2025 Volume 32 Issue 12 Pages 1471-1481
Hyperuricemia, the biochemical precursor to gout, is usually defined as the theoretical limit of solubility of serum uric acid (UA) of ＞7.0 mg/dL. Hyperuricemia is closely associated with hypertension, diabetes mellitus, and dyslipidemia, which are well known to be related to risk factors for coronary artery disease (CAD). Furthermore, hyperuricemia has been associated with increased mortality in both the general population and individuals with cardiovascular diseases. Elevated UA in patients with CAD is accompanied by surrogate markers of atherosclerosis, including C-reactive protein, platelet activation, and endothelial dysfunction, which can contribute to possible pathogenic links between hyperuricemia and subsequent adverse cardiovascular events. Similarly, patients with gout have higher rates of cardiovascular diseases than those without it, independent of traditional cardiovascular risk factors. Gout is a disease with variable levels of inflammation, driven by deposition of monosodium urate (MSU) crystals. Recent imaging technology has revealed that deposition of MSU crystals can occur in the coronary arteries as well as the joints. However, current evidence does not support the efficacy of urate-lowering therapy on reducing cardiovascular events in patients with hyperuricemia; therefore, identifying individuals who may benefit from a sustained decrease in UA is crucial. We herein review the current understanding and future perspectives for management of hyperuricemia as a residual risk in patients with CAD.
The level of serum uric acid (UA), the circulating end product of purine catabolism, is an important independent risk factor for coronary artery disease (CAD)1). Furthermore, UA elevation is positively correlated with severity of CAD2) and may have a role in predicting the prognosis in patients with CAD3). Similarly, it has long been recognized that there are associations among hyperuricemia, gout, and cardiovascular diseases4). In Asia, Westernization of dietary habits and sedentary lifestyle have increased metabolic phenotypes, causing greater elevation of serum UA5, 6). However, difficulties in defining UA as a marker for future cardiovascular events may be partly explained by the clustering of many cardiometabolic risk factors in patients with increased UA7). Mendelian randomization studies have shown that the serum UA level is a causal factor for gout, but similar studies have not found consistent evidence indicating that elevated UA is causal for CAD8, 9). Thus, whether or not hyperuricemia is relevant to the observed relationship between UA and atherosclerosis remains uncertain.
Gout is characterized by low-grade inflammation with reactive oxygen species, endothelial dysfunction, platelet hyperactivity, and elevated proinflammatory cytokines that are involved in pathogenesis of atherosclerosis at various stages10). Based on observational data, the risk of cardiovascular disease appears to be higher in patients with concomitant hyperuricemia and gout than in those with hyperuricemia alone11). Since current evidence does not support the efficacy of urate-lowering therapy for reducing cardiovascular events in patients with hyperuricemia, there is a need to identify individuals with an increased risk of cardiovascular events who may benefit from a sustained decrease in UA.
We herein review the current understanding and future perspectives of management of hyperuricemia and gout as modifiable factors for secondary cardiovascular disease prevention in patients with CAD.
Gout is a prevalent disorder, the frequency of which is increasing worldwide12). Chronic kidney disease (CKD), hypertension, diabetes mellitus, and dyslipidemia have all been shown to be increased in patients with gout13, 14). In addition to traditional cardiovascular risk factors, inflammation is an important risk factor for progression of cardiovascular disease15). Gout flare activates the NLRP3 inflammasome, resulting in the production of interleukin-1β16). The efficacy of canakinumab in reducing both cardiovascular events and gout flares provides a further proof-of-concept that controlling inflammation can prevent cardiovascular events17, 18). This may explain the association between a prior episode of gout and a transient increase in the incidence of myocardial infarction19). A systemic review and meta-analysis found a significant association between gout and mortality, primarily due to cardiovascular disease20), and a deleterious role of gout in patients with established cardiovascular disease has also been reported21).
