High-resolution transcriptomic and epigenetic profiling identifies novel regulators of COPD.

Patients with chronic obstructive pulmonary disease (COPD) are still waiting for curative treatments. Considering its environmental cause, we hypothesized that COPD will be associated with altered epigenetic signaling in lung cells. We generated genome-wide DNA methylation maps at single CpG resolution of primary human lung fibroblasts (HLFs) across COPD stages. We show that the epigenetic landscape is changed early in COPD, with DNA methylation changes occurring predominantly in regulatory regions. RNA sequencing of matched fibroblasts demonstrated dysregulation of genes involved in proliferation, DNA repair, and extracellular matrix organization. Data integration identified 110 candidate regulators of disease phenotypes that were linked to fibroblast repair processes using phenotypic screens. Our study provides high-resolution multi-omic maps of HLFs across COPD stages. We reveal novel transcriptomic and epigenetic signatures associated with COPD onset and progression and identify new candidate regulators involved in the pathogenesis of chronic lung diseases. The presence of various epigenetic factors among the candidates demonstrates that epigenetic regulation in COPD is an exciting research field that holds promise for novel therapeutic avenues for patients.

The endophytic fungus Serendipita indica affects auxin distribution in Arabidopsis thaliana roots through alteration of auxin transport and conjugation to promote plant growth.

Plants share their habitats with a multitude of different microbes. This close vicinity promoted the evolution of interorganismic interactions between plants and many different microorganisms that provide mutual growth benefits both to the plant and the microbial partner. The symbiosis of Arabidopsis thaliana with the beneficial root colonizing endophyte Serendipita indica represents a well-studied system. Colonization of Arabidopsis roots with S. indica promotes plant growth and stress tolerance of the host plant. However, until now, the molecular mechanism by which S. indica reprograms plant growth remains largely unknown. This study used comprehensive transcriptomics, metabolomics, reverse genetics, and life cell imaging to reveal the intricacies of auxin-related processes that affect root growth in the symbiosis between A. thaliana and S. indica. Our experiments revealed the sustained stimulation of auxin signalling in fungus infected Arabidopsis roots and disclosed the essential role of tightly controlled auxin conjugation in the plant-fungus interaction. It particularly highlighted the importance of two GRETCHEN HAGEN 3 (GH3) genes, GH3.5 and GH3.17, for the fungus infection-triggered stimulation of biomass production, thus broadening our knowledge about the function of GH3s in plants. Furthermore, we provide evidence for the transcriptional alteration of the PIN2 auxin transporter gene in roots of Arabidopsis seedlings infected with S. indica and demonstrate that this transcriptional adjustment affects auxin signalling in roots, which results in increased plant growth.

Protective effect of Achyranthes aspera against compound 48/80, histamine and ovalbumin-induced allergic disorders in murine model.

BACKGROUND: Achyranthes aspera L. (family Amaranthaceae) is a plant species valued in Ayurveda for the treatment of respiratory ailments. Scientific validation of its antiallergic potential was aimed. METHODS AND RESULTS: Three extracts of A. aspera [aqueous (AaAq), hydroalcoholic (AaHA), ethanolic (AaEt)] were evaluated for their potency against C48/80-induced anaphylaxis in mice at 200 mg/kg BW oral dose. The effective dose of the most potent extract was determined through its effect on C48/80-induced anaphylaxis, and was further analyzed through its effect on mast cell degranulation, histamine-induced bronchospasm and ovalbumin (OVA)-induced asthma in a murine model. Among the three extracts, AaAq was found to be most potent at 200 mg/kg BW. AaAq 400 (400 mg/kg BW) was found to be the most effective dose in terms of inhibition of mortality and histamine level. AaAq 400 prevented the peritoneal and mesenteric mast cells from undergoing morphological changes due to degranulation induced by C48/80. Further, AaAq 400 delayed pre-convulsive time in histamine-induced bronchospasm. In the OVA-induced asthma model, AaAq 400 inhibited the level of inflammatory cell count in blood, bronchoalveolar lavage fluid and peritoneal fluid of mice. The Th2 cytokines (IL-4, IL-5, IL-13), TGF-ß and OVA-specific IgE were also reduced as evaluated by ELISA. Also, significant reduction in IL-5 (an eosinophilia indicator) transcript abundance and lung inflammatory score was observed. AaAq was safe up to 4000 mg/kg BW. CONCLUSIONS: Thus AaAq 400 possesses significant antiallergic potential and acts via attenuation of C48/80-induced anaphylaxis and inhibition of mast cell degranulation. It reduces pre-convulsive dyspnea in histamine-induced bronchospasm and Th2 cytokines in asthmatic mice.

