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European Journal of Heart Failure 2000 2(4):393-398; doi:10.1016/S1388-9842(00)00110-0
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© 2000 European Society of Cardiology

Serum erythropoietin in heart failure patients treated with ACE-inhibitors or AT1 antagonists

Bidisha Chatterjeea, Urs E. Nydeggerb and Paul Mohacsia,*

a Cardiology, Swiss Cardiovascular Center Bern, University Hospital CH-3010 Bern, Switzerland
b Clinic for Cardiovascular Surgery Bern, Switzerland

* Corresponding author. Tel.: 41-31-6322111; fax: 41-31-6324299. E-mail address: paul.mohacsi{at}insel.ch (P. Mohacsi).


   Abstract
Top
 Abstract
1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 References
 
Background: Erythropoietin (Epo), a growth factor produced by the kidney, is important in heart failure patients to promote oxygen delivery to tissues. Seventy-two chronic heart failure (CHF) patients at our outpatient clinic were subjected to morning serum Epo-level measurements and classified according to NYHA criteria.

Results: Forty-eight patients of classes III and IV had a significantly elevated serum Epo-level of 42.9±40.3 mIU/ml (mean±1 S.D.) when compared to the mean level of 24 patients of classes I and II who had a normal range mean value of 13.4±6.2 mIU/ml (P<0.05). Patients on angiotensin-converting enzyme (ACE) inhibitors showed a trend towards lower serum Epo-levels compared to patients treated with angiotensin-II type-1 receptor antagonists (AT1 antagonists) (levels: 33.3±35.6 mIU/ml and 43.6±38.1 mIU/ml). This trend did not, however, reach statistical significance (P=0.36).

Conclusion: We suggest that a desirable Epo increase in class III and IV CHF patients could be achieved by either recombinant human Epo administration or, possibly, by appropriate selection of the concomitant medical therapy. A large prospective study shall investigate the possible advantage of AT1 antagonists over ACE-inhibitors with regard to Epo effect.

Key Words: Heart failure • Anaemia • Erythropoietin • ACE-inhibitor • AT1 antagonists

Received January 5, 2000; Revised March 6, 2000; Accepted June 20, 2000


   1. Introduction
Top
 Abstract
 1. Introduction
2. Patients and methods
 3. Results
 4. Discussion
 References
 
Anaemia in CHF patients is common. It can be also observed in patients on haemodialysis due to impaired synthesis of erythropoietin (Epo) by the failing kidneys [1]. The renal anaemia can be treated with recombinant human erythropoietin (rHu-Epo) [2] but this treatment may lead to hypertension and thrombosis [3]. Nephrologists are successfully addressing such kinds of rHu-Epo side-effects with ACE-inhibitors to down-regulate blood pressure. This strategy led also to the finding that ACE-inhibitors are inhibiting the synthesis of endogenous Epo [4].

Anaemia in CHF patients is originated by different mechanisms: (1) cardiac forward and backward failure leads to impaired renal perfusion with consecutive anaemia; (2) low cardiac output may impair bone marrow function [5]; and (3) right heart failure may cause a nutritional deficit and an impaired metabolism. The use of ACE-inhibitors in CHF might be deleterious by further accentuating anaemia. Others have reported that Epo-levels depend on the severity of CHF [6]. Studies show that AT1 antagonists are equivalent to ACE-inhibitors in the treatment of CHF [7–9], while ongoing larger studies evaluate the effect of combined ACE-inhibitor and AT1 antagonist treatment [10,11]. Therefore we were interested in comparing the effect of ACE-inhibitors and AT1 antagonists upon endogenous Epo production.


   2. Patients and methods
Top
 Abstract
 1. Introduction
 2. Patients and methods
3. Results
 4. Discussion
 References
 
2.1. Patients
The study was performed in male (M) and female (F) Caucasian patients who are treated at the heart failure outpatient clinic, Cardiology, Swiss Cardiovascular Center Bern (Switzerland). Patients referred to our outpatient clinic were always pre-treated with ACE-inhibitors or AT1 antagonists for at least 3 weeks. There were no exclusion criteria. The protocol, approved by the local ethical committee, conformed with the principles outlined in the Declaration of Helsinki [12] and informed consent by the patients was requested in order to participate in the study.