Whether or not gout increases the risk of cardiovascular diseases outside the UA pathway is unclear. In this regard, certain common lifestyle factors observed in patients with gout should be considered. Regular and moderate exercise can reduce measurable anti-inflammatory effects, which decreases the frequency of gout attacks, alleviates joint swelling, and lowers pain scores in patients with gout22), while physical activity in patients with hyperuricemia reduces mortality risk23). There is a need for further verification, but these findings show the need for feasible lifestyle interventions in patients with gout and suggest that residual cardiovascular risk is not addressed by standard medical therapy.
An association between high UA levels and cardiovascular events was first reported in the Framingham study in 1967 24). A meta-analysis of 29 prospective studies confirmed an independent association between the UA concentration and CAD, with a hazard ratio of 1.13 per 1-mg/dL increase25). Consequently, the serum UA level as an independent factor for predicting mortality in patients with cardiovascular disease remains an issue of ongoing discussion. Elevated serum UA is a predictor of poor outcomes in patients with angiographically proven CAD26), and elevated UA is associated with adverse outcomes after percutaneous coronary intervention (PCI)27). Elevation of UA in patients with CAD is accompanied by surrogate markers of atherosclerosis, including C-reactive protein (CRP), platelet activation, endothelial dysfunction, and arterial stiffness, which may contribute to pathogenic mechanisms linking UA with subsequent cardiovascular events28-31). However, in clinical practice, UA is closely correlated with known cardiovascular risk factors, and testing the contribution of each factor has proven difficult7). The detailed mechanisms underlying the harmful effects of elevated UA in patients with CAD remain unclear, but several potential pathways have been proposed to explain the association between hyperuricemia and cardiovascular pathologies. The mechanisms that might explain the harmful effects of hyperuricemia in patients with CAD are presented in Fig.1 and discussed below.
AKI: acute kidney injury; CAD: coronary artery disease; PCI: percutaneous coronary intervention
There has been a decline in all-cause and cardiac mortality following acute coronary syndrome (ACS) in the past three decades, but recent trends in the incidence of recurrent cardiovascular events remain unresolved32). Under these conditions, serum UA has been identified as a residual cardiovascular risk in patients with ACS, despite better implementation of secondary prevention programs, including guideline-recommended therapy33). The causality of hyperuricemia for cardiovascular disease remains inconclusive, but several potential mechanisms have been proposed. First, an experimental study showed that UA promoted atherosclerosis and exacerbated plaque vulnerability by facilitating foam cell apoptosis through inhibition of autophagy34). Several imaging studies have also indicated associations of elevated UA with vulnerable plaque characteristics. Thus, hyperuricemia has been independently associated with greater lipid content of coronary plaque in patients with ACS35), and a recent study using optical coherence tomography (OCT) in patients with ACS showed more frequent plaque rupture and red thrombi in those with hyperuricemia than those without36). High-risk morphologic plaque features detected by intracoronary OCT in patients with hyperuricemia were also noted in non-culprit lesions in ACS cases37). Furthermore, near-infrared spectroscopy intravascular ultrasound in patients with stable CAD has shown that plasma xanthine oxidoreductase activity is associated with formation and destabilization of coronary artery plaques38). These imaging studies demonstrate an association, but not causality, between hyperuricemia and lesion morphology. However, the strict relationship between UA and coronary plaque characteristics in patients with CAD may promote pathological disorders, leading to adverse outcomes after PCI.
3) Relationship of UA and In-Stent Restenosis after PCISeveral factors have been proposed as predictors of in-stent restenosis following PCI, including a long lesion, minimal stent area, and risk scoring system39, 40). However, simple indices such as prognostic biomarkers for predicting recurrent revascularization have not been well studied. Serum UA directly stimulates vascular smooth muscle cell proliferation and neointimal formation through proinflammatory reactions41). Most cardiovascular intervention studies have focused on the mortality-UA relationship, rather than progression of atherosclerosis, but UA assessment for predicting in-stent restenosis has recently been proposed42-46). Larger clinical studies are warranted to verify whether serum UA in patients with CAD is a reliable marker to predict restenosis after treatment with drug-eluting stents or drug-coated balloons.
