Galectin-3 in heart failure:From biomarker to target for therapy

This thesis describes the role of galectin-3 in heart failure. Galectin-3 is a protein that is secreted in our body during inflammation and tissue damage. It becomes released into the blood stream and can be measured with a blood test. As a biomarker, galectin-3 can be used for risk stratification in patients with heart failure. In our studies, we show that repeated measurements provide incremental prognostic information. Furthermore, galectin-3 is a marker of subclinical disease: it can be used to identify subjects in the general population that will develop heart failure in the future. Galectin-3 is also involved in cardiac fibrosis and is released after myocardial infarction. Baseline galectin-3 measurements in patients with a myocardial infarction predict infarct size and cardiac function. Another goal of this thesis was to further unravel galectin-3 biology. We show that galectin-3 levels increase upon severe hypertension or micro-albuminuria. In addition, renal function is an important determinant of the present galectin-3 level. Furthermore, blood group also determines galectin-3 level. Possibly, the biological activity of galectin-3 is regulated by glycosylation, the addition of sugar groups. However, the most important feature of galectin-3 is to serve as a target for therapy. Pectins, which are complex sugars extracted from natural food sources, are able to inhibit galectin-3-mediated effects. Administration of pectins in an animal model attenuates cardiac fibrosis and preserves cardiac function. The concept of galectin-3 inhibition could be an interesting addition to the current heart failure treatment regimen

Simulation of SMAP and AMSR2 observations and estimation of multi-frequency vegetation optical depth using a discrete scattering model in the Tibetan grassland

Passive microwave observation at multiple frequencies has received increasing research interests due to its capability to provide comprehensive information of land surface properties. This paper contributes to the simulation of land surface emission and estimation of vegetation optical depth (VOD) at multiple frequencies using a discrete scattering model with a single set of model parameter values. Validity of the Tor Vergata (TVG) discrete scattering model in simultaneously reproducing the Soil Moisture Active Passive (SMAP) L-band (1.4 GHz) and Advanced Microwave Scanning Radiometer 2 (AMSR2) C- (6.925 GHz) and X-band (10.7 GHz) observations over the Tibetan grassland ecosystem is evaluated. Frequency-specific and multi-frequency calibration strategies are implemented to find the suitable set of model parameter values and to isolate the impact of frequency on parameter values. On this basis, the calibrated TVG model is further used to estimate the VOD, and to investigate the impact of microwave frequency and observation angle on the emission simulations and VOD parameterization. The results show that both frequency-specific and multi-frequency calibration strategies achieve comparable and reasonable simulations of SMAP and AMSR2 observations, confirming the feasibility of using an identical physically-based model (i.e. the calibrated TVG model) to simulate multi-frequency land emission driven by a single set of model parameter values. As such, the dependence of emission components and VOD on frequency can be elaborated after isolating the impact of frequency on parameter values. The VOD values derived from the TVG simulations generally increase with increasing frequency and can be linearly correlated to the LAI variations, while current satellite-based retrievals have almost the same magnitude at the L-, C-, and X-band. The explanation for this can be that the retrieved VOD is different from the theoretical definition. Sensitivity test performed using the calibrated TVG model further shows that polarization-dependence of VOD becomes more apparent with the increasing observation angle and frequency. New parameterization has thus been developed to characterize the dependence of VOD on the frequency, observation angle, and polarization for grassland based on the results of sensitivity test. This study may provide new insights in improving model of land emission and retrievals of SM and VOD with physical interpretability based on multi-frequency satellite observations.</p

Effects of Roughness Length Parameterizations on Regional-Scale Land Surface Modeling of Alpine Grasslands in the Yangtze River Basin

Abstract Current land surface models (LSMs) tend to largely underestimate the daytime land surface temperature for high-altitude regions. This is partly because of underestimation of heat transfer resistance, which may be resolved through adequate parameterization of roughness lengths for momentum and heat transfer. In this paper, the regional-scale effects of the roughness length parameterizations for alpine grasslands are addressed and the performance of the Noah LSM using the updated roughness lengths compared to the original ones is assessed. The simulations were verified with various satellite products and validated with ground-based observations. More specifically, four experimental setups were designed using two roughness length schemes with two different parameterizations of (original and updated). These experiments were conducted in the source region of the Yangtze River during the period 2005–10 using the Noah LSM. The results show that the updated parameterizations of roughness lengths reduce the mean biases of the simulated daytime in spring, autumn, and winter by up to 2.7 K, whereas larger warm biases are produced in summer. Moreover, model efficiency coefficients (Nash–Sutcliffe) of the monthly runoff results are improved by up to 26.3% when using the updated roughness parameterizations. In addition, the spatial effects of the roughness length parameterizations on the simulations are discussed. This study stresses the importance of proper parameterizations of and for LSMs and highlights the need for regional adaptation of the and values.</jats:p

