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Uric acid and cardiovascular risk stratification in the acute coronary syndromes: a friend we should mind

Published:February 17, 2022DOI:https://doi.org/10.1016/j.ejim.2022.02.017
      Uric acid (UA) is the end product of purine metabolism. Whilst being primarily known as the leading risk factor for the onset of gout [
      • Dalbeth N.
      • Choi H.K.
      • Joosten L.A.B.
      • Khanna P.P.
      • Matsuo H.
      • Perez-Ruiz F.
      • Stamp L.K.
      Gout.
      ], UA has also been acknowledged as a significant CV risk factor [
      • Virdis A.
      • Masi S.
      • Casiglia E.
      • et al.
      Identification of the uric acid thresholds predicting an increased total and cardiovascular mortality over 20 years.
      ]. However, international guidelines report as pathological threshold only the saturation point of UA (6.0 mg/dL in women and ≥7.0 mg/dL in men) [
      • Li Q.
      • Li X.
      • Wang J.
      • et al.
      Diagnosis and treatment for hyperuricemia and gout: a systematic review of clinical practice guidelines and consensus statements.
      ], yet failing to identify a specific CV prevention cut-off [
      • Visseren F.L.J.
      • Mach F.
      • Smulders Y.M.
      • et al.
      2021 ESC guidelines on cardiovascular disease prevention in clinical practice.
      ]. This somewhat neglects UA predictive role in CV disease [
      • Kaufman M.
      • Guglin M.
      Uric acid in heart failure: a biomarker or therapeutic target?.
      ]. 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) [
      • Virdis A.
      • Masi S.
      • Casiglia E.
      • et al.
      Identification of the uric acid thresholds predicting an increased total and cardiovascular mortality over 20 years.
      ]. Several other observations have also found that UA enhances the CV mortality and morbidity risk stratification across the totality of the cardiometabolic spectrum using the same lower cut-offs [
      • Pugliese N.R.
      • Mengozzi A.
      • Virdis A.
      • et al.
      The importance of including uric acid in the definition of metabolic syndrome when assessing the mortality risk.
      ,
      • Muiesan M.L.
      • Salvetti M.
      • Virdis A.
      • et al.
      Serum uric acid, predicts heart failure in a large Italian cohort: search for a cut-off value the uric acid right for heart health study.
      ]. 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) [
      • Maloberti A.
      • Biolcati M.
      • Ruzzenenti G.
      • et al.
      The role of uric acid in acute and chronic coronary syndromes.
      ].
      In the present issue of the Journal, Rebora et al [
      • Rebora P.
      • Centola M.
      • Morici N.
      • et al.
      Uric acid is associated with acute heart failure and shock at presentation in ACS patients.
      ]. 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 [
      • Magnoni M.
      • Berteotti M.
      • Ceriotti F.
      • et al.
      Serum uric acid on admission predicts in-hospital mortality in patients with acute coronary syndrome.
      ]. 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) [
      • Terada L.S.
      • Guidot D.M.
      • Leff J.A.
      • Willingham I.R.
      • Hanley M.E.
      • Piermattei D.
      • Repine J.E.
      Hypoxia injures endothelial cells by increasing endogenous xanthine oxidase activity.
      ]. A recent work cited by the authors shows that XO inhibition during the acute phase following myocardial infarction in murine models prevents skeletal muscle impairment and exercise intolerance [
      • Nambu H.
      • Takada S.
      • Maekawa S.
      • et al.
      Inhibition of xanthine oxidase in the acute phase of myocardial infarction prevents skeletal muscle abnormalities and exercise intolerance.
      ]. Furthermore, XO leads to LDL oxidation and indirectly activates the inflammasome [
      • Terada L.S.
      • Guidot D.M.
      • Leff J.A.
      • Willingham I.R.
      • Hanley M.E.
      • Piermattei D.
      • Repine J.E.
      Hypoxia injures endothelial cells by increasing endogenous xanthine oxidase activity.
      ]. Recently, an epidemiological observation showed how UA could also directly influence proinflammatory variant rs10754555 of NLRP3 inflammasome [
      • Schunk S.J.
      • Kleber M.E.
      • März W.
      • et al.
      Genetically determined NLRP3 inflammasome activation associates with systemic inflammation and cardiovascular mortality.
      ]. Higher levels of UA reflect a vascular phenotype characterized by microvascular remodelling and endothelial dysfunction [
      • Masi S.
      • Georgiopoulos G.
      • Alexopoulos G.
      • et al.
      The complex relationship between serum uric acid, endothelial function and small vessel remodeling in humans.
      ]. Finally, we know that, though few data are available, UA levels’ trajectories during hospitalization [
      • Yamamoto H.
      • Nagatomo Y.
      • Mahara K.
      • Yoshikawa T.
      In-hospital serum uric acid change predicts adverse outcome in patients with heart failure.
      ] and UA levels’ reduction mediated by hypouricemic drugs [
      • Pavlusova M.
      • Jarkovsky J.
      • Benesova K.
      • et al.
      Hyperuricemia treatment in acute heart failure patients does not improve their long-term prognosis: a propensity score matched analysis from the AHEAD registry.
      ] 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 [
      • Pugliese N.R.
      • Mengozzi A.
      • Virdis A.
      • et al.
      The importance of including uric acid in the definition of metabolic syndrome when assessing the mortality risk.
      ], 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 [
      • Virdis A.
      • Masi S.
      • Casiglia E.
      • et al.
      Identification of the uric acid thresholds predicting an increased total and cardiovascular mortality over 20 years.
      ]. 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.
      Fig. 1
      Fig. 1Higher serum uric acid levels in patients with acute coronary syndromes translate to a higher risk of developing acute heart failure and relative complications. Pathophysiologic hypothesis speculates that uric acid levels at admission might reflect chronic levels and thus be a marker of a cardiometabolic damaged phenotype. ER: Emergency room; ICU: Intensive cardiology unit.
      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.

      Acknowledgements

      Figure is created with biorender.com.

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      Linked Article

      • Uric acid associated with acute heart failure presentation in Acute Coronary Syndrome patients
        European Journal of Internal MedicineVol. 99
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          Uric Acid (UA) has been related to the development of fatal and non-fatal Cardio-Vascular (CV) events in the general population [1] as well as in patients experiencing an Acute Coronary Syndromes (ACS) [2] and in those affected by Heart Failure (HF) [3]. 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 [4]. Furthermore, UA was also associated with the development of new-onset HF [5] and with a lower Left Ventricular Ejection Fraction (LVEF) and exercise capacity and a higher NYHA class [6].
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