Systemic Proinflammatory State Research Articles

The Systemic Inflammation Index on Admission Predicts In-Hospital Mortality in COVID-19 Patients.

Background. The rapid onset of a systemic pro-inflammatory state followed by acute respiratory distress syndrome is the leading cause of mortality in patients with COVID-19. We performed a retrospective observational study to explore the capacity of different complete blood cell count (CBC)-derived inflammation indexes to predict in-hospital mortality in this group. Methods. The neutrophil to lymphocyte ratio (NLR), derived NLR (dNLR), platelet to lymphocyte ratio (PLR), mean platelet volume to platelet ratio (MPR), neutrophil to lymphocyte × platelet ratio (NLPR), monocyte to lymphocyte ratio (MLR), systemic inflammation response index (SIRI), systemic inflammation index (SII), and the aggregate index of systemic inflammation (AISI) were calculated on hospital admission in 119 patients with laboratory confirmed COVID-19. Results. Non-survivors had significantly higher AISI, dNLR, NLPR, NLR, SII, and SIRI values when compared to survivors. Similarly, Kaplan–Meier survival curves showed significantly lower survival in patients with higher AISI, dNLR, MLR, NLPR, NLR, SII, and SIRI. However, after adjusting for confounders, only the SII remained significantly associated with survival (HR = 1.0001; 95% CI, 1.0000–1.0001, p = 0.029) in multivariate Cox regression analysis. Conclusions. The SII on admission independently predicts in-hospital mortality in COVID-19 patients and may assist with early risk stratification in this group.

Neuropathophysiology of preeclampsia and eclampsia: A review of cerebral hemodynamic principles in hypertensive disorders of pregnancy.

Preeclampsia and eclampsia are hypertensive disorders of pregnancy associated with abnormal placental vascular development. The systemic angiogenic imbalance, endothelial dysfunction and proinflammatory state caused by abnormal placental development results in abnormalities in renal, hepatic, pulmonary and neurologic function. Neurosensory symptoms related to pregnancy induced hypertension (PIH), the most devastating of which are intracranial hemorrhage and seizure, are among the leading causes of maternal and perinatal morbidity and mortality globally, yet risk stratification strategies and targeted therapies remain elusive. Current treatment for preeclampsia with severe features is limited to delivery, antihypertensive therapy, and magnesium sulfate seizure prophylaxis. Magnesium sulfate reduces seizure rates among severe preeclamptics, but predisposes patients to weakness, uterine atony, pulmonary edema and respiratory depression. Therefore, this drug should ideally be administered only to the subset of preeclamptics who are at increased risk for neurologic complications. While there are no objective methods validated to predict eclampsia, we hypothesize that measurement of optic nerve sheath diameters, optic disc height and middle cerebral artery transcranial doppler resistance indices may be useful in identifying subclinical cerebral edema, potentially allowing us to recognize those patients at highest risk for seizures. This summary of the current literature provides an initial framework for developing more sophisticated and noninvasive methods for identifying, monitoring and treating parturients who are at highest risk for neurologic complications from preeclampsia.

Proteomic Evaluation of the Comorbidity-Inflammation Paradigm in Heart Failure With Preserved Ejection Fraction: Results From the PROMIS-HFpEF Study.

A systemic proinflammatory state has been hypothesized to mediate the association between comorbidities and abnormal cardiac structure/function in heart failure with preserved ejection fraction (HFpEF). We conducted a proteomic analysis to investigate this paradigm. In 228 patients with HFpEF from the multicenter PROMIS-HFpEF study (Prevalence of Microvascular Dysfunction in Heart Failure With Preserved Ejection Fraction), 248 unique circulating proteins were quantified by a multiplex immunoassay (Olink) and used to recapitulate systemic inflammation. In a deductive approach, we performed principal component analysis to summarize 47 proteins known a priori to be involved in inflammation. In an inductive approach, we performed unbiased weighted coexpression network analyses of all 248 proteins to identify clusters of proteins that overrepresented inflammatory pathways. We defined comorbidity burden as the sum of 8 common HFpEF comorbidities. We used multivariable linear regression and statistical mediation analyses to determine whether and to what extent inflammation mediates the association of comorbidity burden with abnormal cardiac structure/function in HFpEF. We also externally validated our findings in an independent cohort of 117 HFpEF cases and 30 comorbidity controls without heart failure. Comorbidity burden was associated with abnormal cardiac structure/function and with principal components/clusters of inflammation proteins. Systemic inflammation was also associated with increased mitral E velocity, E/e' ratio, and tricuspid regurgitation velocity; and worse right ventricular function (tricuspid annular plane systolic excursion and right ventricular free wall strain). Inflammation mediated the association between comorbidity burden and mitral E velocity (proportion mediated 19%-35%), E/e' ratio (18%-29%), tricuspid regurgitation velocity (27%-41%), and tricuspid annular plane systolic excursion (13%) (P<0.05 for all), but not right ventricular free wall strain. TNFR1 (tumor necrosis factor receptor 1), UPAR (urokinase plasminogen activator receptor), IGFBP7 (insulin-like growth factor binding protein 7), and GDF-15 (growth differentiation factor-15) were the top individual proteins that mediated the relationship between comorbidity burden and echocardiographic parameters. In the validation cohort, inflammation was upregulated in HFpEF cases versus controls, and the most prominent inflammation protein cluster identified in PROMIS-HFpEF was also present in HFpEF cases (but not controls) in the validation cohort. Proteins involved in inflammation form a conserved network in HFpEF across 2 independent cohorts and may mediate the association between comorbidity burden and echocardiographic indicators of worse hemodynamics and right ventricular dysfunction. These findings support the comorbidity-inflammation paradigm in HFpEF.

