Hyperuricemia and the risk of stroke incidence and mortality: a systematic review and meta-analysis

doi:10.21203/rs.3.rs-3131829/v1

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Hyperuricemia and the risk of stroke incidence and mortality: a systematic review and meta-analysis

https://doi.org/10.21203/rs.3.rs-3131829/v1

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Background.

The relationship between hyperuricemia (HUA) and stroke remains controversial. The aim of this systematic re-view was to assess the association between hyperuricemia and stroke.

Methods.

PubMed, Embase, Web of Science and Cochrane Library were searched from their earliest records to June 5th, 2023, additional papers were identified through a manual search. Prospective studies that provided a multivariate-adjusted estimate of the association between hyperuricemia and risk of stroke incidence and mortality, represented as relative risks (RRs) with 95% confidence intervals (CIs), were eligible.

Results.

A total of 22 studies including 770532 adults were eligible and included. Hyperuricemia was associated with a significantly increasing risk of both stroke incidence (combined RR, 1.42; 95%CI, 1.31–1.53) and stroke mortality (combined RR, 1.53; 95%CI, 1.18–1.99) in our meta-analyses. Relative risk of stroke incidence: females (combined RR, 1.67 ; 95%CI, 1.44–1.92) and males (combined RR, 1.13; 95%CI, 1.02–1.25). Relative risk of mortality: female (combined RR, 1.41 ; 95%CI, 1.31–1.52) and males (combined RR, 1.27; 95%CI, 1.20–1.34). The association between hyperuricemia and ischemic stroke (IS) (combined RR, 1.39; 95%CI, 1.31–1.47) was more significant than that of hemorrhagic stroke (HS) (combined RR, 1.13; 95%CI, 1.02–1.26).

Conclusion.

Our study verified an association between hyperuricemia and risk of stroke, which was more pronounced in females.

stroke

hyperuricemia

cohort study

meta-analysis

Stroke is the leading cause of disability and the second most common cause of death worldwide. In 2019, stroke caused 6.6 million deaths and 143 million disabilities worldwide[1]. According to the World Health Organization (WHO), strokes could cause 7.8 million deaths by 2030[2]. Therefore, primary prevention of stroke has been a major public health priority. Hypertension, hyperlipidemia, diabetes mellitus, obesity, and smoking are main risk factors for stroke[2, 3] .

Serum uric acid (SUA) is an organic substance. It is the final product of purine metabolism in the body[4]. The hyperuricemia is usually defined as serum uric acid concentration in excess than 6.8mg/dL[5]. The prevalence of hyperuricemia was high in mainland Chinese. Hyperuricemia in male was 21.6% (95% CI: 18.9–24.6%), and that in female was 8.6% (95% CI: 8.2–10.2%)[6]. Hyperuricemia is the key to gout[5], and a lot of evidence indicates that hyperuricemia may be involved in the emergence of hypertension and chronic kidney disease[7].

There have been several proposed pathophysiological mechanisms linking hyperuricemia to cardiovascular disease, including endothelial dysfunction, oxidative metabolism, platelet adhesiveness, and aggregation[8–10]. Current studies have shown an association between hyperuricemia and stroke incidence & mortality[11–24]. However, the results are inconsistent[25–31], probably due to a small sample size or different study designs. Moreover, it is unclear if the association between hyperuricemia and the risk of stroke differs between men and women. It is also unclear if the association between hyperuricemia and the risk of stroke differs between stroke subtype.

We conducted this meta-analysis of prospective studies to determine the association between hyperuricemia and stroke incidence & mortality, and whether sex and stroke subtype modifies the association. Clarifying this potential sex-specific and subtype-specific association is also of great importantance for precise and effective prevention of stroke.

Search strategy

We searched four major databases through June 2023, including PubMed, EMBASE, Web of Science, and the Cochrane library (including CENTRAL). The terms searched were as follows : “uric acid” OR “hyperuricemia” OR “urate” OR “hyperuric” AND “stroke” OR “brain ischemic” OR “transient brain ischemia” OR “cerebra arterial disease”. In addition, we identified additional articles by manually searching the references of included articles.

