Prognostic Significance of Hyperuricemia in Patients With Acute Heart Failure

Prognostic Significance of Hyperuricemia in Patients With Acute Heart Failure

Prognostic Significance of Hyperuricemia in Patients With Acute Heart Failure Alberto Palazzuoli, MD, PhDa, Gaetano Ruocco, MDa, Marco Pellegrini, MDa,...

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Prognostic Significance of Hyperuricemia in Patients With Acute Heart Failure Alberto Palazzuoli, MD, PhDa, Gaetano Ruocco, MDa, Marco Pellegrini, MDa, Matteo Beltrami, MDa, Nicola Giordano, MDa, Ranuccio Nuti, MDa, and Peter A. McCullough, MD, MPHb,c,* Serum uric acid (UA) is associated with death and hospitalization in chronic heart failure (HF). However, UA in acute HF has not been well studied with respect to its relation to renal dysfunction and vascular congestion. We measured admission serum UA along with baseline variables in 281 patients with acute HF screened from the Loop Diuretics Administration and Acute Heart Failure (Diur-HF) trial. Hyperuricemia was defined as serum UA >7 mg/dl in men and >6 mg/dl in women. Chronic kidney disease (CKD) was defined as an estimated glomerular filtration rate <60 ml/min/1.73 m2 before hospital admission. Death or HF hospitalization at 6 months was the primary outcome. The mean UA concentration was 6.4 – 2.5 mg/dl, and 121 patients (43.1%) were classified as hyperuricemic. UA values were significantly increased in patients with CKD compared to patients without CKD (6.8 – 2.7 vs 6.1 – 2.1 mg/dl; p [ 0.02); however, UA was not associated with the development of acute kidney injury. Patients with hyperuricemia had greater degrees of pulmonary and systemic congestion than normouricemic patients (congestion score 3.5 vs 2.1, p <0.01). Hyperuricemia was associated with higher risk of death or HF rehospitalization (univariate hazard ratio 1.46 [1.02 to 2.10]; p [ 0.04, multivariate hazard ratio 1.69 [1.16 to 2.45]; p [ 0.005). In conclusion, hospitalized patients with acute HF, elevated UA levels were associated with both CKD and pulmonary congestion. After controlling for potential confounders, hyperuricemia was associated with rehospitalization and death at 6 months. Ó 2016 Elsevier Inc. All rights reserved. (Am J Cardiol 2016;-:-e-) Uric acid (UA) is the final product of purine catabolism and is excreted by the kidneys. The enzymes responsible of UA metabolism and production are xanthine oxidase (XO) and xanthine dehydrogenase. Both enzymes catalyze the oxidation hypoxanthine to xanthine; however, most of purines are metabolized by XO particularly during hypoxia, acidosis, and inflammation. During this process, reactive oxygen species and the hydroxyl radical are generated. Free radicals produced lead to reduced nitric oxide release and synthesis with increased oxidative stress.1 In addition, oxidative stress and nitric oxide imbalance could enhance inflammatory pathways and further increase cytokine production.2 Although data regarding XO expression in the myocardium and vasculature are controversial, many nonhuman studies suggest that XO polymorphisms have physiological effects on the vascular endothelium.3,4 In patients with heart failure (HF) and associated

hyperuricemia, both oxidative stress and proinflammatory cytokines could influence clinical symptoms by reducing the anaerobic threshold, depleting adenosine triphosphate in the sarcoplasmic reticulum, and impairing both systolic and diastolic energetics.5 Accordingly, many reports have demonstrated the relation between increased UA levels and functional class, reduced exercise tolerance, systemic congestion, and decreased left ventricular function in patients with chronic HF.6 Little is known, however, about the association if any between elevated UA concentration and outcomes in acute HF after controlling for chronic kidney disease (CKD), acute kidney injury (AKI), pulmonary congestion, and relative intravascular volume expansion. Thus, in this study, we sought to explore the relations between baseline UA, CKD, and congestion and to determine the independent relations, if any, between these variables and the outcome of HF hospitalization or death at 6 months. Methods


Department of Internal Medicine, Cardiology Unit, University of Siena, Siena, Italy; bBaylor University Medical Center, Baylor Jack and Jane Hamilton Heart and Vascular Hospital, Baylor Heart and Vascular Institute, Dallas, Texas; and cThe Heart Hospital Baylor, Plano, Texas. Manuscript received January 2, 2016; revised manuscript received and accepted February 16, 2016. The study was partially funded by the The Menarini Group. Trial registration: Identifier: NCT01441245. Registered on September 23, 2011. See page 5 for disclosure information. *Corresponding author: Tel: (248) 444-6905; fax: (214) 820-7533. E-mail address: [email protected] (P.A. McCullough). 0002-9149/16/$ - see front matter Ó 2016 Elsevier Inc. All rights reserved.

