As a common comorbidity in patients with chronic cardiac insufficiency (CHF), anemia is an independent risk factor affecting the course of heart failure. Further understanding of the relationship between anemia and heart failure will help us to gain a deeper understanding of heart failure and its related comorbidities for clinical workup guidance. 1. Incidence and epidemiology of anemia in patients with heart failure 1.1 Correlation between heart failure and anemia Anemia can increase cardiac load, with the result that heart rate and output per beat increase; in response to the increased cardiac load, the heart may remodel, causing left ventricular hypertrophy and dilation, gradually leading to chronic cardiac insufficiency. The incidence of anemia in patients with cardiac insufficiency correlates with the severity of the patient’s heart failure, the left ventricular ejection fraction (LVEF), and the patient’s survival status. According to the New York Heart Association (NYHA), the incidence of anemia in patients with class IV cardiac function can be close to 80%, while the incidence of anemia in patients with class I and II is less than 10%, indicating that the incidence of anemia in patients with poor cardiac function is significantly higher than that in patients with good cardiac function; in addition, in the range of erythrocyte volume 25-37, if its value In addition, for every 1% decrease in erythrocyte volume in the range of 25 to 37, there was an 11% increase in the risk of death associated with it. In another large case study of 153,180 patients with heart failure, the prevalence of anemia was 37.2%, and at 6-month follow-up, the mortality rate was 46.8% in patients with anemia compared with 29.5% in patients with non-anemic heart failure, and the risk of death was the same in both systolic and diastolic CHF. In a randomized controlled study of 294 heart failure patients with long-term survival, 162 of whom were combined with anemia and 132 without anemia, the mean survival was 37.8±1.8 months for patients with anemia and 44.9±1.8 months for patients without anemia at 5 years of follow-up, indicating that anemia can significantly increase the risk of death in long-term surviving heart failure patients. Another group of 1518 patients with CHF followed for 15 years showed that the prevalence of anemia in this group was 43%, with mild, moderate, and severe anemia occurring in 17%, 10%, and 7%, respectively. Compared with those without anemia, the risk of death was 1.27, 1.48 and 1.82 in patients with mild, moderate and severe anemia, respectively, which were significantly higher; the risk of death was significantly higher even after multivariate factor analysis; the landmark analysis of mortality was in the first 2 years of the disease for mild anemia, at least 5 years for moderate anemia and 5 years for severe anemia. The impact of severe anemia on the increase of mortality after 5 years is significant. Data show that the prevalence of anemia in the first year is 10% in patients without anemic base who have cardiac complications due to the progression of heart failure. An epidemiological survey in Omlsted County, Minnesota, USA, showed that the prevalence of anemia in heart failure patients was 40% in a retrospective cohort analysis, with an expected annual growth rate of 0.67%, compared with 53% in a prospective cohort analysis. The prevalence of anemia was 57.9% in patients with preserved ejection fraction (preserved ejection fraction ≥50%) and 47.6% in patients with reduced ejection fraction (reduced ejection fraction <50%), with significant differences between the two. Cohort analysis in both groups showed that anemia was associated with decreased creatinine clearance and coronary artery disease, as well as with older patients; prospective cohort analysis showed that anemia was associated with high brain natriuretic peptide (BNP). Mortality was significantly higher in both groups of anemic patients, with a 2-year mortality rate of 41% (36-47%) in the prospective cohort analysis group of anemic patients and 24% (19-29%) in non-anemic patients. However, when they did the relationship between anemia and hemoglobin values and mortality, they found that anemic heart failure patients had a high mortality rate associated with hemoglobin values, with a J-shaped curve in both groups, and that two-year mortality was increased below 14.0 mg/dL and above 16.0 mg/dL. For example, the prospective cohorts with expected two-year mortality rates of ≥16.0 mg/dL, 14.0-15.9 mg/dL, 12.0-13.9 mg/dL, 10.0-11.9 mg/dL, and <10.0 mg/dL had mortality rates of 30% (6-48%), 19% (11-26%), 28% (21-34%), 41% (34-49%), and 49% (49%), respectively. -Cox proportional risk regression analysis also demonstrated that hemoglobin less than 14.0 mg/dL and greater than 16.0 mg/dL had higher mortality rates. Risk ratios for death in heart