High-level Exposure of Uric Acid in Asymptomatic Hyperuricemia Could Be An Isolated Risk Factors of Cardio-Cerebrovascular Diseases: A Prospective Cohort Study

doi:10.21203/rs.3.rs-230583/v1

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High-level Exposure of Uric Acid in Asymptomatic Hyperuricemia Could Be An Isolated Risk Factors of Cardio-Cerebrovascular Diseases: A Prospective Cohort Study

https://doi.org/10.21203/rs.3.rs-230583/v1

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published 31 Jul, 2021

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Background: Whether the asymptomatic hyperuricemia (AH) raises the risk of cardiovascular disease with or without hyperuricemia-related comorbidities still remains contentious. Our study was aimed to quantitatively access the incidence risk of coronary heart disease (CHD) and stroke associated with AH.

Methods: Multivariate-adjusted Cox regression models were applied to evaluate the risk of cardiovascular disease (CVD). Serum uric acid beyond normouricemia was quarterly stratified based on the distribution of healthy population without CVD onset.

Results: 1,062 CVD first attack cases were collected among the 48,001 cohort participants (age range: 18-92, mean age: 47.2±13.9 years-old) with a mean follow-up duration of 5.78±0.83 years. 14,464 baseline population with comorbidities were excluded to further study the association between AH and CVD incidence. The AH showed overall non-association with CVD incident. However, significantly increased adjusted hazard ratio (HR) of CVD with 95% confidence interval (CI) were observed when the fourth quartile compared with normouricemia stratum in the total cohort population (CHD: 1.70, 1.34-2.16; stroke: 1.55, 1.13-2.13), male (CHD: 1.94, 1.47-2.56), female (CHD: 1.71, 1.03-2.35; stroke: 2.02, 1.14-3.58) and aged over 50 years-old population. Meanwhile, the age-standardized incidence rate of CVD in the fourth quartile was 2 to 3 time higher than the normouricemia population. Consistent results were also observed in the AH population in absence of comorbidities (CHD: 2.40, 1.39-4.14; stroke: 1.85, 1.12-3.59).

Conclusion: Asymptomatic hyperuricemia patients exposed to higher level of uric acid (male>487 mmol/L, female>422 mmol/L) could significantly increase the incidence risk of CHD and stroke, with or without hyperuricemia-related comorbidities.

Cardiac & Cardiovascular Systems

Asymptomatic hyperuricemia

coronary heart diseases

stroke

prospective cohort study

Hyperuricemia (HUA) is usually caused by the overbalanced exogenous and endogenous pool of serum uric acid (SUA) which universally defined as serum UA≥420 μmol /L（7 mg/dl） in male population and UA≥357 μmol/L（6 mg/dl）in female population. Although experimental studies suggested high level exposure of UA could increase the cardio-cerebrovascular disease (CVD) risk var in vitro vascular endothelial dysfunction and increased platelet aggregation by reactive oxygen species (ROS) damage[1, 2], epidemiological evidences demonstrated a controversial association which may not support hyperuricemia exposure could be an independent risk factor of CVD [3-6]. This discrepancy results may be ascribable by the complex expanding epidemic factors including obesity, purine-rich dietary, alcohol and fructose. More importantly, comorbidities like hypertension, type II diabetes, dyslipidemia, and etc. have a natural implication with hyperuricemia, it was extremely difficult to tease out the association that SUA impersonated in CVD from the coexistence and collinearity of the other comorbidities’ conditions[7-9]. Thus, the treatment/management of the hyperuricemia-related comorbidities noteworthy to attention, particularly for the hyperuricemia under asymptomatic condition.

Asymptomatic hyperuricemia (AH) applied to setting in those hyperuricemia patients who neither symptoms nor signs of monosodium urate (MSU) crystal deposition diseases including gout, SUA-related kidney injury, and etc. It caused less concern for both clinicians and patients themselves which may further lead to adverse outcomes without caution. Studies have documented that over 80% of the hyperuricemia patients were asymptomatic and remain throughout their entire lifetime[10-12]. Although proof of the association between hyperuricemia and renal diseases, vascular, and metabolic diseases were under inconsistently evidential results, nevertheless, consensus on urate-lowering therapy (ULT) was recommended for the symptomatic hyperuricemia patients. However, the frequent condition of asymptomatic hyperuricemia on the question of ‘to treat or not to treat’ was still confronting a heavily debated condition, only few study strengthen the importance of AH on the prediction of CVD incident[13]. Currently, limited counties such as Japan (2002) and China (2016) revised their guidelines for the management of hyperuricemia, which suggested conditional AH patients need to be treated with pharmacotherapy[14]. In other regions, given the absence of any data and the potential risks of treatment, it is still regarded as a general rule that asymptomatic hyperuricemia should not be treated, even ultrasonographic exam results showed that UA crystal has already deposited in soft tissues.

Using a full age-range cohort population, our study focused on evaluating long-term association linking UA exposure to CVD incidence in the asymptomatic hyperuricemia patients, and synchronously access the incidence risk of CVD among the population who do not have any cardiovascular, metabolic diseases, and renal diseases to further strength the study efficiency.

