Key Points
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There are a number of in vitro and in vivo models supporting a complex potential relation of hyperuricemia to both cardiovascular and renal outcomes.
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Definitive evidence of clinical benefits of urate reduction for cardiovascular endpoints is lacking from randomized controlled trials, although preliminary evidence from trials suggests potential efficacy for hypertension in adolescents and for renal disease.
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Whether any potential clinical effects are mediated by urate-lowering versus xanthine oxidase inhibition itself is unclear.
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Clinical trials of urate-lowering, including agents that act via mechanisms other than xanthine oxidase inhibition, specifically designed to assess cardiovascular endpoints are needed to address potential clinical benefits of such a strategy.
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There are insufficient data at the present time to recommend treatment of asymptomatic hyperuricemia in the absence of clinical gout.
Hyperuricemia: Definition
Uric acid, a product of purine metabolism, is degraded in most mammals by the hepatic enzyme urate oxidase (uricase) to more highly soluble allantoin, which is freely excreted in the urine. During the Miocene epoch (24 to 6 million years ago), mutations occurred in early hominids that rendered the uricase gene nonfunctional. As a consequence, humans and the great apes have higher urate levels than do most other mammals, resulting in an inability of the liver to convert uric acid to the more soluble compound allantoin as the end product of purine metabolism. Hyperuricemia is best defined by serum urate concentrations in excess of 6.8 mg/dL, the limit of urate solubility in vitro at physiologic temperature, and pH. Hyperuricemia, due to uric acid overproduction or, more commonly, renal uric acid underexcretion, is necessary but not sufficient to cause clinical gout; only 22% of individuals with urate levels of 9.0 mg/dL or higher developed gout over 5 years in one cohort study. Hyperuricemia in the absence of clinical gout, tophi, or urolithiasis is considered “asymptomatic” and currently is not itself an indication for urate-lowering therapy.
Hypothetical Evolutionary Advantages of Hyperuricemia
It has been hypothesized that, because independent functional mutations in different evolutionary lineages are unlikely to occur due to chance, the loss of uricase may have had evolutionary advantages, particularly since 90% of urate filtered by the kidneys is reabsorbed rather than being eliminated.
One hypothesis is that the advantage conferred was related to uric acid functioning as an antioxidant. The loss of uricase was preceded by the loss of ability to synthesize ascorbic acid (vitamin C), another antioxidant, during a period in which primates consumed large quantities of fruits containing vitamin C. In later epochs, when diets contained lower levels of vitamin C, the higher serum urate levels related to the loss of uricase could have become an important source of antioxidant activity necessary for the prevention and repair of oxidative damage. For example, some have postulated that the relative “hyperuricemia” of higher primates and humans may have promoted the evolution of higher intelligence through antioxidant, neuroprotective effects of extracellular soluble urate.
Another hypothesis is related to salt sensitivity. The low-salt intakes of early hominids, combined with a shift toward more arid conditions occurring in the middle to late time periods of this epoch, could have led to selection pressure on early hominids toward a genotype that would enhance sodium retention to maintain blood pressure. This hypothesis has been supported by the observation of maintenance or a rise in blood pressure among rats in which hyperuricemia was induced while being maintained on a low-salt dietary condition.
The latest hypothesis for the evolutionary benefit of uricase loss appears more sound than the blood pressure hypothesis and is related to complex effects of uric acid on fructose disposition, with hyperuricemia promoting increased fat stores in part by effects on hepatic fructose metabolism. The potentially important linkages between hyperuricemia and fructose intake and metabolism (and consequent metabolic effects on liver and adiposity, and potentially vascular disease) are partially reviewed later, but a full discussion is beyond the scope of the summary provided here.
Potential Adverse Effects of Hyperuricemia in the Modern Era: Cardiovascular and Renal Consequences
In modern times, there has been a change to a higher salt diet in combination with food abundance throughout the seasons, eliminating the need to undergo physiologic adaptation for periods of hibernation or fasting. Further, average serum urate concentrations have been increasing over the past several decades, likely contributed to by increased consumption of purine-rich foods and fructose intake. Thus, while there may have been potential evolutionary advantages for elevated serum urate concentrations in early hominids, some of those very same benefits are now potentially harmful to humans in the modern era, particularly with changes that have led to even higher urate levels.
