Search

Background: Augusto Bonome (1857–1922), professor at the University of Padua until 1922, was involved in a study about a particular kind of pulmonary leprosy, being the first to testify the lepromatous alterations also in the deepest parts of the respiratory tract, even though the same Gerhard Hansen (1841–1912) had denied the possibility that lungs could host Mycobacterium leprae. Objectives: It is necessary to reevaluate the research done by Bonome to also demonstrate how it can still be relevant today in further comprehension of leprosy. Methods: Bonome's advances in leprosy studies are testified by some specimens from the Morgagni Museum of Pathological Anatomy of the University of Padua. Among the specimens, there is a peculiar case of advanced tuberous leprosy in an adolescent, who died in 1908, of which the face, the larynx, the hands and genitals are still preserved today in the Museum. Results: Through autoptic and histological analysis of this specimen, Bonome succeeded in identifying a peculiar case of bone toxoid‐infectious dystrophy besides characteristic leprous laryngitis, which caused the death of the young leprosy patient. Conclusions: The results confirmed the innovative research carried on by Bonome during his medical career, being among the first to offer an important contribution to improving and revolutionary knowledge on leprosy which could still be useful today. [ABSTRACT FROM AUTHOR]

Summary: Atomic force microscopy (AFM) besides X‐ray crystallography and electron microscopy is one of the most attractive methods to study bio/nonbio complexes. Information on how biomacromolecules interact with nanomaterials under different environmental conditions has important implications for the practice of nanomedicine and concerning the safety of nanomaterials. These complexes cover a broad range both in terms of stability and composition. AFM offers a wealth of structural and functional data about such assemblies. The variety of samples investigated using AFM in biology includes nanometre‐sized proteins, lipids, DNA, amyloid fibrils, as well as larger objects such as cells. Herein we choose to review the significance of AFM to study various biological aspects of selected assemblies. We have focused on the exploitation of AFM operating in the air. The presented AFM research offers a unique and often unexpected insight into the structure and function of the bio/nonbio complexes. Lay Description: Atomic force microscopy (AFM) besides X‐ray crystallography and electron microscopy is one of the most attractive methods to study bio/nonbio complexes. Information on how biomacromolecules interact with nanomaterials under different environmental conditions has important implications for the practice of nanomedicine and concerning the safety of nanomaterials. These complexes cover a broad range both in terms of stability and composition. AFM offers a wealth of structural and functional data about such assemblies. The variety of samples investigated using AFM in biology includes nanometre‐sized proteins, lipids, DNA, amyloid fibrils, as well as larger objects such as cells. Herein we choose to review the significance of AFM to study various biological aspects of selected assemblies. The presented AFM research offers a unique and often unexpected insight into the structure and function of the bio/nonbio complexes. Nature has set us a perfect example of how to elegantly optimise and fine tune different types of processes. The relatively young field of nanotechnology has studied biological processes and exploited their unique strengths as novel materials. The resulting area of bionanotechnology has adopted interaction schemes presented to us by biology, to provide enhanced selectivity, efficiency or versatility of molecular attachment strategies. Two scenarios of this synergistic scheme are: the conjugation of nanostructures as a tool for research in biological science and the conjugation of biological particles as a tool for nanotechnology. The use of nanotechnologies for medical applications raises high expectations regarding diagnosis, drug delivery, gene therapy, and tissue engineering. There is an increasing number of reports using AFM as a nanodiagnostic tool with patient cells. The use of AFM, in combination with more conventional analytical approaches, could inform decisions related to recommendations for treatments. Applying AFM techniques in nanomedicine is becoming well established. Atomic force microscopy (AFM) is one of the most functional and powerful microscopy technology for studying biological and material samples at the nanoscale. It is advantageous because an atomic force microscope can image three‐dimensional topography of very small objects. It also provides various types of surface measurements to the needs of scientists and engineers if combined with other electromagnetic waves. It is powerful because an AFM can generate images at atomic resolution with 10‐9m scale resolution height information, with minimum sample preparation. AFM gives details on how biological molecules, such as nucleic acids, proteins, and amyloid aggregates, interact with nanomaterials under different environmental conditions. Here, we have shown several examples of relevant applications of AFM to study structural, functional and mechanical properties useful for the medicine and concerning the safety of nanomaterials. [ABSTRACT FROM AUTHOR]