Study Selection

Study was considered eligible if they met the following inclusion criteria : (1) Prospective cohort study of the population; (2) Exposure to hyperuricemia ; (3) The literature reported stroke incidence or mortality, multivariable adjusted RR values, and 95% confidence intervals; (4) Over one year's follow-up was conducted on all patients; (5) Participants without renal disease, stroke or other serious diseases, such as a tumor at the beginning of the study. Studies with the following conditions would be excluded: (1) The study design was a non-prospective cohort study; (2)Exposure to non-hyperuricemia; (3) Unadjusted RRs and 95% CIs were reported; (4) Follow-up was less than one year; (5) Study populations had previous stroke or kidney disease.

Two authors(H.J, Y.S) independently screened the titles, abstracts and/or full text of articles for potential inclusion. Any disagreements were resolved through consulting the third author(Y.l).

Main outcome variables

The following data was extracted from each included study: first author's surname, year of publication, study country, follow-up data, sample size, mean age, definition of outcome, and percentage of men, number of outcome events, and adjusted (included age, comorbidity, using of diuretics) RR.

Based on the adjusted RRs and 95% CIs published in each study, we examined the relationship between HUA levels and stroke risk. ORs and HRs were regarded as equivalent to RRs. Natural logarithms were used in every study to convert these values. When some studies included in our meta-analysis reported serum uric acid levels using the International System of Units, we converted those measurements to conventional units by using a conversion rate of 16.81 (1 mg/dL = 59.48 µmol/L).

Risk of bias assessment

Study methodological quality was evaluated using the Newcastle-Ottawa Scale (NOS)[32]. Cohort studies were scored according to three major aspects: selection of study groups (0–4 points), comparability of study groups (0–2 points), and measurement of the outcome (0–3 points). Better methodological quality is reflected in a higher score.

Analysis

We used the I² test to measure statistical heterogeneity between the studies. In effect estimates, the I² statistic describes the percentage of variance that is attributable to heterogeneity rather than chance. An I² statistic above 50% may indicate significant heterogeneity, and pooled analysis with random-effects model was done. There is considered to be less heterogeneous if I² is less than or equal to 50%, and pooled analysis with fixed-effects model was done.

To further investigate potential causes of heterogeneity, we carried out meta-regression and subgroup analysis. As we identified sources of heterogeneity by meta-regression, no further sensitivity analyses were performed. Funnel plots and Egger’s test were used to detect publication bias. All statistical analyses were performed in STATA 16 (STATA Corp).

In total, 5037 articles were identified from the initial database search. The final analysis included 770532 participants from twenty-two prospective cohort studies[11–31, 33]. The characteristics of the studies and their participants are presented in Table 1. Among the twenty-two included studies, 3 were performed in the United States[25, 28, 31], 7 from Europe[14, 15, 17, 19, 20, 24, 26], and 12 from Asian countries[11–13, 16, 18, 21–23, 27, 29, 30, 33]. The number of participants ranged from 920 in the study by Jiménez et al.[28] to 417734 in the Apolipoprotein MOrtality RISk study (AMORIS) by Holme et al.[19].The duration of follow-up ranged from 1 years[30] to 23 years[20, 33]. Of the 22 articles included, 15 covered gender. 11 studies[11, 12, 19, 21–25, 27, 30, 33] included both men and women, 3 studies[15, 20, 29] only men, and 1 study only women[28]. Among these studies, 13 studies[11, 12, 14, 15, 19, 20, 23, 24, 26, 28, 30, 31, 33] distinguished between ischemia and hemorrhagic strokes, while 9 studies[13, 16–18, 21, 22, 25, 27, 29] mentioned either ischemia or hemorrhagic strokes. The definition of hyperuricemia varied among studies. The quality score of studies ranged from 6 to 9, overall quality of included studies was good.