Partial anomalous pulmonary venous return after orthotopic heart transplantation case report.

BACKGROUND: Partial anomalous pulmonary venous return (PAPVR) is a congenital heart defect. Reports of repair and treatment in pediatric cases have been published, but incidence of PAPVR in adults is not common. To our knowledge, there has not been a diagnosis of left-sided PAPVR after a heart transplant an in adult patient. CASE PRESENTATION: A 62-year-old patient with ischemic cardiomyopathy and systolic heart failure underwent orthotopic heart transplantation. The immediate post-operative course was remarkable for an elevated cardiac index and pulmonary artery pressures as well as decreased systemic vascular resistance. The post-operative echocardiogram did not reveal an intra-cardiac shunt. However, computed tomographic angiography (CTA) showed a left superior pulmonary vein draining into the innominate vein. Operative repair of the left superior pulmonary venous connection to the left atrial appendage was completed under cardiopulmonary bypass with beating heart. Her hemodynamics improved immediately, and she had an unremarkable postoperative course. CONCLUSIONS: While uncommon, any patient with a high cardiac output and abnormal hemodynamics after heart transplant should be evaluated for the existence of a shunt. While not a part of all traditional preoperative imaging protocols, a chest CTA should be considered if PAPVR is suspected as it can both diagnose the condition and enable a plot of the corrective course of surgical action.

Granulomatous fungal and non-tuberculous mycobacterial infestation complicating chronic lung disease: Outcomes in patients undergoing lung transplantation.

INTRODUCTION: Granulomatous infections are common in patients with chronic lung disease. We aim to study the incidence and clinicopathological features of granulomatous infections in a cohort of patients undergoing lung transplantation for end-stage chronic lung disease. METHODS: Pathology reports of 50 explanted native lungs of patients who underwent lung transplantation since 2015 at our institution were reviewed. Four cases with granulomatous lesions were identified. Correlation was made with clinical findings in the 4 cases. RESULTS: The granulomatous infections include non-necrotizing cryptococcal pneumonitis (case 1), necrotizing pneumonia due to Scedosporium sp. and Mycobacterium avium Complex (MAC) (Cases 2 and 3), and invasive Aspergillus pneumonia (Case 4). One patient received pre-transplant fungal prophylaxis (Case 4). Post-transplant infectious complications included invasive (Cases 2 and 4) and non-invasive (Case 1) fungal infections and bacterial pneumonia (Cases 1 and 2). Two patients (Cases 3 and 4) developed acute cellular rejection (ACR) in the first 30 days. The third patient (Case 1) was identified with ACR in the 9 months post-transplant and chronic lung allograft dysfunction at 29 months. In terms of mortality, 1 patient (Case 1) died at 30 months post-transplant from pseudomonal sepsis and chronic graft failure. Two patients with invasive fungal infections (Cases 2 and 4) are on secondary prophylaxis and doing well. One patient (Case 3) remains infection-free and on MAC prophylaxis. CONCLUSIONS: In our case series, patients with chronic lung diseases with superimposed granulomatous infestations frequently experienced post-transplant complications. These include invasive infections and repeat ACRs that predispose patients to chronic graft dysfunction. Pre- and post-transplant antifungal prophylaxis reduces fungal load and complication risk post-transplant.

Inter-hospital COVID ECMO air transportation.

The Coronavirus Disease 2019 (COVID-19) pandemic has required rapid and effective protocol adjustments at every level of healthcare. The use of extracorporeal membrane oxygenation (ECMO) is pivotal to COVID-19 treatment in cases of refractory hypoxemic hypercapnic respiratory failure. As such, our large, metropolitan air ambulance system in conjunction with our experts in advanced cardiopulmonary therapies modified protocols to assist peripheral hospitals in evaluation, cannulation and initiation of ECMO for rescue and air transportation of patients with COVID-19 to our quaternary center. The detailed protocol is described alongside initial data of its use. To date, 14 patients have been placed on ECMO support at an outside facility and successfully transported via helicopter to our hub hospital using this protocol.

Tracheostomy while on Extracorporeal Membrane Oxygenation: A Comparison of Percutaneous and Open Procedures.

