cardiovascular diseases are among the most frequent causes of death worldwide [ 1 , 2 ] .
heart failure is an enormous medical and societal burden and a leading cause of hospitalization .
it is estimated that 2.6 millions hospitalizations annually in the usa are due to heart failure as a primary or secondary diagnosis . in the last 19 years
the role of several immunological , metabolic , and neurohormonal abnormalities has been recognized in the pathophysiology and progression of the congestive heart failure ( chf ) [ 4 , 5 ] . among them ,
the cardio renal anemia syndrome ( cras ) represents a pathological triangle in which the primary failing organ is the heart or the kidney and the dysfunction of one organ leads to dysfunction of the other .
the presence of anemia or renal dysfunction increases morbidity and mortality in patients with heart failure .
it seems that there is an impaired mechanism operating between congestive heart failure , chronic kidney disease ( ckd ) , and anemia , where each might cause or worsen the other .
therefore , correction of anemia would be a major part of this vicious circle in the reduction of the severity of the heart failure .
this could be explained by the fact that a significant feature of the congestive heart failure is impaired energy metabolism and therefore the failing heart is an energy - starved heart .
oxygen delivery through hemoglobin ( hb ) is essential for energy production and improvement of hb levels could also improve energy production in cardiomyocytes .
using the historical definition by the world health organization , anemia is defined when hb concentration is less than 13  g / dl for men or less than 12  g / dl for women . however , particularly in the setting of heart failure
, this definition has not been subjected to rigorous clinical validation and its appropriateness and clinical applicability continues to be debated
. therefore , some investigators use more conservative definitions ( e.g. , < 12  g / dl for men and < 11  g / dl for women ) to ensure a higher confidence in capturing the affecting population .
a recent meta - analysis of 153,180 patients with chf , reported in 34 published studies from 2001 to 2007 , estimated the prevalence of anemia to be 37.2% ( 1049% ) .
similarly , the latest prospective stamina - hfp ( study of anemia in a heart failure population ) registry estimated a prevalence of 34% .
the variability in the estimated prevalence of anemia is partly attributable to use of different definitions of anemia , whereas patients in the acute decompensated states experience more dilutional anemia and therefore the prevalence may be increased .
patients with chf and anemia tend to be older than their nonanemic counterparts , whereas , in patients less than 55 years , the age of anemic and nonanemic patients does not appear to differ .
concerning the gender , in studies of chf and anemia enrolling a preponderance of men , the proportion of women steadily increases as hb concentration falls to the point that women can predominate among patients with chf and severe anemia .
one of the most frequent comorbid conditions in patients with chf is ckd ( as defined by an estimated glomerular filtration rate ( egfr ) < 90  ml / min/1.72  m ) .
chf and ckd share some common causes ( e.g. , hypertension ) , features ( e.g. , malnutrition , impaired performance status ) , and risk factors ( e.g. , older age ) . in a meta - analysis of 16 studies
, it was found that 63% of 80,098 patients with chf had some degree of concomitant impaired renal function and 29% of them had severe ckd .
this is associated with an increased risk of adverse outcome , being probably a stronger predictor of mortality than ejection fraction ( ef ) or new york heart association ( nyha ) functional classes .
anemia is more prevalent when chf and ckd coexist in both ambulatory and hospitalized settings . in large chf registries
the degree of anemia closely parallels to egfr , although primary renal disease is relatively uncommon in chf [ 17 , 18 ] .
this justifies that kidneys play a major role in the pathophysiology of anemia in chf .
it is important that patients with chf and ckd develop anemia in higher values of egfr than patients with ckd alone .
this provides indirect evidence that other factors than ckd are involved in the pathophysiology of anemia of chf .
there is an impaired mechanism in which tissue hypoxia and release of nitric oxide ( no ) cause decreased arteriolar resistance and peripheral vasodilatation .
these in turn lead to decreased blood pressure , increased sympathetic activation , renal vasoconstriction , reduced renal function , and activation of renin - angiotensin aldosterone system .
the results are production of antidiuretic hormone , fluid retention , left ventricular ( lv ) hypertrophy and dilation , worsening of heart failure , release of brain natriuretic peptide ( bnp ) , and signs from stress on myocardium .
this , however , implies that in the presence of volume overload there might be a decrease in hb concentration and also oxygen content , although red cell mass remains stable .
