Iron Supplementation Research Articles

Effect of Intravenous Iron on Functional Capacity in Patients with Ischemic Cardiomyopathy

Background: Iron deficiency is common in heart failure with reduced ejection fraction. Intravenous (IV) iron supplementation has been found to reduce morbidity in heart failure. However, the effect of IV iron on Bangladeshi patients with heart failure are not known. Objects: The study was done to see the effect of IV iron on functional capacity in Bangladeshi patients with ischaemic cardiomyopathy (ICM) and iron deficiency. Methodology: In this quasi-experimental study, out of 80 hospitalized patients with ICM and iron deficiency, 40 were given IV ferric carboxymaltose (FCM) in addition to standard therapy of heart failure, while another 40 were randomized to standard therapy alone. Primary outcome measure was changes in six-minute walk test (6MWT) distance, while secondary outcome measures were changes in New York Heart Association (NYHA) functional class, left ventricular ejection fraction (LVEF) and plasma NT-proBNP at Weeks 4 and 12. Results: 6MWT distance improved significantly in patients receiving IV iron therapy compared to the patients not receiving IV iron. LVEF improved and plasma NT-proBNP decreased significantly in IV irontreated patients than in patients receiving standard therapy. However, improvement in NYHA functional class was not statistically significant. Conclusion: In Bangladeshi patients with ICM and iron deficiency, IV FCM on top of standard heart failure therapy was associated with improved functional capacity. J Inv Clin Cardiol 2023; 5(2): 32-37

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) <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 <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 <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.

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 <100 ug/L or between 100 and 300 ug/L if the transferrin saturation was <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<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

Improvement of myocardial contractility after iron replacement in stable heart failure patients

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 Observational, analytical, longitudinal and prospective study that included 73 patients with stable HFrEF who presented iron deficiency without anemia defined as serum ferritin <100 ug/L or between 100 and 300 ug/L if the transferrin saturation was <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 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). 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

Prevalent and incident anemia in PARAGON-HF

Abstract Background Anemia is a common comorbidity in patients with heart failure (HF) and is associated with adverse prognosis. Renin-angiotensin system inhibitors (RASi) have been shown to lower hemoglobin levels, potentially related to direct reductions in erythropoetin levels and hematopoiesis. We examined whether sacubitril/valsartan might attenuate this effect of RASi alone on incident anemia in patients with HF with mildly reduced or preserved ejection fraction. Methods PARAGON-HF was a global, multicenter randomized clinical trial of sacubitril/valsartan versus the RASi valsartan in patients with HF and left ventricular ejection fraction≥45%. Anemia was defined as hemoglobin <120 g/L in women and <130 g/L in men. We evaluated changes in hemoglobin, risks of incident anemia and new oral iron initiation during follow-up. We also assessed treatment effects on the primary composite endpoint of total HF hospitalizations (HFH) and cardiovascular (CV) death according to anemia status. Results Among 4,795 participants with a hemoglobin measurement available, 1,111 (23.2%) had anemia at randomization of which 3.5%, 77.7%, and 18.8% were characterized as micro-, normo-, and macrocytic anemia. 5.6% were treated with oral iron at baseline. Over a 2.7-year median follow-up period, patients with anemia were at nearly twice the risk of the primary outcome (21.6 vs. 11.5 per 100py; rate ratio 1.90; 95% CI: 1.62-2.21; P<0.001). Compared with valsartan, sacubitril/valsartan significantly slowed the decline in hemoglobin levels by 1.4 g/L (95% CI: 0.4-2.4 g/L; P = 0.005; Figure 1 Panel A). Participants treated with sacubitril/valsartan were at significantly lower risk of developing anemia (30.3% vs. 37.6%; HR 0.76; 95% CI: 0.68-0.85; P<0.001; Figure 1 Panel B) and starting oral iron therapy (8.1% vs. 10.0%; HR 0.81; 95% CI: 0.67-0.97; P = 0.026; Figure 2). Treatment effects of sacubitril/valsartan vs. valsartan on the primary endpoint were consistent among patients with and without anemia (Pinteraction=1.00). Conclusions Among patients with HF with mildly reduced or preserved ejection fraction, treatment with sacubitril/valsartan resulted in slower declines in hemoglobin, lower rates of incident anemia, and fewer new initiations of iron therapy compared with RASi.

