Relation of serum uric acid to an exaggerated systolic blood pressure response to exercise testing in men with normotension

Abstract

The authors investigated the hypothesis that high serum uric acid concentrations may be related to an exaggerated systolic blood pressure (SBP) response to maximal exercise testing in men with normotension, independent of potential confounding variables. In 4640 healthy men with normotension who underwent maximal treadmill exercise testing and fasting blood chemistry studies, including serum uric acid concentrations, an exaggerated SBP response, defined as SBP ≥ 210 mm Hg, was detected in 152 men (3.3%). After adjusting for potential confounders, participants in the highest quartile of serum uric acid (>6.6 mg/dL) had a higher odds ratio of demonstrating an exaggerated SBP to maximal exercise (odds ratio, 2.19; 95% confidence interval, 1.24–3.86) compared with participants in the lowest quartile of serum uric acid (<5.1 mg/dL). High serum uric acid concentrations are associated with an exaggerated SBP response to maximal exercise testing in men with normotension, independent of established coronary risk factors.

1. INTRODUCTION

Despite a normal blood pressure (BP) at rest, some individuals may demonstrate an exaggerated systolic BP (SBP) response to peak or symptom‐limited exercise testing, which is commonly referred to as “exercise‐induced hypertension.”1 In particular, an exaggerated SBP response to exercise testing has been independently associated with an increased risk of incident hypertension and subsequent cardiovascular events.1 Previous studies involving relatively small sample sizes have suggested that an exaggerated SBP response to exercise testing may be associated with selected cardiovascular risk factors (eg, abnormal metabolic profiles, insulin resistance, inflammation, activated angiotensin II, vascular dysfunction, and decreased nitric oxide bioavailability),2, 3, 4, 5, 6, 7 but the mechanisms underlying the hypertensive response to exercise remain unclear.

Serum uric acid is associated with an increased risk of incident or uncontrolled hypertension.8, 9 The potential mechanisms by which a heightened serum uric acid level exerts a vasoconstrictor influence on the blood vessels10 and increased BP may involve activation of the renin‐angiotensin‐aldosterone system,11 reduced nitric oxide bioavailability, increased oxidative stress and endothelial dysfunction,12 increased insulin resistance,13 or combinations thereof. It is possible that high serum uric acid concentrations may contribute to the exaggerated SBP to maximal exercise via the above‐referenced mechanisms.14 However, it remains unclear whether high serum uric acid concentrations are independently associated with an excessive SBP response to maximal exercise testing. The aim of this study was to evaluate the hypothesis that high serum uric acid concentrations are related to an exaggerated SBP response to maximal exercise testing in healthy men with normotension, independent of potential confounding variables.

2. METHODS

2.1. Participants

From a total of 5616 individuals who underwent standardized health examinations in 2009 at Samsung Medical Center (Seoul, South Korea), 4640 men (aged 21–80 years) who were free of known cardiovascular disease, hypertension, and type 2 diabetes mellitus were included in the subsequent analysis. Written informed consent was obtained from all participants before undergoing health screening, and the study was approved by Samsung Medical Center's institutional review board.

Body mass index was calculated as weight (kg) divided by the square of the height (meters). Smoking habits were evaluated via a self‐reported questionnaire. Resting BP was measured with the patient in the seated position by a nurse following at least 5 minutes of quiet rest using an automated BP monitor (Dinamap PRO 100). The lowest value of two measurements was used as resting BP.