Coronavirus 2019 Disease (COVID-19), Systemic Inflammation, and Cardiovascular Disease.

Acute respiratory failure associated with the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), has rapidly spread worldwide and presents critical challenges for the public health and medical communities The World Health Organization (WHO) has declared SARS-CoV-2 a public health emergency of international concern, with a global estimate of over 7 million human infections and more than 400000 deaths worldwide as of June 12, 2020 A 2020 report by the China Medical Treatment Expert Group for Coronavirus disease 2010 (COVID-19) (2) showed that the clinical spectrum of the viral infection is dominated by fever (up to 88 7% of patients during hospitalization) and cough (67 8% of patients) followed by symptoms such as headache, fatigue, or shortness of breath

The secretory senescence of the airway

Secretory senescence of the upper and lower airway represents the most important risk factor for respiratory complication in the elderly. In most cases, patients present with high health care costs due to the relevant number of hospitalizations and medical cares. A growing evidence is accumulating on the role of immunosenescence in the pathogenesis of chronic rhinosinusal disorders, and on defect in the lubrication of the corneal, conjunctival and scleral mucosa, delicate structures of the external eye, and of trachea-bronchial diseases, dependent on a failure of the gland system and reduction of mucociliary clearance (MCC). The presence of multiple comorbidities in the elderly may significantly contribute to a systemic pro-inflammatory state which negatively affects the airway. Secretory senescence promotes systemic inflammation and exacerbates the pre-existing pathologies. The role of cytokines is associated to a pro-inflammatory state of breathing apparatus. Several observations support the hypothesis that the secretory senescence can act in a paracrine and vasocrine manner to influence the structure and function of glands, mucus and lacrimal secretions, thus contributing to fraility and hospitalizations in the elderly. Given the recognized role of secretory senescence in the pathophysiology of airway disease, it should be desirable to identify specific therapies targeting the nasal, lacrimal and tracheo- bronchial secretory system able to modulate its pro-inflammatory profile and the negative effect of the inflammatory burden on the elderly.

Abstract 342: A Description of Cardiac Outcomes in Patients With Sickle Cell Trait and Chronic Kidney Disease: Evaluated in a National Inpatient Data Sample

Introduction: Sickle cell trait (SCT) is an independent risk factor for chronic kidney disease (CKD). CKD is a well-established risk factor for progressive cardiovascular dysfunction. Sickle Cell trait has been noted to promote a persistent systemic pro-inflammatory state. This pro-inflammatory state could potentially increase the risk of systemic endothelial dysfunction when accompanied with other cardiotoxic conditions. We aim to investigate cardiovascular outcomes in patients with SCT and CKD, compared to SCT alone. Methods: Patients with CKD were identified in the National Inpatient Sample (NIS) database 2016 using the International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM), and subsequently were divided into two groups, those with and without SCT. Both population sets were paired using 1:1 propensity score matching based on Age, Sex and co-morbidities to address potential confounding factors. Outcomes of interest were overall mortality, rates of stroke, sudden cardiac arrest (SCA) and cardiomyopathy. Results: Mean age of patients with CKD alone was 72.98 ± 13.2 years, while for CKD and SCT 56.68 ± 17.3 years. There was no significant difference between the two group in the rates of stroke (1.3% vs 1.0%; P= 0.125), and SCA (1.0% vs 1.1%; P= 0.841). Overall mortality (5.7% vs 2.2%; P&lt;0.0001) and rates of cardiomyopathy (10.1% vs 2.9%; P&lt;0.0001) were significantly lower in patients with CKD and SCT, compared to CKD alone. Multivariate logistic regression followed a similar trend, compared to those with CKD alone, the adjusted odds ratio (aOR) for overall mortality aOR; 0.625 (0.372-1.049) and cardiomyopathy aOR; 0.451 (0.293-0.696) were significantly lower in patients with CKD and SCT. Conclusion: Compared to patients with CKD alone, those with CKD and SCT have a lower risk for overall mortality and cardiomyopathy. Further studies are needed to replicate this finding and look at the possible protective role of SCT in patients with CKD.