failure patients adjusted by hemoglobin values also showed significantly higher mortality rates for those with >16.0 mg/dL and <14.0 mg/dL, and were consistent with patient age, sex, coronary artery disease, diabetes, smoking, prior malignancy, body mass index, creatinine clearance, NYHA classification, ejection fraction, and BNP. 1.2 Risk assessment of anemia in heart failure patients Groenveld et al. searched the Medline database for literature on the relationship between anemia and risk of death in CHF from 1966 to the end of November 2007 and obtained the results of 34 well-documented studies that included a total of 153,180 patients with CHF, whose anemia prevalence was 37.2%. During a per capita follow-up of 6 months to 5 years, the risk of death was significantly higher in patients with CHF with anemia at baseline compared with those without anemia, 46.8% and 29.5%, respectively (OR 1.96, p<0.001), especially in those with anemia with low baseline creatinine, and lower baseline hemoglobin was also associated with an increased risk of subsequent death (r=-0.396, p=0.025); baseline anemia remained an independent predictor of increased risk of subsequent death even after correction for other confounding factors (HR1.46, p<0.001). Further subgroup analysis showed that the association between baseline anemia and increased risk of subsequent death was not affected by differences in the etiology of systolic or diastolic CHF, and that the risk of subsequent death was equally significantly increased in both groups with anemia (OR1.96,p<0.001; OR2.09,p<0.001). These findings suggest that anemia is significantly associated with an increased risk of subsequent death in both systolic and diastolic CHF patients, and therefore, anemia can be both a valid prognostic marker for CHF patients and a target for a treatment strategy to improve patient prognosis by increasing hemoglobin levels in CHF patients. In a retrospective analysis of 1415 patients with CHF, Ye et al. showed a 29.2% prevalence of anemia and a positive correlation between the prevalence of anemia and the patient's cardiac function class, with a significant difference (p < 0.01) between the prevalence of anemia in severe heart failure (32.2%) compared with that in mild heart failure (24.3%). Hemoglobin level was associated with increased in-hospital mortality in patients in a U-shaped curve. By multivariate logistic regression analysis, adjusting for the effects of age, sex, underlying cause, diabetes, cardiac function class, and serum creatinine concentration, hemoglobin level remained an independent influencing factor on in-hospital mortality in patients with CHF. A group of data from California, USA, from 2000 to 2006 showed that a total of 596,456 heart failure patients had a prevalence of 27.4% and 27.1% of renal insufficiency and anemia, respectively, both of which were strongly associated with heart failure patients (OR 2.45 and 1.27, CI 2.39-2.52 and 1.24-1.30, respectively), adjusting for After influencing factors renal failure and anemia remained closely associated independent adverse factors in heart failure patients, and the risk rate of death was closely related to the degree and duration of anemia. 2. Etiology and pathogenesis of anemia in heart failure patients 2.1 Renal insufficiency Chronic heart failure and renal failure are two separate but often coexisting diseases, with a prevalence of 20%-40%. Renal insufficiency plays a very important role in the etiology of anemia in patients with CHF, and renal failure is a very useful predictor of morbidity and mortality in patients with HF, both in terms of damage to those organs and in terms of preserved ejection fraction. Renal insufficiency is strongly associated with HF and anemia, and in a meta-analysis of 16 groups of 80,098 patients with HF, 63% had varying degrees of renal impairment and 29% had severe chronic kidney disease (CKD). Heart failure, anemia and CKD are causally related to each other, making heart failure more complex and the prognosis more aggressive. In a 2-year follow-up study of 1,136,201 patients with interaction between renal failure, CHF and anemia, the interaction was found to have a significantly higher mortality rate. The annual mortality rate increased from 4% without anemia, HF and renal failure to 23% with anemia, HF and renal failure. Anemia increases heart rate and output per beat, causing cardiac remodeling, left ventricular hypertrophy and dilation, leading to chronic cardiac insufficiency; renal failure itself causes heart failure through hypertension and accelerated coronary atherosclerosis, and chronic heart failure and anemia will also impair cardiac function, thus increasing the risk of death in patients; on the other hand, because chronic heart failure decreases cardiac output and blood pressure, it makes the kidneys underfilled with venous stasis On