Although the ideal timing of tracheostomy for critically ill patients is controversial, transitioning from an endotracheal tube can be beneficial. Concerns arise for patients under extracorporeal membrane oxygenation (ECMO) support. Studies have described percutaneous and open tracheostomy approaches for critically ill patients but, to our knowledge, have not compared the two specifically in ECMO patients. This study analyzed safety and aimed to identify if there was a difference in major bleeding or other tracheostomy-associated complications. A single-center retrospective cohort study of all patients who received tracheostomy while on ECMO from July 2013 to May 2019 was completed. The primary endpoint was a significant difference in the incidence of a major bleeding adverse event at 48 hours. Secondary endpoints included differences in the incidence of complications (e.g., procedure-related mortality, ECMO decannulation, tracheal/esophageal injury, and pneumothorax/pneumomediastinum) and survival to discharge. A secondary analysis separated the groups further by comparing those with bleeding events and those without. The study included 27 ECMO patients: 16 (59%) in the percutaneous arm and 11 in the open arm. The median number of ECMO days before tracheostomy was 10 vs. 13, respectively. There were no statistically significant differences between the two groups for major bleeding events (percutaneous 44% vs. open 27%, p = .45), procedure-related mortality, or procedure-related complications. Both percutaneous and open tracheostomies in patients on ECMO require a multidisciplinary approach to minimize adverse effects. Major bleeding does occur, but there was no statistically significant correlation between bleeding events and the type of the tracheostomy approach. Thus, both open and percutaneous tracheostomy approaches have a favorable safety profile.

Extracorporeal Membrane Oxygenation Utility in Postpartum Patients.

Although extracorporeal membrane oxygenation (ECMO) has been used in many different populations, its use in pregnant or postpartum patients has not been widely studied. This article reviews the ECMO experience in this population at a large urban hospital. Electronic medical records for all pregnant or postpartum patients who required ECMO between 2012 and 2019 were retrospectively reviewed. Data on clinical characteristics, outcomes, and complications were gathered. Comparisons between survivors and nonsurvivors were completed. Ten postpartum patients were identified. The patients presented as follows: four with cardiac arrest, one with a massive pulmonary embolism, three with acute respiratory distress syndrome (ARDS), one with combined ARDS and cardiogenic shock, and one with suspected amniotic embolism. Survival to decannulation was 70%, and survival to discharge was 60%. When comparing survivors vs. nonsurvivors, ECMO survivors tended to have shorter support times vs. nonsurvivors. Otherwise, no differences were noted in age, mechanical ventilation time, or length of stay. Disseminated intravascular coagulation was a common phenomenon in this patient cohort. After initiation of ECMO, elevated serum lactate levels, lower systolic blood pressure, and acute renal failure were predictors of mortality. In a single institution at a large metroplex, we present data regarding the use of ECMO in postpartum patients. ECMO can be successfully used in selected postpartum patients with severe cardiac or respiratory dysfunction. Multidisciplinary collaboration on a regular basis will streamline the ECMO referral in a timely manner. Furthermore, larger studies are indicated to understand the utility of ECMO in larger cohorts.

Perioperative Impella 5.5 Support for Surgical Aortic Valve Replacement: Pull Back/Push Through Technique, Safeguards, and Pitfalls.

In patients undergoing aortic valve surgery, preoperative reduced left ventricular ejection fraction is not uncommon and is associated with poor outcomes. Mechanical circulatory support (MCS) may be preemptively used in patients presenting with high periprocedural risk. The Impella 5.5 is a percutaneous left ventricular assist device that has been increasingly used in various cardiac surgeries. In this article, we present a step-by-step guide, safeguards, and pitfalls on how to replace the aortic valve and preserve this transaortic MCS device for postoperative support in patients with concomitant aortic valve pathology and left ventricular dysfunction.

Open Surgical Insertion of TandemHeart Device for Left Ventricular Unloading.

TandemHeart (Cardiac Assist Inc., Pittsburgh, PA) is a valuable mechanical circulatory support (MCS) device that provides left atrial to femoral artery bypass and directly unloads the left ventricle. The device is inserted under fluoroscopic guidance in the cardiac catheterization laboratory without requiring invasive surgical exposure. However, this device is unique because it directly unloads the oxygenated blood from the left atrium and may be needed for postoperative support in patients undergoing various open cardiac surgeries. In this article, we provide a detailed description of the open surgical insertion of a TandemHeart device.

Surgical Explantation of Impella 5.5 With Inflow Thrombus in Patients Undergoing Durable Left Ventricular Assist Device Implantation.

