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Serial galectin-3 for the monitoring of optimally treated stable chronic heart failure: A pilot study
... Previous studies identified Gal-3 as a proinflammatory protein that regulates immune responses [24][25][26]. Gal-3 is associated with inflammatory diseases such as systemic lupus erythematosus, rheumatoid arthritis, and systemic sclerosis, and Gal-3 inhibition is associated with neuropathic pain attenuation [27][28][29][30]. Gal-3 also modulated TLR pathways in synovial fibroblasts [31]. ...
... After stimulation with pathogens or LPS, Gal-3 can be detected both intracellularly and extracellularly [58,59]. Gal-3 is involved in both inflammation and neuropathic pain [27][28][29][30]. TLR-4 is correlated with noninfectious inflammatory diseases. ...
Hyperbaric oxygen (HBO) treatment has been proven to decrease neuroinflammation in rats. This study aimed to determine the potential mechanism underlying the anti-inflammatory effects of HBO treatment on burn-induced neuroinflammation in rats. Thirty-six adult male Sprague-Dawley (SD) rats were randomly assigned to the following six groups (n = 6 per group): (1) sham burn with sham HBO treatment; (2) sham burn with HBO treatment; (3) burn with one-week sham HBO treatment; (4) burn with two-week sham HBO treatment; (5) burn with one-week HBO treatment; and (6) burn with two-week HBO treatment. SD rats that received third-degree burn injury were used as a full-thickness burn injury model. Subsequently, we analyzed the expression of proteins involved in the galectin-3 (Gal-3)-dependent Toll-like receptor-4 (TLR-4) pathway through enzyme-linked immunosorbent assay (ELISA), immunohistochemistry (IHC) analysis, and Western blotting. A behavior test was also conducted, which revealed that HBO treatment significantly suppressed mechanical hypersensitivity in the burn with HBO treatment group compared to the burn with sham HBO treatment group (p < 0.05). ELISA results showed that tumor necrosis factor α (TNF-α) and interleukin 1 beta (IL-1β) levels in the dorsal horn of the spinal cord and the skin significantly decreased in the burn with HBO treatment group compared with the burn with sham HBO treatment group (p < 0.05). Western blotting results demonstrated that HBO treatment significantly reduced the expression of Gal-3 and TLR-4 in the dorsal horn of the spinal cord in the burn with HBO treatment group compared with the burn with sham HBO treatment group (p < 0.05). IHC analysis showed that the expression of Gal-3, TLR-4, CD68 and CD45 in the dorsal horn of the spinal cord was significantly lower in the burn with HBO treatment group than in the burn with sham HBO treatment group (p < 0.05), and the expression of CD68 and macrophage migration inhibitory factor (MIF) in the right hind paw skin was significantly lower. The expression of vimentin and fibroblast growth factor in the right hind paw skin was significantly higher after HBO treatment (p < 0.05). This study proved that early HBO treatment relieves neuropathic pain, inhibits the Gal-3-dependent TLR-4 pathway, and suppresses microglia and macrophage activation in a rat model.
... Previous studies have identified Gal-3 as a proinflammatory protein that regulates immune responses [25][26][27]. Gal-3 is associated with inflammatory diseases such as systemic lupus erythematosus, rheumatoid arthritis, and systemic sclerosis, and Gal-3 inhibition is associated with neuropathic pain attenuation [28][29][30][31]. Gal-3 also modulated TLR pathways in synovial fibroblasts [32]. ...
... After stimulation with pathogens or LPS, Gal-3 can be detected intracellularly and extracellularly [59,60]. Gal-3 is involved in both inflammation and neuropathic pain [28][29][30][31]. TLR-4 is correlated to noninfectious inflammatory diseases. ...