Study design and assessment of covariates

As previously described [15], the Jinchang Cohort Study is an ongoing prospective cohort study in Gansu Province, China. Briefly, the Jinchang Cohort was established on the basis of biannually nonprofit medical examination for all employees by the Jinchuan Nonferrous Metals Corporation (JNMC). Also, the decline rate of participation was further minimized by uniform organization by the labor union and JNMC corporation. The baseline survey of the Jinchang Cohort was established through a cross-sectional biannual medical exam conducted from January 2011 to June 2013. All of the 48,001 JNMC employees and retirees completed all 4 parts of the health examinations, including in-person epidemiology interviews, physical exams, laboratory tests, and donation of bio-samples (blood and urine), with a mean age of 47.2±13.9 years (range from 18 to 91). The first-round follow-up study was initiated from June 2016 to December 2018; 37,040 participants were collected, with a follow-up rate of 81.09% and a mean follow-up duration of 5.78±0.83 years. All of the enrolled participants were required a normal diet on two separate days and fasting at least 8 hours before health examination, the biochemical examinations were performed at the Workers’ Hospital of the Jinchuan Company. Blood biochemical indicators including serum uric acid (SUA), total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), fasting plasma glucose (FPG) and etc. were automatically testing by biochemical analyzers (Hitachi 7600-020).

Study population

Initially, 2,327 baseline participants and 3,685 follow-up participants were excluded from 48,001 and 37,040 follow-up population due to the inadequacy of any part of questionnaire or physical examination information. After employee-ID or health insurance-ID match with baseline population, 2,057 newly recruited participants during the first follow up period were also excluded. Additionally, 1,324 CVD patients, 191 acute or chronic renal nephritides patients, and 296 gout patients diagnosed before or at baseline were excluded from the baseline population. As a result, a total of 29,974 participants who were 100%-matched between baseline and 1^st phase follow-up were selected as our study population. 14,464 baseline population (including those participants with at least two types of metabolic syndromes) who has any of dyslipidemia (n=9,877), hypertension (n=7,119), or diabetes (type I and type II, n=2,141) were excluded to further study the association between asymptomatic hyperuricemia and CVD incidence risk under non-comorbidities conditions. Details of excluding and including criteria will be showed as figure 1.

Outcomes and study variables

Data collection and definition of metabolic syndromes

Basic demographic characteristics including detailed dietary survey, lifestyle behaviors such as smoking, alcohol drinking, and physical exercise status, past medical history, occupational history reproductive history in female population and etc. At least two measurements of brachial BP were automatically measured by well-trained staffs both in baseline and follow-up surveys. Smoking index (pack-year) and alcohol index (Kilogram-year) were uniformly calculated for the further statistical adjustment. The smoking index (pack-year) was calculated as smoking packets per day × years of smoking; The alcohol index (Kilogram-year) was calculated as volume of daily alcohol beverage uses per day × years of drinking × coefficient of alcohol content. In detail, coefficient of alcohol content was defined as the average alcoholicity of each types of alcoholic beverages, the detailed alcohol coefficients were defined as follow: liquor was 54%, wine was 12.0%, and beer was 3.0%.

Hyperuricemia was defined as serum uric acid level beyond 416 μmol /L (7 mg/dl) in male population and UA beyond 357 μmol/L (6 mg/dl) in female population or with clear anti-hyperuricemia treatment. Furthermore, hyperuricemia population without gout, uric acid renal disease, or UA crystal deposition diseases with ultrasonographic diagnosis were defined as asymptomatic hyperuricemia; All participants were requested to rest at least 10 minutes in the hospital exam room, at least two measurements of each participants' brachial blood pressure (BP) were taken at the seated position by a bimonthly calibrated clinical electronic sphygmomanometer (AMpall BP750, Seoul, Korea). The mean value of the 2 measurements was recorded as the final BP records. Any participants’ blood pressure beyond SBP 140 mmHg or/and DBP 90 mmHg or with definite hypertension pharmacotherapy or clinical treatment history were defined as hypertension patients; Diabetes was defined as any participants with self-reported history of diabetes, or FPG ≥ 7.0 mmol/l or glucose tolerance test ≥ 11.0 mmol/l or with definite inpatient medical history records or medication intake history; dyslipidemia was defined as serum level of total cholesterol ≥ 5.71 mmol/l or serum level of triglyceride ≥ 2.26 mmol/l or LDL ≥ 3.36 mmol/l or HDL≤1.10 mmol/l or any participants with clinical treatment of dyslipidemia. All of the metabolic syndromes were uniformly coded based on the International Classification of Diseases, 10th revision (ICD-10) for further adjustment.

Definition of CVD

Only the first-time nonfatal and fatal coronary heart disease (CHD) and stroke attack cases were selected as CVD incidence cases. All of the CVD incidence cases were collected by biannually in-person epidemiology questionnaires. Meanwhile, annually or semi-annually reviewing inpatient medical history records and death records with definitive clinical diagnostics to dynamically ascertain CVD incident during active surveillance of all Jinchang Cohort participants from the Worker’s Hospital of JNMC. Among the 29,974 CVD-free population with metabolic syndromes at the baseline, 1,062 first-time CVD attack cases or CVD fatal events were collected during the follow-up period with a total of 212,942.8 person-years of follow-up (including 691 CHD incidence cases and 409 stroke cases, of which 38 incidence cases both have CHD and stroke).

All of the CHD incidence cases were coded by ICD-10, which covers heart failure (ICD-10 code: I50), myocardial infarction (ICD-10 code: I21-I25), coronary angioplasty implant and graft (ICD-10 code: Z95.1, Z95.5). The stroke incidence cases were included as follow: ischemic stroke (ICD-10 code: I63), hemorrhagic stroke (ICD-10 code: I60- I62), and hypertensive heart disease (ICD-10 code: I11). The follow-up time for each participant was calculated from the date of the baseline survey to the date of the first CVD diagnosis or death, whichever came first. Furthermore, considering the pathogenesis complexity of kidney failure could bring potential bias and the focus of our study was the circulation system diseases (particularly for CVD), the acute and chronic kidney failure (ICD-10 code: N17-19) cases will not be discussed in this study.

