Anemia in Heart Failure: Pathophysiology, Pathogenesis, Treatment ...

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Caramelo C et al. Anemia in Heart Failuregenerated by hypoxia. 70 The administration of exogenousAng II, which increases HIF-1 and its target gene, VEGF,also increases the EPO concentrations in a dose-dependentmanner. 71 Likewise, transgenic mice carrying both humanrenin and human angiotensinogen have persistenterythrocytosis, via the AT1 receptor. 72 These results canbe explained by findings in in vitro studies that establishthat Ang II not only plays a role in EPO production, butalso stimulates erythroid precursors by means of AT1activation in the erythroid burst-forming units. 41 Despitethe fact that we have all this information, it can be saidthat, as a whole, the effect of Ang II on anemia has yetto be fully defined.Signaling in Erythropoietin ProductionThe regulation of EPO production is controlled by anenhancer that binds HIF-1 and, thus, is referred to asHRE (hypoxia responsive element). In addition, thereare elements that coregulate gene expression, theimportance of which is still not fully known, but thatmight explain the differences in EPO mRNA synthesisobserved under conditions equivalent to hypoxia. Amongthem, we should mention two transcription factors, GATAand nuclear factor kappa beta (NFκβ), which negativelyregulate the expression of EPO mRNA. These 2 factorscan be increased in the presence of inflammation, andthus, constitute plausible explanations for the decreasein EPO synthesis in inflammatory conditions. With respectto the stimulation of EPO gene expression, it should bementioned that there is an inverse relationship betweenGATA and nitric oxide, a circumstance that indicates arole of the decrease in the latter in the reduced EPOproduction. 73Erythropoietin Signaling in its Target CellsErythropoietin signals through a receptor with proteinkinase activity, which mediates proliferative andantiapoptotic effects in the erythroid precursors. For theformer, EPO stimulates the Ras/mitogen-activated proteinkinase (MAPK) pathway and, above all, the Janus kinase2 (JAK2) pathway, which acts without intermediarymetabolites on transcription factors of the STAT (signaltransducer and activator of transcription) family, especiallySTAT5. The antiapoptotic effects can also employ theJAK2/STAT pathway, but the main enzymatic step occursin phosphatidylinositol-3 kinase. There are EPO receptors(EPO-R) in the erythroblasts, but they are also found inthe placenta, heart, retina, brain, and endothelial cells. 74The EPO-R is a transmembrane receptor that sharesproperties with the receptors of other hematopoieticfactors. While the intracellular transduction of EPO isknown to take place, there are considerable gaps in ourknowledge with respect to how this hormone regulatesthe survival, proliferation and differentiation of erythroidprogenitor cells. 75The inhibitory effect of apoptosis does not only concernthe erythroblasts. In this respect, it has recently beendemonstrated that EPO is a potent trophic and apoptoticfactor, with protective effects in brain and retinal cells,in the renal epithelium and, as mentioned above, inmyocardial cells, as well. 51Resistance to ErythropoietinIn studies that relate an increase in EPO to a poorerprognosis in HF (severity and mortality), the patientswith elevated erythropoietin levels are usually moreanemic. In the absence of bleeding, this suggests peripheralresistance to the action of endogenous EPO. 68 Thecirculating EPO concentrations, as well as the severityof anemia, increase in parallel with the NYHA functionalclass 38 and, thus, we should look for additional pathogenicelements to explain the anemia.Other factors that have been implicated in thepathogenesis of resistance to EPO in HF are the mediationof cytokines and generalized bone marrow dysfunction. 11,44The latter has been postulated on the basis of the decreasedleukocyte/lymphocyte counts in patients with HF andanemia, but its importance is marginal.The causes for resistance to EPO in HF should bestudied in accordance with findings associated with otherdiseases (Table 3). There are no studies that systematicallyanalyze resistance to exogenous EPO in HF, a subjectthat requires a specific examination.PHARMACOLOGICAL TREATMENTOF ANEMIA IN HEART FAILURETo date, there are no studies that systematically comparedifferent treatment regimens in the anemia of HF. Theresults of the survey that we mentioned above indicatethat only a minority of cardiologists and internists employrecombinant erythropoiesis-stimulating agents (ESA)and intravenous iron. For this reason, we have based ourstudy on the experience accumulated in the nephrologysetting, with over 15 years of continuous use of ESA,intravenous iron, and other supplements. The nephrologysocieties have at least 2 large practice guidelines, theKidney Disease Outcome Quality Initiative (KDOQI) 76-78in the United States, and the European guidelines,which provide a considerable body of knowledge, withaspects that are reasonably adaptable to the cardiologysetting.Existing Erythropoiesis-Stimulating Agentsand Those Being DevelopedThe first generation of ESA included recombinantEPO-alpha (Epogen, Amgen; and Procrit/Eprex, Johnson& Johnson/Janssen-Cilag) and EPO-beta (NeoRecormon,Roche). The demand for longer-acting ESA led to thedevelopment of darbepoetin (Aranesp, Amgen), aRev Esp Cardiol. 2007;60(8):848-60 855
