top of page

Freedom 515 - Illinois

Public·139 members
Hudson Martin
Hudson Martin

Hearts Of Iron 2

Hearts Of Iron 4 Discord ??? ??? Download --->>> =2sTXTWThis is a friendly discord community for people who play hearts of iron 4. Get a role based on your played hours from steam.?????????????????? ????????? ???????????? ????????????+ ??????????? ?? ?????? ?????? 7ad9723583 -simu-tc-v3-work -live-suite-10212-keygen-crack-patch-better-full-version -electrical-expert-v4-crack

Hearts Of Iron 2


Iron deficiency (ID) and anaemia are among the most frequently observed comorbidities in HF, and both are independently associated with worse clinical status and outcomes [9,10,11]. Not only the presence of these comorbidities has been associated with worse prognosis, but also the severity, with advancing severity associated with higher mortality rates [10]. Although ID has traditionally been linked with anaemia, commonly referred to as iron deficiency anaemia (IDA), the two conditions do not necessarily coexist [12]. In fact, ID is poorly linked with red cell indices in HF, indicating that ID in these patients should be seen independently of erythropoietic status [13].

ID is substantially more prevalent than anaemia in HF, with a prevalence reaching up to 59% even in non-anaemic ambulatory HF patients [10,14,15,16,17]. In acute HF, the prevalence of ID among non-anaemic patients is even higher at 57% in men and 79% in women [18]. Iron status, independently of haemoglobin (Hb) levels, is associated with reduced exercise capacity, impaired quality of life and increased risk of death and hospital (re-)admissions [12,14,16,19,20,21]. Intravenously correcting ID was shown to improve quality of life, exercise performance and symptoms regardless of Hb levels [22,23,24,25]. These observations underscore the crucial role of iron beyond erythropoiesis [26]. Additionally, although the recent AFFIRM-AHF study statistically missed its primary endpoint (i.e., combined recurrent hospitalisations or cardiovascular mortality), administering intravenous (IV) iron in patients with acute HF significantly reduced recurrent hospitalisations [27,28]. The evidence on mortality is yet to be ascertained [29].

Overview of the multifaceted roles of iron in diverse organs and molecular processes. TCA: tricarboxylic acid cycle; miRNA: microRNA, ROS: reactive oxygen species (Created with, accessed on 24 November 2021).

The underlying causes of ID are poorly characterised. Multiple mechanisms are likely to be operational. A variety of postulated mechanisms have gained great attention to explain the high prevalence of ID in HF beyond anaemia. Several factors were shown to be independently associated with ID in HF, including advanced age, kidney failure, female gender, malnutrition, chronic inflammation, reduced iron absorption, increased iron loss and heart failure severity [15,16,26,51]. Of note, many of the aforementioned risk factors are postulated based on observational studies and have not yet been confirmed as a cause in patients with HF and thus, remain hypothetical.

Increasing iron intake orally in HF patients using Forceval (mix of micronutrients including 12 mg of iron) for 12 months did not significantly increase serum ferritin or serum iron [94]. Furthermore, in the IRONOUT-HF study, it was found that taking oral iron polysaccharide tablets (150 mg twice daily) for 16 weeks did not improve functional capacity and quality of life in patients with HFrEF in spite of the minimal improvement in iron stores [95]. It is worth noting that the cumulative amount of oral iron received within the study period exceeds the recommended dosage intravenously to correct ID by more than 15 times [8,95]. Knowing that the main source of iron used by the body is endogenously obtained as a result of scavenging iron from senescent erythrocytes by macrophages [67], these results may implicate mechanisms other than insufficient dietary iron intake alone as a cause of ID in HF.

A study showed that in rats with IDA, morphological and functional compensatory mechanisms are important adaptive mechanisms to increase intestinal absorption of iron [112,113]. These mechanisms include increased cell proliferation, mucosal thickness, epithelial surface area, villus length and width. Given the altered intestinal morphology and function in HF, these adaptive mechanisms might not be operational to correct ID physiologically [114].

In addition to impaired intestinal morphological adaptations in patients with HF, studies in animals showed that adaptive transcriptional mechanisms to counteract ID are defective in HF models. Unlike IDA rats without HF, in Dahl salt-sensitive HF rats, it was found that intestinal expression of important genes for intestinal iron absorption such as duodenal cytochrome b (Dcyt-b), divalent metal transporter 1 (DMT-1) and ferroprotein was not upregulated in spite of reduced hepcidin expression [114]. Remarkably, the expression of intestinal hypoxia-inducible transcription -2 (HIF-2α) did not increase in IDA-HF rats but increased in IDA rats without HF [114]. Upregulation in intestinal HIF-2α is an essential adaptive mechanism to counteract ID by increasing iron absorption [115,116]. Taken together, this suggests an abnormal iron regulating system in HF, which impairs adaptive responses to correct ID physiologically. Interestingly, gut microbiome-derived metabolites are capable of modulating HIF-2α signaling [117,118]. There is accumulating evidence implicating changes in the composition of the gut microbiome in the pathogenesis and perpetuation of HF [119]. Whether gut dysbiosis observed in patients with HF plays a role in ID pathogenesis is currently unknown.