Statistical analysis

Age-specific incidence rates (ASIR) were calculated in each BP category and present as n/100,000 person-years. Adjusted Cox proportional-hazards regression models were employed to compute hazard ratios (HR) with a 95% confidence interval (CI). For all the Cox regression analyses, SUA above normal diagnostic criteria (man ≥416 μmol/L and female ≥360 μmol/L) has been stratified into quartile stratums dependent on the quartile distribution of SUA within the CVD-free male and female population, respectively. The detailed criteria of the quartile stratums were showed as follow: Male population: Normal: ≤420 mmol/L, quartile 1 (Q1): 421-434 mmol/L, Q2: 435-455 mmol/L, Q3: 456-487 mmol/L, Q4, >487 mmol/L. Female population: Normal: ≤360 mmol/L; Q1: 361-372 mmol/L, Q2: 373-392 mmol/L, Q3: 393-422 mmol/L, Q4, >422 mmol/L; The non-hyperuricemia population was set as the reference group in all Cox regression morels.

After multiple adjustments for the Cox regression models, confounders that changed the adjusted hazard ratio by less than 10% were excluded from the final model. The excluded potential confounders are listed as follows: physical exercise, education levels, household income per capita monthly, tea consumption. The following confounders were included in the regression models for final adjustment: age at diagnosis (continues variables), gender (male/female), BMI (continues variables), smoking index, pack-year (no smoking, 0-6.3, 6.4-14.0, 14.1-23.2, ≥23.3), lifetime total alcohol intake, kilogram-year (no drinking, 0-72.2, 72.3-167.5, 167.5-380.1, ≥380.1), diabetes status (yes/no), triglyceride (<1.80 mmol/L, 1.80~2.20 mmol/L, >=2.20 mmol/L), high-density lipoprotein (Male: <1.16 mmol/L, 1.16-1.42 mmol/L, ≥1.43 mmol/L; Female: <1.29 mmol/L, 1.29-1.55 mmol/L, ≥1.56 mmol/L), and low-density lipoprotein (<2.60 mmol/L, 2.60-4.11 mmol/L, ≥4.12 mmol/L). Participants with normal BP (<120/80 mmHg) were considered as the reference group. Survival time was defined as continuous measurement by month from the first time the participants enrolled in the cohort study to the month of CVD diagnosis or death, whichever came first (maximum of 91 months). All the fitted variables in the Cox regression model passed the proportionality assumption test. Meanwhile, restricted cubic splines (RCS) model was used to testing the association between UA exposure level and the risk of CHD and stroke in different subgroups. The Cox regression analyses were two-sided and performed by the SAS program, version 9.4 (SAS Institute Inc. 100 SAS Campus Drive Cary, NC, USA). All of the statistical analyses were set as two-sided, and r<0.05 was set as the significance level for all tests.

Table 1 demonstrated the selected the demographic characteristics and bio-chemistry indicators in total population with asymptomatic hyperuricemia and population without metabolic syndromes. Demographic variables including age categories, smoking index, and et al. were demonstrated as cases and frequency of each column. Bio-chemistry indicators were presented as means±standard deviation. As expected, non-significant differences were observed in age distribution, smoking index, alcohol index, exercise quantity, and BMI categories between two populations. Except for the HDL, all of the selected bio-chemistry indicators were showed a lower serum level in the MS-free population in both genders.

Table 2 presented the overall CHD, stroke, and CVD incidence risk associated with the asymptomatic hyperuricemia with or without hyperuricemia-related comorbidities. Higher age-standardized incidence rates of CHD, stroke, and CVD were all observed in the hyperuricemia population, however, no substantially incremental risk of CHD, stroke, and CVD was observed in the asymptomatic hyperuricemia population after adjusted for the potential confounders, respectively.

Table 3 showed the ASIR and adjusted HR of CHD and stroke among all SUA stratums in the selected total cohort population. The highest ASIR of CHD was observed in the Q4 category (1223.60/100k) which was 2.75-fold higher than the reference group. The second highest ASIR group was Q2 category (943.62/100k), and the population without symptomatic hyperuricemia has the lowest ASIR of CHD (444.87/100k). Compared with reference group, Q4 category demonstrated the highest adjusted HR (1.70, 95%CI:1.34-2.16) which followed by the Q2 category (HR:1.45, 95%CI: 1.11-1.90). Similar results were also observed for the stroke incident, the highest ASIR of stroke was appeared in the Q4 strata (679.78/100k) which was 2.52-fold higher than the reference group, and only the Q4 strata demonstrated a statistically significant increase of stroke incidence risk (HR: 1.55, 95% CI: 1.13-2.13).

Table 4 represented the ASIR and adjusted HR of CHD and stroke in the male population. The highest CHD ASIR was observed in the Q4 stratum (1262.56/100k) which was nearly 2.78-fold higher than the normal SUA population (453.81/100k). After adjusted for the potential confounding factors, only the Q4 stratum showed a significantly increased incidence risk of CHD (HR:1.94, 95%CI: 1.47-2.56). Meanwhile, the highest stroke ASIR was also appeared in the Q4 stratum (615.88/100k) which was 1.96-times higher than the normal SUA population. The Q4 strata still showed the highest stroke incidence risk (HR:1.34, 95%CI: 0.91-1.97), however, no SUA stratum in the male population showed a statistically increased risk of stroke after adjusted for the potential confounding factors.

Table 5 demonstrated the ASIR and adjusted HR of CHD and stroke in the female population. The highest CHD ASIR was observed in the Q2 stratum (1636.35/100k) which followed by the Q4 stratum (1043.67/100k). The ASIR of these two stratums was 3.79 and 2.58-fold higher than the normal SUA group. As expected, the highest adjusted HR was observed in the Q2 stratum (HR:1.80, 95%CI: 1.21-2.70) and Q4 stratum (HR: 1.71, 95%CI: 1.03-2.35). The highest ASIR of stroke was observed in the Q4 stratum (857.75/100k) which was nearly 4.21-fold higher than the normal SUA population. After adjusted for the potential confounding factors, only the Q4 stratum showed a statistically increased risk of stroke incidence (HR:2.02, 95%CI:1.14-3.58).

