Transferrin Saturation Research Articles

Prognostic impact of iron deficiency in new-onset chronic heart failure: Danish Heart Failure Registry insights.

Iron deficiency (ID) is prevalent in chronic heart failure (HF) but lacks a consensus definition. This study evaluates the prevalence and the prognostic impact of ID using different criteria on all-cause and cardiovascular mortality, as well as first hospitalization for HF in patients with new-onset chronic HF. In this nationwide registry-based cohort, we explored four definitions of ID: the current European Society of Cardiology (ESC) guidelines [ferritin <100ng/mL or ferritin 100-299ng/mL and transferrin saturation (TSAT) <20%], ferritin level <100ng/mL, TSAT<20% and serum iron ≤13μmol/L. Patients were identified through the Danish Heart Failure Registry. Of 9477 new-onset chronic HF patients registered in the Danish Heart Failure Registry from April 2003 to December 2019, we observed ID prevalence rates ranging from 35.8% to 64.3% depending on the ID definition used. Among patients with ID defined by iron ≤13μmol/L or TSAT<20%, 26% and 15.5%, respectively, did not meet the ESC guidelines definitionfor ID. Conversely, 11% of patients meeting the ESC criteria exhibited serum iron >13μmol/L and TSAT>20%. Regardless of anaemia status, ID defined by TSAT<20% or serum iron ≤13μmol/L was associated with all-cause mortality [non-anaemic, hazard ratio (HR): 1.57, 95% confidence interval (CI): 1.30-1.89 and HR: 1.47, 95% CI: 1.24-1.73; anaemic, HR: 1.22, 95% CI: 1.07-1.38 and HR: 1.25, 95% CI: 1.09-1.44, respectively] and cardiovascular mortality (non-anaemic, HR: 2.21, 95% CI: 1.59-3.06 and HR: 1.47, 95% CI: 1.12-1.95; anaemic, HR: 1.37, 95% CI: 1.11-1.69 and HR: 1.28, 95% CI: 1.02-1.61, respectively), as well as increased risk of first hospitalization for HF (non-anaemic, HR: 1.28, 95% CI: 1.09-1.1.50 and HR: 1.27, 95% CI: 1.10-1.46; anaemic, HR: 1.25, 95% CI: 1.08-1.44 and HR: 1.22, 95% CI: 1.05-1.42, respectively). ID defined by ESC guidelines was associated with all-cause and cardiovascular mortality only in non-anaemic patients (HR: 1.41, 95% CI: 1.18-1.1.70 and HR: 1.58, 95% CI: 1.18-2.12.). Furthermore, the ESC guideline definition was associated with increased risk of first hospitalization for HF, regardless of anaemia status (non-anaemic, HR: 1.26, 95% CI: 1.08-1.1.47; anaemic, HR: 1.34, 95% CI: 1.17-1.53). ID, when defined by TSAT<20% or serum iron ≤13μmol/L, is associated with increased risk of all-cause and cardiovascular mortality, as well as first hospitalization for HF in patients with new-onset chronic HF, regardless of anaemia status. Conversely, ID defined as ESC guidelines is associated with all-cause and cardiovascular mortality only in non-anaemic patients.

Association of Clinical and Paraclinical Factors with Pain Crisis Severity in Sickle-Thalassemia Patients in Iran

Objectives: This study aimed to evaluate the effects of several factors, including hospitalization frequency, inflammatory and hemolytic markers, and the numbers of blood transfusions and crises, on the severity of pain crises in sickle-thalassemia patients. Methods: Of all patients visiting hematologists in university-affiliated hospitals and clinics, only 75 sickle cell disease (SCD) and sickle-thalassemia patients met the inclusion criteria for this study. Disease severity was measured based on pain crises per year and laboratory markers, including hemolytic and inflammatory indicators, outpatient or inpatient status, the number of hospital admissions, and the number of blood units transfused over one year. Results: In sickle cell patients, a significant correlation was observed between hospital admission and WBC (0.01), ALP (0.001), MCHC (0.001), ferritin (0.021), and ESR (0.006). Additionally, pain crises were positively correlated with transferrin saturation (TS) (+0.28) and the number of transfused blood units (+0.49) and negatively correlated with Hb (-0.30) and total iron binding capacity (TIBC) (-0.23). Blood unit transfusions showed a positive correlation with serum iron (+0.44), RDW (+0.36), ferritin (+0.39), pain crises (+0.49), and TS (+0.49), along with a negative correlation with Hb (-0.75) and MCHC (-0.33). When categorizing pain crises into two groups, patients experiencing more frequent crises generally exhibited lower hemoglobin levels and a higher number of blood units transfused. Hemoglobin also showed a significant negative correlation with lactate dehydrogenase (LDH) level in both groups: -0.604 (P = 0.005) in patients with ≥ 3 crises per year and -0.368 (P = 0.006) in patients with &lt; 3 crises per year. Patients with hemoglobin levels of 7.5 or higher tended to maintain an LDH level below 1000. Among patients referred with pain crises, hemoglobin was negatively correlated with hemolytic markers such as LDH (-0.41) and retic (-0.29). Conclusions: Hemoglobin and LDH can serve as follow-up markers, as they are routinely measured in all sickle cell patients and, in this study, hemoglobin levels of 7.5 or higher and LDH levels below 1000 were associated with fewer and less severe pain crises. Regular monitoring of hemolytic markers may help in pain crisis prevention, as this study found that hemolytic crises frequently coincided with pain crises. Further research is needed to provide conclusive evidence in this area.

