Decreased Extracellular Vesicle Vasorin in Severe Preeclampsia Plasma Mediates Endothelial Dysfunction.

Background: Preeclampsia (PE) is a serious pregnancy complication affecting 5-8% of pregnancies globally. It is a leading cause of maternal and neonatal morbidity and mortality. Despite its prevalence, the underlying mechanisms of PE remain unclear. This study aimed to determine the potential role of vasorin (VASN) in PE pathogenesis by investigating its levels in extracellular vesicles (EV) and its effects on vascular function. Methods & Results: We conducted unbiased proteomics on urine-derived EV from severe PE (sPE) and normotensive pregnant women (NTP), identifying differential protein abundances. Out of one hundred and twenty proteins with ≥ ±1.5-fold regulation at P<0.05 between sPE and NTP, we focused on Vasorin (VASN), which is downregulated in sPE in urinary EV, in plasma EV and in the placenta and is a known regulator of vascular function. We generated EV with high VASN content from both human and murine placenta explants (Plex EV), which recapitulated disease-state-dependent effects on vascular function observed when treating murine aorta rings (MAR) or human aortic endothelial cells (HAEC) with murine or human plasma-derived EV. In normal murine pregnancy, VASN increases with gestational age (GA), and VASN is decreased in plasma EV, in placenta tissue and in Plex EV after intravenous administration of adenovirus encoding short FMS-like tyrosine kinase 1 (sFLT-1), a murine model of PE (murine-PE). VASN is decreased in plasma EV, in placenta tissue and in EV isolated from conditioned media collected from placenta explants (Plex EV) in patients with sPE as compared to NTP. Human sPE and murine-PE plasma EV and Plex EV impair migration, tube formation, and induces apoptosis in human aortic endothelial cells (HAEC) and inhibit acetylcholine-induced vasorelaxation in murine vascular rings (MAR). VASN over-expression counteracts the effects of sPE EV treatment in HAEC and MAR. RNA sequencing revealed that over-expression or knock down of VASN in HAEC results in contrasting effects on transcript levels of hundreds of genes associated with vasculogenesis, endothelial cell proliferation, migration and apoptosis. Conclusions: The data suggest that VASN, delivered to the endothelium via EV, regulates vascular function and that the loss of EV VASN may be one of the mechanistic drivers of PE. CLINICAL PERSPECTIVE: What is NewVASN in circulating plasma EV in sPE is reduced compared with VASN content in plasma EV of gestational age-matched pregnant women.VASN is encapsulated and transported in EV and plays a pro-angiogenic role during pregnancy.VASN should be explored both for its pro-angiogenic mechanistic role and as a novel biomarker and potential predictive diagnostic marker for the onset and severity of PE.What Are the Clinical Implications?VASN plays a role in maintaining vascular health and the normal adaptive cardiovascular response in pregnancy. A decrease of VASN is observed in sPE patients contributing to cardiovascular maladaptation.Strategies to boost diminished VASN levels and/or to pharmacologically manipulate mechanisms downstream of VASN may be explored for potential therapeutic benefit in PE.The decrease in EV-associated VASN could potentially be used as a (predictive) biomarker for PE.

Echocardiography for extracorporeal membrane oxygenation.

Extracorporeal membrane oxygenation (ECMO) provides advanced cardiopulmonary life support for patients in cardiac and/or respiratory failure. Echocardiography provides essential diagnostic and anatomic information prior to ECMO initiation, allows for safe and efficient ECMO cannula positioning, guides optimization of flow, provides a modality for rapid troubleshooting and patient evaluation, and facilitates decision-making for eventual weaning of ECMO support. Currently, guidelines for echocardiographic assessment in this clinical context are lacking. In this review, we provide an overview of echocardiographic considerations for advanced imagers involved in the care of these complex patients. We focus predominately on new cannulas and complex cannulation techniques, including a special focus on double lumen cannulas and a section discussing indirect left ventricular venting. Echocardiography is tremendously valuable in providing optimal care in these challenging clinical situations. It is imperative for imaging physicians to understand the pertinent anatomic considerations, the often complicated physiological and hemodynamic context, and the limitations of the imaging modality.