Hyperbaric oxygen (HBO) treatment has been proven to attenuate neuroinflammation in rats. This study aimed to determine the potential mechanism underlying the anti-inflammatory effects of HBO treatment on burn-induced neuroinflammation in rats. Thirty-six adult male Sprague–Dawley (SD) rats were randomly assigned to the following six groups (n = 6 per group): (1) sham burn with sham HBO treatment, (2) sham burn with HBO treatment, (3) burn with 1-week sham HBO treatment, (4) burn with 2-week sham HBO treatment, (5) burn with 1-week HBO treatment, and (6) burn with 2-week HBO treatment. SD rats that received third-degree burn injury were used as a full-thickness burn injury model. Subsequently, we analyzed the expression of proteins involved in the galectin-3 (Gal-3)-dependent Toll-like receptor-4 (TLR-4) pathway through enzyme-linked immunosorbent assay (ELISA), immunohistochemistry (IHC) analysis, and Western blotting, and a behavior test was also conducted. The behavior test revealed that HBO treatment significantly suppressed mechanical hypersensitivity in the burn with HBO treatment group compared with the burn with sham HBO treatment group (p < 0.05). ELISA results showed that tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β) levels in the dorsal horn of the spinal cord and the skin were significantly decreased in the burn with HBO treatment group compared with the burn with sham HBO treatment group (p < 0.05). Western blotting results demonstrated that HBO treatment significantly reduced the expression of Gal-3 and TLR-4 in the dorsal horn of the spinal cord in the burn with HBO treatment group compared with the burn with sham HBO treatment group (p < 0.05). IHC analysis results showed that the expression of Gal-3, TLR-4, CD68, and CD45 in the dorsal horn of the spinal cord was significantly lower in the burn with HBO treatment group than in the burn with sham HBO treatment group (p < 0.05), and the expression of CD68 and macrophage migration inhibitory factor (MIF) in the right hind paw skin was significantly lower. The expression of vimentin and fibroblast growth factor (FGF) in the right hind paw skin was significantly higher after HBO treatment (p < 0.05). This study proved that early HBO treatment relieves neuropathic pain, inhibits the Gal-3-dependent TLR-4 pathway, and suppresses microglia/macrophage activation in a rat model.
... Recently, it is identified as a proinflammatory protein and modulates immune responses either as damage-associated molecular patterns or as pattern recognition receptors (Arad et al., 2015;Li et al., 2008;Zhang et al., 2015). Increased circulating levels of galectin-3 are associated with inflammatory severity in some inflammatory diseases, for example, systemic lupus erythematosus, rheumatoid arthritis, heart failure, and systemic sclerosis (Koca et al., 2014;Nielsen et al., 2014;Ohshima et al., 2003;Piper, de Courcey, Sherwood, Amin-Youssef, & McDonagh, 2016). Of note, activated glia can express galectin-3 during neuroinflammation (Boza-Serrano et al., 2014;Chen, Liao, Lin, & Liu, 2014;Sirko et al., 2015). ...
... Galectin-3 is reported to be involved in inflammation (Koca et al., 2014;Nielsen et al., 2014;Ohshima et al., 2003;Piper et al., 2016). ...
Objective
Inflammation correlates with delirium. Galectin‐3 is a proinflammatory protein. This study aimed to determine relation of serum galectin‐3 levels to delirium of postpartum intensive care unit (ICU) women.
Materials and Methods
In this prospective observational study, serum galectin‐3, S100B, and C‐reactive protein levels of 412 postpartum ICU women and 412 healthy women were measured. Delirium and Acute Physiology and Chronic Health Care Evaluation II (APCHCE II) scores were recorded.
Results
Serum levels of galectin‐3, S100B, and C‐reactive protein were significantly elevated in the postpartum women than in the healthy women. Galectin‐3 levels were highly associated with APCHCE II scores and S100B and C‐reactive protein levels. Galectin‐3, C‐reactive protein, and S100B levels and APCHCE II scores were identified as independent predictors for delirium. Area under the curve (AUC) of serum galectin‐3 levels was similar to that of S100B levels, and significantly exceeded those of C‐reactive protein levels and APCHCE II scores. Moreover, galectin‐3 significantly improved the AUCs of APCHCE II scores, S100B levels, and C‐reactive protein levels.
Conclusions
Galectin‐3, involved in inflammatory process underlying delirium‐related brain injury, might be a potential biomarker to predict delirium of postpartum ICU women.
... In addition to its unique biological niche, galectin 3 dysregulation has also been observed in a wide variety of disease contexts from cancer to diabetes and heart disease (45)(46)(47)(48)(49)(50)(51)(52). Hence, understanding the molecular mechanisms driven by galectin-glycan interactions and how galectin 3 secretion is modulated will provide us with valuable insights into how galectins and glycosylation drive the progression of several diseases and how the nutritional environment can impact disease progression. ...
Endomembrane glycosylation and cytoplasmic O-GlcNAcylation each play essential roles in nutrient sensing, and characteristic changes in glycan patterns have been described in disease states such as diabetes and cancer. These changes in glycosylation have important functional roles and can drive disease progression. However, little is known about the molecular mechanisms underlying how these signals are integrated and transduced into biological effects. Galectins are proteins that bind glycans and that are secreted by a poorly characterized non-classical secretory mechanism. Once outside the cell, galectins bind to the terminal galactose residues of cell surface glycans and modulate numerous extracellular functions, such as clathrin-independent endocytosis (CIE). Originating in the cytoplasm, galectins are predicted substrates for O-GlcNAc addition and removal; and, as we have shown, galectin 3 is a substrate for OGT. In this study, we also show that galectin 3 secretion is sensitive to changes in O-GlcNAc levels. We determined using immunoprecipitation and western blotting that there is a significant difference in O-GlcNAcylation status between cytoplasmic and secreted galectin 3. We observed dramatic alterations in galectin 3 secretion in response to nutrient conditions which were dependent on dynamic O-GlcNAcylation. Importantly, we showed that these O-GlcNAc-driven alterations in galectin 3 secretion also facilitated changes in CIE. These results indicate that dynamic O-GlcNAcylation of galectin 3 plays a role in modulating its secretion, and can tune its function in transducing nutrient-sensing information coded in cell surface glycosylation into biological effects.
