Physiological serum uric acid concentrations correlate with arterial stiffness in a sex-dependent manner

Abstract

Background: In humans, uric acid is a product of purine metabolism that impacts the vascular system. In addition to effects on arterial vascular tone, associations between serum uric acid concentrations-even in the physiological range-and arterial hypertension and vascular-mediated end-organ damage due to an impact on vascular stiffness have been postulated.

Methods: Therefore, we aim to investigate a possible cross-sectional association between serum uric acid concentrations in the physiological range and differences in arterial pulse wave velocity (PWV), an indicator of vascular remodeling, with a focus on possible differences between female and male individuals. We analyzed cross-sectional phenotypic and laboratory parameters, including PWV from 70,649 individuals in the population-based German National Cohort (NAKO) in a sex-specific manner. In parallel, we applied a machine learning approach to identify and quantify factors associated with PWV in a hypothesis-free manner.

Results: Our analysis uncovered a positive association between serum uric and PWV which was detected even if only individuals with urate values in the physiological range were included (n = 64,095). This correlation was more pronounced in women than in men. In multivariable linear regression models, we observed an association of uric acid (mmol/l) with PWV (m/s) of β = 1.12 (95% confidence interval (CI): 0.78; 1.45) in males and β = 1.35 (1.05; 1.66) in females, independent of other factors known to affect vascular stiffness. In addition, the machine learning approach identified uric acid as a major factor associated with PWV. The positive association was not restricted to hyperuricemia but evident even in the physiological concentration range. Based on the data from studies on the impact of aging on PWV, it is estimated that an increase in serum uric acid concentration by 0.1 mmol/l corresponds to an increase of approx. 7 years of age in females and of 4 years in males.

Conclusions: Already in the physiological concentration range, uric acid is positively associated with parameters of arterial stiffness. This association is more pronounced in females as compared to males. This finding provides a mechanistic explanation for the increased risk of vascular end-organ damage associated with higher serum uric acid concentrations and supports the observed greater benefit of therapeutic uric acid lowering in female. Future intervention studies have to address the mechanistic causality of the observed effect.

Keywords: Female health; Hyperuricemia; Pulse wave velocity; Urate; Vascular damage; Vascular stiffness.

Fig. 1

Frequency distribution of the arterial pulse wave velocity in the study population and stratified by sex

Fig. 2

Association of pulse wave velocity and serum urate level for male (n = 33,803) and female (n = 37,953) persons. Serum urate was classified in low (male: ≤ 180 µmol/l, female: ≤ 140 µmol/l), normal (male: 180 < – ≤ 420 µmol/l, female: 140 < – ≤ 360 µmol/l), and high (male: > 420 µmol/l, female: > 360 µmol/l) values. The regression lines were calculated from all individual data in the respective sex group (not adjusted for other covariates). For the presentation, the data were grouped and the means ± SD of serum urate and PWV for each group are shown

Fig. 3

Feature importance measured by mean %IncMSE using random forests in a tenfold CV scheme; values are reported by mean and standard deviation. Hypertension = measured systolic ≥ 140 or diastolic blood pressure ≥ 90; hypertension (disease) = self-reported diagnosis of hypertension; self-reported cardiovascular diseases = intermittent claudication or circulatory disorders in the legs, also known as intermittent claudication or arterial occlusive disease; 1 st cancer type = entity of the first diagnosed cancer if cancer has ever been diagnosed