Table 1

Characteristics of included cohort studies
	Author, year of publication, country	Participants (%male)	Age range or mean	Follow-up	Hyperuricemia definition
STROKE INCIDENCE	Chien et al, 2005, China[21]	3602 (47.28)	NA	11 years	M ≥ 7.7 mg/dL F ≥ 6.6 mg/dL
	Tu et al, 2019, China[12]	3243 (55)	70.8 ± 6.0	35.5 ± 3.0 months	M > 7.0 mg/dl F ≥ 6.0 mg/dl
	Cheng et al, 2021, China[22]	29,974 (61.49)	47.2 ± 13.9	5.78 ± 0.83 years	≥ 6 mg/dl
	Hu et al, 2021, China[30]	11,841 (45.67)	62.95 ± 9.14	612.14 ± 32.12 days	M > 420 µmol/L F > 360 µmol/L
	Bos et al, 2006, Netherlands[24]	4385 (35.37)	69.0 (62.5–76.2)	8.4 years	≥ 381 mmol/L
	Tscharre et al, 2018 Austria[26]	1215 (66.4)	62.9 ± 13.4	5.5 ་ 2.9 years	M > 7.0 mg/dl F > 6.0 mg/dl
	Jiménez et al, 2016 America[28]	920 (0)	61	17 years	> 6.8 mg/dL
	Hozawa et al, 2006 America[31]	15792 (51.4)	53.97	12.6 years	≥ 6.9 mg/dL
	Li et al, 2020, Japan[33]	13420 (39.01)	55.03	23.1 years	M > 6.7 mg/dL F > 5.2 mg/dL
	Lehto et al, 1998 Finland[17]	1017 (54.18)	58.05	7 years	> 295 µmol/L
	Strasak et al, 2008 Austria[14]	28613 (0)	62.3	15.2 years	≥ 5.41 mg/dL
	Chen et al, 2009 China[23]	90393 (46.33)	51.5	7 years	> 7 mg/dL
STROKE MORTALITY	Sakata et al, 2001, Japan[16]	8,172 (44)	49.81 ± 13.06	14 years	M ≥ 386 mmol/L F ≥ 291 mmol/L
	Tomita et al, 2000, Japan[13]	49,413 (100)	25–60	5.4 years	≥ 6.5 mg/dl
	Holme et al, 2009, Sweden[19]	417 734 (52.95)	48.15 ± 11.76	11.8 years	M > 362 mmol/L F > 327 mmol/L
	You et al, 2009, America[25]	15 583 (48.28)	55.8	7.4 years	> 7.5 mg/dL
	Gerber et al, 2006, Israel[20]	9125 (100)	49	23 years	> 5.6 mg/dL
	Strasak et al, 2008, Austria[15]	83683 (100)	41.6	13.6 years	> 398.81 mmol/L
	Jee et al, 2004, Korea[29]	22698 (100)	44.6	9 years	> 414 mmol/L
	Sakata et al, 2020, Japan[16]	2633 (16.2)	59.23	19 years	M > 412 mmol/l F > 311 mmol/l
	Kuo et al, 2013, China [18]	354110 (54.71)	49.8	4.65 years	> 7 mg/dL
	Zhang et al, 2015, China [11]	36313(43.04)	53.54	10 years	M > 6.7 mg/dL F > 5.1 mg/dL

The multi-variable adjusted RRs of stroke incidence in relation to hyperuricemia are presented in Fig. 1. Based on the incidence of stroke, there is a statistically significant difference between the normouricemic and hyperuricemic groups (combined RR, 1.42; 95%CI, 1.31–1.53)[12, 14, 21–23, 26, 28, 30, 31, 33]. The multi-variable adjusted RRs of stroke mortality in relation to hyperuricemia are presented in Fig. 2. Based on the mortality of stroke, there was a statistically significant difference between the normouricemic and hyperuricemic groups (combined RR, 1.53; 95%CI,1.18–1.99)[11, 13, 15, 16, 18–20, 25, 27, 29]

In the subgroup analysis of hyperuricemia and stroke incidence, we found that the similar association was held for both sexes. And female (combined RR,1.67 ; 95%CI,1.44–1.92) were at a higher risk of stroke than male (combined RR, 1.13 ; 95%CI,1.02–1.25)[12, 21–24, 28, 30, 33]. For a subgroup analysis for different types in stroke, there was no difference between ischemic and hemorrhagic stroke (p = 0.846)[12, 14, 23, 24, 26, 28, 30, 31, 33] (Fig. 3).

