The impact of anaemia and kidney function in congestive heart failure and preserved systolic function
Sebastian Philipp1,
Henrike Ollmann1,
Tania Schink2,
Rainer Dietz1,
Friedrich C. Luft1 and
Roland Willenbrock1,3
1 Department of Cardiology, Campus Buch and Virchow, Charité, Humboldt University, Berlin, 2 Department of Medical Biometry, Charite, Berlin, 3 St Elisabeth Hospital Halle, Germany
Correspondence and offprint requests to: Roland Willenbrock, MD, St Elisabeth Hospital, Mauerstraße 5, D-06110 Halle/Saale, Germany. Email: willenbrock{at}krankenhaus-halle-saale.de
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Abstract
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Background. The importance of anaemia in chronic heart failure was highlighted recently by different cohort studies. The aim of this study was to assess the prevalence of anaemia and its relationship to renal function, left ventricular function and symptoms of heart failure.
Methods. We surveyed cases of patients admitted to the Department of Cardiology during 22 consecutive months. Laboratory measurements, blood pressure and echocardiographic parameters were obtained with standardized methods.
Results. Out of a total number of 2941 patients, 238 patients (8.1%) had haemoglobin values <11 g/dl. There was a positive association of anaemia with the symptoms of heart failure with a lowering of the median haemoglobin from 14.2 g/dl [New York Heart Association (NYHA) I] to 12.9 g/dl (NYHA IV, P<0.001). Interestingly, anaemia was not associated with left ventricular function or any left ventricular parameters. Symptoms of heart failure, however, were associated with kidney function. The estimated glomerular filtration rate (GFR) was 82 ml/min at NYHA I and 59 ml/min at NYHA IV, P<0.05. There was an association between impaired renal function and haemoglobin values. Haemoglobin was 14.2 g/dl in the group with normal renal function and 11.1 g/dl in the group with a GFR <25 ml/min (P<0.001). Even in patients with normal renal function (878 patients, GFR >85 ml/min), we still found an association of anaemia with the symptoms of heart failure. Haemoglobin was 14.5 g/dl at NYHA I and 13.4 g/dl at NYHA IV, P<0.0001.
Conclusion. Anaemia is found in 8.1% of patients admitted to cardiology service. Anaemia was clearly associated with symptoms of congestive heart failure even in patients with normal renal function. Anaemia was not associated with left ventricular function.
Keywords: anaemia; diastolic heart failure; heart failure; NYHA; renal function
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Introduction
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In recent years, the occurrence of anaemia in patients with chronic heart failure (CHF) has received increasing attention. Anaemia may aggravate existing heart disease in patients with CHF and negatively affect the outcome of the disease. The causes of anaemia in CHF have been pointed out recently by Okonoko et al. [1]. Discussion on the causes of anaemia in CHF leads from impaired erythropoietin (EPO) production to EPO resistance, iron and other haematinic deficiencies, inflammation and haemodilution [1]. A number of studies documented a higher prevalence of anaemia than previously suspected. Anaemia has been related to symptoms, functional impairment and poor outcomes [24]. Furthermore, it has been shown that anaemia and renal insufficiency are independent risk factors for death among patients with CHF [5,6]. Two small recent studies demonstrated that treatment of anaemia with combined EPO and intravenous ferric sucrose not only increased heamoglobin concentrations, but also, and more importantly, was associated with improved cardiac function and reduced hospitalization [7,8]. Most of the studies had been focusing on patients with heart failure and severe left ventricular dysfunction [9]. Two recent studies also included patients with diastolic heart failure. They were able to demonstrate that anaemia is common in patients with preserved systolic function [10,11]. Both of these studies looked at a selective population. Information on a representative sample including the entire spectrum of heart failure has not yet appeared.
A substantial portion of patients (40%) with heart failure have a normal ejection fraction (EF) and are considered to have diastolic heart failure [12,13]. Patients with diastolic dysfunction have similar exercise limitation and neurohormonal activation as patients with CHF and reduced EF [14].
While previous studies focused on selected patients with mostly impaired systolic function, our intent was to analyse the prevalence of anaemia in a non-selected population presenting with any type of complaints related to heart disease. In this group of patients, we analysed the relationship between anaemia and symptoms of CHF as well as evidence of left ventricular dysfunction. We hypothesized that (i) anaemia is common in patients admitted to a referral cardiology service; and (ii) anaemia is correlated with the degree of cardiac dysfunction, with symptoms of heart failure and with renal dysfunction.