Imaging treatment efficacy of repeated photodynamic therapy in glioblastoma using chemical exchange transfer saturation MRI.

To observe the tumor responses during photodynamic therapy in a murine glioblastoma model using chemical exchange saturation transfer (CEST) MRI and to compare the treatment effectiveness between single photodynamic therapy (sPDT) and repeated PDT (rePDT). After tumor cell implantation in NSG mouse brain(n = 27), mice were subjected to four PDT sessions (rePDT), sPDT after the administration of 5-aminolevulinic acid 6 h before each session, and a non-PDT session (control). A 630-nm LED light was used to effectuate PDT. After 24 h for each PDT session, T2-weighted and CEST MRI were performed over 7 days. We observed that rePDT resulted in a continuous suppression of tumors according to T2-weighted images; thus, the tumor volume was the smallest among three groups on Day 7. Both CEST contrasts at 3.5 ppm (amide proton transfer, APT) and 3.5 ppm (relayed nuclear Overhauser enhancement, rNOE) in the rePDT group were significantly lower (p < 0.05) than those in the control group starting from Day 5, which corresponds to lower protein and cellularity in tumors in the rePDT group, respectively. CEST contrast decreased by 17.9% at 3.5 ppm and 11.3% at 3.5 ppm for rePDT group. This was validated by histology, where we observed moderatecorrelations between APTwith cell proliferation (R = 0.730, p < 0.01) and cell apoptosis (R = 0.715, p < 0.05) and moderate correlation between rNOE with cellularity (R = 0.796, p < 0.01). rePDT has a better effect in tumor growth suppression when compared with sPDT, and CEST could be a robust and noninvasive mean to assess the molecular changes related to treatment efficacy.

Serum iron and transferrin saturation variation are circadian regulated and linked to the harmonic circadian oscillations of erythropoiesis and hepatic Tfrc expression in mice.

Serum iron has long been thought to exhibit diurnal variation and is subsequently considered an unreliable biomarker of systemic iron status. Circadian regulation (endogenous ~24-h periodic oscillation of a biologic function) governs many critical physiologic processes. It is unknown whether serum iron levels are regulated by circadian machinery; likewise, the circadian nature of key players of iron homeostasis is unstudied. Here we show that serum iron, transferrin saturation (TSAT), hepatic transferrin receptor (TFR1) gene (Tfrc) expression, and erythropoietic activity exhibit circadian rhythms. Daily oscillations of serum iron, TSAT, hepatic Tfrc expression, and erythropoietic activity are maintained in mice housed in constant darkness, where oscillation reflects an endogenous circadian period. Oscillations of serum iron, TSAT, hepatic Tfrc, and erythropoietic activity were ablated when circadian machinery was disrupted in Bmal1 knockout mice. Interestingly, we find that circadian oscillations of erythropoietic activity and hepatic Tfrc expression are maintained in opposing phase, likely allowing for optimized usage and storage of serum iron whilst maintaining adequate serum levels and TSAT. This study provides the first confirmatory evidence that serum iron is circadian regulated, discerns circadian rhythms of TSAT, a widely used clinical marker of iron status, and uncovers liver-specific circadian regulation of TFR1, a major player in cellular iron uptake.

High correlation of quantitative susceptibility mapping and echo intensity measurements of nigral iron overload in Parkinson's disease.

Quantitative susceptibility mapping (QSM) and transcranial sonography (TCS) offer proximal evaluations of iron load in the substantia nigra. Our prospective study aimed to investigate the relationship between QSM and TCS measurements of nigral iron content in patients with Parkinson's disease (PD). In secondary analyses, we wanted to explore the correlation of substantia nigra imaging data with clinical and laboratory findings. Eighteen magnetic resonance imaging and TCS examinations were performed in 15 PD patients at various disease stages. Susceptibility measures of substantia nigra were calculated from referenced QSM maps. Echogenicity of substantia nigra on TCS was measured planimetrically (echogenic area) and by digitized analysis (echo-intensity). Iron-related blood serum parameters were measured. Clinical assessments included the Unified PD Rating Scale and non-motor symptom scales. Substantia nigra susceptibility correlated with echogenic area (Pearson correlation, r = 0.53, p = 0.001) and echo-intensity (r = 0.78, p < 0.001). Individual asymmetry indices correlated between susceptibility and echogenic area measurements (r = 0.50, p = 0.042) and, more clearly, between susceptibility and echo-intensity measurements (r = 0.85, p < 0.001). Substantia nigra susceptibility (individual mean of bilateral measurements) correlated with serum transferrin saturation (Spearman test, r = 0.78, p < 0.001) and, by trend, with serum iron (r = 0.69, p = 0.004). Nigral echogenicity was not clearly related to serum values associated with iron metabolism. Susceptibility and echogenicity measurements were unrelated to PD duration, motor subtype, and severity of motor and non-motor symptoms. The present results support the assumption that iron accumulation is involved in the increase of nigral echogenicity in PD. Nigral echo-intensity probably reflects ferritin-bound iron, e.g. stored in microglia.