Table 6 showed the CVD ASIR and adjusted HR of CVD incidence among different age sub-groups. The results showed a tremendous difference on the ASIR among different age group, most of the CVD incidence cases was incident after the age 50. In age under 50 population, no significantly difference of ASIR was observed among all SUA stratums, and no stratum showed a significantly changed risk of CVD incidence. In age between 50 to 69 age group, the highest ASIR was appeared in the Q2 (2230.15/100k) and Q4 (2113.08/100k) stratums which was 1.78-fold and 1.69-fold higher than the reference group. As expected, significantly increased incidence risks of CVD were also founded in the Q2 (HR:1.39, 95%CI:1.05-1.83) and Q4 stratums (HR:1.43, 95%CI: 1.08-1.89). In the age over 70 population, the highest ASIR of CVD was also observed in the Q4 stratum (4803.90/100k) which was 1.47-times higher than the normal SUA population. The Q4 stratum has the highest adjusted HR (HR:1.24, 95%CI:0.93-1.67) when compared with reference group, however, no stratums showed a statistically increased incidence risk of CVD.

Appendix tables 1 to 3 showed the sub-analysis of CVD ASIR and adjusted HR in the cohort baseline population without hyperuricemia-related metabolic syndromes, which further stratified by different gender and age group, respectively. The highest ASIR of CHD was observed in the Q4 stratum (886.46/100k) which was 3.77-times higher than the normal SUA population (234.98/100k). After adjusted for the potential confounders, only the Q4 stratum demonstrated a statistically significant increased incidence risk of CHD (HR: 2.40, 95% 1.39-4.14) when compared with reference group. The highest ASIR of stroke was also appeared in the Q4 stratum (443.23/100k) which was 3.41-fold higher than the normal SUA population, and the only the Q4 stratum demonstrated a statistically significant increase adjusted HR of stroke when compared with reference group (HR:1.85, 95%CI: 1.12-3.59). After stratified by gender and age group, only the Q4 stratums in the male population (HR:2.19, 95%CI: 1.35-3.55) and aged >=70 population (HR:2.23, 95%CI: 1.13-4.39) demonstrated a significantly increased CVD incidence risks with biases adjustments. In particular, the CVD ASIR of Q4 stratum (1457.27/100k) was 3.44-times higher than the normal SUA group (423.73/100k) in the male population without metabolic syndromes.

In this prospective cohort study, we investigated the association between various SUA exposure levels and CVD risk among the asymptomatic hyperuricemia population and found that no substantial association was observed between the overall incidence risk of cardio-cerebrovascular diseases and asymptomatic hyperuricemia with or without comorbidities. When we stratified the SUA based on the quartile distribution of CVD-free population, however, there was a significantly increased incidence risks of CVD when the fourth quartile of SUA stratum (male>487 mmol/L [8.2 mg/dl], female>422 mmol/L [7.1 mg/dl]) compared with normouricemia population for both male and female population. The excess risk of CVD was evident in both gender and aged over 50 population, female asymptomatic hyperuricemia population may face a more serious threat of high-level SUA exposure on the CVD incidence risk. To eliminate the coexistence and collinearity effects of metabolic syndromes on the CVD risk, all of the participants diagnosed with hypertension, dyslipidemia, and diabetes were excluded for further analyses. The negative health effects of high-level SUA exposure among the MS-free population were also evidential in the male and aged over 70 years old population. However, these negative effects were not convincible in the female population due to the relatively smaller CVD incidence cases.

The association linking hyperuricemia as an independent risk factor to CVD onset event is controversial, whether or not the hyperuricemia is only an indicator or a pathophysiology cause in cardiovascular disease remains undetermined [16]. Multiple pioneer studies from the Framingham Heart Cohort did not support the conclusion that hyperuricemia is an independent predictive role for the coronary heart diseases. The significant risk elevation of CHD was only found in those gouty patients without diuretics treatment[17, 18]. Additional Framingham Heart study point out hyperuricemia did not have a causal role in the development, and death of CVD, and further apparent association with CVD incident or mortality may be due to the association of uric acid level with other risk factors [19]. Similar results from the National Health and Nutrition Examination Survey I (NHANES I) showed that after followed the 5,421 participants from 1971 to 1987, no association was found linking the hyperuricemia to coronary artery diseases in male but with positive linear correlation between all-cause mortality rate and serums uric level [3]. Wannamethee et al.[20] followed 7,688 male aged from 40-59 for 16.8 years. Although the results showed a significant association between uric acid level and coronary heart disease in men, however, this correlation was respectively depended on the pre-existing myocardial infarction, atherosclerosis, and a cluster of risk factors associated with diabetes. It needs to be emphasized that these studies with non-significant associations showed above were all conducted in a relatively early time which may not further imply to current period. Since the serum uric acid level and the hyperuricemia prevalence are constantly increasing within decades [21-23]. More importantly, the dependency of cardiovascular-related risk factors may impede the association form hyperuricemia to cardiovascular diseases among those previous studies.