Clarifying the relation of uric acid to cardiovascular and renal disease risk has clinical implications and public health importance. First, there is an ongoing secular increase in the incidence and prevalence of gout and hyperuricemia in recent years. Second, asymptomatic hyperuricemia is presently not an indication for urate-lowering therapy. If hyperuricemia is indeed an independent risk factor for cardiovascular or renal disease, it might motivate a change in traditional treatment recommendations.
Link Between Uric Acid and Hypertension
Hypertension is a well-known strong risk factor for cardiovascular disease. A potential mechanistic link between uric acid and hypertension has been postulated. In vitro studies have pointed toward potential vascular effects of soluble urate. In the presence of urate concentrations seen in vivo in human plasma, levels of vasodilatory nitric oxide are suppressed, and vascular smooth muscle cells proliferate, migrate, and express inflammatory mediators, as do cultured endothelial cells. The soluble urate–induced vascular smooth muscle cell proliferation has been linked to suggested urate-related increased platelet-derived growth factor expression, local thromboxane production, cyclooxygenase-2 stimulation, and activation of the renin-angiotensin system in these cells. Additionally, results of in vitro studies have suggested that soluble urate could modulate intravascular C-reactive protein (CRP) production, endothelial cell function, inflammation, and platelet adhesiveness. Intracellular pro-oxidant effects of soluble uric acid have been proposed to be responsible for many of these changes, but conclusive proof is lacking. Also, one caveat to interpretation of soluble exogenous uric acid effects in some in vitro studies is a concern that contamination of the uric acid with endotoxin has not been adequately addressed in all studies.
In vivo evidence of a relation between uric acid and hypertension also exists. A rat model of mild hyperuricemia without crystalline disease affecting the renal parenchyma has been developed by use of oxonic acid, a uricase inhibitor. In this rat model, salt-sensitive hypertension and vascular remodeling were induced by hyperuricemia and prevented by treatment with a urate-lowering drug but not by treatment of the hypertension alone with hydrochlorothiazide. Further, both a xanthine oxidase inhibitor and a uricosuric agent prevented the rise in blood pressure and arteriolar thickening, supporting a specific role for uric acid in the vascular remodeling and resultant hypertension. In another model of spontaneously hypertensive rats, uric acid was associated with vascular smooth muscle cell proliferation, while allopurinol suppressed neointimal formation in the carotid artery. The hypertension related to elevated urate in rats in vivo appears to occur, at least partly, via effects on the renin-angiotensin system and afferent glomerular arteriolopathy. Additionally, after removing oxonic acid, which was used to induce hyperuricemia, maintenance of the rats on a low-salt diet still resulted in blood pressure elevations and arteriolar thickening, despite no longer being hyperuricemic. It is not known, however, whether oxonic acid has nonspecific effects at work in vivo other than uricase inhibition. Nonetheless, the hyperuricemia itself can lead to decreased renal plasma flow and glomerular filtration rate, as well as interstitial renal parenchymal changes without any urate crystal deposition, contributing to renal disease that can itself contribute to hypertension.
These findings have led to the development of a two-stage hypertension model with respect to serum urate effects: early hypertension being dependent on the renin-angiotensin system and nitric oxide pathways, while at later stages, when preglomerular vascular disease develops, hypertension is driven by the kidney and arteriosclerosis, at which time lowering serum urate levels is no longer protective ( Figure 19-1 ). To test this hypothesis, the response of pediatric/adolescent “essential” hypertension (i.e., in the absence of a secondary cause) to urate-lowering therapy with allopurinol has been studied in a randomized, double-blind, placebo-controlled crossover trial. In this study, the mean change in systolic blood pressure for allopurinol was –6.3 mm Hg (95% confidence interval [CI] 3.8 to 8.9 mm Hg) compared with 0.8 mm Hg for placebo (95% CI –2.9 to 3.4 mm Hg), and two thirds of participants achieved a normal blood pressure while taking allopurinol compared with only one participant while taking placebo ( p < .001). Interpretation of these results as attributable to urate lowering is of course limited by the antioxidant effects of xanthine oxidase (the primary target of allopurinol and an enzyme that is active in the vasculature ), let alone the lack of specificity of allopurinol, which affects pyrimidine metabolism and acts at several points in purine metabolism (see Chapter 13 ).
