Elsevier

Atherosclerosis

Volume 187, Issue 2, August 2006, Pages 401-407
Atherosclerosis

Serum uric acid and risk of ischemic stroke: The ARIC Study

https://doi.org/10.1016/j.atherosclerosis.2005.09.020Get rights and content

Abstract

Aims

Since serum uric acid (UA) is strongly associated with cardiovascular risk factors, it has been debated whether serum UA is a stroke risk factor or whether UA may be simply “marking” subjects with other, causal risk factors. We therefore investigated the relation between UA and ischemic stroke in the Atherosclerosis Risk in Communities (ARIC) Study.

Methods and results

Of 15,792 ARIC participants, 13,413 who were free of recognized stroke or coronary heart disease (CHD) at baseline and had a baseline UA measurement were included in the analysis. We followed the participants for ischemic stroke incidence (N = 381) over 12.6 years. Although serum UA was independently and positively related to ischemic stroke incidence when we adjusted for age, sex, race, and education, the positive relation was weakened when additionally adjusted for possible confounding variables. The positive multivariate-adjusted association between serum UA and ischemic stroke was observed among subjects not using diuretics (adjusted relative hazard in the highest quartile versus the lowest: relative hazard (RH) = 1.49; 95% confidence interval (CI): 1.00–2.23) (P for trend: 0.02), but not among diuretic users (P for interaction: 0.08).

Conclusion

Our findings suggest that UA is an independent predictor of ischemic stroke among subjects not using diuretics, but that elevated UA itself may not cause ischemic stroke.

Introduction

Elevated serum uric acid (UA) has been associated with an increased risk of cardiovascular disease in studies spanning five decades [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11]. However, since UA is frequently elevated in subjects with other cardiovascular disease risk factors [1], [2], it has been debated whether UA is an independent cardiovascular disease risk factor through an ability to induce inflammatory and vascular mechanisms, or whether UA may be simply “marking” subjects with other, causal risk factors [1], [2], [12], [13], [14]. Alternatively, it has been hypothesized that hyperuricemia may be in part a compensatory mechanism to counteract oxidative damage related to atherosclerosis and aging [15], [16], [17]. We previously investigated the relation between UA and coronary heart disease (CHD) in the Atherosclerosis Risk in Communities (ARIC) Study and found that UA was not an independent risk factor for CHD [12].

Prior studies of the relation between UA and stroke incidence have been inconsistent [4], [5], [6], [7], [8], [9], [10], [18], [19]. Some studies reported a positive independent relation between UA and stroke [4], [5], [6], [7], [8]; others demonstrated that UA did not relate significantly to stroke occurrence [9], [10], [18], [19].

Diuretics are known to increase serum UA. If UA itself is harmful, the relation between UA and stroke should be similar between diuretic users and non-users. However, if elevated UA is simply “marking” subjects with other, causal risk factors or part of a compensatory mechanism to oxidative damage, the relation between UA and stroke might differ between diuretic users and non-users. Reyes has proposed a compensatory mechanism hypothesis that elevation in serum UA caused by drugs that reduce its renal excretion, such as diuretics, may actually be beneficial to cardiovascular prognosis [16], [17]. Therefore, we believed that analyzing the relation between UA and ischemic stroke separately for diuretic users and non-users may help address whether UA itself is harmful to ischemic stroke. However, there are no prior studies of the effect of serum UA on ischemic stroke in diuretic users and non-users.

Therefore, in this study, we investigated the relation between UA and ischemic stroke incidence in the middle-aged general population. We also investigated whether the association varied by use of diuretics to help clarify whether UA itself increases ischemic stroke risk.

Section snippets

Study design and subjects

The Atherosclerosis Risk in Communities Study is a multi-center prospective cohort study investigating the natural history of atherosclerotic disease in four US communities: Forsyth County, NC; Jackson, MS; Washington County, MD; the northwest suburbs of Minneapolis, MN [20]. The cohort comprised 15,792 men and women aged 45–64 years who were selected by probability list or area sampling. Only African Americans were recruited in the Jackson study center.

From 1987 to 1989, a baseline home

Uric acid and other cardiovascular risk factors

The mean value ± S.D. of UA was 5.97 ± 1.52 mg/dL (range 0.5–15.9 mg/dL). Table 1 shows the association between UA and other potential risk factors for stroke. Mean values of age, systolic BP, ethanol intake, serum albumin, vWF, WHR, and BMI were higher in higher UA categories. Similarly, the proportions of subjects who were men, diabetic, or ever smoked; who had less than a high school education, used anti-hypertensive medications, or had low HDL cholesterol; or who had ECG LVH, increased IMT, or

Discussion

In this prospective cohort study, we demonstrated an independent positive moderate association between UA and ischemic stroke incidence restricted to those not using diuretics.

A motivation of this study was to clarify whether UA itself is a risk factor for ischemic stroke by analyzing the relation between UA and ischemic stroke separately for diuretic users and non-users.

Some mechanisms have been proposed to explain a potential relation between UA and atherosclerosis. First, the relation

Conclusions

In conclusion, UA was independently and positively associated with ischemic stroke incidence among subjects not using diuretics. However, we found no significant relation between UA and ischemic stroke among diuretic users. This finding suggests that UA is independent predictor of ischemic stroke among subjects not using diuretics, but that elevated UA itself may not cause ischemic stroke.

Acknowledgements

Dr. Hozawa was supported by a grant (14010301) from the Japan Society for the Promotion of Science Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan and the Banyu Fellowship Program sponsored by Banyu Life Science Foundation International.

The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020,

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