the patient complains of shortness of breath , tachycardia , dizziness , faintness , and fatigue .
thus , there is a greater prevalence of anemia in hospitalized patients than ambulatory ones . on the other hand
, the presence of more advanced nyha functional classes has been associated with greater prevalence of anemia [ 21 , 22 ] .
furthermore , anemic patients with chf have more commonly diabetes mellitus and more advance disease , with higher nyha class and more severe symptoms .
those symptoms include lower exercise capacity , worse quality - of - life scores , greater peripheral edema , lower dry weight and blood pressure , higher use of diuretics and other cardiovascular medications , and worse neurohormonal profile ( such as renal dysfunction , high bnp and c - reactive protein , low serum albumin ) ( range , 30% to 61% versus range , 4% to 23% for less symptomatic ambulatory patients ) [ 23 , 24 ] .
it is remarkable that anemia does not seem to be related to lv dysfunction , whereas in few studies hb levels were inversely related to ef .
that means that patients with lower values of hb had higher ef , whereas increase of hb could decrease lvef , especially in ckd , in a dose - dependent manner [ 22 , 2527 ] .
finally , most studies indicate that the prevalence of anemia is increased in patients with chf who also have co - morbid kidney disease , advanced age , and more severe symptoms when compared to less symptomatic ambulatory populations .
the major factors contributing to chf - related anemia involve ckd , renin - angiotensin system , hematinic abnormalities , mainly iron deficiency , chronic inflammation , and hemodilution ( figure 1 ) .  
a major factor contributing to anemia of chf is kidney dysfunction , being associated with the cardiac disorder .
the renal damage in the chf is mainly hypoxic , due to reduced renal flow , caused by the reduced cardiac output [ 14 , 24 ] .
hypoxia induces erythropoietin ( epo ) production by peritubular fibroblasts , although renal blood flow in chf is relatively maintained until the late stages of the syndrome , especially when receiving angiotensin - converting enzyme ( ace ) inhibition .
this suggests that renal dysfunction plays a role in the blunted epo production in anemic patients with chf , resulting in increased epo levels but not as expected for the degree of anemia , suggesting that in chf there is both blunted epo production and resistance to epo .
furthermore , the coexistence of chf with ckd is associated with reduced epo production from the kidney , as well as with urinary losses of serum epo and transferrin [ 29 , 30 ] , which further deteriorate the anemia .
the renin - angiotensin system seems also to be involved in the control of erythropoiesis .
angiotensin ii reduces renal blood flow , increases the oxygen demands , and thereby stimulates epo production .
it also stimulates the proliferation of normal bone marrow early erythroid progenitors in a direct manner . both ace inhibition and angiotensin receptor blockade decrease erythropoiesis , causing a modest reduction in hb , up to 0.3  g / dl [ 14 , 32 ] .
this suppression is attributed to a mild reduction of epo production and also to prevention of hematopoiesis inhibitor n - acetyl - seryl - aspartyl - lysyl - proline ( acsdkp ) breakdown .
ace inhibition should be expected to cause a mild reduction of erythropoiesis , although various knockout mice models , involving different ace components , do not support this theory .
iron deficiency is common in patients with chf especially when accompanied by ckd , whereas vitamin b12 and folic acid deficiencies or iron overload are not .
it is of interest that the incidence of iron deficiency is increasing with the severity of heart failure . in half cases ,
iron deficiency is absolute ( with low transferrin saturation and serum ferritin , usually associated with decreased iron stores and reduced iron deposits in the bone marrow ) . in the other half cases iron deficiency
is functional - relative ( with low transferrin saturation and normal or elevated serum ferritin , usually associated with normal or elevated iron stores and iron deposits in the bone marrow ) .
it has been reported that in 17% of anemic patients with chf the iron deficiency is both absolute and functional .
there are many causes of absolute iron deficiency associated with chf , especially in coexistence with ckd .