Abnormal Distribution and Function of Circulating Monocytes and Enhanced Bacterial Translocation in Major Depressive Disorder.

Introduction: Major depressive disorder (MDD) patients experience a systemic inflammatory stage. Monocytes play an important role in innate inflammatory responses and may be modulated by bacterial translocation. Our aim was to investigate the subset distribution and function of circulating monocytes, levels of proinflammatory cytokines, gut barrier damage, and bacterial translocation in MDD patients.Methods: Twenty-two MDD patients without concomitant diseases and 14 sex- and age-matched healthy controls were studied. The levels of circulating CD14++CD16- (classical), CD14++CD16++ (intermediate) and CD14-CD16++ (nonclassical) monocytes and the intracytoplasmic tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-10 expression in the presence or absence of lipopolysaccharide (LPS) stimulation were analyzed by polychromatic flow cytometry. The serum TNF-α, IL-1β, IL-6, and IL-10 levels were measured by Luminex. LPS-binding protein (LBP), intestinal fatty acid-binding protein (I-FABP), and zonulin were measured by enzyme-linked immunosorbent assay (ELISA).Results: MDD patients had a significant increase in the frequency of intermediate monocytes and a significant decrease in the frequency of classical monocytes compared to those in the healthy controls. MDD patients had a significantly increased percentage of classical monocytes that expressed IL-1β, intermediate monocytes that expressed IL-1β and IL6 and nonclassical monocytes that expressed IL-1β, and decreased levels of nonclassical monocytes that expressed IL6 compared to those in the healthy controls. MDD patients had significantly increased levels of circulating TNF-α, IL-1β, LBP, and I-FABP compared to those in the healthy controls. MDD patients with high LBP levels had a significant reduction in the number of circulating monocytes compared to that in the normal-LBP MDD patients, which can be mainly ascribed to a decrease in the number of intermediate and nonclassical monocytes.Conclusions: We have demonstrated that compared to the healthy controls, MDD patients show a marked alteration in circulating monocytes, with an expansion of the intermediate subset with increased frequency of IL-1β and IL-6 producing cells. These patients also exhibited a systemic proinflammatory state, which was characterized by the enhanced serum TNF-α and IL-1β levels compared to those in the healthy controls. Furthermore, MDD patients showed increased LBP and I-FABP levels compared to those in healthy controls, indicating increased bacterial translocation and gut barrier damage.

The elevated systemic cytokine levels in HIV patients are not associated with an elevated pulmonary cytokine environment

BackgroundHIV-positive patients on anti-retroviral therapy (ART) are at higher risk of developing many non-AIDS related chronic diseases, including chronic obstructive pulmonary disease (COPD), compared to HIV-negative individuals. While the mechanisms are not clear, a persistent pro-inflammatory state appears to be a key contributing factor. The aims of this study were to investigate whether HIV-positive patients without COPD present evidence of potentially predisposing abnormal pulmonary cytokine/chemokine environment and to explore the relationship between pulmonary and systemic cytokine levels. MethodsThis study included 39 HIV-seropositive and 34 HIV-seronegative subjects without COPD. All were subjected to outpatient bronchoscopy with bronchoalveolar lavage fluid (BALF) aspiration and blood sample collection. The levels of 21 cytokines and chemokines were measured in plasma and BALF using a bead-based multi-analyte assay. ResultsIn plasma, HIV-infected patients showed significantly increased circulating levels of pro-inflammatory (TNFα) and Th1-associated cytokines (IL-12p70) as well as several chemokines (CXCL11 and CX3CL1). However, no statistically significant differences were found in the numbers of cells, the concentrations of protein and urea as well as cytokine levels in the BALFs of HIV-positive patients when compared to controls. Correlation analysis indicated a potential modulatory effect of the BMI in HIV-seropositive individuals. ConclusionsWhile our results are consistent with the existence of a systemic pro-inflammatory state in HIV-infected patients, they did not detect significant differences in cytokine levels and other inflammatory markers in the lungs of HIV-positive individuals when compared to HIV-negative controls.