... In addition to its unique biological niche, galectin 3 dysregulation has also been observed in a wide variety of disease contexts from cancer to diabetes and heart disease (45)(46)(47)(48)(49)(50)(51)(52). Hence, understanding the molecular mechanisms driven by galectin-glycan interactions and how galectin 3 secretion is modulated will provide us with valuable insights into how galectins and glycosylation drive the progression of several diseases. ...
Endomembrane glycosylation and cytoplasmic O-GlcNAcylation each play essential roles in nutrient sensing, and in fact, characteristic changes in glycan patterns have been described in disease states such as diabetes and cancer. These changes in glycosylation have important functional roles and can drive disease progression. However, little is known about the molecular mechanisms underlying how these signals are integrated and transduced into biological effects. Galectins are proteins that bind glycans that are secreted by a poorly characterized non-classical secretory mechanism. Once outside the cell, galectins bind to terminal galactose residues of cell surface glycans and modulate numerous extracellular functions like clathrin independent endocytosis (CIE). Originating in the cytoplasm, galectins are predicted substrates for O-GlcNAc addition and removal. This study shows that galectin 3 is O-GlcNAcylated, and that changes in O-GlcNAc cycling alters its secretion. Moreover, we determined that there is a significant difference in O-GlcNAcylation status between cytoplasmic and secreted galectin 3. We observed dramatic alterations in galectin 3 secretion in response to nutrient conditions and that these changes were dependent on dynamic O-GlcNAcylation. Finally, we showed that alterations in galectin 3 secretion via disrupted O-GlcNAcylation drove changes in CIE. These results indicate that dynamic O-GlcNAcylation of galectin 3 plays a role in modulating its secretion and can tune its function of transducing nutrient sensing information coded in cell surface glycosylation into biological effects.
... Elevated serum galectin 3 levels are also associated with almost all types of cardiovascular disease and are generally a prognostic marker for poorer outcomes. [60][61][62] High levels of circulating galectin 3 were found to be associated with depression in patients with type 1 diabetes. 63 Elevated serum levels of galectin 3 are also found to precede chronic kidney disease 64 and are known to be associated with schizophrenia. ...
In contrast to clathrin mediated endocytosis (CME) which is well characterized and understood, little is known about the regulation and machinery underlying clathrin independent endocytosis (CIE). There is also a wide variation in the requirements each individual CIE cargo has for its internalization. Recent studies have shown that CIE is affected by glycosylation and glycan interactions. We briefly review these studies and explore how these studies mesh with one another. We then discuss what this sensitivity to glycan interactions could indicate for the regulation of CIE. We address the spectrum of responses CIE has been shown to have with respect to changes in glycan interactions and attempt to reconcile disparate observations onto a shared conceptual landscape. We focus on the mechanisms by which cells can alter the glycan interactions at the plasma membrane and propose that glycosylation and glycan interactions could provide cells with a tool box with which cells can manipulate CIE. Altered glycosylation is often associated with a number of diseases and we discuss how under different disease settings, glycosylation‐based modulation of CIE could play a role in disease progression.
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... 8,9 Gal-3 has been shown to have direct and indirect effect on cardiac fibrosis and has been studied extensively in the context of heart failure, in which it was found to be a relatively sensitive and specific marker of ventricular dysfunction, as well as mortality. [10][11][12] FGF-23, principally studied in the context of its action on phosphate homeostasis in kidney disease and heart failure, has been associated with AF, increased LV mass, and cardiovascular death. [13][14][15] Results of studies assessing its association with incident AF are mixed. ...
