Influence Of Endogenous Erythropoietin Levels On Anemia And Prognosis In Patients With Chronic Heart Failure

Objective:To exam the adequacy of endogenous erythropoietin(EPO) levels for the degree of anemia and analyze the clinical and prognostic value of EPO levels in patients with chronic heart failure(CHF).Method:In 115 inpatients with CHF(age,73.6±9.3years; New York Heart Association class,ⅡtoⅣat least 1 month), hemoglobin(Hb) levels and plasma concentrations of EPO and C-reactive protein(CRP) and urine Albumin/creatinine ratio(ACR) were determined and used the simplified Modification of Diet in Renal Disease (MDRD) equation to estimate glomerular filtration rate(GFR). Based on the data of 32 control patients, an exponential regression equation of serum EPO vs. Hb was calculated. This equation was used to predict the EPO levels based on the Hb levels. The adequacy of endogenous EPO levels was assessed by derived observed/predicted logEPO(O/P) ratio. These patients were followed up for any hospitalization due to HF or all-cause mortality.Results:Anemia(Hb<12g/dl in women and Hb<13g/dl in men) was present in 66 patients (57%). Anemia was more common in older and higher New York Heart Association (NYHA) class. Patients with the more severe forms of CHF exhibited significantly declined levels of Hb and elevated levels of EPO. Median endogenous EPO levels was 24.2U/L (interquartile range,15.2 to 34.4) in CHF patients, patients with NYHA classesⅡ,Ⅲ, andⅣhad levels of 17.2,24.3, and 29.5U/L, respectively. Only patients with NYHA classⅣof CHF exhibited significant elevated levels of EPO compared with control patients (median 22.9U/L; interquartile range,14.2 to 31.0), P=0.005. The levels of Hb and EPO were comparable between systolic and diastolic CHF patients.Brain natriuretic peptide (BNP), ACR and GFR were significantly different in anemic subjects compared with that in non-anemic subjects (P=0.043 and P=0.006 and P=0.044, respectively). EPO levels were comparable between anemic and non-anemic CHF patients (24.8U/L vs.22.5U/L, P=0.252), but O/P ratio was significantly reduced in anemic subjects (1.01±0.20 vs.1.09±0.20, P=0.041).During a median follow-up of 1131 days,55 patients (48%) died. Non-survivors had significant higher age, lower Hb, higher NYHA classes and higher BNP levels than survivors. The Kaplan-Meier survival curve clearly demonstrated increased mortality in patients with anemia, hazard ratio 2.50 (95% confidence interval,1.38 to 4.54), P=0.002. The Kaplan-Meier analysis also revealed that CHF patients with elevated EPO levels (=44.4U/L) and elevated BNP levels (=752pg/ml) had a significantly increased mortality (P=0.036 and P<0.001, respectively). Cox regression analysis revealed that higher age, lower Hb, higher NYHA classes and higher BNP levels were independent predictors of increased mortality risk in CHF patients. Furthermore, anemia and elevated BNP levels were also found to be good predictors of CHF hospitalizations (P=0.001 and P<0.001, respectively). Multivariate Cox regression analysis revealed that a higher EPO level was an independent predictor of increased mortality risk adjusted for variables including age, sex, Hb, NYHA class, LVEF, BNP and renal function parameters in anemic patients of CHF (hazard ratio,2.86; 95% confidence interval,1.18 to 6.94; P=0.020).In anemic CHF patients, EPO levels lower than expected (O/P ratio<1) were observed in 30 patients (45%), whereas EPO levels higher than expected (O/P ratio=1) in 36 patients(55%). CHF patients displayed a relatively moderate negative correlative tendency between logEPO and Hb levels (r=-0.188, P=0.045). It tended to have correlations between Hb and NYHA class (r=-0.352, P=0.002) and logBNP (r=-0.245, P=0.043)and logACR(r=-0.293, P=0.003). The tendency of correlation was observed between logEPO and NYHA class (r=0.361, P=0.003) instead of other heart or renal function parameters in CHF patients. A trend of correlation was also found between O/P ratio and logCRP in tatal CHF patients (r=0.168, P=0.042) and non-anemic CHF patients (r=0.372, P=0.009).Conclusions:1. Anemia was common in CHF. The degree of anemia was correlated with the severity of heart failure and was associated with an impaired prognosis(all cause mortality and CHF hospitalizations) in patients with CHF.2. In CHF patients, circulation EPO levels increased in subjects with higher NYHA class. Endogenous EPO levels were correlated with increased mortality rates in anemic CHF patients.3. In the CHF patients, EPO levels poorly correlated with the Hb levels.4. The O/P ratio was significantly reduced in anemic subjects compared with non-anemic CHF patients, which reflected that the inability to produce sufficient levels of EPO to stimulate the bone marrow adequately could be one of the cause of anemia in CHF patients.5. In some anemic CHF patients, O/P ratio was high. The correlation between O/P ratio and CRP suggested that elevated EPO production was related to an enhanced inflammatory state in CHF. Anemia in CHF could be partially explained by this enhanced inflammatory state which inhibited erythropoiesis and could eventually result in elevated EPO requirements.