2.2. Procedures

Blood samples were collected following an overnight fast (12 hours) and analyzed by the hospital clinical laboratory. Total cholesterol, low‐density lipoprotein cholesterol, high‐density lipoprotein cholesterol, and triglycerides were analyzed by enzymatic colorimetric and liquid selective detergent methods, respectively, using a Modular D2400 (Roche Diagnostics). Fasting glucose levels were determined using the Hexokinase, UV method (Hitachi‐7600). Fasting insulin concentration was measured with an immunoradiometric assay (TFB). Serum uric acid levels were assessed by the enzymatic colorimetric method using a clinical chemistry auto analyzer (Aeroset, Abbott Lab, Abbott). High‐sensitivity C‐reactive protein (hs‐CRP) was measured using a C‐reactive protein (II) Latax X2 turbidimetric method (Hitachi Corporation). Fibrinogen was measured by a clotting method using an STA coagulation analyzer (Stago S.A.). White blood cell count was determined using a quantitative automated hematology analyzer (Sysmex Corporation). Hyperuricemia was defined as uric acid levels >7.0 mg/dL. The homeostatic model assessment for insulin resistance (HOMA‐IR) was employed to estimate insulin resistance based on the following formula: fasting glucose [mg/dL] × fasting insulin [μU/L]/405 for insulin resistance.

Treadmill exercise testing was conducted using the Bruce or modified Bruce protocol. Cardiorespiratory fitness was directly measured during progressive testing to volitional fatigue (Jaeger Oxycon Delta, Erich Jaeger) and defined as the highest or peak attained oxygen consumption (VO_2peak), expressed as mL/kg per min, recorded during the test. BP was measured using an automated BP monitor designed for exercise testing (STBP‐680 Colin) during the last minute of each 3‐minute stage and at peak effort, with the arm relaxed at the side without holding onto the treadmill handrail. This equipment uses auscultation with R‐wave gating in the identification of Korotkoff sounds. The use of an integrated headset was employed by testers to ensure a standardized and consistent identification of Korotkoff sounds by the automated monitor. Peak SBP was defined as the highest value achieved during the progressive exercise test to volitional fatigue or adverse signs/symptoms. Detailed methods of exercise testing have been previously described.15 Relative SBP responses were calculated as the difference between seated resting SBP before exercise testing and peak SBP achieved during peak or symptom‐limited treadmill testing. An exaggerated BP was defined as SBP ≥ 210 mm Hg during treadmill testing to volitional fatigue.16

2.3. Statistical analysis

Data are expressed as mean ± standard deviation for continuous variables and as proportion for categorical variables. hs‐CRP and triglyceride values were reported as median and interquartile range by reason of skewed distributions. For the two group comparisons by the presence of an exaggerated SBP response (≥210 mm Hg), variables were analyzed using an independent t test and χ² tests for continuous and categorical variables, respectively. The hs‐CRP and triglycerides were analyzed using a nonparametric t test (Mann‐Whitney test). Pearson correlations were used to determine the relationships between exercise SBP variables and uric acid concentrations. Analysis of variance was used to compare the relative exercise‐induced increases in SBP with serum uric acid quartiles.

To determine the association between uric acid concentrations and the exaggerated SBP response, participants were divided into quartiles according to uric acid concentrations. We then performed multivariable logistic regression analyses based on the lowest quartile as a reference. We also calculated odds ratios with 95% confidence intervals from logistic regression to determine the relation of uric acid to an exaggerated SBP response using continuous variables. Multivariate logistic regression models were calculated after adjusting for potential confounding variables, including age, body mass index, SBP, total cholesterol, high‐density lipoprotein cholesterol, triglycerides, HOMA‐IR, hs‐CRP, fibrinogen, white blood cell count, cigarette smoking, and VO_2peak. All analyses were conducted using SPSS (IBM, SPSS version 22.0), and α was set at P < .05.

3. RESULTS

Characteristics of all participants as delineated by their maximal SBP response to exercise testing (ie, normal vs exaggerated) are shown in Table 1. Of 4640 participants, 152 (3.3%) demonstrated an exaggerated SBP response to exercise. Participants with an exaggerated SBP response had greater body mass index, resting SBP/diastolic BP, triglycerides, glucose, insulin, fibrinogen, HOMA‐IR, white blood cell count, hs‐CRP, and uric acid levels and were more likely to be smokers. In contrast, they demonstrated a lower VO_2peak than their counterparts who exhibited normal SBP responses to exercise testing.

Table 1.