Efficacy and safety of intravenous iron therapy in heart failure patients with iron deficiency: a systematic review and meta-analysis of randomized controlled trials

Abstract Background Heart failure is a diverse life-threatening condition with complex biology and demanding therapeutic goals. Even when anemic patients are excluded, up to 59% of heart failure patients have low ferritin levels, making them especially vulnerable to iron deficiency. Purpose To assess the complete data derived from Randomized controlled trials concerning the benefits and safety of IV ferric carboxymaltose therapy among patients with heart failure with iron deficiency. Methods A systematic review and meta-analysis of randomized controlled trials obtained from PubMed, WOS, SCOPUS, EMBASE, and Cochrane up to August 31, 2023. We used RevMan V. 5.4 to pool dichotomous data using a risk ratio (RR) with a 95% confidence interval (CI). Results We included 14 randomized controlled trials with a total of 6,626 patients. The IV iron group was favored over the control group in reducing hospital admissions for heart failure (first event) (RR= 0.83, 95% CI 0.71 to 0.97; p = 0.02) and (total events) (RR= 0.81, 95% CI 0.74 to 0.89; p < 0.0001). Also, the iron group had a 21% lower risk in terms of cardiovascular death and hospital admission for HF (number of events, rate per 100 patients in a year) (RR= 0.79, 95% CI 0.74 to 0.85; p < 0.00001). Concerning the adverse events, both ferric carboxymaltose and ferric derisomaltose showed a beneficial effect in reducing the cardiac disorder (RR= 0.81, 95% CI 0.76 to 0.87; p <0.0001), and (RR= 0.82, 95% CI 0.71 to 0.95; p = 0.009), respectively. Conclusion IV iron infusion in patients with heart failure has a favorable safety profile. It reduces total hospitalizations for heart failure and cardiovascular mortality, with no effect on all-cause mortality, cardiovascular mortality alone, or first-time hospitalization for heart failure.

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>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 <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<0.01). Hemoglobin concentration was associated with strong negative correlation with NTproBNP levels but with less statistical significance (coefficient -0.9 p<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.

Myocardial performance improvement after iron replacement in heart failure patients with LVEF <50% and TSAT <20%: The IRON-PATH II echo-substudy

Abstract Background Iron deficiency (ID) is a prevalent comorbidity in patients with heart failure (HF) and left ventricular ejection fraction (LVEF) <50%. ID leads to impaired myocardial global function. Some echocardiographic parameters have demonstrated an additive value in advanced assessment of cardiac performance, like global longitudinal strain (GLS), myocardial work (MW) and its derivatives constructive work (CW), wasted work (WW) and work efficiency (WE). The usual definition of ID may have limitations in rightly identifying systemic iron status, especially those with isolated hypoferritinemia. However, the impact on cardiac function measured by echocardiography after intravenous iron replacement according to TSAT values has never been explored. Purpose Describe the myocardial performance associated with systemic ID defined as TSAT <20% in patients with HF compared to patients with HF without ID (TSAT ≥20%). Afterwards, we aimed to explore changes in myocardial function after iron replacement by echocardiography. Methods The IRON-PATH II was a multicenter, prospective, observational study. The total number of patients to be recruited was 210 in 7 centers across Spain and Portugal. Patients with HF and LVEF ≤50%, without signs of fluid overload or low cardiac output, and haemoglobin ≥11 g/dL were included. The IRON-PATH II echo-substudy included 100 patients who undergone a specific pilot evaluation of echocardiographic. All patients undergone an echocardiography at baseline, ID-patients received a second echocardiography three months after ID replenishment. Results The final study cohort included in the echo-substudy consisted of 98 patients, 41 (42%) were classified in the ID group (TSAT <20%). Regarding the usual definition of ID, 7 patients (15%) in the ID group had TSAT ≥20%, while 4 (7%) in the non-ID group showed TSAT <20%. Mean age was 72±10 years, 22 (22%) were women and most were in NYHA functional class II (71%). Ischemic was the main etiology of HF (50%). The ID group presented worse LV function expressed by LVEF (34% vs. 38%), WW (302[235.5-439,75] mmHg% vs. 209.5[136-297.25] mmHg%) and WE (74±10% vs. 80±10%) (Figure 1). Right ventricle function was also worse in the ID group when measured by fractional area change (FAC) (41.76[33.26-50.33] % vs 46.79[39.23 – 54.94] %) and RV coupling ratio (0.52±0.21 vs 0.64±0.24) but not by TAPSE. Strikingly, no differences were observed in any echocardiographic parameter of myocardial function between the non-ID patients compared with the ID-patients after iron replenishment (Table 1). Conclusions TSAT <20% identified ID status that causes impaired myocardial performance in HF patients. This can be reversed with intravenous iron repletion. This reversible damage to cardiac function can be detected by advanced echocardiographic parameters, both for LV (GLS, WE, MW, WW) and for RV (RVFW strain, RV coupling), but not by LVEF or TAPSE.Figure 1Table 1

