Cross-sectional and longitudinal associations of Iron biomarkers and cardiovascular risk factors in pre- and postmenopausal women: leveraging repeated measurements to address natural variability.

BACKGROUND: The association between iron biomarkers and cardiovascular disease risk factors (CVD-RFs) remains unclear. We aimed to (1) evaluate the cross-sectional and longitudinal associations between iron biomarkers (serum ferritin, transferrin saturation (TSAT), transferrin) and CVD-RFs among women, and (2) explore if these associations were modified by menopausal status. METHOD: Cross-sectional and longitudinal analyses including 2542 and 1482 women from CoLaus cohort, respectively. Multiple linear regression and multilevel mixed models were used to analyse the associations between Iron biomarkers and CVD-RFs. Variability of outcomes and iron markers between surveys was accessed using intraclass correlation (ICC). RESULTS: After multivariable adjustment, elevated serum ferritin levels were associated with increased insulin and glucose levels, while higher transferrin levels were linked to elevated glucose, insulin and total cholesterol, and systolic and diastolic blood pressure (p < 0.05). No association was observed between CVD-RFs and TSAT (p > 0.05). Iron biomarkers demonstrated low reliability across reproductive stages but exhibited stronger associations in the perimenopausal group. In longitudinal analysis, we found association only for transferrin with lower glucose levels [ß = - 0.59, 95% CI (- 1.10, - 0.08), p = 0.02] and lower diastolic blood pressure [ß = - 7.81, 95% CI (- 15.9, - 0.56), p = 0.04]. CONCLUSION: In cross-sectional analysis, transferrin was associated with several CVD-RFs, and the associations did not change according to menopausal status. Conversely, in the longitudinal analyses, changes in transferrin were associated only with lower glucose and diastolic blood pressure levels. These differences might stem from the substantial longitudinal variation of iron biomarkers, underscoring the need for multiple iron measurements in longitudinal analyses.

The complementary roles of iron and estrogen in menopausal differences in cardiometabolic outcomes.

Biological hormonal changes are frequently cited as an explanatory factor of sex and menopause differences in cardiometabolic diseases (CMD) and its associated risk factors. However, iron metabolism which varies between sexes and among women of different reproductive stages could also play a role. Recent evidence suggest that iron may contribute to CMD risk by modulating oxidative stress pathways and inflammatory responses, offering insights into the mechanistic interplay between iron and CMD development. In the current review, we provide a critical appraisal of the existing evidence on sex and menopausal differences in CMD, discuss the pitfall of current estrogen hypothesis as sole explanation, and the emerging role of iron in CMD as complementary pathway. Prior to menopause, body iron stores are lower in females as compared to males, but the increase during and after menopause, is tandem with an increased CMD risk. Importantly, basic science experiments show that an increased iron status is related to the development of type 2 diabetes (T2D), and different cardiovascular diseases (CVD). While epidemiological studies have consistently reported associations between heme iron intake and some iron biomarkers such as ferritin and transferrin saturation with the risk of T2D, the evidence regarding their connection to CVD remains controversial. We delve into the factors contributing to this inconsistency, and the limitation of relying on observational evidence, as it does not necessarily imply causation. In conclusion, we provide recommendations for future studies on evaluating the potential role of iron in elucidating the sex and menopausal differences observed in CMD.

Changes in Iron Status Biomarkers with Advancing Age According to Sex and Menopause: A Population-Based Study.

BACKGROUND: The risk of chronic diseases increases markedly with age and after menopause. An increase in bodily iron following menopause could contribute to this phenomenon of increased risk of chronic diseases. We aimed to investigate how various iron biomarkers change with advancing age, according to sex and menopausal status. METHODS: We enrolled community-dwelling individuals with available information on ferritin, transferrin, iron, hepcidin, and soluble transferrin receptor levels from the Prevention of Renal and Vascular Endstage Disease study. The association of the iron biomarkers with age, sex, and menopausal status was investigated with linear regression models. RESULTS: Mean (SD) age of the 5222 individuals (2680 women [51.3%], among whom 907 [33.8%] were premenopausal, 529 [19.7%] perimenopausal, and 785 [29.3%] postmenopausal), was 53.4 (12.0) years. Iron biomarkers showed a constant increase in women throughout their life course, in some cases at older ages surpassing values in men who, in turn, showed consistently higher levels of iron status compared to women in most age categories. Ferritin, hepcidin, and transferrin saturation levels were 3.03, 2.92, and 1.08-fold (all p < 0.001) higher in postmenopausal women compared to premenopausal. CONCLUSIONS: We found that iron accumulates differently depending on sex, age, and menopausal status. An increased iron status was identified in women, especially during and after menopause.