the other hand, chronic heart failure decreases cardiac output and blood pressure, which decreases the effective perfusion of the kidneys, leading to renal failure; insufficient renal perfusion leads to chronic renal ischemia, resulting in decreased erythropoietin (EPO) levels and eventually anemia, which further increases the cardiac load, forming a vicious circle called "cardiorenal anemia syndrome" (CRAS). Age, body mass index, diabetes, ischemia, left ventricular ejection fraction, and treatment with renin-angiotensin inhibitors are all independent factors associated with CRAS, and its incidence and mortality are causal and probably related to serum high molecular weight (HWM) fat-linked protein. In 2679 patients with CHF, the correlation between regression and hematology revealed that red blood cell distribution width (RDW) and regression of CHF were highly correlated with morbidity and mortality in heart failure, and that increased RDW was an independent predictor of adverse outcomes in patients with CHF, even in model trials containing urinary natriuretic peptide levels and hemoglobin, yielding the same conclusions. In another meta-study of 6,159 CHF patients with RDW values, the median baseline RDW value was 14.9%, and RDW > 16% baseline was significantly associated with higher mortality than RDW ≤ 16%, with a hazard ratio of 1.17 (p<0.0001) for all-cause mortality for every 1% increase in baseline RDW. However, why RDW can act as an independent factor for poor prognosis in CHF is unclear, and a possible explanation is that RDW acts as a variable for a measure of red blood cell size that represents changes in red blood cells during circulation. Typically, increased RDW manifests itself in ineffective red blood cell production (e.g., iron, folic acid, and vitamin B12 deficiency and hemoglobinopathies), increased red blood cell destruction (e.g., hemolysis), and after blood transfusion. Therefore, it is conceivable that increased RDW in CHF patients may represent a multifactorial pathological process, such as malnutrition, renal insufficiency, liver congestion, and inflammatory response . In addition, increased RDW has been associated with several other pathological processes such as liver disease, malnutrition, occult colon cancer and bone marrow metastasis of tumors. Other factors that influence RDW in CHF include inappropriate production of erythropoietin, various comorbidities, and inflammatory cytokines. 2.2 Role of cytokines Patients with CHF are clinically found to have higher TNF and lower hemoglobin levels. Studies have shown that HF itself produces an inflammatory environment in which many cytokines are increased, such as interleukins 1, 6, and 18 and tumor necrosis factor alpha (TNF-α). These inflammatory cytokines contribute to the development of anemia by diminishing the differentiation of erythroid progenitor cells, diminishing erythropoietin, decreasing iron absorption at the small intestinal level by increasing hepcidin, and blocking iron release from macrophages [1,14]. TNF-α, produced by cardiomyocytes as an injurious response, has been shown to further exacerbate cardiac damage, while increased cytokines are also associated with the progression of chronic disease anemia and worsen it in patients with CKD and CHF. In addition, the two most prominent inflammatory cytokines associated with heart failure, TNF-α and IL-6, can directly affect bone marrow hematopoiesis, and increased production of these cytokines leads to decreased EPO production, preventing the benefits of EPO on bone marrow erythropoiesis, further inhibiting the release of iron from the reticuloendothelial system thus leading to impaired hemoglobin utilization in bone marrow hematopoiesis, and ultimately also inhibiting iron absorption in the intestine These effects are mediated by the cellular product iron-regulated protein in the liver. However, it has also been shown that iron-regulated proteins do not have significant pathophysiological significance in the development of anemia in CHF. 2.3 Decreased bone marrow function The REN2 rats made into a heart failure model were treated with EPO, and bone marrow fluid was taken for erythroid colony progenitor cell (BFU-E) culture after execution and compared with normal SD rats experimented under the same conditions, and it was found that the number of bone marrow BFU-E was significantly lower in REN2 rats than in SD rats (6.4±1.7 and 50±6.2, respectively, p<0.01) EPO treatment significantly improved BFU-E in both REN2 and SD rats, but REN2 rats were not able to reach the level of improvement in the control group; several genes related to erythroid value-added differentiation in bone marrow such as differentiation gene (LMO2), activation gene (SDF-1) and iron-binding gene (transferrin receptor) were also significantly different in the two groups of rats. The expression of LMO2 