Iron deficiency and all-cause mortality after myocardial infarction

Abstract Introduction Iron deficiency (ID) is commonly associated with cardiovascular diseases, including myocardial infarction (MI). However, the data on the clinical significance of ID in patients with MI are conflicting. This may be related to the use of various ID criteria. Purpose Our study aimed to compare the association of different ID criteria with all-cause mortality after MI. Methods Consecutive patients hospitalized at a large tertiary heart center for type 1 MI without previous history of coronary artery disease were included. We evaluated the association of different iron metabolism parameters measured on the first day after hospital admission with all-cause mortality during the follow-up. Results Of a cohort of 1,156 patients included (aged 64±12 years, 25% women), 194 (16.8%) died during the median follow-up of 3.4 years (IQR 626-1782 days). A total of 51,7% of post-MI patients had low iron levels (≤13 µmol/L), and 16,3% of them had iron level ≤12.8 µmol/L and soluble transferrin receptor (sTfR) ≥3 mg/L. After multivariate adjustment, iron level ≤13 µmol/L (HR 1.67, 95% CI 1.19-2.34) and the combination of iron level ≤12.8 µmol/L and sTfR ≥3 mg/L (HR 2.56, 95% CI 1.64-3.99) were associated with an increased risk of mortality. This information provided additional predictive value to the GRACE score. No association between ferritin level and mortality was found. Compared to the model which contains iron level, the addition of sTfR improved risk stratification (net reclassification improvement 0.61, 95% CI 0.52-0.69) by reclassifying patients into a higher-risk group. Conclusion ID is common among patients with the first MI. The criteria based on iron and soluble transferrin receptor levels provide the best prediction of mortality, and should be evaluated in future interventional studies with intravenous iron therapy.Kaplan-Meier survival for iron levelsK-M survival for combined ID parameters

Drug-drug interactions of empagliflozin and dapagliflozin

Abstract Introduction The sodium glucose co-transporter2-inhibitors dapagliflozin (Dapa) and empagliflozin (Empa), initially developed as antihyperglycemic agents, are increasingly also prescribed for non-diabetic patients with heart failure (HF). Glucuronidation by uridine-diphosphate glucuronosyltransferase (UGT)1A9 is the main mechanism of metabolism of Dapa, whereas Empa is eliminated mainly by excretion. Both Dapa and Empa are substrates of P-glycoprotein. The risk for drug-drug interactions (DDI) of Empa and Dapa is assumed to be low. Aim of this study was to summarize reports of DDI of Empa and Dapa from the literature. Methods Search-terms in PubMed were "drug-drug interaction" and AND "sodium glucose co-transporter2-inhibitors" OR "SGLT2" OR "dapagliflozin" OR "empagliflozin". The drugs were classified according the Anatomical Therapeutic Chemical (ATC) system. Included were randomized trials, pharmacovigilance studies, case series, case reports, studies in healthy subjects and in vivo data. The funding of the study and the disclosures of the authors were registered. Results In 45 reports DDI of Empa and Dapa with 29 drugs were described (Table). According to the ATC system, these were drugs for the alimentary tract and metabolism (n=5), blood and blood forming organs (n=2), cardiovascular system (n=11), genitourinary system and sex hormones (n=2), antiinfectives (n=2), antineoplastic and immunomodulating agents (n=3), musculo-skeletal system (n=2) and nervous system (n=2). The reports comprised studies in healthy subjects (n=28), case reports (n=7), case series (n=6), pharmacovigilance studies (n=2), a subgroup analysis of a randomized trial (n=1) and in vivo data (n=1). Most of the reports found no clinically relevant DDI (n=32). Dapa and Empa both had a synergistic diuretic effect with bumetanide, and led to severe infections when combined with the interleukin-17-inhibitors secukinumab or ixekizumab. Empa administered with intravenous iron was reported to increase cell-iron availability, with lithium to reduce lithium exposure and with valproate to increase valproate exposure. Dapa administered with sacubitril-valsartan was reported to lead to severe hypotension, with linezolid to pancytopenia, with donafenib to an increased exposure to donafenib, with rifampicin to a reduction and mefenamic acid to an increase in Dapa exposure. Of the 45 reports, 33 were funded by a pharmaceutical company marketing Dapa or Empa and 33 had authors with conflicts of interest with pharmaceutical companies marketing Dapa or Empa. Conclusions Most data about DDI of Empa and Dapa derive from studies in healthy subjects and from the marketing companies. The clinical relevance DDI of Empa and Dapa in polymorbid patients with polymedication is largely unknown. There is an urgent need for independent studies on DDI of these drugs in diabetic and non-diabetic patients with HF.Table