Marked microcytosis and increased transferrin saturation: Think about variants in SLC11A2 (DMT1)

Congenital microcytic anemias are rare diseases associated with decreased hemoglobin synthesis and red blood cells of low corpuscular volume. DMT1/NRAMP2 is a highly conserved divalent cation transporter encoded by the SLC11A2 gene, expressed at the membrane of various cells. It ensures ferrous iron absorption from the apical membrane of enterocytes, iron recovery from urine by renal tubules, and acidified endosome uptake after transferrin internalization. Pathogenic DMT1 variants have been described in 10 individuals to date, associated with recessive hypochromic anemia and iron overload. Herein, we report a new variant of SLC11A2 (c.469A>G, p.Ile157Val) compound with known p.Arg416Cys associated with a frankly microcytic anemia and increased transferrin saturation. The clinical picture observed in the patient was exceptionally mild, extending the field of the DMT1 phenotypes to borderline anemias.

Multifrequency-STD NMR unveils the first Michaelis complex of an intramolecular trans-sialidase from Ruminococcus gnavus

RgNanH is an intramolecular trans-sialidase expressed by the human gut symbiont Ruminococcus gnavus, to utilise intestinal sialylated mucin glycan epitopes. Its catalytic domain, belonging to glycoside hydrolase GH33 family, cleaves off terminal sialic acid residues from mucins, releasing 2,7-anhydro-Neu5Ac which is then used as metabolic substrate by R. gnavus to proliferate in the mucosal environment. RgNanH is one of the three intramolecular trans-sialidases (IT-sialidases) characterised to date, and the first from a gut commensal organism. Here, saturation transfer difference NMR (STD NMR) in combination with computational techniques (molecular docking and CORCEMA-ST) were used to elucidate the specificity, kinetics and relative affinity of RgNanH for sialoglycans and 2,7-anhydro-Neu5Ac. We propose the first 3D model for the Michaelis complex of an IT-sialidase. This confirms the sialic acid to be the main recognition element for the interaction in the enzymatic cleft and highlights the crucial role of Trp698 to make CH-π stacking with the galactose residue of the substrate 3′-sialyllactose. The same contact is shown not to be possible for 6′-sialyllactose, due to geometrical constrains of the α-2,6 linkage. Indeed 6′-sialyllactose is not a substrate, even though it is shown to bind to RgNanH by STD NMR. These findings corroborate the role of Trp698 for the α-2,3 specificity of trans-sialidases. In this structural study, the use of Differential Epitope Mapping STD NMR (DEEP-STD NMR) approach allowed the validation of the proposed 3D models in solution. These structural approaches are shown to be instrumental in shedding light on the molecular mechanisms underpinning enzymatic reactions in the absence of enzyme-substrate X-ray structures.

Identification of new potential inhibitors of pteridine reductase-1 (PTR1) via biophysical and biochemical mechanism-based approaches: Step towards the treatment of Leishmaniasis

Leishmaniasis is a parasitic disease, which spreads from the bite of an infected Phlebotomine fly to human hosts. The disease is characterized by a number of clinical manifestations, such as ulcerative lesions at the site of sandfly bite (cutaneous form), inflammation of mucosal membranes (mucosal leishmaniasis) or the deadly visceral form. This study was aimed to target pteridine reductase-1 (PTR1), a member of short chain dehydrogenases, which accounts for the reduction of conjugated and unconjugated pterins in Leishmania parasite. The ptr1-pET28a+-tev construct was expressed using BL21 (DE3) cells, followed by two tandem purification steps including affinity and gel permeation chromatography. In the next phase, functional studies of PTR1 were performed via screening of an in-house library of 500 compounds. The biochemical-mechanism based assay of PTR1 identified 11 hits that were also found to be non-cytotoxic against human fibroblast cell line (BJ) (except compound 6), and thus further studied via computational technique and saturation transfer difference-nuclear magnetic resonance (STD-NMR) spectroscopy. These high throughput techniques identified six compounds 2, 4, 5, 7, 9, and 11 as active, which were then assessed via in-vitro assay. Among them, compounds 2, 4, and 7 showed substantial leishmanicidal activity, comparable to the standard drug, miltefosine (IC50 value: 31.8 ± 0.2 μM). These results narrowed down the search to 3 compounds as potential leads, with prominent protein-ligand interaction profiles. Hence, the respective compounds can be further assessed for their therapeutic potential against leishmaniasis.