Increased hepcidin levels have been directly linked to the pathogenesis of IDA associated with chronic inflammatory diseases such as cancer [121], CKD and autoimmune diseases [124,132]. In HF, however, data on associations between hepcidin, inflammation and ID are not consistent. In acutely decompensated HF patients admitted to the hospital, the prevalence of ID decreased after 30 days of discharge. This change in iron parameters was correlated, albeit weakly, with changes in inflammatory markers suggesting that inflammation may influence iron status [133]. In line with these findings, increased plasma IL-6 concentration was found to be associated with lower iron levels and higher hepcidin levels in an international cohort containing 2329 HF patients [134]. In contrast, a study by Jankowska et al. found an inverse relationship between IL-6 and hepcidin [132]. However, in the BIOSTAT-CHF cohort, iron-deficient HF patients (defined as TSAT

Observational studies show that the prevalence of ID is substantially higher in older HF patients [15,16,51,149]. Most patients with HF are elderly [4]. ID in the elderly is almost always due to non-dietary factors [150,151], with colorectal cancer, colonic polyps and angiodysplasia being the most common causes [39]. Other potential causes of occult upper and lower GI bleeding include esophagitis, gastritis, peptic ulcer, or inflammatory bowel disease [152,153]. In developing countries, hookworm infection could also lead to iron loss [39]. In otherwise healthy individuals presenting with idiopathic IDA with no GI symptoms, more than half of the patients have GI abnormalities upon endoscopic investigations [149,154,155]. Another study, including 151 individuals with ID older than 70 years (83 6 years), found a higher prevalence of GI lesions irrespective of anaemia (66% in IDA vs. 65% in iron-deficient nonanemic patients) [156]. Of note, GI malignancies (gastric, oesophageal or colon cancer) were also found in 15% of them, independently of the presence of anaemia. Similar findings were also found in a larger Korean cohort [157]. In a study conducted by Martens et al. including 699 HF patients who underwent a full endoscopic workup, it was found that GI malignancies in iron-deficient HF patients were present in around 10%, with no statistically significant difference between those with IDA and ID without anaemia (9.3% vs. 10.5%, respectively; p = 0.551) [158].

Contrastingly, increasing evidence suggests that patients with HF have an increased risk of developing cancer [163,164,170]. Interestingly, iron has emerged as a potential cause for tumorigenesis, especially in colorectal cancer [171,172,173,174]. The contribution of ID to the incidence of cancer in HF patients is not yet elucidated and worth further investigation.

Neurohormonal activation, which is a hallmark feature of HF [181], is thought to be the main cause behind myocardial ID. Maeder et al. showed lower iron content in the myocardium of patients with HF correlating with a lower mRNA expression of transferrin receptor 1 (TFR1), which is the main pathway by which iron enters cardiomyocytes [182]. Experimentally, using cardiomyocytes from neonatal rats, they found that a reduction in TFR1 expression is linked to increased activation of the neuroendocrine system, particularly aldosterone and norepinephrine [182]. This suggests that myocardial ID is likely to be caused via neurohormonal activation by downregulating TFR1. Furthermore, HF patients with MID had a lower rate of using beta-blockers compared to non-MID HF patients [183]. Moreover, Haddad et al. highlighted the importance of iron-regulatory proteins (IRP-1 and IRP-2) to the heart in securing myocardial iron [178]. More recently, Tajes et al. demonstrated in mice with isoproterenol (β-adrenoceptor agonist)-induced HF that neurohormonal activation leads to MID accompanied by mitochondrial dysfunction by reducing extracellular iron uptake and increasing intracellular iron release [33]. These findings were validated using embryonic rat heart-derived H9c2 cells challenged with norepinephrine and/or angiotensin 2, which led to similar results [33]. This implies that neurohormonal activation worsens HF by decreasing myocardial iron, suggesting that ID may be more than merely a comorbidity. In line with these findings, cardiac iron content is two times lower in patients with end-stage HF compared to non-advanced HF (New York Heart Association class II or III) with reduced ejection fraction, which may suggest that MID develops or worsens during the course of HF [70]. 041b061a72


Welcome to the group! You can connect with other members, ge...
Group Page: Groups_SingleGroup
bottom of page