Background and Objective Current evidence suggests that statins exert an anabolic effect on bone and may therefore impact on osteogenic differentiation and proliferation. These effects can be useful for their use in guided bone regeneration. The objective of this study was to determine the in vitro effects of simvastatin on the differentiation and proliferation of MG63 human osteoblast tumor cells. Material and Methods MG63 human osteosarcoma cells were cultured in the presence of simvastatin or solvent alone for 72 hours, and their proliferation was assessed by MTT assay. Cells from the culture were prepared for light, transmission and scanning electron microscopy studies. immunocytochemical was used to analyze the differentiation and proliferation markers Musashi-1, Ki-67, CD56 and CD44. Results Cultured MG63 control cells showed spheroid morphology with numerous secretion vesicles accumulated on the surface, observing no cytoplasmic projections with intercellular connections. However, cells cultured with simvastatin had a polygonal and spindle-shaped morphology, with cytoplasmic projections that interconnected cells. There were numerous microvilli-like filamentous projections on the surface with no defined pattern. At 72 hours of culture, CD56, Ki-67 and Musashi-1 expression was significantly reduced ( P < .001) in simvastatin-treated cells. CD44 expression was intense in both groups and was not affected by simvastatin treatment. Conclusion MG63 cells cultured with simvastatin for 72 hours undergo morphological and surface changes. Simvastatin treatment exerts antiproliferative and differentiating effects on these cells as well as promoting recovery of cellular homeostasis. [ABSTRACT FROM AUTHOR]

Neobenedenia melleni is a monogenean parasite that causes significant mortality and economic losses in fish aquaculture. Changes in the antigenic composition of this parasite occur during its developmental stages. In this study, we evaluated humoral parameters in serum and transcriptional immune responses of yellowtail naturally infected with N. melleni. In addition, in vitro assays were performed to study the stimulatory effects of antigens from larvae and adults on spleen leucocytes from non-infected fish at 6 and 24 h post-stimulation. The results showed enhanced total protein, myeloperoxidase and antiprotease activities in N. melleni-infected fish compared with non-infected ones. The induction of Toll-like receptors (TLRs) and pro-inflammatory cytokines in spleen leucocytes during natural infection with N. melleni suggests that these immune-related genes play an important role in the initiation of the immune defence mechanism for controlling parasite infection. Interestingly, the magnitude of in vitro responses of spleen leucocytes was dependent on the parasitic stage. An important stimulation of gene expression by adult antigens on spleen leucocytes was observed. Differential expression patterns of TLRs and target cytokines in yellowtail leucocytes in both in vivo and in vitro studies suggest that the quality of yellowtail immune response is conditioned by N. melleni development. [ABSTRACT FROM AUTHOR]

The loss in performance during fuel cell operation is one of the critical factors that hamper fuel cells commercialization. This paper presents a research activity related to high temperature polymer electrode membrane fuel cell (HT-PEMFC) degradation. The aim of the study is to investigate catalyst degradation of membrane electrode assemblies (MEAs) subjected to load cycles. Two HT-PEM MEAs have been subjected to accelerated ageing tests based on load cycling. The cycles profile has been chosen in order to enhance catalyst degradation. Both the tests show a fuel cell performance loss lower than 30mV after 100,000 cycles at 600 mA cm-2. In order to analyze the catalyst evolution, synchrotron small angle X-ray scattering (SAXS) has been employed. The catalyst degradation of the two conditioned samples has been compared with the data obtained from a new MEA that has been used as reference sample. The SAXS results showed a mean size increase of the platinum nanoparticles up to the 100%. [ABSTRACT FROM AUTHOR]