4) Hyperuricemia and Contrast-Induced Acute Kidney Injury (AKI)Contrast-induced AKI is a significant complication following cardiovascular intervention47). The mechanisms underlying contrast-induced AKI during PCI include direct nephrotoxic effects of contrast agents, hemodynamic changes, oxidative stress, and immune/inflammation responses48). Meta-analyses have shown that hyperuricemia is a risk factor for AKI49, 50). Pre-existing CKD also increases the risk of AKI51) and there is mounting evidence that UA is an independent risk factor for development of CKD52). Therefore, patients with increased UA may already have subclinical renal dysfunction, making them more vulnerable to occurrence of AKI. There is consistent evidence showing an association of hyperuricemia with an increased risk of contrast-induced AKI in patients undergoing PCI53). Inflammation and subsequent formation of reactive oxygen species are among the postulated mechanisms of contrast-induced AKI, suggesting that statins, which inhibit inflammatory mediators, may be a useful adjunctive treatment for prevention of contrast-induced AKI54). Theoretically, inhibition of xanthine oxidase using allopurinol may block generation of oxygen radicals and consequently mitigate the nephrotoxic effect of contrast agents55). A recent systematic review and meta-analysis supports the efficacy of allopurinol in reducing the risk of contrast-induced nephropathy in patients undergoing PCI56). Therefore, clinical investigations of urate-lowering therapy for preventing contrast-induced AKI are needed to establish evidence-based guidelines for use in patients with CAD who require PCI.
5) UA and Subsequent Heart Failure in Patients with CADMany studies have associated elevated serum UA with a poor prognosis in patients with heart failure57). Use of diuretics is a clinically important factor that induces hyperuricemia via increasing UA reabsorption and decreasing UA secretion58). In addition, reduced renal clearance of UA due to renal hypotension induced by heart failure, as well as tissue hypoxemia, which activates the xanthine oxidase system, might contribute to elevation of UA in patients with heart failure59). Thus, observational studies have shown that elevated UA is associated with an increased risk of heart failure in patients with CAD60, 61). These results demonstrate the need for studies of urate-lowering therapy for reduction of the heart failure burden in patients with CAD.
6) UA and Functional Significance of the Coronary ArteryEndothelial dysfunction is one of the initial pathological processes of atherosclerosis. Physiologically, UA can scavenge oxygen radicals and other reactive free radicals as a water-soluble antioxidant, and this role accounts for half of the antioxidant capacity of human fluids10). However, when UA is exposed to the environment of atherosclerotic plaque, it is converted into a pro-oxidant that promotes oxidative stress and exacerbates progression of cardiovascular disease10). Several studies have also suggested that the serum UA level may be related to high-sensitivity CRP since it is a sensitive marker for underlying inflammation and remodeling in the arterial vessel wall and myocardium62). In a coronary angiography study, high levels of UA were associated with a slow coronary blood flow and poor coronary collateral circulation in patients with CAD63, 64). Therefore, UA may have a crucial role in regulation of the coronary blood flow.
Strict indications are required for coronary revascularization, such as angina despite optimal medical therapy and/or demonstrable ischemia, or severe stenosis due to epicardial coronary angiography. However, determining the need for revascularization in patients with intermediate stenosis is difficult. Under these conditions, fractional flow reserve (FFR)-guided PCI is a more successful strategy with a better prognosis than angiographically guided PCI65). Endothelial dysfunction in patients with hyperuricemia and intermediate coronary stenosis leads to an impaired hyperemic response during physiologic assessments66) and causes UA to be an independent risk factor for major adverse outcomes after stratification with FFR67).
