The prevalence of hyperuricaemia is rising globally, with high-income countries affected more significantly. Increased levels of serum uric acid (SUA), even within the normal to high range (5.2–6 mg/dl), have been associated with the development and progression of cardiovascular disease, including ischaemic heart disease (IHD).1,2 One of the first reports on the association between hyperuricaemia and IHD dates back to 1959.3 Since then, multiple studies have confirmed the association. However, the therapeutic and prognostic implications remain subject to debate.
Hyperuricaemic Phenotypes
Hyperuricaemia can occur due to excessive production or, more commonly, decreased excretion of uric acid (UA).4 Increased activity of aldose reductase and xanthine oxidase (XO), both primary or secondary to dehydration and ischaemia, has been proven to significantly raise serum uric acid (SUA) levels.5 Excessive UA production may also occur in cases of acute breakdown of purines, such as during adenosine triphosphate, DNA and RNA degradation. Diets high in purines (e.g. from meat and seafood) or rich in fructose, alcohol and sodium are also known to increase SUA levels.5,6 Defects in other enzymes involved in purine metabolism (e.g. adenosine monophosphate deaminase) can contribute to elevated SUA levels.7
Additionally, hyperuricaemia can result from increased reabsorption or decreased secretion of UA by renal tubules, which may be caused by hypothyroidism, metabolic acidosis or treatment with certain drugs (e.g. β-blockers, diuretics including furosemide and thiazides, immunosuppressants such as cyclosporine, chemotherapeutic agents, antiaggregant compounds as salicylates and ticagrelor, nicotinic acid or L-dopa).8,9 Other drugs may induce hyperuricaemia with renal-independent mechanisms, such as omeprazole, sildenafil or topiramate.9 Lastly, a recently approved medication for dyslipidaemia – bempedoic acid – is associated with an increased risk of hyperuricaemia.
Gut microbiome and various renal and intestinal transport proteins also play a role in SUA homeostasis.10
Therefore, it is clear that impaired kidney function can lead to SUA underexcretion and hyperuricaemia. However, some studies suggest that hyperuricaemia may precede the onset of kidney disease.7,11
Hyperuricaemia should not be referred to without the underlying mechanism being specified, as different phenotypes may be associated with various prognostic and therapeutic implications. For this reason, the SUA to serum creatinine ratio (SUA/sCr) has been proposed to differentiate between UA hyperproducers and underexcreters.12
SUA/sCr has been shown to be associated with cardiovascular outcomes in large epidemiological studies.13,14 Furthermore, its prognostic role in specific cardiovascular risk factors and diseases has been postulated, including regarding acute MI.15–18
Pathophysiological Mechanisms
Oxidative stress plays a key role in the occurrence and progression of several cancerous and non-cancerous diseases, so an appropriate antioxidant response is necessary to protect cells from intracellular oxidative damage.19−25 UA generally acts as an antioxidant but, in the intracellular compartment, exerts pro-oxidant effects due to the stimulation of nicotinamide adenine dinucleotide phosphate oxidase and the generation of reactive oxygen species.26
Several pathophysiological mechanisms may explain the association of UA with IHD. UA may activate peroxynitrite-mediated oxidation of lipids with direct atherogenic potential.27 UA is also involved in the reduction of nitric oxide synthesis, which impairs endothelial cell homeostasis and proper vascular tone.28
Angiogenesis is a key process that is tightly regulated and its impairment leads to several conditions including cardiovascular disease.29,30 It has been reported that UA increases the secretion of various vasoactive and angiogenetic substances, including endothelin, thromboxane and angiotensin II, both locally and systemically.31,32
Angiogenic balance plays a role in the development and progression of IHD and may represent a novel therapeutic option for coronary artery disease.33 The impact of UA in coronary artery tone through interference in vasoactive and angiogenic homeostasis may lead to impairment in the compensatory dilation in response to physiological or pathological stimuli, such as an unstable atherosclerotic plaque.
Increased UA levels also stimulate the transcription of mitogen-activated protein kinases, growth factors, nuclear factor κ-light-chain-enhancer of activated B cells and chemokines, increasing inflammatory levels.34
Lastly, UA is associated with an increased activation of the renin–angiotensin–aldosterone system at a local and systemic level.35
All the above-mentioned mechanisms are crystal independent. However, for SUA concentrations higher than 6 mg/dl – the threshold for UA solubility in blood – SUA precipitates, forming monosodium urate crystals.
