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European Journal of Heart Failure 2007 9(5):518-524; doi:10.1016/j.ejheart.2006.09.001
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© 2006 European Society of Cardiology

Hyperuricaemia and long-term outcome after hospital discharge in acute heart failure patients

Domingo A. Pascual-Figal*, Jose A. Hurtado-Martínez, Belen Redondo, Maria J. Antolinos, Juan A. Ruiperez and Mariano Valdes

Cardiology Department, University Hospital Virgen de la Arrixaca, University of Murcia Spain

* Corresponding author. Cardiology Department, University Hospital Virgen de la Arrixaca, Ctra. Madrid-Cartagena s/n, 30120 Murcia, Spain. Tel.: +34 968 369445; fax: +34 968 369662. E-mail address: dapascual{at}servicam.com


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: Uric acid (UA) may be involved in chronic heart failure (HF) pathogenesis, entailing a worse outcome. The purpose of this study was to examine the role of hyperuricaemia as a prognostic marker after hospital discharge in acute HF patients.

Methods: We studied 212 patients consecutively discharged after an episode of acute HF with LVEF<40%. Blood samples for UA measurement were extracted in the morning prior to discharge. The evaluated endpoints were death and new HF hospitalization.

Results: Mean UA levels were 7.4±2.4 mg/dl (range 1.6 to 16 mg/dl), with 127 (60%) of patients being within the range of hyperuricaemia. Hyperuricaemia was associated with a higher risk of death (n=48) (HR 2.0, 95% CI 1.1–3.9, p=0.028), new HF readmission (n=67) (HR 1.8, 95% CI 1.1–3.1, p=0.023) and the combined event (n=100) (HR 1.9, 95% CI 1.2–2.9, p=0.004). At 24 months, cumulative event-free survival was lower in the two higher UA quartiles (36.9% and 40.7% vs. 63.5% and 59.5%, log rank=0.006). After adjustment for potential confounders, hyperuricaemia remains an independent risk factor for adverse outcomes (HR 1.6, 95% CI 1.1–2.6, p=0.02).

Conclusions: In hospitalized patients with acute HF and LV systolic dysfunction, hyperuricaemia is a long-term prognostic marker for death and/or new HF readmission.

Key Words: Acute • Heart failure • Systolic function • Prognosis • Uric acid

Received March 13, 2006; Revised June 22, 2006; Accepted September 5, 2006


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Despite therapeutic advances, heart failure (HF) is currently the most costly cardiovascular disorder in industrialized nations; it is the leading cause of hospitalization in adults aged over 65 years, and is associated with high morbidity and mortality [1-3]. Around 75% of HF expenditure relates to in-patient care. Patients hospitalized due to an acute HF episode have a poor prognosis: about 45% of patients will be rehospitalized at least once within 12 months and estimates of the risk of death or rehospitalization within 60 days of admission vary from 30% to 60%, depending on the population studied [4-6]. In this clinical setting, it is important to have reliable prognostic variables to identify patients at higher risk after hospital discharge.

Beyond haemodynamic disturbances, HF is a complex clinical syndrome associated with a wide range of abnormalities, which include neuroendocrine, metabolic and immunological alterations [7-9]. Uric acid (UA) is the final product of purine metabolism and its levels are often elevated in patients with chronic HF, as a consequence of increased production and probably smaller renal excretion [10,11]. Prospective studies suggest that UA levels are markers of a deteriorated oxidative metabolism, hyperinsulinaemia, inflammatory cytokine activation and endothelial dysfunction, all of which are present in patients with HF [10-12]. Anker et al. have shown the prognostic value of UA in patients with chronic HF [13]. Nevertheless, the prognostic role of serum UA in acute HF syndromes is still unknown despite the fact that it is a simple and easily measurable parameter.

The hypothesis of the present study was that hyperuricaemia could be a prognostic marker of adverse long-term outcome, following hospital discharge in acute HF patients.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Population studied
During a 1-year period (from January 2002 to December 2002), we studied all patients admitted to the cardiology department of a tertiary university hospital with acute HF. Acute HF was diagnosed on the basis of the European Society of Cardiology criteria and defined as a rapid or gradual onset of signs and symptoms of HF, resulting in unplanned hospitalization and including new onset acute HF (without previously known cardiac dysfunction) and acute decompensation of chronic HF [14,15]. An echocardiographic study was performed in all patients during the index hospitalization (Sonos 5500, Hewlett-Packard) and patients with left ventricular systolic dysfunction (LVEF<40%, Simpson's method) were included. Standardized projections and measurements were made for the study of cardiac anatomy, ventricular function and valve competence; mitral flow E wave and A wave velocities and their ratio were measured [16,17]. Patients taking xanthine-oxidase inhibitors (e.g. allopurinol) were excluded from the study. All other clinical variables (age, sex, body mass index, diabetes, hypertension, blood pressure, hypercholesterolemia, myocardiopathy aetiology, rhythm, NYHA class, medication at discharge) were registered at the time of discharge from the hospital. The local ethics committee approved the study and all patients gave informed consent.