Frequency of Coronary Microvascular Dysfunction and Diffuse Myocardial Fibrosis (Measured by Cardiovascular Magnetic Resonance) in Patients With Heart Failure and Preserved Left Ventricular Ejection Fraction

Heart failure with preserved ejection fraction (HFpEF) is frequently accompanied by co-morbidities and a systemic proinflammatory state, resulting in coronary microvascular dysfunction (CMD), as well as myocardial fibrosis. The purpose of this study is to examine the relation between myocardial perfusion reserve (MPR) and diffuse myocardial fibrosis in patients with HFpEF using cardiovascular magnetic resonance. A single center study was performed in 19 patients with clinical HFpEF and 15 healthy control subjects who underwent quantitative first-pass perfusion imaging to calculate global MPR. T1 mapping was used to assess fibrosis and to calculate extracellular volume. Spiral cine displacement encoded stimulated echo was used to calculate myocardial strain. Comprehensive 2D echocardiograms with speckle tracking, cardiopulmonary exercise testing, and brain natriuretic peptide levels were also obtained. In patients with HFpEF, mean left ventricular EF was 61% ± 9% and left ventricular mass index 45 ± 12 g/m2. Compared with controls, HFpEF patients had reduced global MPR (2.29 ± 0.64 vs 3.38 ± 0.76, p = 0.002) and VO2 max (16.5 ± 6.8 vs 30.9 ± 7.7 ml/kg min, p <0.001) whereas extracellular volume (0.29 ± 0.04 vs 0.25 ± 0.04, p = 0.02), pulmonary artery systolic pressure (35.4 ± 13.7 vs 22.3 ± 5.4 mm Hg, p = 0.004), and average E/e' (15.0 ± 7.6 vs 8.6 ± 2.0, p = 0.005) were increased. Displacement encoded stimulated echo peak systolic circumferential strain (p = 0.60) as well as echocardiographic derived global longitudinal strain (p = 0.07) were similar between both groups. The prevalence of CMD, defined as global MPR <2.5, in the HFpEF group was 69%. In conclusion, HFpEF patients have a high prevalence of CMD and diffuse fibrosis. These parameters may be useful clinical end points for future therapeutic trials.

Biomarkers of Inflammation in Left Ventricular Diastolic Dysfunction.

Left ventricular diastolic dysfunction (LVDD) is an important precursor to many different cardiovascular diseases. Diastolic abnormalities have been studied extensively in the past decade, and it has been confirmed that one of the mechanisms leading to heart failure is a chronic, low-grade inflammatory reaction. The triggers are classical cardiovascular risk factors, grouped under the name of metabolic syndrome (MetS), or other systemic diseases that have an inflammatory substrate such as chronic obstructive pulmonary disease. The triggers could induce myocardial apoptosis and reduce ventricular wall compliance through the release of cytokines by multiple pathways such as (1) immune reaction, (2) prolonged cell hypoxemia, or (3) excessive activation of neuroendocrine and autonomic nerve function disorder. The systemic proinflammatory state causes coronary microvascular endothelial inflammation which reduces nitric oxide bioavailability, cyclic guanosine monophosphate content, and protein kinase G (PKG) activity in adjacent cardiomyocytes favoring hypertrophy development and increases resting tension. So far, it has been found that inflammatory cytokines associated with the heart failure mechanism include TNF-α, IL-6, IL-8, IL-10, IL-1α, IL-1β, IL-2, TGF-β, and IFN-γ. Some of them could be used as diagnosis biomarkers. The present review aims at discussing the inflammatory mechanisms behind diastolic dysfunction and their triggering conditions, cytokines, and possible future inflammatory biomarkers useful for diagnosis.

486-P: Hyperglycemia Promotes Epigenetic Priming of RELA/p65 Gene in Cord Blood-Derived CD34+ Stem Cells and Their Differentiation into Proinflammatory CD16 Myeloid Cell Population

Background: Diabetic patients are characterized by a systemic pro-inflammatory state and an increased propensity to develop atherosclerosis. Since epigenetic mechanisms are known to be involved in the regulation of inflammatory genes of vascular cells under diabetic conditions, we hypothesized that uncontrolled hyperglycemia may epigenetically skew circulating CD34+ progenitors towards an inflammatory phenotype. Results: We investigated the impact of hyperglycemia on the epigenetic makeup of NFkB gene, a gate-keeper of the inflammatory control of CD34+ cells, and on the differentiation into myeloid progenitors. CD34+ cells exposed to high glucose (HG) showed a significant reduction of the repressive epigenetic modification H3K9me3 on RELA/p65 gene encoding for nuclear factor NF-kappa-B p65 subunit. This epigenetic alteration coincided with an increased recruitment of RNA polymerase II at level of p65 promoter and with a significant transcription up-regulation. Interestingly, the KAT2B/PCAF gene, an histone acetyltransferase implicated in NFkB-p65 acetylation and nuclear stabilization, was also overexpressed. Consistently, HG-CD34+ cells showed higher acetylation of NFkB in the lysine-310 and increased expression and secretion of the NFkB-p65 target cytokines, TNFα and IL6. Moreover, in vitro differentiation of HG-CD34+ cells into myeloid lineage generated higher level of pro-inflammatory CD16+ and CD14+ CD16+ monocyte subsets when compared to the normoglycemic counterpart. Conclusions: These results suggest that elevated glucose exposure might epigenetically prime CD34+ cells for a pro-inflammatory response as well as skew CD34+ cell differentiation into inflammatory cell lineages. Disclosure M. Vinci: None. V. Vigorelli: None. S. Genovese: Advisory Panel; Self; Novartis Pharmaceuticals Corporation, Sanofi. Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Hikma Pharmaceuticals. Speaker's Bureau; Self; Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Mundipharma, Novo Nordisk A/S, Takeda Pharmaceutical Company Limited. G. Pompilio: None. Funding Ricerca Finalizzata, Ministero della Salute (PE-2011-02348537)

Sick fat: the good and the bad of old and new circulating markers of adipose tissue inflammation.