A recent study using dual-energy CT material separation technology demonstrated that, among patients with coronary plaques, almost 2% had urate deposition plaques and 19.3% had mixed forms, with both atherosclerotic and urate deposition plaques.36 Monosodium urate crystals have been shown to increase the gout-associated risk of IHD.37
Urate crystals can also occur in the renal medulla, leading to a gouty nephropathy that may impair kidney function leading to the development of chronic kidney disease.38 This can also affect IHD, since chronic kidney disease not only increases the risk of IHD but also influences IHD clinical presentation.39
A summary of common causes of hyperuricaemia and pathophysiologic pathways leading to coronary artery disease is given in Figure 1.
Epidemiologic Studies
Almost one in four patients with an acute coronary syndrome has hyperuricaemia.40 The problem with the regular assessment of SUA levels in coronary syndromes and its use for prognostic and therapeutic guiding is attributable to the conflicting results yielded by some epidemiological studies and the lack of adequately powered controlled studies with positive results. American guidelines on the management of chronic coronary disease do not mention UA measurement, and European guidelines suggest SUA assessment in the investigation of kidney function since hyperuricaemia may impair this.41,42
Large epidemiological studies have shown a positive association between SUA and the incidence and outcomes of coronary artery disease, including cardiovascular death. The largest positive epidemiological studies are based on the US National Examination and Nutritional Health Survey, the British Regional Heart Study, the Rotterdam Study, the Japanese Coronary Artery Disease Study and the Italian URRAH study.43–47
A meta-analysis of studies involving more than 400,000 patients has confirmed that hyperuricaemia is independently associated with the incidence of and mortality from IHD, finding a 12% increase in the overall risk of death for each 1 mg/dl rise in SUA.48 On the other hand, the ARIC study, the Framingham Heart Study and a prospective Irish case-control study and meta-analysis did not show a significant association between uricaemia levels and IHD.43,49,50
In negative studies, the association between SUA and coronary artery disease was found to be influenced by other cardiovascular risk factors and identified sex-related differences. In most negative studies, the association between SUA and IHD was present in univariate analysis but lost significance after multiple adjustments.
A possible explanation for the inconsistency of some results is the inclusion or not of gout, namely symptomatic hyperuricaemia versus asymptomatic hyperuricaemia. In the late 1980s, research based on the Framingham Heart Study found an independent association between gout and the risk of coronary artery disease.51 Stack et al. described an independent and combined association of gout and SUA with total and cardiovascular mortality.52 They observed that the mortality risk in gout patients increased with rising SUA concentrations, even at normal to high levels, namely <6.0 mg/dl. Multivariate regression analysis of the Multiple Risk Factor Intervention Trial database identified hyperuricaemia as an independent risk factor for acute MI.53 In another study, authors found an increased risk of total mortality and fatal coronary events in individuals with a history of gout.54 Since gout is associated with systemic inflammation, which in turn is associated with atherosclerosis progression and coronary artery disease, it may be possible that asymptomatic hyperuricaemia is associated with a lower risk of IHD compared to symptomatic hyperuricaemia.
Another possible explanation is the indirect effect of hyperuricaemia on cardiovascular disease. Hyperuricaemia may precede the development of hypertension and chronic kidney disease among all, increasing the risk of developing IHD.11 Elevated SUA levels have also shown to mediate the effect of obesity on the development of hypertension.55 It is thus possible that hyperuricaemia only indirectly affects the risk of developing IHD. This may explain why in negative epidemiological studies the adjustment for multiple risk factors reduced the strength of the association between SUA and IHD.
As previously described, hyperuricaemia is not an isolated entity. High SUA levels due to hyperactivity of XO may be associated with an increased risk of IHD versus hyperuricaemia due to reduced excretion of SUA. This hypothesis is corroborated by the findings of an association between increased XO activity and endothelial dysfunction in patients with coronary artery disease.56 Another study also showed an association between XO activity and the severity of heart failure due to IHD or not.57 SUA may also increase due to heightened purine metabolism caused by hypoxia and tissue catabolism that enhance purine release from ischaemic cells and has a direct impact on XO activity.58
As stated above, alternative methods to select patients with hyperuricaemia due to overproduction of SUA instead of underexcretion may be normalising SUA for kidney function such as SUA/sCr or SUA/estimated glomerular filtration rate. Indeed, reports on coronary syndromes and heart failure have shown an association between renal function-adjusted SUA and in-hospital and long-term outcomes, with even stronger associations compared to SUA alone.59–61
Together, these results may support the hypothesis that hyperuricaemia due to hyperactivity of XO may be even more relevant than hyperuricaemia due to reduced renal excretion in the context of IHD.
Last but not least, it is well known that SUA has a U-shaped relationship with cardiovascular disease and coronary artery disease specifically.62 The fact that low levels of SUA can be detrimental may have an impact on the similarities between high and low SUA levels and the development of coronary artery disease. Several studies have compared the highest with the lowest quartiles of SUA, without considering the U-shaped relationship. However, it must be noted that both positive and negative studies share analogous methods.
