Department of Pharmacology, Government Medical College, Surat, Gujarat, India
Received date: 28/06/2014; Revised date: 19/07/2014; Accepted date: 30/07/2014
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In many studies, a vicious link is found between heart failure (HF), kidney and Anemia. Anemia is common in HF patients, but its high prevalence in HF patients is directly related to itself or other comorbid conditions. Multiple potential mechanisms of interaction exist between anemia and the clinical syndrome of HF, including hemodilution, inflammatory activation, renal insufficiency, and malnutrition. Anemia is an independent risk factor for adverse outcomes in patients with HF as well as, it itself can precipitate HF. Anemia is an important comorbid condition and potentially novel therapeutic target in patients with heart failure (HF). Available data suggest that treatment of anemia isassociated with significant symptomatic improvement in HF.Simultaneously, aggressive treatment of anemia with erythropoietin (EPO) associated with increased risk of hypertension and thrombosis. Here this review article highlights the possible mechanisms for anemia in HF and balanced treatment approach to minimise treatment associated risk.
Cardio renalnemia, CHF, EPO, Erythropoietin Stimulatinggent (ESA).
Cardio-renal-anemia syndrome: In simple terms, it can be vieweds relatively low level of hemoglobin because of impact of diseased heart on kidney with thessumption that, in the presence of healthy heartnd the same kidney it will be normal or near normal.nemia has recently been demonstrated to be common comorbid condition in patients with HF,nd multiple observational studies have demonstratedn independentssociation between lower hemoglobin (Hb)nddverse clinical outcomes in this syndrome.lthough these findings have generated substantial interest innemias potentially important therapeutic target in patients with HF, current HF guidelines provide no specific recommendations for evaluation or treatment ofnemia. [1,2] The purpose of this review is to outline the current understanding of thessociation betweennemiand HFndssess the existingnd emerging data onnemias potential treatment target, including the potential benefitsnd risks of treatingnemia in the setting of HF.
As early recognition of dysfunction in one organ may prove important in mitigating the spiral of co-dysfunction in both, the need for earlynd treatment-guiding biomarkers,long with their characteristics.  Heart failure is eitherncute or chronic condition. diseased heart has numerous negative effects on kidney function but,t the same time, renal insufficiency can significantly impair cardiac function.  Directnd indirect effects of each organ that is dysfunctional can initiatend perpetuate the combined disorder of the two organs through complex combination of neurohormonal feedback mechanisms.
Anemia isssociated withn increased mortality in wide variety of patients ranging fromsymptomatic left ventricular dysfunction todvanced CHF. [5,6] nemia isn independent risk factor for the development of CHF  nd could contribute to the worsening of CHF. [7,8] nemia could exacerbate CHF by increasing myocardialnd peripheral hypoxia, promoting left ventricular hypertrophy ,ndctivating neurohormonalnd cytokine systems.  Volume overload that occurs with hemodilution couldlso contribute to worse outcome. Hypervolemia may be linked to increased mortality risk since beta natriuretic peptide (BNP), cardiac-derived hormone closely correlated to left ventricular end-diastolic pressure, has been shown to ben independent predictor of survival in CHF patients.  Volume overload may be key mechanism contributing to the increased mortality in CHF patients withnemia.  Thus it is possible that in CHF vicious circle is set in motion wherein CHF causesnemiand thenemia then worsens the CHF. Thenemia in long standing hypertension or CHF could be due to several factors.
2.nemia of chronic renal failure (CRF).
CRF or end stage renal disease is consequence of long standing hypertension or CHF. Thenemia of CRF is due to combination of many factors of which the most important is the reduced production of erythropoietin (EPO) in the kidneynd hemodilution due to sympathetic overactivity. [14,15]
3. Loss of EPOnd transferrin in the urine.
4. Use ofngiotensin converting enzyme (ACE) inhibitorsndngiotensin receptor blockers.CE inhibitors, especially in high doses, may interfere with both EPO production in the kidneynd EPOctivity in the bone marrow.  The mechanistic basis forntihypertensive medication-related changes in hemoglobin concentration includes hemodilution, hemolyticnemia,nd suppression of red blood cell production. [19-21]
5. Increasedctivity of cytokines suchs tumor necrosis factor-α (TNF-α). TNFlpha is very elevated in chronic diseasesnd CHF  nd has been shown to interfere with erythropoietin (EPO) production in the kidney, the erythropoietic response to EPO in the bone marrow, [23,24] nd with the release of iron from the reticulo-endothelial system for use in the production of red cells in the bone marrow.  The resistance to EPO in the bone marrow may explain whynemia can be present in CHF even when the levels of EPO in the serumre elevated,s they frequentlyre, in CHF. 
The increase in sympatheticctivity in CHF is responsible forn increase in renalfferentrteriolar constriction, leading ton increase in renin secretionnd ultimately,n increase inldosterone secretion.  Renin, through the effect ofngiotensinnd onldosterone, isn important factor for sodiumnd water retention in the body. The resultant increase in blood volume leads to hemodilutionnd may be the cause for low haemoglobin in hypertensives.  The increased plasma volume in stress induced hypertension (symapatho-adrenalxis overactivity) or CHF may cause reduced Hb.[10,27,28]
7. Chronic heart failure isssociated with profoundnd general bone marrow dysfunction, simultaneouslyffecting multiple hematopoietic lineages. 