these include low iron intake ( due to low protein diets and anorexia ) , gastrointestinal blood loss ( due to platelet dysfunction or coagulation abnormalities ; caused by platelet inhibitors , anticoagulants , or uremia ) , iron malabsorption ( due to either chf or uremia related - bowel edema , causing intestinal cell dysfunction , or to proton pump inhibitors or to phosphate binders , that also bind iron ) ,   removal of blood for tests . in chf
the functional iron deficiency is related to iron disuse , resembling anemia of chronic disease , as evidenced by iron acquisition by the reticuloendothelial system . in patients with severe chf ,
elevation of several inflammatory cytokines serum levels has been found . among them , interleukin-1 ( il-1 ) , interleukin-6 ( il-6 ) , tumor necrosis factor- ( tnf- ) , and less frequently interleukin-18 ( il-18 ) seem to be the most important , whereas il-6-induced hepcidin expression also participates in the phenomenon [ 14 , 38 , 39 ] .
this inflammatory process causes reduced epo production , through activation of gata 2 binding protein and nuclear factor-b , and impaired response to bone marrow erythroblasts .
it also causes hepcidin - induced blockade of iron absorption from the gut and iron trapping in reticuloendothelial system 's stores .
hepcidin is an acute phase antibacterial protein , induced by il-6 , through jak / stat3 pathway , released from the liver and excreted from the urine .
therefore , in chf with a concomitant ckd , there is a reduced hepcidin removal from the kidney , implying a further increase of its levels .
hepcidin inhibits ferroportin , a protein expressed on intestinal cells , macrophages , and hepatocytes that releases the iron from those cells into the blood .
hepcidin - induced inhibition of ferroportin causes decreased iron absorption from the gut and blockade of iron release from its stores , in hepatocytes and macrophages , into the blood .
this implies inadequate iron delivery to the bone marrow erythroblasts , although the total stores may be adequate , causing a functional iron deficiency .
iron metabolism is crucial for energy production in the body and most importantly for cells with high energy demands , such as cardiomyocytes .
iron plays a crucial role in oxygen transportation ( as a component of hb ) , oxygen storage ( as a component of myoglobin ) , oxidative metabolism ( as a component of oxidative enzymes and respiratory chain processes ) , and in metabolism of lipids , carbohydrates , nucleic acids , collagen , tyrosine , and catecholamines [ 41 , 42 ] . in chf , an energy - starved situation ,
iron deficiency , absolute or functional , can impair oxidative metabolism , cellular energetic , and cellular immune mechanisms .
iron deficiency in rat hearts causes mitochondrial ultrastructural aberrations , irregular sarcomere organization , and release of cytochrome c . in addition ,
experimental animal models with severe iron deficiency have major disruption in energy production causing cardiac damage , with diastolic dysfunction and heart failure , accompanied by reduced epo and increased tnf- serum levels and worsening of molecular signaling pathways .
those defects may participate in the transition from adaptive cardiac hypertrophy to permanent cardiac impairment in chronic iron deficiency . on the other hand
it has been shown that hemodialysis patients receiving epo with iv iron supplementation had lower inflammation markers ( lower levels of proinflammatory tnf- and free radicals , as expressed by total peroxides , and higher levels of anti - inflammatory interleukin-4 ) compared to patients receiving epo alone .
furthermore iron deficiency anemia seems to enhance red cell oxidative stress   and has been associated with lower peak oxygen consumption and higher ratios of ventilation to carbon dioxide production . in a recent study the disordered iron homeostasis has been identified as an independent risk factor for death .  
chf is a hypercoagulable state , where the co - existence with iron deficiency - related thrombocytosis   increases the risk of thrombosis and the mortality rate .
furthermore , it has been shown that the concomitant administration of iv iron with epo ( which can cause iron deficiency ) in hemodialysis patients significantly reduces the platelet counts , compared to patient receiving epo alone .
it has also been shown that the use of erythropoiesis - stimulating agents ( esas ) in iron - deficient patients increases the risk of thrombocytosis and thrombosis .   except iron disuse
it has been suggested that there is a diminished responsiveness of erythroid cells to epo , being accompanied by increased levels of inflammatory cytokines , such as il-6 , soluble tnf receptor 2 , and tnf- levels [ 52 , 53 ] .
their activation does not result in epo receptor downregulation , but in blunted epo - induced jak - stat signaling .
this is confirmed by the partial abrogation of the inhibitory effects of anaemic sera on erythroid colony growth by anti - tnf- neutralising antibodies .
endothelial dysfunction associated with heart failure may alter endothelial no synthase activity , hence further augmenting myocardial dysfunction due to increased oxidative stress . paralleling these cardiodepressive actions , no seems to have a direct inhibitory effect on bone marrow hematopoietic activity [ 55 , 56 ] .