Enhanced and robust contrast in CEST MRI: Saturation pulse shape design via optimal control.

To employ optimal control for the numerical design of Chemical Exchange Saturation Transfer (CEST) saturation pulses to maximize contrast and stability against inhomogeneities. We applied an optimal control framework for the design pulse shapes for CEST saturation pulse trains. The cost functional minimized both the pulse energy and the discrepancy between the corresponding CEST spectrum and the target spectrum based on a continuous radiofrequency (RF) pulse. The optimization is subject to hardware limitations. In measurements on a 7 T preclinical scanner, the optimal control pulses were compared to continuous-wave and Gaussian saturation methods. We conducted a comparison of the optimal control pulses with Gaussian, block pulse trains, and adiabatic spin-lock pulses. The optimal control pulse train demonstrated saturation levels comparable to continuous-wave saturation and surpassed Gaussian saturation by up to 50 % in phantom measurements. In phantom measurements at 3 T the optimized pulses not only showcased the highest CEST contrast, but also the highest stability against field inhomogeneities. In contrast, block pulse saturation resulted in severe artifacts. Dynamic Bloch-McConnell simulations were employed to identify the source of these artifacts, and underscore the robustness of the optimized pulses. In this work, it was shown that a substantial improvement in pulsed saturation CEST imaging can be achieved by using Optimal Control design principles. It is possible to overcome the sensitivity of saturation to B0 inhomogeneities while achieving CEST contrast close to continuous wave saturation.

Prediction of Successful Amorphous Solid Dispersion Pairs through Liquid State Nuclear Magnetic Resonance.

Amorphous solid dispersions (ASDs) function in part via a "parachute effect", i.e., polymer-enabled prolonged drug supersaturation, presumably through drug-polymer interactions in the liquid state. We aim to expand the utility of liquid state nuclear magnetic resonance (1HNMR) to streamline polymer selection for ASDs. Our hypothesis is that strong molecular interactions between polymer and drug in 1HNMR anticipate reduced precipitation kinetics in supersaturation studies. For three drug-polymer pairs (i.e., etravirine with each HPMC, HPMCAS-M, and PVP-VA), 1HNMR findings were compared to more common supersaturation studies. Drug-polymer interactions were assessed by saturation transfer difference NMR (STD-NMR) and T1 relaxation time. 2D-1H NOESY experiments were also performed. Supersaturation studies involved precipitation inhibition using the solvent-shift methodology. The results from STD-NMR and T1 relaxation time indicate etravirine bound preferably to HPMCAS-M > HPMC ≫ PVP-VA. STD-NMR and T1 relaxation time yielded insight into which fragments of etravirine structure bind with HPMCAS-M and HPMC. The strong interactions from STD-NMR and T1 relaxation time changes indicated that HPMCAS-M and HPMC, but not PVP-VA, are suitable polymers to maintain etravirine supersaturation and inhibit drug precipitation. 2D-1H NOESY results corroborate the findings of STD-NMR and T1 relaxation time, showing that etravirine interacts preferably to HPMCAS-M than to PVP-VA. Supersaturation studies using solvent-shift technique corroborated our hypothesis as predissolved HPMCAS-M and HPMC, but to a less extent PVP-VA, markedly promoted etravirine supersaturation and inhibited drug precipitation. Supersaturation studies agreed with STD-NMR and T1 relaxation time predictions, as HPMC and HPMCAS-M maintained etravirine in solution for longer time than PVP-VA. The results show promise of 1HNMR to streamline polymer selection in a nondestructive and resource sparing fashion for subsequent ASD development.

Numerical Modeling of Two-Phase Fluid Filtration for Carbonate Reservoir in Two-Dimensional Formulation

This work considers the isothermal process of incompressible viscous fluid filtration in an oil-saturated, fractured-porous reservoir. A study of the pressure and water saturation distribution process is carried out for a case in which a production well is put into operation. For this problem, i.e., a mathematical model in a two-dimensional formulation, a numerical method and a parallel algorithm are proposed. The mathematical model of two-phase filtration is written in accordance with the classical laws of continuum mechanics and Darcy’s law and also includes a function of fluid exchange between low-permeability pores and high-permeability natural fractures within the framework of the Warren–Root model. The numerical solution is based on the finite-difference method and a splitting scheme of physical processes and spatial coordinates. For a split system with respect to piezoconductivity, an implicit finite-difference scheme with fixed saturations is constructed, and with respect to saturation transfer, explicit and implicit difference schemes are constructed. For parallel implementation of the developed numerical approach, a method based on geometric parallelism is selected. Testing of the developed method is performed using the example of calculating liquid mass transfer for a wide range of parameters. To verify the model, the obtained calculated pressure curves are compared with field data recorded by a deep-well measuring device. The results allow for estimation of the distribution of reservoir pressure and water saturation depending on the permeability of the fracture set and the pore part. The obtained results allow for monitoring of well operations, reducing unexpected accident risks and optimizing the development system in order to increase oil production in fractured-porous reservoirs. Computational experiments confirm the efficiency of the developed numerical algorithm and its parallel implementation.