This was a retrospective single-center study including consecutively 281 subjects, screened from the Loop Diuretics Administration and Acute Heart Failure (DiurHF) trial (NCT01441245) from January 2011 to October 2014. Patients had a primary diagnosis of acute HF, left ventricular ejection fraction <45%, with evidence of volume overload and were within <24 hours from hospital presentation defined as pulmonary/systemic congestion as assessed by 2 independent clinicians. A congestion score was evaluated considering 5 principal signs and giving for each sign 1 point in a scale ranging from 1 to 5: the clinical


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signs considered were: third heart sound, pulmonary rales, jugular venous stasis, hepatomegaly, and peripheral edema.7 Exclusion criteria were end-stage renal disease or the need for a renal replacement therapy (dialysis or ultrafiltration), recent myocardial infarction, systolic blood pressure <90 mm Hg, serum creatinine level >4.0 mg/dl, sepsis, systemic inflammatory diseases, severe liver, disease, or neoplastic disease. Results from the Diur-HF Trial were published elsewhere but in brief, 92 (from 281 screened) subjects were randomized to a continuous infusion versus bolus strategy for loop diuretic administration.8 The overall findings were mixed with continuous infusion associated with greater reductions in B-type natriuretic peptide (BNP). However, this appeared to occur at the consequence of worsened renal filtration function, the use of additional treatment, and higher rates of rehospitalization or death at 6 months. This study included the 281 screened with baseline laboratories available and was approved by our local institutional review board, and all patients gave their signed informed consent. We defined as hyperuricemia as serum UA >7 mg/dl in men and >6 mg/dl in women. CKD was defined as estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 at baseline. The eGFR was calculated using the Modification of Diet in Renal Disease equation. AKI was defined as creatinine increase 0.3 mg/dl at any time from admission to discharge or eGFR decrease 20% from baseline at any time. Serum creatinine (Jaffe reaction; CREJ2 cobas; Roche system, Mannheim, Germany), UA, blood urea nitrogen, and BNP were assessed with 24 hours from admission and at discharge at a central laboratory. UA measurement was performed by enzymatic colorimetric test where uricase cleaves UA to form allantoin and hydrogen peroxide. In the presence of peroxidase, 4-aminophenazone is oxidized by hydrogen peroxide to a quinone-diamine dye. The color intensity of the quinone-diamine formed is directly proportional to the UA concentration and is determined by measuring the increase in absorbance (UA 2; Cobas; Roche system). Plasma BNP was measured with Triage BNP test (Biosite Inc., San Diego, California). The primary outcome was death or hospitalization at 6 months. A secondary outcome was the occurrence of AKI during hospitalization. Patients were followed for 6 months after discharge with clinical visits or telephone contacts. If the hospitalization was not for HF, but related events such as pump failure, acute coronary syndromes complicated by HF, ventricular arrhythmias associated with left ventricular dysfunction, or HF associated with worsened renal function, for analytical purposes these were all considered as hospitalization for HF. Continuous variables are expressed as mean (SD), whereas discrete variables are presented as counts with proportions. Patients’ laboratory parameters were compared using the Student t test for independent groups. Analysis of variance was done by the Levine’s test. For discrete variables, we used the chi-square test. Receiver operating characteristic curve analysis was used to assess the prognostic value of UA through a range of values on the primary outcome. Cox regression analysis was used to assess the independent effect of baseline UA on rehospitalization and death at 6 months. The treatment assignment in the Diur-HF