Adipose tissue (AT)is one of the largest endocrine organs contributing to metabolic homeostasis. The functional pleiotropism ofAT depends on its ability to secrete a large number of hormones, cytokines, extracellular matrix proteins and growth factors, all influencing many local and systemic physiological and pathophysiological processes. In condition of chronic positive energy balance, adipocyte expansion, hypoxia, apoptosis and stress all lead to AT inflammation and dysfunction, and it has been demonstrated that this sick fat is a main risk factor for many metabolic disorders, such as type 2 diabetes mellitus, fatty liver, cardiovascular disease and cancer. AT dysfunction is tightly associated with aberrant secretion of bioactive peptides, the adipocytokines, and their blood concentrations often reflect the expression in the AT. Despite the existence of an association between AT dysfunction and systemic pro-inflammatory state, most of the circulating molecules detectable in obese and dysmetabolic individuals do not identify specifically the condition of sick fat. Based on this premise, thisreview provides a concise overview of "classic" and novel promising adipocytokines associated with AT inflammation and discusses possible critical approaches to their interpretation in clinical practice.

Western diet‐induced insulin resistance impairs recovery after experimental spinal cord injury

The cardinal signs of systemic metabolic dysfunction, including insulin resistance, hypertension and a systemic pro‐inflammatory state are risk factors for the development of cardiovascular disease, type 2 diabetes, and neurodegenerative conditions, but there is limited information regarding the impact on recovery after spinal cord injury (SCI). To address this gap, we investigated the impact of systemic insulin resistance generated by consumption of a diet high in fat and sucrose, often referred to as a Western Diet, on neuropathophysiological outcomes in a murine compression model of incomplete SCI. Ten‐week‐old female C57BL6 mice were provided a regular diet (RD) or a diet high in fat and sucrose (HFHS) for 7 weeks prior to experimental compression SCI.Mice consuming a Western Diet showed signs of systemic insulin resistance such as evaluated blood glucose. In addition, signs of insulin resistance within the substance of the spinal cord were also observed, including reductions in the abundance of insulin‐like growth factor 1 receptor (IGF‐1R). Impairments in motor recovery evaluated by BMS score and subscore were present in mice consuming HFHS at 14 and 30 days post injury (dpi). Consumption of a diet rich in fat and sucrose also impaired the mean maximal angle achieved on the inclined plane test and resulted in significant impairments in bladder release. Immunochemical analysis of the spinal cord revealed a number of differences in markers of neural injury between the two groups. First, mice consuming HFHS exhibited significant increases in astrogliosis measured by glial fibrillary acidic protein (GFAP) prior to injury, compared to mice consuming a RD. In fact, the prominent increases in GFAP observed in the intact spinal cord of mice consuming HFHS were equivalent to those observed after SCI in mice consuming a regular chow. In the subacute period, markers of microglial/monocyte activation were elevated in all mice with SCI; however, the increase was substantially greater in the spinal cords of mice consuming HFHS. The spinal cord white matter of mice consuming HFHS also showed reductions in the number of oligodendrocyte progenitor and mature myelinating cells prior to SCI and HFHS‐associated reductions in myelin producing cells persisted at 14 and 30 dpi. In addition, loss of serotonergic axons in the spinal cord after SCI was exacerbated in mice consuming HFHS. Growth associated protein 43 (GAP43), a marker of axonal growth cones was elevated after SCI in the spinal cords of mice consuming a RD or a HFHS diet; however, the magnitude of the increase in growth cones was severely impaired in mice consuming HFHS.These findings suggest that consumption of a Western Diet increases the risk of insulin resistance within the central nervous system and impairs neurobehavioral recovery after SCI. These studies highlight insulin resistance as a new mechanism that limits nervous system repair after SCI and as a potential target for intervention to improve functional outcomes.Support or Funding InformationNIH R01 NS052741 and The Minnesota State SCI and TBI Research Grant Program.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Effect of repeated intravenous lipopolysaccharide infusions on systemic inflammatory response and endometrium gene expression in Holstein heifers