Aims: Measurement of circulating biomarkers of fibrosis may have a role in selecting patients and treatment strategy for catheter ablation. Pro-collagen type III N-terminal pro-peptide (PIIINP), C-telopeptide of type I collagen (ICTP), fibroblast growth factor 23 (FGF-23), and galectin 3 (gal-3) have all been suggested as possible biomarkers for this indication, but studies assessing whether peripheral levels reflect intra-cardiac levels are scarce. Methods and results: We studied 93 patients undergoing ablation for paroxysmal atrial fibrillation (AF) (n = 63) or non-paroxysmal AF (n = 30). Femoral venous, left and right atrial, and coronary sinus blood were analysed using ELISA to determine biomarker levels. Levels were compared with control patients (n = 36) and baseline characteristics, including left atrial voltage mapping data. C-telopeptide of type I collagen levels were higher in AF than in non-AF patients (P = 0.007). Peripheral ICTP levels were higher than all intra-cardiac levels (P < 0.001). Peripheral gal-3 levels were higher than left atrial levels (P = 0.001). Peripheral levels of FGF-23 and PIIINP were not significantly different from intra-cardiac levels. CS levels of ICTP were higher than right and left atrial levels (P < 0.001). gal-3 was higher in women vs. men (P ≤ 0.001) and with higher body mass index (P ≤ 0.001). ICTP levels increased with reducing ejection fraction (P ≤ 0.012). Conclusions: Atrial fibrillation patients have higher levels of circulating ICTP than matched non-AF controls. In AF ablation patients, intra-cardiac sampling of FGF-23 or PIIINP gives no further information over peripheral sampling. For gal-3 and ICTP, intra-cardiac sampling may be necessary to assess their association with intra-cardiac processes. None of the biomarkers is related to fibrosis assessed by left atrial voltage.
... However, HF therapeutic strategies including angiotensin-converting-enzyme inhibitors, angiotensin II receptor blockers and thiazide diuretic exhibited no clear effects on galectin-3 expression levels (29). In patients with stable chronic HF, the change in galectin-3 expression levels over time, including that at 6 months, are improved predictors of cardiovascular events compared with baseline galectin-3 levels (36). In contrast, Miller et al (37) identified that serial galectin-3 monitoring in ambulatory HF patients provided no additional prognostic benefit. ...
Galectin-3 is a member of the galectin family, which are β‑galactoside‑binding lectins with ≥1 evolutionary conserved carbohydrate‑recognition domain. It binds proteins in a carbohydrate‑dependent and ‑independent manner. Galectin‑3 is predominantly located in the cytoplasm; however, it shuttles into the nucleus and is secreted onto the cell surface and into biological fluids including serum and urine. It serves important functions in numerous biological activities including cell growth, apoptosis, pre‑mRNA splicing, differentiation, transformation, angiogenesis, inflammation, fibrosis and host defense. Numerous previous studies have indicated that galectin‑3 may be used as a diagnostic or prognostic biomarker for certain types of heart disease, kidney disease and cancer. With emerging evidence to support the function and application of galectin‑3, the current review aims to summarize the latest literature regarding the biomarker characteristics and potential therapeutic application of galectin‑3 in associated diseases.
... 8,9 Gal-3 has been shown to have direct and indirect effects on cardiac fibrosis and has been studied extensively in the context of heart failure, in which it was found to be a relatively sensitive and specific marker of ventricular dysfunction, as well as mortality. [10][11][12] Fibroblast growth factor 23, principally studied in the context of its action on phosphate homeostasis in kidney disease and heart failure, has been associated with AF, increased LV mass, and cardiovascular death. [13][14][15] Results of studies assessing its association with incident AF are mixed. ...
Measurement of circulating biomarkers of fibrosis may have a role in selecting patients and treatment strategy for catheter ablation. Pro-collagen type III N-terminal pro-peptide (PIIINP), C-telopeptide of type I collagen (ICTP), fibroblast growth factor 23 (FGF-23), and galectin 3 (gal-3) have all been suggested as possible biomarkers for this indication, but studies assessing whether peripheral levels reflect intra-cardiac levels are scarce.
We studied 93 patients undergoing ablation for paroxysmal atrial fibrillation (AF) (n = 63) or non-paroxysmal AF (n = 30). Femoral venous, left and right atrial, and coronary sinus blood were analysed using ELISA to determine biomarker levels. Levels were compared with control patients (n = 36) and baseline characteristics, including left atrial voltage mapping data. C-telopeptide of type I collagen levels were higher in AF than in non-AF patients (P = 0.007). Peripheral ICTP levels were higher than all intra-cardiac levels (P < 0.001). Peripheral gal-3 levels were higher than left atrial levels (P = 0.001). Peripheral levels of FGF-23 and PIIINP were not significantly different from intra-cardiac levels. CS levels of ICTP were higher than right and left atrial levels (P < 0.001). gal-3 was higher in women vs. men (P ≤ 0.001) and with higher body mass index (P ≤ 0.001). ICTP levels increased with reducing ejection fraction (P ≤ 0.012).
Galectin-3 is a chimeric galectin involved in diverse intracellular and extracellular functions. Galectin-3 is synthesized in the cytoplasm and then released extracellularly by a poorly understood non-canonical secretion mechanism. As a result, it can play important roles both inside and outside the cell. One important extracellular role of galectin-3 is in modulating clathrin-independent endocytosis (CIE), a form of cellular internalization that is still not well understood. CIE, unlike clathrin-mediated endocytosis, has neither defined signaling sequences nor cytoplasmic machinery. As a result, extracellular interactions like the galectin-glycan interactions are thought to directly drive changes in CIE. This chapter discusses the methods designed to study the role of galectin-glycan interactions in CIE, which have provided us with insight into the functions of galectin-3 and cell surface glycans during CIE cargo internalization. These methods include media supplementation for metabolic glycoengineering, antibody internalization assays, lectin panels to assay changes in glycan patterns, exogenous galectin-3 supplementation, galectin-3 secretion assays, and in vitro assays to monitor the effect of galectins on CIE.