Perioperative Implications of the 2020 American Heart Association/American College of Cardiology Guidelines for the Diagnosis and Treatment of Patients with Hypertrophic Cardiomyopathy: A Focused Review.

Hypertrophic cardiomyopathy is a complex disease with significant implications for patients and the physicians called upon to care for them during the perioperative period. In this article, the 2020 American Heart Association and American College of Cardiology clinical practice guidelines for the evaluation and management of pediatric and adult patients with hypertrophic cardiomyopathy are reviewed, with a particular focus on perioperative considerations for the anesthesiologist.

Bivalirudin as a Systemic Anticoagulant and Flush Solution Additive for Sequential Mitral and Tricuspid Valve Percutaneous Edge-to-Edge Repair in a Patient With Heparin-Induced Thrombocytopenia.

Herein the case of a patient with a prior history of heparin-induced thrombocytopenia who underwent percutaneous mitral valve edge-to-edge repair that was followed by a tricuspid edge-to-edge repair two months later is presented. Recommendations exist for systemic anticoagulant alternatives for percutaneous mitral valve edge-to-edge repair with the MitraClip device (Abbott, Chicago, IL), but minimal guidance and experience are present regarding alternative systemic anticoagulation during the performance of right-sided interventions, including tricuspid edge-to-edge repair (TriClip; Abbott). Notably, there is no clear consensus regarding the use of an alternative anticoagulant in the catheter flush solution for the delivery systems used during these procedures, particularly for right-sided interventions.

Halogen-Induced Chemical Injury to the Mammalian Cardiopulmonary Systems.

The halogens chlorine (Cl2) and bromine (Br2) are highly reactive oxidizing elements with widespread industrial applications and a history of development and use as chemical weapons. When inhaled, depending on the dose and duration of exposure, they cause acute and chronic injury to both the lungs and systemic organs that may result in the development of chronic changes (such as fibrosis) and death from cardiopulmonary failure. A number of conditions, such as viral infections, coexposure to other toxic gases, and pregnancy increase susceptibility to halogens significantly. Herein we review their danger to public health, their mechanisms of action, and the development of pharmacological agents that when administered post-exposure decrease morbidity and mortality.

Halogen gas exposure: toxic effects on the parturient.

The elemental halogens include chlorine, bromine, and phosgene. Halogen gas can be directly weaponized and employed in warfare or terrorism. Industrial stockpiles or halogen transport can provide targets for terrorist attack as well as an origin for accidental release creating a risk for potential mass-casualty incidents. Pregnant and post-partum women represent a substantial and vulnerable subset of the population who may be at particular risk during an attack or accidental exposure. We review the effects of halogen exposure on the parturient with a focus on bromine toxicity. Bromine is the most extensively studied agent in the context of pregnancy and to-date murine models form the basis for the majority of current knowledge. Pregnancy potentiates the acute lung injury after halogen exposure. In addition, halogen exposure precipitates a preeclamptic-like syndrome in mice. This phenotype is characterized by systemic and pulmonary hypertension, endothelial dysfunction, decreased cardiac output, placental injury and fetal growth restriction. This constellation contributes to increased maternal and fetal mortality observed after bromine exposure. Angiogenic imbalance is noted with overexpression of the soluble fms-like tyrosine kinase-1 (sFlt-1) form of the vascular endothelial growth factor receptor 1 reminiscent of human preeclampsia. Additional research is needed to further explore the effect of halogen gas exposure in pregnancy and to develop therapeutic interventions to mitigate risk to this unique population.

The Year in Cardiothoracic and Vascular Anesthesia: Selected Highlights from 2020.