Given the postulated model of later stages of hypertension being independent of prior hyperuricemia that could have driven the earlier stages, one may expect the relationship between serum urate and hypertension in adults to be less clear cut. In the largest meta-analysis to date, representing data from over 55,000 participants in 18 prospective cohorts, hyperuricemia was associated with a 41% increased risk of incident hypertension (95% CI for risk ratio (RR) 1.23 to 1.58). However, the possibility of reverse causation cannot be excluded since preclinical hypertension can potentially drive renal changes leading to hyperuricemia itself. Further, the randomized clinical trials of febuxostat, a xanthine oxidase inhibitor that results in substantial urate lowering, did not report beneficial blood pressure lowering effects despite having substantial proportions of hypertensive participants included in the trials. In one study, the incidence of hypertension was higher in the febuxostat 80 mg/day arm compared with allopurinol but was no different than placebo, and allopurinol had a lower incidence of hypertension than placebo, while the other doses of febuxostat did not differ from placebo or allopurinol with regard to incidence of hypertension. Thus, the specific role of uric acid in adult hypertension requires further clarification.
It may well be that antihyperuricemic therapy is only beneficial at the earliest stages of the onset of hypertension. This is somewhat supported by the finding that the risk ratios for incident hypertension are higher among those of a younger age ( Figure 19-2 ), although this may represent the phenomenon of being able to demonstrate larger relative risks among lower risk populations. That is, it is easier to demonstrate larger risk ratios in a population whose baseline risk is low. Nonetheless, there are likely numerous pathways that can lead to hypertension, and therefore better mechanistic phenotyping will be needed to identify those in whom hyperuricemia may be playing a role and to identify the particular stage at which hyperuricemia may be important.
Link Between Uric Acid and Metabolic Syndrome and Diabetes
Persons with metabolic syndrome and diabetes are also at increased risk for cardiovascular disease. Elevated serum urate in the metabolic syndrome has historically been attributed to hyperinsulinemia given that insulin decreases renal excretion of uric acid. However, hyperuricemia may predate hyperinsulinemia, obesity, and diabetes. For example, using data from two cohorts of the Framingham Study (Original and Offspring), the Finnish Diabetes Prevention Study, the Rancho Bernardo Study, and the Rotterdam Study, serum urate levels were associated with an increased risk of developing type 2 diabetes. Although only a cross-sectional association, persons with higher serum urate levels have a substantially higher prevalence of the metabolic syndrome, even among those without hypertension, those without diabetes, and those who are not overweight. At the very least, such an association should encourage physicians to evaluate hyperuricemic (gout) patients for the presence of the metabolic syndrome.
Interestingly, fructose may be a potential link between uric acid and the metabolic syndrome. Fructose intake in the forms of table sugar (sucrose, which is a crystalline disaccharide of glucose and fructose) and the widely used beverage and food sweetening additive high-fructose corn syrup (which is enriched in monosaccharide fructose) has increased dramatically over the past two to three decades and is associated with increased incidence of obesity and diabetes as well as with hyperuricemia and incident gout. Hepatic adenosine triphosphate (ATP) depletion via fructose metabolism could be a component in nonalcoholic steatotic hepatic disease (NASH). In an animal study, fructose-fed rats, but not those that were dextrose-fed, developed the metabolic syndrome. Further, use of either allopurinol or benzbromarone (a uricosuric agent) in the fructose-fed rats prevented or reversed features of the metabolic syndrome. The effects of fructose in this animal model were seen even with caloric restriction. The fructose transporter SLC2A9 (also known as GLUT9) was recently noted to also be a urate transporter (and more potent as a urate than a hexose transporter), and genetic studies have demonstrated an association of single nucleotide polymorphisms of the gene with gout and urate levels. In sum, these studies provide a potential link between fructose, hyperuricemia, and the metabolic syndrome.
