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I read the article by Hwang et al. [1], titled “Relationship between serum uric acid level and hypertension: a retrospective cohort study.” The investigators showed that 2,353 patients who initially underwent general medical examinations went on to develop hypertension 10 years later, and that this development was associated with their baseline uric acid levels [1].
From the perspective of causality assessment (Figure 1), primarily including the Bradford Hill criteria for causation [2], the present study provides evidence that high uric acid levels can cause hypertension. First, by the nature of a cohort study, this study could establish a clear timeline that uric acid levels preceded hypertension (temporality). Second, elevated uric levels were independently associated with the development of hypertension in this study (specificity). Elevated uric acid and high blood pressure (BP) share common risk factors, including age, sex, body mass index, fasting blood glucose level, lipid profile, estimated glomerular filtration rate, smoking, and alcohol consumption. After adjusting for these cofactors, the association between uric levels and hypertension persisted. Third, the incidence of hypertension in the tertile groups was significantly different. Adjusted odds ratios (95% confidence interval [CI]) for incident hypertension, compared with the 1st tertile, were 1.53 (1.11‒2.10) and 1.66 (1.17‒2.37) for the 2nd and 3rd tertiles, respectively. Dose-response relationship between uric acid level and hypertension is considered strong evidence for a causal relationship.
Several cross-sectional studies [3,4] and cohort studies [5-7] have reported that an elevated uric acid level is an associated factor or risk factor of hypertension (consistency). The relationship between serum uric acid levels and BP was dose-dependent and linear. Two meta-analyses demonstrated that each 1 mg/dL increase in serum uric acid concentration contributed to a 13%‒15% increase in hypertension [8,9], ad that hyperuricemia is a strong predictor of hypertension, with an approximately 2-fold risk within 5 years [10]. Contrary to our general belief, elevated uric acid levels are strongly linked with the development of hypertension as obesity, salt intake, and smoking (strength of the association). In recent studies, uric acid levels below the normal range were significantly associated with hypertension, creating a J-shaped curve [5,11]. In the present study, the 1st tertile of uric acid levels was categorized as 0.6‒4.3 mg/dL. This group included most individuals with the lower limit of normal and relatively few individuals with lower-than-normal uric acid levels. This may explain why the J-curve phenomenon was not observed in the present study.
It is intriguing to note that uric acid plays contradictory, double-edged roles in the body [12-14]. Uric acid has antioxidant properties that protect against free radicals and reactive oxygen species [13,14]. In contrast, it can exert harmful effects by inducing oxidative stress, inflammation, reduced nitric oxide (NO), and endothelial dysfunction [13,14]. Additionally, uric acid can induce the activation of the renin-angiotensin system [14,15]. Regarding the deleterious effects of uric acid, it is biologically plausible that many studies, including the present study, have shown a positive linear relationship between elevated uric acid levels and hypertension. However, the precise mechanism underlying the J-curve between elevated uric acid levels and hypertension remains unclear. In my opinion, when the uric acid level is in the normal range or above, the harmful effect of uric acid on BP could be relatively prominent compared to its protective role. Conversely, when the uric acid level is lower than normal, the reduction in the protective effect of uric acid could become relatively evident (Figure 2). Depending on its concentration, the differential effects of uric acid can explain the J-curve effect between uric acid and hypertension. Furthermore, the J-shaped association of uric acid with cardiovascular diseases and mortality in several longitudinal studies [16-18] could be interpreted similarly. Uratelowering treatment (ULT) has been shown to reduce BP in a few randomized controlled studies [19,20]. Recently, a meta-analysis of 14 randomized controlled trials showed a favorable effect (‒2.55 [95% CI, ‒4.06 to ‒1.05]) of ULT on systolic BP [21]. The effect of ULT on BP control (reversibility) suggests that the relationship between uric acid levels and hypertension is causal.
Uric acid is an additional risk factor for cardiovascular diseases, including hypertension [13-15]. Accordingly, several guidelines, such as the 2023 guidelines of the European Society of Hypertension [22] and Japanese guidelines on asymptomatic hyperuricemia [23], have suggested the importance of uric acid as a modifiable cardiovascular risk factor. Fortunately, some cardiovascular drugs (angiotensin II receptor blockers [particularly losartan], statins [particularly atorvastatin], fenofibrate, sodium/glucose cotransporter 2 inhibitors) commonly used in primary care can have indirect urate-lowering effects [24,25].
Notes
Conflict of interest
No potential conflict of interest relevant to this article was reported.
Funding
None.
Data availability
Not applicable.
Author contribution
All the work for the preparation of this letter was done by Ki Dong Ko.
Figure. 1.
Causality assessment viewpoints, primarily including Bradford Hill criteria for causation.
Figure. 2.
The differential effect of uric acid depending on its concentration, explaining the J-curve effect between uric acid and hypertension.
References
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