THIS SPECIAL article is the 13th in an annual series for the Journal of Cardiothoracic and Vascular Anesthesia. The authors thank the editor-in-chief, Dr Kaplan, and the editorial board for the opportunity to continue this series; namely, the research highlights of the past year in the specialty of cardiothoracic and vascular anesthesiology.1 The major themes selected for 2020 are outlined in this introduction, and each highlight is reviewed in detail in the main body of the article. The literature highlights in the specialty for 2020 begin with an update on valvular disease, with a focus on updates in management of aortic and mitral valve disorders. The second major theme is an update on coronary artery disease, with discussion of both medical and surgical management. The third major theme is focused on the perioperative management of patients with coronavirus disease 2019 (COVID-19), with the authors highlighting literature discussing medical, surgical, and anesthetic considerations for their cardiac care. The fourth major theme is an update in heart failure, with discussion of medical, psychosocial, and procedural aspects of this complicated disease process. The fifth and final theme focuses on the latest analyses regarding survival in heart transplantation. The themes selected for this 13th special article are only a few of the diverse advances in the specialty during 2020. These highlights will inform the reader of key updates on a variety of topics, leading to improvement of perioperative outcomes for patients with cardiothoracic and vascular disease.

Utility of three-dimensional transesophageal echocardiography to guide transseptal positioning of a single multistage venous cannula to provide both venous drainage and indirect left ventricular venting in veno-arterial extracorporeal membrane oxygenation.

A patient with heart failure due to dilated ischemic cardiomyopathy presented in cardiogenic shock for institution of veno-arterial extracorporeal membrane oxygenation as a bridge to cardiac transplantation. To provide adequate venous drainage and simultaneous decompression of the left atrium (indirect left ventricular venting), a single venous cannula was placed across the interatrial septum so that the distal orifice and side ports were located within the left atrium and the proximal set of side ports were positioned at the cavoatrial junction. Three-dimensional transesophageal echocardiography demonstrated utility in guiding cannula placement and appropriate positioning within the left atrium.

Codeployment of a percutaneous edge-to-edge mitral valve repair device and a ventriculoseptal defect occluder device to address complex mitral regurgitation with leaflet perforation.

An 80-year-old male with severe, complex mitral regurgitation (MR) after recent transcatheter aortic valve replacement presented in heart failure for percutaneous mitral valve repair and possible tricuspid valve repair. Transesopheageal echocardiography (TEE) demonstrated mixed Carpentier Types 1 and 2 components with annular dilation, two leaflet perforations, and excessive leaflet motion (P2 flail). There were three distinct MR jets appreciated reflecting a central coaptation defect and two posterior mitral valve leaflet perforations emanating from a cystic dilatation. Under TEE guidance transseptal puncture and percutaneous edge-to-edge mitral valve repair was performed with a MitraClip XTR device (Abbott, IL). A 10 mm Amplatzer Muscular VSD Occluder (Abbott, Abbott Park, IL) was deployed to close one of the perforations on the posterior leaflet with a significant reduction in MR severity. Attempts at crossing the remaining defect were unsuccessful and the procedure was concluded. The patient recovered uneventfully and transthoracic echocardiography on postoperative day (POD) 1 and again on POD 34 demonstrated normal systolic dominance on pulmonary venous Doppler interrogation, mild to moderate MR, and a mean transvalvular gradient of 5 mmHg. Both devices appeared firmly attached and stable. This is the first documented use of a VSD occluder device in this clinical scenario. Management of complex MR with an approach combining edge-to-edge repair for a central coaptation defect and leaflet flail with codeployment of a VSD occluder device to address a perforated leaflet is feasible and can achieve durable results.

Halogen exposure injury in the developing lung.

Owing to a high-volume industrial usage of the halogens chlorine (Cl2 ) and bromine (Br2 ), they are stored and transported in abundance, creating a risk for accidental or malicious release to human populations. Despite extensive efforts to understand the mechanisms of toxicity upon halogen exposure and to develop specific treatments that could be used to treat exposed individuals or large populations, until recently, there has been little to no effort to determine whether there are specific features and or the mechanisms of halogen exposure injury in newborns or children. We established a model of neonatal halogen exposure and published our initial findings. In this review, we aim to contrast and compare the findings in neonatal mice exposed to Br2 with the findings published on adult mice exposed to Br2 and the neonatal murine models of bronchopulmonary dysplasia. Despite remarkable similarities across these models in overall alveolar architecture, there are distinct functional and apparent mechanistic differences that are characteristic of each model. Understanding the mechanistic and functional features that are characteristic of the injury process in neonatal mice exposed to halogens will allow us to develop countermeasures that are appropriate for, and effective in, this unique population.

