Association of plasma xanthine oxidoreductase activity with severity and clinical outcome in patients with chronic heart failure

doi:10.1016/j.ijcard.2016.11.077

International Journal of Cardiology

Volume 228, 1 February 2017, Pages 151-157

https://doi.org/10.1016/j.ijcard.2016.11.077 Get rights and content

Abstract

Background

Oxidative stress due to purine degradation is associated with the development of chronic heart failure (CHF). Xanthine oxidoreductase (XOR) is a rate-limiting enzyme of purine degradation that plays a key role in uric acid (UA) production with a resultant increase in reactive oxygen species. However, the relationship between plasma XOR activity and CHF severity and clinical outcome remains unclear.

Methods and results

We measured XOR activity in 440 patients with CHF and 44 control subjects. Abnormally high and low XOR activities were identified based on the results for 95% of the control subjects (high and low XOR activities ≥ 120 and < 33 pmol/100 μL/h, respectively). The prevalence rates of high and low XOR activities increased with advancing New York Heart Association functional class. There were 158 cardiac events during a median follow-up period of 1034 days. Multivariate Cox proportional hazard regression analysis showed that both high and low XOR activities were significantly associated with cardiac events in patients with CHF after adjustment for confounding risk factors including serum UA and loop diuretic use. Kaplan–Meier analysis revealed that the cardiac event rate was significantly higher in patients with either high or low XOR activity. The net reclassification index was significantly improved by adding XOR activity to the basic risk factors.

Conclusions

We provide the first evidence of an association of plasma XOR activity with CHF severity and clinical outcome. Plasma XOR activity could be used to identify high-risk CHF patients and could be a therapeutic target for XOR inhibitors.

Introduction

Chronic heart failure (CHF) is a major and increasing public health problem with a high mortality rate [1]. Oxidative stress is closely associated with CHF development and the major cause of excessive oxidative stress in heart failure is considered to be increased levels of reactive oxygen species (ROS) [2], [3].

Xanthine oxidoreductase (XOR) is a rate-limiting enzyme of the last step of purine degradation in nucleic acid metabolism [4], [5]. When XOR catalyzes the oxidation of hypoxanthine to xanthine and xanthine to uric acid (UA), ROS are generated in this process. Therefore, XOR is recognized as a significant source of ROS contributing the development of oxidative stress-related tissue injury [4]. Both XOR level and activity in myocardial tissue are reportedly increased in animal heart failure models [6], [7]. Circulating XOR can exacerbate oxidative stress in myocardial tissues, and levels are increased in patients with acute phase myocardial infarction [8], [9], [10].

Hyperuricemia increases the risk of heart failure through XOR-dependent ROS production and is considered a therapeutic target [11]. As XOR activity is very low in healthy human [12], [13], no existing studies have examined plasma XOR activity in patients with CHF.

The aims of the present study were to (1) investigate the association between XOR activity and UA level, and (2) assess the prognostic importance of XOR activity in patients with CHF.

Section snippets

Study subjects

This was a prospective observational study to elucidate the clinical utility of plasma XOR activity in patients with CHF. We included 440 patients who were admitted to our hospital for the diagnosis or treatment of CHF, as well 44 age- and gender-matched control subjects without heart disease. The diagnosis of CHF was made by two cardiologists who used the generally accepted Framingham criteria, including a history of dyspnea, symptomatic exercise intolerance with signs of pulmonary congestion

Baseline characteristics of control subjects and CHF patients

The patients' baseline characteristics are presented in Table 1. There were 266 and 174 patients in NYHA functional classes II and III/IV, respectively. Hypertension, diabetes mellitus, and hyperlipidemia were identified in 355 (81%), 116 (26%), and 115 (26%) patients, respectively. The etiology of heart failure was ischemic heart disease in 104 (24%) patients, dilated cardiomyopathy in 109 (25%), and other conditions in the remaining 227 (51%) patients. CKD and acidic urine were identified in

Main findings

In the present study, (1) the prevalence rates of high and low XOR activities increased with advancing NYHA functional class, (2) serum UA levels were not different among XOR groups, but higher UA was noted in the high XOR group in patients without CKD or acidic urine, (3) multivariate logistic analysis revealed that abnormal XOR activity level was closely associated with poor clinical outcomes in patients with CHF, (4) the prediction model including XOR activity had an improved C index, NRI,

Study limitations

As this analysis was performed at a single center and XOR activity is highly population dependent, a validation study is needed to better delineate the prognostic value of XOR activity. Second, further investigations are required to determine the pathological mechanism by which abnormal XOR activity deteriorates cardiac prognosis. Finally, although the mean LVEF in the present study was equivalent to those reported in the Japanese heart failure study and heart failure registry [27], [28], it

Conclusions

We provide the first evidence of an association between plasma XOR activity with CHF severity and clinical outcome. Measuring XOR activity could help identify high-risk patients and XOR may be a useful therapeutic target in CHF.

Conflict of interest

None.

Acknowledgment of grant support

This work was in part supported by the consigned research fund from Sanwa Kagaku Kenkyusho Co., Ltd.

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Association of plasma xanthine oxidoreductase activity with severity and clinical outcome in patients with chronic heart failure

Abstract

Background

Methods and results

Conclusions

Introduction

Section snippets

Study subjects

Baseline characteristics of control subjects and CHF patients

Main findings

Study limitations

Conclusions

Conflict of interest

Acknowledgment of grant support

J. Mol. Cell. Cardiol.

J. Mol. Cell. Cardiol.

J. Am. Coll. Cardiol.

J. Chromatogr. B Analyt. Technol. Biomed. Life Sci.

J. Label. Compd. Radiopharm.

Am. J. Kidney Dis.

J. Mol. Cell. Cardiol.

J. Biol. Chem.

Lifetime risk for developing congestive heart failure: the Framingham Heart Study

Circulation

Oxidative stress and apoptosis in heart failure progression

Circ. Res.

HECT-type ubiquitin E3 ligase ITCH interacts with thioredoxin-interacting protein and ameliorates reactive oxygen species-induced cardiotoxicity

J. Am. Heart Assoc.

Pathophysiology of circulating xanthine oxidoreductase: new emerging roles for a multi-tasking enzyme

Biochim. Biophys. Acta

Therapeutic effects of xanthine oxidase inhibitors: renaissance half a century after the discovery of allopurinol

Pharmacol. Rev.

Circulating xanthine oxidase in human ischemia reperfusion

South. Med. J.