2.2. Methods
Cardiac index (CI), ejection fraction (EF) and left ventricular end-diastolic diameter (LVEDD) were determined from right heart catheterisation and from the most recent echocardiogram.

Blood samples were taken on the day of a regularly scheduled routine control exam usually between 08.00 and 11.00 h. Haemoglobin, haematocrit and red cell indices were defined with a Coulter-STCKR Machine, Miami, USA. Creatinine was assessed by the method described by Jaffé [13] on a Hitachi 717 machine, Roche-Boehringer, Switzerland, and ferritin was determined with an ELISA on a Dade Stratus machine, USA.

The blood volume was estimated with a nomogram computing body weight, gender and age [14].

2.3. Assessment of Epo-levels
Serum was obtained from clotted blood and stored at –20°C until the time of analysis. To determine the EPO levels we used an Epo-ELISA kit (Medac AG, Hamburg, Germany) in our laboratory according to the manual given with the kit.

2.4. Statistics
We used statistical analysis provided by the software Excel 98TM, especially mean±1 S.D., t-test and different chart wizards. To analyse the Epo-ELISA regression plots of STATVIEW 4.5TM were used.


   3. Results
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
4. Discussion
 References
 
3.1. Study population
Clinical, haematological and chemical laboratory data were collected from January to July 1999. The baseline characteristics with respect to demography, aetiology of CHF, drug therapy and measurements are summarised in Table 1.


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  		Table 1 Clinical data of 72 heart failure patients studied in relation to NYHA classificationa

 
Half of the patient group suffered from ischaemic heart disease (36/72); the non-ischaemic heart disease was mainly dilatative cardiomyopathy (25/36, 70%). These aetiologies were represented across the board in all New York Heart Association (NYHA) classes [15].

The majority of patients participating in the study had dyspnoea, were NYHA class III, male, above 50 years, with normal weight and were ambulatory (Table 1). Patients results from NYHA group I and II were combined for further analysis as were results from groups III and IV, since there were no differences between these subgroups.

3.2. Drug therapy
ACE-inhibitors, given for at least 3 weeks or longer, were mainly enalapril (23.7±12.8 mg/day) and captopril (41.7±23.9 mg/day), and in the group treated with AT1 antagonists, losartan (49±21.6 mg/day) or candesartan (9±9.9 mg/day). Additional drug therapy for CHF included diuretics, β-blockers, aldosterone antagonists, nitrates, digitalis, antiarrhythmics, statins and anticoagulants (Table 1).

3.3. Clinical and laboratory measurements
Cardiac index and EF decreased with progression of disease, but LVEDD remained stable within the whole range of NYHA classes.

Most of the patients showed mild renal insufficiency (only 20 of 72 patients had a serum creatinine above 116 µmol/l, the anaemic group of patients had a mean creatinine level of 126.3±43 µmol/l). Twenty-eight of 72 patients presented a moderate anaemia (haemoglobin of 116±16 g/l) the origin of which was left undetermined because of its low degree. The level of anaemia was independent from the NYHA classes. None of the evaluated patients had received any red blood cell transfusions or any other treatment for anaemia, except for two patients on iron therapy.

The mean serum ferritin levels measured in 35 of 72 patients fell within the normal range with three exceptions, i.e. 400 µg/l, 1012 µg/l and 1740 µg/l (69-year-old male; 54-year-old male, 35-year-old female). The mean corpuscular volume (MCV) in 72 patients measured was within normal ranges (89±5 fl).