Vascular permeability disruption explored in the proteomes of mouse lungs and human microvascular cells following acute bromine exposure.

Bromine (Br2) is an organohalide found in nature and is integral to many manufacturing processes. Br2 is toxic to living organisms, and high concentrations can prove fatal. To meet industrial demand, large amounts of purified Br2 are produced, transported, and stored worldwide, providing a multitude of interfaces for potential human exposure through either accidents or terrorism. To identify the key mechanisms associated with acute Br2 exposure, we have surveyed the lung proteomes of C57BL/6 male mice and human lung-derived microvascular endothelial cells (HMECs) at 24 h following exposure to Br2 in concentrations likely to be encountered in the vicinity of industrial accidents. Global discovery proteomics applications combined with systems biology analysis identified robust and highly significant changes in proteins associated with three biological processes: 1) exosome secretion, 2) inflammation, and 3) vascular permeability. We focused on the latter, conducting physiological studies on isolated perfused lungs harvested from mice 24 h after Br2 exposure. These experiments revealed significant increases in the filtration coefficient (Kf) indicating increased permeability of the pulmonary vasculature. Similarly, confluent monolayers of Br2 and Br-lipid-treated HMECs exhibited differential levels of zona occludens-1 that were found to be dissociated from cell wall localization, an increase in phosphorylation and internalization of E-cadherin, as well as increased actin stress fiber formation, all of which are consistent with increased permeability. Taken as a whole, our discovery proteomics and systems analysis workflow, combined with physiological measurements of permeability, revealed both profound and novel biological changes that contribute to our current understanding of Br2 toxicity.

Chronic Pain in HIV.

The evolution of therapeutics for and management of human immunodeficiency virus-1 (HIV-1) infection has shifted it from predominately manifesting as a severe, acute disease with high mortality to a chronic, controlled infection with a near typical life expectancy. However, despite extensive use of highly active antiretroviral therapy, the prevalence of chronic widespread pain in people with HIV remains high even in those with a low viral load and high CD4 count. Chronic widespread pain is a common comorbidity of HIV infection and is associated with decreased quality of life and a high rate of disability. Chronic pain in people with HIV is multifactorial and influenced by HIV-induced peripheral neuropathy, drug-induced peripheral neuropathy, and chronic inflammation. The specific mechanisms underlying these three broad categories that contribute to chronic widespread pain are not well understood, hindering the development and application of pharmacological and nonpharmacological approaches to mitigate chronic widespread pain. The consequent insufficiencies in clinical approaches to alleviation of chronic pain in people with HIV contribute to an overreliance on opioids and alarming rise in active addiction and overdose. This article reviews the current understanding of the pathogenesis of chronic widespread pain in people with HIV and identifies potential biomarkers and therapeutic targets to mitigate it.

Vascular Endothelial Growth Factor-121 Administration Mitigates Halogen Inhalation-Induced Pulmonary Injury and Fetal Growth Restriction in Pregnant Mice.

Background Circulating levels of sFLT-1 (soluble fms-like tyrosine kinase 1), the extracellular domain of vascular endothelial growth factor (VEGF) receptor 1, and its ratio to levels of placental growth factor are markers of the occurrence and severity of preeclampsia. Methods and Results C57BL/6 pregnant mice on embryonic day 14.5 (E14.5), male, and non-pregnant female mice were exposed to air or to Br2 at 600 ppm for 30 minutes and were treated with vehicle or with VEGF-121 (100 µg/kg, subcutaneously) daily, starting 48 hours post-exposure. Plasma, bronchoalveolar lavage fluid, lungs, fetuses, and placentas were collected 120 hours post-exposure. In Br2-exposed pregnant mice, there was a time-dependent and significant increase in plasma levels of sFLT-1 which correlated with increases in mouse lung wet/dry weights and bronchoalveolar lavage fluid protein content. Supplementation of exogenous VEGF-121 improved survival and weight gain, reduced lung wet/dry weights, decreased bronchoalveolar lavage fluid protein levels, enhanced placental development, and improved fetal growth in pregnant mice exposed to Br2. Exogenous VEGF-121 administration had no effect in non-pregnant mice. Conclusions These results implicate inhibition of VEGF signaling driven by sFLT-1 overexpression as a mechanism of pregnancy-specific injury leading to lung edema, maternal mortality, and fetal growth restriction after bromine gas exposure.

