Abstract
Background
Serum uric acid (UA) is involved in the development of hypertension. However, its impact on mortality in hypertension remains unclear. We aimed to assess the association of cardiovascular and all-cause mortality with UA in a hypertensive population.
Material/Methods
This study included 15 583 hypertensive patients from the NHANES study during 1999–2014. Weighted Cox regression analyses and cubic spline fitting were used to assess the relationship between UA and mortality risk.
Results
Over a median follow-up of 7.4 years (116 351 person-years), a total of 3291 deaths occurred. Mortality was examined according to 5 predefined UA levels: ≤3.5, 3.5–5, 5–6, 6–7.5, and >7.5 mg/dL. In multivariable analysis with 5–6 mg/dL as a reference, the hazard ratios (95% confidence interval) of total mortality across the 5 groups were 1.40 (1.05–1.88), 1.08 (0.95–1.21), 1.00 (reference), 1.14 (1.02–1.29), and 1.74 (1.50–2.02), respectively. According to a restricted cubic spline, we noted a U-shaped relationship between UA and total mortality. The U-shaped relationship between UA and cardiovascular mortality remained in both females and males. The increased cardiovascular mortality in the lowest and highest UA groups was attributed to stroke and heart-specific mortality, respectively. However, serum UA was not significantly associated with cancer mortality.
Conclusions
Our findings showed a U-shaped relationship between serum UA levels and total and cardiovascular mortality in patients with hypertension. Furthermore, low UA was associated with stroke mortality, while higher UA was associated with heart-related mortality. Further research is needed to identify the potential mechanisms of UA in hypertension.
Keywords: Antioxidant Response Elements, Cardiovascular Diseases, Hypertension, Oxidative Stress, Uric Acid
Background
Hypertension is a well-known and strong risk factor for cardiovascular diseases (CVD), which are the major cause of mortality [1,2]. Uric acid (UA), an end-product metabolite of purine nucleotide in great apes and humans, has been considered as one of the cardiometabolic risk factors in CVD, diabetes, and hypertension [3–5]. Increased serum UA is one of the strongest factors for hypertensive development [6]. Experimental results support that raising uric acid levels causes hypertension in rats [7]. Moreover, pilot studies indicate that lowering serum UA levels can decrease blood pressure in hypertensive patients [8–10].
Interestingly, numerous experimental studies demonstrated that uric acid exerts a beneficial role due to its antioxidant properties [3,11]. It has been demonstrated that uric acid explains about 50% of the total antioxidant capacity in vivo [3]. However, under the setting of pathological acidic or hydrophobic milieu, such as atherosclerotic plaque and cytoplasm, UA becomes a pro-oxidant factor that promotes redox disorder and exerts a deleterious effect in the development and progression of cardiovascular disease [3,11].
Currently, the association of UA levels with adverse outcomes is largely controversial. So far, previous studies noted positive [12–14], negative [15,16], and neutral [17,18] relationships between serum UA concentrations and risks of cardiovascular and total mortality in general adult populations, CVD, and renal disease. Insufficient sample size and variations in study populations and analysis strategies may partly account for the heterogenicity. Two recent large population-based cohorts noted a U-shaped association of total mortality with serum UA in general adult populations [19,20]. The increased mortality risk in adults with hypo- or hyper-uricemia suggests the complex biological roles of UA in humans. In particular, the benefit and harm of strict hypouricemic therapy should be considered.
However, the evidence regarding the link between UA levels and cardiovascular mortality in hypertensive individuals is unclear. To identify this association may provide new insights into the management of UA levels in hypertension, especially the intensive anti-uric acid therapy for hypertensive patients with hyperuricemia. This study aimed to assess the association of serum UA with all-cause and cause-specific mortality among 15 583 participants with hypertension.
Material and methods
Study Population and Design
Our analysis was based on a dataset from a nationally representative study, the National Health and Nutrition Examination Surveys (NHANES) of the United States [21], which is a stratified and multistage probability-sampling study to assess the characteristics of the nationally non-institutionalized population. The protocols of NHANES have been reported previously [21–23]. The dataset has been built since 1999 and is released in 2-year survey cycles. The protocols and procedures of this study were agreed to by the Research Ethics Review Board of the Centers of Disease Control and Prevention of the United States (Protocol Number. 98–12, 2005–06, and 2011–17). All participants provided written informed consent. The NHANES datasets are available to all researchers to reproduce the results. (https://www.cdc.gov/nchs/index.htm) [21].
We performed the primary analysis using the datasets of 8 two-year survey cycles from 1999–2000 to 2013–2014. In those cycles, there were 38 943 participants aged ≥20 years old with serum UA measurements. Hypertension was defined by blood pressure-lowering treatment and systolic/diastolic blood pressure ≥140/90 mmHg at baseline [21]. We excluded individuals without hypertension (n=22 908). Given the possibility of reverse causality, we further excluded individuals with hypouricemic therapy in the preceding month at baseline (n= 440). Further, we excluded individuals with missing information on mortality status (n=12). In total, 15 583 hypertensive individuals were included for analysis. The flow of the study is presented in Figure 1.
Figure 1.
Flow diagram of this study.
Serum Uric Acid Measurement
The exposure variable of interest was serum uric acid concentrations as tested by the Roche Hitachi Model 917/704 multichannel analyzer, Beckman Synchron LX20, or Beckman UniCel® DxC800 Synchron, as described in prior studies [19]. The protocols have been validated. In brief, UA was oxidized with specific enzyme uricase to generate allantoin and H2O2. The H2O2 further reacted with 2,4,6-tribromo-3-hydroxybenzoic acid and 4-aminophenazone to form quinone-imine dye and hydrogen bromide [19]. The intensity of red color was used to quantify results. The coefficient of variation for UA measurements in each cycle was approximately 2%, suggesting good repeatability. All laboratory variables were assessed by validated protocols and procedures. The details were available at https://www.cdc.gov/nchs/nhanes.
Covariates
Demographic and lifestyle factors at baseline, including age, gender, race/ethnicity, smoke, alcohol intake, and physical activity, and family income level were recorded during personal interviews via standardized questionnaires [21,22]. Physical examinations were performed according to standardized protocols and processes at a mobile examination center. Body mass index (BMI) was calculated as weight (kilograms) divided by height (meters) squared [21]. Average systolic blood pressure and diastolic pressure were assessed as the means of 3 measurements. The detection of biosamples was conducted in special central laboratories with validated methods. Laboratory determinations of triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), glycosylated hemoglobin (HbA1c), and creatinine were detected in each survey cycle [21]. C-reactive protein (CRP) was measured in NHANES 1999–2006. The Chronic Kidney Disease Epidemiology Collaboration method was applied to calculate the estimated glomerular filtration rate (eGFR) [21]. History of diseases and prescription agents in the preceding 30 days was also solicited at a screening interview. Diabetes mellitus was defined as taking diabetic medication or HbA1c ≥6.5% [21]. Emphysema or chronic bronchitis was identified as chronic obstructive pulmonary disease (COPD). Malignant disease was identified according to self-report [21]. Antihypertensive agents were categorized as angiotensin-converting enzyme inhibitor/angiotensin II receptor antagonist (ACEI/ARBs), β-blocker, calcium-channel blockers (CCB), diuretics, and other antihypertensive drugs [4].
Outcomes
The outcomes of this study were total and cause-specific mortality. All participants were linked to the National Death Index in the National Center for Health Statistics of the US [21,22]. Mortality data were available through December 31, 2015. Using the codes of International Classification of Diseases 10th Revision (ICD-10), cause-specific mortality was categorized as death caused by CVD (heart disease: I00–I09, I11, I13, and I20–I51; stroke: I60–I69), and malignant neoplasms (C00–C97) [21].
Statistical Analysis
The statistical analyses were conducted following the analytical guidelines. Sampling weights, the masked variance of the primary sampling unit, and strata were used to explain the complex study design and acquire nationally representative estimates [21]. Variables are presented as weighted means (standard error, SE) and proportions unless otherwise noted. We used weighted linear regression or logistics regression to assess the difference across serum UA groups, when necessary. Restricted cubic spline based on Cox regression was applied to show the link between serum UA and total mortality, after adjustment for age, sex, race, smoking, alcohol intake, exercise, poverty-to-income ratio (PIR), BMI, cancer, COPD, diabetes, cardiovascular disease, TG, TC, HDL-C, eGFR, lipid-lowering agents, antiplatelet treatment, ACEI/ARBs, β-blocker, CCB, diuretics, and other antihypertensive drugs [21,24]. All hypertensive patients were stratified into 5 prespecified groups according to uric acid levels: ≤3.5, 3.5–5, 5–6, 6–7.5, and >7.5 mg/dL. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated by crude and multivariable Cox regression models for the relationship between UA and total or cause-specific mortality, with UA 5–6 mg/dL as a reference. Three multivariable models were applied. Model 1 was adjusted for demographic variables, including age, sex, and race/ethnicity (non-Hispanic white, black, Hispanic-Mexican, or other). Model 2 was further adjusted for PIR, BMI, smoking status, alcohol intakes, physical activity, TG, TC, HDL-C, eGFR, CVD, diabetes, COPD, and cancer. Model 3 was additionally adjusted for lipid-lowering agents, antiplatelet drugs, ACEI/ARBs, β-blocker, CCB, diuretics, and other antihypertensive drugs [21]. In secondary analyses, the association between baseline UA and all-cause, cardiovascular, heart-specific, and stroke mortality was ascertained in subgroups by age (<65 and ≥65 years), sex (female and male), race (non-Hispanic white and non-white), BMI (<30 and ≥30 kg/m2), eGFR (<60 and ≥60 mL/min/1.73 m2), and anti-hypertension medications (yes/no), with the fully adjusted model except for stratification factors [21]. We also assessed whether the main results were altered after additional adjustment for inflammation marker CRP in NHANES 1999–2006. All tests with a 2-sided P value <0.05 were considered significant using Stata (version 15) software.
Results
Baseline Characteristics
Overall, 15 583 participants with hypertension (7524 men and 8059 women) were identified in the dataset from NHANES 1999–2000 to 2013–2014 cycles (Figure 1). The mean age was 55.8 years, and 47.6% were males in the study population. The median of serum UA level was 5.7 mg/dL (interquartile range [IQR], 4.8–6.7 mg/dL). Baseline characteristics of hypertensive patients across the strata of uric acid (≤3.5, 3.5–5, 5–6, 6–7.5, and >7.5 mg/dL) are shown in Table 1. Compared to those with lower UA, the participants with higher levels of UA were older and mostly males, and had higher alcohol consumption, TG, and CRP levels. The higher-UA groups were more likely to have adiposity, prior CVD, and to be taking antihypertensive agents. They also had less smoking and vigorous exercise, as well as lower eGFR.
Table 1.
