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

More documents

Recommendations

Info

Caramelo C et al. Anemia in Heart Failurecomplications. An interesting question is the fact that thedecrease in hematocrit could be a marker for other factorsthat increase the mortality in patients with severe HF, forexample, CRD. 44MECHANISMS BY WHICH ANEMIA CANINCREASE THE MORBIDITY AND MORTALITYIN HEART FAILUREAgain, we are faced by the lack of sufficient scientificevidence. Lower hemoglobin concentrations are associatedwith a poorer hemodynamic function, increases in serumurea nitrogen and creatinine, decreases in albumin,cholesterol and body mass index, a worse functionalclass, and a lower VO 2(peak oxygen consumption). 6,10,13A relationship between anemia and a less favorable coursehas been reported in patients with CRD, 50 asymptomaticleft ventricular dysfunction, 45 and advanced HF. 7,13 Thereare not sufficient data in cases of severe systolicdysfunction.In patients with preserved ventricular function, thehyperdynamic state can play a role in ventricularhypertrophy, which, in turn, can promote a disproportionbetween the oxygen supply to the myocardium and theincreased ventricular mass, a circumstance that is criticalin the presence of significant coronary artery disease.Cardiac output has been found to be sharply increased,with hemoglobin < 10 mg/dL (hematocrit < 30%-33%). 44In the Prospective Randomized Amlodipine SurvivalEvaluation (PRAISE), anemia is associated with deathdue to pump failure. Studies carried out in animals showthat an ischemic or hypertrophic heart is more vulnerableto slight decreases in hemoglobin than a normal heart,with a marked deterioration in the ischemia and themyocardial dysfunction. Under these conditions, thetreatment with EPO is even more interesting because ofits cytoprotective properties with respect to themyocardium. 9,51,52In a recent review, Roig pointed out that anemia couldprincipally be a marker of advanced disease, since it isassociated above all with a worse functional class, andthat its correction improves the symptoms, but notnecessarily the mortality rate. 11 On the other hand, it hasbeen shown that hemoglobin is, in itself, an independentpredictive factor of mortality in HF, in both anemic andpolycythemic individuals. 53 Even more important, thehematocrit range that we should consider as excessivein patients with HF and, in particular with ischemic heartdisease, has yet to be clearly established.In HF, anemia also influences hospital admissions, anda relationship between the hemoglobin levels and thenumber of admissions due to HF over the preceding yearhas been observed; in this respect, low hematocrit maybe more of a risk factor for hospital admission than formortality. 47-49Anemia can favor the progression of CRD in patientswith HF 38 and be, in itself, a risk factor 50 and a predictorfor the development of HF in patients with end-stageCRD. 44 In turn, renal function, together with the ejectionfraction and the NYHA class, may be an indirect markerof cardiac function. 25,26 Finally, anemia (hemoglobin< 13 g/dL is an independent predictor of the exercisecapacity in HF, whereas in patients with hemoglobin >13g/dL, there is no correlation between VO 2andhemoglobin. 54Cellular and Molecular Biologyof Erythropoietin Production: Hypoxia,Transcription Factors, and Other RegulatoryStimuliErythropoiesisProduction characteristics, site, and stimuli. Theproduction and action of EPO are the critical points oferythropoiesis. Erythropoietin is a glycoprotein that, inextrauterine life, is produced nearly exclusively in theperitubular fibroblasts of the renal cortex, without directcontact with the capillaries and tubular cells. 55,56 The EPOgene belongs to a set of hypoxia-sensitive genes that areoverexpressed when there is a decrease in the cellularpartial pressure of oxygen (pO 2). 57 The production ofEPO exhibits circadian fluctuations and the kidneyintervenes in its catabolism. Hypoxia can lead to a severalhundred-fold increase in EPO. In the experimental setting,the increase in the intensity of hypoxia is accompaniedby an exponential increase in the number of fibroblastsexpressing the EPO gene. 58 There are no data concerningthis finding in models of HF.Why in the kidneys? The possible physiological reasonsand consequences of the localization of EPO productionin the kidney is a question that has not been fully resolved.The simple fact that blood is made up of red cells andplasma provides a clue: what the organism regulates isthe proportion of plasma that is constituted by circulatingred cells (hematocrit). The specific mechanisms of thiscoordination are relatively unknown, although we assumethat there is an intrarenal connection between the pathwaysthat monitor and regulate the fluid volume and those thatcontrol the erythroid cell volume. 56 In other words, thecapacity of the kidney to detect the status of theextracellular volume (ECV) and produce EPO enablesit to “create” a normal hematocrit level. This phenomenonmay be of importance in HF, in which the accumulationof extracellular fluid and hemodilution can change the“perception” of the hematocrit on the part of the kidney.On the other hand, the kidney extracts only a small partof the oxygen delivered to it, a circumstance that makesit possible to detect slight changes in oxygenation.Moreover, the constancy of the ratio of the work performed(oxygen consumption) to the renal blood flow (oxygendelivery) makes it possible to separate the renal pO 2fromthe metabolic activity, meaning that the regulation ofRev Esp Cardiol. 2007;60(8):848-60 853
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
Page 5: Caramelo C et al. Anemia in Heart F
Page 9 and 10: Caramelo C et al. Anemia in Heart F
Page 11 and 12: Caramelo C et al. Anemia in Heart F
Page 13: Caramelo C et al. Anemia in Heart F

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

Create successful ePaper yourself

Delete template?

Save as template?