3.4. Erythropoietin levels
First, the Epo-levels were compared to the degree of anaemia in all patients. Six patients (66-year-old male; 62-year-old male; 62-year-old female; 48-year-old male; 35-year-old female; 24-year-old male) with anaemia below 100 g/l showed an increased Epo-level (>25 mIU/ml). The occurrence of an anaemia in these particular patients showed no obvious relationship to the therapy with an ACE-inhibitor (two patients) or an AT1 antagonists (four patients). Two patients, both under enalapril therapy (58 years male; 66 years male), although with an overt anaemia, kept low Epo-levels. There was no correlation between the haemoglobin- and Epo-levels (Fig. 1a). Concerning the Epo index [16], with the exception of two, no patient fell below the observed/predicted ratio-range between Epo and haematocrit of 0.8–1.2. The aforementioned two patients had a very low index (0.2; 0.3) without having a kidney disease.


Figure 1
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  		Fig. 1 Serum erythropoietin levels according to haemoglobin values (left panel) and NYHA class (right panel). (a) Levels are compared in 72 chronic heart failure patients and there is no significant correlation (P-value>0.05) as one would expect [54]. (b) Serum Epo-levels of the same 72 patients are depicted. Please note that abnormally increased Epo-levels occur predominantly in NYHA classes III and IV.

 
Second, the Epo-levels were compared to the NYHA classes. The mean values (±1 S.D.) of the Epo-levels in patients with severe CHF (NYHA classes III and IV, 42.9±40.3 mIU/ml) were significantly increased as compared with patients with mild to moderate CHF (NYHA classes I and II, 13.4±6.2 mIU/ml), P<0.05 (Fig. 1b).

Third, because of the existing suggestion from the literature [1] that enalapril may inhibit Epo secretion, we further classified our patients receiving ACE-inhibitors or AT1 antagonists according to normal and increased Epo-levels: 19 patients (10 female and nine male) under ACE-inhibitors and seven patients (two female and five male) under AT1 antagonists had Epo-levels >25 mIU/ml. Analysing these data as percentage of total patients receiving the respective drug show that the ACE-inhibitor patient group generally had lower serum Epo-levels (33.3±35.5 mIU/ml) than the group treated with an AT1 antagonists (43.6±38.1 mIU/ml); this difference, however, did not reach statistical significance (P-value=0.36).


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
References
 
We have initially analysed Epo-levels to evaluate their relationship to CHF therapy with ACE-inhibitors, AT1 antagonists and to anaemia. We are able to confirm the original report published by Volpe which showed an accumulation of hypererythropoietinaemic patients in the severely affected CHF group [6].

ACE-inhibitors reduce the response to exogenous Epo in anaemic haemodialysis patients [4,17]. This is consistent and, at least in part, explains the well-known phenomenon, that ACE-inhibitors exacerbate anaemia in patients with chronic renal failure and end-stage renal disease as well as in renal transplant recipients [18–23].

The prescription of ACE-inhibitors or AT1 antagonist in this population has raised concerns about these drugs aggravating anaemia and reducing the effect of exogenously administered rHu-Epo [24]. Clinical trials have shown that AT1 antagonists reduce haematocrit in patients suffering from post-transplant erythrocytosis [25–28]. However, in a total of 5064 patients on candesartan only a very slight, non-progressive reduction (1–2%) in haemoglobin concentrations was noted [29]. Schiffl et al. reported that captopril but not losartan worsened renal anaemia and led to hyporesponsiveness to rHu-Epo in haemodialysis patients [30,31]. Plasma Epo-levels decreased in patients with severe CHF, when enalapril was added as long-term treatment for at least 3 weeks [6]. A deficit of endogenous Epo production in heart failure with or without ACE-inhibitor treatment could constitute a substantial rationale to administer rHu-Epo to such patients.

The approach on gaining more insight into regulation of Epo-levels in CHF patients was started 10 years ago [32,33]. Since then, the study of Epo physiopathology in cardiovascular diseases has yielded interesting results: Epo has mitogenic and proliferative properties on endothelial cells [34,35], promotes endothelin expression via tyrosine phosphorylation [36] and can modulate the Na+/K+-pump in neuronal cells, cells of thrombopoiesis and myocytes [37].

The rare side-effects of Epo can be traced to the occurrence of Epo receptors not only on erythroblasts [38] but also on vascular endothelium [34] with enhancement of vasoconstrictive tone via endothelin-1 and constrictor prostanoids [39] and to the formation of thrombin–antithrombin complexes [40].