Effect of Iron Deficiency Anemia on HbA1c Levels in a cohort of patients with Type 2 diabetes mellitus in a tertiary care hospital

Introduction: Studies have reported that HbA1c levels can be changed by iron deficiency (ID) which is the commonest nutritional anaemia globally. This study was aimed at determining the effect of iron deficiency anaemia (IDA) on HbA1c levels in a cohort of type 2 diabetes mellitus (T2DM) attending a tertiary care hospital in Sri Lanka. Methods: A retrospective analytical study was performed for a period of six months from January 2021. Laboratory records of 281 adult T2DM patients both, anaemic (n=135) with Hb &lt;12g/dL in females and &lt;13g/dL males and transferrin saturation &lt;16%, and nonanaemic (n=146) with Hb &gt;12g/dL in females and &gt;13g/dL in males were analyzed. Data were analyzed using (SPSS) version 20, descriptive statistical methods, Pearson’s Correlation test, independent sample t-test, one-way analysis of variance (ANOVA) and Chi-Square test were used. P&lt;0.05 was considered significant. Results: Out of the total 281 patients diagnosed with T2DM, 150 were female, and 131 were male, spanning an age range of 22 to 96 years. The mean ± standard deviation (SD) values for HbA1c in both anaemic and non-anemic groups were 7.4±2.2% g/dL and 7.3±2.36% g/dL, respectively. Importantly, no statistically significant relationship was observed between the two groups (p=0.889). Furthermore, there was no significant correlation between HbA1c levels with serum iron (p=0.617), total Iron Binding Capacity (TIBC) (p=0.340), and transferrin saturation (p=0.168). Conclusion: The study reveals, HbA1c in T2DM patients with and without IDA show no significant difference. Therefore, HbA1c could be reliably used in monitoring patients with T2DM and IDA. Keywords: T2DM, HbA1c, iron deficiency anaemia, red blood cell indices

Peptide Nucleic Acids in Saturation Transfer Difference Nuclear Magnetic Resonance Experiments: A Simple and Valuable Tool for Studying HuR–Small Molecule Complexes

Peptide Nucleic Acids in Saturation Transfer Difference Nuclear Magnetic Resonance Experiments: A Simple and Valuable Tool for Studying HuR–Small Molecule Complexes

Advanced quantitative magnetic resonance imaging of lower extremity muscle microtrauma after marathon: a mini review

This article reviews the existing literature and outlines recent advances in quantitative Magnetic Resonance Imaging (MRI) techniques for the assessment of lower extremity muscle microtrauma following a marathon. Single-modality quantitative MRI techniques include T2 mapping to assess the dynamics of muscle inflammatory edema and variability at the site of injury, Diffusion Tensor Imaging (DTI) to detect subclinical changes in muscle injury, Intravoxel Incoherent Motion (IVIM) imaging to provide simultaneous information on perfusion and diffusion in muscle tissue without the need for intravenous contrast, and Magnetic Resonance Spectroscopy (MRS) to noninvasively detect intramyocellular lipid (IMCL) content in muscle before and after marathon exercise to explain the use of fatty acids as an energy source in skeletal muscle during long-distance running. As well as Chemical Exchange Saturation Transfer (CEST) is particularly suitable for detecting changes in free creatine, pH values and lactate concentrations in muscles before and after exercise, providing a more detailed picture of muscle physiology and chemistry. These metabolic MRI methods enhance the understanding of biochemical alterations occurring in muscles pre- and post-exercise. Multimodal techniques combine different modalities to provide a comprehensive evaluation of muscle structural and functional changes. These advanced techniques aim to better assess microtrauma and guide clinical treatment, though further validation with larger studies is needed to establish their potential over traditional qualitative methods.

Saturation transfer (CEST and MT) MRI for characterization of U-87 MG glioma in the rat.