This study aimed to evaluate the effect of repeated intravenous lipopolysaccharide (LPS) infusions in nonlactating heifers on (1) the systemic proinflammatory state as measured by biomarkers in blood and plasma, and (2) endometrial gene expression of candidate transcripts on d 15 of gestation. Our hypothesis was that target transcripts related to a major functional group would be negatively modified in the preimplantation endometrium by the LPS treatments. In the first experiment (n = 13), a systemic proinflammatory state [defined as increased plasma concentrations of tumor necrosis factor (TNF)-α and haptoglobin for 2 wk] was established using 2 different sequential LPS infusion protocols. In the second experiment, heifers (n = 22; 11 mo of age) had their time of ovulation synchronized by a modified Ovsynch protocol and were enrolled in 1 of 2 treatments: control (CON; n = 11), which received sterile saline solution i.v., and LPS treatment (LPS; n = 11), submitted to repeated i.v. LPS injections (0.10, 0.25, 0.50, 0.75, 1.00, and 1.25 µg/kg) starting 2 d after artificial insemination (AI; d 0) and then every other day until d 15 after AI. At each LPS injection, rectal temperatures were measured hourly for 6 h. Blood samples were collected from d -1 to d 13 for analyses of progesterone, TNF-α, and haptoglobin in plasma, along with white blood cell (WBC) count and differential analysis. On d 15, endometrium tissue biopsies were taken and kept at -80°C until quantitative real-time PCR analysis of 30 target transcripts related to the immune system, adhesion molecules, and endometrium receptivity. Data were checked for normality and analyzed by repeated-measures ANOVA using PROC UNIVARIATE and PROC MIXED of SAS (SAS Institute Inc., Cary, NC). After each LPS injection, temperature was greater in the first 4 h in the LPS group compared with CON. Both TNF-α and haptoglobin increased in the LPS treatment with a significant treatment by day interaction. Total leukocyte count did not differ between treatments, but the differential count increased for neutrophils, band cells, and monocytes, and decreased for lymphocytes and eosinophils in LPS compared with CON. Progesterone concentrations in plasma did not differ between treatments during the experimental period. Out of 30 target genes analyzed, 3 transcripts were differentially expressed: indoleamine 2,3-dioxygenase (IDO; fold-change = 0.48) and pentraxin-3 (PTX3; fold-change = 0.38) were downregulated, whereas myxovirus-resistance protein (MX1; fold-change = 2.85) was upregulated in the LPS group. Sequential LPS injections were able to induce a prolonged systemic proinflammatory state, but effects on gene expression were limited to transcripts associated with the immune system. These results suggest that a mechanism for subfertility is linked to a proinflammatory state in dairy heifers.

Evaluation and Management of Right-Sided Heart Failure: A Scientific Statement From the American Heart Association.

The diverse causes of right-sided heart failure (RHF) include, among others, primary cardiomyopathies with right ventricular (RV) involvement, RV ischemia and infarction, volume loading caused by cardiac lesions associated with congenital heart disease and valvular pathologies, and pressure loading resulting from pulmonic stenosis or pulmonary hypertension from a variety of causes, including left-sided heart disease. Progressive RV dysfunction in these disease states is associated with increased morbidity and mortality. The purpose of this scientific statement is to provide guidance on the assessment and management of RHF. The writing group used systematic literature reviews, published translational and clinical studies, clinical practice guidelines, and expert opinion/statements to summarize existing evidence and to identify areas of inadequacy requiring future research. The panel reviewed the most relevant adult medical literature excluding routine laboratory tests using MEDLINE, EMBASE, and Web of Science through September 2017. The document is organized and classified according to the American Heart Association to provide specific suggestions, considerations, or reference to contemporary clinical practice recommendations. Chronic RHF is associated with decreased exercise tolerance, poor functional capacity, decreased cardiac output and progressive end-organ damage (caused by a combination of end-organ venous congestion and underperfusion), and cachexia resulting from poor absorption of nutrients, as well as a systemic proinflammatory state. It is the principal cause of death in patients with pulmonary arterial hypertension. Similarly, acute RHF is associated with hemodynamic instability and is the primary cause of death in patients presenting with massive pulmonary embolism, RV myocardial infarction, and postcardiotomy shock associated with cardiac surgery. Functional assessment of the right side of the heart can be hindered by its complex geometry. Multiple hemodynamic and biochemical markers are associated with worsening RHF and can serve to guide clinical assessment and therapeutic decision making. Pharmacological and mechanical interventions targeting isolated acute and chronic RHF have not been well investigated. Specific therapies promoting stabilization and recovery of RV function are lacking. RHF is a complex syndrome including diverse causes, pathways, and pathological processes. In this scientific statement, we review the causes and epidemiology of RV dysfunction and the pathophysiology of acute and chronic RHF and provide guidance for the management of the associated conditions leading to and caused by RHF.