Link Between Uric Acid and Cardiovascular Disease (Coronary Heart Disease)
There are many potential mechanisms linking uric acid to cardiovascular disease. While not all individuals with hyperuricemia have clinical gout despite urate’s ability to promote inflammation, a proinflammatory state is likely associated with hyperuricemia. The insulin resistance so often associated with hyperuricemia can also contribute to both a low-grade inflammatory state and cardiovascular risk. Further, in addition to its elevated levels in atherosclerotic plaques, soluble urate has been reported by approximately half a dozen different research groups to promote proliferative and proinflammatory responses in cultured vascular smooth muscle cells and a variety of inflammatory responses in cultured endothelial cells. As outlined earlier, there is in vivo evidence from rat models that hyperuricemia may have a pathogenic role through vascular effects, partly via effects on nitric oxide metabolism and on the renin-angiotensin system. On the other hand, direct effects of soluble urate on the vasculature have not been conclusively established. For example, urate infusion into the human circulation in vivo failed to demonstrate impairment of cardiovascular function, possibly related to antioxidant effects of soluble extracellular urate. However, urate may also be pro-oxidative under certain conditions, particularly when inside the cell, and when other antioxidants are at low levels, which could potentially contribute to promotion of cardiovascular abnormalities through oxidative stress. The net effects of these complex and, in some cases, competing functions of soluble urate are unknown, although they provide considerable support for the possibility that uric acid may have direct biological effects on the vasculature.
The difficulty with such indirect evidence is that hyperuricemia is also associated with a number of comorbidities that could contribute to cardiovascular disease risk. Persons with gout and underlying hyperuricemia have an increased risk for cardiovascular disease and increased prevalence of associated cardiovascular comorbidities than expected. These comorbidities include obesity, diabetes, dyslipidemia, and hypertension. Thus, it is unclear as to whether the increased association between hyperuricemia and cardiovascular disease is due to the associated cardiovascular comorbidities or the demographic characteristics of persons who are typically hyperuricemic (males who are often older and overweight) or whether uric acid itself plays a role in the development of cardiovascular disease. Epidemiologic studies have been conflicting with respect to whether hyperuricemia is independently associated with cardiovascular disease, with some showing a positive independent association and others demonstrating no independent association.
Approximately two thirds of more than 30 observational cohort studies over the years have demonstrated an association of uric acid and cardiovascular disease. Contradictory results can be due to differences in adjustment for certain covariates and definitions used for such covariates, resulting in residual confounding. Some prior studies, with both negative and positive associations reported, have either failed to adjust for low-dose aspirin use or for renal insufficiency (both of which can increase serum urate levels and risk for cardiovascular disease ), have not used current standard definitions for hypertension, and/or have adjusted for the presence of hypertension and use of antihypertensive agents, which may cause problems of collinearity. Additionally, the definition for hyperuricemia can vary from study to study, and most studies have only assessed urate levels at a single time point, whereas it is possible that a cumulative effect of serum urate could be important in conferring risk of cardiovascular events.
Another problem is in the statistical modeling of the potential effects of serum urate on cardiovascular disease in such observational studies. Most analyses aim to determine whether serum urate has a direct effect on cardiovascular disease, independent of other risk factors. Such an approach does not allow for consideration of the possibility that uric acid may exert its effects indirectly through other risk factors, such as hypertension or renal disease ( Figure 19-3 ). For example, assume that hyperuricemia is causally related to hypertension, which in turn is itself a strong risk factor for cardiovascular disease, and that uric acid has no other direct effects on cardiovascular disease. In this example, hypertension is on the causal pathway between uric acid and cardiovascular disease (i.e., an intermediate). In the typical approach to statistical modeling, hypertension would be adjusted for to discern the independent effects of uric acid. However, by doing so, no effect of uric acid would be seen if uric acid has no other effects on cardiovascular disease except through hypertension. With such a modeling approach, one would correctly conclude that uric acid has no association with cardiovascular disease independent of hypertension but will have importantly missed identifying hyperuricemia as an important modifiable risk factor for hypertension, which in turn is a risk factor for cardiovascular disease.