Criteria to predict midterm outcome after stenting of chronic iliac vein obstructions (PROMISE trial).

BACKGROUND: Endovenous stent placement has become a first-line approach to prevent post-thrombotic syndrome in patients with chronic post-thrombotic obstruction (PTO) or nonthrombotic iliac vein lesions if conservative management fails. This study aims to identify factors associated with loss of patency to facilitate patient selection for endovenous stenting. METHODS: We retrospectively analyzed 108 consecutive patients after successful endovenous stenting for chronic vein obstruction performed at a single institution from January 2008 to July 2020. Using multivariable logistic regression, we explored potential predictive factors for loss of stent patency, including baseline demographics, post-thrombotic changes, and peak flow velocities measured in the common femoral vein (CFV), deep femoral vein, and femoral vein (FV) using duplex ultrasound examination. RESULTS: The mean follow-up duration was 41 ± 26 months, and participants had a mean age of 47.4 ± 15.4 years with 46.3% women. Ninety (83.3%) patients had PTO and 18 (16.7%) had nonthrombotic iliac vein lesions, predominantly due to May-Thurner syndrome. Loss of patency occurred in 20 (18.5%) patients, all treated for PTO. Comorbidities, side of intervention, and sex did not differ between patients with occluded and patent stents. Stent occlusion was more common with increasing number of stents implanted (P < .001) and with distal stent extension into and beyond the CFV (P < .001). Preinterventional predictive factors for stent occlusion were lower duplex ultrasound peak velocity in the CFV (odds ratio [OR]: 7.52, 95% confidence interval [CI]: 2.54-22.28; P < .001) and FV (OR: 10.75, 95% CI: 2.07-55.82; P < .005), and post-thrombotic changes in the deep femoral vein (OR: 4.51, 95% CI: 1.53-13.25; P = .006) and FV (OR: 3.62: 95% CI: 1.11-11.84; P = .033). Peak velocities of ≤7 cm/s (interquartile range: 0-20 cm/s) in the CVF and ≤8 cm/s (interquartile range: 5-10 cm/s) in the FV were significantly associated with loss of patency. CONCLUSIONS: Insufficient venous inflow as assessed by low peak velocities in the CFV and FV as well as post-thrombotic findings represent reliable risk predictors for stent occlusions, warranting their inclusion into the decision-making process for invasive treatment of PTO.

Sex and N-terminal pro B-type natriuretic peptide: The potential mediating role of iron biomarkers.

Background: Levels of N-terminal pro B-type natriuretic peptide (NT-proBNP), a marker of heart failure and cardiovascular risk, are generally higher in women than men. We explored whether iron biomarkers mediate sex differences in NT-proBNP levels. Methods: We included 5,343 community-dwelling individuals from the Prevention of Renal and Vascular Endstage Disease study. With linear regression analyses, we investigated the association of sex and iron biomarkers with NT-proBNP levels, independent of adjustment for potential confounders. The assessed iron biomarkers included ferritin, transferrin saturation (TSAT), hepcidin, and soluble transferrin receptor (sTfR). Next, we performed mediation analyses to investigate to which extent iron biomarkers influence the association between sex and NT-proBNP. Results: Of the included 5,343 participants, the mean standard deviation age was 52.2 ± 11.6 years and 52% were females. After adjustment for potential confounders, women compared to men, had higher NT-proBNP (ß = 0.31; 95%CI = 0.29, 0.34), but lower ferritin (ß = -0.37; 95%CI = -0.39, -0.35), hepcidin (ß = -0.22, 95%CI = -0.24, -0.20), and TSAT (ß = -0.07, 95% CI = -0.08, -0.06). Lower ferritin (ß = -0.05, 95%CI = -0.08, -0.02), lower hepcidin (ß = -0.04, 95%CI = -0.07, -0.006), and higher TSAT (ß = 0.07; 95%CI = 0.01, 0.13) were associated with higher NT-proBNP. In mediation analyses, ferritin and hepcidin explained 6.5 and 3.1% of the association between sex and NT-proBNP, respectively, while TSAT minimally suppressed (1.9%) this association. Conclusion: Our findings suggest that iron biomarkers marginally explain sex differences in levels of NT-proBNP. Future studies are needed to explore causality and potential mechanisms underlying these pathways.