Characteristics of participants according to maximal SBP response to treadmill exercise testing (n = 4640)

Variables	Normal SBP (<210 mm Hg) (n = 4488)	Exaggerated SBP (≥210 mm Hg) (n = 152)	P value
Age, y	49.1 (7.4)	49.4 (7.8)	.632
BMI, kg/m2	24.2 (2.5)	25.7 (2.8)	<.001
Current smokers, %	19.2	27.0	.017
SBP, mm Hg	115.6 (11.3)	125.8 (10.1)	<.001
DBP, mm Hg	74.7 (8.3)	78.8 (7.2)	<.001
TC, mg/dL	200.8 (33.8)	203.7 (32.1)	.301
HDL‐C, mg/dL	49.5 (12.2)	47.7 (11.4)	.070
LDL‐C, mg/dL	128.1 (29.5)	128.8 (28.4)	.789
Triglycerides, mg/dL	121.0 (87.0–172.0)	153 (119.3–210.8)	<.001
Glucose, mg/dL	94.1 (9.9)	96.0 (10.5)	.021
Insulin, mg/dL	7.9 (4.0)	9.4 (5.8)	<.001
HOMA‐IR	1.87 (1.04)	2.24 (1.33)	<.001
Fibrinogen, mg/dL	276.2 (56.2)	289.5 (52.2)	.004
WBC, x109 cells/L	5.90 (1.6)	6.36 (1.9)	.001
hs‐CRP, mg/L	0.06 (0.03–0.11)	0.08 (0.04–0.16)	.002
Uric acid, mg/dL	5.86 (1.2)	6.26 (1.0)	<.001
Hyperuricemia, %	16.0	25.0	.003
Maximal heart rate, bpm	157.1 (11.5)	155.7 (11.8)	.151
VO2peak, mL/kg per min	33.3 (4.6)	31.8 (4.1)	<.001
Maximal exercise SBP, mm Hg	170.1 (17.2)	221.4 (8.6)	<.001
Exercise‐induced increases in SBP, mm Hg	48.9 (14.3)	85.3 (11.2)	<.001

Data are expressed as mean (standard deviation), percentage, or median (interquartile range). BMI, body mass index; DBP, diastolic blood pressure; HDL‐C, high‐density lipoprotein cholesterol; HOMA‐IR, homeostasis model assessment for insulin resistance; hs‐CRP, high‐sensitivity C‐reactive protein; LDL‐C, low‐density lipoprotein cholesterol; SBP, systolic blood pressure; TC, total cholesterol; WBC, white blood cell count; VO_2peak, peak oxygen uptake.

Serum uric acid was correlated with maximal SBP responses (r = .11, P < .001) and the relative exercise‐induced increase in SBP (r = .09, P < .001). The Figure 1 shows mean ± standard deviation comparisons of the relative exercise‐induced increases in SBP according to serum uric acid quartiles. Participants in the highest quartile of serum uric acid concentrations (>6.6 mg/dL) had higher relative exercise‐induced increases in SBP (51.6 ± 16.5 mm Hg vs 48.2 ± 14.9 mm Hg, P < .001) than those in the lowest quartile of serum uric acid concentrations (<5.1 mg/dL). In addition, participants with hyperuricemia (>7.0 mg/dL) had a greater prevalence of exaggerated SBP responses to maximal exercise than did participants without hyperuricemia (25% vs 16%, P = .003).

Figure 1.

Comparison of the relative exercise‐induced increases in systolic blood pressure (SBP) according to serum uric acid quartiles (P < .001)

Multivariable logistic regression analyses showed that participants in the highest quartile of serum uric acid concentration (>6.6 mg/dL) demonstrated a higher odds ratio of having an exaggerated SBP response to exercise (odds ratio, 2.19; 95% confidence interval, 1.24–3.86) as compared with participants in the lowest quartile of serum uric acid (<5.1 mg/dL), after adjusting for age, body mass index, SBP, total cholesterol, high‐density lipoprotein cholesterol, triglycerides, HOMA‐IR, hs‐CRP, fibrinogen, white blood cell count, cigarette smoking, and VO_2peak (Table 2). Each unit increment in serum uric acid was associated with a 16% increased prevalence of having an exaggerated SBP response to maximal exercise testing in the adjusted model (odds ratio, 1.16; 95% confidence interval, 1.00–1.34) (Table 2).