Characteristics of patients with hypertension in NHANES 1999–2014 at baseline.
| Variables | Serum uric acid, mg/dl | ||||
|---|---|---|---|---|---|
| ≤3.5 | 3.5–5.0 | 5.0–6.0 | 6.0–7.5 | >7.5 | |
| Age,year | 55.5 (0.93) | 56.8 (0.33) | 57.2 (0.33) | 56.4 (0.34) | 57.4 (0.52) |
| Male, % | 12.63 | 26.07 | 48.26 | 62.6 | 69.67 |
| Race/ethnicity, % | |||||
| Hispanic-Mexican | 65.78 | 70.58 | 73.13 | 74.25 | 72.00 |
| Other ethnicity | 13.8 | 12.33 | 12.47 | 12.68 | 15.68 |
| Non-Hispanic White | 7.898 | 6.969 | 5.343 | 4.52 | 3.563 |
| Non-Hispanic Black | 12.52 | 10.12 | 9.065 | 8.554 | 8.756 |
| Poverty to income ratio | 2.6 (0.10) | 2.8 (0.04) | 3.0 (0.05) | 3.0 (0.04) | 2.9 (0.06) |
| Alcohol intakes, g | 2.6 (0.34) | 3.5 (0.28) | 5.8 (1.07) | 6.6 (0.53) | 6.7 (0.43) |
| Smoking status, % | |||||
| Never smoking | 52.69 | 52.46 | 50.87 | 46.78 | 44.37 |
| Former smoker | 25.51 | 27.01 | 30.03 | 34.39 | 38.36 |
| Current smoker | 21.8 | 20.54 | 19.1 | 18.83 | 17.27 |
| Physical activity, % | |||||
| Inactive | 49.84 | 49.49 | 49.52 | 50.13 | 54.03 |
| Moderate activity | 30.12 | 31.51 | 32.04 | 31.96 | 29.29 |
| Vigorous activity | 20.04 | 19.01 | 18.44 | 17.91 | 16.69 |
| BMI, kg/m2 | 26.5 (0.33) | 28.8 (0.12) | 30.4 (0.14) | 31.6 (0.13) | 32.7 (0.24) |
| Waist circumference, cm | 91.6 (0.79) | 98.2 (0.31) | 103.7 (0.31) | 107.5 (0.29) | 110.5 (0.51) |
| Systolic BP, mmHg | 136.5 (1.50) | 136.6 (0.40) | 135.3 (0.38) | 134.4 (0.42) | 134.5 (0.57) |
| Diastolic BP, mmHg | 73.7 (0.83) | 73.5 (0.34) | 73.8 (0.30) | 74.4 (0.31) | 73.2 (0.59) |
| Triglycerides, mmol/L | 1.6 (0.12) | 1.7 (0.03) | 1.8 (0.03) | 2.1 (0.04) | 2.4 (0.07) |
| Total cholesterol, mmol/L | 5.2 (0.06) | 5.2 (0.02) | 5.2 (0.03) | 5.2 (0.02) | 5.3 (0.04) |
| HDL-C, mmol/L | 1.6 (0.02) | 1.5 (0.01) | 1.4 (0.01) | 1.3 (0.01) | 1.2 (0.01) |
| eGFR,mL/min per 1.73 m2 | 95.8 (1.18) | 90.9 (0.44) | 86.0 (0.51) | 82.7 (0.47) | 74.7 (0.70) |
| Cretinine,umol/L | 67.0 (1.26) | 73.1 (0.85) | 81.5 (0.83) | 88.3 (0.63) | 102.3 (0.99) |
| C-reactive protein, mg/dL | 0.4 (0.04) | 0.5 (0.02) | 0.5 (0.02) | 0.5 (0.02) | 0.7 (0.03) |
| CVD, % | 12.95 | 14.13 | 15.44 | 17.94 | 24.69 |
| Diabetes, % | 16.84 | 17.33 | 16.37 | 17.75 | 21.74 |
| Cancer, % | 12.79 | 14.56 | 13.8 | 13.61 | 14.07 |
| COPD, % | 14.23 | 11.53 | 9.671 | 9.39 | 9.344 |
| Lowering lipid, % | 25.58 | 26.23 | 29.92 | 29.79 | 31.47 |
| Antiplatelet agents, % | 2.877 | 4.201 | 4.199 | 4.472 | 6.534 |
| Antihypertensive agents, % | 48.36 | 55.01 | 59.99 | 62.63 | 71.28 |
| ACEI/ARBs, % | 28.42 | 33.65 | 38.06 | 40.25 | 45.77 |
| Beta-blockers, % | 17.64 | 18.33 | 21.00 | 23.51 | 29.61 |
| Calcium-channel blockers, % | 16.23 | 16.05 | 17.02 | 17.26 | 19.64 |
| Diuretics, % | 12.07 | 19.05 | 24.86 | 30.62 | 47.22 |
| Other antihypertensive drugs, % | 2.649 | 4.087 | 4.856 | 6.475 | 10.13 |
All variables are shown as the weighted mean±standard error or proportion (%). BMI – body mass index; BP – blood pressure; HDL-C – high-density lipoprotein cholesterol; eGFR – estimated glomerular filtration rate; ACEI – angiotensin-converting enzyme inhibitor; ARBs – angiotensin II receptor antagonist; COPD – chronic obstructive pulmonary disease; CVD – cardiovascular disease.
Associations of UA with Total and Cause-specific Mortality
The median duration of follow-up was 7.4 (IQR, 4.1–11.3) years. Over 116 351 person-years of follow-up, 3291 deaths occurred among the 15 583 patients with hypertension, including 639 (19.4%) heart-related deaths and 630 (19.1%) cancer deaths. Among hypertensive participants in NHANES 1999–2006, 152 died due to stroke. The weighted mortality rates per 1000 person-years of follow-up are shown in Table 2, with 21.2 (95% CI, 20.3–22.1) for all-cause mortality, 3.9 (95% CI, 3.5–4.3) for heart-related and 4.1 (95% CI, 3.7–4.5) for cancer-related mortality, and 1.3 (95% CI 1.1–1.6) for stroke mortality. In multiple restricted cubic spline fitting, there was a U-shaped trend between UA and risks of total and cardiovascular mortality (Figure 2).
Table 2.
The relationship between serum uric acid and all-cause and cause-specific mortality in hypertensive patients.
| Uric acid, mg/dl | Person-years* | Events* | Mortality rate | Model1 | p Value | Model 2 | p Value | Model 3 | p Value |
|---|---|---|---|---|---|---|---|---|---|
| HR (95% CI) | HR (95% CI) | HR (95% CI) | |||||||
| All-cause mortality | 116350.6 | 3291 | 28.3 | ||||||
| ≤3.5 | 5241.8 | 130 | 24.8 | 1.40 (1.05–1.88) | 0.024 | 1.50 (1.09–2.07) | 0.014 | 1.47 (1.07–2.03) | 0.019 |
| 3.5–5.0 | 34376.8 | 838 | 24.4 | 1.08 (0.95–1.21) | 0.236 | 1.13 (0.98–1.29) | 0.090 | 1.12 (0.97–1.28) | 0.112 |
| 5.0–6.0 | 28414.9 | 721 | 25.4 | 1.00 (ref.) | 1.00 (ref.) | 1.00 (ref.) | |||
| 6.0–7.5 | 33643.8 | 964 | 28.7 | 1.14 (1.02–1.29) | 0.027 | 1.10 (0.96–1.27) | 0.168 | 1.09 (0.95–1.25) | 0.231 |
| >7.5 | 14673.3 | 638 | 43.5 | 1.74 (1.50–2.02) | 0.000 | 1.41 (1.19–1.67) | 0.000 | 1.35 (1.16–1.59) | 0.000 |
| CVD mortality** | 75196.8 | 622 | 8.3 | ||||||
| ≤3.5 | 3664.6 | 24 | 6.5 | 1.69 (1.06–2.68) | 0.027 | 1.92 (1.08–3.42) | 0.027 | 1.92 (1.08–3.42) | 0.027 |
| 3.5–5.0 | 23074.5 | 150 | 6.5 | 1.15 (0.82–1.60) | 0.409 | 1.27 (0.89–1.81) | 0.184 | 1.27 (0.88–1.81) | 0.194 |
| 5.0–6.0 | 18322.9 | 139 | 7.6 | 1.00 (ref.) | 1.00 (ref.) | 1.00 (ref.) | |||
| 6.0–7.5 | 21187.9 | 190 | 9.0 | 1.24 (0.98–1.59) | 0.076 | 1.25 (0.96–1.64) | 0.101 | 1.19 (0.92–1.55) | 0.191 |
| >7.5 | 8946.9 | 119 | 13.3 | 2.03 (1.50–2.74) | 0.000 | 1.52 (1.10–2.10) | 0.012 | 1.37 (1.00–1.90) | 0.053 |
| Heart-related mortality | 116350.6 | 639 | 5.5 | ||||||
| ≤3.5 | 5241.8 | 20 | 3.8 | 1.31 (0.79–2.16) | 0.296 | 1.31 (0.74–2.33) | 0.346 | 1.31 (0.73–2.36) | 0.361 |
| 3.5–5.0 | 34376.8 | 140 | 4.1 | 1.13 (0.82–1.56) | 0.464 | 1.17 (0.84–1.63) | 0.358 | 1.16 (0.84–1.62) | 0.364 |
| 5.0–6.0 | 28414.9 | 139 | 4.9 | 1.00 (ref.) | 1.00 (ref.) | 1.00 (ref.) | |||
| 6.0–7.5 | 33643.8 | 201 | 6.0 | 1.29 (1.02–1.64) | 0.036 | 1.24 (0.95–1.62) | 0.109 | 1.18 (0.91–1.52) | 0.218 |
| >7.5 | 14673.3 | 139 | 9.5 | 2.26 (1.73–2.94) | 0.000 | 1.64 (1.21–2.21) | 0.002 | 1.46 (1.10–1.95) | 0.010 |
| Stroke mortality** | 75196.8 | 152 | 2.0 | ||||||
| ≤3.5 | 3664.6 | 11 | 3.0 | 4.09 (1.86–9.01) | 0.001 | 4.32 (1.66–11.21) | 0.003 | 4.34 (1.66–11.35) | 0.003 |
| 3.5–5.0 | 23074.5 | 41 | 1.8 | 1.20 (0.69–2.08) | 0.503 | 1.35 (0.73–2.49) | 0.337 | 1.30 (0.71–2.39) | 0.393 |
| 5.0–6.0 | 18322.9 | 31 | 1.7 | 1.00 (ref.) | 1.00 (ref.) | 1.00 (ref.) | |||
| 6.0–7.5 | 21187.9 | 44 | 2.1 | 1.23 (0.64–2.36) | 0.520 | 1.34 (0.67–2.68) | 0.396 | 1.32 (0.67–2.58) | 0.413 |
| >7.5 | 8946.9 | 25 | 2.8 | 1.80 (0.89–3.64) | 0.100 | 1.40 (0.61–3.19) | 0.422 | 1.27 (0.54–3.01) | 0.574 |
| Cancer mortality | 116350.6 | 630 | 5.4 | ||||||
| ≤3.5 | 5241.8 | 31 | 5.9 | 1.68 (0.97–2.92) | 0.064 | 1.73 (0.98–3.04) | 0.060 | 1.72 (0.97–3.04) | 0.063 |
| 3.5–5.0 | 34376.8 | 162 | 4.7 | 1.07 (0.81–1.39) | 0.639 | 1.04 (0.78–1.40) | 0.785 | 1.05 (0.78–1.41) | 0.758 |
| 5.0–6.0 | 28414.9 | 148 | 5.2 | 1.00 (ref.) | 1.00 (ref.) | 1.00 (ref.) | |||
| 6.0–7.5 | 33643.8 | 179 | 5.3 | 1.15 (0.85–1.56) | 0.354 | 1.13 (0.83–1.54) | 0.434 | 1.12 (0.82–1.52) | 0.474 |
| >7.5 | 14673.3 | 110 | 7.5 | 1.37 (0.94–2.01) | 0.102 | 1.29 (0.86–1.94) | 0.220 | 1.26 (0.86–1.86) | 0.235 |
Unweighted values;
estimated in NHANES 1999–2006. Model 1 (n=15 583): adjusted for age, sex, and race/ethnicity. Mode 2 (n=15 159): additionally adjusted for PIR (<1.3, 1.3–3.5, ≥3.5, or missing), BMI (<18.5, 18.5–25, 25–30, or ≥30 kg/m2), smoking status, alcohol intake (none, <5, 5–30, ≥30 g/d, or missing), leisure physical activity, TG, TG, HDL-C, eGFR, diabetes, COPD, CVD, and cancer. Model 3 (n=15 159): additionally adjusted for lipid-lowing agents, antiplatelet treatment, ACEI/ARBs, β-blocker, CCB, diuretics, and other antihypertensive drugs.