trial was not included as a covariate because our study included more than half of patients who were screened and not randomized. KaplaneMeier methods were used to generate survival plots that compared the 2 groups using the log-rank test for the time to first occurrence of HF hospitalization or death. All reported probability values were 2tailed, and a p value 0.05 was considered statistically significant. Statistical analysis was performed using the SPSS 20.0 statistical software package (SPSS Inc., Chicago, Illinois). Using the rates of primary events that had occurred by 6 months, our study had an observed power of 52% to observe a relative risk of 1.25 with an assumed alpha error of 0.05 and a sample size of 140 subjects in each group. Results A total of 281 patients with acute HF were evaluated, and we lost 11 because of sudden death, 8 for incomplete data during follow-up. A total of 121 of 281 patients (43.1%) met the definition of hyperuricemia. The resulting study sample is described in Table 1. Mean congestion scores stratified by UA levels and CKD are shown in Figure 1. The rates of AKI were 20 (17%) versus 22 (16%), for those with and without hyperuricemia, respectively, p ¼ 0.904. AKI rates stratified UA levels, and CKD are reported in Figure 2. The rates of HF hospitalization, death, and the composite end point were 61 (50%) versus 41 (29%), p <0.001; 36 (30%) versus 27 (19%) p ¼ 0.045; and 97 (80%) versus 68 (48%) p <0.001; for those with and without hyperuricemia, respectively. Among those with CKD, the rates for the composite outcome were 72 (58%) and 69 (50%), for those with and without hyperuricemia, respectively, p ¼ 0.155. Among those without CKD, the rates for the composite outcome were 45 (68%) and 28 (51%), for those with and without hyperuricemia, respectively, p ¼ 0.05. Using survival analysis, hyperuricemia was a significant univariate predictor of the primary end point (hazard ratio [HR] 1.46 [1.02 to 2.10]; p ¼ 0.04). Using the Cox proportional hazards model and adjusting for age, gender, the presence of CKD, blood urea nitrogen, BNP, congestion, anemia, hypertension, dyslipidemia, smoking, diabetes, peripheral atherosclerosis, and coronary artery disease, we found that hyperuricemia remained significantly associated with the primary end point (HR 1.69 [1.16 to 2.45]; p ¼ 0.005; Table 2). The KaplaneMeier survival curves for those with and without hyperuricemia are shown in Figure 3, (log-rank p ¼ 0.009). Dividing into 3 UA level groups (<6 mg/dl, 6 8 mg/dl, >8 mg/dl), we found that there was a significant relation between survival and UA levels <6 mg/dl but no graded affect above that concentration (log-rank p ¼ 0.03) as shown in Figure 4. Receiver operating characteristic curve analysis demonstrated that baseline UA concentrations were significant predictors of HF hospitalization or death (area under the curve 0.70 [0.64 to 0.77], p <0.001, Figure 5). Discussion We found that baseline UA levels were associated with baseline renal function and evidence of pulmonary and systemic congestion yet were independent predictors of HF hospitalization and death at 6 months. The UA levels

Heart Failure/Hyperuricemia and Outcomes in Acute Heart Failure


Table 1 Laboratory parameters and risk factors analyzed according to uric acid levels Parameters

Uric Acid Level Elevated (N¼121)

Normal (N¼141)


816 49 (41%) 1.60.5 8150 4613 948929 3.50.5 11.91.8 8.51.7 389 3.51.0 94 (78%) 67 (55%) 30 (25%) 56 (46%) 44 (36%) 69 (57%) 56 (46%)

814 65 (%) 1.30.4 7246 5510 899868 3.10.5 11.31.9 4.71.1 409 2.21.0 92 (65%) 59 (42%) 42 (30%) 63 (45%) 34 (24%) 39 (28%) 38 (30%)

0.851 0.431 0.05 0.141 0.02 0.733 0.002 0.02 <0.001 0.486 <0.001 0.02 0.04 0.374 0.991 0.04 <0.001 0.001

Age (years) Men Creatinine (mg/dl) Blood urea nitrogen (mg/dl) Estimated glomerular filtration rate ( ml/min/1.73 m2) B-type natriuretic peptide (pg/ml) Albumin (g/dL) Hemoglobin (g/dL) Uric acid (mg/dL) Ejection fraction (%) Congestion signs Admission blood urea nitrogen >50 mg/dL Chronic kidney disease Current smoking Dyslipidemia Diabetes mellitus Hypertension Atrial fibrillation

Dyslipidemia ¼ low-density lipoprotein >130 mg/dl or treated with lipid-lowering therapy, hypertension ¼ blood pressure >140/85 mm Hg or on antihypertensive therapy.

