In 2010, the estimated annual incidence of myocardial infarction (MI) in the US was 610,000 new attacks and 325,000 recurrent attacks [1]. Following MI, 16% and 22% of men and women, respectively, between the ages of 40 and 69 years, experience a recurrent MI or fatal coronary heart disease (CHD) [1]. Since the underlying pathophysiology of disease in patients with acute coronary syndrome (ACS) varies widely, accurate risk stratification to determine appropriate management and improve outcomes is essential. As such, the use of prognostic biomarkers may facilitate the ability to anticipate complications following MI and provide timely preventive care to at-risk individuals [2]. For example, increased concentration of cardiac troponin can predict adverse events following MI or ACS [3]. Other markers of post-MI or post-ACS outcomes include N-terminal pro-B-type natriuretic peptide, inflammatory markers such as C-reactive protein (CRP), monocyte chemoattractant protein-1, and interleukin-6 [2, 4, 5].

Hyperuricemia is known to be correlated with a greater risk for coronary artery calcification, a surrogate measure of coronary atherosclerosis [6]. Both asymptomatic hyperuricemia and gout have been identified as independent risk factors for the development and progression of cardiovascular disease (CVD), CVD mortality, and all-cause mortality, in a variety of populations [7, 8]. However, it is unknown whether this excess risk extends beyond the initial coronary event. In this study, we hypothesized that mortality rates increase with serum urate levels (sUA) in patients with established CHD. To test this, we analyzed data from a three-year prospective, observational study that monitored levels of sUA in patients with histories of MI.

The novelty of this study lies in the selection of the previously unstudied, yet high-risk, population of patients with existing coronary artery disease, and in the observed disparities in the outcomes with respect to gout treatments. Our observations that the patients with untreated gout have a significantly increased risk for all-cause death, CHD mortality, and coronary incidence and that participants with gout on treatment had risk comparable to those of participants without gout are important, yet must not be over-interpreted, given the modest sample size. As previously mentioned, the association between gout and the risk for CV outcomes is well recognized. The results reported here provide yet another reason for improving the treatment of gout [13, 14].

Findings from this present study support the potential use of sUA as a biomarker for mortality outcomes in adult patients with pre-existing MI. Among participants of the AMIS Study, there is an association between sUA and risk of all-cause death, CHD mortality, and coronary incidence in individuals with a history of MI. Similar results were reported in a recent Israeli study, where, among 2,966 patients with documented CHD followed for 6.2 years, including those with a history of MI in the 6 months to 5 years prior to enrollment, there was a significant and positive correlation between the occurrence of fatal MI, nonfatal MI, or sudden cardiac death and increasing baseline sUA (P = 0.0009) [15]. These results also corroborate the results of the study by Ioachimescu et al. in which post-MI risk for poor outcomes was predicted by sUA [16].

Among patients with a history of heart failure (HF), a history of gout increased the risk of readmission due to HF or death by 63%, and recent acute gout (within 60 days) doubled the risk for HF readmission or death and increased the risk for all-cause mortality by 76%, after adjusting for confounders [17]. Of interest, we observed no association between sUA/gout and stroke outcomes, which is inconsistent with previous studies [18, 19]. It is uncertain if this is due to the relatively small number of stroke events that occurred during the AMIS study [20].

At low doses (less than 1 g per day), aspirin reduces urate excretion in the kidney [21]. At the higher doses used in this study, aspirin is known to be uricosuric [22]. Since the two arms of the AMIS were systematically different all our initial analyses were done separately for each and the results were pooled only when the findings were comparable.

The causal relationship between uric acid, gout, and the pathogenesis of CHD is under investigation. A growing body of literature, comprehensively reviewed elsewhere [23], points toward the role of uric acid in promoting atherosclerosis through increased oxidative stress and inflammation in both gouty and asymptomatic hyperuricemic patients. In vitro studies have demonstrated that soluble uric acid promotes inflammation [24], generates intermediate reactive oxidative species [25] and leads to endothelial dysfunction and proliferation [26]. The presence of the urate transporter, URAT1, in human vascular smooth muscle cells [27] provides another link between uric acid and endothelial dysfunction, but studies are needed to determine if this and other polymorphisms responsible for hyperuricemia and gout are also linked to CHD. Several studies have suggested a pathogenic role for uric acid in hypertension and increased platelet adhesiveness and lysis [28]. Uric acid has been shown to promote oxygenation of low-density lipoprotein (LDL) cholesterol, and gout patients have significantly higher levels of oxidized LDL [23].