Nevertheless, weight of the recent studies favored a more direct perspective that hyperuricemia played an important role in the incident or mortality of cardio-cerebrovascular event[24-27]. A NHANES phase I study documented the results that the cardiovascular mortality rate was positively correlated with the increasement of the serum uric acid concentration in both genders when the forth quartile compared with the lowest quartile (male: risk ratio [RR]=1.77, 95%CI 1.08-3.98; female: RR=3.00, 95%CI 1.45-6.28) [4]. A prospective study followed 417,734 man and women for 11.8 years found a gradual increase in the risk of nonfatal myocardial infarction, stroke, and congestive heart failure. While the SUA concentration demonstrated a U-shape correlation with stroke in both genders[28]. Two large cohort studies in Australia population demonstrated a significant association between SUA exposure and the incidence risk of CVD. A male-focused cohort involved 83,683 Austrian males (mean age, 41.6 years old) with 14 years follow-up duration, the results proved that the risk of stroke (adjusted HR=1.59, 95%CI 1.23-2.04) and congestive heart failure (CHF) (HR=1.51, 95%CI 1.03-2.22) were significantly associated with the higher SUA concentration when the highest quintile compared with the lowest quintile. However, non-association was also founded with the mortality from acute, subacute or chronic forms of CHD[29]. Another female-focused Australia cohort study with 28,613 female participants also found a similar results that high level SUA exposure was isolatedly link to the risk of CHD, CHF or stroke[30]. Considering SUA may have ethnical variations in the prevalence of hyperuricemia and distribution of SUA concentrations, studies conducted in Asian region should also be referred. Two large prospective cohort studies from Taiwan reported a significant association between SUA level and risk of CVD or stroke[31, 32]. Likewise, other studies[33-36] also demonstrated a presence or strong evidence that high level SUA exposure may have a severity correlation with the incidence risk of CVD and stroke. However, none of them evaluated the cardio-cerebrovascular risk in asymptomatic hyperuricemia patients.

Although the inconsistent results were controversially existed about the role SUA played in the onset of CVD event, an increased risk of CVD associated with serum levels of uric acid is biologically plausible. An experimental study form Marilda M et al. [37] found a direct correlation (r=0.75, ρ<0.05) between 10 mmHg blood pressure increasement and 0.03 mmol/L incremental SUA rise of mild hyperuricemia rat model, both ischemic types of injury and renal injury were found by a crystal-independent mechanism. Takahiko et al.[38] further documented a manifested results that uric acid dose dependently inhibited the endothelial function by decreasing the vasodilatory response of aortic artery rings to acetylcholine, and the abnormal elevation of uric acid may be a causal cause of other metabolic syndromes such as type II diabetes, hypertriglyceridemia, obesity and et al. Considering the symptomless may indicate the early stage of hyperuricemia or even the initial state preceding gouty arthritis, and further reduce the hyperuricemia-related comorbidities can minimize the potential bias induced by the collinearity of hyperuricemia, dyslipidemia, pathoglycemia, hypertension, and et al. These results may further strength the importance that uric-acid-related study among the asymptomatic hyperuricemia patients may better reveal the natural association between SUA exposure and the risk of cardio-cerebrovascular diseases.

Results from our study showed that although the overall adjusted HR showed no significantly increased risk of CVD with asymptomatic hyperuricemia, nevertheless, at least quartile of asymptomatic hyperuricemia patients demonstrated a substantial increased incidence risk of CVD when compared with normouricemia population. These results consistent with previous studies, Bickel C et al[33] found an increased mortality risk of coronary artery disease in both gender (female: HR:1.30, 95%CI: 1.14-1.36, male: HR1.39, 95%CI: 1.21-1.59) when the highest quartile stratum of SUA compared with the lowest; Demonstrated by Lin GM and et al[39], significantly increased risk of cardiac mortality (HR: 2.08, 95%CI: 1.19-3.62) and risk of overall mortality (HR: 1.68, 95%CI: 1.10-2.57) were observed when the highest quartile (>487 μmol/L) compared with the lowest quartile. And these evidences may documents the highlights that asymptomatic hyperuricemia linking to the adverse outcome of cardiovascular may have a clear borderline. Moreover, our results also suggested that the SUA-related injury tolerance threshold for the cardio-cerebrovascular system was much smaller than that for the renal system [40-43]. These findings may indicate the fact that the cardio-cerebrovascular systems may much susceptible and fragile to SUA exposure when compared with kidney. Intensity from the evidence seen above, ultra-low therapy (ULT) which is commonly used for acute gout attack, monosodium urate deposition , and et al.[44] was worthy of consideration for use in patients with asymptomatic hyperuricemia, particularly for those with a higher exposure level of SUA[45-47]. Nevertheless, given the discrepancies and lacking evidence of the side-effects/benefit ratio of the ULT in preventing cardiovascular events. Currently, ULT treatment is still remaining uncertain for recommendation in asymptomatic hyperuricemia patients, even for CVD at-risk population. Thus, prospective cohort study can replicate our results and large interventional trials involves in evaluating the effects of ULT on cardiovascular disease precaution were still strongly warranted.

One of the major advantages of our study is its prospective perspective of the study design. By evaluating the asymptomatic hyperuricemia population under comorbidities condition or not, our study was able to quantitatively control for some of the major potential confounders, such as type II diabetes, hypertension, dyslipidemia, and et al. Statistic analyzes further adjusted the bio-indicators linked to hyperuricemia substantially improve the reliability of our study. However, limitations of our study should also be mentioned. First, considering the relatively short follow-up period in our study (maximum duration of 91 months), the predictive efficiency could have been affected by the small sample size in subgroups analyze, particularly for the non-comorbidity’s subgroup analyze. However, The Jinchang Cohort is an on-going prospective cohort study, and the second-round follow-up will be completed at the end of 2020 with a duration of 10 years; thus, our results could be further improved in subsequent studies. Second, all participants in our study came from a relatively solid population and region that may not be fully representative of the total Chinese population. However, a demographic differential was not found when compared with national data, which suggests our results may not have been influenced by this potential bias.

