Introduction
Iron deficiency (ID) is currently one of the most prominent nutrient deficiencies worldwide [1]. There are many possible causes of ID, such as increased demand and loss of iron, decreased absorption and inadequate dietary intake, and impaired iron release [2, 3]. According to current ESC guidelines, ID in HF patients is defined as either a serum ferritin concentration < 100 µg/mL or as 100–299 µg/mL with transferrin saturation (TSAT) < 20% [4].
However, ID still continues to be undertreated and underdiagnosed in the clinical setting [5]. Concurrent ID and HF can have profound negative effects on the patient’s condition leading to a decreased exercise capacity and quality of life (QoL), higher morbidity, and mortality [4, 6, 7]. ID may also cause a wide range of hematological complications within patients, such as predisposing the patient to thromboembolic events [8].
The aim of this paper is to emphasize connections made through the most current literature on the issue of cerebrovascular events connected with ID in HF patients and to indicate the most needed directions of further research.
Iron deficiency
Iron is an essential mineral for the body and is vital for a multitude of different functions, such as oxygen transport, metabolism and storage, cardiac and skeletal muscle metabolism, erythropoiesis, mitochondrial preservation and function, a cofactor for various enzymes or cellular metabolism [5, 7, 9]. Iron exists either in the ferrous form (Fe2+), during absorption in the small intestine, or bound intracellularly to ferritin or as the ferric form (Fe3+) coupled to the transport protein transferrin during circulation [5].
Iron homeostasis is solely regulated by absorption, as no means of iron excretion exists [9]. In the physiological state, only about 5–10% of the dietary iron is absorbed.
Iron absorption, taking place mainly in the duodenum and upper jejunum [5], can occur in three pathways according to the chemical form of iron present. Those pathways are shown in Figure 1. Free ferrous ions are absorbed via the divalent-metal-transporter-1 pathway, whereas heme-bound iron is absorbed via the heme-carrier-protein-1 pathway. In the enterocyte, iron can be stored bounded by ferritin or it can be transported directly to the basolateral side by mobilferrin to release iron to the circulation via the intramembranous channel ferroportin. Hepcidin, produced in the liver, is the main regulator of iron absorption as it binds to ferroportin to decrease its expression as well as by inhibiting the mobilization of stored iron in macrophages of the reticuloendothelial system [10].
Iron deficiency anemia (IDA) is a consequence of prolonged ID where the ID is severe enough to reduce erythropoiesis in the bone marrow [11]. The prevalence of iron deficiency has been extensively studied and well summarized by Savarese et al. [12], about one in every two persons with HF has ID. It seems that regardless of anemia, ID is present in about 50% of patients with HF [12]. On the contrary, ID and anemia in HF coexist rarely [13]. Moreover, anemia does not influence mitochondrial functions, and its treatment relieved HF symptoms, but at the same time increased thromboembolic events’ risk [13]. IDA leads to structural and functional alterations in tissues with a high mitotic index and oxygen demand, such as neoplastic, immune and cardiac cells, which are especially sensitive to anemia [5]. It has a significant impact on HF pathology and is an established predictor of a worse prognosis [10]. Previous studies have shown accelerated left ventricular (LV) remodeling, mitochondrial damage, and low iron content in cardiomyocytes in HF patients, possibly explaining reduced peak oxygen consumption and LV dysfunction associated with HF [7]. Furthermore, skeletal muscle dysfunction can ultimately lead to inspiratory muscle weakness, dramatically lowering the QoL of HF patients [5]. Impaired exercise capacity is the result of crucial patient characteristics and multisystem dysfunction, including aging, impaired pulmonary reserve, peripheral and respiratory skeletal muscle dysfunction as well as ID [14, 15].
Despite the significant prevalence of ID in HF, the etiology is often unrecognized [3]. The main suggested mechanisms include reduced iron intake and absorption, increased iron loss, and impaired iron release [2]. The summary of the possible etiologies of ID in HF is seen in Figure 2.
Reduced iron intake
Iron requirements and thus recommended iron intake depend mainly on sex, age and pregnancy status. In a large international HF cohort, Van Der Wal et al. [3] showed that a poor nutritional status with low serum albumin level might be an etiological pathway for ID in HF. As iron intake was not studied itself, and the underlying reason for the poor nutritional status is not clear yet, further studies need to be done. A cross-sectional study from Christina Andreae [16] identified a significant prevalence of loss of appetite with a high risk of weight loss in patients with HF. It needs to be emphasized that increasing the intake of iron such as in oral iron therapy is not effective and due to excessive polypharmacy and possible side effects is not recommended [5].
