Is uric acid protective or deleterious in acute ischemic stroke? A prospective cohort study
Introduction
Uric acid, which exists almost entirely in its ionized form urate at physiological pH and is hence referred to as urate, is derived from adenine- and guanine-based purine compounds [1]. The ability of urate to scavenge peroxynitrite, hydroxyl radical and singlet oxygen, and chelate transition metals, suggests an antioxidant role of urate in humans [1]. Urate is degraded in most mammals by the hepatic enzyme, urate oxidase (uricase), to allantoin [1]. In humans, however, mutations in early hominoids that rendered the uricase gene nonfunctional have resulted in urate levels in human plasma that are approximately 10 times those of most other mammals [1], [2]. The brain is particularly susceptible to damage mediated by free radicals, given its relatively high consumption of oxygen, presence of high concentrations of readily peroxidizable lipids and high concentration of iron [3]. Moreover, during cerebral ischemia and reperfusion, free radicals and oxidative damage products are released from brain tissues into the circulation [3].
The role of urate in ischemic stroke is poorly understood. A retrospective analysis of hospitalization data of 2498 patients in Glasgow suggested that higher serum urate on admission predicted poor outcome (dead or in care) and higher vascular event rate following ischemic stroke [4]. By contrast, a prospective hospital-based study involving 881 patients found that higher levels of serum urate predicted better outcomes following stroke [5], suggesting that serum urate may be beneficial and protect against poor outcomes. The discrepancies in findings could be contributed to by differences in measurement of clinical outcomes: one group used outcome at 90 days (alive at home, dead or in care) [4] and the other neurological disability at hospital discharge [5]. As these outcomes may vary according to the socio-economic setting and local discharge policies, their use may not be suitably applied in different populations. On the other hand, the modified Rankin scale and recurrent vascular events are well established outcome measures for clinical trials and studies of stroke [6].
Given the above discrepancies, we used a prospective cohort study design to investigate the relationship between serum urate and longer term outcomes 12 months following ischemic stroke. The modified Rankin scale and vascular outcomes were considered as primary endpoints [6]. Serum urate was measured using high-performance liquid chromatography within 72-h from the onset of stroke.
Section snippets
Patients
We included 503 patients diagnosed with transient ischemic attack, first or recurrent ischemic stroke who were admitted to the acute stroke inpatient program at the Department of Neurology, Singapore General Hospital, Singapore, from May 2002 to May 2004. The hospital is a 1515-bed acute-care tertiary hospital in Singapore that provides multidisciplinary medical care to a population of approximately 4 million, comprising 77% Chinese, 14% Malays, and 8% Indians [7]. Brain imaging (either CT or
Results
The mean age of study patients was 63 years (SD, 12 years; range, 27–93 years). Demographic and risk factors are shown in Table 1, which were similar to previously reported community- [9] and hospital-based [10] studies. Serum samples were obtained at a mean of 2.31 (SD 0.68) days following the onset of stroke. The mean (SD) serum urate of 354 (115) μM tended to be higher compared to age-matched community-based healthy subjects in our population (mean, 328 (104) μM) (p = 0.20). Although a linear
Discussion
In this study, we observed a U-shaped relationship between the serum urate level and the proportion of patients with poor functional outcomes, especially clear at the higher urate levels but also evident at the lower levels. The lowest occurrence of poor outcome was observed in the middle ranges of urate (340–410 μM). The strengths in this study lie in the longer period of follow-up, use of a functional scale widely accepted in clinical therapeutic trials, an accurate method of measuring serum
Financial disclosure
None reported.
Funding/support
This study was supported by the Biomedical Research Council (BMRC 04/1/21/19/324) and SingHealth Cluster Research Fund (EX 023/2001).
References (21)
Towards the physiological function of uric acid
Free Radic Biol Med
(1993)- et al.
Potential markers of oxidative stress in stroke
Free Radic Biol Med
(2005) - et al.
Classification and natural history of clinically identifiable subtypes of cerebral infarction
Lancet
(1991) - et al.
Plasma antioxidants are similarly depleted in mild cognitive impairment and in Alzheimer's disease
Neurobiol Aging
(2003) - et al.
Myocardial malondialdehyde and uric acid release after short-lasting coronary occlusions during coronary angioplasty: potential mechanisms for free radical generation
Am J Cardiol
(1991) Ascorbate prevents prooxidant effects of urate in oxidation of human low density lipoprotein
FEBS Lett
(1999)- et al.
Uric acid and serum antioxidant capacity: a reaction to atherosclerosis?
Atherosclerosis
(2000) - et al.
Two independent mutational events in the loss of urate oxidase during hominoid evolution
J Mol Evol
(1992) - et al.
Serum urate as an independent predictor of poor outcome and future vascular events after acute stroke
Stroke
(2003) - et al.
Prognostic significance of uric acid serum concentration in patients with acute ischemic stroke
Stroke
(2002)
Cited by (79)
Association between uric acid levels and the risk of futile reperfusion in stroke after thrombectomy: A propensity score matching study
2024, Journal of Stroke and Cerebrovascular DiseasesAssociation between uric acid and the prognosis of acute ischemic stroke: A systematic review and meta-analysis
2021, Nutrition, Metabolism and Cardiovascular DiseasesCitation Excerpt :In addition, the results of the subgroup analysis were in line with the results of the initial meta-analysis (Table 3). Two studies [10,14] have reported the association between uric acid levels and poor outcomes of ischemic stroke. The I2 statistic test showed significant statistical heterogeneity among them (I2 = 89.2%, p = 0.002, Fig. 2C).
Hyperuricaemia as a prognostic factor for acute ischaemic stroke
2021, Neurologia