The Impella 5.5® (Abiomed, Danvers, MA, USA) is a microaxial flow pump that promotes left ventricular unloading and improves end-organ perfusion before durable left ventricular assist device (LVAD) implantation. Thrombus formation after Impella 5.5 insertion can occur and represents a significant challenge to device explantation. Durable LVAD implantation is typically performed without aortic cross-clamping, so a dislodged thrombus can potentially embolize and lead to catastrophic events. We describe our technique to safely explant an Impella 5.5 in patients who develop a thrombus on the inflow portion of the device before surgical LVAD implantation.

Use of Percutaneous Left Ventricular Assist Device Before Durable Device Implantation in Patients With Cardiac Cachexia: Case Series.

Frailty and malnutrition in patients with heart failure are barriers to durable left ventricular assist device (D-LVAD) support and heart transplantation. Moreover, cachexia in patients with advanced heart failure carries a high mortality risk. There are no guidelines for these patients other than increased caloric intake and rehabilitation. Patients suffering from cardiac cachexia and heart failure may benefit from temporary, percutaneous assist device support to improve the underlying heart disease and reverse the catabolic state. We retrospectively reviewed patients from January 2017 to January 2022. All patients who received Impella support (5.0 or 5.5, Abiomed) before D-LVAD implantation were screened. Those who met the criteria for cardiac cachexia were included. Patient demographics, nutritional and biochemical markers, and survival data were collected. A total of 14 patients were included. The majority of patients were male (85.7%) with ischemic cardiomyopathy (64.3%). Caloric intake, physical strength, and ambulation improved. Prealbumin levels improved from a median of 13.7-18.0 mg/dl ( p < 0.006) while on Impella 5.0 or 5.5 support. All patients survived to discharge and the 6 month follow-up. In conclusion, use of the Impella device improves cardiogenic shock symptoms and, consequently, may improve cachexia status prior to D-LVAD implantation.

Impella CP to Impella 5.5 Uninterrupted Upgrade Using a Double Device Technique.

For the first time, we present a novel technique that enables the exchange of the Impella CP (Abiomed Inc., Danvers, Massachusetts, USA) to the Impella 5.5 (Abiomed Inc.) with no interruption of mechanical support in patients with minimal left ventricular reserve. Specifically, the aortic valve is crossed with the Impella 5.5 whereas the Impella CP is still functioning within the left ventricle. The Impella 5.5 is then initiated, and the Impella CP is weaned. Finally, the Impella CP is pulled out into the descending aorta. This exchange provides continuous support with no hemodynamic disarrangement.

Left Ventricular Assist Device Reinsertion for Recurrence of End-Stage Heart Failure Eleven Years after Device Removal: Case Report.

After demonstrated myocardial recovery in patients with durable left ventricular assist device (LVAD) support, the device may occasionally be explanted. A 38-year-old female with nonischemic cardiomyopathy underwent implantation of an LVAD as a bridge-to-transplant therapy. After one year, the patient demonstrated sufficient myocardial recovery allowing the LVAD to be explanted. A Teflon felt strip plug was created and placed within the apical sewing ring to occlude the opening into the left ventricle. Eleven years later, the patient presented with recurrence of severe heart failure. Due to morbid obesity, the patient was not a heart transplant candidate. Therefore, a second LVAD was implanted with a concomitant gastric sleeve procedure. When the plug was surgically removed from the sewing ring, no thrombus was observed; however, the ventricular surface was completely endothelialized. The patient recovered without any complications, was discharged from the hospital, and is currently listed for a heart transplant. This case demonstrates remission from heart failure lasting for more than a decade. If a second LVAD is needed due to exacerbation of severe heart failure, it can be safely introduced through the previous sewing ring after removing the Teflon plug.

Aortic Root Dissection Due to an Automated Fastener Device.

Minimally invasive aortic valve replacement through a right thoracotomy is frequently performed in patients with aortic valve disease. The Cor-Knot Device (LSI Solutions) is an automated fastener that secures valve sutures. This case report is for a patient who developed postcardiotomy shock during a minimally invasive aortic valve surgery. The patient was found to have an aortic root dissection involving 90% of the aortic root circumference, including bilateral coronary ostia. The autopsy revealed that the aortic damage could be explained by a direct aortic intimal tear from the distal tip of the device shaft. The device was most likely not in perfect apposition to the sewing ring because of the restricted angle and space between the ribs.

Surgically Implanted Impella Device for Patients on Impella CP Support Experiencing Refractory Hemolysis.

