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

Caramelo C et al. Anemia in Heart FailureEPO synthesis can be reasonably, although not totally,independent of the reabsorptive activity.Baseline hematopoietic stimulation originates in thephysiological destruction of red blood cells, but itsgreatest intensity is observed in hemorrhage. Anemiaof HF is usually mild, persistent and adaptive. Thus,its effects would be analogous to minor hemorrhagewith limited, but long-term, hemodynamic impact. Thekidney has to restore volume depending on the amountof fluid lost and produce red cells to replace those lost,but nothing more. Moreover, it has to be able to discernthe proportion in which fluid is conserved and new redcells are produced. The joint regulation of these 2mechanisms is more complex than that of eachseparately, and is 1 of the keys to research in a diseaselike HF.What makes up the chain of signals and mechanismsthat increase endogenous erythropoietin? Thephysiological sequence involved in the stimulation ofEPO production is based on 2 transcription factors thatcan be activated by hypoxia, hypoxia-inducible factors 1,and 2 (HIF-1 and HIF-2). 59,60 Hypoxia-inducible factor1 is a molecule that regulates an overall multigenicresponse, rather than isolated effects. The great advancein recent years has been the discovery that transcriptionallyactive HIF-1 depends on a group of non-heme-irondependentprolyl hydroxylases that constitute the trueoxygen-sensing mechanism. 59,61 . In contrast, HIF-2appears to play a selective role in EPO expression, whichis practically abolished in the knockouts for this gene. 61,62The activation state of HIF in HF is unknown, andthere are no data published concerning its measurement.Thus, references to its role are limited to supposition,firm, but still conjectural. Although the patient with HFcan go through periods of systemic hypoxia, they areusually transient; brief hypoxia does not constitute astrong enough stimulus for sustained EPO induction. 57On the other hand, the measurement of tissue oxygenationis a challenge that has yet to be resolved by clinicalresearch and the tissue oxygen levels reached duringperiods of decompensation and compensation in HF arebasically unknown.Hypoxia-inducible factor 1 is activated by means ofphosphorylation under hypoxic conditions. It acts bytransactivating more than 70 genes, at least 4 of whichare highly relevant to the final effect of EPO: the transferringene, supplying iron to the erythroid cells; the vascularendothelial growth factor (VEGF) gene, a cofactor in thestimulation of these same cells and a determining elementin angiogenesis and tissue perfusion; the tyrosinehydroxylase gene, involved in dopamine synthesis andrespiratory regulation; and the nitric oxide synthase gene,which maintains normal arterial blood pressure underthe potentially pressor effect of EPO. 63Hypoxia-inducible factor 1 is activated at oxygenconcentrations of around 4% to 5% (saturation of 30 to35 mm Hg). 64 The presence of elevated EPO levels inpatients with HF can be taken as an indirect sign of HIFstimulation, but, as yet, there is no direct scientificevidence in this respect.Hemodynamics and ErythropoietinThe blood flow rate in the kidneys is elevated(approximately 20% of the cardiac output). In the renalmedulla, the pO 2is permanently under 10 mm Hg,whereas in the cortex, it is more variable, with a meanclose to the threshold for HIF stimulation (30 mm Hg).Changes in these concentrations are determinant ininduction of the EPO gene. 65 Thus, it is assumed that, inpatients with more severe HF (NYHA functional classIII-IV), since the renal flow rate is reduced, the decreasedperitubular oxygen tension would be the main stimulusto trigger EPO production. 17 Other studies point out theassociation between EPO synthesis in HF and renalhemodynamic dysfunction, although no correlationbetween plasma EPO levels and arterial pO 2, oxygensaturation, or glomerular filtration has been found. 66Role of Angiotensin IIIn HF, the low renal output stimulates renin production,and this, in turn, that of angiotensin II (Ang II). A higherAng II level results in greater sodium reabsorption and,thus, an increased adenosine triphosphate and oxygenconsumption, secondary to the increased tubularreabsorptive function. In healthy subjects, the EPOconcentrations are correlated with the proximal tubularsodium reabsorption rate. 67 Diuretics that act on Henle’sloop, the distal tubule and collecting duct (furosemide,hydrochlorothiazide, and amiloride, respectively) do notaffect EPO formation. In contrast, acetazolamide, whichacts on the proximal tubule, significantly decreases EPOproduction in response to normobaric hypoxia andfunctional anemia. 67These data are consistent with the simultaneity of theincrease in EPO levels and the poorer prognosis of HF. 68Thus, if proximal hyperreabsorption is proportional tothe degree of decompensation in HF, it can be assumedthat those patients who are decompensated will reabsorbmore sodium and will produce more EPO. To date, studiesaddressing this assumption have not been performed inhumans.One relevant question is whether the changes observedin Ang II are due to a direct stimulation of the peritubularfibroblasts that synthesize EPO or to hemodynamic effectsinduced by Ang II. In vitro, in HepG2 tumor cells, whichexpress AT1 receptors, Ang II, and the AT1 antagonist,losartan, have no effects on EPO production, acircumstance that supports the idea that the in vivo effectsof Ang II are mainly due to hemodynamic changes. 69However, there are data that indicate that Ang II is capableof activating HIF-1α to levels even higher than those854 Rev Esp Cardiol. 2007;60(8):848-60