In summary, in this prospective cohort study of CVD risk and asymptomatic hyperuricemia, we found a significantly increased CVD risk associated with higher SUA exposure level of asymptomatic hyperuricemia in both genders. And this substantial association was more evidential in female and population aged over 50. The observed association between SUA exposure and CVD risk was independent from the hyperuricemia-related comorbidities and cannot be easily explained by selection bias, differential misclassification of exposure or known confounding. These results may suggest the necessity of pharmacotherapy or intervention for the ultra-high SUA exposed asymptomatic hyperuricemia patients for the precaution of cardiovascular diseases, a 30 mmol/L abatement of SUA could decreased the ASIR of CVD by 2 to 3 times in the high-level SUA exposure population.

Ethics approval and consent to participate

All appropriate ethical and regulatory permissions were obtained before the initiation of our study. This study was approved by the Ethics Committees of Lanzhou University and the Jinchuan Nonferrous Metal Corporation, conforming to the ethical principles of the Declaration of Helsinki 2008 (sixth revision). All participants signed written informed consent before enrolling in the study.

Consent for publication

This study does not contain any personal privacy information in any form whatsoever (including any individual details, images or videos). All the information provided by the participants was anonymized during the entire data analysis, paper writing and review process. The author assumes full responsibility for any release or disclosure related to this paper on behalf of any and all co-authors.

Availability of data and materials

The datasets generated during the current study are not publicly available due to the protection of privacy of all enrolled participants. However, qualified scientific and medical researchers can request the data that underlie the results reported in this article. Proposals for data will be evaluated and approved by corresponding author in her sole discretion. All approved researchers must sign a data access agreement before accessing the data by bleaching all identification information of all participants.

Competing interests

The author(s) declare(s) that there is no potential conflict of interest with respect to the research, authorship, and/or publication in this paper.

Sources of Funding

This work was supported by several grants: Belt and Road Special Project of Lanzhou University (2018ldbrzd008), Natural Science Foundation of China (No. 81673248), and the National Institutes of Health (U.S.) (NIH Grant Number: 1R01ES029082). The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.

Authors’ contributions

Yana Bai had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept, design,data collection, the provision of the study materials and participant recruitment: Tongzhang Zheng, Desheng Zhang, Chun Ying, Xiaowei Ren, Juansheng Li, Na Li, and Yana Bai.

Acquisition, analysis, or interpretation of data: Zhiyuan Cheng, Jingli Yang, Tongzhang Zheng, Yana Ba.

Drafting of the manuscript: Zhiyuan Cheng, Tongzhang Zheng, Yana Ba.

Data analysis discussion and consulting: Dian Shi, Xiaobin Hu, Shan Zheng, and Minzhen Wang

Statistical analysis: Zhiyuan Cheng and Yana Ba

Obtained funding: Yana Ba and Tongzhang Zheng

All authors contributed to the interpretation of data, critical review, editing, revision of the manuscript drafts. The final version for submission was approved by all coauthors.

Acknowledgments

We would like to sincerely thank all of the participants and researchers from Jinchang Nonferrous Metal Company, the Worker's Hospital of JNMC, Brown University, and Lanzhou University in the Jinchang Cohort Study for their contributions, collaboration, and enthusiasm.

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Table 1. Baseline characteristics of selected cohort population, stratified by gender
Demographic	Total population		MS-free population*
	Male	Female	Male	Female
	n (freq %)	n (freq %)	n (freq %)	n (freq %)
Age (years), n (%)
<30	1,513 (8.21)	633 (5.48)	1,137 (12.52)	533 (8.29)
30~	3,026 (16.42)	1,436 (12.44)	1,926 (21.20)	1,188 (18.49)
40~	6,850 (37.17)	5,047 (43.72)	3,573 (39.33)	3,349 (52.12)
50~	2,964 (16.08)	2,171 (18.81)	1,105 (12.16)	860 (13.38)
60~	2,476 (13.43)	1,763 (15.27)	859 (9.46)	421 (6.55)
70~	1,319 (7.16)	472 (4.09)	402 (4.43)	72 (1.12)
≥80	283 (1.54)	21 (0.18)	82 (0.90)	3 (0.05)
Education, n (%)
Uneducated	464 (2.52)	546 (4.73)	164 (1.81)	131 (2.04)
High school or less	11,495 (62.37)	7,210 (62.48)	5,220 (57.48)	3,575 (55.66)
Undergraduate	6,314 (34.26)	3,701 (32.07)	3,607 (39.72)	2,650 (41.26)
Graduated or above	156 (0.85)	83 (0.72)	91 (1.00)	67 (1.04)
Smoking index (pack-year), n (%)**
No	5,284 (28.67)	11,412 (98.87)	2,708 (29.81)	6,364 (99.04)
0~6.62	3,103 (16.84)	76 (0.66)	1,838 (20.23)	37 (0.58)
6.63~14.07	3,272 (17.75)	28 (0.24)	1,661 (18.28)	13 (0.20)
14.08~23.28	3,150 (17.09)	19 (0.16)	1,509 (16.61)	9 (0.14)
≥23.29	3,622 (19.65)	8 (0.07)	1,368 (15.06)	3 (0.05)
Alcohol index (kilogram-year), n (%)†
No	11,324 (61.44)	11,217 (97.18)	5,908 (65.04)	6,244 (97.17)
0~72.26	1,548 (8.40)	269 (2.33)	896 (9.86)	155 (2.41)
72.27~167.53	1,743 (9.46)	34 (0.29)	801 (8.82)	20 (0.31)
167.54~380.11	1,877 (10.18)	14 (0.12)	803 (8.84)	3 (0.05)
≥380.12	1,939 (10.52)	9 (0.08)	676 (7.44)	4 (0.06)
Exercise, n (%) ‡
No	2,103 (11.41)	1,033 (8.95)	1,089 (11.99)	650 (10.12)
Occasionally	7,939 (43.07)	4,648 (40.27)	4,201 (46.25)	2,896 (45.07)
Often	8,389 (45.52)	5,862 (50.78)	3,794 (41.77)	2,880 (44.82)
BMI Categories, n (%)
≤18.5	600 (3.26)	785 (6.80)	448 (4.93)	615 (9.57)
18.5~	8,312 (45.10)	7,088 (61.41)	4,823 (53.09)	4,432 (68.97)
24.0~	7,707 (41.82)	2,908 (25.19)	3,277 (36.07)	1,193 (18.57)
≥28	1,812 (9.83)	762 (6.60)	536 (5.90)	186 (2.89)
Total Cholesterol (mmol/L) §	4.69±0.90	4.76±0.88	4.26±0.56	4.31±0.54
HDL cholesterol (mmol/L)	1.32±0.37	1.49±0.40	1.32±0.36	1.52±0.38
LDL cholesterol (mmol/L)	2.89±0.95	2.66±0.90	2.66±0.72	2.49±0.72
Triglyceride (mmol/L)	1.97±1.46	1.52±1.00	1.63±0.98	1.25±0.69
Serum fasting blood-glucose (mmol/L)	5.71±1.71	5.44±1.31	5.23±0.67	5.10±0.58
Serum Lactate Dehydrogenase-L (U/L)	195.46±41.21	192.04±37.83	190.49±39.55	182.71±34.75
Serum Uric Acid (μmol/L)	348.21±73.91	270.47±64.66	336.41±69.40	254.78±57.45