Case Start Time Affects Intraoperative Transfusion Rates in Adult Cardiac Surgery: A Single-Center Retrospective Analysis.

OBJECTIVE: The goal of the study was to investigate the role time of day plays in perioperative outcomes. The authors examined intraoperative transfusion rates throughout the day in adult cardiac surgery patients. They hypothesized that the rate of transfusion changes with later case start times in scheduled cardiac surgery. DESIGN: Retrospective observational study. SETTING: Single academic medical center. PARTICIPANTS: Adults undergoing cardiac surgery involving cardiopulmonary bypass. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was a composite variable of transfusion. The association between the time of day and the rate of transfusion was explored with a multivariate logistic regression to fit the effect of starting time as a cubic spline. There were 1,421 cases that met inclusion criteria. There were 1,220 cases that were matched for modeling. The estimated probability of a patient receiving a transfusion changed significantly with later case start times in the multivariable model after adjusting for initial hemoglobin, age, sex, height, ideal body weight, diabetes, peripheral vascular disease, stroke, chronic kidney disease, chronic obstructive pulmonary disease, duration of cardiopulmonary bypass, aortic cross clamp time, attending surgeon, and attending anesthesiologist (p = 0.032, C-statistic = 0.807, n = 1220). The estimated probability of receiving an intraoperative red blood cell transfusion increased with later case start times in the multivariable model (p = 0.027, C-statistic = 0.902, n = 1220). There was no difference in the probability of transfusion for plasma, cryoprecipitate, or platelets. CONCLUSIONS: The observed rate of intraoperative blood product transfusion changed with later case start times in a multivariable model of scheduled cardiac surgery.

Discharge diagnoses versus medical record review in the identification of community-acquired sepsis.

INTRODUCTION: We evaluated the accuracy of hospital discharge diagnoses in the identification of community-acquired sepsis and severe sepsis. METHODS: We reviewed 379 serious infection hospitalizations from 2003 to 2012 from the national population-based reasons for geographic and racial differences in stroke (REGARDS) cohort. Through manual review of medical records, we defined criterion-standard community-acquired sepsis events as the presence of a serious infection on hospital presentation with ≥2 systemic inflammatory response syndrome criteria. We also defined criterion-standard community-acquired severe sepsis events as sepsis with >1 sequential organ failure assessment organ dysfunction. For the same hospitalizations, we identified sepsis and severe sepsis events indicated by Martin et al. and Angus et al. International Classifications of Diseases 9th edition discharge diagnoses. We evaluated the diagnostic accuracy of the Martin and Angus criteria for detecting criterion-standard community-acquired sepsis and severe sepsis events. RESULTS: Among the 379 hospitalizations, there were 156 community-acquired sepsis and 122 community-acquired severe sepsis events. Discharge diagnoses identified 55 Martin-sepsis and 89 Angus-severe sepsis events. The accuracy of Martin-sepsis criteria for detecting community-acquired sepsis were: sensitivity 27.6%; specificity 94.6%; positive predictive value (PPV) 78.2%; negative predictive value (NPV) 65.1%. The accuracy of the Angus-severe sepsis criteria for detecting community-acquired severe sepsis were: sensitivity 42.6%; specificity 86.0%; PPV 58.4%; NPV 75.9%. Mortality was higher for Martin-sepsis than community-acquired sepsis (25.5% versus 10.3%, P = 0.006), as well as for Angus-severe sepsis than community-acquired severe sepsis (25.5 versus 11.5%, P = 0.002). Other baseline characteristics were similar between sepsis groups. CONCLUSIONS: Hospital discharge diagnoses show good specificity but poor sensitivity for detecting community-acquired sepsis and severe sepsis. While sharing similar baseline subject characteristics as cases identified by hospital record review, discharge diagnoses selected for higher mortality sepsis and severe sepsis cohorts. The epidemiology of a sepsis population may vary with the methods used for sepsis event identification.