The focus of this work was to identify the optimal magnetic resonance imaging (MRI) contrast between orthotopic U-87 MG tumours and normal appearing brain with the eventual goal of treatment response monitoring. U-87 MG human glioblastoma cells were injected into the brain of RNU nude rats (n= 9). The rats were imaged at 7T at three timepoints for all animals: 3-5, 7-9, and 11-13 days after implantation. Whole-brain T1-weighted (before and after gadolinium contrast agent injection), diffusion, and fluid-attenuated inversion recovery scans were performed. In addition, single-slice saturation-transfer-weighted chemical exchange saturation transfer (CEST), magnetization transfer (MT), and water saturation shift referencing (WASSR) contrast Z-spectra and T1 and T2 maps were also acquired. The MT and WASSR Z-spectra and T1 map were fitted to a two-pool quantitative MT model to estimate the T2 of the free and macromolecular-bound water molecules, the relative macromolecular pool size (M0, MT), and the magnetization exchange rate from the macromolecular pool to the free pool (RMT). The T1-corrected apparent exchange-dependent relaxation (AREX) metric to isolate the CEST contributions was also calculated. The lesion on M0, MT and AREX maps with a B1 of 2μT best matched the hyperintensity on the post-contrast T1-weighted image. There was also good separation in Z-spectra between the lesion and contralateral cortex in the 2-μT CEST and 3- and 5-μT MT Z-spectra at all time points. A pairwise Wilcoxon signed-rank tests with Holm-Bonferroni adjustment on MRI parameters was performed and the differences between enhancing lesion and contralateral cortex for the MT ratio with 2μT saturation at 3.6ppm frequency offset (corresponding to the amide chemical group) and M0, MT were both strongly significant (p< 0.001) at all time points. This work has identified that differences between enhancing lesion and contralateral cortex are strongest in MTR with B1=2μT at 3.6ppm and relative macromolecular pool size (M0, MT) images over entire period of 3-13 days after cancer cell implantation.

Transferrin saturation is a superior prognostic biomarker for iron deficiency after acute decompensated heart failure: a retrospective clinical real-world cohort study

Abstract Background Iron deficiency (ID) is the most common extracardiac comorbidity in heart failure (HF) and associated with worse outcomes. While a uniform definition of ID in HF remains lacking, several biomarkers for ID, including ferritin and transferrin saturation (TSAT), are used in both clinical trials and clinical practice. However, which biomarker is a superior prognostic predictor for ID in HF remains unsettled. In addition, real-world clinical data on ID screening and intravenous (IV) iron treatment is largely missing. Purpose To determine which biomarker is a superior prognostic predictor for the composite endpoint of HF rehospitalisation (HHF) and all-cause mortality in a real-world cohort of patients with HF and coexisting ID, and to investigate frequency and predictors of ID screening and IV iron treatment. Methods In this retrospective cohort study, all patients aged 18-85 years hospitalised at a tertiary university hospital with new onset HF with reduced ejection fraction (HFrEF) in 2016-2020 were consecutively included from medical records by ICD-10 code I50.0-I50.9 and followed until 31 December 2021. Patient characteristics, comorbidities, medications, laboratory results and data on follow-up, including if ID was tested for, IV iron administration, HHF and all-cause mortality was collected. First available iron status after admission for index hospitalisation was used. Predictors for ID screening and IV iron use were identified with univariate logistic regression. The association between ID markers and the composite endpoint was analysed with Cox regression adjusted for age, sex, baseline anemia, estimated glomerular filtration rate (eGFR) &amp;lt;30 mL/min/1.73 m2 and N-terminal pro-B type natriuretic peptide (NT-proBNP) below median value with median ferritin and TSAT values set as references respectively. Results In all, 753 patients were included (66.5 ± 12.7 years, 508 (67.5%) men, ejection fraction 29.5 ± 6.9% and mean NT-proBNP 6241 ± 7183 ng/L). Of these, 484 (64.3%) were screened for ID and 235 (48.6%) fulfilled criteria for ID. Of these, 94 (40.0%) received IV iron. Of screened patients, 28.6% had ID with anemia and 20.8% ID without anemia (Table 1). Factors associated with screening for ID were follow-up at hospital, anemia, eGFR &amp;lt;30 mL/min/1.73 m2 and ischemic heart disease, and for IV iron additionally chronic kidney disease and peripheral artery disease. Median ferritin was 140 µg/L and TSAT 0.2. Both ferritin and TSAT displayed an inversely linear association with outcomes, while TSAT &amp;lt;0.2 showed a stronger association with increased risk of HHF and all-cause mortality compared to median values (Figure 1-2). Conclusions In a real-world clinical setting, TSAT was a superior prognostic biomarker for worse outcomes compared to ferritin in patients hospitalised for acute HF. While both ID screening and IV iron use remained greatly underutilised in clinical practice, identification of a reliable biomarker for ID is critical.