The effect of vitamin D supplementation on the progression of benign prostatic hyperplasia: A randomized controlled trial.

BACKGROUND AND AIMS: Inflammation and proliferation are the cause of benign prostatic hyperplasia (BPH) and are the key components of its mechanism of action. In this study we sought to determine the role of 25-hydroxyvitamin D in BPH, because of its anti-inflammatory activities, and its effect on prostate volume and BPH symptoms. METHODS: This randomized clinical trial (RCT) was conducted on 108 participants >50 years of age who had either asymptomatic or mild BPH symptoms according to the International Prostate Symptom Score (IPSS) questionnaire. Patients were randomly divided into two groups, intervention and control. The intervention group received 50 000 units of vitamin D3 and the control group received a placebo every two weeks for six months. Prostate ultrasound, routine clinical examinations, toucher rectal (TR), and laboratory tests were performed for all patients. After six months, the patients underwent another ultrasound evaluation, measurement of prostate-specific antigen (PSA) levels and completed the IPSS. Results of the evaluations before and after the intervention were compared between the groups using the chi-square, t-test, and logistic regression analysis. Repeated measure analysis was used to evaluate the effect of vitamin D intervention on the changes in the IPSS score. RESULTS: The mean age of the participants was 56 ± 9 years. In the control group, the mean prostate volume was higher compared to the intervention group (p < 0.001). The control group had a higher mean PSA level than the intervention group (p < 0.001). Although the IPSS score decreased over time in both groups, analysis of variance showed that the amount of change or decrease in IPSS score in the intervention group was significantly more than the control group (p < 0.001). CONCLUSIONS: The results of our study support the effect of vitamin D in reducing prostate volume and PSA levels, and in improving BPH symptoms. Further studies are needed to confirm these findings to verify the use of vitamin D as a treatment for BPH.

Short stay in general intensive care units: is it always necessary?

BACKGROUND: There are challenges ahead of short-term hospitalization of low-risk patients hospitalized only for monitoring of severe disease who may die soon after admission. The purpose of this study was to suggest strategies forthe management of ICU stay lengths and to ensure optimal use of ICU resources. METHODS: The study was conducted retrospectively on 246 patients admitted to 9 general ICUs in Tehran, from September 2011 to March 2012. Patients staying for≤2 days in the ICU were compared to each other after being categorized into two medical and surgical groups. RESULTS: Of 129 patients with≤2 days ICU stay (52.4%), 88.4% survived. Of these, 25 (19.4%) were placed in the medical and 104 (80.6%) to surgical groups. Survival rates were significantly greater in surgical group; only 7.7% of them were in need of mechanical ventilation in the first 24 hours of admission (p<0.001). In contrast to medical group, the average Acute Physiology and Chronic Health Evaluation (APACHE) II score in the surgical group was significantly lower (9.8±3.6 and 17.3±5.8) (p<0.001). CONCLUSION: The majority of patients with≤2 days LOS in the surgical group hospitalized for monitoring after surgery had low mortality rate and APACHE-II score. Therefore, it would seem that transferring such patients to the intermediate care unit leads to more efficient and optimal use of ICU resources.

The relationship between body mass index and outcomes in leukemic patients undergoing allogeneic hematopoietic stem cell transplantation.

Hematopoietic stem cell transplantation (HSCT) is being used increasingly in an attempt to cure many hematological disorders. Obesity has become a world wide phenomenon and is a known risk factor for numerous medical conditions, but its role in transplant outcomes remained controversial. Total of 192 patients with acute leukemia who underwent sibling HLA matched HSCT were analyzed to find the effect of pre-transplant body mass index (BMI) on transplant outcomes such as time to engraftment, infections, graft vs. host disease (GvHD), and overall survival (OS) for the period of three yr (April 2006-March 2009). There was a significant correlation between higher pre-transplant BMI and shorter engraftment time (p = 0.010); but no relation between BMI and GvHD, infection, and OS was found. The results of this study showed that patients with higher BMI may have a shorter engraftment time; but lower, although not significant, survival rate compared to non-obese patients.

Comparison of peripheral blood stem cell transplant with bone marrow transplant in class 3 thalassemic patients.