Background
Inflammatory responses are correlated with secondary brain injury after aneurysmal subarachnoid hemorrhage (aSAH). Galectin‐3 (Gal‐3) is a novel biomarker reflecting inflammation status, and its elevated circulating levels are associated with poor prognosis of some inflammatory diseases. The aim of this study was to evaluate the relationship between Gal‐3 plasma levels and prognosis in a group of aSAH patients.
Materials and Methods
We assessed plasma Gal‐3 levels in 120 patients and 120 healthy individuals. 6‐month clinical outcomes included mortality and unfavorable outcome (Glasgow Outcome Scale score of 1–3). Associations of plasma Gal‐3 levels with clinical outcomes were investigated using multivariate analysis.
Results
Patients showed significantly higher Gal‐3 levels as compared to controls. Circulating Gal‐3 was significantly and independently associated with 6‐month clinical outcomes in the logistic regression analysis. Moreover, we observed a significant correlation between circulating Gal‐3 and World Federation of Neurological Surgeons scores and modified Fisher scores. Furthermore, Gal‐3 possessed high area under receiver operating characteristic curve for prognostic assessment.
Conclusion
Our findings indicate the associations between Gal‐3 levels and the severity and poor prognosis following aSAH. This suggests the possible role of Gal‐3 in the prognostic prediction after aSAH.
Objective:
Inflammation is involved in pathophysiological mechanisms underlying secondary brain injury after intracerebral hemorrhage. Enhanced circulating levels of galectin-3, a proinflammatory cytokine, have close relation to poor prognosis of some inflammatory illnesses. This study was designed to investigate whether plasma galectin-3 levels are related to the inflammation, severity and prognosis following intracerebral hemorrhage.
Methods:
In this observational, prospective study, plasma galectin-3 levels of 110 patients and 110 controls were determined. We further assessed the association of galectin-3 levels with inflammation reflected by systemic C-reactive protein levels, severity indicated by hematoma volumes and National Institutes of Health Stroke Scale (NIHSS) scores, and endpoints including 1-week mortality, 6-month mortality, 6-month overall survival and 6-month unfavorable outcome (modified Rankin Scale score>2).
Results:
Plasma galectin-3 levels of patients were significantly higher than those of controls. Galectin-3 was identified as an independent prognostic predictor for 1-week mortality, 6-month mortality, 6-month overall survival and 6-month unfavorable outcome, as well as had strong relation to C-reactive protein levels, hematoma volumes and NIHSS scores. Compared with NIHSS scores and hematoma volumes, plasma galectin-3 levels had similar areas under receiver operating characteristic curve (AUC). Moreover, galectin-3 levels significantly improved AUCs of NIHSS scores or hematoma volumes alone for prediction of 6-month mortality and 6-month unfavorable outcome.
Conclusions:
Elevated plasma galectin-3 levels are strongly associated with the inflammation, severity and poor prognosis after intracerebral hemorrhage, indicating galectin-3, involved in brain inflammation, might have the potential to be a prognostic biomarker for hemorrhagic stroke.
Background:
Galectin-3 plays a significant role in microglia activation. Its increased circulating concentration has been associated with some inflammatory diseases. In-hospital major adverse events (IMAEs), including acute traumatic coagulopathy, progressive hemorrhagic injury and posttraumatic cerebral infarction, have high prevalence and are strong predictors of mortality after severe traumatic brain injury (STBI). The present study was designed to investigate the relationships between plasma galectin-3 concentrations and trauma severity, in-hospital mortality and IMAEs following STBI.
Methods:
Plasma galectin-3 concentrations of 100 STBI patients and 100 controls were determined. Diagnosis of progressive hemorrhagic injury and posttraumatic cerebral infarction was made on the follow-up computerized tomography scan. Acute traumatic coagulopathy was defined based on coagulation test.
Results:
Plasma galectin-3 concentrations were significantly higher in patients as compared to controls and also associated highly with Glasgow coma scale scores and plasma C-reactive protein concentrations. Galectin-3 emerged as an independent predictor for in-hospital mortality and IMAEs. Areas under receiver operating characteristic curve of plasma galectin-3 concentrations were similar to those of Glasgow Coma Scale scores for prediction of in-hospital morality and IMAEs.