The Impella CP (Abiomed Inc., Danvers, MA) is widely used in cardiac catheterization laboratories for patients presenting with cardiogenic shock, but it is also known to cause significant hemolysis. The risk of hemolysis can be reduced by properly positioning the device, ensuring an adequate volume status, and using full anticoagulation strategies; however, in some cases hemolysis persists. We present a case series of eight patients that were diagnosed with cardiogenic shock, underwent Impella CP placement, and then suffered from refractory hemolysis which was treated by upgrading the Impella device to the 5.0 or 5.5 version. Fifty percent (4/8) of the patients in this series were already receiving continuous renal replacement therapy, and the levels of plasma free hemoglobin (pFHb) and lactate dehydrogenase continued to increase after the implantation of the Impella CP. The median time between Impella CP placement and the diagnosis of refractory hemolysis was 16.5 hours (interquartile range [IQR], 8.0-26.0). The median time between the diagnosis of hemolysis to Impella upgrade was 6.0 hours (IQR, 4.0-7.0). A total of 87.5% (7/8) of patients experienced a drop in pFHb to below 40 mg/dl at 72 hours post-Impella upgrade, and they were discharged without any further need of dialysis. One patient expired due to irreversible multiple organ failure. We propose that early identification of hemolysis by close monitoring of pFHb and upgrading to the Impella 5.5 reduces hemolysis, prevents further kidney damage, and significantly improves clinical outcomes.

Transaortic Placement of Percutaneous Mechanical Support Device via Partial Sternotomy: Feasible Option for Unsuitable Axillary Artery Access.

Acute decompensated refractory cardiogenic shock is an emergency in which the prompt instauration of mechanical circulatory support improves outcomes. The typical, initial approach for device delivery is via femoral vessels due to easy access and safety. If longer support is needed, the femoral access will severely impair the patient's mobility and can also limit the amount of support given as the new-generation devices are too large for direct arterial insertion. Upper-body arterial conduits (UBACs) are used for the delivery of larger, percutaneous ventricular assist devices (pVADs). The Impella 5.5 (Abiomed, Danvers, MA, USA) is a pVAD that can be deployed through a UBAC by either axillary/subclavian access or a transaortic approach. The latter approach is typically used in cases of postcardiotomy shock, in which the ascending aorta is already exposed through a full sternotomy. However, in some cases, the axillary artery is not suitable due to size (<6 mm in diameter), and a smaller pVAD is delivered into the heart. To avoid providing suboptimal support, we present an alternative, minimally invasive approach in which the larger device is delivered through the ascending aorta. This article summarizes the details of this approach through a mini upper partial sternotomy and reviews the relevant technical considerations.

Intraoperative Management for Left Ventricular Assist Device Implantation With Concurrent Laparoscopic Sleeve Gastrectomy: A Case Series.

The increasing coincidence of obesity with heart failure may preclude eligibility for orthotopic heart transplantation, requiring continuous-flow left ventricular assist devices (LVADs) as destination therapy. This report describes intraoperative considerations for patients who underwent LVAD implantation with concurrent laparoscopic sleeve gastrectomy (LSG) to promote weight loss. In particular, right ventricular dysfunction associated with acute left ventricular unloading may be compounded by pneumoperitoneum for LSG due to the difficulty in ventilating patients with obesity, hypercarbia-mediated increase in pulmonary vascular resistance, and variable cardiac loading conditions. We identify specific anesthetic challenges and discuss methods of monitoring and management.

Off-Pump Continuous-Flow Left Ventricular Assist Device Implantation.

Continuous-flow left ventricular assist device implantation is the typical treatment for end-stage heart failure. Improvements in device engineering and technology, surgical experience and technique, and perioperative management have advanced the field, and short-term results approach those of heart transplantation. Further improvements may be achieved by minimizing adverse physiologic effects associated with cardiopulmonary bypass. Therefore, we have developed an off-pump implantation approach for continuous-flow left ventricular assist devices. We detail our surgical technique for off-pump implantation of the HeartWare device.

Intraoperative Management of Carotid Endarterectomy in Patients With Left Ventricular Assist Devices-The Challenge of Continuous Flow: A Case Report.

Symptomatic carotid artery disease stenosis warrants open surgical carotid endarterectomy (CEA). However, patients with continuous-flow left ventricular assist devices (CF-LVADs) present unique challenges when vasopressors and volume are used to maintain cerebral perfusion pressure after carotid cross-clamping. This report describes patients with CF-LVADs who underwent CEA. We identify how preload, contractility, afterload, pump speed, mean arterial pressure, and anticoagulation should be addressed to maintain CF-LVAD outflow and cerebral perfusion during the procedure. Anesthesiologists can combine an understanding of continuous-flow physiology with invasive monitors to optimize cardiac output and cerebral blood flow during CEA procedures.