Thus understanding the potential biologic mechanisms is crucial to appropriate statistical modeling. Indeed, if the question is about the sum total effect of uric acid on cardiovascular disease, both those that are direct and those that are indirect , then special analytic methods need to be used as one should not simply adjust for risk factors that are intermediates along the pathway from uric acid to cardiovascular disease (see Figure 19-3 ) since such an approach can introduce bias. This is a particularly difficult and prevalent problem since many factors, such as hypertension, can be considered to be both a confounder and an intermediate, and therefore the standard approach of simply adjusting for such factors results in biased effect estimates.
Finally, as any effect of serum urate is likely to be small given the multifactorial nature of cardiovascular disease, studies with relatively small numbers of events may not be able to demonstrate an association, particularly when populations studied are at low risk for the outcome under study. Thus, individual studies may be underpowered to detect a small effect. An approach to dealing with potential lack of power in individual studies is to perform a meta-analysis. One of the first such meta-analyses to evaluate the relationship between serum urate and coronary heart disease included close to 9,500 cases from 16 studies and found a 13% increased risk (RR = 1.13, 95% CI 1.07 to 1.20) of coronary heart disease among those in the top tertile of serum urate levels compared with the lowest tertile ( Figure 19-4 ). The authors of this report downplay their main results and state that their results indicate that serum urate does not appear to be an important predictor of coronary heart disease when taking into account other potential risk factors, and in fact, conclude no association despite a statistically significant result. However, most cardiac risk factors have small effects. Further, a modifiable risk factor that has a high prevalence in the population can have a substantial public health impact if intervened upon, even if the noted effect estimate appears to be small.
A more recently updated meta-analysis that included 26 studies (only 8 of which were included in the previous meta-analysis) with data from over 400,000 participants reported similar results, with 9% (RR = 1.09, 95% CI 1.03 to 1.16) and 16% (RR = 1.16, 95% CI 1.01 to 1.30) increased risk of coronary heart disease incidence and mortality, respectively, among those who were hyperuricemic compared with those who were normouricemic ( Figure 19-5 ). This largest meta-analysis to date supports a significant but modest association between hyperuricemia and cardiovascular events, independent of traditional cardiovascular risk factors.
In addition to attempting to discern whether hyperuricemia is associated with adverse cardiovascular outcomes, many investigators have focused on potential differential risk by sex. Such differences reflect effect measure modification, which is typically formally assessed by a statistical test for interaction to discern whether the differences in effect estimates between the groups being compared are truly statistically significantly different from one another. However, not all studies addressing this question support their conclusions by such formal statistical evaluations. Another difficulty in interpretation of differences in effect estimates is that, as discussed above, a higher relative risk may be a reflection of a lower baseline risk rather than a true difference in absolute risk difference. In a study using data from the National Health and Nutrition Examination Survey (NHANES) I, the authors concluded that although higher urate levels were associated with cardiovascular outcomes for both men and women, the risk was higher among women. The highest quartile of serum urate was associated with 1.77 times higher risk of ischemic heart disease mortality among men, and a 3.00 times higher risk among women than the lowest quartiles, respectively. However, in terms of absolute rate differences, the highest quartile of serum urate was associated with 3.55 more deaths per 1000 person-years among men, and 4.03 more deaths per 1000 person-years among women than the lowest quartiles, respectively. This example illustrates that the absolute risk differences were similar between the sexes, despite the seemingly large disparities in the relative measures of effect. Further, the cut-points for the quartiles were different between men and women, making direct comparison difficult. This is one reason that biologically meaningful cut-points are potentially better than sample-specific quartiles to aid in interpretation of the data.