Conclusions:
Plasma galectin-3 concentrations have close relation to inflammation, trauma severity and clinical outcome, suggesting galectin-3 should have the potential to be a good prognostic biomarker after STBI.
Soluble ST2 (sST2) is an emerging biomarker of cardiac remodelling and fibrosis. Studies indicate that it is predictive of mortality in acutely decompensated heart failure. The role of sST2 in chronic heart failure (CHF) is less well defined. No studies have examined serial measurements in optimised patients as a potential monitoring tool. This study aimed to prospectively determine the prognostic utility of serial sST2 in patients with pharmacologically optimised stable CHF.
41 patients with pharmacologically optimised CHF and left ventricular ejection fraction ≤40% were recruited. Clinical review and blood sampling took place at baseline, and one, three and six months. N-terminal pro-brain natriuretic peptide (NTproBNP), sST2 and renal profile were measured on all samples. 12 lead electrocardiogram (ECG) was performed at baseline. Decompensation was defined as a composite endpoint of cardiovascular admission or worsening renal function (≥25% increase in serum creatinine from baseline).
Receiver operator curve analysis of percentage change in sST2 from baseline to six months was strongly reflective of decompensation with area under the curve (AUC) of 0.778. This was significantly better than NTproBNP (AUC 0.425; p=0.013). Correlation of baseline concentrations to surface ECG showed that both sST2 and NTproBNP were positively correlated with duration of the QRS wave, with higher level of significance demonstrated by sST2 (0.415 (p=0.007) and 0.362 (p=0.020) respectively).
Percentage changes in sST2 are better able to predict cardiovascular admission or worsening renal function in patients with pharmacologically optimised CHF than NTproBNP. Compared with NTproBNP, sST2 appears to be a promising candidate for monitoring these patients.
Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
galectin-3 is an emerging biomarker which has been studied in relatively small heart failure (HF) cohorts with predominantly systolic HF. We studied the prognostic value of base-line galectin-3 in a large HF cohort, with preserved and reduced left ventricular ejection fraction (LVEF), and compared this to other biomarkers.
we studied 592 HF patients who had been hospitalized for HF and were followed for 18 months. The primary end-point was a composite of all-cause mortality and HF hospitalization.
a doubling of galectin-3 levels was associated with a hazard ratio (HR) of 1.97 (1.62-2.42) for the primary outcome (P < 0.001). After correction for age, gender, BNP, eGFR, and diabetes the HR was 1.38 (1.07-1.78; P = 0.015). Galectin-3 levels were correlated with higher IL-6 and CRP levels (P < 0.002). Changes of galectin-3 levels after 6 months did not add prognostic information to the base-line value (n = 291); however, combining plasma galectin-3 and BNP levels increased prognostic value over either biomarker alone (ROC analysis, P < 0.05). The predictive value of galectin-3 was stronger in patients with preserved LVEF (n = 114) compared to patients with reduced LVEF (P < 0.001).
galectin-3 is an independent marker for outcome in HF and appears to be particularly useful in HF patients with preserved LVEF.
AimsGalectin-3 is a prognostic heart failure (HF) biomarker that may mediate cardiac fibrosis. We examined the value of serial galectin-3 measurement for prognosis and response to therapy in chronic HF.Methods and resultsA total of 151 subjects with LV systolic dysfunction (LVSD) were followed through 908 visits over 10 ± 3 months. The amount of time spent with a galectin-3 level ≤ 20.0 ng/mL and changes between baseline and subsequent values were considered across visits, and used to assess risk for adverse cardiovascular (CV) events and associations with LV remodelling. Medication effects on galectin-3 were examined. Median galectin-3 values at baseline, 3 months, and 6 months were higher in patients with CV events (21.7 vs. 18.4 ng/mL, P = 0.03; 21.7 vs. 16.5 ng/mL, P = 0.03; 23.2 vs. 16.0 ng/mL, P = 0.007). Galectin-3 concentration changed in 35.2% of subjects during study procedures; time spent at ≤ 20.0 ng/mL was significantly associated with a lower rate of CV events, independently predicted fewer CV events even adjusted for relevant variables including study allocation, NT-proBNP, and renal function [odds ratio (OR) = 0.90; P = 0.05], and predicted increase in LV ejection fraction (OR = 1.20; P = 0.04). Serial galectin-3 measurement at 6 months added prognostic value beyond the baseline level (P = 0.02). There were no significant effects of medications on galectin-3 levels.Conclusion
In chronic HF due to LVSD, serial galectin-3 measurement adds incremental prognostic information and predicts LV remodelling. In this study, HF therapies had no clear effects on galectin-3 levels.
Background:
In several cross-sectional analyses, circulating baseline levels of galectin-3, a protein involved in myocardial fibrosis and remodeling, have been associated with increased risk for morbidity and mortality in patients with heart failure (HF). The importance and clinical use of repeated measurements of galectin-3 have not yet been reported.