Figure 2.
The non-linear associations between uric acid levels and all-cause and cardiovascular mortality. The restricted cubic spline shows the relationship between UA and all-cause (A) and cardiovascular (B) mortality risk. The fitting includes 5 knots: the 5th, 27.5th, 50th, 72.5th, and 95th percentiles. HR (95% CI) was estimated with multivariable Cox regression analysis after adjustment for Model 3. The solid and dashed lines represent point estimates and 95% CIs, respectively. The non-linear trend was significant for the relationship between UA and all-cause and cardiovascular mortality (P for non-linearity ≤0.035).
The relationships between serum UA levels and risks of all-cause, heart disease, stroke, and cancer-related mortality are shown in Table 2, assessed by several weighted multivariable Cox regression analyses with UA 5.0–6.0 mg/dL as reference. The age- and sex-adjusted HRs (95% CIs) of total mortality from ≤3.5 mg/dL to 3.5–5 mg/dL, 5–6 mg/dL, 6–7.5 mg/dL, and >7.5 mg/dL were 1.40 (1.05–1.88), 1.08 (0.95–1.21), 1.00 (reference), 1.14 (1.02–1.29), and 1.74 (1.50–2.02), respectively. The risks remained significant after adjusting for demographics, income, smoking, amateur sports activity, alcohol intakes, BMI, cancer, COPD, diabetes, cardiovascular disease, TG, TC, HDL-C, eGFR, lipid-lowering agents, antiplatelet treatment, ACEI/ARBs, β-blocker, CCB, diuretics, and other antihypertensive drugs. Compared with patients with UA 5–6 mg/dl, those with UA ≤3.5 and >7.5 mg/dL had an elevated risk of all-cause mortality, by 47% and 35%, respectively.
As expected, a similar trend of association of UA with cardiovascular mortality was noted (Table 2). In multivariable-adjusted model, the HRs (95% CI) of cardiovascular mortality from the lowest to the highest group were 1.92 (1.08–3.42), 1.27 (0.88–1.81), 1.00 (ref.), 1.19 (0.92–1.55), and 1.37 (1.00–1.90), respectively. Further, compared with patients with UA 5–6 mg/dl, the increased cardiovascular mortality in patients with UA ≤3.5 mg/dl was mainly due to stroke (HR 4.34, 95% CI 1.66–11.35), while the increased mortality in patients with UA >7.5 mg/dl was mainly due to ischemic heart disease (HR 1.46, 95% CI 1.10–1.95). However, neither lower serum UA nor higher UA was significantly related to cancer mortality.
In prespecified stratification analyses (Supplemenatry Tables 1–6), the associations of serum concentrations of UA with total and cardiovascular mortality were similar in the subgroups of hypertensive patients regarding sex (female versus male), eGFR (≥60 versus <60), and other subgroups. In the further sensitivity analysis, we assessed the relationship between UA and mortality in participants with CRP measurement. After additionally adjusting for CRP, the results did not alter significantly (Supplemenatry Table 7).
Discussion
In this nationally representative sample of hypertensive patients, both lower and higher serum UA levels were significantly associated with elevated risks of total and cardiovascular mortality after fully adjusting for potential confounders. This association remained statistically significant in males and females. Our findings highlight the significantly increased stroke mortality in patients with low UA (≤3.5mg/dL) and increased heart-specific mortality in patients with high UA levels (>7.5 mg/dl).
Previous observational studies suggested that serum UA is an independent predictor for the development from prehypertension to hypertension [4,6]. Compared with individuals with normal uric acid, hyperuricemic individuals with normal blood pressure had a more than 2-fold elevated risk of hypertension over a 5-year follow-up [4]. A prospective cohort study of 2757 Chinese hypertensive patients found that hyperuricemia significantly predicted increased cardiovascular and total mortality during the 6 years of follow-up compared with those with non-hyperuricemia. Although they distinguished between hyperuricemia and non-hyperuricemia, whether lower uric acid level had advantageous or disadvantageous effects in the progression of hypertension remained unclear [25]. To the best of our knowledge, the present study is the first to report a U-shaped association between serum UA and all-cause and CVD mortality in patients with hypertension independent of various potential confounders. The present results and those of others support that hyperuricemic individuals may be the ideal group to target to evaluate the role of uric acid-lowering treatment to prevent mortality risk in hypertensive patients [4,6,25]. Although our findings highlight the increased mortality risk in patients with low UA levels (<3.5 mg/dL), the benefits of intensive hypouricemic therapy should be rigorously assessed in clinical trials of anti-uric acid therapy.
The association of serum UA with mortality risk has been reported by numerous cohort studies, but results varied widely. Most studies only observed that higher UA was linearly associated with increased risks of total and cardiovascular mortality in the general population, and in patients with diabetes, kidney disease, and CVD [5,12–14,25]. Two small-cohort studies indicated that serum UA was inversely related to all-cause and CVD mortality in patients receiving hemodialysis and peritoneal dialysis [15,16]. The heterogeneous conclusions may be partly due to the discrepancy in subjects, clinical characteristics, sample size, grouping strategy, and adjustment for confounders [19]. Although the severity of renal disease and treatment may also influence the relationship, our limited simple size may hinder the power of the test. Grouping methods to estimate hazard ratios may also conceal the increased mortality in participants with low UA, such as tertiles or quartiles of UA, hyperuricemia (>6.5 mg/dL) or not, and per 1 mg/dL increase of UA. Use of predefined groups according to UA levels may be a good approach to identify the non-linear association.
Recently, several studies noted a U-shaped association of mortality risk with UA in the general population. According to the Taipei City Elderly Health Examination Program, which included 127 771 elderly adults, compared with UA 4–5 mg/dL, serum UA< 4 and ≥8 mg/dL independently predicted the elevated risks of cardiovascular and total mortality in elderly people, especially in participants with malnutrition [26]. Another prospective cohort study of 9118 general adults from the US also found a U-shaped relationship between UA levels and mortality risk [19]. Consistently, another cohort study, including 375 163 adults in South Korea, demonstrated that both low and high levels of serum UA were significantly related to higher all-cause and CVD mortality [20]. In the present study, a similar U-shaped relationship between UA and total and CVD mortality was observed in hypertensive patients. Interestingly, we found that the increased cardiovascular mortality in the lowest and highest UA groups was attributed to stroke and heart-specific mortality, respectively, which has not been previously reported. Indeed, the occurrence of stroke or ischemic heart disease has distinct pathophysiological mechanisms, such as poor blood pressure control and vulnerable atherosclerotic plaque, respectively. Although the difference was statistically insignificant, systolic blood pressure at baseline was higher in the low-UA groups, which may help explain our conclusions. Our findings show that uric acid plays complex roles in the regulation of blood pressure and plaque instability. However, the particular mechanism by which UA affects the progression of hypertension warrants further clarification.
The relationship between serum UA and cancer-related deaths was statistically insignificant in our analysis, consistent with the findings of Cho et al in the general population [20]. The heterogeneity of types of tumors may partly explain the neutral results, and more research with larger sample sizes is required.
The biological mechanism underlying this link remain unclear [19,27]. Endothelial dysfunction and arterial stiffness are thought to be early manifestations of vascular dysfunction in the development of prehypertension and hypertension [28]. UA is involved in the progression of endothelial dysfunction. Intracellular uric acid stimulates adenosine monophosphate dehydrogenase to inhibit the enzyme activity of adenosine monophosphate kinase and decreases endothelial NO synthase (eNOS) activity [29]. Treatment of hyperuricemia with allopurinol for 3 months resulted in a significant decrease in inflammation biomarkers [30]. High UA exposure activates the inflammatory cascade process via inducing NLRP3 inflammasome and interleukin-1β [19,31]. Experimental studies demonstrated that intracellular UA activates the generation of reactive oxygen species/reactive nitrogen species to aggravate endothelial dysfunction [29]. According to prior studies, UA may act as a crucial antioxidant molecule that takes 50% of the total antioxidant capacity. It has been suggested that high uric acid levels are an adaptive alteration to protect from atherosclerosis progression, due to its antioxidant function [3]. Also, lower uric acid levels may reflect the insufficient intake of purine-rich foods, which may indicate poor nutritional conditions, and a study observed lower UA level was associated with vitamin deficiency [26,32]. Those reports may partly explain the U-shaped relationship between UA and mortality. The potential mechanisms underlying this link need further investigation.
Strengths and Limitations
Our study has several limitations. First, the residual confounders unmeasured may not be completely ruled out. Second, the causality of this link between serum UA and mortality risk could not be determined because of the observational nature of the study, although prior experimental studies observed that UA-related metabolism activated inflammation and oxidative stress in the process of cardiovascular disease. Third, the enrolled participants in this study were US civilians, so the results extrapolated to other populations need further verification. Fourth, information on distinguishing primary and secondary hypertension was lacking in this community-based cohort, and further investigation in special hospital-based cohorts is warranted. This study may have some strengths. The NHANES study was a national sampling dataset that favored repeatability and generalization. The sample size and long-term follow-up provide favorable statistical effectiveness. We have adjusted for a variety of potential confounders, including lifestyle, laboratory data, chronic disease, and detailed information of antihypertensive agents, and the relationship between UA and all-cause and cardiovascular mortality remained significant.
Conclusions
Our findings suggest a U-shaped relationship between serum UA and risks of total and cardiovascular mortality in hypertensive patients. Both low and high levels of uric acid were independently associated with increased risks of cardiovascular mortality. Nonetheless, low UA may mainly increase stroke-related mortality, and high UA may mainly increase heart-related mortality. Further investigations are needed to elucidate the potential mechanisms and validate the role of uric acid in the progression of hypertension.
Supplementary Data
Supplementary Table 1.