Pectins from various sources inhibit galectin-3-related cardiac fibrosis

Purpose of the study: A major challenge in cardiology remains in finding a therapy for cardiac fibrosis. Inhibition of galectin-3 with pectins attenuates fibrosis in animal models of heart failure. The purpose of this study is to identify pectins with the strongest galectin-3 inhibitory capacity. We evaluated the in vitro inhibitory capacity, identified potent pectins, and tested if this potency could be validated in a mouse model of myocardial fibrosis. Methods: Various pectin fractions were screened in vitro. Modified rhubarb pectin (EMRP) was identified as the most potent inhibitor of galectin-3 and compared to the well-known modified citrus pectin (MCP). Our findings were validated in a mouse model of myocardial fibrosis, which was induced by angiotensin II (Ang II) infusion. Results: Ang II infusion was associated with a 4–5-fold increase in fibrosis signal in the tissue of the left ventricle, compared to the control group (0•22±0•10 to 1•08±0•53%; P < 0•001). After treatment with rhubarb pectin, fibrosis was reduced by 57% vs. Ang II alone while this reduction was 30% with the well-known MCP (P = NS, P < 0•05). Treatment was associated with a reduced cardiac inflammatory response and preserved cardiac function. Conclusion: The galectin-3 inhibitor natural rhubarb pectin has a superior inhibitory capacity over established pectins, substantially attenuates cardiac fibrosis, and preserves cardiac function in vivo. Bioactive pectins are natural sources of galectin-3 inhibitors and may be helpful in the prevention of heart failure or other diseases characterized by fibrosis. Funding: Dr. Meijers is supported by the Mandema-Stipendium of the Junior Scientific Masterclass 2020-10, University Medical Center Groningen and by the Netherlands Heart Foundation (Dekkerbeurs 2021)Dr. de Boer is supported by the Netherlands Heart Foundation (CVON SHE-PREDICTS-HF, grant 2017-21; CVON RED-CVD, grant 2017-11; CVON PREDICT2, grant 2018-30; and CVON DOUBLE DOSE, grant 2020B005), by a grant from the leDucq Foundation (Cure PhosphoLambaN induced Cardiomyopathy (Cure-PLaN), and by a grant from the European Research Council (ERC CoG 818715, SECRETE-HF)

Renal Handling of Galectin-3 in the General Population, Chronic Heart Failure, and Hemodialysis

Background-Galectin-3 is a biomarker for prognostication and risk stratification of patients with heart failure (HF). It has been suggested that renal function strongly relates to galectin-3 levels. We aimed to describe galectin-3 renal handling in HF. Methods and Results-In Sprague-Dawley rats, we infused galectin-3 and studied distribution and renal clearance. Furthermore, galectin-3 was measured in urine and plasma of healthy controls, HF patients and hemodialysis patients. To mimic the human situation, we measured galectin-3 before and after the artificial kidney. Infusion in rats resulted in a clear increase in plasma and urine galectin-3. Plasma galectin-3 in HF patients (n=101; mean age 64 years; 93% male) was significantly higher compared to control subjects (n=20; mean age 58 years; 75% male) (16.6 ng/mL versus 9.7 ng/mL, P Conclusions-In this small cross-sectional study, we report that urine levels of galectin-3 are not increased in HF patients, despite substantially increased plasma galectin-3 levels. The impaired renal handling of galectin-3 in patients with HF may explain the described relation between renal function and galectin-3 and may account for the elevated plasma galectin-3 in HF

Variability of biomarkers in patients with chronic heart failure and healthy controls

Aims Biomarkers can be used for diagnosis, risk stratification, or management of patients with heart failure (HF). Knowledge about the biological variation is needed for proper interpretation of serial measurements. Therefore, we aimed to determine and compare the biological variation of a large panel of biomarkers in healthy subjects and in patients with chronic HF. Methods and results The biological variability of established biomarkers [NT-proBNP and high-sensitivity troponin T (hsTnT)], novel biomarkers [galectin-3, suppression of tumorigenicity 2 (ST2), and growth differentiation factor 15 (GDF-15)], and renal/neurohormonal biomarkers (aldosterone, phosphate, parathyroid hormone, plasma renin concentration, and creatinine) was determined in 28 healthy subjects and 83 HF patients, over a period of 4 months and 6 weeks, respectively. The analytical (CVa), intraindividual (CVi), and interindividual (CVg) variations were calculated, as well as the reference change value (RCV), which reflects the percentage of change that may indicate a 'relevant' change. All crude biomarker levels were significantly increased or decreased in HF patients compared with controls (all P <0.01). Variation indices were comparable in healthy individuals and HF patients. CVi was not influenced by the individual levels of the biomarker itself. NT-proBNP and GDF-15 had relatively high CVi (21.8% and 16.6%) and RCV (61.7% and 64.3%), whereas ST2 (CVi, 15.0; RCV, 42.9%), hsTnT (CVi, 11.1; RCV, 31.4%), and galectin-3 (CVi, 8.1; RCV, 25.0%) had lower indices of variation. Conclusion Biological variation indices are comparable between healthy subjects and HF patients for a broad spectrum of biomarkers. NT-proBNP and GDF-15 have substantial variation, with lower variation for ST2, hsTnT, and galectin-3. These data are instrumental in proper interpretation of biomarker levels in HF patients