Reduced iron absorption
Venous congestion leads to gastrointestinal wall edema, which might reduce the absorption of nutrients such as iron [3]. Other factors like concomitant diseases such as inflammatory bowel disease or the high prevalence of proton pump inhibitor usage in HF patients, might also play an etiological role in ID in HF [3]. Furthermore, recent studies showed that hepcidin levels are decreased in HF patients, suggesting that the iron concentration is a dominating factor over the inflammatory state to determine the rate of hepcidin synthesis [3, 5, 10]. In conclusion, ID is more likely caused by an absolute decrease in iron availability than by a metabolic mechanism induced by a chronic inflammatory state [5].
Increased iron loss
Increased iron loss is another factor that contributes ID in HF. Firstly, as a recent study by Meijers et al. [17] identified HF as a novel risk for incident cancer, blood loss, and as a consequence, iron loss in HF might therefore be due to malignancies or gastrointestinal diseases such as gastritis or peptic ulcers [2]. Secondly, patients with ID have a higher prevalence of antiplatelet use [3]. Thus, iron loss in these patients might be due to an increased tendency for bleeding.
All in all, the etiology of ID in HF is highly complex, multifactorial, and not well understood. Further research on the etiopathogenesis of ID in HF needs to be conducted to establish recognized causal factors which can help in finding sufficient treatment of ID in HF, as a predictor of a worse prognosis [7].
Stroke and ID in heart failure
The etiology of HF varies depending on the phenotype. HFrEF results as a consequence of the necrosis of cardiomyocytes, due to myocardial ischemia, myocarditis, or cardiotoxins, and it has the predisposition to affect males more [18]. HFpEF occurs most often in patients suffering non-cardiac comorbidities such as hypertension, pulmonary disease, diabetes mellitus, sleep apnea or obesity and it has the predisposition to affect females more often [18]. It is known that HF, even in its earliest stage, is a risk factor for stroke [19, 20]. Among stroke patients, 9% had HF as the cause of the event [20]. Furthermore, 10–24% of stroke patients also have HF [20]. The Framingham Heart Study emphasized that patients with HF are two to 3 times more likely to suffer from a stroke than those without HF [21]. On the other hand, one of the pathomechanisms of HF is chronic inflammation which may either be a consequence of HF or it may precede and be one of the causative factors which led to HF. In consequence, chronic inflammation leads to hypercoagulability. Finally, endothelial damage is also responsible for the pathogenesis of HF, which may be caused by various different vasculopathies [20, 21]. The above-mentioned factors form the Virchow’s Triad, which are at the same time the most important elements for the formation of thrombosis [22]. That makes HF a disease of a higher risk of thromboembolism forming.
Aside from the already proven fact that ID in HF patients leads to a decreased QoL and exercise tolerance, as well as to increased patient mortality and morbidity [4], it should also be The combination of both these diseases may prove deleterious consequences in patients ultimately leading to an increased probability of stroke occurring. Kandinata et al. [23] presented a case of a 34-year-old patient with ID who suffered from a stroke. It implies that ID may be a great predictive value for stroke, and even greater if it is combined with comorbidities. Gillum et al. proved there may be a U-shaped connection between iron status and the risk of stroke [24]. However, the data on iron status and its influence on stroke prevalence is limited and conflicting, there is a need to conduct further research on the prognostic significance and treatment ID in patients with cerebrovascular events [12]. Current trends indicate the possible use of hematologic parameters such as ID as biomarkers in HF [25].