Methods and results:
Plasma galectin-3 was measured at baseline and at 3 months in patients enrolled in the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA) trial (n=1329), and at baseline and at 6 months in patients enrolled in the Coordinating Study Evaluating Outcomes of Advising and Counseling Failure (COACH) trial (n=324). Patient results were analyzed by categorical and percentage changes in galectin-3 level. A threshold value of 17.8 ng/mL or 15% change from baseline was used to categorize patients. Increasing galectin-3 levels over time, from a low to high galectin-3 category, were associated with significantly more HF hospitalization and mortality compared with stable or decreasing galectin-3 levels (hazard ratio in CORONA, 1.60; 95% confidence interval, 1.13-2.25; P=0.007; hazard ratio in COACH, 2.38; 95% confidence interval, 1.02-5.55; P=0.046). In addition, patients whose galectin-3 increased by >15% between measurements had a 50% higher relative hazard of adverse event than those whose galectin-3 stayed within ±15% of the baseline value, independent of age, sex, diabetes mellitus, left ventricular ejection fraction, renal function, medication (β-blocker, angiotensin converting enzyme inhibitor, and angiotensin receptor blocker), and N-terminal probrain natriuretic peptide (hazard ratio in CORONA, 1.50; 95% confidence interval, 1.17-1.92; P=0.001). The impact of changing galectin-3 levels on other secondary end points was comparable.
Conclusions:
In 2 large cohorts of patients with chronic and acute decompensated HF, repeated measurements of galectin-3 level provided important and significant prognostic value in identifying patients with HF at elevated risk for subsequent HF morbidity and mortality.
Aims:
This study was conducted to determine whether galectin-3, a β-galactoside-binding lectin, plays a role in the pathogenesis of heart failure (HF).
Methods and results:
Galectin-3 was measured at baseline (n = 1650), after 4 months (n = 1346), and after 12 months (n = 1097) in the Valsartan Heart Failure Trial (Val-HeFT). Galectin-3 levels at baseline ranged from 4.8 to 53 ng/mL. Higher levels were associated with features of worse HF. In a fully adjusted Cox regression model comprising 23 other prognostic variables, baseline galectin-3 was not associated with the risks of all-cause mortality, the composite of the first morbid event, or hospitalization for HF. However, when changes in galectin-3 over time were examined, the increases in galectin-3 between baseline and 4 months were independently and significantly associated with the risks of subsequent all-cause mortality, first morbid event, and hospitalizations for HF, even after adjusting for all baseline and concurrent changes in all variables including estimated glomerular filtration rate (eGFR) and NT-proBNP. The strongest correlate of galectin-3 levels was eGFR, which accounted for 20% of the variability in galectin-3 levels at baseline. There was a significant interaction (P = 0.03) between baseline galectin-3 and the effect of valsartan on hospitalizations for HF. Valsartan caused a significant 44% reduction in hospitalizations for HF in patients with galectin-3 levels below the median level of 16.2 ng/mL, but not in patients with levels above the median.
Conclusions:
Galectin-3 levels are elevated in a substantial proportion of patients with HF, particularly those with more severe HF and renal dysfunction. Galectin-3 increased over time in this cohort, and the increase was independently associated with worse outcomes. Valsartan use was associated with a reduction in hospitalizations for HF in patients with low galectin-3, but not in those with higher levels of galectin-3.
The aim of this study was to examine the relation of galectin-3 (Gal-3), a marker of cardiac fibrosis, with incident heart failure (HF) in the community.
Gal-3 is an emerging prognostic biomarker in HF, and experimental studies suggest that Gal-3 is an important mediator of cardiac fibrosis. Whether elevated Gal-3 concentrations precede the development of HF is unknown.
Gal-3 concentrations were measured in 3,353 participants in the Framingham Offspring Cohort (mean age 59 years; 53% women). The relation of Gal-3 to incident HF was assessed using proportional hazards regression.
Gal-3 was associated with increased left ventricular mass in age-adjusted and sex-adjusted analyses (p = 0.001); this association was attenuated in multivariate analyses (p = 0.06). A total of 166 participants developed incident HF and 468 died during a mean follow-up period of 11.2 years. Gal-3 was associated with risk for incident HF (hazard ratio [HR]: 1.28 per 1 SD increase in log Gal-3; 95% confidence interval [CI]: 1.14 to 1.43; p < 0.0001) and remained significant after adjustment for clinical variables and B-type natriuretic peptide (HR: 1.23; 95% CI: 1.04 to 1.47; p = 0.02). Gal-3 was also associated with risk for all-cause mortality (multivariable-adjusted HR: 1.15; 95% CI: 1.04 to 1.28; p = 0.01). The addition of Gal-3 to clinical factors resulted in negligible changes to the C-statistic and minor improvements in net reclassification improvement.