Subjects and methods
In a retrospective analysis, we assessed all patients admitted to the cardiology service between January 1998 and October 2000. Patients were admitted either by a referring doctor or through the emergency room with complaints of chest pain or shortness of breath. Initially >4000 patients were screened. Patients with chronic lung disease (clinical diagnosis, current medication or past medical history) or acute myocardial infarction (positive troponin T/I and/or creatinine kinase-MB >2-fold, or known medical history if transferred from another hospital) were excluded. Patients with valvular disease (n = 719; stenosis of any valve >II°, insufficiency of any valve >II°) were included, but a separate subgroup analysis was performed. After excluding patients with the above criteria and patients with missing records, echo or other necessary data, we were able to include 1858 men and 1083 women, aged between 12 and 94 years, in this retrospective cohort study. For each patient, we were able to obtain a standardized set of personal data and laboratory values. Available were blood pressure values on the day of admission and detailed information on the past medical history. Within 7 days, each patient had an echocardiography performed, yielding information on left ventricular function, wall thickness and left ventricular diameters. On standardized admission protocols, information on symptoms of heart failure according to the New York Heart Association (NYHA) class was obtained. The glomerular filtration rate (GFR) was estimated using the creatinine clearance calculated by the CockcroftGault formula [15]. Data were analysed with SPSS v 10.0 (SPSS Inc., Chicago, IL). Pearson or Spearman correlation coefficients were used to analyse univariate associations between independent variables. To test the significance of the medians of haemoglobin between groups as NYHA, left ventricular EF and GFR, the MannWhitney U-tests were used for pair-wise, and KruskalWallis tests were used for overall comparison of groups regarding haemoglobin values or NYHA classification. A P-value <0.05 was considered to be statistically significant. In addition, we performed a logistic regression analysis on the influence of GFR, NYHA class, diabetes and hypertension on anaemia.
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Results
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Out of the 2941 patients, 238 (8.1%) had haemoglobin concentrations <11 g/dl, a level at which guidelines for patients with chronic kidney disease suggest patients might benefit from the correction of anaemia (Table 1) [16]. We found a significant association between haemoglobin values and symptoms of heart failure (Figure 1). As expected, anaemia was an independent predictor for CHF severity [relative risk (RR) 0.198, P = 0.019]. Heart failure symptoms were also significantly associated with renal function, as indicated by a decreasing GFR, estimated using the CockcroftGault formula [15], from 82 ml/min in patients with NYHA I to 59 ml/min in patients with NYHA IV, P<0.05. Surprisingly, the degree of anaemia was not associated with either left ventricular systolic function (RR 1.04, P = NS) or any of the left ventricular parameters, such as left ventricular diameter, left ventricular wall thickness or left ventricular mass index (RR 0.77, P = NS). A subgroup analysis of patients with cardiovascular risk factors such as arterial hypertension (n = 1731), diabetes mellitus (n = 753) and hyperlipoproteinaemia (n = 1428) showed a similar reduction of haemoglobin with increasing symptoms of heart failure (Table 2). Patients with anaemia had no increase in severity of angina according to CCS class (data not shown). Additionally, we performed a logistic regression analysis to evaluate the relative risk for different independent variables (GFR, diabetes, hypertension and different NYHA classes) on anaemia (Table 3). Diabetes mellitus is an independent risk factor, with an increase of the RR ratio of 80%, while GFR had only a small but significant influence, and arterial hypertension itself had no influence on anaemia. Out of the parameters evaluated as independent risk factors, NYHA class had the greatest effect on anaemia, with an RR of 3.39 in patients with NYHA class IV.

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Fig. 1. A negative association between haemoglobin and symptoms of heart failure (New York Heart Association) was identified in the cohort.
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Table 2. Association of haemoglobin values and NYHA class in the subgroup of patients with different cardiovascular risk factors
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In our study, we were able to find an association between left ventricular EF and symptoms of heart failure (Figure 2). More than 80% of our heart failure patients had a preserved EF, equal to or exceeding 40%. The high prevalence of diastolic dysfunction may be related to the fact that hypertension was extremely common; almost 60% reported a history of hypertension (Table 1). The high prevalence of hypertension in patients with signs of heart failure but preserved systolic function has also been stated by other groups [17].
As expected, we found an association between impaired renal function and haemoglobin values (Figure 3). To exclude a possible confounding effect of patients with renal insufficiency and anaemia, we performed two additional analyses. First, we excluded all patients with a GFR <85 ml/min from the analysis. Here we found a correlation between haemoglobin and symptoms of heart failure despite normal renal function (878 patients; GFR >85 ml/min, Figure 4). Secondly, we performed a logistic regression analysis to examine the influence of GFR and symptoms of heart failure on anaemia. Worsening of symptoms of heart failure increased the risk of anaemia independent of the GFR in this study (Table 3). In a subgroup analysis of patients with impaired renal function (GFR <60 ml/min), we found a significant correlation between renal function and haemoglobin (r = 0.372, n = 720, P<0.0001). Hence, in the subgroup of patients with impaired renal function, the impact of anaemia is dependent on GFR.