OBJECTIVES: This study aimed to compare outcome of bone marrow transplant with peripheral blood stem cell transplant in class 3 thalassemic patients. MATERIALS AND METHODS: Respectively, 32 and 20 class 3 thalassemic patients received bone marrow transplant and peripheral blood stem cell transplant from human leukocyte antigen identical sibling donors. Conditioning regimen consisted of busulfan (16 mg/kg) and cyclophosphamide (160 mg/kg) followed by cyclosporine and methotrexate as graft-versus-host disease prophylaxes. RESULTS: Median time to absolute neutrophil count was significantly shorter in the peripheral blood stem cell transplant group (12 vs 23 days); however, there was no significant difference regarding platelet recovery between the 2 groups (20 vs 28 days). Acute graft-versus-host disease occurred in 47% of patients. Chronic graft-versus-host disease developed in 28% of patients which was significantly higher in the peripheral blood stem cell transplant group (P = .06). During 50 months follow-up, thalassemia recurrence, overall survival, and thalassemia-free survival were 17%, 80%, and 65%, respectively, and there were no significant differences between the 2 groups. CONCLUSIONS: These results showed that stem cell transplant is an effective treatment in class 3 thalassemic patients with the outcome relatively similar to bone marrow transplant. Although engraftment time is shorter in peripheral blood stem cell transplant method, it is associated with higher rate of chronic graft-versus-host disease.

Stem cell transplantation; Iranian experience.

From March 1991 through 31st December 2007, 2042 patients underwent stem cell transplantation at the Hematology-Oncology and Stem Cell Transplantation Research Center, affiliated to Tehran University of Medical Sciences. These transplantations included 1405 allogeneic stem cell transplantation, 624 autologous stem cell transplantation, and 13 syngeneic stem cell transplantation. Stem cell transplantation was performed for various diseases including acute myelogenous leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, chronic lymphoblastic leukemia, thalassemia major, sickle cell thalassemia, sickle cell disease, multiple myeloma, myelodysplasia, mucopolysaccharidosis, paroxysmal nocturnal hemoglobinuria, non-Hodgkin's lymphoma, Hodgkin's disease, severe aplastic anemia, plasma cell leukemia, Niemann-Pick disease, Fanconi anemia, severe combine immunodeficiency, congenital neutropenia, leukocyte adhesion deficiencies, Chediak-Higashi syndrome, osteopetrosis, histiocytosis X, Hurler syndrome, amyloidosis, systemic sclerosis, breast cancer, Ewing's sarcoma, testicular cancer, germ cell tumors, neuroblastoma, medulloblastoma, renal cell carcinoma, nasopharyngeal carcinoma, ovarian cancer, Wilms' tumor, rhabdomyosarcoma, pancreatoblastoma, and multiple sclerosis. We had 105 cellular therapies for postmyocardial infarction, multiple sclerosis, cirrhosis, head of femur necrosis, and renal cell carcinoma. About 30 patients were retransplanted in this center. About 74.9% of the patients (1530 of 2042) remained alive between one to 168 months after stem cell transplantation. Nearly 25.1% (512 of 2042) of our patients died after stem cell transplantation. The causes of deaths were relapse, infections, hemorrhagic cystitis, graft versus host disease, and others.

Hematopoietic stem cell transplantation in Iran: 1991 to 2008.

Since 1991, 2042 first hematopoietic stem cell transplants (HSCT) have been performed at the Hematology-Oncology and Stem Cell Transplantation Research Center at Tehran University of Medical Sciences. Acute myelogenous leukemia (548 patients), thalassemia major (335 patients) and acute lymphoblastic leukemia (275 patients) have been the most common transplanted disorders. There were 1418 cases that received allogeneic HSCT and 624 cases that have received autologous HSCT. The numbers of allogeneic and autologous HSCT have increased, but the allogeneic to autologous ratio has remained constant. The first peripheral blood hematopoietic stem cell transplantation was performed in 1996; since then, 1671 have been done. The donor types for 1418 allogeneic first HSCT were 1367 (96.4%) human leukocyte antigen (HLA) matched-identical siblings, 29 (2%) HLA-mismatched sibling/other relative, 13 (0.9%) syngeneic twins, 5 (0.4%) HLA-matched other relatives and 4 (0.3%) unrelated. The first cord blood hematopoietic stem cell transplantation was performed in 1998 and since then there have been 14 patients that have obtained cord blood transplantations. Recently, new methods have been used like donor lymphocyte infusion (DLI) and cellular therapy. There were 111 patients with cellular therapy for post-myocardial infarction, cirrhosis, thalassemia major, multiple sclerosis, head of femur necrosis and renal cell carcinoma.