Impact of various iron deficiency definitions on mortality risk in chronic heart failure across the spectrum of left ventricular ejection fraction spectrum

Abstract Introduction Iron deficiency (ID) is prevalent in chronic heart failure (HF) but lacks a consensus definition. Purpose This study evaluates the prevalence of ID and its association with all-cause mortality and first hospitalization for HF, using current European Society of Cardiology (ESC) guidelines, transferrin saturation (TSAT) &amp;lt;20%, ferritin &amp;lt;100 ng/ml, and serum iron ≤13 μmol/L as ID criteria. Methods and Results Of 8587 new-onset HF patients registered in the Danish Heart Failure Registry from April 2003 to July 2021, we found varying ID prevalence (35.4% to 67%) based on different definitions. In heart failure with reduced ejection fraction (HFrEF) patients, irrespective of anemia, ID defined by TSAT &amp;lt;20% and serum iron ≤13 μmol/L was associated with all-cause mortality (non-anemic, HR: 1.42, 95% CI:1.22-1.64 and HR: 1.25, 95% CI: 1.1-1.43; anemic, HR: 1.22, 95% CI: 1.1-1.35 and HR: 1.26, 95% CI: 1.12-1.41, respectively) and first HF hospitalization (non-anemic, HR:1.41, 95% CI:1.23-1.62, HR: 1.33, 95% CI: 1.18-1.51; anemic, HR:1.27, 95% CI:1.12-1.45 and HR: 1.26, 95% CI:1.09-1.45, respectively). ID per ESC guidelines was only associated to mortality in non-anemic HFrEF (HR: 1.24, 95% CI:1.09-1.42) and first HF hospitalization in HFrEF, irrespective of anemia (non- anemic, HR:1.24, 95% CI:1.09-1.42; anemic, HR:1.35, 95% CI:1.2-1.52). No association was observed between the various definitions and outcomes in patients with heart failure with mildly reduced ejection fraction and heart failure with preserved ejection fraction. Conclusion ID, when defined by TSAT &amp;lt;20% or serum iron ≤13 μmol/L, is associated with increased mortality and first hospitalization in HFrEF patients, regardless of anemia. Conversely, ID as per ESC guidelines is associated with mortality in non-anemic HFrEF patients and first hospitalization in HFrEF, irrespective of anemia status.Figure 1:Forest plot mortalityFigure 2:Forest plot hospitalization

Anemia and sideropenia in patients with decompensated heart failure

Abstract Introduction Anemia is highly prevalent in patients with heart failure (HF). In the latest ESC guidelines, intravenous. iron supplementation is recognized as substantial for improving quality of life, exercise capacity and reducing the risk of future hospitalizations in patients diagnosed with HF of reduced ejection fraction (HFrEF). We hypothesized that patients diagnosed with HF of preserved EF (HFpEF) and midly reduced EF (HFmrEF), who also exhibit iron deficiency, may benefit from intravenous iron supplementation. Method We evaluated the prevalence and parameters of anemia from medical histories of hospitalized patients with HFrEF and HFmrEF/HFpEF, from March 2023 to January 2024, and compared them to NTproBNP levels. Results We included 134 hospitalized patients with HF, mean age 71 ± 10 (41% women). Of total 134, 77 patients exhibited acute worsening of chronic HFrEF or were newly diagnosed HFrEF (group A), whereas 57/134 patients had decompensated HFmrEF/HFpEF (11 and 46, respectively - group B) whose iron status was analyzed on admission. General prevalence of anemia in all HF patients was 50.8% (cut off value - hemoglobin concentration less than 12 g/dL in women, and less than 13 g/dL in men), 54.4% of HFpEF/HFmrEF group and 48.1% of HFrEF group had anemia, 46.6% patients with anemia had EF&amp;gt;40%, without any statistical difference among groups (hemoglobin concentration group A/group B – 12.33±2.54/11.89­±2.63 g/dL, CV 0.2). Reduced transferrin saturation, which is defined as less than 20.0%, had 44.0% of all HF patients, and that was more common in HFrEF patients (62.0%), but statistically insignificant (group A/group B - 0.1843±0.10/0.1877±0.11, CV 0.6). Among group A and group B - 63.6% and 62.5% had transferrin saturation less than 0.2, respectively. There was no difference in the prevalence of serum ferritin &amp;lt;100 μg/L in group A and B (41.6% and 47.4% respectively; group A/group B – 177.26±176.7/137.01±126.6, CV 0.9). Spearman’s rank test implied no correlation between NTproBNP levels and serum ferritin or transferrin saturation. Serum iron had a mild negative (coefficient -2.8) correlation with NTproBNP levels (p&amp;lt;0.01). Hemoglobin concentration was associated with strong negative correlation with NTproBNP levels but with less statistical significance (coefficient -0.9 p&amp;lt;0.05). Conclusion Results of our study suggest that anemia and sideropenia are common in our HF population, with no difference between the spectrum of HF subgroups based on EF. There seems to be a correlation between anemia and serum iron and level of NTproBNP which may imply that anemia and low iron worsen the degree of HF decompensation.