2.2. Biochemical measurements
Blood samples were obtained prior to hospital discharge, a median of 9.5 days (IQR: 7-15 days) after admission, following an overnight fast and a 10-min rest in supine position. Samples were immediately processed for the determination of all biochemical parameters. A Roche/Hitachi Modular analyzer was used (Roche Diagnostics, Manheim, Germany) for all biochemical measurements. Levels of UA in serum were determined using an enzymatic colorimetric test through the uricase-peroxidase method (uric acid plus, Roche Diagnostics, Manheim, Germany). The measuring range was 0.2 to 25 mg/dl and the inter- and intra-assay variability were 0.5% and 1.7% respectively. Units used were mg/dl (1 mg/dl=59.48 µmol/l). Hyperuricaemia was defined as a level of UA higher than 7 mg/dl (420 µmol/l) in male patients and 6 mg/dl (360 µmol/l) in female patients [18]. Renal function was determined through the estimated glomerular filtration rate (GFR, ml/min per 1.73 m2) using the abbreviated MDRD formula [19], the rate of creatinine clearance (CrCl, ml/min) using the Cockcroft-Gault equation [20], urea and creatinine plasma levels and the calcium-phosphate product. Other biochemical measurements were: sodium, proteins, albumin, total cholesterol, high-density lipoprotein cholesterol (HDL-C), triglycerides, haemoglobin, fibrinogen, C-reactive protein and glycosylated haemoglobin A1C.

2.3. Events and follow-up
The primary endpoint was the composite of death and/or new HF hospitalization. All-cause mortality was predefined as a secondary endpoint. Patient follow-up was performed by means of telephone calls, personal interviews, revision of clinical reports and revision of National Death Records.

2.4. Statistical analysis
All variables were tested for normal distribution by the Kolmogorov-Smirnov test. Continuous variables with normal distribution are expressed as mean±standard deviation (S.D.). Continuous variables with non-normal distribution are summarized as median (interquartile range, IQR). Categorical variables are expressed as number (percentage). Comparisons between independent groups were made using Student's t-test and variance analysis. In the case of non-normal distribution, the Mann-Whitney U-test was used. Categorical data were compared with the chi-square test, and Fischer's exact test was performed if relevant. All the tests performed were two-sided. Single linear regression analysis was used to examine correlations between UA levels and continuous variables. Kaplan-Meier accumulated survival curves were drawn and Log Rank values were calculated in order to assess their statistical significance. Univariate Cox proportional risk analyses were used to evaluate the association between each baseline variable and the evaluated endpoints. A stepwise multivariate Cox proportional analysis was applied to determine the independent prognostic value of hyperuricaemia. Variables included in the multivariate model were: fixed variables, which are known confounders and risk factors (age, sex, diuretics, CrCl, LVEF and NYHA class), and those variables with p<0.10 in the univariate analysis. Hazard ratios (HR) are expressed, as well as their confidence intervals at 95% (95% CI). A p-value <0.05 was considered statistically significant. SPSS v.12.0 software (SPSS Inc., Chicago, Illinois) was used.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1. Population studied and UA
A total of 212 consecutive patients hospitalized due to acute HF was studied. Clinical presentation was considered to be new onset acute HF in 92 patients (43%) and acute decompensation of chronic HF in 120 patients (57%). The median duration of HF was 687 days (IQR: 191-2168 days) and 56 patients (26%) had previously been hospitalized with acute HF. In 55 cases (26%) acute HF was related to an acute coronary syndrome. The aetiology of LV systolic dysfunction was established as ischaemic in 123 patients (58%), dilated myocardiopathy in 55 patients (26%) and valvular in 34 patients (16%).

Table 1 shows the clinical characteristics recorded at hospital discharge for the total of the population and for the subgroups with and without hyperuricaemia. The mean UA level at time of discharge (9.5 days, IQR: 7-15 days) was 7.4±2.4 mg/dl (range between 1.6 and 16 mg/dl), with 127 patients (60%) within the range for hyperuricaemia. Hyperuricaemia was significantly associated with female sex, arterial hypertension and poorer NYHA functional class (Table 1). Mean UA levels were 6.7±1.8 mg/dl in NYHA class I, 6.8±1.7 mg/dl in class II, 7.6±2.6 mg/dl in class III and 8.2±2.8 mg/dl in class IV (p=0.006). Patients with hyperuricaemia were more frequently receiving loop diuretics, spironolactone and digitalis. UA levels were significantly correlated with the equivalent dose of furosemide in mg/day (R=0.328, p<0.001). Also, patients with hyperuricaemia showed a greater deterioration of renal function parameters (Table 2) and a lower level of HDL-C. Furthermore, linear regression analysis showed that UA levels were significantly correlated with GFR (R=0.34, p<0.001), creatinine clearance (R=0.32; p<0.001), urea (R=0.40; p<0.001) and creatinine (R=0.23; p=0.001) levels, calcium-phosphate product (R=0.237, p=0.002), phosphor (R=0.26; p<0.001) and HDL-cholesterol (R=–0.28; p<0.001).