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Fig. 3. According to the National Kidney Foundation (NKF) clinical practice guidelines (K/DOQI) for different stages of chronic kidney disease, the glomerular filtration rate (GFR) was divided into five different groups to separate severe renal failure and normal renal function. There was a positive association between lower haemoglobin values and worsening of renal function.
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Fig. 4. Excluding patients with a glomerular filtration rate <85 ml/min (established by the CockcroftGault formula), the negative association of haemoglobin values with increasing symptoms of heart failure still remains.
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Discussion
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The main novel finding of this study is that anaemia is not related to left ventricular function but to symptoms of heart failure in this population. This association is independent of the renal function even though severe impairment of renal function further aggravates anaemia.
Severe anaemia is common in patients admitted to a cardiology service, and was observed in 8.1% of the patients. We used a haemoglobin value of <11 g/dl as a cut-off to define anaemia. We chose this level since guidelines for patients with chronic kidney disease suggest that those patients might benefit from the correction of anaemia [16]. Compared with the World Health Organization criteria (<12 g/dl for women and <13 g/dl in men, Geneva 1968), this value would be considered to be severe anaemia. Previous studies suggested that anaemia aggravates the symptoms of heart failure, and that treatment of anaemia improves the symptoms and signs of heart failure and reduces the need for hospitalization [7,8]. These findings suggest that anaemia is a novel therapeutic target in the management of congestive heart failure. Struthers and colleagues described the anaemia found in heart failure patients as a chronic disorder, which might be caused in part by renal impairment and in part by unknown causes [18]. On the basis of the SOLVD database, Al-Ahmad et al. [3] reported that anaemia is frequently present in patients with asymptomatic and symptomatic left ventricular dysfunction and is related to adverse outcome. The link between anaemia and poor prognosis was strengthened further by Horwich et al. [2], who reported that in a large cohort of patients with advanced CHF referred to transplant evaluation, relatively mild degrees of anaemia were associated with impaired functional and haemodynamic status, and higher mortality. In a prospective study performed by Szachniewicz et al., the relevance of anaemia as a prognostic indicator in CHF patients was emphasized further [19]. Two recent studies showed that patients with signs of CHF have a high prevalence of anaemiaindependent of the presence of systolic dysfunction or preserved systolic function [10,11]. Anaemia has been associated in one of these studies with a worse prognosis [11].
The primary goal of this study was to quantify the prevalence of anaemia in a widespread population-based study. Previous studies focused on patients with signs of CHF. The prevalence and importance of anaemia in patients admitted to a cardiac service were unknown. In our study, left ventricular systolic dysfunction was not associated with the severity of anaemia. We believe that this finding is not related to a possible under-representation of patients with poor ventricular systolic function in our study, since patients with EFs <20% were not unusual (n = 85). Our referral centre receives numerous patients with severe heart failure, some of whom are prepared for transplantation.
Apparently, symptoms of heart failure are closely linked to the frequency of anaemia, not only in the group with impaired systolic function, but even in patients with left ventricular diastolic dysfunction. Recent heart failure research demonstrates an increased interest in diastolic dysfunction, which presents with the same clinical symptoms as systolic dysfunction. We cannot determine for certain how many of our heart failure patients had predominant diastolic heart failure. Careful Doppler echo measurements over the mitral valve or pulmonary veins were not invariably reported in these studies. However, based on criteria of diastolic heart failure, as defined by heart failure symptoms and a preserved ejection fraction (
40%), we conclude that diastolic heart failure was common in our study.
We found that anaemia was clearly correlated with symptoms of CHF, even in patients with preserved renal function and EF. Anaemia was not associated with left ventricular systolic function and not necessarily related to a decreased renal function. Symptoms of heart failure are linked to anaemia not only in the group with impaired systolic function but also in patients with preserved systolic function. We found that anaemia was correlated with symptoms of CHF, even in patients with preserved systolic function and normal renal parameters. Although a cross-sectional design, as used in this study, is not able to determine cause or effect, it is conceivable that anaemia treatment for heart failure should be based on symptoms, rather than ventricular systolic function. Whether these patients benefit from anaemia treatment to a similar degree as reported for patients with systolic heart failure remains to be determined.
Conflict of interest statement. None declared.
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Received for publication: 1. 8.04
Accepted in revised form: 28. 1.05