Table 1 presents selected studies regarding HF and ID and their correlation with cerebrovascular events.
|
Author |
Year |
Type of study |
N |
Results/conclusions |
|
Gillum et al. [24] |
1995 |
Follow-up of a national cohort |
5033 |
There is a significant U-shaped association of transferrin saturation with risk of incident stroke |
|
Dubyk et al. [26] |
2012 |
Prospective, cohort |
94 |
IDA as a risk factor in elderly patients at hospital admission for TIA or first stroke |
|
Shovlin et al. [27] |
2014 |
Prospective, cohort |
497 |
Iron deficient patients with pulmonary malformations at a higher risk of ischemic stroke |
|
Potaczek et al. [28] |
2016 |
Prospective, cohort |
229 |
ID may represent a risk factor for thrombosis recurrence |
|
Adelborg et al. [19] |
2017 |
General population cohort |
1 446 765 |
HF is an important risk factor for all types of stroke. |
|
Gill et al. [29] |
2018 |
Mendelian randomized |
48 972 |
Higher iron status is associated with increased stroke risk |
|
Tang et al. [30] |
2020 |
Prospective, cohort |
795 |
ID and CC are risk factors for thromboembolic diseases |
|
Szulc-Bagrowska et al. [31] |
2022 |
Retrospective, observational |
150 |
ID in HF is associated with a higher risk of stroke/TIA |
|
Doehner et al. [32] |
2022 |
Prospective, observational |
746 |
ID and anemia significantly lower functional capacity after acute stroke |
Significance and solutions — IRONMAN study
The only efficacious and recommended treatment for reversing ID is intravenous (IV) ferric carboxymaltose. However, the approved treatment of ID in the setting of left ventricle ejection fraction < 50%, there is currently no approved treatment for ID in the setting of HFpEF [4]. To our knowledge, IRONMAN was the first large clinical trial that investigated the long-term effect of IV ferric derisomaltose (FDI) administration on cardiovascular (CV) outcomes, including recurrent hospitalizations for HF [33]. 1137 patients were randomized, 569 received IV FDI treatment and 568 usual care. The primary endpoint, which included a composite of CV deaths and hospitalizations for HF occurred for FDI treatment vs. standard of care: (336 primary events [22.4 per 100 patient-years] vs. 411 [27.5 per 100 patient-years] RR [rate ratio] 0.82; 95% CI [confidence interval]: 0.66–1.02; p = 0.070) [33], what was on the borderline of statistical significance, such as in AFFIRM trial [34]. IRONMAN study proved that IV administration of iron reduced the combined secondary endpoint (CV death, hospital admissions for stroke, HF, and myocardial infarction) (HR = 0.82; 95% CI: 0.69–1.00; p = 0.045) [33]. The recommended COVID-19 analysis showed consistent results (HR = 0.78; 95% CI: 0.62–0.98; p = 0.030 respectively) [33]. To our knowledge, previous studies of ID in HF did not include stroke hospitalization as endpoint, which needs to be strongly emphasized [33]. Subsequently, important differences between IRONMAN and another clinical trial regarding ID, for instance, AFFIRM-AHF, are worth noticing [34]. Firstly, the follow-up was longer in IRONMAN (median follow-up 2.7 years [IQR 1.8–3.6]) than in AFFIRM-AHF, in which IV iron treatment was finalized after 24 weeks [33, 34]. Hence, IRONMAN study confirmed the long-term safety of IV FDI, since there were no excessive serious adverse events [33]. Subsequently, there was no collection of phosphate samples in IRONMAN, since the risk of hypophosphataemia is significantly lower in FDI [35]. A comparison of selected clinical trials is shown in Table 2.