Figure 1. Paired congestion scores for those with and without hyperuricemia according to baseline CKD.

Figure 2. Rates of AKI for those with and without hyperuricemia according to baseline CKD.

measured on admission tracked in the same direction with hemoglobin and albumin, suggesting some influence from hemoconcentration. However, after adjustment for multiple determinants of the UA concentration including renal filtration function, we found a persistent excess hazard

associated with hyperuricemia. Interestingly, when allowed to range across values, UA >6.0 mg/dl appeared to be a critical level at which we saw the increase in hazard despite having a priori definitions for men and women. In contrast, we did not find an association between AKI and UA in hospitalized patients suggesting the risk relations between these 2 variables and outcomes are explained by different mechanisms. Several studies have found an association between UA concentrations and HF outcomes9,10 with most of reports concerning patients with coronary artery disease, hypertension, and chronic stable HF.11,12 However, these observations are remarkably consistent, particularly among clinical trials of stable patients with HF where central core laboratories and more controlled conditions exist.12 Our data are partially in agreement with the study by Filippatos et al13 in chronic patients revealing a greater impact of hyperuricemia only in patients without CKD defined as eGFR <60 ml/ min1/73 m2. Similar results were recently confirmed by a post hoc analysis from the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan14 where hyperuricemia was significantly associated with allcause, adjusted mortality in patients selected for the trial with eGFR >30 ml/min/1.73 m2. In this study, however, the UA levels were much higher w9.2 mg/dl (median) and were associated with decreased renal filtration function. In patients with eGFR <30 ml/min/1.73 m2, UA was not related with either hospitalization or death (both p >0.4) A recent report from the Acute Heart Failure Database registry on 1,255 patients found very similar median values (7.3 mg/dl) and cut points for UA of 8.4 mg/dl that were associated with long-term mortality.15 A recent meta-analysis found hyperuricemia to be associated with a 19% increase of incident HF risk for every UA 1 mg/dl elevation.16 Because subjects without CKD should


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Table 2 Univariate and multivariate analysis for the primary outcome of heart failure hospitalization or death Parameters

Univariate HR (95% CI of HR)

Hyperuricemia Acute kidney injury Blood urea nitrogen > 50 mg/dL B-type natriuretic peptide > 400 pg/mL Left ventricular ejection fraction < 40% Signs of vascular congestion at admission

1.46 0.73 1.46 0.88 0.98 1.11

(1.02-2.10) (0.44-1.22) (0.94-2.25) (0.57-1.38) (0.61-1.56) (0.89-1.38)

Multivariate* p-value 0.04 0.23 0.09 0.59 0.93 0.36

HR (95% CI of HR)* 1.69 0.76 1.46 0.81 1.02 1.09

(1.16-2.45) (0.45-1.24) (0.94-2.26) (0.52-1.28) (0.64-1.61) (0.87-1.38)

p-value 0.005 0.27 0.08 0.37 0.93 0.42

CI ¼ confidence interval, HR ¼ hazard ratio. * Variable included in the final model included the ones listed previously and age, gender, chronic kidney disease, anemia, current smoking, hypertension, diabetes, dyslipidemia, peripheral atherosclerosis, coronary artery disease.

Figure 3. KaplaneMeier survival plots in of those with and without hyperuricemia for the outcome of HF hospitalization or death at 6 months.

Figure 5. Receiver operating characteristic curve analysis of serum UA for the outcome of HF hospitalization or death at 6 months. AUC ¼ area under the curve.