The efficacy of IV iron in anemic heart failure patients: a systemic review and meta-analysis of randomised controlled trials

Abstract Introduction Iron deficiency in the context of heart failure is a multifaceted concern, where the intricate interplay between diminished iron stores, impaired absorption mechanisms, and reduced recycled iron in the reticuloendothelial system adds a layer of complexity to patient management. Initial attempts to address this issue with oral iron treatments have been questioned due to its poor absorption. Intravenous iron therapy is now preferred, as it has been shown to reduce heart failure hospitalisations and cardiovascular mortality. However, there is a lack of randomised studies specifically focused on heart failure patients, highlighting the need for more targeted investigations. Purpose The aim of this review is to provide reliable evidence from published randomised controlled trials (RCTs) regarding the beneficial effect of IV iron in heart failure patients. Methods We systematically searched PubMed, Web of Science, Scopus, and Cochrane Central, and EMBASE from inception until December 2023. We included randomised controlled trials (RCTs) comparing the effect of IV iron in heart failure patients versus placebo. The primary outcomes were 6MWT mean change, ferritin concentration mean change, transferrin saturation mean change and worsening heart failure. All data were pooled as either Mean difference in the random effect model with the corresponding SD or pooled as RR and 95% CI for dichotomous data. Results Twelve RCTs involving 6800 patients were included in the analysis. The overall effect on the measured primary outcomes was in favour of IV iron in terms of 6MWT mean change (MD= 34.45, 95% CI [ 29.58 to 39.31], P=<0.0001), ferritin concentration mean change (MD= 219.18, 95% CI [ 208.7 to 229.66], P=<0.0001), transferrin saturation mean change (MD= 9.77, 95% CI [ 8.14 to 1.39], P=<0.0001) and worsening heart failure (RR= 0.46, 95% CI [ 0.31 to 0.69], P=0.002). Conclusion The introduction of the IV iron therapy to heart failure patients showed a beneficial effect in terms of the measured haematological and cardiovascular metrics, which include 6MW test mean change, ferritin concentration mean change, and worsening heart failure.6MWT mean changeFerritin mean change

Ferroptosis contributes to the development of cardiac dysfunction in iron overload cardiomyopathy

Abstract Background Ferroptosis is a novel form of cell death, and its role in iron overload cardiomyopathy (IOC) has not been elucidated. Purpose To explore whether ferroptosis of cardiomyocytes contributes to cardiac dysfunction in IOC by cardiac MR (CMR) and molecular biology techniques in vivo. Methods A total of 14 Sprague-Dawley (SD) rats were randomly divided into two groups: the control group (n=6) and the IOC group (n=8). The latter was induced by intraperitoneal injection of iron dextran on alternate days for 9 weeks and underwent a 7T CMR for assessment of cardiac function, including left ventricular ejection fraction (LVEF) and global longitude strain (GLS), along with the assessment of iron overload severity and fibrosis using Cine, T2 mapping, and late gadolinium enhancement (LGE), respectively. Circulating iron overload was determined via blood biochemistry analysis, measuring serum iron, ferritin, and transferrin levels. Furthermore, Prussian blue and Masson staining were employed to identify iron and fibrosis deposition within the myocardium, respectively. Cardiac ultrastructure, especially mitochondria, was examined via transmission electron microscopy (TEM). A sensitive fluorescent probe, dihydroethidium (DHE), was employed for the detection of reactive oxygen species (ROS) levels. Malondialdehyde (MDA), prostaglandin-endoperoxide synthase 2 (PTGS2), and glutathione peroxidase 4 (GPX4) were utilized to identify and quantify levels of lipid peroxidation, thereby providing comprehensive insights into cardiac cellular ferroptosis. Results 6 rats survived in the control group and 5 in the IOC group. Compared with the control group, the IOC rats had reduced T2 values of the cardiac septum (P<0.001), with normal LVEF (P>0.05) but decreased GLS (P<0.01), seen in Fig 1A. Based on blood biochemistry and Prussian blue staining, they were evident that IOC rats exhibited both circulating and cardiac iron overload, as seen in Figure 1B, C. Masson staining showed no obvious myocardial fibrosis, which was consistent with negative CMR LGE results, seen in Fig 1A, B. TEM further elucidated cardiac mitochondrial injuries in IOC rats, including focal vacuolization, swelling, crest disruption, and even disappearance, seen in Fig 2A. The fluorescent probe results revealed a striking increase in red fluorescence within the myocardium of IOC rats, seen in Fig 2B. Additionally, IOC rats exhibited significantly elevated levels of MDA and PTGS2mRNA (P<0.001), accompanied by notable downregulation of GPX4mRNA expression (P<0.001), seen in Fig 2C. These findings suggested the occurrence of ferroptosis in the myocardium of IOC rats. Conclusions In IOC, ferroptosis rather than necrosis is the primary driver of cardiac dysfunction, which is characterized by maintaining normal LVEF but experiencing a reduction in GLS without accompanying myocardial fibrosis. Our study sheds light on the potential involvement of ferroptosis in the pathogenesis of IOC.