Table 2.

Prevalence of an exaggerated SBP (≥210 mm Hg) response to exercise according to serum uric acid quartiles

Variables	Cases( (No., %)	Unadjusted model OR (95% CI)	Adjusted model OR (95% CI)
Quartile 1 (n = 1173) (<5.1 mg/dL)	19 (1.6)	1 (ref)	1 (ref)
Quartile 2 (n = 1209) (5.2–5.8 mg/dL)	35 (2.9)	1.81 (1.13‐3.18)	1.53 (0.85‐2.76)
Quartile 3 (n = 1055) (5.9–6.5 mg/dL)	37 (3.5)	2.21 (1.26‐3.86)	1.82 (1.01‐3.27)
Quartile 4 (n = 1203) )(>6.6 mg/dL)	61 (5.1)	3.24 (1.93‐5.47)	2.19 (1.24‐3.86)
Per 1‐mg/dL increase		1.32 (1.16‐1.51)	1.16 (1.00‐1.34)

Adjusted for age, body mass index, systolic blood pressure (SBP), total cholesterol, high‐density lipoprotein cholesterol, triglycerides, homeostatic model assessment for insulin resistance, high‐sensitivity C‐reactive protein, fibrinogen, white blood cell count, cigarette smoking, and peak oxygen uptake. CI, confidence interval; OR, odds ratio.

4. DISCUSSION

We found that healthy men with normotension who had elevated serum uric acid concentrations as categorical and/or continuous variables demonstrated an exaggerated SBP response to maximal exercise testing. This association remained significant even after adjusting for confounding variables, including resting SBP and insulin resistance, which have been previously shown to predict an exaggerated SBP response to maximal exercise.14 To our knowledge, this is the first study to report a relationship between increased serum uric acid concentration and an excessive BP response to maximal exercise testing in healthy men with normotension.

During progressive dynamic exercise to maximum exertion, SBP normally rises with increasing cardiac output, whereas diastolic BP generally remains unchanged or slightly decreases as a result of vasodilatation and decreased peripheral vascular resistance.14 An exaggerated SBP response to exercise in individuals who have normotension at rest is associated with an increased risk for incident hypertension and serves as an independent predictor of subsequent cardiovascular events and mortality.1 Thus, an exaggerated SBP response to maximal exercise testing has prognostic significance. In the present study, the prevalence of an exaggerated SBP response to treadmill exercise testing was 3.3%. This rate is consistent with that reported in a previous systematic review, which demonstrated that the prevalence of an exaggerated BP across multiple apparently healthy cohorts of varying age, sex, and ethnicity was approximately 3% to 4%.17 Although a disproportionate BP response to physical exertion is clinically significant and associated with an abnormal risk factor profile and impaired vascular function,2, 3, 4, 5, 6, 7 the mechanisms underlying exercise‐induced hypertension remain unclear. Moreover, the prevalence of an exaggerated exercise BP response may partially depend on the exercise test modality, test protocol (maximal or submaximal test), criteria for an exaggerated exercise BP response, study population, sample size, or combinations thereof.14

The role of serum uric acid has been implicated in the pathogenesis of primary hypertension in the young.18 Although elevated uric acid concentrations are associated with an increased risk of incident or uncontrolled hypertension,8, 9, 10 the relationship between high uric acid concentrations and an exaggerated BP response to maximal exercise testing in men with normotension has not been previously reported. In the present study, high serum uric acid was associated with an exaggerated SBP response to exercise in healthy men with normotension. Our data indicate that a high serum uric acid level is linked with an exaggerated SBP response to exercise, which is a potential harbinger of resting hypertension.16 Alternatively, an elevated uric acid level may serve as a biomarker for individuals at risk for exercise‐induced hypertension and associated cardiovascular sequelae.