Figure 4. KaplaneMeier survival plots for the outcome of death or hospitalization at 6 months according to 3 groupings of UA concentration.

have normal clearance and reabsorption, elevated UA levels in patients with HF may be to be attributable to overproduction because of XO activity much more than to reduced clearance.9 Although some epidemiologic studies suggest that UA predicts the development of new onset kidney disease; however, we found no association between UA and the risk of AKI.17,18 Type 1 cardiorenal syndrome

(AKI after HF admission) affects patients with more systemic hemodynamic impairment, neurohormonal overdrive, tubular dysfunction, reduced glomerular filtration, and more elevated diuretic dose.19 We surmise that UA elevation is probably due to different mechanisms as inflammatory activation and oxidative stress.1 XO is a potent trigger of free radical species, and it is related to myocardial fibrosis decreased skeletal muscle performance and reduced vascular tone activity. Nevertheless, it is possible that the UA we observed may be due to changes in renal handling (tubular reabsorption) that is not reflected by dynamic changes in serum creatinine.20 We believe that UA may be a reflection of pulmonary and systemic congestion as shown in our data. This observation is in accordance with 2 reports demonstrating the relation between hyperuricemia and left ventricular restrictive filling patterns and right ventricular dysfunction in patients with chronic HF.21,22 There is considerable interest in lowering UA to improve cardiovascular and in particular HF outcomes. Animal

Heart Failure/Hyperuricemia and Outcomes in Acute Heart Failure

studies have shown improved endothelial function and myocardial performance with XO inhibition; however, in human studies no significant improvement in systolic function or exercise tolerance has been observed.23e25 It is possible that XO regulation and increases in reactive oxygen species themselves are the pathogenic mechanism that UA is a bystander.26 Recently, a multicenter trial with allopurinol has been proposed in patients with HF with end points including death, hospitalization, and patient global assessment during a mean follow-up of 24 weeks.27 Febuxostat, a newer XO inhibitor, is being tested in 2 randomized trials recruiting patients with gout but assessing cardiovascular outcomes surrogate measures and major adverse cardiac events; however, HF is not included in this end point.28 Our study has all the limitations of small, retrospective studies. However, we took advantage of systematic screening and exclusion criteria, complete laboratory data on all subjects, and adjudicated assessments of pulmonary and systemic congestion from 2 examiners. We were limited by our sample size and had low observed power to see a 25% effect size in the binary outcome. However, our adjusted HR for the time to the first primary end point event was 1.69, suggesting an excess hazard with hyperuricemia in excess of a conventional effect size for observational studies of this size. In addition, we did not have considerable background information with respect to diet, gout, or kidney stones to make inferences on the origin or duration of hyperuricemia. Finally, we did not have serial measures of UA or urine concentrations over time to fully understand the role of hemoconcentration. In conclusion, among patients hospitalized and confirmed to have acute HF, hyperuricemia is associated with renal filtration function, pulmonary and systemic congestion, and is an independent risk factor for HF hospitalization and death at 6 months. Disclosures The authors have no conflicts of interest to disclose. 1. Leyva F, Anker S, Swan JW, Godsland IF, Wingrove CS, Chua TP, Stevenson JC, Coats AJ. Serum uric acid as an index of impaired oxidative metabolism in chronic heart failure. Eur Heart J 1997;18: 858e865. 2. Ruggiero C, Cherubini A, Ble A, Bos AJ, Maggio M, Dixit VD. Uric acid and inflammatory markers. Eur Heart J 2006;27:1174e1181. 3. Khan SA, Lee K, Minhas KM, Gonzalez DR, Raju SV, Tejani AD. Neuronal nitric oxide synthase negatively regulates xanthine oxidoreductase inhibition of cardiac excitation-contraction coupling. Proc Natl Acad Sci U S A 2004;101:15944e15948. 4. Mazzali M, Hughes J, Kim YG, Jefferson JA, Kang DH, Gordon KL. Elevated uric acid increases blood pressure in the rat by a novel crystalindependent mechanism. Hypertension 2001;38:1101e1106. 5. Cooper D, Stokes KY, Tailor A, Granger DN. Oxidative stress promotes blood cell-endothelial cell interactions in the microcirculation. Cardiovasc Toxicol 2002;2:165e180. 6. Borghi C, Cosentino ER, Rinaldi ER, Cicero AF. Uricaemia and ejection fraction in elderly heart failure outpatients. Eur J Clin Invest 2014;44:573e578. 7. Metra M, Davison B, Bettari L, Sun H, Edwards C, Lazzarini V, Piovanelli B, Carubelli V, Bugatti S, Lombardi C, Cotter G, Dei Cas L. Is worsening renal function an ominous prognostic sign in patients with acute heart failure? the role of congestion and its interaction with renal function. Circ Heart Fail 2012;5:54e62.


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