Caramelo C et al. Anemia in Heart Failurehyperglycosylated derivative with a 3-fold longer halflife,thus making it possible to administer weekly,bimonthly, or even monthly injections; the efficacy ofthe latter periodicity has been tested in HF patients. 80A pegylated derivative, a continuous erythropoiesis receptoractivator (CERA, Roche), with an even longer half-life, 52,81will soon be made commercially available. Other highlyinteresting products capable of inducing hematopoiesisare in an advanced state of development. These includethe synthetic EPO receptor agonist developed by Affymax,Hematide, a peptide that is not related to the compoundsutilized up to now and that has been shown to producelong-term erythroid induction (1 month), with goodtolerance and stability at room temperature. Finally,FibroGen is developing a new approach to the problemof anemia, which involves the stabilization of HIF-1 bymeans of prolyl hydroxylase inhibitors of small molecularsize. In HF, the important potential advantages of agentsof this type do not lie solely in their oral administration,but in the induction not only of EPO, but of the multiplegenes involved in the antianemic and hypoxic response. 52,81Recently, for the purpose of acting exclusively on thetrophic effects (see below), EPO derivatives that have aweak action in erythroid precursors, but are potent inother cell types, are being developed.TREATMENT WITH ERYTHROPOIETININ HEART FAILURE PATIENTSAND ITS CONSEQUENCESThe critical points of the treatment of anemia in HFare the pharmacological tools and the therapeutic target,that is, the point of optimal yield. While this target hasto be individualized, to date, there is not sufficientconsensus as to the optimal hemoglobin and hematocritvalues to be reached and maintained. 6,7 There arehemoglobin levels that are not considered to be harmfulin normal subjects, but are deleterious in HF. 6 It is alsonecessary to take into account the fact that a rapid increasein hematocrit or its increase beyond normal levels worsensthe prognosis. Available studies indicate that a hematocritvalue of around 35%-36% and a hemoglobin level ofapproximately 12 g/dL are safe. 7,9Among the beneficial effects of treatment with EPO, 7,11different authors point out that the correction of anemiaincreases the ejection fraction, decreases left ventricularmass and improves the oxygen-carrying capacity andoxygen utilization (peak consumption) during exercise,thus lengthening its duration. 82 It also improves the NYHAclass and myocardial ischemia during the stress test,stabilizes the creatinine levels, enables the reduction ofthe doses of diuretics and iron, and improves the qualityof life index. All these effects play a role in the reductionin the number and duration of hospital stays. 13,29,82 In astudy in which subcutaneous EPO and intravenous ironwere administered to HF patients in NYHA functionclass III-IV with a hemoglobin level < 12 g/dL who hadTABLE 3. Common Causes of Resistanceto Erythropoietin*Blood lossIron deficiency: absolute and relativeChronic renal disease: also provokes endogenous EPO deficiencyAcute and chronic inflammationAntagonist agents: ACE inhibitors, nonsteroidal antiinflammatorydrugsMalnutrition and deficiency of factors, such as vitamin B 12,folic acidBone marrow depression*ACE indicates angiotensin-converting enzyme; EPO, erythropoietin.not responded to conventional therapy, the correction ofanemia was associated with a marked improvement incardiac function and a reduction in the number of hospitaladmissions and the use of diuretics. 9Of special interest is the improvement in the exercisecapacity in patients with moderate-to-severe HF beingtreated with EPO, with an increase in the oxygen deliveryand a reduction in oxidative stress. 82 In patients withchronic HF, a functionally important relationship hasbeen reported between a hemoglobin < 13 g/dL andexercise capacity; it is highly interesting to observe thatthis relationship does not exist when the hemoglobin is> 13 g/dL. 54Some of the undesirable effects of EPO reported inthe past, such as, for example, hypertension, thromboses,and pure red cell aplasia, have disappeared or have beenreduced to a minimum. Despite its angiogenic effects, 74there are no consistent data that allow us to attribute aworsening of malignant tumors or diabetic retinopathyto EPO.In the economic aspect, the cost of treatment with EPOand iron is lower than that of hospital readmission, 29 butthere are no specific studies on this question, and theyare necessary.THE PHARMACOLOGY OF ERYTHROPOIETINThe existing preparations can be administered eithersubcutaneously or intravenously, although for practicalreasons, the former is preferred; discomfort at the injectionsite is minimal. It is essential to keep in mind theimportance of maintaining the cold chain at 4 o C topreserve a high efficacy. 83The duration of the effect of EPO (up to 1 week) isshorter than that of darbepoetin, which lasts 15 to 30days, although the therapeutic yield is equivalent. Theindications for EPO, originally limited to patients withCRD, are being extended to all the groups that mightbenefit, including patients with myelodysplastic syndromeor human immunodeficiency virus, premature infantsand cancer patients undergoing chemotherapy, as wellas in cases of sickle cell anemia, prior to autologous856 Rev Esp Cardiol. 2007;60(8):848-60
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