Apart from the association between SUA levels and the development of coronary syndromes, several studies have also showed that SUA levels are directly related to in-hospital outcomes such as AF development and length of hospital stay as well as long-term outcomes such as cardiovascular mortality.63
Additionally, SUA levels are associated with the type and extent of coronary plaque, with a more significant relationship with more accurate IHD scores (e.g. SYNTAX score) and newly diagnosed coronary disease.64–67 In a study by Hasic et al., SUA was not only associated with IHD but also could differentiate between patients presenting with acute MI and those with unstable angina pectoris.68
Therapeutic Perspectives
Whether to treat asymptomatic hyperuricaemia remains subject to debate, with only Japanese guidelines explicitly recommending treatment in individuals with high cardiovascular risk or very high levels of SUA in the absence of gout.69
Hypouricaemic agents act on multiple targets: XO inhibition; recombinant and polyethylene glycol-modified uricase administration; and uricosuric mechanisms.70 Differentiating between UA hyperproducing and underexcreting phenotypes may help with choosing the right drug, leading to a personalised treatment with possible improvement of clinical outcomes. However, to date, selection of patients for clinical trials on hypouricaemic agents has not considered specific hyperuricaemic phenotypes nor in some cases SUA levels, with studies even including individuals without hyperuricaemia. Corroborating this hypothesis, allopurinol induced an improvement in endothelial function that was not observed with uricosuric agents.71,72
Another study showed that treatment with XO inhibitors alleviated endothelial dysfunction and reduced oxidative stress in patients with stable coronary artery disease versus no effects from uricosuric agents.73
Together, these results suggest that oxidative stress and XO hyperactivity may be the culprits and not SUA levels itself. In the FREED trial, patients with asymptomatic hyperuricaemia treated with febuxostat had lower rates of the composite of cerebral, cardiovascular and renal events and death.74 Corroborating the cardioprotective properties of XO inhibitors, in a case-control study on more than 2,000 patients with acute myocardial infarction and more than 4,000 matched controls, the use of allopurinol was associated with a decreased risk of MI (OR 0.73) after adjustment for sex and hypertension status.75
However, in the small cross-over APEX trial, 6 weeks’ treatment with allopurinol 600 mg/day was not superior to placebo in reducing endothelial dysfunction in patients with microvascular angina.76 Analogously, in the ALL-HEART trial, a multicentre, prospective, randomised, open-label, blinded-endpoint trial on more than 5,000 participants aged ≥60 years with IHD but no history of gout, allopurinol did not reduce non-fatal MI, non-fatal stroke or cardiovascular death compared to usual care in a mean follow-up time of 4.8 years.77
A possible explanation for these conflicting results may reside in the characteristics of study populations and the duration of treatment and follow-up. Elderly people with higher levels of SUA may respond differently from younger adults with lower levels of SUA. Furthermore, patients with gout may be included or gout may be an exclusion criterion. Since SUA levels are associated with other cardiovascular comorbidities, the prevalence of the latter also plays a crucial role.
Thus, to definitely understand the role of XO inhibitors in patients with IHD, we will need to better and uniformly select the study population to avoid confounders and select patients with a specific hyperuricaemic phenotype (e.g. hyperproducers versus underexcretors, levels <6 mg/dl or >7 mg/dl, with or without history of gout or with or without kidney impairment).
Regarding how XO inhibitors compare, febuxostat seems to be more potent than allopurinol in reducing SUA levels. However, a few trials have focused on the novel XO inhibitor topiroxostat.70 A randomised, open-label, multicentre study of patients with chronic heart failure and hyperuricaemia showed that topiroxostat may reduce left ventricular end-diastolic pressure more effectively than allopurinol.78
Other cardiovascular medications may indirectly reduce SUA levels and should be considered in the optics of personalised treatment in individuals with asymptomatic, mild hyperuricaemia. Examples of such medications are losartan, sodium-glucose cotransporter 2 inhibitors, atorvastatin and simvastatin, fenofibrate and dihydropyridine calcium channel blockers.70,79–82
Conclusion
Hyperuricaemia with or without gout is a significant and independent risk factor for the development and progression of IHD.
Although some of the current literature highlights the potential benefits of treatment with XO inhibitors, future studies are needed to clarify the opportunities to treat patients with asymptomatic hyperuricaemia and IHD.
To date, SUA is a valid prognostic marker in patients with IHD and is associated with the clinical phenotype at presentation and short- and long-term outcomes, including worsening of kidney function, which in turn has an important impact on IHD-associated outcomes. Adjustment of SUA for kidney function may help in phenotyping patients with hyperuricaemia and in selecting patients with XO hyperactivity who may benefit the most from treatment with XO inhibitors, including those with a normal SUA range.