was significantly lower in REN2 rats than in SD rats (34% lower), and after stimulation with EPO, its expression was increased in SD rats but not in REN2 rats, suggesting that the differentiation of bone marrow erythroid progenitor cells was inhibited in heart failure rats; the expression of SDF-1 was significantly higher in REN2 rats, 3.5 times higher than in SD rats, and increased to 5.6 times after EPO treatment, indicating that the activation of bone marrow erythroid progenitor cells was also inhibited in heart failure rats; transferrin receptor was also inhibited. The expression of transferrin receptor mRNA was not significantly different between the two groups of rats, and its expression was significantly increased in SD rats but not in REN2 rats after EPO treatment, demonstrating that EPO treatment in REN2 rats did not increase the binding and transport of iron by erythrocytes. 2.4 Iron, folic acid, and B12 deficiency In a study of 317 patients hospitalized with HF, it was observed that the prevalence of anemia was 40.7% in males and 59.3% in females. 32.8% of these anemic patients had iron deficiency associated with low ferritin concentration and/or transferrin concentration, 1.3% had vitamin B12 deficiency, and the in-hospital mortality associated with vitamin B12 and iron deficiency In another group of 173 ambulatory CHF patients, the prevalence of anemia was approximately 20%, with vitamin B12, iron, and folic acid deficiencies in 6%, 13%, and 8% of these anemic patients, respectively. The causes of deficiencies in these nutritional factors may be related to a recent decrease in iron and vitamin intake, as well as to malnutrition, malabsorption and cardiac cachexia. In addition, the use of aspirin and oral anticoagulants can lead to trace amounts of gastrointestinal blood loss, which can lead to anemia associated with iron deficiency. However, it is difficult to monitor the iron nutritional status of patients with heart failure, and certain tests such as ferritin and transferrin are acute phase proteins whose elevation is associated with inflammatory conditions such as HF; therefore, it is very difficult to determine the presence of iron deficiency in patients with HF by serum markers. A group of 39 patients with anemia with severe heart failure, all of whom underwent bone marrow biopsy and had their bone marrow iron levels measured, were found to have bone marrow iron deficiency in 73% of the patients, despite having normal serum iron and ferritin levels. Iron plays an extremely critical role in oxygen uptake, transport, storage, metabolism, and energy production and is closely related to erythropoiesis; therefore, iron deficiency may be associated with reduced functional capacity and poor physiological conditions, regardless of anemia. Since it is not possible to routinely perform bone marrow biopsies in CHF patients to determine whether anemia in CHF patients is due to iron deficiency, newer markers less influenced by inflammatory factors such as hepcidin and soluble transferrin receptors may become more valuable. 2.5 Dilutional anemia A clinical analysis of data from 317 patients with heart failure with anemia showed that hemodilution-related anemia accounted for 12.6% of cases. It was shown that hemodilution exists in patients with CHF and that renal damage can cause activation of the renin-angiotensin system (RAS), leading to water and sodium retention, which increases extracellular fluid (ECV) volume. 100 patients with HF, with a mean age of 61.0 ± 10.6 years, had red blood cell volume (RCV) as well as plasma volume measured by 51Cr labeling, and it was found that the anemic The mean value of hemoglobin in HF patients with anemia was 11.7±0.8 mg/dL, while that in patients without anemia was 14.4±1.2 mg/dL, and in patients with anemic HF, the corrected reticulocytes were significantly lower and the plasma volume was significantly higher. There is a significant correlation between increased ECV and low hemoglobin levels in patients with anemic heart failure. Increased ECV in patients with chronic heart failure can cause hemodilution, and this hemodilution can lead to pseudoanemia. Although a large number of diuretics are used in patients with anemic heart failure, their ECV remains elevated despite this. Importantly, although fluid retention is associated with anemia, the lack of signs of fluid retention on physical examination may suggest that hemodilution may have been present before the clinical manifestations of fluid retention were detected. 