|
FAIR-HF [36] |
CONFIRM-HF [37] |
EFFECT-HF [38] |
AFFIRM-HF [34] |
IRONMAN [33] |
|
|
Type of study |
Prospective, randomized, multicenter |
Prospective, randomized, multicenter |
Prospective, randomized, open-label, SoC-controlled |
Prospective, randomized, multicenter |
Prospective, randomized, open-label, SoC-controlled |
|
N |
FCM: 305 Placebo: 154 |
FCM: 152 Placebo: 152 |
FCM: 88 SoC: 86 |
FCM: 559 Placebo: 551 |
FDI: 569 SoC: 568 |
|
Study population |
Chronic HF NYHA class II (LVEF ≤ 40%) or III (LVEF ≤ 45%) with ID |
Chronic HF NYHA class II/III (LVEF ≤ 45%)BNP > 100 pg/mL and/or NT-proBNP > 400 pg/mL with ID |
Chronic HF NYHA class II/III (LVEF ≤ 45%)BNP > 100 pg/mL and/or NT-proBNP > 400 pg/mL with ID Peak VO2 10–20 mL//kg/min |
Acute HF Hospitalized for acute HF, treated with at least 40 mg furosemide (or equivalent) LVEF < 50% with ID |
Chronic HF NYHA II–IV and recent HF hospitalization or elevated NPs (LVEF ≤ 45%)Ferritin < 100 µg/L or TSAT < 20% |
|
Primary endpoint result |
Improvement in self-reported PGA (50% for FCM vs. 28% placebo; OR 2.51; 95% CI: 1.75–3.61; p < 0.001) and NYHA class I/II at 24 week (47% vs. 30%; OR 2.40; 95% CI: 1.55–3.71; p < 0.001) |
Change in 6WMT distance from baseline to week 24 for FCM vs. placebo — both LS means ± SE (18 ± 8 meters vs. 16 ± 8 meters; difference FCM vs. placebo: 33 ± 11 meters; p = 0.002) |
Change from baseline in peak VO2 at week 24 for FCM vs. control (SoC) — LS mean ± SE (−0.16 ± 0.387 vs. −1.19 ± 0.389 mL/min/kg; p = 0.020) Sensitivity analysis in which missing data were not imputed for FCM vs. control: (−0.16 ± 0.37 vs. −0.63 ± 0.38 mL/min/kg; p = 0.23) |
Composite of total HF hospitalizations and CV deaths up to 52 weeks after randomization for FCM vs. placebo (293 primary events [57.2 per 100 patient-years] vs. 372 [72.5 per 100 patient-years] RR 0.79; 95% CI: 0.62–1.01; p = 0.059)(Pre-COVID-19 sensitivity analysis: 274 primary events [55.2 per 100 patient-years] vs. 363 [73.5 per 100 patient-years] RR 0.75; 95% CI: 0.59–0.96; p = 0.024) |
Composite of CV deaths and hospitalizations for HF for FDI vs. SoC: (336 primary events [22.4 per 100 patient-years] vs. 411 [27.5 per 100 patient-years] RR 0.82; 95% CI: 0.66–1.02; p = 0.070) |
|
Secondary endpoint result |
Improvement (p < 0.001) with FCM vs. placebo in:
|
Improvements with FCM vs. placebo in:
|
|
Total CV hospitalizations and CV deaths with FCM vs. placebo:
|
Composite of CV deaths or hospital admission for HF, stroke or MI with FDI vs. placebo: 209 vs. 246 (RR 0.83; 95% CI: 0.69–1.00; p = 0.045) |
Conclusions
HF with ID may predispose the patient to a higher risk of suffering from cerebrovascular events. Numerous studies emphasize that ID in clinical practice is often unrecognized and definitely underdiagnosed even though it is in the ESC treatment guidelines for HF. Better screening for ID should be implemented to reverse this health issue. HF with ID should be recognized and promptly treated by the clinician and the risk of stroke should be assessed as ID is a positive predictive value for stroke. Finally, upcoming randomized clinical trials should focus on assessing whether IV iron administration is an effective treatment for ID in HF patients with LVEF ≥ 45%
Conflict of interest
None declared.
|
Streszczenie Niewydolność serca (HF) jest główną przyczyną hospitalizacji wśród pacjentów w wieku 65 lat i starszych. Jedną z najczęstszych chorób współistniejących w HF jest niedobór żelaza (ID), występujący u około 50% wszystkich pacjentów z HF. Wykazano, że ID w HF zmniejsza wydolność wysiłkową, zwiększa ryzyko incydentów naczyniowo-mózgowych, chorobowość i śmiertelność pacjentów. Udowodniono, że związek między niewydolnością serca z obniżoną frakcją wyrzutową (HFrEF) a ID prowadzi do zwiększonego ryzyka incydentów sercowo-naczyniowych, a niektóre badania wskazują na podobny związek między niewydolnością serca z zachowaną frakcją wyrzutową (HFpEF) a ID. ID może prowadzić do nadkrzepliwości, co w HF może wiązać się ze zwiększonym ryzykiem udaru mózgu/przemijającego ataku niedokrwiennego. Chociaż obecne wytyczne dotyczące leczenia HF uznają ID za istotny problem, jest ono nadal rzadko rozpoznawane i niedostatecznie leczone. Słowa kluczowe: niedobór żelaza, niewydolność serca, udar mózgu, TIA, incydenty mózgowo-naczyniowe Folia Cardiologica 2023; 18, 1: 16–23 |