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  		Table 1 Clinical characteristics (recorded at discharge)

 


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  		Table 2 Biochemical parameters

 
3.2. Clinical events and UA levels
The median duration of follow-up was 20.4 months (IQR: 12.2-25.4 months). During this follow-up period, 48 patients died (23%) and 67 patients (32%) were taken into hospital due to a new episode of acute HF. The combined event of death or readmission due to HF occurred in 100 patients (47%). In the Kaplan-Meier analysis, the cumulative incidence of adverse outcomes was 20% at 3 months, 38% at 12 months and 50% at 24 months.

UA levels were higher among patients with events (7.8±2.4 vs. 6.9±2.3 mg/dl, p=0.01) and were associated with a higher risk (p=0.006, HR 1.13, 95% CI 1.04-1.23). As shown in Fig. 1, patients with hyperuricaemia showed a lower survival free from all-cause death (HR 2.0, 95% CI 1.1-3.9, p=0.028, {chi}2=5.3), from a new readmission due to acute HF (HR 1.8, 95% CI 1.1-3.1, p=0.023, {chi}2=5.6) and from the combined event (HR 1.9, 95% CI 1.2-2.9, p=0.004, {chi}2=9.1). Fig. 2 shows the Kaplan-Meier analysis according to UA quartiles adjusted for sex; at 24 months, cumulative event free survival was lower in the two higher UA quartiles (36.9% and 40.7% vs. 63.5% and 59.5%, log rank=0.006). In the multivariate model of Cox regression analysis, the presence of hyperuricaemia identified patients at higher risk of death (Table 3) and the combined endpoint of death and/or new HF hospitalization (Table 4) independently of other clinical variables.


Figure 01
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  		Fig. 1 Kaplan-Meier curves showing the cumulative survival free from all-cause death, new HF hospitalization and the composite endpoint, according to the presence or absence of hyperuricaemia.

 


Figure 02
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  		Fig. 2 Kaplan-Meier curves showing cumulative survival free from the composite endpoint of all-cause death and/or new HF hospitalization, according to the UA quartile (adjusted for sex).

 


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  		Table 3 Cox regression analysis of predictors of death

 


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  		Table 4 Cox regression analysis of predictors death and/or new HF hospitalization

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
This study supplies new evidence about the prognostic value of UA, by showing that, after hospitalization due to acute HF, hyperuricaemia identifies patients at higher risk of death and/or new hospitalization due to HF. Moreover, UA levels provided independent information from functional ability, heart function and kidney function.

Although the relationship between UA and cardiovascular disease has been studied for almost a century, the precise role of UA in cardiovascular pathophysiology is not well defined [21-24]. The increase in UA levels in patients with chronic HF has been previously described [10,11] and thus, 60% of patients hospitalized due to acute HF showed UA levels within the range for hyperuricaemia in this study. However, there are few studies which have assessed the prognostic value of UA levels in this setting.

In a study of 139 patients with mild to moderate chronic HF, Bettencourt et al. found that UA was associated with a lower survival rate, but only in the univariate analysis [25]. In a larger population of 552 patients with chronic HF and more advanced functional class (64% NYHA III-IV), Batin et al. found that high levels of UA predicted mortality [26]. More recently, in a population of 112 patients, Anker et al. identified UA as a metabolic factor associated with a higher risk of mortality and heart transplant, independently of functional and haemodynamic variables [13]. It should be noted that selected chronic HF patients were studied for a relatively long period (5-7 years), and a significant number of patients, such as those with high levels of creatinine, were excluded. Moreover, in all of these studies, the rate of use of beta-blockers was low (6% in the study by Anker et al.). In our study, patients were consecutive and presented with an acute HF episode, the majority of patients had severe clinical impairment (55% were in NYHA functional class III-IV at discharge). However, beta-blocker usage rate was higher (57%) in accordance with current clinical practice. Therefore, the results of our study extend the findings of Anker et al., to a non-selected population of acute HF patients, at high risk of adverse outcomes, treated in accordance with current clinical hospital practice. In our population, the prognostic value of hyperuricaemia was also independent of other established risk factors such as LVEF, age and NYHA functional class.