Stratification analysis of the association between uric acid and mortality by sex.
| Uric acid, mg/dl | Female (n=7,850) | p Value | Male (n=7,309) | p Value |
|---|---|---|---|---|
| HR (95% CI) | HR (95% CI) | |||
| All-cause mortality | ||||
| ≤3.5 | 1.33 (0.93–1.91) | 0.118 | 2.46 (1.57–3.86) | 0.000 |
| 3.5–5.0 | 1.11 (0.90–1.35) | 0.322 | 1.17 (0.96–1.42) | 0.115 |
| 5.0–6.0 | 1 (ref.) | 1 (ref.) | ||
| 6.0–7.5 | 1.27 (1.04–1.56) | 0.022 | 0.97 (0.81–1.16) | 0.736 |
| >7.5 | 1.48 (1.18–1.85) | 0.001 | 1.29 (1.04–1.60) | 0.019 |
| CVD mortality* | ||||
| ≤3.5 | 2.28 (1.14–4.55) | 0.020 | 1.52 (0.45–5.14) | 0.491 |
| 3.5–5.0 | 1.23 (0.75–2.03) | 0.407 | 1.41 (0.92–2.17) | 0.112 |
| 5.0–6.0 | 1 (ref.) | 1 (ref.) | ||
| 6.0–7.5 | 1.48 (0.89–2.44) | 0.126 | 1.04 (0.70–1.54) | 0.849 |
| >7.5 | 1.56 (0.90–2.68) | 0.108 | 1.49 (0.92–2.42) | 0.105 |
| Heart-related mortality | ||||
| ≤3.5 | 1.34 (0.66–2.73) | 0.419 | 1.16 (0.27–5.08) | 0.840 |
| 3.5–5.0 | 1.02 (0.62–1.67) | 0.937 | 1.39 (0.92–2.09) | 0.114 |
| 5.0–6.0 | 1 (ref.) | 1 (ref.) | ||
| 6.0–7.5 | 1.28 (0.82–2.02) | 0.278 | 1.10 (0.77–1.57) | 0.611 |
| >7.5 | 1.47 (0.86–2.52) | 0.160 | 1.55 (1.04–2.31) | 0.032 |
| Stroke mortality* | ||||
| ≤3.5 | 2.28 (1.16–4.50) | 0.018 | 1.50 (0.13–17.07) | 0.741 |
| 3.5–5.0 | 1.21 (0.73–2.01) | 0.460 | 1.47 (0.58–3.76) | 0.411 |
| 5.0–6.0 | 1 (ref.) | 1 (ref.) | ||
| 6.0–7.5 | 1.39 (0.83–2.30) | 0.203 | 1.23 (0.47–3.22) | 0.665 |
| >7.5 | 1.36 (0.79–2.34) | 0.256 | 1.26 (0.35–4.60) | 0.719 |
Estimated in NHANES 1999–2006. Hazard ratio (95% confidence interval) was estimated via weighted cox regression analysis after adjustment for age (years, continuous), race/ethnicity (non-Hispanic white, black, Hispanic-Mexican, or other), poverty to income ratio (<1.3, 1.3–3.5, ≥3.5, or missing), body mass index (<18.5, 18.5–25, 25–30, or ≥30 kg/m2), smoking status, alcohol intake (no, <5, 5–30, ≥30 g/d, or missing), physical activity (inactive, moderate, or vigorous), TG, total cholesterol (mmol/L, continuous), high-density lipoprotein cholesterol (mmol/L, continuous), estimated glomerular filtration rate (mL/min/1.73 m2, continuous), cardiovascular diseases (no/yes), diabetes (no/yes), chronic obstructive pulmonary disease (no/yes), cancer (no/yes), lowing lipid agents (no/yes), antiplatelet treatment (no/yes), ACEI/ARBs (no/yes), β-blocker (no/yes), CCB (no/yes), diuretics (no/yes) and other antihypertensive drugs (no/yes).
Supplementary Table 2.
Stratification analysis by estimated glomerular filtration rate.
| Uric acid, mg/dl | Non-CKD (n=12,643) | p Value | CKD* (n=2,516) | p Value |
|---|---|---|---|---|
| HR (95% CI) | HR (95% CI) | |||
| All-cause mortality | ||||
| ≤3.5 | 1.42 (1.02–1.98) | 0.036 | 1.57 (0.77–3.21) | 0.211 |
| 3.5–5.0 | 1.09 (0.93–1.27) | 0.311 | 1.10 (0.86–1.41) | 0.435 |
| 5.0–6.0 | 1 (ref.) | 1 (ref.) | ||
| 6.0–7.5 | 0.99 (0.84–1.18) | 0.948 | 1.31 (1.06–1.62) | 0.013 |
| >7.5 | 1.37 (1.09–1.71) | 0.007 | 1.52 (1.21–1.90) | 0.000 |
| CVD mortality* | ||||
| ≤3.5 | 1.73 (0.94–3.21) | 0.078 | 4.95 (1.29–19.01) | 0.021 |
| 3.5–5.0 | 1.25 (0.81–1.93) | 0.308 | 1.32 (0.70–2.49) | 0.383 |
| 5.0–6.0 | 1 (ref.) | 1 (ref.) | ||
| 6.0–7.5 | 0.94 (0.65–1.35) | 0.731 | 1.69 (0.97–2.94) | 0.063 |
| >7.5 | 1.79 (1.06–3.00) | 0.029 | 1.43 (0.80–2.58) | 0.226 |
| Heart-related mortality | ||||
| ≤3.5 | 1.31 (0.67–2.55) | 0.421 | 1.49 (0.15–14.55) | 0.727 |
| 3.5–5.0 | 1.19 (0.78–1.80) | 0.420 | 1.12 (0.63–1.99) | 0.706 |
| 5.0–6.0 | 1 (ref.) | 1 (ref.) | ||
| 6.0–7.5 | 1.05 (0.78–1.43) | 0.731 | 1.43 (0.86–2.36) | 0.166 |
| >7.5 | 1.75 (1.11–2.77) | 0.017 | 1.57 (0.93–2.67) | 0.092 |
| Stroke mortality* | ||||
| ≤3.5 | 4.04 (1.32–12.44) | 0.016 | 13.12 (2.33–73.86) | 0.004 |
| 3.5–5.0 | 1.22 (0.55–2.70) | 0.625 | 1.04 (0.26–4.16) | 0.958 |
| 5.0–6.0 | 1 (ref.) | 1 (ref.) | ||
| 6.0–7.5 | 0.93 (0.37–2.32) | 0.878 | 2.23 (0.84–5.92) | 0.107 |
| >7.5 | 1.18 (0.37–3.77) | 0.775 | 1.50 (0.43–5.28) | 0.518 |
CKD was defined as estimated glomerular filtration rate less than 60 mL/min/1.73 m2;
estimated in NHANES 1999–2006. Hazard ratio (95% confidence interval) was estimated via weighted cox regression analysis after adjustment for age (years, continuous), sex (female or male), race/ethnicity (non-Hispanic white, black, Hispanic-Mexican, or other), poverty to income ratio (<1.3, 1.3–3.5, ≥3.5, or missing), body mass index (<18.5, 18.5–25, 25–30, or ≥30 kg/m2), smoking status, alcohol intake (no, <5, 5–30, ≥30g/d, or missing), physical activity (inactive, moderate, or vigorous), TG, total cholesterol (mmol/L, continuous), high-density lipoprotein cholesterol (mmol/L, continuous), cardiovascular diseases (no/yes), diabetes (no/yes), chronic obstructive pulmonary disease (no/yes), cancer (no/yes), lowing lipid agents (no/yes), antiplatelet treatment (no/yes), ACEI/ARBs (no/yes), β-blocker (no/yes), CCB (no/yes), diuretics (no/yes) and other antihypertensive drugs (no/yes).
Supplementary Table 3.
Stratification analysis by race/ethnicity.
| Uric acid, mg/dl | White (n=7,378) | p Value | Non-white (n=7,781) | p Value |
|---|---|---|---|---|
| HR (95% CI) | HR (95% CI) | |||
| All-cause mortality | ||||
| ≤3.5 | 1.82 (1.25–2.65) | 0.002 | 0.69 (0.47–1.02) | 0.064 |
| 3.5–5.0 | 1.19 (1.03–1.37) | 0.018 | 0.89 (0.71–1.12) | 0.316 |
| 5.0–6.0 | 1 (ref.) | 1 (ref.) | ||
| 6.0–7.5 | 1.11 (0.94–1.31) | 0.204 | 1.03 (0.85–1.24) | 0.798 |
| >7.5 | 1.42 (1.17–1.72) | 0.000 | 1.17 (0.90–1.5) | 0.237 |
| CVD mortality* | ||||
| ≤3.5 | 2.91 (1.62–5.22) | 0.001 | 0.53 (0.16–1.77) | 0.296 |
| 3.5–5.0 | 1.53 (1.02–2.28) | 0.039 | 0.58 (0.32–1.08) | 0.083 |
| 5.0–6.0 | 1 (ref.) | 1 (ref.) | ||
| 6.0–7.5 | 1.24 (0.88–1.74) | 0.216 | 0.94 (0.56–1.57) | 0.814 |
| >7.5 | 1.63 (1.08–2.47) | 0.022 | 0.72 (0.37–1.38) | 0.317 |
| Heart-related mortality | ||||
| ≤3.5 | 2.01 (1.07–3.77) | 0.029 | 0.32 (0.11–0.90) | 0.031 |
| 3.5–5.0 | 1.41 (0.97–2.06) | 0.072 | 0.59 (0.33–1.07) | 0.080 |
| 5.0–6.0 | 1 (ref.) | 1 (ref.) | ||
| 6.0–7.5 | 1.19 (0.86–1.67) | 0.294 | 1.06 (0.67–1.68) | 0.810 |
| >7.5 | 1.65 (1.16–2.34) | 0.006 | 0.95 (0.56–1.61) | 0.847 |
| Stroke mortality* | ||||
| ≤3.5 | 5.53 (1.79–17.1) | 0.004 | 2.01 (0.42–9.75) | 0.379 |
| 3.5–5.0 | 1.44 (0.75–2.78) | 0.268 | 0.95 (0.21–4.35) | 0.945 |
| 5.0–6.0 | 1 (ref.) | 1 (ref.) | ||
| 6.0–7.5 | 1.7 (0.76–3.79) | 0.191 | 0.67 (0.17–2.58) | 0.554 |
| >7.5 | 1.6 (0.55–4.72) | 0.383 | 0.78 (0.17–3.58) | 0.747 |
| Cancer mortality | ||||
| ≤3.5 | 1.76 (0.84–3.68) | 0.133 | 1.62 (0.86–3.06) | 0.136 |
| 3.5–5.0 | 1.04 (0.71–1.52) | 0.842 | 1.07 (0.71–1.60) | 0.753 |
| 5.0–6.0 | 1 (ref.) | 1 (ref.) | ||
| 6.0–7.5 | 1.17 (0.81–1.69) | 0.412 | 1.00 (0.63–1.59) | 0.999 |
| >7.5 | 1.30 (0.80–2.13) | 0.284 | 1.23 (0.77–1.99) | 0.381 |
Supplementary Table 4.
Stratification analysis by BMI.
| Uric acid, mg/dl | BMI <30 (n=8,396) | p Value | BMI ≥30 (n=7,150) | p Value |
|---|---|---|---|---|
| HR (95% CI) | HR (95% CI) | |||
| All-cause mortality | ||||
| ≤3.5 | 1.41 (1.02–1.94) | 0.035 | 2.05 (1.29–3.26) | 0.003 |
| 3.5–5.0 | 1.08 (0.94–1.24) | 0.280 | 1.22 (0.94–1.58) | 0.129 |
| 5.0–6.0 | 1 (ref.) | 1 (ref.) | ||
| 6.0–7.5 | 1.13 (0.96–1.33) | 0.152 | 1.01 (0.81–1.25) | 0.948 |
| >7.5 | 1.43 (1.20–1.70) | 0.000 | 1.23 (0.93–1.63) | 0.142 |
| CVD mortality* | 1 (ref.) | 1 (ref.) | ||
| ≤3.5 | 2.42 (1.25–4.66) | 0.009 | 1.37 (0.30–6.32) | 0.682 |
| 3.5–5.0 | 1.29 (0.86–1.95) | 0.213 | 1.46 (0.79–2.68) | 0.220 |
| 5.0–6.0 | 1 (ref.) | 1 (ref.) | ||
| 6.0–7.5 | 1.34 (0.92–1.94) | 0.123 | 0.94 (0.62–1.43) | 0.768 |
| >7.5 | 1.24 (0.75–2.05) | 0.397 | 1.51 (0.80–2.84) | 0.197 |
| Heart-related mortality | 1 (ref.) | 1 (ref.) | ||
| ≤3.5 | 1.67 (0.90–3.09) | 0.105 | 1.57 (0.46–5.35) | 0.467 |
| 3.5–5.0 | 1.22 (0.85–1.73) | 0.275 | 1.43 (0.77–2.68) | 0.259 |
| 5.0–6.0 | 1 (ref.) | 1 (ref.) | ||
| 6.0–7.5 | 1.32 (0.94–1.86) | 0.112 | 0.97 (0.66–1.44) | 0.896 |
| >7.5 | 1.17 (0.74–1.84) | 0.494 | 1.74 (1.02–2.99) | 0.044 |
| Stroke mortality* | 1 (ref.) | 1 (ref.) | ||
| ≤3.5 | 4.24 (1.46–12.34) | 0.009 | 5.74 (0.60–54.82) | 0.126 |
| 3.5–5.0 | 1.28 (0.62–2.63) | 0.498 | 0.77 (0.27–2.22) | 0.620 |
| 5.0–6.0 | 1 (ref.) | 1 (ref.) | ||
| 6.0–7.5 | 1.17 (0.51–2.67) | 0.706 | 1.07 (0.38–2.95) | 0.901 |
| >7.5 | 1.71 (0.58–5.06) | 0.326 | 0.99 (0.25–3.84) | 0.985 |
| Cancer mortality | 1 (ref.) | 1 (ref.) | ||
| ≤3.5 | 1.48 (0.71–3.12) | 0.295 | 2.88 (1.41–5.86) | 0.004 |
| 3.5–5.0 | 1.06 (0.75–1.49) | 0.736 | 1.06 (0.66–1.70) | 0.810 |
| 5.0–6.0 | 1 (ref.) | 1 (ref.) | ||
| 6.0–7.5 | 1.09 (0.79–1.50) | 0.611 | 1.10 (0.64–1.89) | 0.721 |
| >7.5 | 1.45 (0.96–2.20) | 0.076 | 1.01 (0.57–1.78) | 0.972 |
Supplementary Table 5.