Twelve soil-preparation techniques used in afforestation were applied and 16 environmental variables were measured to test their effects on vegetation abundance, diversity, and cover in semiarid abandoned farmland located in southeastern Spain. The soil-preparation techniques consisted of punctual treatments-making a hole and constructing a plantation bench with different types of machinery; linear treatments-making furrows along contour lines; and surface treatments-that prepare the soil in general all over the plantation surface. Variables measured were the surface and volume affected by the soil-preparation treatments, distance from sample quadrats to the remnants of natural vegetation, surface runoff estimated by slope angle, and some edaphic characteristics such as gravel content, active lime, CaCO3, phosphorus, oxidizable organic matter, total soil nitrogen, pH, potassium, salinity, and clay, silt and sand content. The multivariate contrasts obtained demonstrated the existence of a significant relationship between species, samples and environmental variables. Both the distance of the quadrats from the remnants of natural vegetation and the volume of soil removed in different treatments were very weighty variables in the explanation of the variance of data, negatively affecting overall vegetation development. The accumulation or loss of surface runoff and the CaCO3 content in soil were also important variables to explain abundance and diversity data. However, not all the species responded to the variables analysed in the same way. Identification of non-uniform spatial patterns that significantly affect vegetation suggests that afforestation policies and conservation and management strategies in these semiarid abandoned lands should always take into consideration the quality of the whole landscape. Voluminous soil treatments for afforestation should be avoided. Copyright © 2006 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Functional dendritic cells (DC) are professional antigen-presenting cells (APC) and can be generated in vitro from healthy as well as from leukaemic cells from acute myeloid leukemia (AML) patients giving rise to APC of leukaemic origin-presenting leukaemic antigens. We describe the generation and characterization of DC from different mononuclear cell (MNC) fractions from 50 AML patients under different serum-free culture conditions, determine the optimal culture conditions and compare the results with that from 23 healthy donors. In parallel cultures, we compared DC harvests after 7- or 14-day culture, with total or adherent MNC or T-cell depleted MNC or peripheral blood (PB) or bone marrow-MNC (BM–MNC), thawn or fresh MNC, in Xvivo or CellGro serum-free media, ±10% autologous plasma or ±FL. In detail, we could show that AML–DC harvests were higher after 10–14 days culture (healthy DC: 7 days); total or adherent PB or BM–MNC fractions yield comparable DC counts, however, from magnetic cell sorting (MACS)-depleted MNC fractions or thawn MNC lower DC counts can be generated. Whereas the addition of FL increases the DC harvest, the addition of autologous plasma in many cases has inhibitory influence on DC maturation. CellGro and Xvivo media yield comparable DC counts. Optimal harvest of vital and mature DC from AML samples was obtained with a granulocyte/macrophage-colony stimulating factor, interleukin-4, FL and tumour necrosis factor-α-containing serum-free Xvivo medium after 10–14 days of culture (36/26% DC; 38/64% vital DC; 46/51% mature DC were generated from AML/healthy MNC samples). Surface marker profiles (e.g. costimulatory antigen expressing) of DC obtained from AML samples were comparable with that of healthy DC. The leukaemic derivation of AML–DC was demonstrated by the persistence of the clonal cytogenetic aberration in the DC or by coexpression of leukaemic antigens on DC. Autologous T-cell activation of leukaemia-derived DC was demonstrated in cases with AML. Autologous T cells proliferate and upregulate DC-contact-relevant antigens. We demonstrate that the generation of leukaemia-derived DC is feasable in AML under serum-free culture conditions giving rise to DC with comparable characteristics as healthy DC and offering an anti-leukaemia-directed immunotherapeutical vaccination strategy in AML. [ABSTRACT FROM AUTHOR]

Functional dendritic cells (DC) are professional antigen-presenting cells (APC) and can be generated in vitro from healthy as well as from leukaemic cells from AML patients giving rise to APC of leukaemic origin presenting leukaemic antigens. In a comparative methodological analysis of 50 AML samples, we could already show that leukaemia-derived DC can regularly be generated under serum-free culture conditions. In this study, we describe the generation and characterization of DC from different mononuclear cell (MNC) fractions from 24 myelodysplastic syndrome (MDS) patients under those different serum-free culture conditions, determine the optimal culture conditions and compare the results with that from 23 healthy donors. In parallel cultures, we compared DC harvests after 7- or 14-day culture, with total or adherent MNC or T-cell-depleted MNC or PB or BM–MNC, thawn or fresh MNC, in Xvivo or CellGro serum-free media, ±10% autologous plasma or ±FL. In detail, we could show that MDS–DC harvests compared to healthy DC were higher after 10- to 14-day culture; total or adherent PB or BM–MNC fractions yield comparable DC counts; however, from MACS-depleted MNC fractions or thawn MNC lower DC counts can be generated. Whereas the addition of FL increases the DC harvest, the addition of autologous plasma in many cases has inhibitory influence on DC maturation, CellGro and Xvivo media yield comparable DC counts. Optimal harvest of vital and mature DC from MDS samples was obtained with a GM-CSF, IL-4, FL and TNF-α containing serum-free Xvivo medium after 10–14 days of culture (18/26% DC; 54/64% vital DC; 59/51% mature DC were generated from MDS/healthy MNC samples). Surface marker profiles (e.g. costimulatory antigen expression) of DC obtained from MDS samples were comparable with that of healthy DC. The leukaemic derivation of MDS–DC was demonstrated by the persistence of the clonal cytogenetic aberration in the DC or by coexpression of leukaemic antigens on DC. Autologous T-cell activation of leukaemia-derived DC was demonstrated in cases with MDS. Autologous T cells proliferate and upregulate DC-contact-relevant antigens. We are the first who demonstrate that the generation of leukaemia-derived DC is feasible not only in AML but also in MDS under serum-free culture conditions giving rise to DC with comparable characteristics as healthy DC and offering an antileukaemia-directed immunotherapeutical vaccination strategy in AML and MDS. [ABSTRACT FROM AUTHOR]