For a subgroup analysis of hyperuricemia and stroke mortality for different sexes, we found that the association also held for both sexes, and female(combined RR,1.41 ; 95%CI,1.31–1.52) were at a higher risk of stroke mortality than male(combined RR, 1.27 ; 95%CI,1.20–1.34) [11, 15, 19, 20, 25, 27, 29]. For a subgroup analysis for different stroke types, we found that the association also held for both stroke types. And the association between hyperuricemia and ischemic stroke (combined RR,1.39 ; 95%CI,1.31–1.47) was higher than that of hemorrhagic stroke (combined RR,1.13 ; 95%CI,1.02–1.26)(Fig. 4)[11, 15, 19, 20]

For stroke incidence there was no statistical evidence of publication bias among the included studies by using Egger’s test (P = 0.264). For stroke mortality, there was no publication bias either (P = 0.371). The funnel plots were examined .

A meta-regression was carried out to investigate the predefined potential source of heterogeneity because significant heterogeneity was found among the individual studies. The results of regression suggested that gender, ethnicity were not significant sources of heterogeneity of the mortality, while the follow-up time was a significant source of heterogeneity (P = 0.039) .

In this systematic review and meta-analysis, we summarized the relationship between hyperuricemia and stroke incidence & mortality including 22 studies with 770,532 participants. Pooled data showed that hyperuricemia have a sinificant risk of stroke incidence and mortality, and the risk is higher in women than man. In terms of stroke types, patients with hyperuricemia had a higher incidence risk of ischemic stroke than hemorrhagic stroke.

Many studies have been carried out at home and abroad. For prospective cohort studies, some studies have shown a positive association between hyperuricemia and risk of stroke [25–31], while others have shown no association[25–31, 33]. With relative clinical studies, we verified the relationship between hyperuricemia and stroke incidence and mortality.

Stroke is regarded as a heterogeneous, multifactorial disease caused by atrial fibrillation, obesity, smoking, diabetes, high blood pressure, and other risk factors. HUA plays a direct and indirect role in increasing the risk of stroke. The positive association of hyperuricemia with stroke incidence and mortality may be due to: firstly, uric acid may play a direct role in the development of atherosclerosis and indirectly lead to the occurrence of stroke[34]. HUA can further promote the oxidation of LDL cholesterol and lipid peroxidation. Lipid peroxidation leads to an increase in the generation of oxygen free radicals and their involvement in inflammatory reactions, thus affecting the function of vascular intimal smooth muscle. Fibrosis and thickening of the inner lining of the arteries occur, which promote the formation and progression of atherosclerosis[35–37]. Secondly, hypertension is a major risk factor for hemorrhagic stroke[38, 39]. Some studies suggested that hypertension may mediate the effect of HUA on stroke risk[40–42]. The mechanism may be due to that uric acid first activates the renin-angiotensin system (RAS system) and inhibits nitric oxide (NO), leading to increased vascular resistance in the system, and then uric acid mediates renal entry into bulbar arterioles and leads to sodium-sensitive hypertension[43, 44]. Besides, uric acid can induce the production of vascular endothelial inflammatory factors and directly participate in the occurrence of stroke[40, 45, 46]. In all, numerous pathophysiological mechanisms, such as endothelial dysfunction [45, 46], oxidative metabolism, platelet adhesiveness, and aggregation, elevated circulating levels of systemic inflammatory mediators have been proposed to link hyperuricemia to cardiovascular disease [40, 42, 44–53]. The detailed mechanisms associated with hyperuricemia and stroke need to be further explored.

The prevalence of hyperuricemia in males is higher than that in females[6], and the definition of hyperuricemia in males and females is not completely uniform, internationally. Therefore, we conducted a subgroup analysis to investigate the gender differences in the risk of stroke in patients with hyperuricemia. We found that the relationship between HUA and incidence and mortality of stroke were higher in females than in males. Of course, we think that this may be due to that estrogen may play a heart protective role in women[23, 54]. In women, hyperuricemia may be a sign of evasive estrogen protection [23].