Iron chelation therapy failed to improve cardiac dysfunction caused by mitochondrial injury in rats with iron overload cardiomyopathy a 7T Cardiac MR research in vivo

Abstract Purpose To assess the efficacy of iron chelation therapy in improving cardiac function in iron overload cardiomyopathy (IOC) rats by using Cardiac magnetic resonance feature-tracking (CMR-FT). Methods The IOC rat model was induced by intraperitoneal injection of iron dextran over 2 months. Subsequently, 7 rats with IOC were assigned as IOC group to receive continued intraperitoneal injections of saline for an additional 2 months, while another group of 5 rats received intraperitoneal injections of deferoxamine (DFO) for the same duration, forming the IOC+DFO group. Meanwhile, a control group consisting of 7 healthy rats received intraperitoneal injections of saline for the entire duration of 4 months. All rats underwent a 7T CMR scan to assess cardiac function, myocardial iron overload, and myocardial fibrosis via cine, T2 mapping, and late gadolinium enhancement (LGE) scanning, respectively. The cardiac function analysis included left ventricular ejection fraction (LVEF) and left ventricular global longitudinal strain (GLS) using cine images. Following CMR scans, all rats underwent open-chest blood collection to detect serum iron levels, and cardiac gross specimens were then subjected to pathological staining, including hematoxylin and eosin (HE) for cardiomyocytes injury, Prussian blue for iron deposition , and Masson staining for myocardial fibrosis. Furthermore, the ultrastructure of cardiomyocyte was examined using transmission electron microscopy (TEM). Results The T2 value, measured in the septum wall at the mid-layer of the LV, and LVEF, and GLS exhibited a significant decrease in the IOC or IOC+DFO group, compared to the control group, while there were no significant difference observed between the IOC and IOC+DFO group (Fig. 1A, B, C). Myocardial fibrosis was not detected in the LGE images in both IOC and IOC+DFO group. Compared to the control group (37.5±12.5μmol/L) , serum iron levels were significantly elevated in the IOC group (368.6±181.0μmol/L) and in chelation treatment group (106.1±32.2μmol/L). Histological examination with HE staining revealed a normal arrangement of myocardial cells in all rats, without cellular degeneration or necrosis. Prussian blue staining highlighted the presence of iron particles within the myocardial interstitium in the IOC and IOC+DFO groups. Masson staining demonstrated intact myocardial muscle bundles without any evidence of myocardial fibrosis. Transmission electron microscopy (TEM) revealed myocardial mitochondria injury, characterized by ruptured outer membranes, reduced cristae, and vacuolization. Conclusions Following iron chelation therapy, the excessive iron burden in the bloodstream was alleviated. However, myocardial iron overload persisted in IOC rats, with no significant improvement in cardiac function observed. This persistence may be attributed to mitochondrial injury. The findings underscore the importance of monitoring cardiac dysfunction in patients with iron overload.CMR parameters analysis in IOC rats

Impact of global longitudinal strain and anemia for predicting cardiovascular mortality in patients hospitalized for acute heart failure with atrial fibrillation