While the above evidence suggests a direct role for uric acid in the progression of CVD, other data suggest that the oxidative stress may be due to the activity of xanthine oxidase (XO), of which sUA is a marker. Urate lowering therapy (ULT) with allopurinol reduced the level of oxidized LDL in gout patients, while treatment with benzbromarone did not [29]. In patients with mild to moderate HF (mean sUA 7.12 mg/dL), allopurinol improved vascular blood flow (endothelium-dependent vasodilation) in a steep dose-dependent manner, while probenecid did not have this effect [30]. Three months of allopurinol treatment in hyperuricemic patients led to improvements in endothelial function directly related to the extent of sUA reduction, and this improvement was not seen in normouricemic controls treated with allopurinol [30]. In mice with experimental MI, treatment with allopurinol slowed down subsequent left ventricular remodeling (dilation, hypertrophy, and interstitial fibrosis), resulting in substantially improved left ventricular function. This effect was attributed to the inhibition of XO in the myocardium, leading to reduced oxidative stress [31]. Other studies have demonstrated improved CV outcomes when allopurinol was used in patients with documented CHD undergoing various interventions [32–34]. These data support the hypothesis that the oxidative species generated by XO activity contribute to the progression of CVD. However, recent work in newly hypertensive adolescents has demonstrated the beneficial effects of ULT with allopurinol [35]. It may be that both uric acid and XO are involved in the etiology of CVD through independent and common pathways. Regardless, since sUA is a direct reflection of XO activity, it serves as a useful biomarker for CVD risk.

Important caveats are due. First, the results on gout treatment and improved cardiovascular outcomes should be treated as hypothesis generating and not causative, since channeling bias (that is, getting treatment for gout might be a marker for healthier/health conscious individuals who may have better outcomes) can make it impossible to assess the true impact of ULT. Another piece of evidence suggesting a non-random 'allocation' of therapy might be the serum urate concentrations. The fact that serum urate concentration is not lower in the treated group suggests that these individuals had higher serum urate/more severe gout to begin with. With such a bias, the mortality benefit associated with urate lowering might be an underestimate. Another data-related issue is our inability to exclude colchicine from urate lowering therapies. Our study examined risk factors for coronary events among those who survived such an event in the past. The influence of survivor effect and the importance of lifestyle modification following a diagnosis of coronary artery disease is difficulty to model in our study. Another important facet of this study is that it was performed in the 1970s, before the advent of current sophisticated diagnostic tools to detect subtle coronary syndromes. The patients with MI included in the trial are likely to be survivors from a more definitive, more severe, acute myocardial infarction. In that context there is a survival bias in that these individuals are likely to be hardier than those who survive a non-ST-elevation acute myocardial infarction. Nevertheless, the outcome we studied, mortality, was applied uniformly across all strata of urate levels as well as gout status, and arguably there were no differential biases.

Other factors can be expected to attenuate the relationship between hyperuricemia and gout and coronary events. When multiple risk factors contribute to the risk of an outcome, the risk factors for the recurrence of the event tend to be correlated with each other leading to index event bias. This bias could have resulted in the underestimation of the true relationship between hyperuricemia and gout and coronary events in our study. Our study data did not have the granularity or statistical power to discern any differences by the type of gout medication used. Finally, the effect of residual confounding by unobserved and unadjusted risk factors could not be estimated in our study.

The data presented here suggest that hyperuricemia is an independent predictor of all-cause and CHD mortality, as well as coronary incidence, in individuals with confirmed CHD. Analysis of sUA levels in patients following MI may be a reliable and inexpensive method for distinguishing patients at risk for mortality. Measurement of sUA levels may contribute to existing strategies that stratify risk for secondary CHD events, including mortality, in patients with previous MI.