furthermore , it is of interest that no inhibits blood cell formation in nonischemic murine chf , whereas inflammatory cytokines , such as tnf- , impair hematopoiesis in chf following myocardial infraction .
a recent study suggests that vitamin d deficiency is independently associated with anemia in end - stage heart failure , based on the fact that vitamin d may stimulate erythropoiesis . on this study circulating
1,25-dihydroxyvitamin d was a better predictor of anemia than circulating 25-hydroxyvitamin d. prospective randomized studies with administration of vitamin d will have to clarify if the association of vitamin d deficiency with anemia is causal . in conclusion anemia in chf
two major factors contributing and exacerbating to its appearance are kidney dysfunction and iron deficiency . in 2003
this abnormality was described as cardio renal anemia syndrome ( cras ) , whereas the correction of anemia could play a major role in this vicious circle in improving the severity of chf . in the last years , the role of iron has been recognized , as a major component of many energy - producing systems . in view of a possible independent association of iron deficiency and cardiac failure , renal failure and anemia ,
the same authors rename the syndrome as cardiorenal anemia iron deficiency ( craid ) syndrome .
it is the final common pathway of other conditions , where renal failure and anemia contribute to the progression to a more severe disease status .
since the two major components of chf anemia are iron deficiency and reduced epo activity ( absolute or functional in both cases ) , the main goals of intervention would be to increase their levels .
anemia treatment strategies in heart failure patients include erythropoiesis - stimulating agents ( esas ) and red blood cell transfusions .
iron replacement in iron - deficient patients with or without anemia has also been investigated . before starting any treatment for anemia in chf
, it is necessary to exclude and treat , if possible , any other causes of anemia , such as active bleeding , hemolysis , vitamin b12 or folate deficiency , or even more chronic situations such as myelodysplastic syndromes and other malignancies .  
health services research & development service 's evidence - based synthesis program has collected the literature from 1949 until november 2010 and published a review regarding the treatment of anemia in chf and coronary heart disease patients . despite the association with poorer outcomes , it remains unclear whether treating anemia or iron deficiency may improve outcomes .
it has been suggested that a small reduction of hb levels may worsen the outcomes and symptoms of chf , whereas the correction of anemia may improve nyha classification , lvef , lvh , and diuretic response [ 6063 ] .
treatment has been centered on administration of erythropoiesis - stimulating agents ( esas ) and parenteral iron supplementation , but most studies are poorly powered and therefore with limited validity . on the other hand , the only way to cause a rapid increase of ht and therefore tissue oxygenation is the blood transfusion . nevertheless , the only recommendations referring to anemia of chf suggest treating any correctable causes of anemia , if this is evitable , such as iron , folate , or vitamin b12 deficiencies . the goal of hb correction is also
transfusion of packed red cells in hb values lower than 9  g / dl or ht less than 30% may be suggested , but in the setting of acute coronary syndromes this has been associated with higher mortality .
there are many data supporting that iron deficiency may contribute to the increased mortality in chf patients .
it has also been shown that correction of iron deficiency could improve symptoms and status of the syndrome . nevertheless , this has not been adequately confirmed .
there are several studies in chf , with iron deficiency , with and without anemia , suggesting that correction of iron deficiency , using iv preparations , could improve symptoms and signs of chf , such as s-wave , e / e ratio , peak systolic strain rate , nyha class , 6-minute walk distance , even without improvement of ef or rise of hb levels , without major side effects [ 6670 ] .
it is suggested , with high evidence , that correction of iron deficiency can improve exercise tolerance and duration , as well as the quality of life , in patients with stable chf and mild ckd .
there are also other studies suggesting that anemia in chf can be corrected only with iv iron and not the oral forms [ 7174 ] , whereas long - term oral iron does not seem to improve any chf parameters [ 75 , 76 ] .
this seems reasonable since in chf there is increased hepcidin expression that blocks iron use , even if it is absorbed . in general terms
it is preferred to administrate iv instead of oral iron , even though it can cause oxidative stress .
when using intravenous preparations , the majority of the dose is deposited in long - term storage .
there is a small portion of this iron that is rapidly bound to transferrin and available for transport to the bone marrow , bypassing the restrictions on iron release imposed by hepcidin .
