Oxidative stress and hyperuricaemia: pathophysiology, clinical relevance, and therapeutic implications in chronic heart failure

Abstract

Heart failure (HF) is a state of chronic deterioration of oxidative mechanisms due to enhanced oxidative stress and consequent subcellular alterations. In this condition, oxidant-producing enzymes, in particular xanthine oxidase (XO), the major cardiovascular source of reactive oxygen species (ROS), are up-regulated. Growing evidence shows that this impaired oxidative metabolism due to enhanced ROS release is implicated in the development of cardiac hypertrophy, myocardial fibrosis, left ventricular remodelling, and contractility impairment responsible for worsening of cardiac function in CHF. Uric acid (UA) has long been linked with cardiovascular diseases, and hyperuricaemia is a common finding in patients with CHF. Hyperuricaemia is associated with impairment of peripheral blood flow and reduced vasodilator capacity, which relate closely to clinical status and reduced exercise capacity. Recent studies also suggest an association between UA levels and parameters of diastolic function; more importantly, UA has emerged as a strong independent prognostic factor in patients with CHF. In this review, we describe the up-to-date experimental and clinical studies that have begun to test whether the inhibition of XO translates into meaningful beneficial pathophysiological changes. This treatment gives evidence that myocardial energy, endothelial dysfunction, and vasodilator reactivity to exercise are improved by reducing markers of oxidative stress responsible for vascular dysfunction, so it represents an interesting therapeutic alternative for better outcome in CHF patients.--

Serum uric acid is associated with bone health in older men: A cross-sectional population-based study

“…(1,2) More recently, evidence has accrued for a role of UA as a risk factor for other diseases. Experimental, clinical, and epidemiologic evidence suggests that hyperuricemia may cause endothelial cell damage and hence play a role in the pathogenesis of certain disease processes such as cardiovascular disorders, (1,(3)(4)(5) chronic heart failure, (6) hypertension and progressive renal disease, (7)(8)(9) stroke, (10) type 2 diabetes mellitus, (11,12) insulin resistance, and the metabolic syndrome. (13)(14)(15) Conversely, it has been hypothesized that a mutation in the urate oxidase gene occurring early during hominoid evolution and resulting in higher serum UA levels provided an evolutionary advantage because high UA levels help to maintain blood pressure under low-salt dietary conditions.…”

One year survival of ambulatory patients with the end-stage heart failure: the analysis of prognostic factors

“…21 Recently, it was reported that the association between UA levels and poor outcome in patients with HF was significant only when hyperuricemia was a marker of increased xanthine oxidase activity and not a consequence of decreased renal excretion in chronic kidney disease. 22 The sources of UA are the liver and endothelium. Therefore, UA produced in hypoxic states originates from endothelial cells, and hyperuricemia in HF patients may reflect the metabolic effect of hypoxia on the microvasculature.…”

Do We Need Another Look at Serum Uric Acid in Cardiovascular Disease? Serum Uric Acid as a Predictor of Outcomes in Acute Myocardial Infarction

“…Similarly, a study in acute HF patients demonstrated an increased risk of death in patients with SUA >458 mol/L as compared to those with SUA <416 mol/L (adjusted RR=1.45, 95% CI 1.03-2.05) and increase in RR by around 8% (CI 1-15%) for each 60 mol/L increase in SUA (Alimonda et al, 2009). As reviewed by Pacher et al (2006) and Bergamini et al (2009), several randomized trials indicated improvements in cardiac and hemodynamic parameters in CHF patients treated with allopurinol (an XO inhibitor), even with indications of improved survival, but not all trials have been "positive" and uricosuric agents seemingly were not effective.…”

“…It is far beyond the scope of this text to discuss in detail all the aspects of the complex relationship between SUA and CVD. For this purpose, reader is referred to comprehensive reviews on the topic, some (Johnson at al., 2003, Baker et al, 2005, Duan&Ling 2008, Naquibullah et al, 2007, Lippi et al, 2008, Feig et al, 2008, Doehner et al, 2008, Gagliardi et al, 2009, Bergamini et al, 2009, Kim et al, 2009, Wechter et al, 2010. The main points could be summarized as follows:…”

“…Chronic heart failure (CHF) is a typical setting in which the dilemma about UA as a "cause" or a (mere) "marker" is particularly actual (Duan & Ling, 2008, Doehner et al, 2008, Bergamini et al, 2009. Numerous animal models have clearly confirmed the role of reactive oxygen species (ROS) in pathophysiology of the heart failurethere is a clear correlation between increased markers of oxidative stress within the heart and systemically, poorer survival and a number of functional measures of cardiac functions and hemodynamic consequences.…”