Association between low-grade chronic inflammation and depressed left atrial compliance in heart failure with preserved ejection fraction: A retrospective analysis.

A novel paradigm of diastolic heart failure with preserved ejection fraction (HFpEF) proposed the induction of coronary microvascular dysfunction by HFpEF comorbidities via a systemic pro-inflammatory state and associated oxidative stress. The consequent nitric oxide deficiency would increase diastolic tension and favor fibrosis of adjacent myocardium, which implies not only left ventricular (LV), but all-chamber myocardial stiffening. Our aim was to assess relations between low-grade chronic systemic inflammation and left atrial (LA) pressure-volume relations in real-world HFpEF patients. We retrospectively analyzed medical records of 60 clinically stable HpEFF patients in sinus rhythm with assayed high-sensitive C-reactive protein (CRP) during the index hospitalization. Subjects with CRP >10 mg/L or coexistent diseases, including coronary artery disease, were excluded. LV and LA diameters and mitral E/E' ratio (an index of LA pressure) were extracted from routine echocardiographic records. A surrogate measure of LA stiffness was computed as the averaged mitral E/e' ratio divided by LA diameter. With ascending CRP tertiles, we observed trends for elevated mitral E/e' ratio (p <0.001), increased relative LV wall thickness (p = 0.01) and higher NYHA functional class (p = 0.02). The LA stiffness estimate and log-transformed CRP levels (log-CRP) were interrelated (r = 0.38, p = 0.003). On multi- variate analysis, the LA stiffness index was independently associated with log-CRP (β ± SEM: 0.21 ± 0.07, p = 0.007) and age (β ± SEM: 0.16 ± 0.07, p = 0.03), which was maintained upon adjustment for LV mass index and relative LV wall thickness. Low-grade chronic inflammation may contribute to LA stiffening additively to age and regardless of the magnitude of associated LV hypertrophy and concentricity. LA stiffening can exacerbate symptoms of congestion in HFpEF jointly with LV remodeling.

Associations of Statins and Diabetes with Diagnosis of Ulcerated Cutaneous Melanoma

Ulcerated primary melanomas are associated with an inflammatory tumor microenvironment. We hypothesized that systemic proinflammatory states and anti-inflammatory medications are also associated with a diagnosis of ulcerated melanoma. In a cross-sectional study of 787 patients with newly diagnosed clinical stage IB or II melanoma, we estimated odds ratios for the association of proinflammatory factors (high body mass index, diabetes, cardiovascular disease, hypertension, and smoking) or the use of anti-inflammatory medications (statins, aspirin, corticosteroids, and nonsteroidal anti-inflammatory drugs), with ulcerated primary melanoma using regression models and subgroup analyses to control for melanoma thickness and mitotic rate. On the basis of information from 194 patients with ulcerated and 593 patients with nonulcerated primary melanomas, regular statin users had lower likelihood of a diagnosis of ulcerated primary melanoma (odds ratio 0.67, 95% confidence interval 0.45-0.99), and this association remained after adjusting for age, sex, thickness, and mitosis. When analysis was limited to melanomas that were ≤2 mm thick and had ≤2 mitoses/mm2 (40 ulcerated; 289 without ulceration), patients with diabetes had significantly raised odds of diagnosis of ulcerated melanoma (odds ratio 2.90, 95% confidence interval 1.07-7.90), adjusted for age, sex, body mass index, and statin use. These findings support our hypotheses that statin use is inversely associated, and diabetes is positively associated, with ulcerated melanoma.

139 - Comorbidity Management in Patients Referred to a Heart Failure with Preserved Ejection Fraction Clinic