The mechanisms underlying the association between increased serum uric acid concentration and an exaggerated SBP response to exercise are unclear, but several possible explanations may apply. Increased serum uric acid induces vasoconstriction by augmenting renin‐angiotensin‐aldosterone activity11 and by reducing circulating nitric oxide concentration,12 which may contribute to exercise‐induced hypertension. Additionally, endothelial dysfunction following high uric acid exposure19 may be associated with an exaggerated BP response to exercise.20 Furthermore, a heightened level of vascular stiffness may be triggered by an elevated serum uric acid concentration in healthy adults21 and patients with untreated hypertension,22 potentially contributing to the abnormal rise in exercise BP.23 However, it is noteworthy that, in the present study, increased uric acid was associated with an exaggerated SBP response to maximal exercise, independent of insulin resistance. A previous study has suggested that insulin resistance using HOMA‐IR was closely related to an exaggerated SBP response to maximal exercise.3 It is well known that insulin reduces uric acid excretion from the kidneys, which highlights the potential interactions between uric acid, insulin resistance, and an exaggerated SBP response to maximal exercise.3, 13 Because uric acid was associated with an exaggerated SBP response to maximal exercise even after adjusting for insulin resistance in the present study, it is possible that higher serum uric acid concentrations may potentially contribute to an exaggerated BP response to exercise, independent of insulin resistance. However, our study was not designed to investigate the associated underlying mechanisms, and, thus, further studies are needed in this regard.

An exaggerated BP response to exercise in individuals who have normotension at rest may potentially indicate the presence of masked hypertension.24 Accordingly, serum uric acid concentrations have been reported to be higher in individuals with masked hypertension than in those with normotension.25 Thus, our results contribute to an increased understanding of the relationship between uric acid concentration and masked hypertension via the detection of an exaggerated BP response to exercise. On the other hand, it is unknown whether decreasing serum uric acid concentration by medications, such as allopurinol, or via lifestyle interventions may attenuate the risk of developing an excessive BP response to exercise.

5. STUDY LIMITATIONS

We acknowledge several methodological limitations to our study. Given the cross‐sectional design, we could not determine causality. Our study population included only men, which limits the generalizability of our findings to women. Further studies are needed to clarify the potential impact of sex and age differences in these relationships. Our database did not contain information regarding dietary practices, purines, or urinary sodium excretion, which may also serve as confounding variables. Furthermore, we did not consider the confounding effects of gout, underlying renal disease, and related medications in the present study. Increased serum uric acid levels are closely associated with renal disease26 and, therefore, we cannot exclude the possibility that high uric acid levels are indicative of early chronic kidney disease. We did not control for family history of hypertension, although some studies have reported that family history may be unrelated to an exaggerated exercise BP.27 In addition, BP during exercise testing was measured only once; therefore, we were unable to provide BP reproducibility data. Nevertheless, previous studies have reported that BP measured during exercise testing has been shown to be reliable, reproducible, and accurate. Finally, we acknowledge that HOMA‐IR is only a surrogate marker of insulin resistance, and that a residual confounding effect of “true” insulin resistance cannot be excluded in the interpretation of our findings. Thus, it may represent an additional study limitation.

6. CONCLUSIONS

Our results suggest that high serum uric acid concentrations are associated with an exaggerated SBP response to maximal exercise, independent of established risk factors in men with normotension. As such, hyperuricemia in individuals with normotension may be a predictive biomarker for patients at risk for exercise‐induced hypertension and its associated comorbidities.

CONFLICT OF INTEREST

The authors report no relationships that could be construed as a conflict of interest.

Jae SY, Bunsawat K, Choi Y‐H, et al. Relation of serum uric acid to an exaggerated systolic blood pressure response to exercise testing in men with normotension. J Clin Hypertens. 2018;20:551–556. 10.1111/jch.13219