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]. In a large (n=22,714) Italian-population based observation cohort study, we have described how UA markedly impact all-cause and CV mortality starting from lower serum levels (respectively, 4.7 and 5.6 mg/dL) [
]. However, whilst in the current literature the relationship between UA in CV disease has been explored mainly in a chronic context (i.e. diabetes, hypertension, chronic kidney disease), little evidence is available to help us in defining whether the predictive power of UA holds true also for the acute setting, such as the acute coronary syndrome (ACS) [
]. designed their study according to this relatively uncharted field of investigation. They inquired about the role of UA in a population of 1269 ACS patients admitted to a cardiology intensive care unit. The authors found that UA is associated with acute heart failure and its major complication, cardiogenic shock, but also with the need for non-invasive ventilation (NIV) and a lower ejection fraction at admission. This is not the first report to describe a relationship of UA with incident acute heart failure in the ACS [
]. However, no study had explored by far the consistency of the predictive power of UA in the whole gamut of acute heart failure related issues in patients with ACS. The strength and the solidity of the relationship are what come at first sight. In fact, these associations remain strong even after adjustment for several confounders, including diuretics.
However, the article also allows speculations on UA's behaviour in the acute setting. From a pathophysiological point of view, we know that hypoxic conditions lead to an overexpression of xanthine oxidase (XO). This, in turn, produces reactive oxygen species (ROS) [
] are not related to CV mortality. Such the above mentioned current literature, together with the findings by Rebora et al., lead to a fascinating hypothesis. It might be that UA levels at admission do possess a strong predictive value because they reflect chronic UA levels rather than the influence of the acute disease. And chronic higher UA levels are a marker of a damaged cardiometabolic phenotype. In these subjects, the hypoxic state, the microvascular impairment, the metabolic derangement, the pro-oxidant unbalance and the hyperinflammatory response all concur to a non-favourable prognosis following the acute event, i.e. ACS.
We should remember that the cross-sectional setting mitigates the findings’ relevance and substantially hinders any pathophysiological inquiry. Instead, from a pragmatic point of view, the investigation of Rebora et colleagues cleverly suggests looking at UA when, in the emergency room or in the intensive care unit, we need aid in the risk stratification. This is the clinical context in which the work by Rebora et al. takes place. Indeed, UA proves to be a formidable, readily available, and cost-effective biomarker of cardiovascular risk, which, as already demonstrated for the chronic disease [
], might substantially help the CV risk stratification in a setting, the ACS one, in which there is an urgent need. In this sense, the paper depicts the strength of UA as a marker of disease, related not only to the ACS risk but also the wholeness of its complications.
Few words should be spent on the UA's levels that alert us. The exploratory analysis of a specific cut-off for an outcome including the main ACS complications, acute HF and cardiogenic shock returned a specific value (7.1 mg/dL) flawed, though, by a poor sensitivity. As discussed by the authors, this may be due to the many factors involved in the ACS natural history, which also affect UA levels. We have already shown how UA is relevant to cardiovascular risk, starting from a level far below the gout threshold/UA saturation point [
]. Thus, a lower cut-off is probably needed, and this should undoubtedly be included in a score encompassing all the readily available biomarkers that better describe ACS Fig 1.
To conclude, this well-conducted study raises a rhetorical question: why should we not consider UA in the acute setting? Being a readily available and easily measurable marker, its levels might guide us to a more accurate stratification without affecting the decision time. Still, the direction of the relationship between UA and ACS (and its complication) and the putative mechanisms are yet to be defined. Also, a more precise (and probably lower) cut-off should be explored. Rebora et colleagues have left us with many fascinating questions that wait to be addressed.
Conflict of Interests
The authors declare they have no conflict of interest.
Uric Acid (UA) has been related to the development of fatal and non-fatal Cardio-Vascular (CV) events in the general population  as well as in patients experiencing an Acute Coronary Syndromes (ACS)  and in those affected by Heart Failure (HF) . In this latter group, results were also confirmed in the context of acute decompensated HF with a significant relationship between UA, measured at the time of admission, and subsequent long-term mortality and re-hospitalization . Furthermore, UA was also associated with the development of new-onset HF  and with a lower Left Ventricular Ejection Fraction (LVEF) and exercise capacity and a higher NYHA class .