Abstract Background Iron deficiency is a prognostic factor in heart failure (HF) with reduced ejection fraction (EF). In patients with atrial fibrillation (AF) and HF, left ventricular EF (LVEF) measurements are imprecise due to irregular tachycardia, but it is unclear whether global longitudinal strain (GLS) and anemia assessment are prognostic. Purpose We examined whether GLS and anemia predict cardiovascular death (CD) in patients with acute HF complicated by AF. Methods We retrospectively enrolled patients aged 18 years or older with acute HF complicated by AF who were consecutively admitted to our hospital from January 2014 to December 2018. Exclusion criteria were acute coronary syndromes, no transthoracic echocardiogram performed within 30 days before or after admission, and missing data. All patients were followed up from admission to CD (due to myocardial infarction, HF, stroke or sudden death), or were censored at the date of last contact or 3 years. Anemia was defined as hemoglobin < 12 g/dL in females and hemoglobin < 13 g/dL in males. Patients were divided into four groups according to median GLS and anemia status. Results A total of 320 patients (mean age 79 ± 12 years, 163 females) were included in the analysis. The median duration of AF was 1.2 years; 11% (36/320) had paroxysmal AF. The median brain natriuretic peptide value was 623 pg/ml, and 52% of the patients (165/320) were in New York Heart Association functional class 4. During a median follow-up of 528 days, 24% (77/320) patients were observed with CDs: 2 myocardial infarctions, 51 HF-related deaths, 6 strokes, and 18 sudden cardiac deaths. At the 3-year follow-up, the survival rate by the Kaplan-Meier curve was 89% (95% confidence interval (CI) 76%-95%) in the no anemia group with high GLS (< -10%) and 40% (95% CI 25%-54%) in the anemia group with low GLS (≥ -10%) (p < 0.001, log-rank test). In multivariate Cox regression analysis, GLS (adjusted hazard ratio (aHR) 1.06, 95% CI 1.01-1.14, p = 0.017) and hemoglobin (aHR 0.85, 95% CI 0.76-0.96, p = 0.009) were independent factors for CD, with a significantly increased risk in the anemia group with low GLS compared to the no anemia group with high GLS (aHR 4.11, 95% CI 1.59-10.6, p = 0.004). The results were consistent with no interaction by gender or LVEF 50%. Conclusions Anemic patients with low GLS with AF and HF may have poor prognosis. Prospective studies are needed to determine whether iron supplementation improves prognosis in such patients.

Effects of eHealth literacy on maternal and neonatal outcomes

ABSTRACT eHealth literacy plays a crucial role during pregnancy, as maternal health behavior can influence health outcomes for both mother and child. This study assessed the impact of eHealth literacy on maternal-fetal health outcomes through a cross-sectional analysis of 1,265 pregnant women admitted to a tertiary maternity hospital in Turkey between April and July 2022. Data on sociodemographic information, obstetric variables, birth outcomes, Internet usage, and eHealth Literacy Scale (eHEALS) were collected. Kolmogorov-Smirnov, Mann – Whitney U, Kruskal-Wallis, and Spearman correlation were used for data analysis. The median age of women was 28 years, and the mean gestational age was 38.6 weeks. Median eHealth literacy score was 21 (range:8-40). Pregnant women who had planned pregnancies, received spousal support, attended 9–12 antenatal care visits, received vaccinations, adhered to iron and folic acid supplementation, engaged in regular physical activity, and maintained regular sleep patterns exhibited higher eHealth scores (all p < .001). eHEALS scores were higher in women who experienced normal vaginal deliveries (p < .001), while lower eHEALS scores were noted in those with comorbidities (p = .001). The study suggested that higher eHealth literacy among pregnant women was associated with improved health-promoting behaviors, more favorable health perceptions, increased utilization of health services, and better maternal and fetal outcomes.

Safety of an Accelerated Ferric Gluconate Inpatient Infusion Regimen

Background: Inpatient use of intravenous iron has been increasing. Ferric gluconate is traditionally given once daily. Twice-daily dosing provides faster iron repletion, but there are limited data to support the safety of twice-daily dosing. Objective: The aim of this study was to investigate the safety of twice-daily dosing for ferric gluconate compared with daily dosing. Methods: This was an institutional review board-approved retrospective observational study of hospitalized adult patients who received intravenous ferric gluconate 250 mg daily or twice daily between January 1 and April 3, 2022. The primary composite safety outcome included hypotension, infusion reaction, rapid response alert, or escalation in level of care. Secondary outcomes included total amount of iron received, hospital length of stay, and changes in laboratory values. Results: A total of 126 patients were included in this study, with 63 patients in each group. The primary outcome occurred in 29 patients (46%) in the twice-daily group compared with 36 patients (57.1%) in the daily group (relative risk = 0.81; 95% CI, 0.57-1.13; P = 0.212). Changes in iron, hemoglobin, and transferrin saturation were similar between the 2 groups. Median length of stay was statistically shorter in the twice-daily group (7.79 days) compared with the daily group (12.9 days; p = 0.006). Conclusions: In this retrospective single-center study of hospitalized adult patients, those who received intravenous ferric gluconate twice daily did not experience an increased rate of a composite safety outcome of hypotension, infusion reactions, or escalation in level of care compared with those with daily dosing.

