ABSTRACT
INTRODUCTION: The perioperative cardiovascular management of patients undergoing noncardiac surgery is particularly challenging in those with pre-existing heart failure (HF). This study was designed to evaluate the effectiveness of nurse-based pre- and postoperative specialized HF management in reducing postoperative HF-associated complications in patients with known HF undergoing noncardiac surgery. METHODS: This prospective, randomized pilot study included patients with established HF requiring intermediate- to high-risk noncardiac surgery. Patients received postoperatively either standard care (control group, CG) or nurse-supported HF management (intervention group, IG). The primary endpoint was a composite of HF-related postoperative complications at 30 days. Secondary endpoints included length on intensive care unit, length of hospital stay, death, hospitalization for HF, and quality of life assessment using the SF-12 questionnaire. RESULTS: The trial was halted prematurely for futility. A total of 34 patients (median age 70.5 [IQR 67-75] years; with 15 HfpEF, 9 HfmrEF,10 HfrEF), with an average NT-proBNP of 1.413 [463-2.832] pg/mL were included. The IG had a lower rate of postoperative primary events (25%; n = 4) compared with the CG (33%; n = 6). There were no differences in secondary endpoints between the groups. Quality-of-life scores improved slightly in both groups (δ 5.6 ± 0.9 [CG] and 3.1 ± 1.2 [IG]). CONCLUSION: Nurse-based pre- and postoperative HF care appears to be feasible and may reduce HF-associated complications in patients undergoing noncardiac surgery. Larger clinical trials are needed to further evaluate the effectiveness of this approach in reducing postoperative complications in this high-risk patient population.
Subject(s)
Feasibility Studies , Heart Failure , Postoperative Complications , Quality of Life , Humans , Pilot Projects , Female , Male , Aged , Prospective Studies , Postoperative Complications/prevention & control , Postoperative Complications/etiology , Treatment Outcome , Postoperative Care/methods , Preoperative Care/methods , Surgical Procedures, Operative/adverse effects , Time Factors , Middle AgedABSTRACT
Introduction: Remote pulmonary artery pressure (PAP)-guided heart failure (HF) therapy for NYHA class III patients has been shown to reduce hospitalizations and increase survival. We aimed to assess whether PAP monitoring allows for the increase in HF directed medication in an elderly German cohort of advanced HF patients already receiving clinically optimized HF medication. Methods: We analyzed PAP and HF medication dosage, including diuretics, in 24 patients (mean age, 76 years) using implanted PAP-sensors during the first 12 months of PAP-guided HF care in an interdisciplinary HF unit. Results: During 12 months of PAP-guided HF therapy, PAP decreased significantly (â³PAP systolic−6 ± 10, â³PAP diastolic−4 ± 7, â³PAP mean−4 ± 8 mm Hg, p < 0.01 for all). 16% of patients had an unplanned HF hospitalization. There was no significant change over time with respect to the dosage of RAAS inhibitors (ACE-I/ARB/ARNI), Beta blockers, or MRA treatments. In contrast, the dosage of loop diuretics increased significantly (2.1 ± 0.5-fold) over time. In the comparison of a "responder" (patients with PAP and diuretic dose decline) and "non-responder" (patients with PAP and diuretic dose increase) group, there were no significant differences between any of the baseline, medication, or HF hospitalization characteristics between the two groups. Conclusions: In elderly patients treated with clinically optimized HF medication, no further evidence-based medication increase could be achieved using PAP-guided HF care. However, by individual adjustment of diuretic dosage, a significant decline in PAP over time occurred, which could not be predicted by any of the baseline characteristics.
ABSTRACT
Recent evidence reveals a crucial role for acetylcholine and its receptors in the regulation of inflammation, particularly of nicotinic acetylcholine receptor α7 (Chrna7) and muscarinic acetylcholine receptor 3 (Chrm3). Immunohistochemistry is a key tool for their cellular localization in functional tissues. We evaluated nine different commercially available antibodies on back skin tissue from wild-type (Wt) and gene-deficient (KO) mice. In the immunohistochemical analysis, we focused on key AChR-ligand sensitive skin cells (mast cells, nerve fibers and keratinocytes). All five antibodies tested for Chrm3 and the first three Chrna7 antibodies stained positive in both Wt and respective KO skin. With the 4th antibody (ab23832) nerve fibers were unlabeled in the KO mice. By western blot analysis, this antibody detected bands in both Wt and Chrna7 KO skin and brain. qRT-PCR revealed mRNA amplification with a primer set for the undeleted region in both Wt and KO mice, but none with a primer set for the deleted region in KO mice. By 2D electrophoresis, we found ß-actin and ß-enolase cross reactivity, which was confirmed by double immunolabeling. In view of the present results, the tested antibodies are not suitable for immunolocalization in skin and suggest thorough control of antibody specificity is required if histomorphometry is intended.
