The URRAH study

BACKGROUND: Uric acid has long been considered responsible for a single specific disease, namely gout. In recent years, novel knowledge has emerged linking serum uric acid with a variety of conditions and related risk factors, from hypertension, metabolic syndrome, and type 2 diabetes, to fatal/nonfatal cardiovascular diseases and all-cause death, with the underlying mechanisms involving disrupted neurohormonal and metabolic signaling as well as oxidative stress and inflammation. Importantly, the cut-off value of serum uric acid that predicts the risk of incident events is within the range of normality and below the threshold for increased risk of gout. A large contribution to the advancement in knowledge in the cardiovascular implications of uric acid derives from the Italian study URic acid Right for heArt Health (URRAH).METHODS: The URRAH study is an Italian nationwide, multicenter retrospective, observational cohort study combining data from outpatients attending hypertension clinics, as well as individuals recruited in prospective observational cohort studies with a follow-up period of at least 20 years up to July 31st, 2017. Data were retrospectively collected from different databases. At the end of the follow-up, the following hard endpoints were evaluated: fatal myocardial infarction; non-fatal acute myocardial infarction; heart failure; fatal stroke; non-fatal stroke; coronary revascularization.RESULTS: A total of 22,714 subjects were included in the analysis. During a median follow-up time of 134 months, a total of 3279 deaths were recorded, of which 1571 were due to cardiovascular causes. Multivariate Cox regression analyses identified an independent association between serum uric acid concentrations and both total (HR=1.53, 95% CI 1.21-1.93, P<0.001) and cardiovascular deaths (HR=2.08, 95% CI 1.146-2.97; P<0.001). Of note, the cut-off values of serum uric acid that were identified as those able to predict total mortality were largely within the normal range (4.7 mg/dL, 95% CI 4.3-5.1 mg/dL). Similarly, the cut-off value that better predicted cardiovascular death was within the normal range (5.6 mg/dL, 95% CI 4.99-6.21 mg/dL). The information on serum uric acid levels provided a significant net reclassification improvement of 0.26 and 0.27 over the Heart Score risk chart for total and cardiovascular mortality, respectively (P<0.001). Serum uric acid levels >= 4.7 or <4.7 mg/ dL incrementally predicted all-cause mortality over the Heart Score.CONCLUSIONS: The results of studies from the URRAH database further strengthen the role of uric acid in cardiovascular disease, including heart failure, and total mortality. The identified cut-off values support clinicians in investigating serum uric acid levels in their patients and to consider uric acid as an additional cardiovascular risk factor. Taken together, the published papers deriving from the URRAH database emphasize the role of uric acid in favoring cardiovascular events, and strongly suggest the existence of "grey" areas, i.e. close but lower than the "traditional" threshold for hyperuricemia, which deserve further characterization.