used safely in adult subjects supported with ECMO and is not associated with significant hemodynamics changes, bleeding, or mechanical complications during ECMO support., (Copyright © 2016 by Daedalus Enterprises.)

This manuscript describes a protocol at the University of Kentucky that allows a translational research team to collect human myocardium that can be used for biological research. We have gained a great deal of practical experience since we started this protocol in 2008, and we hope that other groups might be able to learn from our endeavors. To date, we have procured ~4000 samples from ~230 patients. The tissue that we collect comes from organ donors and from patients who are receiving a heart transplant or a ventricular assist device because they have heart failure. We begin our manuscript by describing the importance of human samples in cardiac research. Subsequently, we describe the process for obtaining consent from patients, the cost of running the protocol, and some of the issues and practical difficulties that we have encountered. We conclude with some suggestions for other researchers who may be considering starting a similar protocol.

Mortality of severe acute respiratory distress syndrome (ARDS) remains high. Once conventional mechanical ventilation fails, alternative modes of therapy are used; most of which have limited evidence to support their use. No definitive guidelines exist for the management of these patients with alternate modalities of treatment. We conducted a cross-sectional national survey of 302 adult critical care training programs in the United States to understand the current preferences of intensivists regarding the use of different therapies for severe ARDS, including the use of extracorporeal membrane oxygenation (ECMO). A total of 381 responses were received: 203 critical care faculty and 174 critical care trainees. Airway pressure release ventilation was the initial choice of treatment reported by most when conventional mechanical ventilation strategy failed followed by inhaled nitric oxide and prone positioning. Extracorporeal membrane oxygenation availability was reported by 80% of the respondents at their institutions. Most respondents (83%) would consider ECMO in patients who fail optimal mechanical ventilation strategies, and the majority (60%) believed that ECMO use can facilitate lung protective ventilation, but few favored its use as a first-line modality. The majority of respondents reported limited knowledge of ECMO and desired specific ECMO education during training.

This report presents a falsely incompatible B cell crossmatch by flow cytometry in a lung transplant recipient. The patient was a 35-year-old Caucasian male with end-stage lung disease secondary to cystic fibrosis whose pretransplantation serologic workup did not disclose the presence of anti-HLA class II antibodies by single antigen bead testing. Unexpectedly, crossmatch of recipient sera with pronase-treated donor lymphocytes resulted in antibody binding to B cells only. The positive reactivity was reproducible in pronase-treated autologous B cells. Recipient sera did not react with nontreated donor or autologous lymphocytes. Herein, we describe our approach to this unexpected crossmatch result and consider the implications of false-positive crossmatch results on transplantation., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Heart failure is associated with pump dysfunction and remodeling but it is not yet known if the condition affects different transmural regions of the heart in the same way. We tested the hypotheses that the left ventricles of non-failing human hearts exhibit transmural heterogeneity of cellular level contractile properties, and that heart failure produces transmural region-specific changes in contractile function. Permeabilized samples were prepared from the sub-epicardial, mid-myocardial, and sub-endocardial regions of the left ventricular free wall of non-failing (n=6) and failing (n=10) human hearts. Power, an in vitro index of systolic function, was higher in non-failing mid-myocardial samples (0.59±0.06μWmg(-1)) than in samples from the sub-epicardium (p=0.021) and the sub-endocardium (p=0.015). Non-failing mid-myocardial samples also produced more isometric force (14.3±1.33kNm(-2)) than samples from the sub-epicardium (p=0.008) and the sub-endocardium (p=0.026). Heart failure reduced power (p=0.009) and force (p=0.042) but affected the mid-myocardium more than the other transmural regions. Fibrosis increased with heart failure (p=0.021) and mid-myocardial tissue from failing hearts contained more collagen than matched sub-epicardial (p<0.001) and sub-endocardial (p=0.043) samples. Power output was correlated with the relative content of actin and troponin I, and was also statistically linked to the relative content and phosphorylation of desmin and myosin light chain-1. Non-failing human hearts exhibit transmural heterogeneity of contractile properties. In failing organs, region-specific fibrosis produces the greatest contractile deficits in the mid-myocardium. Targeting fibrosis and sarcomeric proteins in the mid-myocardium may be particularly effective therapies for heart failure., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