Higher concentration of Gal-3, a marker of cardiac fibrosis, is associated with increased risk for incident HF and mortality. Future studies evaluating the role of Gal-3 in cardiac remodeling may provide further insights into the role of Gal-3 in the pathophysiology of HF.
To determine the relationship between galectin-3 concentrations and cardiac structure in patients with acute dyspnoea, and to evaluate the impact of galectin-3 independent of echocardiographic measurements on long-term mortality.
One hundred and fifteen patients presenting to the emergency department with acute dyspnoea who had galectin-3 levels and detailed echocardiographic studies on admission were studied. Galectin-3 levels were associated with older age (r = 0.26, P = 0.006), lower creatinine clearance (r = -0.42, P < 0.001), and higher levels of N-terminal-proBNP (r = 0.39, P < 0.001). Higher galectin-3 levels were associated with tissue Doppler E/E(a) ratio (r = 0.35, P = 0.01), a lower right ventricular (RV) fractional area change (r = -0.19, P = 0.05), higher RV systolic pressure (r = 0.37, P < 0.001), and more severe mitral (r = 0.30, P = 0.001) or tricuspid regurgitation (r = 0.26, P = 0.005). In patients diagnosed with heart failure (HF), the association between galectin-3 and valvular regurgitation and RV systolic pressure persisted. In a multivariate Cox regression model, galectin-3 remained a significant predictor of 4-year mortality independent of echocardiographic markers of risk. Dyspnoeic patients with HF and galectin-3 levels above the median value had a 63% mortality; patients less than the median value had a 37% mortality (P = 0.003).
Among dyspnoeic patients with and without ADHF, galectin-3 concentrations are associated with echocardiographic markers of ventricular function. In patients with ADHF, a single admission galectin-3 level predicts mortality to 4 years, independent of echocardiographic markers of disease severity.
This study sought to explore the role of new biomarkers in heart failure (HF).
We investigated the utility of novel serum markers alone or together with natriuretic peptide testing for diagnosis and short-term prognosis estimation in subjects with acute HF.
Plasma levels of amino-terminal pro-brain natriuretic peptide (NT-proBNP), apelin, and galectin-3 were measured in 599 patients presenting with dyspnea at the emergency department, of which 209 (35%) had acute HF.
The NT-proBNP was superior to either apelin or galectin-3 for diagnosis of acute HF, although galectin-3 levels were significantly higher in subjects with HF compared with those without. Receiver operating characteristic analysis for mortality prediction showed that, for 60-day prognosis, galectin-3 had the greatest area under the curve (AUC) at 0.74 (p = 0.0001), whereas NT-proBNP and apelin had an AUC of 0.67 (p = 0.009) and 0.54 (p = 0.33). In a multivariate logistic regression analysis, an elevated level of galectin-3 was the best independent predictor of 60-day mortality (odds ratio 10.3, p < 0.01) or the combination of death/recurrent HF within 60 days (odds ratio 14.3, p < 0.001). The Kaplan-Meier analyses showed that the combination of an elevated galectin-3 with NT-proBNP was a better predictor of mortality than either of the 2 markers alone.
Our data show potential utility of galectin-3 as a useful marker for evaluation of patients with suspected or proven acute HF, whereas apelin measurement was not useful for these indications. Moreover, the combination of galectin-3 with NT-proBNP was the best predictor for prognosis in subjects with acute HF.
In this study we analyzed putative biomarkers for myocardial remodeling in plasma from 55 endstage heart failure patients with the need for mechanical circulatory support (MCS). We compared our data to 40 healthy controls and examined if MCS by either ventricular assist devices or total artificial hearts has an impact on plasma concentrations of remodeling biomarkers.
Plasma biomarkers were analysed pre and 30 days post implantation of a MCS device using commercially available enzyme linked immunosorbent assays (ELISA). We observed that the plasma concentrations of remodeling biomarkers: tissue inhibitor of metalloproteinase 1 (TIMP1), tenascin C (TNC), galectin 3 (LGALS3), osteopontin (OPN) and of neurohumoral biomarker brain natriuretic peptide (BNP), are significantly elevated in patients with terminal heart failure compared to healthy controls. We did not find elevated plasma concentrations for matrix metalloproteinase 2 (MMP2) and procollagen I C-terminal peptide (PCIP). However, only BNP plasma levels were reduced by MCS, whereas the concentrations of remodeling biomarkers remained elevated or even increased further 30 days after MCS. LGALS3 plasma concentrations at device implantation were significantly higher in patients who did not survive MCS due to multi organ failure (MOF).
Our findings indicate that mechanical unloading in endstage heart failure is not reflected by a rapid reduction of remodeling plasma biomarkers.