The mechanisms through which UA could affect prognosis in these patients are uncertain. UA is the final product of purine metabolism. Xanthine oxidase (XO) catalyses the two terminal steps of purine metabolism, from hypoxanthine to xanthine to UA. In patients with chronic HF this reaction is upregulated, because of the greater quantity and activity of XO and increased amount of substrate [27]. This reaction is an important source of free oxygen radicals and superoxide anions, which goes together with an increase in oxidative stress and greater impairment of the nitric oxide system [28]. In the HF patient, XO could be the link between UA and a series of detrimental processes, such as increased cytokine production, cell apoptosis, mechanoenergetic uncoupling in the myocardium and endothelial dysfunction in the failing circulation, which may contribute to the progression of HF [29,30]. Hyperuricaemia has been shown to be a marker for impaired oxidative metabolism, and UA levels reflect the degree of activation of XO [11], despite the fact that UA in itself is an anti-oxidant molecule. Beyond XO, experimental studies suggest that UA potently stimulates vascular smooth muscle cell proliferation in vitro and causes increased endotoxin-stimulated tumor necrosis factor-{alpha} production and hence proinflammatory immune activation [31-33].

Apart from the deleterious effects that an increase in XO and UA can have on patients with HF, hyperuricaemia can also be a marker for other conditions. In our population, as in others [11], hyperuricaemia was associated with a poorer NYHA functional class and, accordingly, the use of spironolactone, digitalis and diuretics was higher in these patients. Functional ability is dependent not only upon heart function, but also upon the peripheral circulation and its vasodilatory function, which worsen in the presence of hyperuricaemia [34]. Associations between UA and hypertension, hypercholesterolemia, insulin resistance and obesity have been reported [35]. In our study, hyperuricaemia correlated with the presence of hypertension, and female sex, and showed a trend with increasing age. It is important to note that we found a relationship between the level of UA and low levels of HDL-C, which could be related to an increase in oxidative stress. Although the impairment of glycolytic metabolism could increase metabolites in the purine pathway and the synthesis of UA [36], we found no relationship with levels of glycosylated haemoglobin A1C as a marker for resistance to insulin. In chronic HF, weight loss is related to low survival rate and also to hyperuricaemia [37]. In our study we did not find a relationship between UA and body mass index. Among echocardiographic parameters, we observed a trend according to increase in E/A ratio and left atrium diameter, which suggest more elevated filling pressures in patients with hyperuricaemia. These findings are in accordance with the study of Cicoria et al. [38], which showed that elevated UA levels are associated with diastolic dysfunction and restrictive mitral filling pattern in chronic HF patients.

Another element for discussion is the relationship between UA levels, diuretic treatment and kidney damage in patients with HF. UA is excreted primarily by the kidney and a low renal perfusion can contribute to an increase in the levels of UA, mainly through a smaller excretion of urate in the proximal tubule due to tissue ischaemia [39]. On the other hand, angiotensin II and noradrenaline increase tubular absorption of UA, so that hyperuricaemia can also reflect an increase of these neurohormones, whose higher activation is known to be associated with a worse prognosis. The use of diuretics also implies a greater net reabsorption of UA in the proximal tubule. In our study, the levels of UA were correlated with the worsening of all parameters of kidney function and with diuretic treatment, but its prognostic value, as in many other studies, was independent of these variables.

Our study provides new evidence of the prognostic value of hyperuricaemia in acute HF patients. It remains to be determined whether UA plays an active role in HF progression, either directly or indirectly through XO, whether it is just a marker of other multiple deleterious processes, or whether both of these possibilities are true. From the above, it is suggested that hyperuricaemia is a clinical marker for the multiple processes involved in the progression of HF. On the other hand, XO may also be a causal factor in HF pathophysiology, and thus constitutes a therapeutic target. In experimental models, XO inhibition favourably affects myocardial energetics and vascular function in animal models of acute and chronic HF [40]. Long-term clinical trials with XO inhibitors will help to clarify whether XO activation is a significant causal factor and therefore whether its inhibition is associated with any clinical benefit.

4.1. Limitations
A limitation of this study was the lack of measurement of B-type natriuretic peptide (BNP), which correlates with severity and prognosis in HF populations, and the analysis of an interaction between BNP and UA could be useful. Another limitation was the lack of repeated measures of UA levels during follow-up.

4.2. Conclusions
In patients hospitalized because of acute HF and left ventricular systolic dysfunction, the presence of hyperuricaemia was associated with a higher risk of death and/or new hospitalizations in the long-term, independently of ventricular function, renal function and functional ability. These findings pose the question of whether UA levels should be determined routinely and whether these levels should be included in risk models in patients previously hospitalized due to acute HF.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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 Arch Intern MedHome page
J. S. Ross, G. K. Mulvey, B. Stauffer, V. Patlolla, S. M. Bernheim, P. S. Keenan, and H. M. Krumholz
Statistical Models and Patient Predictors of Readmission for Heart Failure: A Systematic Review
Arch Intern Med, July 14, 2008; 168(13): 1371 - 1386.
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