In the Wheeler et al. meta-analysis, the top tertile of serum urate was associated with higher risk of coronary heart disease to a similar extent with overlapping confidence intervals in both men (RR = 1.12, 95% CI 1.05 to 1.19) and women (RR = 1.22, 95% CI 1.05 to 1.40), compared with the lowest tertile (see Figure 19-4 ). In the Kim et al. meta-analysis, the association of hyperuricemia with incident coronary heart disease was not significant for men (RR = 1.04, 95% CI 0.90 to 1.17) or for women (RR = 1.32, 95% CI 0.57 to 2.07), even though the pooled effect of both sexes combined was significant (see Figure 19-5 , A ). For coronary heart disease mortality, hyperuricemia among men was associated with a nonsignificant 1.09 times higher risk (95% CI 0.98 to 1.19), while among women hyperuricemia was associated with a 1.67 times higher risk (95% CI 1.30 to 2.04) (see Figure 19-5 , B ). Thus the results are conflicting regarding effect measure modification by sex in these two meta-analyses, highlighting the difficulty in definitively answering this question even with the large amounts of data available in these meta-analyses.
Another way to address the question of whether uric acid is harmful is to evaluate whether reducing urate levels improves outcomes. This is best accomplished in a randomized trial (discussed later). Observational studies can also attempt to address such a question by evaluating whether individuals on urate-lowering therapy have better outcomes than those who are not on such therapies. The difficulty in interpreting such observational studies, though, is that people on urate-lowering therapy are systematically different than those who are not, and without taking into account those differences, such studies are prone to substantial bias. In particular, confounding by indication is a common problem in pharmacoepidemiologic studies.
Confounding by indication refers to a type of bias that occurs when one cannot account for factors that influence why individuals receive or do not receive a certain exposure (in this case, urate-lowering therapy). For example, an individual with more comorbidities may be less likely to receive allopurinol than a relatively healthier individual with fewer medical contraindications to allopurinol; individuals who have better medical management of their comorbidities, and are therefore at lower risk of adverse outcomes, may be more likely to have medications such as allopurinol prescribed to them. A recent study concluded that use of urate-lowering therapy was associated with substantially lower risk of cardiovascular mortality and stroke-related mortality based on a clinical database linked to prescription records. However, whether confounding by indication was appropriately accounted for is not clear, and could importantly bias their results to show a protective effect when there may not be one, or at least a much smaller effect. A further caveat is that the event rate was quite low, at 1% or substantially lower for the various outcomes assessed.
Link Between Uric Acid and Associated Cardiovascular Disorders: Congestive Heart Failure and Stroke
Another approach that may mitigate against potential for low event rates is to study related outcomes of potentially higher prevalence. One potential phenotype related to cardiovascular disease is congestive heart failure. Serum urate has been associated with increased risk for incident congestive heart failure, and changes in serum urate have been associated with flares of congestive heart failure. Potentially complementing this latter finding, a study that used data from a universal health care coverage program that included clinical and prescription data found use of allopurinol to be associated with lower risk of heart failure readmission or death among persons with gout, but not among their whole study population. It is possible that by reducing urate levels and the attendant risk for gout flares, that heart failure outcomes could improve. However, it’s not clear as to why a large proportion of individuals would be on allopurinol in the absence of a gout diagnosis, or why that should make a difference for heart failure outcomes. Further, and importantly, a concern about confounding by indication exists in this study since, compared with the cases, a larger proportion of controls were on various cardiovascular medications, potentially suggesting they were more likely to be appropriately medically managed, and by extension, more likely to be prescribed allopurinol.
In terms of urate as a risk factor for another related phenotype, stroke, a meta-analysis demonstrated hyperuricemia to be associated with a 47% increased risk of stroke (95% CI 1.19 to 1.76) after adjusting for known risk factors, and a 26% increased risk for stroke mortality (95% CI 1.12 to 1.39), compared with those who were normouricemic.