Stratification analysis by age groups.
| Uric acid, mg/dl | Age <65y (n=8,716) | p Value | Age ≥65y (n=6,443) | p Value |
|---|---|---|---|---|
| HR (95% CI) | HR (95% CI) | |||
| All-cause mortality | ||||
| ≤3.5 | 1.32 (0.75–2.31) | 0.333 | 1.55 (1.07–2.26) | 0.021 |
| 3.5–5.0 | 0.90 (0.67–1.22) | 0.502 | 1.27 (1.08–1.49) | 0.003 |
| 5.0–6.0 | 1 (ref.) | 1 (ref.) | ||
| 6.0–7.5 | 0.90 (0.70–1.16) | 0.422 | 1.17 (0.99–1.39) | 0.071 |
| >7.5 | 1.27 (0.91–1.78) | 0.165 | 1.30 (1.10–1.54) | 0.003 |
| CVD mortality* | ||||
| ≤3.5 | 1.70 (0.41–7.05) | 0.456 | 2.01 (0.98–4.11) | 0.056 |
| 3.5–5.0 | 0.98 (0.45–2.12) | 0.959 | 1.44 (0.92–2.24) | 0.107 |
| 5.0–6.0 | 1 (ref.) | 1 (ref.) | ||
| 6.0–7.5 | 0.94 (0.53–1.66) | 0.822 | 1.31 (0.93–1.84) | 0.124 |
| >7.5 | 1.64 (0.73–3.67) | 0.225 | 1.15 (0.80–1.64) | 0.453 |
| Heart-related mortality | ||||
| ≤3.5 | 0.88 (0.13–5.86) | 0.893 | 1.46 (0.74–2.89) | 0.275 |
| 3.5–5.0 | 1.32 (0.65–2.66) | 0.436 | 1.16 (0.78–1.73) | 0.455 |
| 5.0–6.0 | 1 (ref.) | 1 (ref.) | ||
| 6.0–7.5 | 1.41 (0.81–2.46) | 0.221 | 1.15 (0.82–1.61) | 0.422 |
| >7.5 | 2.43 (1.15–5.14) | 0.020 | 1.21 (0.85–1.73) | 0.293 |
| Stroke mortality* | ||||
| ≤3.5 | 11.2 (1.80–69.68) | 0.010 | 3.69 (1.34–10.21) | 0.013 |
| 3.5–5.0 | 1.03 (0.12–8.58) | 0.976 | 1.50 (0.84–2.70) | 0.167 |
| 5.0–6.0 | 1 (ref.) | 1 (ref.) | ||
| 6.0–7.5 | 0.37 (0.06–2.37) | 0.286 | 1.52 (0.73–3.19) | 0.262 |
| >7.5 | 0.93 (0.14–6.42) | 0.943 | 1.12 (0.39–3.18) | 0.836 |
| Cancer mortality | ||||
| ≤3.5 | 2.47 (1.23–4.98) | 0.012 | 1.07 (0.46–2.51) | 0.877 |
| 3.5–5.0 | 0.96 (0.52–1.77) | 0.897 | 1.11 (0.79–1.55) | 0.549 |
| 5.0–6.0 | 1 (ref.) | 1 (ref.) | ||
| 6.0–7.5 | 1.06 (0.61–1.85) | 0.835 | 1.08 (0.81–1.44) | 0.596 |
| >7.5 | 1.19 (0.64–2.20) | 0.575 | 1.13 (0.73–1.74) | 0.586 |
Supplementary Table 6.
Stratification analysis by anti-hypertension medications.
| Uric acid, mg/dl | Non-antihypertension agents (n=5,671) | p Value | Anti-hypertension (n=9,488) | p Value |
|---|---|---|---|---|
| HR (95% CI) | HR (95% CI) | |||
| All-cause mortality | ||||
| ≤3.5 | 0.90 (0.53–1.53) | 0.688 | 1.91 (1.38–2.62) | 0.000 |
| 3.5–5.0 | 0.85 (0.68–1.07) | 0.163 | 1.26 (1.08–1.47) | 0.004 |
| 5.0–6.0 | 1 (ref.) | 1 (ref.) | ||
| 6.0–7.5 | 0.9 (0.68–1.18) | 0.427 | 1.17 (1.01–1.34) | 0.031 |
| >7.5 | 1.19 (0.85–1.66) | 0.314 | 1.41 (1.18–1.69) | 0.000 |
| CVD mortality* | 1 (ref.) | 1 (ref.) | ||
| ≤3.5 | 0.85 (0.32–2.24) | 0.734 | 2.87 (1.47–5.58) | 0.002 |
| 3.5–5.0 | 0.65 (0.38–1.13) | 0.126 | 1.60 (1.05–2.44) | 0.029 |
| 5.0–6.0 | 1 (ref.) | 1 (ref.) | ||
| 6.0–7.5 | 0.71 (0.38–1.31) | 0.265 | 1.41 (1.00–1.99) | 0.047 |
| >7.5 | 1.40 (0.61–3.2) | 0.417 | 1.52 (1.01–2.31) | 0.046 |
| Heart-related mortality | 1 (ref.) | 1 (ref.) | ||
| ≤3.5 | 1.40 (0.57–3.45) | 0.461 | 1.17 (0.55–2.51) | 0.675 |
| 3.5–5.0 | 0.79 (0.41–1.52) | 0.484 | 1.28 (0.88–1.87) | 0.191 |
| 5.0–6.0 | 1 (ref.) | 1 (ref.) | ||
| 6.0–7.5 | 1.10 (0.62–1.97) | 0.738 | 1.23 (0.90–1.69) | 0.194 |
| >7.5 | 1.62 (0.6–4.34) | 0.337 | 1.56 (1.10–2.23) | 0.014 |
| Stroke mortality* | 1 (ref.) | 1 (ref.) | ||
| ≤3.5 | 0.38 (0.04–4.06) | 0.419 | 15.92 (5.41–46.88) | 0.000 |
| 3.5–5.0 | 0.38 (0.11–1.35) | 0.131 | 3.50 (1.60–7.65) | 0.002 |
| 5.0–6.0 | 1 (ref.) | 1 (ref.) | ||
| 6.0–7.5 | 0.21 (0.06–0.68) | 0.011 | 3.54 (1.58–7.96) | 0.003 |
| >7.5 | 0.91 (0.20–4.08) | 0.903 | 2.70 (1.02–7.10) | 0.045 |
| Cancer mortality | 1 (ref.) | 1 (ref.) | ||
| ≤3.5 | 1.51 (0.59–3.89) | 0.39 | 1.85 (0.87–3.90) | 0.107 |
| 3.5–5.0 | 1.17 (0.71–1.94) | 0.54 | 0.94 (0.61–1.46) | 0.796 |
| 5.0–6.0 | 1 (ref.) | 1 (ref.) | ||
| 6.0–7.5 | 1.05 (0.61–1.82) | 0.851 | 1.13 (0.79–1.62) | 0.506 |
| >7.5 | 0.71 (0.28–1.81) | 0.471 | 1.39 (0.87–2.20) | 0.163 |
Supplementary Table 7.
Repeated analysis after adjustment for C-reactive protein in NHANES 1999–2006.
| Uric acid, mg/dl | HR (95% CI) | p Value |
|---|---|---|
| All-cause mortality | ||
| ≤3.5 | 1.51 (0.99–2.31) | 0.055 |
| 3.5–5.0 | 1.17 (0.99–1.38) | 0.064 |
| 5.0–6.0 | 1.00 (ref.) | |
| 6.0–7.5 | 1.17 (0.99–1.39) | 0.057 |
| >7.5 | 1.42 (1.16–1.74) | 0.001 |
| Heart-related mortality | ||
| ≤3.5 | 1.18 (0.54–2.56) | 0.676 |
| 3.5–5.0 | 1.24 (0.82–1.86) | 0.306 |
| 5.0–6.0 | 1.00 (ref.) | |
| 6.0–7.5 | 1.16 (0.85–1.57) | 0.343 |
| >7.5 | 1.38 (0.97–1.96) | 0.071 |
| Cancer mortality | ||
| ≤3.5 | 2.15 (1.07–4.34) | 0.033 |
| 3.5–5.0 | 1.14 (0.81–1.61) | 0.451 |
| 5.0–6.0 | 1.00 (ref.) | |
| 6.0–7.5 | 1.3 (0.90–1.89) | 0.158 |
| >7.5 | 1.41 (0.87–2.28) | 0.165 |
| CVD mortality** | ||
| ≤3.5 | 1.93 (1.08–3.44) | 0.027 |
| 3.5–5.0 | 1.26 (0.88–1.81) | 0.204 |
| 5.0–6.0 | 1.00 (ref.) | |
| 6.0–7.5 | 1.19 (0.91–1.54) | 0.193 |
| >7.5 | 1.36 (0.98–1.87) | 0.062 |
| Stroke mortality** | ||
| ≤3.5 | 4.31 (1.64–11.31) | 0.004 |
| 3.5–5.0 | 1.29 (0.70–2.38) | 0.413 |
| 5.0–6.0 | 1.00 (ref.) | |
| 6.0–7.5 | 1.31 (0.67–2.55) | 0.426 |
| >7.5 | 1.25 (0.53–2.96) | 0.599 |
Estimated in NHANES 1999–2006. Hazard ratio (95% confidence interval) was estimated via weighted cox regression analysis after adjustment for age (years, continuous), sex (female or male), race/ethnicity (non-Hispanic white, black, Hispanic-Mexican, or other), poverty to income ratio (<1.3, 1.3–3.5, ≥3.5, or missing), body mass index (<18.5, 18.5–25, 25–30, or ≥30 kg/m2), smoking status, alcohol intake (no, <5, 5–30, ≥30 g/d, or missing), physical activity (inactive, moderate, or vigorous), TG, total cholesterol (mmol/L, continuous), high-density lipoprotein cholesterol (mmol/L, continuous), C-reactive protein (mg/dL, continuous), estimated glomerular filtration rate (mL/min/1.73 m2, continuous), cardiovascular diseases (no/yes), diabetes (no/yes), chronic obstructive pulmonary disease (no/yes), cancer (no/yes), lowing lipid agents (no/yes), antiplatelet treatment (no/yes), ACEI/ARBs (no/yes), β-blocker (no/yes), CCB (no/yes), diuretics (no/yes) and other antihypertensive drugs (no/yes).