*: MS-free population refers to those population did not have any metabolic syndromes except for hyperuricemia at baseline.
**: Smoking index was categorized by the quartile distribution of pack-year based on the distribution of CVD-free population at baseline.
†: Alcohol index was categorized by the quartile distribution of alcohol intake weight based on the distribution of the CVD-free population at baseline.
‡: Exercise last more than 30 minutes was defined as a valid exercise; Occasionally exercise was defined as exercise less than 3 times per week; Often exercise is defined as at least 3 times per week, each time lasts more than 30 minutes.
§: Bio-chemistry data related to metabolism were presented as mean ± standard deviation in each subgroup.

Table 2. Overall CHD, stroke, and CVD risk associated with hyperuricemia with or without hyperuricemia-related comorbidities
		With hyperuricemia-related comorbidities					Without hyperuricemia-related comorbidities
Outcomes	Hyperuricemia	Incidence cases, n	Total, n	*ASIR (1/100k)**	HR^† (95%)	HR^‡ (95%)	Incidence cases, n	Total, n	*ASIR (1/100k)**	HR^† (95%)	HR^‡ (95%)
CHD	No	550	24,688	471.99	1.00	1.00	156	13,671	241.76	1.00	1.00
CHD	Yes	151	4,585	597.74	1.29 (1.11-1.50)	1.07 (0.91-1.25)	32	1,807	335.19	1.34 (0.97-1.84)	1.11 (0.79-1.55)
Stroke	No	321	25,238	329.47	1.00	1.00	82	13,671	167.08	1.00	1.00
Stroke	Yes	96	4,640	418.34	1.41 (1.16-1.71)	1.18 (0.95-1.44)	21	1,839	241.93	1.66 (1.11-2.49)	1.20 (0.79-1.84)
CVD	No	831	25,238	657.60	1.00	1.00	231	13,671	427.99	1.00	1.00
CVD	Yes	231	4,836	812.01	1.31 (1.16-1.48)	1.08 (0.94-1.23)	50	1,839	576.03	1.41 (1.09-0.82)	1.12 (0.85-1.46)

*: Age-standardized Incidence Rate: Standardized by The Sixth National Population Census of the People’s Republic of China. 2010. Available at: http://www.stats.gov.cn/tjsj/pcsj/rkpc/6rp/indexch.htm.
†: Represent the crude hazard ratio
‡: Hazard ratio were adjusted by Age at diagnosis(<30, 30-39, 40-49, 50-59, 60-69, >=70), gender (male/female), BMIs (<18.5, 18.5-23.9, 24.0-27.9, >=28.0), physical exercise (no, occasionally, often), smoking index, pack-year (no smoking, 0-6.3, 6.4-14.0, 14.1-23.2, >=23.3), lifetime total alcohol intake, kilogram-year (no drinking, 0-72.2, 72.3-167.5, 167.5-380.1, >=380.1), diabetes status (yes/no), hypertension stage (normal, elevated, stage I, stage II), triglyceride (<1.80 mmol/L, 1.80~2.20 mmol/L, >=2.20 mmol/L), high-density lipoprotein (Male: <1.16 mmol/L, 1.16-1.42 mmol/L, >=1.43 mmol/L, Female: <1.29 mmol/L, 1.29-1.55 mmol/L, >=1.56 mmol/L) and low-density lipoprotein (<2.60 mmol/L, 2.60-4.11 mmol/L, >=4.12 mmol/L).

Table 3. Age-standardized incidence rate and hazard ratio of CHD and stroke associated with different SUA stratums, total population at baseline
	CHD incidence					Stroke incidence
SUA stratums	Incidence cases, n	Total, n	*ASIR (1/100k)**	HR^† (95%)	HR^‡ (95%)	Incidence cases, n	Total, n	*ASIR (1/100k)**	HR^† (95%)	HR^‡ (95%)
Normal	553	25,783	444.87	1.00	1.00	335	26,336	269.50	1.00	1.00
Quartile 1	26	803	664.47	1.21 (0.87-1.69)	1.11 (0.79-1.54)	15	829	383.35	1.12 (0.73-1.73)	1.02 (0.66-1.58)
Quartile 2	42	901	943.62	1.70 (1.31-2.21)	1.45 (1.11-1.90)	21	943	471.81	1.36 (0.94-1.97)	1.16 (0.80-1.69)
Quartile 3	26	905	591.67	1.07 (0.77-1.49)	0.87 (0.62-1.21)	16	931	364.11	1.05 (0.70-1.61)	0.85 (0.55-1.30)
Quartile 4	54	881	1223.60	2.17 (1.71-2.74)	1.70 (1.34-2.16)	30	935	679.78	1.96 (1.43-2.68)	1.55 (1.13-2.13)