Up to 70% of patients undergoing coronary angiography due to angina do not have significant lesions in the epicardial coronary arteries68). In this context, cardiac syndrome X refers to the triad of typical effort angina, positive stress test, and normal epicardial coronary angiogram. UA may play an important role in the pathogenesis of microvascular angina in patients with cardiac syndrome X69). In addition, endothelial dysfunction of coronary arteries has been implicated in the development of microvascular angina and coronary spastic angina, which frequently overlap70). Coronary spastic angina may be induced by UA elevation with interaction with lipoprotein (a)71). Furthermore, Tanazawa et al. suggested that elevated UA affects development of coronary spastic angina, particularly in young patients72). Allopurinol, which inhibits xanthine oxidase, can reverse impaired endothelial NO production, and trials have shown that allopurinol improves endothelial dysfunction and subsequently enhances exercise capacity in patients with chronic stable angina73). Thus, lowering UA may contribute to improvement of the endothelial function, which is an important prognostic predictor in patients with CAD.
7) UA and Atrial Fibrillation in Patients with CADA relationship between hyperuricemia and atrial fibrillation (AF) has been established in several studies. Thus, the serum UA level is significantly correlated with new-onset AF in a concentration-dependent manner74), and hyperuricemia enhances thromboembolic risk in patients with AF75). Although whether UA is a disease marker or a treatment target is unclear, a meta-analysis of six cross-sectional and three cohort studies confirmed the association of hyperuricemia and AF76). The molecular mechanisms underlying UA elevation and AF are unclear, but intracellular accumulation of UA inducing shortening of the atrial action potential might facilitate development of re-entry circuits in the atrium, resulting in atrial arrythmia, including AF77). Hyperuricemia has also been associated with AF in hypertension, heart failure, and ischemic heart disease78), and it increases the risk of AF after coronary revascularization79). Concomitant AF is also common in patients with CAD and is related to negative outcomes. As hyperuricemia can lead to the onset of AF and increases the risk of cardiovascular events, assessing UA levels may be useful for predicting outcomes in patients with CAD.
Coronary atherosclerosis is a major cause of death worldwide. Most cases of myocardial infarction are caused by erosion or rupture of coronary plaques, and plaque instability is induced by complex interplay among structural plaque features, local hemodynamic forces, and biological processes acting on the plaque surface80). Thus, determining the physical characteristics and chemical composition of coronary plaque by imaging may identify patients at risk for major adverse cardiovascular events (MACEs). Serum UA has been associated with development of subclinical atherosclerosis and metabolism of UA plays an important role in the development of CAD, especially in the early stage of atherosclerosis. The CARDIA study in a cohort of young subjects suggested that elevated serum UA may be a biomarker for early atherosclerosis manifesting as coronary artery calcification81). A meta-analysis in asymptomatic patients supports the association of serum UA with subclinical coronary artery calcification82). In asymptomatic hyperuricemia, silent deposition of MSU crystals, as determined by an ultrasound evaluation of the knees and metatarsophalangeal joints, has been associated with coronary artery calcification83).
Dual-energy computed tomography (DECT), an imaging method that uses simultaneous acquisition at two energy levels to discriminate via specific radiographic attenuation of UA, is more sensitive than X-ray and ultrasound for detection of MSU crystals in peripheral joints84). Cases with a high total tophus volume assessed by DECT have significantly higher systolic blood pressure, diastolic blood pressure, and fasting glucose values and a higher prevalence of CKD than those with negative DECT findings85). Initially, it was believed that deposition of MSU crystals occurs only in the joints with involvement of the periarticular soft tissues, but recent studies have also shown the presence of MSU crystal deposition in extra-articular sites. Early studies revealed MSU deposition in coronary plaques from endarterectomy specimens and explanted hearts86). Conventional imaging techniques cannot distinguish MSU deposition from atherosclerotic plaque; however, with the advent of techniques such as DECT, MSU crystals can be visualized in extra-articular sites, including vascular tissues.
