Our data show that GA is associated with a more unfavourable traditional CV risk profile and a 3.1-fold hazard of first CV events compared to non-GA individuals with normal serum uric acid. In non-GA individuals increasing serum uric acid is associated with increased CV risk, the 3.7 fold hazard of a first CV event in non-GA individuals with a serum uric acid ≥ 0.34 mmol/L being comparable with that of gout patients.
Individual traditional CV risk factors, such as systolic blood pressure, serum lipoproteins, and body mass index, and occurrence of first CV events were increased at the same level in subsequent tertiles of serum uric acid in both RA and OA. These associations thus seem relatively independent from chronic inflammation. Compared to the other rheumatic populations mean serum uric acid values were highest in GA, as were values of traditional CV risk factors. First CV events were also more frequent in GA individuals than in non-GA patients. The frequency of first CV events was particularly high in female GA patients. This may be explained by the age of female GA patients, which was 10 years increased compared to the other patient groups, increasing age beyond the menopause being an important CV risk factor in women. The relatively high age of the female GA patients included in the ACT-CVD cohort is in line with previously published epidemiologic studies . Another explanation could be selection bias due to the small number of female GA patients included.
Individual CV risk parameters and prospective CV events were not related to tertiles of serum uric acid in GA patients. This may be due to confounding by the use of uric acid lowering therapy or more specifically the xantine oxidase inhibitor allopurinol, or to a ceiling effect in the generally high risk GA patients. CV risk factor values were not lower in GA patients treated with UTL or specifically allopurinol, and CV events were as frequent. The only suggestion in our data that treatment with allopurinol may be beneficial was the significantly lower mean level of NT proBNP, a marker of cardiac dysfunction, in this group.
Comparison to the literature
Previously, several large studies found increased CV disease and mortality in patients with gout, approximately two-fold compared to the general population [25–27]. To determine if hyperuricaemia per se confers the same risk of increased CV disease different populations have been studied; the general population, young and elderly, diabetics and patients with chronic kidney disease [4, 6–17, 28–30]. Many studies did find hyperuricaemia to be an independent risk factor, but in others the association disappeared after correction for the traditional CV risk factors obesity, hypertension, dislipidemia and/or insulin resistance. Some studies found a U- or J-shaped association between serum uric acid level and mortality, suggesting an optimal level between 0.30 and 0.41 mmol/L [29–31]. Only one study specifically addressed the role of systemic inflammation in GA related CV disease, and found no association with CV events .
The question remains if serum uric is only a potentially useful marker to improve the selection of high CV risk individuals for CV risk management, or if it is causally related to the progression of CV disease. Different hypotheses have been suggested: 1) the presence of shared risk factors in CV disease and GA, 2) vascular wall activation and accelerated atherosclerosis by chronic systemic inflammation, or 3) a direct interaction of uric acid with diverse metabolic pathways involved in CV disease [18, 19]. Several experimental studies have provided insight into possible actions of uric acid in diverse metabolic pathways, i.e. glucose and lipoprotein handling, nitric oxide metabolism, the renin-angiotensin-aldosterone system (RAAS), and inflammatory signalling and activation [32–34]. These observations suggest that uric acid itself can at least modulate CV risk factors such as blood pressure, cholesterol, diabetes and chronic inflammation . Uric acid clearance may be decreased in states of hypertension and RAAS activation, with consequent increasing hyperuricaemia and amplification of metabolic derangements. However, other studies suggest that the metabolic effects attributed to uric acid are actually mediated by xantine oxidase, which is also the key enzyme in uric acid production in man. Increased serum uric acid may thus only be an epiphenomenon of other pathologic metabolic pathways that cause increased CV risk .
Strengths and limitations
Our study adds to the knowledge on hyperuricaemia and CV risk by comparing the association between serum uric acid and CV-risk in a mixed rheumatic population including GA. Thus we saw that in this population either the presence of GA or a baseline serum uric acid in the upper range are stronger predictors of first CV events than some traditional risk factors or parameters of inflammation. Epidemiologic studies that evaluate associations of serum uric acid with traditional CV risk factors and prospective CV events in a rheumatic population are scarce. In this study the study groups were well defined and measurements of risk factors were performed within the same protocol.
However, this study has some important limitations. First, the observational study design precludes any suggestions on causal relationships. Thus the absence of an association between serum uric acid and CV risk in GA was difficult to interpret due to the pre-treated population. Because we only had data on baseline variables we could not evaluate of the effect of medical interventions and changes in serum uric acid on CV outcome. A possible risk reduction by allopurinol may not have followed from our data due to insufficient numbers of patients, too short period of exposure or too short follow up. Following the data one can only conclude that also in a ULT treated GA population with satisfactory mean uric acid levels CV risk is high.
The prospective analysis, evaluating the associations of a limited set of traditional CV risk factors and serum uric acid tertiles in a mixed population of articular diseases, is a simplification that may ignore any disease specific CV risk factors. Moreover, the rheumatic diseases studied differ importantly in general gender epidemiology, reflected by a male predominance in the GA group versus a female predominance in the non-GA group. Gender is an important traditional CV risk factor. Therefore, gender, diagnosis and hsCRP were considered as variables in the multivariate analysis, but proved non-significant. The influence of some other potential confounders such as use of NSAIDs and relative physical inactivity was not covered by separate variables, but regarded to be limited by only including patients with rheumatic diseases.
Some important questions remain for further research. First, the predictive value of pre-ULT treatment uric acid level for the occurrence of CV events in GA patients. Second, the positioning of uric acid and xantine oxidase in pathophysiologic pathways that cause CV events in GA and hyperuricaemia. And finally, what is the optimal risk intervention strategy in high CV risk patients characterised by an upper range uric acid level.