Table 4. Age-standardized incidence rate and hazard ratio of CHD and stroke associated with different SUA stratums, male population with comorbidities at baseline
	CHD incidence					Stroke incidence
SUA stratums	Incidence cases, n	Total, n	*ASIR (1/100k)**	HR^† (95%)	HR^‡ (95%)	Incidence cases, n	Total, n	*ASIR (1/100k)**	HR^† (95%)	HR^‡ (95%)
Normal	337	15,733	453.81	1.00	1.00	233	15,733	313.76	1.00	1.00
Quartile 1	16	626	541.51	0.98 (0.65-1.50)	0.98 (0.65-1.50)	12	626	406.13	1.04 (0.64-1.69)	1.03 (0.63-1.68)
Quartile 2	23	697	699.12	1.28 (0.90-1.93)	1.20 (0.84-1.72)	16	697	486.35	1.24 (0.81-1.90)	1.17 (0.76-1.80)
Quartile 3	19	687	585.94	1.05 (0.71-1.54)	0.93 (0.63-1.38)	12	687	370.07	0.92 (0.57-1.50)	0.83 (0.51-1.36)
Quartile 4	41	688	1262.56	2.13 (1.62-2.79)	1.94 (1.47-2.56)	20	688	615.88	1.47 (1.01-2.15)	1.34 (0.91-1.97)

Table 5. Age-standardized incidence rate and hazard ratio of CHD and Stroke associated with different SUA stratums, female population with comorbidities at baseline
	CHD incidence					Stroke incidence
SUA stratums	Incidence cases, n	Total, n	*ASIR (1/100k)**	HR^† (95%)	HR^‡ (95%)	Incidence cases, n	Total, n	*ASIR (1/100k)**	HR^† (95%)	HR^‡ (95%)
Normal	216	10,603	431.60	1.00	1.00	102	10603	203.81	1.00	1.00
Quartile 1	10	203	1043.67	1.79 (1.05-3.05)	1.38 (0.81-2.36)	3	203	313.10	1.13 (0.43-2.96)	0.89 (0.34-2.36)
Quartile 2	19	246	1636.35	2.80 (1.89-4.16)	1.80 (1.21-2.70)	5	246	430.62	1.56 (0.73-3.31)	1.06 (0.50-2.28)
Quartile 3	7	244	607.81	1.08 (0.57-2.03)	0.67 (0.35-1.27)	4	244	347.32	1.28 (0.55-2.96)	0.86 (0.37-2.02)
Quartile 4	13	247	1115.08	2.12 (1.33-3.39)	1.71 (1.03-2.35)	10	247	857.75	3.48 (2.02-6.00)	2.02 (1.14-3.58)

Table 6. Age-standardized incidence rate and hazard ratio of CVD incidence associated with different SUA stratums, stratified by age groups
	<50				50-69				>=70
SUA stratums	Incidence cases, n	Total, n	*ASIR (1/100k)**	HR† (95%)	Incidence cases, n	Total, n	*ASIR (1/100k)**	HR† (95%)	Incidence cases, n	Total, n	*ASIR (1/100k)**	HR† (95%)
Normal	125	16,797	157.67	1.00	468	7,916	1252.56	1.00	251	1,623	3276.52	1.00
Quartile 1	5	424	249.84	1.20 (0.56-2.55)	25	323	1639.82	1.10 (0.78-1.54)	9	82	2325.34	0.59 (0.33-1.03)
Quartile 2	2	467	90.73	0.45 (0.14-1.46)	38	361	2230.15	1.39 (1.05-1.83)	20	115	3684.60	0.97 (0.65-1.44)
Quartile 3	4	435	194.82	0.86 (0.37-2.00)	25	393	1347.74	0.86 (0.61-1.21)	10	103	2056.94	0.52 (0.31-0.89)
Quartile 4	3	382	166.39	0.73 (0.28-1.92)	38	381	2113.08	1.43 (1.08-1.89)	39	172	4803.90	1.24 (1.13-1.47)

*: Age-standardized Incidence Rate: Standardized by The Sixth National Population Census of the People’s Republic of China. 2010. Available at: http://www.stats.gov.cn/tjsj/pcsj/rkpc/6rp/indexch.htm.
†: Hazard ratio were adjusted by Age at diagnosis(<30, 30-39, 40-49, 50-59, 60-69, >=70), gender (male/female), BMIs (<18.5, 18.5-23.9, 24.0-27.9, >=28.0), physical exercise (no, occasionally, often), smoking index, pack-year (no smoking, 0-6.3, 6.4-14.0, 14.1-23.2, >=23.3), lifetime total alcohol intake, kilogram-year (no drinking, 0-72.2, 72.3-167.5, 167.5-380.1, >=380.1), diabetes status (yes/no), hypertension stage (normal, elevated, stage I, stage II), triglyceride (<1.80 mmol/L, 1.80~2.20 mmol/L, >=2.20 mmol/L), high-density lipoprotein (Male: <1.16 mmol/L, 1.16-1.42 mmol/L, >=1.43 mmol/L, Female: <1.29 mmol/L, 1.29-1.55 mmol/L, >=1.56 mmol/L) and low-density lipoprotein (<2.60 mmol/L, 2.60-4.11 mmol/L, >=4.12 mmol/L).

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High-level Exposure of Uric Acid in Asymptomatic Hyperuricemia Could Be An Isolated Risk Factors of Cardio-Cerebrovascular Diseases: A Prospective Cohort Study

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