Mid-term efficacy of single anastomosis duodenal-ileal bypass with sleeve gastrectomy in the treatment of obesity and type 2 diabetes mellitus

Objective: To evaluate the mid-term efficacy of single anastomosis duodenal-ileal bypass with sleeve gastrectomy (SADI-S) in the treatment of obesity and type 2 diabetes mellitus. Methods: The cohort of this retrospective observational study comprised 118 obese patients with body mass index (BMI) ≥40 kg/m2 with or without other related metabolic diseases and BMI of (27.5-40.0) kg/m2 with type 2 diabetes mellitus (T2DM) who had been treated with SADI-S. Patients who had undergone modified surgery or been followed up for less than 1 year were excluded. Clinical data of the included patients [56 men and 62 women aged (34.5±9.7) years], who had undergone SADI-S in China-Japan Union Hospital, Jilin University from October 2018 to August 2022, were collected. Their mean preoperative body mass was (125.9±25.0) kg and BMI (42.8±6.8) kg/m2. The 60 patients with T2DM had a mean fasting blood glucose of (9.9±3.2) mmol/L and HBA1c of (8.4±1.7) % before surgery. The main outcome measures were mid-term weight loss after surgery (body mass, BMI, excess weight loss, and total weight loss) 1, 2, 3, and 4 years after surgery and efficacy regarding diabetes mellitus (fasting blood glucose, glycated hemoglobin and diabetes remission rate at 1, 2, and 3 years after surgery). Outcomes were defined as follows. Complete remission: HbA1c <6% or fasting blood glucose <6 mmol/L without hypoglycemic medication; partial remission: HBA1c <6.5% or fasting blood glucose <7 mmol/L without hypoglycemic medication; significant improvement: HBA1c <7.0%, stable decrease of at least 1% compared with preoperative HBA1c, and postoperative dose of hypoglycemic medication significantly less; ineffective: no change in HBA1c and no reduction in dosage of hypoglycemic medication. Other outcome measures included intraoperative and postoperative adverse effects and postoperative nutritional indexes. Results: SADI-S was successful in all patients. There was no significant bleeding, conversion to open surgery, or perioperative death. The operation time was (186.1±41.5) minutes, and the postoperative hospital stay 6 (5-7) days. Surgical complications occurred in four patients, comprising peritoneal effusion, internal jugular vein thrombosis, anastomotic leakage, and gastric fistula. Body weight and BMI 1, 2, 3 and 4 years were significantly lower post- than pre-operatively (all P<0.05). Excess weight loss was (81.9±16.2) %, (82.2±15.5) %, (88.3±20.1) %, and (83.2±18.1) % at 1, 2, 3, and 4 years postoperatively, respectively. Total weight loss was (39.7±8.7) %, (40.6±10.6) %, (42.2±11.5) % and (45.4±10.2) %, respectively. The mean fasting blood glucose concentrations of the 60 patients with T2DM were (5.1±1.0) mmol/L, (5.0±0.7) mmol/L, and (5.4±0.9) mmol/L 1, 2 and 3 years postoperatively, respectively. The values for glycosylated hemoglobin were (4.9±0.6) %, (4.8±0.5) %, and (5.1±0.8) %, respectively, all of which are significantly lower than preoperatively (all P<0.05). The complete remission rate of diabetes was 95.0% (38/40), 90.0% (36/40), and 9/13 1, 2, and 3 years postoperatively, respectively. Additionally, the partial remission rate and significant improvement rate were both 100%. Two years postoperatively, the incidence of anemia was 27.8% (10/36), of hypoproteinemia 11.8% (4/34), and of ferritin deficiency 25.8% (8/31), all of which were improved by conservative treatment such as blood transfusion, iron supplementation, and adjustment of diet. Conclusion: SADI-S has a significant mid-term beneficial effect on weight loss and diabetes remission status in patients with obesity and type 2 diabetes.

Effect of correcting iron deficiency on the risk of serious infection in heart failure: Insights from the IRONMAN trial.

Concerns exist that intravenous (IV) iron might increase the risk of infections. The IRONMAN trial provided an opportunity to investigate whether giving IV ferric derisomaltose (FDI) to patients with heart failure and iron deficiency alters the rate of hospitalization or death due to infections. IRONMAN was a randomized trial of IV FDI versus usual care in patients with symptomatic heart failure, left ventricular ejection fraction (LVEF) ≤45%, and transferrin saturation (TSAT) <20% or ferritin <100 μg/L. Infection was a pre-specified, blindly-adjudicated, safety endpoint. The primary analysis of interest was infection as the main reason for hospitalization or death, using first and recurrent events analyses. The composite primary event of interest tended to be lower in those randomized to FDI when analysed as first (hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.62-1.01, p = 0.055) or recurrent event (rate ratio 0.85, 95% CI 0.64-1.13, p = 0.089). The composite results were driven by fewer hospitalizations for infection (HR 0.76, 95% CI 0.49-0.98, p = 0.032), with 5% fewer patients (absolute reduction) experiencing such an event if assigned to FDI. Similar trends were observed for recurrent events (HR 0.82, 95% CI 0.62-1.10). Further analyses suggested that the reduction in hospitalizations due to infection with FDI was restricted to patients with TSAT <20%. In patients with heart failure and a reduced LVEF, correction of iron deficiency is not associated with an increased risk of hospitalization or death from infection, and may reduce such events, especially when TSAT is <20%. ClinicalTrials.gov, NCT02642562.