Porcelains represent the foundation of the ceramic discipline. The variable-phase assembly within porcelains makes these materials very complex ceramics. Fine porcelains from Buen Retiro were produced between 1760 and 1808 by Spanish court ceramists. The factory and its records were totally destroyed in 1812 during the Peninsular War. Recently, some pieces of porcelain and remains of whiteware belonging to the ancient factory were discovered during an excavation. In the present work, some of the secret formulas that enabled the Spanish ceramists to produce porcelains have been investigated by quantitative full-phase analysis (including amorphous content) using the Rietveld method. Three porcelains belonging to the Sureda period (1803–1808) and another from an earlier time of the factory (1760–1783) have been analyzed. The phase results are discussed and conclusions are derived by using appropriate phase equilibrium diagrams. It has also been found that the Rietveld quantitative amorphous content analysis is effective in determining the glassy content in porcelains. [ABSTRACT FROM AUTHOR]

Most sample preparation methods for scanning probe or electron microscopy require that biomolecules, such as proteins, be fixed. Fixation destroys the molecular functionality and can possibly affect the true molecular structure. Here we report sample preparation conditions that allow the imaging of an unfixed protein, GroEL, under in-vivo conditions, by atomic force microscopy. Under these conditions, the protein should maintain its native structure and biological activity. The typical toroidal shape with pore of the GroEL complex was easily visible in the images. Images of a single complex show dimensions that agree well with crystallographic data. Under in-vivo conditions, it should be possible to study the biological activity and function of proteins. [ABSTRACT FROM AUTHOR]

Determines the plasma concentration of LH and progesterone in ewes of the Canadian breed during the follicular phase of a synchronized cycle. Presence of preovulatory follicles at all times throughout the estrus cycle and during the anestrus state; Stopping of follicular growth by degenerative changes called atresia.

The nutritional qualities of soybean proteins are basically determined by amino acid patterns, amino acid availabilities (digestibility) and contents of biologically active components. Of these factors, the last two are most affected by processing conditions, whereas amino acid analysis is least affected, although it too may be modified in those cases in which soybean proteins are fractionated. In the preparation of the large variety of soya products presently available, soybeans are subjected to many different processes, all of which are discussed. Heat treatment appears to be the process which most affects protein nutritional quality; generally, quality first increases with heat treatment due to inactivation of biologically active factors, passes through a maximum and then decreases due to destruction and/or inactivation of essential amino acids such as cystine and lysine. Other processes affect protein nutritional quality to different degrees, inasmuch as they affect amino acid analysis, digestibility and content of biologically active components. When soybean proteins are used to extend animal proteins, supplement other vegetable proteins, or in vegetable protein mixtures, nutritional quality of the combined proteins appears to be affected in the same manner as that of soya proteins alone. [ABSTRACT FROM AUTHOR]

The nutritional qualities of soybean proteins are basically determined by amino acid patterns, amino acid availabilities (digestibility) and contents of biologically active components. Of these factors, the last two are most affected by processing conditions, whereas amino acid analysis is least affected, although it too may be modified in those cases in which soybean proteins are fractionated. In the preparation of the large variety of soya products presently available, soybeans are subjected to many different processes, all of which are discussed. Heat treatment appears to be the process which most affects protein nutritional quality; generally, quality first increases with heat treatment due to inactivation of biologically active factors, passes through a maximum and then decreases due to destruction and/or inactivation of essential amino acids such as cystine and lysine. Other processes affect protein nutritional quality to different degrees, inasmuch as they affect amino acid analysis, digestibility and content of biologically active components. When soybean proteins are used to extend animal proteins, supplement other vegetable proteins, or in vegetable protein mixtures, nutritional quality of the combined proteins appears to be affected in the same manner as that of soya proteins alone. [ABSTRACT FROM AUTHOR]

