In our study, elevated SUA concentrations indicated a substantially higher risk of future adverse outcomes in a large, contemporary cohort of elderly chronic HF inpatients, independent of other prognostic markers. Importantly, our data are the first to show that the adverse prognostic value of elevated SUA in elderly patients with chronic HF is not confined to HFrEF or HFpEF patients, as can be documented in other HF phenotypes as categorized based on left ventricle EF.

We discovered that SUA is an important factor associated to AF in elderly patients with chronic HF. Existing studies strongly suggest that hyperuricemia is independently associated with the increasing incidence of AF. Experimental and clinical data indicate that SUA is implicated in the pathophysiology of AF via activation of inflammation, oxidative stress, and fibrosis induced atrial remodeling. Briefly, atrial remodeling involves electrophysiological and structural abnormalities that promote the development of SUA induced AF. Also, SUA induced AF activates apoptosis and immune system [10]. The prevalence of AF is increasing as the population ages. HF and AF often coexist and each condition can promote the other, with an associated increase in overall morbidity and mortality [11]. Furthermore, physiological relations between AF and HF are multifactorial and causally intertwined [12]. So, a higher SUA was associated with an increased risk of AF which may make the prognosis of HF become worse in the elderly with chronic HF.

Our study found that SUA levels are associated with poor clinical outcomes in elderly patients with chronic HF, not only because of renal function or diuretic dose, but also because SUA itself has direct effects likely to be harmful in HF [13]. High SUA could also reflect increased xanthine oxidase activity, and this, in turn, might result in oxidative stress, which is thought to play a detrimental role in HF [14]. For example, SUA may have proinflammatory and proliferative actions and cause endothelial dysfunction [15]. Moreover, systemic inflammation and endothelial dysfunction possibly associated with SUA are also postulated to be consequences of HF [16]. Interestingly, recent findings indicate that elevated SUA is associated with higher cytokine levels and a greater inflammatory response, which suggests that inflammation may play an important role [17]. However, we did not measure cytokine concentrations in our study, and therefore, the precise role of elevated SUA in this context remains to be determined.

Our study found that in hospitalized elderly patients with chronic HF, SUA is an independent prognosticator of adverse outcomes, which can be seen in HFrEF and HFmrEF patients. SUA has been incorporated in HF risk scores [18], and the European HF guidelines report that hyperuricemia is common and is associated with worse prognosis in HFrEF patients [2]. HFmrEF is an intermediate clinical entity between HFrEF and HFpEF groups in some respects but is more like HFrEF in others, in particular with regard to the high prevalence of ischemic heart disease in these patients [19]. Elevated SUA is associated with poor outcomes in patients after MI complications due to reduced LV function, HF, or both. Xanthine oxidase is an enzyme that is crucially involved in myocardial degradation of ATP and purine and a source of reactive oxygen species. Previous work has shown that in HF, the xanthine oxidase inhibitor allopurinol reduces oxidative stress and ameliorates myocardial energy deficiency [20]. One may speculate that SUA is an indicator of the degree of myocardial energy status. Moreover, SUA has been identified as a DAMP (danger-associated molecular pattern molecule) that can trigger and maintain proinflammatory responses and may be related to cardiovascular morbidity [21]. Novel mechanistic insights into allopurinol have prompted clinical evaluation as a putative HF therapeutic.

This study has several limitations. First, it was a single center and observational study with a limited number of patients. While follow-up lasted 18 months, it is possible that a longer follow-up would have allowed us to obtain further information so that the results should be considered to support the hypothesis and not to delineate cause and effect. Second, only baseline measurements of SUA levels were available, therefore, it was not possible to assess changes in SUA levels over time and to evaluate the implications of these changes on chronic HF outcomes. Third, unmeasured confounders may have not been considered in our analysis, and there was a difference in sample size among left ventricle EF strata, which could have affected risk estimate precision. Fourth, the proportion of more severe heart failure cases (NYHA heart failure class III/IV) was relatively low; thus, the results support the hypothesis, but future systematic studies are needed to confirm these findings.