Deposition of cardiovascular MSU is also associated with adverse clinical events and mortality87). Recent studies have revealed MSU deposition in coronary arteries, with higher coronary MSU deposition in patients with gout compared with controls88). Cross-polarized micro-OCT has been used to visualize intracoronary MSU crystals in human cadaver coronary arteries89). Intracellular UA may promote production of reactive oxygen species and regulate several intracellular signaling pathways that result in development of atherosclerotic lesions containing MSU crystals in the cardiovascular system62). Since fluctuation of the UA level is common, a single blood test may not reflect the overall exposure from hyperuricemia. Thus, clinicians should consider visualizing subclinical MSU deposition in the cardiovascular system in patients with asymptomatic hyperuricemia (Fig.2).
MSU: monosodium urate
Numerous studies have examined the best cutoff for UA for predicting cardiovascular events. In some studies, slight increases in UA, even below gout-provoking levels, have been associated with an increased risk of cardiovascular mortality. Ndrepapa et al. found that UA ＞6.4 mg/dL was associated with all-cause mortality in patients with CAD after PCI3). In patients with intermediate coronary stenosis who were stratified by FFR, a similar cutoff of UA was a predictor of MACEs67). However, the prognostic implication of elevated UA in patients with CAD seems to differ according to the patient characteristics, including gender, the residual renal function, and severity of heart failure90-92).
Another intriguing aspect is the J-curve phenomenon between UA levels and cardiovascular events, meaning that both high and low levels of UA could be harmful93). For example, Gwang et al. found an increased risk of worse outcomes in patients with vasospastic angina with UA ＜4.8 mg/dL94). A possible explanation is that increased oxidative stress is linked to reduced plasma UA. Indeed, patients with hypouricemia have decreased flow-mediated dilatation, suggesting that very low UA is associated with impaired endothelial function95). Another possible explanation for the J-curve phenomenon may be the sarcopenia and malnutrition in elderly patients; i.e. low UA is related to unfavorable conditions96). Given these findings, in aging societies, attention should be paid to both increased and decreased UA levels in patients with CAD.
Recent interventional studies of urate-lowering therapies in patients with gout have yielded conflicting results in terms of cardiovascular risk reduction97, 98). The Febuxostat for cerebral and caRdiorenovascular events prEvEntion study (FREED) trial compared febuxostat with other treatments in 1,070 subjects without gout but with a high cardiovascular risk or history of cardiovascular events99). The main findings included the absence of differences in cardiovascular events and mortality but a significant reduction in renal events. The All-HEART study, one of the largest cardiovascular outcomes trials of urate-lowering therapy to date, did not find a significant reduction in cardiovascular events in patients allocated allopurinol100). Of note, the baseline serum UA of the trial participants was in the normal range, and participants with gout were excluded, further limiting the number of patients with hyperuricemia. These results suggest that urate-lowering therapy may not be effective for preventing cardiovascular events; therefore, further studies with more targeted groups, such as high-risk populations, are needed.
Elevated UA levels seem to be related to unfavorable outcomes in patients with CAD, but therapeutic intervention for hyperuricemia to reduce cardiovascular risk remains uncertain. Regardless, measurement of UA in patients with CAD is useful for residual risk assessment. In addition to the robust association between gout and cardiovascular risk factors, recent evidence indicates that gout and cardiovascular disease are counteracted by the same therapies17, 18). Thus, it is reasonable to assess cardiovascular risk in patients with gout or hyperuricemia (Fig.3). Accurate prevalence data for asymptomatic deposition of cardiovascular MSU crystals in patients with hyperuricemia and clinical data for cardiovascular outcomes are needed to define the clinical importance of measurement of UA in patients with CAD.
CAD: coronary artery disease; MSU: monosodium urate; UA: uric acid
None.
The authors declare that they have no conflicts of interest.