Background: The role of cellular senescence in human heart failure (HF) remains unclear. The senescence-associated secretory phenotype (SASP) is composed of proteins released by senescent cells. We assessed the prognostic significance and biologic pathways associated with the SASP in human HF using a plasma proteomics approach., Methods and Results: We measured 25 known SASP proteins among 2248 PHFS (Penn HF Study) participants using the SOMAScan V4 assay. We extracted the common variance in these proteins to generate SASP factor scores and assessed the relationship between these SASP factor scores and (1) all-cause death and (2) the composite of death or HF hospital admission. We also assessed the relationship of each SASP factor to 4746 other proteins, correcting for multiple comparisons, followed by pathway analyses. Two SASP factors were identified. Both factors were associated with older age, lower estimated glomerular filtration rate, and more advanced New York Heart Association class, among other clinical variables. Both SASP factors exhibited a significant positive association with the risk of death independent of the Meta-Analysis of Global-Group in Chronic HF score and NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels. The 2 identified SASP factors were associated with 1201 and 1554 proteins, respectively, belonging to various pathways including the coagulation system, complement system, acute phase response signaling, and retinoid X receptor-related pathways that regulate cell metabolism., Conclusions: Increased SASP components are independently associated with adverse outcomes in HF. Biologic pathways associated with SASP are predominantly related to coagulation, inflammation, and cell metabolism.

Background: Kidney disease is common in heart failure with preserved ejection fraction (HFpEF). However, the biologic correlates and prognostic significance of kidney injury (KI), in HFpEF, beyond the estimated glomerular filtration rate (eGFR), are unclear., Methods and Results: Using baseline plasma samples from the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial, we measured the following KI biomarkers: cystatin-C, fatty acid-binding protein-3, Beta-2 microglobulin, neutrophil gelatinase-associated lipocalin, and kidney-injury molecule-1. Factor analysis was used to extract the common variability underlying these biomarkers. We assessed the relationship between the KI-factor score and the risk of death or HF-related hospital admission in models adjusted for the Meta-Analysis Global Group in Chronic Heart Failure risk score and eGFR. We also assessed the relationship between the KI factor score and ~5000 plasma proteins, followed by pathway analysis. We validated our findings among HFpEF participants in the Penn Heart Failure Study. KI was associated with the risk of death or HF-related hospital admission independent of the Meta-Analysis Global Group in Chronic Heart Failure risk score and eGFR. Both the risk score and eGFR were no longer associated with death or HF-related hospital admission after adjusting for the KI factor score. KI was predominantly associated with proteins and biologic pathways related to complement activation, inflammation, fibrosis, and cholesterol homeostasis. KI was associated with 140 proteins, which reproduced across cohorts. Findings regarding biologic associations and the prognostic significance of KI were also reproduced in the validation cohort., Conclusions: KI is associated with adverse outcomes in HFpEF independent of baseline eGFR. Patients with HFpEF and KI exhibit a plasma proteomic signature indicative of complement activation, inflammation, fibrosis, and impaired cholesterol homeostasis.

Prognostication in acute pulmonary embolism (PE) requires reliable markers. While cellular indices such as neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII) appear promising, their utility in PE prognostication needs further exploration. We utilized data from the RIETE registry and the Loyola University Medical Center (LUMC) to assess the prognostic value of NLR, PLR, and SII in acute PE, using logistic regression models. The primary outcome was 30-day all-cause mortality. We compared their prognostic value versus the simplified Pulmonary Embolism Severity Index (sPESI) alone. We included 10 085 patients from RIETE and 700 from the LUMC. Thirty-day mortality rates were 4.6% and 8.3%, respectively. On multivariable analysis, an elevated NLR (>7.0) was associated with increased mortality (adjusted odds ratio [aOR]: 3.46; 95% CI: 2.60-4.60), outperforming the PLR > 220 (aOR: 2.36; 95% CI: 1.77-3.13), and SII > 1600 (aOR: 2.52; 95% CI: 1.90-3.33). The c-statistic for NLR in patients with low-risk PE was 0.78 (95% CI: 0.69-0.86). Respective numbers were 0.66 (95% CI: 0.63-0.69) and 0.68 (95% CI: 0.59-0.76) for intermediate-risk and high-risk patients. These findings were mirrored in the LUMC cohort. Among 9810 normotensive patients in RIETE, those scoring 0 points in sPESI and with an NLR ≤ 7.0 (35% of the population) displayed superior sensitivity (97.1%; 95% CI: 95.5-98.7) and negative predictive value (99.7%; 95% CI: 99.5-99.8) than sPESI alone (87.1%; 95% CI: 83.9-90.3, and 98.7%; 95% CI: 98.4-99.1, respectively) for 30-day mortality. The NLR is a significant prognostic marker for 30-day mortality in PE patients, especially useful to identify patients with very low-risk PE., (© 2024 Wiley Periodicals LLC.)