2.6 Chronic disease anemia Chronic disease is a general term for a group of diseases with insidious onset, long duration, persistent disease, lack of definitive evidence of infectious biological causes, complex etiology, and some not yet fully recognized. Common chronic diseases such as cardiovascular diseases, diabetes mellitus, malignant neoplasm, chronic obstructive pulmonary disease, chronic kidney disease, etc. A group of 37 patients with anemic heart failure underwent rigorous examination, including bone marrow aspiration, and 7 of them (18.9%) were considered to have chronic disease anemia without any specific cause. Abnormalities in inflammatory cytokine-mediated EPO production and response and abnormalities in iron metabolism in chronic disease anemia, including decreased EPO production, blunted response of erythroid progenitor cells to EPO, effects on iron metabolism leading to relative iron deficiency as well as chronic blood loss, malnutrition and hemolysis can manifest clinically in varying degrees of anemia. EPO regulates the value-added of bone marrow erythroid cells, and its expression correlates with tissue oxygenation and The responsiveness of EPO in chronic disease anemia may not be perfectly consistent with the degree of anemia either. Some such responses have been seen in some studies of patients with CHF; in others, endogenous EPO was found to be elevated in patients with heart failure and correlated with the severity of symptoms as an independent indicator of survival. Anemic heart failure has a significantly higher proportion (about one-third) of its EPO levels compared to the expected severity of anemia. These relatively elevated endogenous EPOs suggest that the bone marrow is hormone-resistant in a certain number of patients with anemic heart failure. In contrast, most patients with nephropathy exhibit relatively low levels of EPO, and although their endogenous EPO levels are still elevated in such patients, they show inconsistently low levels of anemia. Patients with CHF have been found to express increased TNFα, a cytokine that decreases the differentiation of hematopoietic stem cells. Experimental data also support this hypothesis, with mice with heart failure having an approximately 50% decrease in the differentiation capacity of their bone marrow progenitor cells compared to control mice. 2.7 Drug therapy and anemia Angiotensin-converting enzyme inhibitors (ACEI) and β-blockers play a pivotal role in the pharmacological treatment of cardiovascular medicine; however, the use of such drugs can also lead to the development of anemia. It has been shown that the renin-angiotensin system (RAS) can reduce hematopoietic cell production activity. A randomized study showed that enalapril significantly increased the incidence of anemia by 56%. Serum from patients with anemic heart failure inhibited the differentiation of bone marrow cells derived from red lineage hematopoietic progenitors in almost 20% of healthy donors under experimental conditions. This hormone with an inhibitory effect on hematopoiesis is N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), a level of hematopoiesis inhibitor that is almost exclusively degraded by ACE, which significantly increases anemia in CHF patients , which clearly demonstrates the relationship between Ac-SDKP levels and erythroid progenitor cell differentiation, that is, the link between hematopoiesis and the RAS system. However, it must be emphasized that the importance of ACEI in the treatment of patients with CHF is unquestionable and its potential side effects in hematopoiesis are by no means a contraindication to the prescription of this drug in patients with anemic chronic heart failure. Little is known about the relationship between beta-blockers and hematopoiesis, and a large randomized study of beta-blockers in patients with CHF suggests that beta-blocker use is associated with the development of anemia. 3. Prevention and treatment of anemia in patients with heart failure Because the etiopathogenesis of anemia in patients with chronic heart failure is very complex, in addition, there are controversies in the identification and diagnosis of anemia in patients with HF as well as in the timing of treatment and the choice of treatment methods. Therefore, the current treatment is mainly focused on the treatment of erythropoietin and iron, as well as the combination of the two. 3.1 Iron therapy Iron therapy for non-CHF patients with iron deficiency has achieved good benefits, however, clinical studies on the application in CHF patients are recent work, and previous studies were basically pilot study work with small samples. A multicenter, double-blind, randomized and placebo-controlled clinical study of a total of 442 anemic CHF patients (FAIR-HF) showed that these iron-deficient patients with ferritin less than 100 μg/L; or transferrin saturation less than 20% and ferritin between 100-299 μg/L, were randomized to intravenous iron therapy or placebo, and although the two groups of cases were There was no significant difference in mortality, but iron treatment significantly improved clinical symptoms and the 6-minute walk test, and treatment with iron is safe and effective for improving