Subject(s)
Antibodies/immunology , Receptor, Muscarinic M3/metabolism , Skin/metabolism , alpha7 Nicotinic Acetylcholine Receptor/metabolism , Actins/metabolism , Animals , Antibody Specificity , Immunoblotting , Immunohistochemistry , Mast Cells/metabolism , Mice, Knockout , Phosphopyruvate Hydratase/metabolism , RNA, Messenger/metabolism , Receptor, Muscarinic M3/genetics , Receptor, Muscarinic M3/immunology , alpha7 Nicotinic Acetylcholine Receptor/genetics , alpha7 Nicotinic Acetylcholine Receptor/immunologyABSTRACT
Development of contact allergy requires cooperation of adaptive and innate immunity. Ni(2+) stimulates innate immunity via TLR4/MD2, the bacterial LPS receptor. This likely involves receptor dimerization, but direct proof is pending and it is unclear if related haptens share this mechanism. We reveal Co(2+) as second metal stimulating TLR4 and confirm necessity of H456/H458 therein. Experiments with a new TLR4 dimerization mutant established dimerization as a mechanism of metal- and LPS-induced TLR4 activation. Yet, in interaction studies only LPS- but not metal-induced dimerization required MD2. Consistently, soluble TLR4 expressed without MD2 inhibited metal- but not LPS-induced responses, opening new therapeutic perspectives.
Subject(s)
Cobalt/toxicity , Dermatitis, Allergic Contact , Lymphocyte Antigen 96 , Nickel/toxicity , Toll-Like Receptor 4 , Adaptive Immunity/genetics , Allergens/toxicity , Animals , Dermatitis, Allergic Contact/genetics , Dermatitis, Allergic Contact/immunology , Dermatitis, Allergic Contact/metabolism , Human Umbilical Vein Endothelial Cells/drug effects , Humans , Immunity, Innate/genetics , Inflammation/chemically induced , Inflammation/metabolism , Lipopolysaccharides/immunology , Lipopolysaccharides/metabolism , Lymphocyte Antigen 96/chemistry , Lymphocyte Antigen 96/genetics , Lymphocyte Antigen 96/metabolism , Mice , Mutant Proteins/chemistry , Mutant Proteins/genetics , Mutant Proteins/metabolism , Protein Multimerization , Signal Transduction/immunology , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , Toll-Like Receptor 4/chemistry , Toll-Like Receptor 4/genetics , Toll-Like Receptor 4/metabolismABSTRACT
Allergies to nickel (Ni(2+)) are the most frequent cause of contact hypersensitivity (CHS) in industrialized countries. The efficient development of CHS requires both a T lymphocyte-specific signal and a proinflammatory signal. Here we show that Ni(2+) triggered an inflammatory response by directly activating human Toll-like receptor 4 (TLR4). Ni(2+)-induced TLR4 activation was species-specific, as mouse TLR4 could not generate this response. Studies with mutant TLR4 proteins revealed that the non-conserved histidines 456 and 458 of human TLR4 are required for activation by Ni(2+) but not by the natural ligand lipopolysaccharide. Accordingly, transgenic expression of human TLR4 in TLR4-deficient mice allowed efficient sensitization to Ni(2+) and elicitation of CHS. Our data implicate site-specific human TLR4 inhibition as a potential strategy for therapeutic intervention in CHS that would not affect vital immune responses.
Subject(s)
Dermatitis, Contact , Nickel/immunology , Toll-Like Receptor 4/immunology , Amino Acid Sequence , Animals , Disease Models, Animal , Humans , Mice , Mice, Transgenic , Models, Molecular , Molecular Sequence Data , Recombinant Proteins/immunology , Signal Transduction , Toll-Like Receptor 4/geneticsABSTRACT
Primary endothelial cells are fully resistant to TNF-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. Here, we demonstrate that certain environmental conditions, such as exposure to the widespread allergen nickel, can dramatically increase the susceptibility of naturally resistant primary endothelial cells or keratinocytes to TRAIL-induced apoptosis. While nickel treatment increased surface expression of the apoptosis-inducing TRAIL receptors TRAIL-R1 and TRAIL-R2, it also up-regulated the apoptosis-deficient TRAIL-R4, suggesting that modulation of TRAIL receptor expression alone is unlikely to fully account for the dramatic sensitization effect of nickel. Further analysis of candidate mediators revealed that nickel strongly repressed c-FLIP at mRNA and protein levels. Accordingly, increased activation of Caspase-8 and Caspase-3 following nickel treatment was observed. Importantly, depletion of c-FLIP by RNA interference could largely recapitulate the effect of nickel and sensitize endothelial cells to TRAIL-dependent apoptosis in the absence of nickel pre-treatment. Conversely, ectopic expression of c-FLIP(L) largely protected nickel-treated cells from TRAIL-mediated apoptosis. Our data demonstrate that one key mechanism of sensitization of primary human endothelial cells or keratinocytes is transcriptional down-regulation of c-FLIP. We hypothesize that environmental factors, exemplified by the contact allergen nickel, strongly modulate death ligand sensitivity of endothelial cells and keratinocytes thus influencing vascular and epidermal function and integrity under physiological and pathophysiological conditions.