Acknowledgments
The authors would like to thank all the participants and investigators in the NHANES survey for their great contributions.
Footnotes
Conflict of Interest
None.
Source of support: This manuscript was completed independently. Kegong Chen received a grant from the Fund of the Key Laboratory of Myocardial Ischemia, Ministry of Education of China (KF201919)
References
- 1.Overwyk KJ, Zhao L, Zhang Z, et al. Trends in blood pressure and usual dietary sodium intake among children and adolescents, national health and nutrition examination survey 2003 to 2016. Hypertension. 2019;74:260–66. doi: 10.1161/HYPERTENSIONAHA.118.12844. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Benjamin EJ, Virani SS, Callaway CW, et al. Heart disease and stroke statistics – 2018 update: A report from the American Heart Association. Circulation. 2018;137:e67–492. doi: 10.1161/CIR.0000000000000558. [DOI] [PubMed] [Google Scholar]
- 3.Ndrepepa G. Uric acid and cardiovascular disease. Clin Chim Acta. 2018;484:150–63. doi: 10.1016/j.cca.2018.05.046. [DOI] [PubMed] [Google Scholar]
- 4.Kuwabara M, Hisatome I, Niwa K, et al. A 5-year Japanese cohort study. Hypertension. 2018;71:78–86. doi: 10.1161/HYPERTENSIONAHA.117.10370. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Pilemann-Lyberg S, Hansen TW, Tofte N, et al. Uric acid is an independent risk factor for decline in kidney function, cardiovascular events, and mortality in patients with type 1 diabetes. Diabetes Care. 2019;42:1088–94. doi: 10.2337/dc18-2173. [DOI] [PubMed] [Google Scholar]
- 6.Liu L, Gu Y, Li C, et al. A population-based prospective cohort study. J Hum Hypertens. 2017;31:116–20. doi: 10.1038/jhh.2016.48. [DOI] [PubMed] [Google Scholar]
- 7.Mazzali M, Hughes J, Kim YG, et al. Elevated uric acid increases blood pressure in the rat by a novel crystal-independent mechanism. Hypertension. 2001;38:1101–6. doi: 10.1161/hy1101.092839. [DOI] [PubMed] [Google Scholar]
- 8.Soletsky B, Feig DI. Uric acid reduction rectifies prehypertension in obese adolescents. Hypertension. 2012;60:1148–56. doi: 10.1161/HYPERTENSIONAHA.112.196980. [DOI] [PubMed] [Google Scholar]
- 9.Higgins P, Walters MR, Murray HM, et al. Allopurinol reduces brachial and central blood pressure, and carotid intima-media thickness progression after ischaemic stroke and transient ischaemic attack: A randomised controlled trial. Heart. 2014;100:1085–92. doi: 10.1136/heartjnl-2014-305683. [DOI] [PubMed] [Google Scholar]
- 10.Madero M, Rodríguez CF, Jalal D, et al. A pilot study on the impact of a low fructose diet and allopurinol on clinic blood pressure among overweight and prehypertensive subjects: A randomized placebo controlled trial. J Am Soc Hypertens. 2015;9:837–44. doi: 10.1016/j.jash.2015.07.008. [DOI] [PubMed] [Google Scholar]
- 11.Becker BF. Towards the physiological function of uric acid. Free Radic Biol Med. 1993;14:615–31. doi: 10.1016/0891-5849(93)90143-i. [DOI] [PubMed] [Google Scholar]
- 12.Kleber ME, Delgado G, Grammer TB, et al. Uric acid and cardiovascular events: A Mendelian randomization study. J Am Soc Nephrol. 2015;26:2831–38. doi: 10.1681/ASN.2014070660. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Xia X, Zhao C, Peng FF, et al. Serum uric acid predicts cardiovascular mortality in male peritoneal dialysis patients with diabetes. Nutr Metab Cardiovasc Dis. 2016;26:20–26. doi: 10.1016/j.numecd.2015.10.011. [DOI] [PubMed] [Google Scholar]
- 14.Basar N, Sen N, Ozcan F, et al. Elevated serum uric acid predicts angiographic impaired reperfusion and 1-year mortality in ST-segment elevation myocardial infarction patients undergoing percutaneous coronary intervention. J Investig Med. 2011;59:931–37. doi: 10.2310/JIM.0b013e318214ebaf. [DOI] [PubMed] [Google Scholar]
- 15.Li M, Ye ZC, Li CM, et al. Low serum uric acid levels increase the risk of all-cause death and cardiovascular death in hemodialysis patients. Ren Fail. 2020;42:315–22. doi: 10.1080/0886022X.2020.1745234. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Lai KJ, Kor CT, Hsieh YP. An inverse relationship between hyperuricemia and mortality in patients undergoing continuous ambulatory peritoneal dialysis. J Clin Med. 2018;7(11):416. doi: 10.3390/jcm7110416. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Panero F, Gruden G, Perotto M, et al. Uric acid is not an independent predictor of cardiovascular mortality in type 2 diabetes: A population-based study. Atherosclerosis. 2012;221:183–88. doi: 10.1016/j.atherosclerosis.2011.11.042. [DOI] [PubMed] [Google Scholar]
- 18.Zalawadiya SK, Veeranna V, Mallikethi-Reddy S, et al. Uric acid and cardiovascular disease risk reclassification: Findings from NHANES III. Eur J Prev Cardiol. 2015;22:513–18. doi: 10.1177/2047487313519346. [DOI] [PubMed] [Google Scholar]
- 19.Hu L, Hu G, Xu BP, et al. U-shaped association of serum uric acid with all-cause and cause-specific mortality in US adults: A cohort study. J Clin Endocrinol Metab. 2020;105(1):dgz068. doi: 10.1210/clinem/dgz068. [DOI] [PubMed] [Google Scholar]
- 20.Cho SK, Chang Y, Kim I, Ryu S. U-shaped association between serum uric acid level and risk of mortality: A cohort study. Arthritis Rheumatol. 2018;70:1122–32. doi: 10.1002/art.40472. [DOI] [PubMed] [Google Scholar]
- 21.Wang S, Liu Y, Liu J, et al. Mitochondria-derived methylmalonic acid, a surrogate biomarker of mitochondrial dysfunction and oxidative stress, predicts all-cause and cardiovascular mortality in the general population. Redox Biol. 2020;37:101741. doi: 10.1016/j.redox.2020.101741. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Wang S, Tian W, Liu Y, et al. Temporal trend of circulating trans-fatty acids and risk of long-term mortality in general population. Clin Nutr. 2020 doi: 10.1016/j.clnu.2020.07.010. [Online ahead of print] [DOI] [PubMed] [Google Scholar]
- 23.Rossato LT, de Branco FMS, Azeredo CM, et al. Association between omega-3 fatty acids intake and muscle strength in older adults: A study from National Health and Nutrition Examination Survey (NHANES) 1999–2002. Clin Nutr. 2020;39(11):3434–41. doi: 10.1016/j.clnu.2020.03.001. [DOI] [PubMed] [Google Scholar]
- 24.Zhang X, Wang S, Liu J, et al. D-dimer and the incidence of heart failure and mortality after acute myocardial infarction. Heart. 2020 doi: 10.1136/heartjnl-2020-316880. [Online ahead of print] [DOI] [PubMed] [Google Scholar]
- 25.Wang J, Wang Y, Zhao D, et al. Association between serum uric acid and mortality in a Chinese population of hypertensive patients. Ren Fail. 2015;37:73–76. doi: 10.3109/0886022X.2014.964148. [DOI] [PubMed] [Google Scholar]
- 26.Tseng WC, Chen YT, Ou SM, et al. Taiwan Geriatric Kidney Disease (TGKD) Research Group. U-shaped association between serum uric acid levels with cardiovascular and all-cause mortality in the elderly: The role of Malnourishment. J Am Heart Assoc. 2018;7(4):e007523. doi: 10.1161/JAHA.117.007523. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Wu AH, Gladden JD, Ahmed M, et al. Relation of serum uric acid to cardiovascular disease. Int J Cardiol. 2016;213:4–7. doi: 10.1016/j.ijcard.2015.08.110. [DOI] [PubMed] [Google Scholar]
- 28.DeMarco VG, Aroor AR, Sowers JR. The pathophysiology of hypertension in patients with obesity. Nat Rev Endocrinol. 2014;10:364–76. doi: 10.1038/nrendo.2014.44. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Sharaf EDU, Salem MM, Abdulazim DO. Uric acid in the pathogenesis of metabolic, renal, and cardiovascular diseases: A review. J Adv Res. 2017;8:537–48. doi: 10.1016/j.jare.2016.11.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Takir M, Kostek O, Ozkok A, et al. Lowering uric acid with allopurinol improves insulin resistance and systemic inflammation in asymptomatic hyperuricemia. J Investig Med. 2015;63:924–29. doi: 10.1097/JIM.0000000000000242. [DOI] [PubMed] [Google Scholar]
- 31.Ruggiero C, Cherubini A, Ble A, et al. Uric acid and inflammatory markers. Eur Heart J. 2006;27:1174–81. doi: 10.1093/eurheartj/ehi879. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Juraschek SP, Miller ER, Gelber AC. Effect of oral vitamin C supplementation on serum uric acid: A meta-analysis of randomized controlled trials. Arthritis Care Res (Hoboken) 2011;63:1295–306. doi: 10.1002/acr.20519. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplementary Table 1.
Stratification analysis of the association between uric acid and mortality by sex.