We assessed the differences between hyperuricemia and the risk of different types of stroke. There are two main types of stroke: IS and HS, of which 79% of patients are IS[55, 56]. Our results held that the association between HUA and the incidence & mortality of IS is stronger than that of HS. However, the specific mechanism is not clear, and some studies suggest that it may be because each of the above factors leading to stroke may potentially stimulate the cascade of clotting, leading to thrombosis and arterial occlusion, and eventually to the development of intracranial atherosclerosis[41]. There is also evidence that hyperuricemia may be an important predictor of atrial fibrillation[57]. Furthermore, elevated HUA may allow cerebrospinal fluid to cross the blood-brain barrier and cause edematous areas, leading to the occurrence of adult cerebral ischemia[8, 58–60].

Heterogeneity analysis of the included studies involving stroke mortality showed that the length of follow-up was responsible for the high heterogeneity. Therefore, the length of follow-up of the included references may indirectly affect the results of this meta-analysis. As it is a lengthy process from high-risk population to stroke onset or death, we recommend that studies should be followed up as long as possible.

Our study has some advantages. This meta-analysis included 22 studies with 770,532 participants. We excluded studies that included patients with kidney disease and prior stroke, because stroke patients are at high risk of recurrent stroke[61], and in patients with chronic kidney disease, serum uric acid levels increase due to reduced clearance[62]. Besides, All RR values from the studies we extracted were adjusted, every study was high quality after assessing the quality of individual studies by using the NewcastleeOttawa Scale. Based on the above advantages, our results should be reliable.

Limitations of the meta-analysis should also be mentioned. First, the studies included in this meta-analysis were prospective cohort studies, like any observational studies, a causal relationship between hyperuricemia and stroke risk could not fully be established. Second, different studies have different definitions of hyperuricemia, which may lead to inconsistent results among different studies. It may have an impact on our results. Third, the data extracted was limited, especially the data that could be used for subgroup analysis was less. Finally, there is the bias caused by English language restrictions. By conducting a non-language-restricted search of four significant electronic databases, we attempted to reduce this bias. However, some non-English articles that have not been published in international journals may be missed.

Our study verified an association between hyperuricemia and risk of stroke & mortality, and which is differrent among sex and stroke subtype. In the future, more basic studies are needed to explain the possible physiological mechanism of hyperuricemia and stroke incidence. Further more, multi-center, double-blind, randomized controlled trials are needed to explore the role of lowering hyperuricemia for stroke prevention.

HUA：	hyperuricemia
IS：	ischemic stroke
HS：	hemorrhagic stroke
WHO：	World Health Organization
SUA：	Serum uric acid
NOS：	the Newcastle-Ottawa Scale
NO：	nitric oxide
RAS system：	the renin-angiotensin system

Ethics approval and consent to participate

Not Applicable.

Consent for publication

All authors approved the final manuscript and thesubmission to this journal.

Availability of data and materials

All data generated or analysed during this study are included in this published article.

Competing interests

None.

Funding

This work was supported by Chengdu Science and Technology Bureau [grant numbers 2020-GH02-00057-HZ] the Special Scientific Research Fund of the First Affiliated Hospital of the First Affiliated Hospital of Chengdu Medical College [grant numbers 2022LHZYYB-16; CYFY2021YB04; CYFY2018ZD01; CYFY2021YB07], and the Key project of Chengdu Medical College-Chengdu Seventh People's Hospital Joint Scientific Research Fund [grant numbers 2021LHJYZD-01].

Authors' contributions

Conceptualization, H.J and Y.S; methodology, H.J and R.L; software, S.Y and X.Z; resources, H.J and Y.S; writing original draft preparation, Y.S; writing—review and editing, H.J; C.H; supervision, J.Y; funding acquisition, H.J and Y.L. All authors have read and agreed to the published version of the manuscript.

ACKNOWLEDGMENTS

We would like to thank all investigators and site staff of hospitals who participated in this study.

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Hyperuricemia and the risk of stroke incidence and mortality: a systematic review and meta-analysis

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INTRODUCTION

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Main outcome variables

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