the use of large amounts of iron , delivered over minutes or hours as pulse therapy , could lead to poor utilization of this iron with tissue deposition , free radical formation , and increased risk of infection , because of a decrease in cellular immunity and promotion of bacterial growth .
other concerns of iron administration have to do with an increased risk of coronary heart disease , but still have not been confirmed . in conclusion , there are not efficient data proving evidence that iron administration in non - iron - deficient patients with chf could improve the cardiac disease .
it is however of great value to recognize iron deficiency , even in the absence of anemia and to correct it .
regarding esas , there are only pilot studies for their use in the treatment of anemia of chf .
they are commonly used with simultaneous administration of iv iron , giving promising results in ameliorating symptoms and improving cardiac function , but only with very limited evidence [ 77 , 78 ] .
moreover , the epo receptor is present in many nonerythropoietic tissues , including myocardium , endothelium , vascular smooth muscle cells , and neurons , where epo has shown tissue protective properties , because of its antiapoptotic action .
treatment with epo in excitable murine and human left ventricular muscle preparations have resulted in an increase in twitch tension and in peak sarcomere shortening .
this suggests that epo exhibits direct positive inotropic and lusitropic effects in cardiomyocytes and ventricular muscle preparation , being mediated through pi3-k and pkc isoform signalling , to directly affect both calcium release dynamics and myofilament function .
therefore , there could be an extra role of epo in ameliorating symptoms , in addition to improving hb levels .
the major concern of epo administration , based on hemodialysis experience , has to do with a possible increase of thrombotic risk , especially by overzealous correction of anemia or when iron - deficiency - associated thrombocytosis coexists . at present ,
there are not clearly defined targets of hb in ckd anemia , although an hb level of 10  g / dl seems to be a widely accepted goal .
recently , there have been many studies of anemia in chf patients with an effort to improve hb levels .
there have been used esa and oral or iv iron and even iv iron without esa , that have shown a positive effect on hospitalization , nyha functional class , cardiac and renal function , quality of life , exercise capacity , and reduced bnp , without any increase in cardiovascular damage related to the therapy
. however , adequately powered long - term placebo - controlled studies of esa and iv iron in chf are still needed and are currently being carried out .
nevertheless , until recently , there is high evidence that the use of esa in stable chf patients with serious renal disease did not have any particular effect on cardiovascular events , whereas there is moderate evidence that their use might have a negative impact on the survival .
recent studies have recognized that dilutional anemia is highly prevalent in chf patients . in this
regard , arginine vasopressin antagonists might be an attractive treatment option , by increasing aquaresis .
therefore , future clinical research should explore the role of arginine vasopressin pathway activation in determining dilutional anemia and , ultimately , assess it as a therapeutic target .
the evidence base to date does not convincingly support a role for esas for anemia correction . on the other hand
, iron treatment may help ameliorate symptoms over the short term in patients with symptomatic heart failure .
it seems that anemia exacerbates chf , causing a vicious circle , where renal dysfunction and neurohormonal and proinflammatory cytokine activation participate in the development of anemia . on the other hand ,
so , it is important to recognize any possible causes of anemia . it would also be beneficial to treat them , if possible .
administration of iron and esas seems to be promising , since they can both also improve factors other than anemia , but still there are many questions to be answered .
these mainly concern their safety , the goals in hb elevation , and probably their cost .
further studies are required to understand the association of anemia with chf outcomes , to recognize the impact of anemia improvement , to asses when to initiate and when to cease the treatment , and finally to estimate the safety of these interventions .
 heart failure is a very common disease , with severe morbidity and mortality , and a frequent reason of hospitalization . 
 anemia and a concurrent renal impairment are two major risk factors contributing to the severity of the outcome and consist of the cardio renal anemia syndrome . 
 anemia in heart failure is complex and multifactorial . 
 hemodilution , absolute or functional iron deficiency , activation of the inflammatory cascade , and impaired erythropoietin production and activity are some pathophysiological mechanisms involved in anemia of the heart failure . 
 furthermore other concomitant causes of anemia , such as myelodysplastic syndrome and chemotherapy , may worsen the outcome . based on the pathophysiology of cardiac anemia 
 , there are several therapeutic options that may improve hemoglobin levels , tissues ' oxygenation , and probably the outcome . 
 these include administration of iron , erythropoiesis - stimulating agents , and blood transfusions but still the evidence provided for their use remains limited . 