| Uric acid, mg/dl | Female (n=7,850) | p Value | Male (n=7,309) | p Value |
|---|---|---|---|---|
| HR (95% CI) | HR (95% CI) | |||
| All-cause mortality | ||||
| ≤3.5 | 1.33 (0.93–1.91) | 0.118 | 2.46 (1.57–3.86) | 0.000 |
| 3.5–5.0 | 1.11 (0.90–1.35) | 0.322 | 1.17 (0.96–1.42) | 0.115 |
| 5.0–6.0 | 1 (ref.) | 1 (ref.) | ||
| 6.0–7.5 | 1.27 (1.04–1.56) | 0.022 | 0.97 (0.81–1.16) | 0.736 |
| >7.5 | 1.48 (1.18–1.85) | 0.001 | 1.29 (1.04–1.60) | 0.019 |
| CVD mortality* | ||||
| ≤3.5 | 2.28 (1.14–4.55) | 0.020 | 1.52 (0.45–5.14) | 0.491 |
| 3.5–5.0 | 1.23 (0.75–2.03) | 0.407 | 1.41 (0.92–2.17) | 0.112 |
| 5.0–6.0 | 1 (ref.) | 1 (ref.) | ||
| 6.0–7.5 | 1.48 (0.89–2.44) | 0.126 | 1.04 (0.70–1.54) | 0.849 |
| >7.5 | 1.56 (0.90–2.68) | 0.108 | 1.49 (0.92–2.42) | 0.105 |
| Heart-related mortality | ||||
| ≤3.5 | 1.34 (0.66–2.73) | 0.419 | 1.16 (0.27–5.08) | 0.840 |
| 3.5–5.0 | 1.02 (0.62–1.67) | 0.937 | 1.39 (0.92–2.09) | 0.114 |
| 5.0–6.0 | 1 (ref.) | 1 (ref.) | ||
| 6.0–7.5 | 1.28 (0.82–2.02) | 0.278 | 1.10 (0.77–1.57) | 0.611 |
| >7.5 | 1.47 (0.86–2.52) | 0.160 | 1.55 (1.04–2.31) | 0.032 |
| Stroke mortality* | ||||
| ≤3.5 | 2.28 (1.16–4.50) | 0.018 | 1.50 (0.13–17.07) | 0.741 |
| 3.5–5.0 | 1.21 (0.73–2.01) | 0.460 | 1.47 (0.58–3.76) | 0.411 |
| 5.0–6.0 | 1 (ref.) | 1 (ref.) | ||
| 6.0–7.5 | 1.39 (0.83–2.30) | 0.203 | 1.23 (0.47–3.22) | 0.665 |
| >7.5 | 1.36 (0.79–2.34) | 0.256 | 1.26 (0.35–4.60) | 0.719 |
Estimated in NHANES 1999–2006. Hazard ratio (95% confidence interval) was estimated via weighted cox regression analysis after adjustment for age (years, continuous), race/ethnicity (non-Hispanic white, black, Hispanic-Mexican, or other), poverty to income ratio (<1.3, 1.3–3.5, ≥3.5, or missing), body mass index (<18.5, 18.5–25, 25–30, or ≥30 kg/m2), smoking status, alcohol intake (no, <5, 5–30, ≥30 g/d, or missing), physical activity (inactive, moderate, or vigorous), TG, total cholesterol (mmol/L, continuous), high-density lipoprotein cholesterol (mmol/L, continuous), estimated glomerular filtration rate (mL/min/1.73 m2, continuous), cardiovascular diseases (no/yes), diabetes (no/yes), chronic obstructive pulmonary disease (no/yes), cancer (no/yes), lowing lipid agents (no/yes), antiplatelet treatment (no/yes), ACEI/ARBs (no/yes), β-blocker (no/yes), CCB (no/yes), diuretics (no/yes) and other antihypertensive drugs (no/yes).
Supplementary Table 2.
Stratification analysis by estimated glomerular filtration rate.
| Uric acid, mg/dl | Non-CKD (n=12,643) | p Value | CKD* (n=2,516) | p Value |
|---|---|---|---|---|
| HR (95% CI) | HR (95% CI) | |||
| All-cause mortality | ||||
| ≤3.5 | 1.42 (1.02–1.98) | 0.036 | 1.57 (0.77–3.21) | 0.211 |
| 3.5–5.0 | 1.09 (0.93–1.27) | 0.311 | 1.10 (0.86–1.41) | 0.435 |
| 5.0–6.0 | 1 (ref.) | 1 (ref.) | ||
| 6.0–7.5 | 0.99 (0.84–1.18) | 0.948 | 1.31 (1.06–1.62) | 0.013 |
| >7.5 | 1.37 (1.09–1.71) | 0.007 | 1.52 (1.21–1.90) | 0.000 |
| CVD mortality* | ||||
| ≤3.5 | 1.73 (0.94–3.21) | 0.078 | 4.95 (1.29–19.01) | 0.021 |
| 3.5–5.0 | 1.25 (0.81–1.93) | 0.308 | 1.32 (0.70–2.49) | 0.383 |
| 5.0–6.0 | 1 (ref.) | 1 (ref.) | ||
| 6.0–7.5 | 0.94 (0.65–1.35) | 0.731 | 1.69 (0.97–2.94) | 0.063 |
| >7.5 | 1.79 (1.06–3.00) | 0.029 | 1.43 (0.80–2.58) | 0.226 |
| Heart-related mortality | ||||
| ≤3.5 | 1.31 (0.67–2.55) | 0.421 | 1.49 (0.15–14.55) | 0.727 |
| 3.5–5.0 | 1.19 (0.78–1.80) | 0.420 | 1.12 (0.63–1.99) | 0.706 |
| 5.0–6.0 | 1 (ref.) | 1 (ref.) | ||
| 6.0–7.5 | 1.05 (0.78–1.43) | 0.731 | 1.43 (0.86–2.36) | 0.166 |
| >7.5 | 1.75 (1.11–2.77) | 0.017 | 1.57 (0.93–2.67) | 0.092 |
| Stroke mortality* | ||||
| ≤3.5 | 4.04 (1.32–12.44) | 0.016 | 13.12 (2.33–73.86) | 0.004 |
| 3.5–5.0 | 1.22 (0.55–2.70) | 0.625 | 1.04 (0.26–4.16) | 0.958 |
| 5.0–6.0 | 1 (ref.) | 1 (ref.) | ||
| 6.0–7.5 | 0.93 (0.37–2.32) | 0.878 | 2.23 (0.84–5.92) | 0.107 |
| >7.5 | 1.18 (0.37–3.77) | 0.775 | 1.50 (0.43–5.28) | 0.518 |
CKD was defined as estimated glomerular filtration rate less than 60 mL/min/1.73 m2;
estimated in NHANES 1999–2006. Hazard ratio (95% confidence interval) was estimated via weighted cox regression analysis after adjustment for age (years, continuous), sex (female or male), race/ethnicity (non-Hispanic white, black, Hispanic-Mexican, or other), poverty to income ratio (<1.3, 1.3–3.5, ≥3.5, or missing), body mass index (<18.5, 18.5–25, 25–30, or ≥30 kg/m2), smoking status, alcohol intake (no, <5, 5–30, ≥30g/d, or missing), physical activity (inactive, moderate, or vigorous), TG, total cholesterol (mmol/L, continuous), high-density lipoprotein cholesterol (mmol/L, continuous), cardiovascular diseases (no/yes), diabetes (no/yes), chronic obstructive pulmonary disease (no/yes), cancer (no/yes), lowing lipid agents (no/yes), antiplatelet treatment (no/yes), ACEI/ARBs (no/yes), β-blocker (no/yes), CCB (no/yes), diuretics (no/yes) and other antihypertensive drugs (no/yes).
Supplementary Table 3.
Stratification analysis by race/ethnicity.
| Uric acid, mg/dl | White (n=7,378) | p Value | Non-white (n=7,781) | p Value |
|---|---|---|---|---|
| HR (95% CI) | HR (95% CI) | |||
| All-cause mortality | ||||
| ≤3.5 | 1.82 (1.25–2.65) | 0.002 | 0.69 (0.47–1.02) | 0.064 |
| 3.5–5.0 | 1.19 (1.03–1.37) | 0.018 | 0.89 (0.71–1.12) | 0.316 |
| 5.0–6.0 | 1 (ref.) | 1 (ref.) | ||
| 6.0–7.5 | 1.11 (0.94–1.31) | 0.204 | 1.03 (0.85–1.24) | 0.798 |
| >7.5 | 1.42 (1.17–1.72) | 0.000 | 1.17 (0.90–1.5) | 0.237 |
| CVD mortality* | ||||
| ≤3.5 | 2.91 (1.62–5.22) | 0.001 | 0.53 (0.16–1.77) | 0.296 |
| 3.5–5.0 | 1.53 (1.02–2.28) | 0.039 | 0.58 (0.32–1.08) | 0.083 |
| 5.0–6.0 | 1 (ref.) | 1 (ref.) | ||
| 6.0–7.5 | 1.24 (0.88–1.74) | 0.216 | 0.94 (0.56–1.57) | 0.814 |
| >7.5 | 1.63 (1.08–2.47) | 0.022 | 0.72 (0.37–1.38) | 0.317 |
| Heart-related mortality | ||||
| ≤3.5 | 2.01 (1.07–3.77) | 0.029 | 0.32 (0.11–0.90) | 0.031 |
| 3.5–5.0 | 1.41 (0.97–2.06) | 0.072 | 0.59 (0.33–1.07) | 0.080 |
| 5.0–6.0 | 1 (ref.) | 1 (ref.) | ||
| 6.0–7.5 | 1.19 (0.86–1.67) | 0.294 | 1.06 (0.67–1.68) | 0.810 |
| >7.5 | 1.65 (1.16–2.34) | 0.006 | 0.95 (0.56–1.61) | 0.847 |
| Stroke mortality* | ||||
| ≤3.5 | 5.53 (1.79–17.1) | 0.004 | 2.01 (0.42–9.75) | 0.379 |
| 3.5–5.0 | 1.44 (0.75–2.78) | 0.268 | 0.95 (0.21–4.35) | 0.945 |
| 5.0–6.0 | 1 (ref.) | 1 (ref.) | ||
| 6.0–7.5 | 1.7 (0.76–3.79) | 0.191 | 0.67 (0.17–2.58) | 0.554 |
| >7.5 | 1.6 (0.55–4.72) | 0.383 | 0.78 (0.17–3.58) | 0.747 |
| Cancer mortality | ||||
| ≤3.5 | 1.76 (0.84–3.68) | 0.133 | 1.62 (0.86–3.06) | 0.136 |
| 3.5–5.0 | 1.04 (0.71–1.52) | 0.842 | 1.07 (0.71–1.60) | 0.753 |
| 5.0–6.0 | 1 (ref.) | 1 (ref.) | ||
| 6.0–7.5 | 1.17 (0.81–1.69) | 0.412 | 1.00 (0.63–1.59) | 0.999 |
| >7.5 | 1.30 (0.80–2.13) | 0.284 | 1.23 (0.77–1.99) | 0.381 |
Supplementary Table 4.
Stratification analysis by BMI.
| Uric acid, mg/dl | BMI <30 (n=8,396) | p Value | BMI ≥30 (n=7,150) | p Value |
|---|---|---|---|---|
| HR (95% CI) | HR (95% CI) | |||
| All-cause mortality | ||||
| ≤3.5 | 1.41 (1.02–1.94) | 0.035 | 2.05 (1.29–3.26) | 0.003 |
| 3.5–5.0 | 1.08 (0.94–1.24) | 0.280 | 1.22 (0.94–1.58) | 0.129 |
| 5.0–6.0 | 1 (ref.) | 1 (ref.) | ||
| 6.0–7.5 | 1.13 (0.96–1.33) | 0.152 | 1.01 (0.81–1.25) | 0.948 |
| >7.5 | 1.43 (1.20–1.70) | 0.000 | 1.23 (0.93–1.63) | 0.142 |
| CVD mortality* | 1 (ref.) | 1 (ref.) | ||
| ≤3.5 | 2.42 (1.25–4.66) | 0.009 | 1.37 (0.30–6.32) | 0.682 |
| 3.5–5.0 | 1.29 (0.86–1.95) | 0.213 | 1.46 (0.79–2.68) | 0.220 |
| 5.0–6.0 | 1 (ref.) | 1 (ref.) | ||
| 6.0–7.5 | 1.34 (0.92–1.94) | 0.123 | 0.94 (0.62–1.43) | 0.768 |
| >7.5 | 1.24 (0.75–2.05) | 0.397 | 1.51 (0.80–2.84) | 0.197 |
| Heart-related mortality | 1 (ref.) | 1 (ref.) | ||
| ≤3.5 | 1.67 (0.90–3.09) | 0.105 | 1.57 (0.46–5.35) | 0.467 |
| 3.5–5.0 | 1.22 (0.85–1.73) | 0.275 | 1.43 (0.77–2.68) | 0.259 |
| 5.0–6.0 | 1 (ref.) | 1 (ref.) | ||
| 6.0–7.5 | 1.32 (0.94–1.86) | 0.112 | 0.97 (0.66–1.44) | 0.896 |
| >7.5 | 1.17 (0.74–1.84) | 0.494 | 1.74 (1.02–2.99) | 0.044 |
| Stroke mortality* | 1 (ref.) | 1 (ref.) | ||
| ≤3.5 | 4.24 (1.46–12.34) | 0.009 | 5.74 (0.60–54.82) | 0.126 |
| 3.5–5.0 | 1.28 (0.62–2.63) | 0.498 | 0.77 (0.27–2.22) | 0.620 |
| 5.0–6.0 | 1 (ref.) | 1 (ref.) | ||
| 6.0–7.5 | 1.17 (0.51–2.67) | 0.706 | 1.07 (0.38–2.95) | 0.901 |
| >7.5 | 1.71 (0.58–5.06) | 0.326 | 0.99 (0.25–3.84) | 0.985 |
| Cancer mortality | 1 (ref.) | 1 (ref.) | ||
| ≤3.5 | 1.48 (0.71–3.12) | 0.295 | 2.88 (1.41–5.86) | 0.004 |
| 3.5–5.0 | 1.06 (0.75–1.49) | 0.736 | 1.06 (0.66–1.70) | 0.810 |
| 5.0–6.0 | 1 (ref.) | 1 (ref.) | ||
| 6.0–7.5 | 1.09 (0.79–1.50) | 0.611 | 1.10 (0.64–1.89) | 0.721 |
| >7.5 | 1.45 (0.96–2.20) | 0.076 | 1.01 (0.57–1.78) | 0.972 |
Supplementary Table 5.