Background: A modern paradigm for heart failure with preserved ejection fraction (HFpEF) pathogenesis proposes that comorbidities including diabetes, hypertension, obesity, CAD, and OSA contribute to a systemic pro-inflammatory state that promotes HFpEF development. Methods: We performed a chart review of 106 patients referred to the University of Michigan HFpEF Clinic. We assessed several comorbid conditions including hypertension, diabetes, obesity (BMI ≥ 30 kg/m2), dyslipidemia, CAD, OSA, chronic renal insufficiency (CRI, GFR < 60 mL/min), and atrial fibrillation (AF). Appropriate blood pressure control was defined as SBP < 140 and DBP < 90 mm Hg. Appropriate glycemic control was defined as a hemoglobin A1c < 7.0%. We assessed medical therapy for CAD and statin utilization as per guidelines. We evaluated whether patients with no history of CAD had received an evaluation for CAD. We reviewed rates of anticoagulant use for patients with a CHADs2VASc score ≥ 2. We also reviewed CPAP use for OSA and assessed if patients at risk for OSA (see Table 1) were referred for polysomnography (PSG). Results: A total of 106 patients were reviewed (median age 67; 37% male). Comorbidities were common (45% hypertension, 45% diabetes, 37% CAD, 76% obesity, 73% statin indication, 48% CRI, 64% OSA, 43% AF). Appropriate blood pressure control was observed in 66% of patients with hypertension. Forty-four of 48 patients with diabetes had a hemoglobin A1c measured within the past 3 years; however, only 48% of those had a reading of < 7.0%. Most patients (>80%) with CAD were receiving appropriate medical therapy but only 51% of those without CAD had an ischemic evaluation in the last 5 years. Of those patients with an indication for a statin, 86% were receiving statin therapy. In those patients with OSA, all patients were prescribed CPAP though only 88% were adherent. Of those with at least 3 risk factors for OSA though, only 50% had been referred for polysomnography. Lastly, 100% of patients with a CHADs2VASc ≥ 2 and no documented contraindication to anticoagulation were receiving anticoagulation for AF. Discussion: Patients referred for evaluation of HFpEF have a significant comorbidity burden. Based on data at initial evaluation, improvements can be made to achieve optimal management of these comorbidities. Since improved comorbidity management may prevent HFpEF progression, this highlights that appropriate care for the HFpEF patient requires a multidisciplinary approach.

Preimplantation Kidney Biopsies of Extended Criteria Donors Have a Heavier Inflammatory Burden Than Kidneys From Standard Criteria Donors.

BackgroundDonors after brain death develop a systemic proinflammatory state that may predispose the kidneys to injury after transplantation. Because it is not known whether this inflammatory environment similarly affects the kidneys from expanded criteria donor (ECD) and standard criteria donors (SCD), we sought to evaluate differences in the gene expression of inflammatory cytokines in preimplantation biopsies (PIBx) from ECD and SCD kidneys.MethodsCytokines gene expression was measured in 80 PIBx (SCD, 52; ECD, 28) and associated with donor variables.ResultsNormal histology and chronic histological lesions were not different between both types of kidneys. ECD kidneys showed significant increase in the transcripts of MCP-1, RANTES, TGF-β1, and IL-10 when compared with SCD. Kidneys presenting normal histology had similar inflammatory profile except by a higher expression of RANTES observed in ECD (P = 0.04). Interstitial fibrosis and tubular atrophy (interstitial fibrosis and tubular atrophy ≥ 1) were associated with higher expression of TGF-β1, RANTES, and IL-10 in ECD compared with SCD kidneys. Cold ischemia time of 24 hours or longer was significantly associated with upregulation of FOXP3, MCP-1, RANTES, and IL10, whereas longer duration of donor hospitalization significantly increased gene expression of all markers. High FOXP3 expression was also associated with lower level of serum creatinine at 1 year. Donor age was not associated with any of the transcripts studied.ConclusionsPIBx of ECD exhibit a higher gene expression of inflammatory cytokines when compared with SCD kidneys. This molecular profile may be a specific ECD kidney response to brain death and may help to predict the posttransplant outcomes of ECD recipients.

Resistance exercise attenuates skeletal muscle oxidative stress, systemic pro-inflammatory state, and cachexia in Walker-256 tumor-bearing rats

The aim of this study was to investigate the effects of resistance exercise training (RET) on oxidative stress, systemic inflammatory markers, and muscle wasting in Walker-256 tumor-bearing rats. Male (Wistar) rats were divided into 4 groups: sedentary controls (n = 9), tumor-bearing (n = 9), exercised (n = 9), and tumor-bearing exercised (n = 10). Exercised and tumor-bearing exercised rats were exposed to resistance exercise of climbing a ladder apparatus with weights tied to their tails for 6 weeks. The physical activity of control and tumor-bearing rats was confined to the space of the cage. After this period, tumor-bearing and tumor-bearing exercised animals were inoculated subcutaneously with Walker-256 tumor cells (11.0 × 107 cells in 0.5 mL of phosphate-buffered saline) while control and exercised rats were injected with vehicle. Following inoculation, rats maintained resistance exercise training (exercised and tumor-bearing exercised) or sedentary behavior (control and tumor-bearing) for 12 more days, after which they were euthanized. Results showed muscle wasting in the tumor-bearing group, with body weight loss, increased systemic leukocytes, and inflammatory interleukins as well as muscular oxidative stress and reduced mTOR signaling. In contrast, RET in the tumor-bearing exercised group was able to mitigate the reduced body weight and muscle wasting with the attenuation of muscle oxidative stress and systemic inflammatory markers. RET also prevented loss of muscle strength associated with tumor development. RET, however, did not prevent the muscle proteolysis signaling via FBXO32 gene messenger RNA expression in the tumor-bearing group. In conclusion, RET performed prior tumor implantation prevents cachexia development by attenuating tumor-induced systemic pro-inflammatory condition with muscle oxidative stress and muscle damage.