Anemia isssociated withn increased mortality, morbiditynd hospitalizations. Compared with nonanemic patients, the presence ofnemia isssociated with worse cardiac clinical status, more severe systolicnd diastolic dysfunction, higher BNP level, increased extracellularnd plasma volume, more rapid deterioration of renal function, lower quality of life,nd increased medical costs. Renal failure, cardiac failure,ndnemia thereforell interact to cause or worsen each other—the so-called cardio-renal-anemia syndrome. 
Symapathetic overactivity which is seen in CHF has major impact on the cardiovascular,utonomicnd hematological parameters. Lesser hemoglobin due to sympatho-adrenalxis induced hemodilution can lead to increased cardiac outputnd heart failure. Whileddressing the complication of CHF hemoglobin level has to be mentioned.
Cannemia cause CHF?
Anemia ofny cause may produce CHF. Vasodilatation caused by theccompanying tissue hypoxia lowers the blood pressure, thusctivating the sympathetic nervous system (SNS).This causes peripheral vasoconstrictionnd tachycardia whichre needed to maintainthe blood pressure. Thessociated renal vasoconstrictionctivates the reninngiotensinldosterone system (RAAS). The highngiotensin II levels further increase renalnd peripheral vasoconstrictionnd increaseldosterone production. The resultant reduction in renal blood flow (RBF)nd glomerular filtration rate (GFR) can cause renal ischemiand fluid retention. The renal insufficiency thus produced maylso causenemia through reduced
EPO productionnd bone marrowctivity. The increasedldosterone further increases the fluid retention. Thus there is marked increase in plasmand extracellular volume which can manifest itselfs ventricular dilationnd centralnd peripheral edema. The long-term effects ofll these factors on the heart can be disastrous. The heart is faced on the one hand withn increased workload with increased heart ratend stroke volume,nd on the other hand, the oxygen carrying capacity of the blood is reduced by thenemia itself. The heart undergoes ‘remodeling’ with ventricular dilationnd left ventricular hypertrophy (LVH). Both the SNSnd RAA Scontribute to this remodeling. Eventually the LV dilationnd hypertrophy lead to myocardial cell death (apoptosisnd necrosis), cardiac fibrosis, myocardiopathynd further CHF. [31,32]
Increased susceptibility of the damaged heart toanemia
In patients with coronaryrtery disease the effects ofnemia on the heart may be even more severe than in normal people. In the damaged heart, ischemia can occurt higher Hb level than in those with normal heart. While patients with normal hearts undergoing surgery can tolerate low hemoglobin levels without increasing cardiovascular (CV) risk, those with coronary heart diseasere more likely to have CV complicationst low Hb levels. [33-36]
Treatment of anemia in HF
There is poorttention paid tonemia, its causesnd treatment. Current treatment strategiesappear to be insufficientt improving patient outcome in terms of rehospitalization rate reduction, generating high costs, which could bevoided throughn optimized treatment strategy. Therefore, more efficacious, efficientnd cost-effective treatment strategiesre required for HF patients withnemia to meet this unmet medical need.  Iron supplementation or replacement is treatment option for patients with HFndnemia, but questionsbout the safety of intravenous ironndbsorption problems with oral formulations have prevented its widespread use to date. Number of studies with intravenous iron has shown promising results. Therefore, this treatmentpproach is likely to becomenttractive option for patients with HFnd iron deficiency, both withnd withoutnemia. 
Erythropoietin (EPO)&Erythropoiesis-Stimulatinggents (ESA)
Meta-analysis of small RCTs suggest that treatment with ESA can improve exercise tolerance, reducend have benefits on clinical outcomes innemic patients with heart failure.  Despite initial studies indicating possible beneficial effect of erythropoiesis-stimulatinggents in the treatment ofnemic heart failurepatients, information on the long-term safety is still lacking. Ongoing large-scale trials will have the potential to provide such information in the future. [40,41] EPO isssociated with seriousdverse effects beginning from hypertension, headaches ton increased number of thrombotic eventsnd death. Moreover, EPO withdrawal may be complicated by neocytolysis – hemolysis of young red blood cells in the presence of increased hematocrit.  The most common side effect of recombinant human erythropoietin (rHuEPO) therapy is hypertension which may occur even in healthy subjects [43,44] nd rHuEPO enhances pro-coagulant pathways.  So better correction ofnemia with higher Hb target isssociated with increased risk for stroke, hypertension, vascular thrombosis compared with lower Hb target.  By keeping in mind these serious side effect that candverselyffect the outcome of HF patient, balancednd short term use of EPO treatment in HF patient withnemia seems more judicious.
Iron deficiency will cause resistance to EPO therapynd increase the need for highernd higher doses to maintain the Hb level. [47,48] Treatment of thenemia with EPOnd IV iron may be usefulddition to the physicians’rmamentarium in CHF. 
Many patients with mild CHFnd most patients with moderate to severe CHFrenemic. The degree ofnemia parallels the degree of deterioration of cardiacnd renal functionnd may contribute to this deterioration. The correction of thenemia isssociated withn impressive improvement in cardiac function that is reflected in marked improvement in the NYHA functional class,n improvement in renal functionnd striking reduction in hospitalizationsnd use of oralnd IV furosemide.