Link Between Uric Acid and Preclinical Atherosclerotic Disease
Noninvasive assessment of preclinical lesions may provide another strategy for avoiding low power resulting from studies using clinical endpoints that suffer from low event rates. Further, as opposed to adverse clinical events such as myocardial infarction or stroke, such studies of preclinical lesions may provide insight into potential pathophysiologic mechanisms of risk factors. Advances in imaging technology have enabled the evaluation of markers of preclinical atherosclerotic disease, such as carotid plaques, which have been associated with prevalent and incident cardiovascular disease and strokes. Carotid plaques as measured by ultrasound may be a result of atherosclerosis causing intimal expansion and/or a result of vascular hypertrophy and remodeling causing an increased thickness in the media. Unfortunately, the association between hyperuricemia and preclinical carotid atherosclerosis has been conflicting, although the majority of studies have supported an association.
Coronary artery calcification is another such preclinical marker of cardiovascular disease. The extent of intimal artery calcification correlates with the extent of atherosclerosis. Coronary artery calcification has been associated with death from coronary disease and all-cause mortality, which may be mediated by the capacity of hydroxyapatite crystals deposited in the calcified intima to promote low-grade inflammation in the artery wall. With regard to atherosclerosis, soluble urate is held to play a pathogenic role in the vascular remodeling of cardiovascular disease by biologic mechanisms detailed above, including low level uptake by endothelial and vascular smooth muscle cells, induction of oxidative stress and inflammatory cytokine expression, and modulation of the renin-angiotensin system. Thus, there may be different atherosclerotic phenotypes reflected by coronary artery calcification versus carotid plaques. While there are many potential mechanisms linking serum urate levels to cardiovascular disease through vascular remodeling and other risk factors, soluble urate has not been investigated as a potential direct inducer of arterial calcification. In observational studies to date, the association of serum urate with coronary artery calcification has been conflicting. In this light, not all vascular calcification is related to atherosclerosis. For example, aging, end-stage renal disease, and diabetes mellitus can cause nonatherosclerotic artery tunica media calcification. Soluble urate potentially decreases nitric oxide bioavailability through suppression of its production, promotion of its inactivation, and stimulation of its degradation. Thus, with respect to reported vascular effects of soluble urate, by suppressing nitric oxide levels in the artery, urate theoretically has the potential to suppress ectopic osteoblastic differentiation of vascular smooth muscle cells, which in theory could result in less vascular calcification than otherwise predicted in a disease such as atherosclerosis.
Again, many of the same potential explanations as have been explored for the contradictory results of the numerous studies of clinical coronary heart disease just presented also apply here, including methodologic and definitional issues.
Lessons Learned From Randomized Clinical Trials of Urate-Lowering Therapies Regarding Potential Cardiovascular Effects
Well-conducted randomized clinical trials avoid many (but not all) of the pitfalls faced by observational studies. If uric acid is truly a causal factor in cardiovascular disease, one should expect that lower serum urate levels would be associated with lower risk for cardiovascular endpoints. Indeed, in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study, approximately a third of the improved cardiovascular mortality was attributed to an independent effect on serum urate levels in those who received losartan, a drug with uricosuric effects, compared with those who received atenolol, a beta-blocker with no such effects. However, such interpretations should be viewed with caution. It is possible that losartan has effects beyond lowering of blood pressure that beta-blockers do not have that mediated such effects and that serum urate is simply a biomarker or epiphenomenon of such an effect. On the other hand, in the Systolic Hypertension in the Elderly (SHEP) trial, the authors found that those who had their hypertension appropriately controlled with a thiazide diuretic but who concomitantly also had an increase in their serum urate levels failed to demonstrate a cardiovascular benefit compared with placebo. A similar mitigation of beneficial effect was not seen for stroke or “any cardiovascular event.” It is not clear as to why this would be the case, and it raises a concern about a false-positive result. Three secondary coronary heart disease studies using sulfinpyrazone, which has both antiplatelet and uricosuric effects, demonstrated reduced risk of sudden cardiac death and fatal and nonfatal myocardial infarction, while another demonstrated no benefit of sulfinpyrazone on risk of cardiac death or nonfatal myocardial infarction among persons with unstable angina. In the Heart and Estrogen/progestin Replacement Study (HERS) trial, the active treatment arm had significantly lower serum urate levels compared with placebo, but this was not associated with lower overall risk for cardiovascular events. These latter two studies provide examples of urate lowering in the context of a trial that was not associated with improved outcomes.