iron deficiency in patients with CHF with or without anemia. Treatment with intravenous iron alone significantly increased hemoglobin levels, and in addition, iron therapy reduced amino-terminal B-type natriuretic peptide precursor (NT-proBNP) levels and improved renal function in patients with anemia with CHF, benefits that were associated with improved quality of life, mobility, and cardiac function. Even in patients who were not iron deficient, iron treatment was able to result in an appropriate increase in hemoglobin levels. Another multicenter clinical study of a large sample of 2348 cases comparing the efficacy of oral versus intravenous iron therapy in patients with anemia showed that intravenous iron therapy was superior to oral iron therapy in terms of efficacy, without significant differences in side effects. Therefore, iron therapy is appropriate for patients with CHF with or without clinical manifestations of anemia, as long as evidence of iron deficiency is present. However, the mechanism of iron therapy, especially intravenous iron therapy in patients with heart failure, is not well understood, and it is possible that the benefit of iron supplementation therapy is in the mitochondrial respiratory chain of skeletal muscle, and the safety of long-term application of intravenous iron therapy in patients with CHF is not known. Iron is known to be an antioxidant factor that inhibits nitric oxide signaling and does not reverse damaged cells; therefore, increasing body iron stores may be associated with vascular endothelial cell dysfunction and an increased risk of coronary events. Therefore, more clinical information is needed to assess its safety. 3.2 Treatment with erythropoietin EPO has long been used to treat renal anemia with good benefit, and in recent years, it has been used to treat anemia due to other etiologies, such as myelodysplastic syndrome, chronic disease anemia and pernicious neoplastic anemia, and newly for the treatment of chronic heart failure anemia. The first article on the treatment of CHF patients with EPO was published 10 years ago and showed good benefits in terms of alternative cardiovascular endpoints including cardiac function, exercise time and renal function. A new randomized controlled study of CHF treated with EPO involving 650 patients at 7 centers showed that EPO treatment resulted in a significant benefit in 41% of low-risk hospitalized heart failure patients and was not associated with increased mortality or disease progression, nor was it significantly different from the development of hypertension and venous thrombosis. However, because the etiology of HF anemia is associated with many factors, including renal insufficiency, gastrointestinal bleeding, and nutritional deficiencies as the main etiology, and even with the chronic inflammatory process of heart failure, there is a lack of guideline treatment guidance for heart failure anemia, and most prior studies have been largely observational in small samples, with few multicenter randomized studies of the clinical benefits of EPO in large samples. Although EPO treatment does increase hemoglobin levels, this treatment does not show an improvement in HYHA functional classification nor does it improve left ventricular ejection fraction. In addition, the target values for improvement in hemoglobin levels could not be determined, and side effects and cardiovascular risk events were observed in oncology patients treated with EPO. The publication of data from a new multicenter study of 2600 patients with cardiac function class II-IV, EF ≤ 40%, and Hb 90-120g/L heart failure, randomized to a double-blind controlled study of the clinical benefit of EPO therapy, will help provide important information on the safety and clinical benefit of EPO use in patients with CHF. 3.3 Other therapeutic measures including appropriate supplementation of folic acid, vitamin B12, correction of chronic renal insufficiency, and removal of various chronic infectious lesions can help improve the clinical status of heart failure. Recently, the effect of desialoEPO (a non-erythrocytic derivative of EPO that removes all of the EPO structure of sialic acid) on mice with heart failure has been investigated. Mice with 5/6 kidneys removed were made into animal models with renal insufficiency, cardiac insufficiency and anemia and treated with EPO, asialoEPO and sialic acid (control). It was found that both EPO and asialoEPO had the same significant reduction in left ventricular dilation and insufficiency, and that mice treated with EPO and asialoEPO showed reduced ventricular hypertrophy, reactive reduction in myocardial hypertrophy, reduced degenerative changes in subcellularity and significant reduction in fibrosis, leukocyte infiltration and oxidized DNA damage. This provides useful inspiration for the development and utilization of new drugs.