Biomolecular studies have shown that Epo acts through phosphokinase C on a Ca-channel [41] and that there is a difference between immunologically detectable and biologically active Epo [42]. Investigating on the different mechanisms of endogenous and exogenous (recombinant) Epo, Conlon et al. [43] pointed out that ACE-inhibitors interact with endogenous Epo secretion but not with the effect of exogenous Epo. Treatment of CHF by blood pressure modulating agents might thus exert an influence on the homeostasis of the physiological Epo/EpoR interplay at the level of vascular endothelium.

The specific interaction of ACE-inhibitors with endogenous Epo, leaving injected Epo uninhibited, is further supported by the finding of independency of haematocrit levels with Epo-levels in chronic renal insufficiency patients [33,44,45]. Kidney-sufficient patients exhibit a linear negative proportionality between Epo-levels and haematocrit [40,46] if treated with rHu-Epo.

The measurements of Epo-levels in our study were performed on samples taken in the early morning to obviate circadian fluctuations [47]. The major feature in NYHA class III and IV patients responsible for hypoxaemia being a reduced cardiac output, it could be possible that the stimulus for Epo secretion is a continuous hypoxaemic trigger to peritubular Epo-producing cells [48]; with such a decreased cardiac output, tissue hypoxaemia could occur without significant anaemia [6]. A hypoxaemia without anaemia in our patients is further possible since they were only slightly kidney insufficient and thus presumably had an intact juxtaglomerular Epo-secreting apparatus.

Hypererythropoietinaemia in CHF could represent a desirable mechanism to improve oxygen transport [49]. Since the present study is a one-time window observation in 72 patients without follow-up, the question whether increased Epo-levels were ultimately favourable or detrimental for the host remains open.

Anaemia is a side effect of many drugs [50], some interfering at medullary red cell maturation and others inducing extracorpuscular, immunological damage to the red cells [51]. Finally drug-induced anaemia may proceed through inhibition of Epo synthesis, as seen with sodium-stibogluconate used to treat visceral leishmaniasis [52].

An impact of ACE-inhibitors on Epo synthesis might be possible [17,45]. It was shown that ACE-inhibitors down-regulate Epo-secretion [6,32,43,53].

If increased Epo-levels should represent a favourable compensatory mechanism in CHF, then drug treatments should preferably not interfere with Epo release. Although our study did not show statistically significant differences between AT1 antagonists and ACE-inhibitors on Epo-levels, we suggest that AT1 antagonist might be a better drug, with less interference with Epo mechanisms than ACE-inhibitors, and with presumably the same cardioprotective and antihypertensive effect on CHF. Our group will now investigate the presumably beneficial effect of AT1 antagonists in a large prospective study.

In fact, a retrospective study has evaluated prevalence of anaemia ([Hb]<120 g/l) in patients with congestive heart failure [55], which increased with severity of CHF and reached almost 80% in those with NYHA class IV. Our results are not contradictory to this observation. In an intervention study, all patients with anaemia (n=26) were treated with subcutaneous rHu-Epo and intravenous iron for a mean of 7.2±5.5 months. The mean haemoglobin level and the mean left ventricular ejection fraction increased significantly. The mean number of hospitalizations fell by 91.9% compared with a similar period before the study. The NYHA class fell significantly, as did the doses of oral and intravenous furosemide. The rate of fall of the glomerular filtration rate was retarded with the treatment.

The authors conclude that anaemia is very common in CHF and its successful treatment is associated with a significant improvement in cardiac function, functional class, renal function and in a marked fall in the need for diuretics and hospitalization.


   Acknowledgements
 
The authors acknowledge Caroline Tinguely, Lic.Phil Nat, for invaluable help; and Ursula von Allmen, RN, who supported the patient recruitment. This work was supported by the K. Huber-Steiner Foundation.


   References
Top
 Abstract
 1. Introduction
 2. Patients and methods
 3. Results
 4. Discussion
 References
 

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