Urate-lowering effects on surrogate endpoints have also been studied. Although oxypurinol improved left ventricular ejection fraction in a post-hoc analysis of a select subset whose baseline ejection fractions were less than 40% in a small trial, another trial for moderate-to-severe congestive heart failure did not demonstrate a beneficial effect except for persons with serum urate levels above 9.5 mg/dL in post-hoc analyses. Another surrogate endpoint that has been examined is exercise capacity. In one study, conducted among persons with unstable angina, exercise capacity increased with use of high-dose (600 mg/day) allopurinol compared with placebo. In another study conducted among persons with chronic heart failure, allopurinol at 300 mg/day did not improve exercise capacity. Whether these discrepancies are related to dose, a difference in underlying pathophysiology of the two conditions or other factors is not clear.
If more effective urate-lowering may be needed to demonstrate a beneficial cardiac effect, as may have been achieved with higher doses of allopurinol in the unstable angina study described earlier, one may expect that randomized clinical trials of febuxostat should demonstrate positive effects. However, such trials have not demonstrated a cardiovascular benefit. In fact, there has even been some concern that there may be a nonsignificant increase in cardiovascular events in those who took febuxostat compared with allopurinol in the initial trial, which necessitated further study into the cardiovascular safety of febuxostat. If urate contributed to cardiovascular disease, drugs with substantial urate-lowering effects in such trials should have been able to demonstrate positive effects. It is possible that such studies were too short in duration, enrolled patients with a high risk of cardiovascular disease, and were not powered for cardiovascular outcomes, all of which could affect one’s ability to detect a small positive effect. Moreover, increased flares of gout, which are well documented to occur with more intense serum urate-lowering regimens, can induce systemic inflammation, with release of cytokines (e.g., interleukin [IL]-1β, tumor necrosis factor [TNF]α, IL-6, IL-8) and other mediators such as CRP, which in turn have the potential to promote a variety of adverse cardiovascular events, including arrhythmia mediated by IL-6. Nonetheless, with the best evidence available to date based on these randomized trials, urate-lowering does not appear to have a substantial cardiovascular benefit. A potentially smaller beneficial effect cannot be ruled out as appropriately designed studies to address cardiovascular outcomes using specifically urate-lowering drugs have not been carried out to date. Ideally, one would need to evaluate a uricosuric agent as well as a xanthine oxidase inhibitor and uricase to demonstrate that the effect is truly due to urate lowering rather than another drug-related mechanism.
Potential Role for Xanthine Oxidase in Cardiovascular Disease
Some investigators have argued that rather than uric acid itself being harmful, it is xanthine oxidase and its capacity for oxidative damage that are the culprits in cardiovascular disease. As such, the potential positive effects of xanthine oxidase inhibition, as would be obtained with allopurinol or febuxostat, are argued to not be related to urate-lowering effects but rather to their effects on suppressing xanthine oxidase activity. Xanthine oxidase itself has been demonstrated in vitro to become activated in mononuclear phagocytes and to contribute to the inflammatory state of the mononuclear phagocyte, the major cell type that drives atherogenesis. The role of xanthine oxidase on the human cardiovascular system has been studied primarily in the setting of congestive heart failure, where it is thought that xanthine oxidase contributes to abnormal excitation-contraction coupling and cardiac remodeling in heart failure. Such features have been altered by use of the xanthine oxidase inhibitor, allopurinol. Treatment in another study with allopurinol improved endothelial function among subjects with heart failure, whereas comparable uric acid reduction with probenecid, a uricosuric agent, did not. These studies suggest that the potential association between hyperuricemia and cardiovascular disease may be due to free-radical generation by xanthine oxidase and that the hyperuricemia–cardiovascular disease link may just be an epiphenomenon ( Figure 19-6 ).
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Crystalline Disorders Associated With Renal Disease Including Oxalate Arthropathy
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