Background: Although several studies have addressed plasma proteomics in heart failure with preserved ejection fraction, limited data are available on the prognostic value of urinary proteomics. The objective of our study was to identify urinary proteins/peptides associated with death and heart failure admission in patients with heart failure with preserved ejection fraction., Methods and Results: The study population included participants enrolled in TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial). The relationship between urine protein levels and the risk of death or heart failure admission was assessed using Cox regression, in both nonadjusted analyses and adjusting for urine creatinine levels, and the MAGGIC (Meta-Analysis Global Group in Chronic Heart Failure) score. A total of 426 (12.4%) TOPCAT participants had urinary protein data and were included. There were 40 urinary proteins/peptides significantly associated with death or heart failure admission in nonadjusted analyses, 21 of which were also significant adjusted analyses. Top proteins in the adjusted analysis included ANGPTL2 (angiopoietin-like protein 2) (hazard ratio [HR], 0.5731 [95% CI, 0.47-0.7]; P =3.13E-05), AMY2A (α amylase 2A) (HR, 0.5496 [95% CI, 0.44-0.69]; P =0.0001), and DNASE1 (deoxyribonuclease-1) (HR, 0.5704 [95% CI, 0.46-0.71]; P =0.0002). Higher urinary levels of proteins involved in fibrosis (collagen VI α-1, collagen XV α-1), metabolism (pancreatic α-amylase 2A/B, mannosidase α class 1A member 1), and inflammation (heat shock protein family D member 1, inducible T cell costimulatory ligand) were associated with a lower risk of death or heart failure admission., Conclusions: Our study identifies several novel associations between urinary proteins/peptides and outcomes in heart failure with preserved ejection fraction. Many of these associations are independent of clinical risk scores and may aid in risk stratification in this patient population.

Background: Identifying novel molecular drivers of disease progression in heart failure (HF) is a high-priority goal that may provide new therapeutic targets to improve patient outcomes. The authors investigated the relationship between plasma proteins and adverse outcomes in HF and their putative causal role using Mendelian randomization., Methods and Results: The authors measured 4776 plasma proteins among 1964 participants with HF with a reduced left ventricular ejection fraction enrolled in PHFS (Penn Heart Failure Study). Assessed were the observational relationship between plasma proteins and (1) all-cause death or (2) death or HF-related hospital admission (DHFA). The authors replicated nominally significant associations in the Washington University HF registry (N=1080). Proteins significantly associated with outcomes were the subject of 2-sample Mendelian randomization and colocalization analyses. After correction for multiple testing, 243 and 126 proteins were found to be significantly associated with death and DHFA, respectively. These included small ubiquitin-like modifier 2 (standardized hazard ratio [sHR], 1.56; P <0.0001), growth differentiation factor-15 (sHR, 1.68; P <0.0001) for death, A disintegrin and metalloproteinase with thrombospondin motifs-like protein (sHR, 1.40; P <0.0001), and pulmonary-associated surfactant protein C (sHR, 1.24; P <0.0001) for DHFA. In pathway analyses, top canonical pathways associated with death and DHFA included fibrotic, inflammatory, and coagulation pathways. Genomic analyses provided evidence of nominally significant associations between levels of 6 genetically predicted proteins with DHFA and 11 genetically predicted proteins with death., Conclusions: This study implicates multiple novel proteins in HF and provides preliminary evidence of associations between genetically predicted plasma levels of 17 candidate proteins and the risk for adverse outcomes in human HF.