Case report: exome sequencing identified mutations in the LRP5 and LGR4 genes in a case of osteoporosis with recurrent fractures and extraskeletal manifestations

BackgroundGenetic mutations have been reported in a number of bone disorders with or without extra-skeletal manifestations. The purpose of the present study was to investigate the genetic cause in a middle-aged woman with osteoporosis, recurrent fractures and extraskeletal manifestations.MethodsA 56-year-old Indian woman presented to the clinic with complaints of difficulty in walking, recurrent fractures, limb bending, progressive skeletal deformities, and poor overall health. At the age of 37, she had experienced severe anemia with diarrhea, significant weight loss, knuckle pigmentation, and a significant loss of scalp hair. She had received multiple blood transfusions and parenteral iron supplementation with normalization of hemoglobin. Subsequently, she had premature menopause at the age of 37. She died at the age of 61 due to liver failure. Exome sequencing followed by Sanger sequencing were undertaken to identify the potential pathogenic mutations.ResultsGenetic investigation identified likely pathogenic mutations in the LRP5 and LGR4 genes. Out of the two mutations, the heterozygous mutation (c.1199C&amp;gt;T) in the LRP5 gene resulted in a non-synonymous substitution of alanine with valine at the 400th position, and the second mutation (c.1403A&amp;gt;C) in the LGR4 gene led to a non-synonymous substitution of tyrosine with serine at the 468th residue of the protein. The minor allele frequencies of the c.1199C&amp;gt;T (LRP5) substitution in the 1000 genomes and IndiGenomes databases are 0.0003 and 0.001, while the c.1403A&amp;gt;C (LGR4) substitution has not been reported in these databases. Various in silico prediction tools suggested LGR4 mutation to be pathogenic and LRP5 mutation to be likely pathogenic.ConclusionHeterozygous mutations in the LRP5 and LGR4 genes had additive deteriorative effects on BMD, resulting in recurrent fractures and bone deformities, and extended the effect to extraskeletal sites, contributing to the poor overall health in this patient.

An assessment of adequate quality antenatal care and its determinants in India

BackgroundAntenatal care (ANC) is an important component in the continuum of care. Providing adequate quality ANC is necessary to prevent maternal and newborn mortality. The coverage of ANC has increased significantly in the last decade in India, but a mere increase in coverage is insufficient if the issue of quality is not simultaneously addressed. This study examines the change in each component of quality ANC between 2015-16 and 2019-21, highlights the factors associated with adequate quality ANC, and observes the state- and district-level distribution of adequate quality ANC during 2019-21.MethodsThis study is based on data from the two most recent rounds of the National Family Health Survey (NFHS), the Indian equivalent of the Demographic and Health Surveys (DHS). These rounds were conducted in 2015-16 and 2019-21 in selected households of India with a total of 190,797 and 176,843 sampled births, respectively. The dependent variable was quality antenatal care, a composite variable consisting of skilled healthcare providers, timeliness, sufficiency, and appropriateness of content. The independent variables were mother’s age, education, wealth quintile, birth order, mass media exposure, health insurance coverage, relationship with the head of household, facility exposure, intended pregnancy, history of adverse pregnancy outcomes, and other socio-demographic variables. Change in each component and dimension of quality antenatal care was assessed using data from both rounds of the survey. A multivariate multinomial logistic regression analysis was employed to identify the determinants of adequate quality ANC using the NFHS-5 data.ResultsThe findings revealed that 32 per cent of mothers received adequate quality antenatal care in 2019–2021, an increase of only 9% points compared to the 2015-16 period. Two significant barriers to achieving adequate quality antenatal care, in terms of appropriateness of content, were the provision of Iron and Folic Acid (IFA) tablets and counselling. The highest utilisation of adequate quality antenatal care was observed in the southern states. The utilisation of quality ANC increased with an increase in women’s education and wealth status; and was more prevalent among those with health insurance coverage and exposure to mass media.ConclusionDespite some improvements in the coverage of antenatal care, the quality of antenatal care continues to be very low and needs urgent attention. Achieving quality antenatal care in both content and experience requires addressing service gaps and developing better measures to capture and improve women’s care experiences.