ATG-Fresenius S (ATG-F) is a polyclonal anti-human-T-lymphocyte immunoglobulin preparation that has been clinically developed to prevent episodes of acute cellular rejection. This study evaluated the efficacy and safety of ATG-F at doses of 5 and 9 mg/kg versus placebo in adult recipients of a primary lung allograft. The primary efficacy composite end point was defined as death, graft loss, acute rejection and/or loss to follow-up within 12 months of transplantation. The interim analysis showed the ATG-F 5 mg/kg treatment to be inefficacious, and it would be impossible to enroll enough patients to power the study to show a difference between the 9 mg/kg arm and the placebo arm. Therefore, the main focus of the study shifted to the safety end points and a descriptive analysis of the primary end point. At 12 months posttransplant, the efficacy failure rate was not significantly different between the ATG-F 9 mg/kg group and the placebo group (40.2% vs. 36.7%, respectively). This large study did not demonstrate a significant reduction in acute cellular rejection, graft loss or death with single-dose induction therapy with ATG-F within the first year after lung transplantation., (© Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons.)

The Impella 5.0 is a minimally invasive heart assist device that can be used to stabilize patients with cardiogenic shock. We present the case of a 49-year-old female in cardiogenic shock who required left ventricular assist device placement, but was not an optimal candidate for surgery due to severe deconditioning and malnutrition. An Impella 5.0 pump was surgically implanted via right axillary artery approach, which allowed the patient time to improve nutritional and functional status before subsequent placement of HeartMate II left ventricular assist device.

Guillain-Barré syndrome (GBS) has been described after solid organ and bone marrow transplantation mostly due to viral infections and possibly calcineurin inhibitors. Incidence after bone marrow transplant is 0.3-0.7%, though incidence in other transplants is not well known. We present the first description of tacrolimus associated GBS in lung transplant recipients in the English language literature. The pathophysiology of tacrolimus-induced polyneuropathy is not known, but some have hypothesized that tacrolimus induces an inflammatory phenomenon by differential effects on T cell subsets. Diagnosis of association may be challenging and requires high index of suspicion. The optimal treatment of GBS-associated with tacrolimus after lung transplantation is unknown, although drug discontinuation may result in improvement in some patients, while some reports suggest that the use of IVIG and/or plasmapheresis may be helpful and safe in organ transplant recipients with severe symptoms.

Objective: Acute clinical deterioration preceding death is a common observation in patients with advanced interstitial lung disease and secondary pulmonary hypertension. Patients with pulmonary arterial hypertension refractory to medical therapy are also at risk of sudden cardiac death (cor pulmonale). The treatment of these patients remains complex, and the findings from retrospective studies have suggested that intubation and mechanical ventilation are inappropriate given the universally poor outcomes. Extracorporeal support technologies have received limited attention because of the presumed inability to either recover cardiopulmonary function in the patient with end-stage disease or the presumed inability to proceed to definitive therapy with transplantation., Methods: A retrospective review was performed of 31 patients from 2 institutions placed on extracorporeal membrane oxygenation as a bridge to lung transplantation compared with similar patients without extracorporeal membrane oxygenation at the same institutions and comparison groups queried from the United Network for Organ Sharing database., Results: We have transplanted 31 patients with refractory lung disease from mechanical artificial lung support. Of the 31 patients, 19 were ambulatory at transplantation. Pulmonary fibrosis (42%), cystic fibrosis (20%), and pulmonary hypertension (16%) were the most common diagnostic codes and acute cor pulmonale (48%) and hypoxia (39%) were the most common indications for device deployment. The average duration of extracorporeal membrane oxygenation support was 13.7 days (range, 2-53 days), and the mean survival of all patients bridged to pulmonary transplantation was 26 months (range, 54 days to 95 months). The 1-, 3-, and 5-year survival was 93%, 80%, and 66%, respectively. The duration of in-house postoperative transplant care ranged from 12 to 86 days (mean, 31 days). Patients requiring an extracorporeal membrane oxygenation bridge had comparable survival to that of the high acuity patients transplanted without extracorporeal membrane oxygenation support in the Scientific Registry of Transplant Recipients database but were at a survival disadvantage compared with the high-acuity patients (lung allocation score, >50) transplanted at the same center who did not require mechanical support (P < .001)., Conclusions: These observations challenge current assumptions about the treatment of selected patients with end-stage lung disease and suggest that "salvage transplant" is both technically feasible and logistically viable. Widespread adoption of artificial lung technology in lung transplant will require the design of clinical trials that establish the most effective circumstances in which to use these technologies. A discussion of a clinical trial and reconsideration of current allocation policy is warranted., (Copyright © 2013 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

The use of ventricular assist devices in patients with complex congenital heart disease has not been well described. We present a case of successful ventricular assist device support in a 38-year-old man with congenitally corrected transposition of the great arteries and severe secondary pulmonary hypertension., (Copyright © 2013 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)