Could Uric Acid Be Considered a Cardiovascular Risk Factor?

Since the 19th century, uric acid (UA) has been related to a higher prevalence of arterial hypertension1 and, during the past decades, an increasing number of studies have been published showing a relationship between UA and incident hypertension,2 heart failure,3 onset of chronic kidney disease,4 metabolic syndrome, obesity, and diabetes.5 However, UA is not accepted as a cardiovascular risk factor by the scientific community, although it has shown an independent and strong association with cardiovascular morbidity and mortality.6, 7

Results from published studies state a weak to moderate association, but not strong in any case, defined as a risk in which the minimum interval value is >2. Moreover, UA level changes caused by pharmacologic treatment did not predict all‐cause or cardiovascular mortality.8 However, it is with the physiopathologic mechanism that more questions arise.

Under normal conditions, UA behaves as an antioxidant molecule that defends the organism against reactive oxygen species, but, for some reason, in select metabolic conditions, UA is responsible for oxidative activity in vascular, liver, and renal cells and adypocites.9

These specific conditions are related to adipocytes activity in the metabolic syndrome, wherein there is an interaction between UA and the immune system, with an increase in proinflammatory cytokines production, which inhibits nitric oxide production and interacts with peripheral vascular tone control and microvascular disturbances.

Thus far, studies have established a relationship between UA, incident arterial hypertension, and cardiovascular morbidity and mortality.2, 6, 7 The study by Çağlı and coworkers10 in this Journal takes a step forward in relating UA levels with blood pressure (BP) variability (BPV), in particular with short‐term BPV. In their paper, UA levels presented on a logarithm scale showed a weak correlation with systolic BPV on ambulatory BP monitoring (ABPM) and a moderate correlation with diastolic BPV on ABPM expressed as the standard deviation. This correlation remained when the standard deviation was weighted by the nocturnal and diurnal period, a variable with better prognostic value than simple standard deviation. BPV showed a modest but significant association with the onset of target organ damage and cardiovascular complications.

Both long‐ and short‐term BPV are independently associated with increased cardiovascular risk but even so are not useful for better stratification of cardiovascular risk compared with the values obtained from ABPM.11, 12 Therefore, BPV could be considered a weak surrogate variable when it comes to prognostic value even if it is justified in studies in which the purpose is to discover the influence of different factors, allowing the creation of a new hypothesis.

A possible explanation for the better correlation between UA and diastolic BPV can be found in the association between peripheral resistance and diastolic BP (DBP). It has been shown that in hypertensive individuals, higher UA levels are associated with higher resting forearm blood flow and lower reactive hyperemia, markers of microvascular function.13 High UA levels can increase DBP variability by means of a disturbance in vascular tone, partly depending on endothelial function and nitric oxide. Because of this we can theorize about the possible link between endothelial dysfunction, peripheral resistance, and UA, with the variability a clinical expression of this interaction.

In addition, the authors presented a positive and independent correlation between waist circumference and systolic and diastolic nighttime BPV. Waist circumference is one of the most important components in the metabolic syndrome that is associated with the UA oxidative effect. However, night breathing alterations may play a role in nocturnal SBP and DBP variability. UA levels are also associated with hemoglobin levels, showing a possible link between the patterns found in the night breathing disorders and nocturnal hypoxemia.

There are some limitations in the work by Çağlı and coworkers. The most important of which is the cross‐sectional design of the study, which makes it impossible to establish a causality relationship, and, therefore, the hypothesis derived from this work should be confirmed in the future by other studies created for this purpose. As stated by the authors, AU levels follow a circadian rhythm, with higher UA levels during the night and the first hours in the morning, possibly caused by a decrease in urine production and renal excretion during this time. However, there was no information about any action to control for this fact, as a fixed hour to collect blood samples, and possibly prevent a potential bias. Finally, to show the relationship between UA and other short‐term variability measures as the ABPM night‐day ratio or the morning surge measure in addition to the simple standard deviation and weighted standard deviation could contribute to a better understanding of this fact.

To define the genetic, metabolic, and environmental factors related to the dual effect of UA with the reactive oxygen species, to establish a physiopathologic model that explains the role of UA levels in the chain of events that lead to cardiovascular disease, and to understand the degree of improvement in risk prediction when incorporating UA into the equations of cardiovascular risk is in fact needed to consider UA as a cardiovascular risk factor.

It may be a long road until UA is considered a cardiovascular risk factor, but the work by Çağlı and colleagues is an interesting contribution to this path.