Stratification analysis by age groups.
| Uric acid, mg/dl | Age <65y (n=8,716) | p Value | Age ≥65y (n=6,443) | p Value |
|---|---|---|---|---|
| HR (95% CI) | HR (95% CI) | |||
| All-cause mortality | ||||
| ≤3.5 | 1.32 (0.75–2.31) | 0.333 | 1.55 (1.07–2.26) | 0.021 |
| 3.5–5.0 | 0.90 (0.67–1.22) | 0.502 | 1.27 (1.08–1.49) | 0.003 |
| 5.0–6.0 | 1 (ref.) | 1 (ref.) | ||
| 6.0–7.5 | 0.90 (0.70–1.16) | 0.422 | 1.17 (0.99–1.39) | 0.071 |
| >7.5 | 1.27 (0.91–1.78) | 0.165 | 1.30 (1.10–1.54) | 0.003 |
| CVD mortality* | ||||
| ≤3.5 | 1.70 (0.41–7.05) | 0.456 | 2.01 (0.98–4.11) | 0.056 |
| 3.5–5.0 | 0.98 (0.45–2.12) | 0.959 | 1.44 (0.92–2.24) | 0.107 |
| 5.0–6.0 | 1 (ref.) | 1 (ref.) | ||
| 6.0–7.5 | 0.94 (0.53–1.66) | 0.822 | 1.31 (0.93–1.84) | 0.124 |
| >7.5 | 1.64 (0.73–3.67) | 0.225 | 1.15 (0.80–1.64) | 0.453 |
| Heart-related mortality | ||||
| ≤3.5 | 0.88 (0.13–5.86) | 0.893 | 1.46 (0.74–2.89) | 0.275 |
| 3.5–5.0 | 1.32 (0.65–2.66) | 0.436 | 1.16 (0.78–1.73) | 0.455 |
| 5.0–6.0 | 1 (ref.) | 1 (ref.) | ||
| 6.0–7.5 | 1.41 (0.81–2.46) | 0.221 | 1.15 (0.82–1.61) | 0.422 |
| >7.5 | 2.43 (1.15–5.14) | 0.020 | 1.21 (0.85–1.73) | 0.293 |
| Stroke mortality* | ||||
| ≤3.5 | 11.2 (1.80–69.68) | 0.010 | 3.69 (1.34–10.21) | 0.013 |
| 3.5–5.0 | 1.03 (0.12–8.58) | 0.976 | 1.50 (0.84–2.70) | 0.167 |
| 5.0–6.0 | 1 (ref.) | 1 (ref.) | ||
| 6.0–7.5 | 0.37 (0.06–2.37) | 0.286 | 1.52 (0.73–3.19) | 0.262 |
| >7.5 | 0.93 (0.14–6.42) | 0.943 | 1.12 (0.39–3.18) | 0.836 |
| Cancer mortality | ||||
| ≤3.5 | 2.47 (1.23–4.98) | 0.012 | 1.07 (0.46–2.51) | 0.877 |
| 3.5–5.0 | 0.96 (0.52–1.77) | 0.897 | 1.11 (0.79–1.55) | 0.549 |
| 5.0–6.0 | 1 (ref.) | 1 (ref.) | ||
| 6.0–7.5 | 1.06 (0.61–1.85) | 0.835 | 1.08 (0.81–1.44) | 0.596 |
| >7.5 | 1.19 (0.64–2.20) | 0.575 | 1.13 (0.73–1.74) | 0.586 |
Supplementary Table 6.
Stratification analysis by anti-hypertension medications.
| Uric acid, mg/dl | Non-antihypertension agents (n=5,671) | p Value | Anti-hypertension (n=9,488) | p Value |
|---|---|---|---|---|
| HR (95% CI) | HR (95% CI) | |||
| All-cause mortality | ||||
| ≤3.5 | 0.90 (0.53–1.53) | 0.688 | 1.91 (1.38–2.62) | 0.000 |
| 3.5–5.0 | 0.85 (0.68–1.07) | 0.163 | 1.26 (1.08–1.47) | 0.004 |
| 5.0–6.0 | 1 (ref.) | 1 (ref.) | ||
| 6.0–7.5 | 0.9 (0.68–1.18) | 0.427 | 1.17 (1.01–1.34) | 0.031 |
| >7.5 | 1.19 (0.85–1.66) | 0.314 | 1.41 (1.18–1.69) | 0.000 |
| CVD mortality* | 1 (ref.) | 1 (ref.) | ||
| ≤3.5 | 0.85 (0.32–2.24) | 0.734 | 2.87 (1.47–5.58) | 0.002 |
| 3.5–5.0 | 0.65 (0.38–1.13) | 0.126 | 1.60 (1.05–2.44) | 0.029 |
| 5.0–6.0 | 1 (ref.) | 1 (ref.) | ||
| 6.0–7.5 | 0.71 (0.38–1.31) | 0.265 | 1.41 (1.00–1.99) | 0.047 |
| >7.5 | 1.40 (0.61–3.2) | 0.417 | 1.52 (1.01–2.31) | 0.046 |
| Heart-related mortality | 1 (ref.) | 1 (ref.) | ||
| ≤3.5 | 1.40 (0.57–3.45) | 0.461 | 1.17 (0.55–2.51) | 0.675 |
| 3.5–5.0 | 0.79 (0.41–1.52) | 0.484 | 1.28 (0.88–1.87) | 0.191 |
| 5.0–6.0 | 1 (ref.) | 1 (ref.) | ||
| 6.0–7.5 | 1.10 (0.62–1.97) | 0.738 | 1.23 (0.90–1.69) | 0.194 |
| >7.5 | 1.62 (0.6–4.34) | 0.337 | 1.56 (1.10–2.23) | 0.014 |
| Stroke mortality* | 1 (ref.) | 1 (ref.) | ||
| ≤3.5 | 0.38 (0.04–4.06) | 0.419 | 15.92 (5.41–46.88) | 0.000 |
| 3.5–5.0 | 0.38 (0.11–1.35) | 0.131 | 3.50 (1.60–7.65) | 0.002 |
| 5.0–6.0 | 1 (ref.) | 1 (ref.) | ||
| 6.0–7.5 | 0.21 (0.06–0.68) | 0.011 | 3.54 (1.58–7.96) | 0.003 |
| >7.5 | 0.91 (0.20–4.08) | 0.903 | 2.70 (1.02–7.10) | 0.045 |
| Cancer mortality | 1 (ref.) | 1 (ref.) | ||
| ≤3.5 | 1.51 (0.59–3.89) | 0.39 | 1.85 (0.87–3.90) | 0.107 |
| 3.5–5.0 | 1.17 (0.71–1.94) | 0.54 | 0.94 (0.61–1.46) | 0.796 |
| 5.0–6.0 | 1 (ref.) | 1 (ref.) | ||
| 6.0–7.5 | 1.05 (0.61–1.82) | 0.851 | 1.13 (0.79–1.62) | 0.506 |
| >7.5 | 0.71 (0.28–1.81) | 0.471 | 1.39 (0.87–2.20) | 0.163 |
Supplementary Table 7.
Repeated analysis after adjustment for C-reactive protein in NHANES 1999–2006.
| Uric acid, mg/dl | HR (95% CI) | p Value |
|---|---|---|
| All-cause mortality | ||
| ≤3.5 | 1.51 (0.99–2.31) | 0.055 |
| 3.5–5.0 | 1.17 (0.99–1.38) | 0.064 |
| 5.0–6.0 | 1.00 (ref.) | |
| 6.0–7.5 | 1.17 (0.99–1.39) | 0.057 |
| >7.5 | 1.42 (1.16–1.74) | 0.001 |
| Heart-related mortality | ||
| ≤3.5 | 1.18 (0.54–2.56) | 0.676 |
| 3.5–5.0 | 1.24 (0.82–1.86) | 0.306 |
| 5.0–6.0 | 1.00 (ref.) | |
| 6.0–7.5 | 1.16 (0.85–1.57) | 0.343 |
| >7.5 | 1.38 (0.97–1.96) | 0.071 |
| Cancer mortality | ||
| ≤3.5 | 2.15 (1.07–4.34) | 0.033 |
| 3.5–5.0 | 1.14 (0.81–1.61) | 0.451 |
| 5.0–6.0 | 1.00 (ref.) | |
| 6.0–7.5 | 1.3 (0.90–1.89) | 0.158 |
| >7.5 | 1.41 (0.87–2.28) | 0.165 |
| CVD mortality** | ||
| ≤3.5 | 1.93 (1.08–3.44) | 0.027 |
| 3.5–5.0 | 1.26 (0.88–1.81) | 0.204 |
| 5.0–6.0 | 1.00 (ref.) | |
| 6.0–7.5 | 1.19 (0.91–1.54) | 0.193 |
| >7.5 | 1.36 (0.98–1.87) | 0.062 |
| Stroke mortality** | ||
| ≤3.5 | 4.31 (1.64–11.31) | 0.004 |
| 3.5–5.0 | 1.29 (0.70–2.38) | 0.413 |
| 5.0–6.0 | 1.00 (ref.) | |
| 6.0–7.5 | 1.31 (0.67–2.55) | 0.426 |
| >7.5 | 1.25 (0.53–2.96) | 0.599 |
Estimated in NHANES 1999–2006. Hazard ratio (95% confidence interval) was estimated via weighted cox regression analysis after adjustment for age (years, continuous), sex (female or male), race/ethnicity (non-Hispanic white, black, Hispanic-Mexican, or other), poverty to income ratio (<1.3, 1.3–3.5, ≥3.5, or missing), body mass index (<18.5, 18.5–25, 25–30, or ≥30 kg/m2), smoking status, alcohol intake (no, <5, 5–30, ≥30 g/d, or missing), physical activity (inactive, moderate, or vigorous), TG, total cholesterol (mmol/L, continuous), high-density lipoprotein cholesterol (mmol/L, continuous), C-reactive protein (mg/dL, continuous), estimated glomerular filtration rate (mL/min/1.73 m2, continuous), cardiovascular diseases (no/yes), diabetes (no/yes), chronic obstructive pulmonary disease (no/yes), cancer (no/yes), lowing lipid agents (no/yes), antiplatelet treatment (no/yes), ACEI/ARBs (no/yes), β-blocker (no/yes), CCB (no/yes), diuretics (no/yes) and other antihypertensive drugs (no/yes).