Changes in echocardiographic and analytical parameters after iron replacement in stable heart failure patients. FER-STRAIN study

Abstract Background Iron deficiency replacement with intravenous ferric carboxymaltose (FCM) has demonstrated to improve clinical and prognostic parameters in patients with heart failure with reduced left ventricular ejection fraction (HFrEF). Improvement of myocardial contractility is proposed as possible hypothesis and strain could behave as an early and high sensitive parameter to assess this improvement in myocardial deformation due to increased iron availability after replacement of iron deficiency. Purpose Evaluate the effect of iron deficiency replacement with FCM in the strain of both ventricles in patients with stable HFrEF. Methods We performed an observational, analytical, longitudinal and prospective study that included 73 patients with stable HFrEF who presented iron deficiency without anemia defined as serum ferritin &amp;lt;100 ug/L or between 100 and 300 ug/L if the transferrin saturation was &amp;lt;20%. They were randomized 2:1 to iron replacement with FCM or control group. A central core lab, blinded to the treatment/control groups performed 3D echocardiograms and strain analysis. Analytical parameters and biomarkers were determined basal and four weeks after the randomization. Results Mean age of the study population was 70 years old, 77% were male, 75% had high blood pressure, 70% dyslipidemia and 41% diabetes. Of the total, 51 patients were assigned to the replacement group and 22 patients to the control group. Mean left ventricular ejection fraction (LVEF) was 33%, without basal differences between both groups. Four weeks after the randomization, a significant improvement of LVEF of 2.47±2.32% (p=0.018) was observed in the replacement group, as well as in the left ventricle global longitudinal strain (LV-GLS) of -0.96±2.08% (p=0.006). In blood tests, a significant improvement of ferritin (130.9±111.98mg/L, p&amp;lt;0.000), hemoglobin (0.3±0.7g/dL, p=0.027) and medium corpuscular volume (1.7±2.16fL, p=0.005), and also an increase of the biomarker myeloperoxidase (40.16±138.36pmol/L, p=0.02) were detected in the treatment group. Nevertheless, these changes were not observed in the control group. Conclusions In patients with stable HFrEF replacement of iron deficiency with FCM is associated with an improvement of myocardial contractility, of LVEF measured by 3D and LV-GLS.Variation of parametersLV-GLS before and after FCM

Associations of different definitions of iron deficiency with cardiac structure and function, congestion, exercise capacity and prognosis in heart failure

Abstract Background It is uncertain how best to diagnose iron deficiency (ID) in patients with heart failure (HF) as different ID definitions have been proposed with discordant results. Objectives To assess the relationship of different ID definitions with cardiac structure and function, congestion, exercise capacity, and prognosis in outpatients with HF. Methods ID was defined according to guidelines (G-ID: ferritin &amp;lt;100 ng/mL or ferritin 100-299 ng/mL with transferrin saturation [TSAT] &amp;lt;20%) or as TSAT &amp;lt;20%. Alternative definitions (iron &amp;lt;13 ¼mol/L, ferritin &amp;lt;100 and &amp;lt;300 ng/mL) were explored. Relationship with rest and exercise ultrasound findings, cardiopulmonary exercise testing and a composite endpoint of cardiovascular hospitalisations or all-cause mortality were assessed. Results Of 1502 patients (72% with left ventricular ejection fraction [LVEF] ≥50%), 471 (31%) had TSAT &amp;lt;20%, while 728 (48%) had G-ID. Compared to those without ID, patients with TSAT &amp;lt;20% or G-ID showed impaired cardiac structure and function at rest and peak exercise and lower peak oxygen consumption; they were also more likely to display a discontinuous renal venous flow pattern and more lung B-lines. Only TSAT &amp;lt;20% was associated with significant inferior vena cava dilatation. Lower TSAT, iron and haemoglobin were associated with more severe effort intolerance and ultrasound signs of congestion, while ferritin and LVEF were not (Picture 1). During a median follow-up of 16 months, 62 (4%) patients died, and 244 (16%) were hospitalised for cardiovascular reasons. No patients were hospitalised immediately after the enrolment visit because of clinical findings. At Kaplan-Meier analyses, TSAT &amp;lt;20% was associated with a greater risk of adverse events, as were iron ≤13 ¼mol/L, ferritin ≥300 ng/mL and &amp;lt;100 ng/mL (p &amp;lt;0.01 vs ferritin 100-299 ng/mL) and G-ID (Picture 2). After adjusting for age, sex, diabetes, haemoglobin, estimated glomerular filtration rate (eGFR), NT-proBNP, rest LVEF and peak VO2 &amp;lt;16 mL/kg/min, TSAT &amp;lt;20% and iron ≤13 ¼mol/L were associated with worse outcomes (hazard ratio 2.41, 95% confidence interval 1.85-3.14 and 1.90, 1.46-2.47), while G-ID or ferritin &amp;lt;100 or &amp;lt;300 ng/mL were not (Picture 1). Conclusions In outpatients with HF, TSAT &amp;lt;20% is more consistently associated with echocardiographic signs of poorer functional capacity and multi-organ congestion than other ID definitions. TSAT &amp;lt;20% and iron ≤13 ¼mol/L, but not G-ID or ferritin-based ID, seem to predict a worse prognosis.Picture 1Picture 2