Purine Metabolism in Heart Failure: Oxidant Biology and Therapeutic Indications

In a manuscript presented in this issue of Congestive Heart Failure, Chrysohoou and colleagues report a statistically significant relationship between an attenuation of left atrial function and impairment of right ventricular performance with serum uric acid (SUA) levels in patients with newly diagnosed heart failure (HF). Their study included the statistical investigation of SUA (segmented by tertiles) in relation to other measured variables from 106 patients with newly diagnosed HF. In this patient population, major findings included an association of SUA with systolic blood pressure, left atrial kinetic energy, and peak tricuspid annulus systolic velocity (determined via tissue Doppler imaging). This report complements several other studies that have documented relationships between SUA and cardiovascular disease in humans and presents 2 interesting observations: elevated levels of SUA were observed in patients with newly diagnosed HF and an association between SUA levels and cardiac function was identified. To date, previous reports have primarily related SUA to mortality and cardiovascular changes in later stages of HF. The observation that hyperuricemia often coincides with coronary heart disease was first described in the 1950s,1,2 and since then several large-scale studies published during the past 5 decades have generally supported the concept that elevated serum urate is an independent risk factor for many forms of heart disease,3 in addition to HF. Perhaps most compelling are the observations presented by the Vorarlberg Health Monitoring and Promotion Program (VHM&PP) study group,4 wherein mortality of women caused by all cardiovascular disease was unanimously predicted by elevated SUA levels, and even modest increases (>4.5 mg/dL) were associated with decreased survival from all cardiovascular/cerebrovascular events. Several other studies have supported the conclusion that elevated SUA levels (especially above 8 mg/dL) portend a poor prognosis for survival. In light of these previous studies, it seems apparent that SUA may serve as an important biomarker of cardiovascular disease, and this current report from Chrysohoou and colleagues suggests that this holds true for the early progression of HF. So what does elevated SUA level actually reflect in HF patients, and how can this observation help to guide therapy in the future? Since uric acid is a final oxidation product of purine catabolism and a primary product of xanthine oxidoreductase, the elevation in SUA levels in HF and other cardiovascular disease settings may be related to increased activity of this pathway. When converted to its oxidase form (xanthine oxidase [XO]) this enzyme is an efficient generator of superoxide anion and hydrogen peroxide, contributing to reactive oxygen and nitrogen species formation. Myocardium vascular and myocyte-localized XO is elevated in patients with coronary heart disease and in settings of ischemic and nonischemic cardiomyopathy. XO inhibition in patients with HF has been shown to enhance myocardial oxygen consumption, improve ejection fraction, and enhance endothelial dysfunction in recent small trials, although the long-term impact on cardiac performance and overall mortality are not defined. One advantage of this pharmacologic approach is the availability of a well-established and safe agent for XO inhibition since allopurinol was first clinically introduced in 1966. Interestingly, allopurinol improves endothelial function5 via direct vascular antioxidant actions rather than affecting SUA levels, illustrating that these 2 end points are not necessarily in equilibrium. Thus, this study by Chrysohoou and colleagues provides evidence to suggest that perhaps the early use of XO inhibitors in newly diagnosed HF has new potential as a therapeutic option. Another contributing mechanism to elevated SUA levels in this study relates to renal function in this patient population. Serum creatinine and calculated creatinine clearance was also found to be highly correlated with measurements of SUA in these patients and, because urate is renally excreted, elevations in SUA levels may also be related to reduction in renal function. In light of a very strong statistical association between SUA and serum creatinine, it is possible that elevated SUA levels in the HF patients described had no causal role but is associated with other risk factors (as has been suggested in the much larger Framingham Heart Study6). The study by Chrysohoou and colleagues is intriguing because it provides further rationale to investigate therapies that target uric acid and XO inhibition, especially in the early stages of HF. Further studies investigating the long-term relationships between SUA and XO to HF progression and related renal function and studies of the long-term efficacy of XO inhibition therapies in relation to cardiac performance and mortality are clearly necessary to translate these observations into improvements in care.