Uric Acid in Heart Disease: A New C-reactive Protein?
Uric Acid in Heart Disease: A New C-reactive Protein?
Purpose of review To review and interpret the recently published data on hyperuricemia and cardiovascular disease to present an opinion on the nature of link between serum uric acid concentration and the risk for cardiovascular outcomes, and to comment on its implications for clinical practice.
Recent findings Evidence has accumulated in prospective observational studies that link hyperuricemia among younger adults with the risk of subsequent hypertension. Such associations have been observed with respect to insulin resistance, diabetes, and other cardiovascular risk factors. Newer data confirm the link between hyperuricemia and cardiovascular mortality. The use of allopurinol has been shown to be associated with reduced mortality risk in longer term observational studies and with reduced blood pressure in short-term randomized controlled trials. None of these findings is confounded by traditional risk factors.
Summary The available evidence has established a link between hyperuricemia and cardiovascular disease and this may be causal. Without waiting for the resolution of causality arguments, one can start using serum uric acid concentration as an inexpensive cardiovascular risk marker.
Elevated levels of serum uric acid (SUA) have been associated in population studies with an increased risk of cardiovascular disease (CVD). What remains unclear is the causality of this relationship, namely does SUA contribute independently to the pathophysiology of CVD or is it simply an epiphenomenon due to the presence of concurrent-related conditions such as hypertension, kidney disease, or the metabolic syndrome? This article will provide an overview of the current evidence linking hyperuricemia and CVD and address potential mechanisms which could implicate it directly with CVD or its risk factors, especially hypertension. Finally, we will use evidence provided by observational and early prospective studies of CVD risk reduction by urate-lowering therapy.
Individual levels of SUA vary according to genetic background, renal function, diet, and metabolic factors. From an epidemiological perspective, a large number of prospective observational studies and case–control studies have linked elevated serum uric acid concentration with adverse outcomes such as acute myocardial infarction, hypertension, heart failure, peripheral vascular disease, stroke, and the metabolic syndrome.
Fortunate is he, who is able to know the causes of things [Virgil 29 BC, Georgica (II, v. 490)].
Animal studies offer the opportunity for interventions well beyond those that can be applied in human studies. Animals, unlike humans, possess the uricase enzyme which breaks down uric acid to easily excretable allantoin. Thus lower animals cannot spontaneously develop hyperuricemia. However, in murine models of hyperuricemia, hypertension has been observed which, on treatment with allopurinol, lowered blood pressure concurrent with a fall in SUA while the antihypertensive agent hydrochlorothiazide had no antihypertensive effect.
Small-scale human studies have observed a similar antihypertensive effect of urate-lowering therapy. In a 12-week study, allopurinol reduced both systolic and diastolic blood pressure in a cohort of 21 hyperuricemic patients. Similarly an antihypertensive effect was demonstrated in obese adolescent males with hypertension and the same investigations have more recently presented evidence in abstract form in which they demonstrate the ability of allopurinol to lower blood pressure and demonstrate that this effect is greater than that seen with the uricosuric/antihypertensive agent losartan.
Regardless of the cause, the presence of dilated cardiomyopathy is associated with left ventricular strain, impaired myocardial oxygen consumption, and endothelial dysfunction. Observational and interventional studies in animals and humans have demonstrated the ability of allopurinol to improve these effects. One study performed in dogs demonstrated that intravenous allopurinol improved myocardial efficiency in animals with dilated cardiomyopathy. Given the four-fold increase of xanthine oxidase activity in the failing heart and therapy limited to a single dose of allopurinol it is possible that this effect was independent of SUA reduction. Similar studies in humans have demonstrated the ability of intracoronary allopurinol to increase myocardial energy metabolism. Upregulation of myocardial xanthine oxidase in this context may indicate that allopurinol is effective via xanthine oxidase inhibition. Doehner et al. demonstrated the ability of allopurinol to improve peripheral vasodilator capacity by randomizing hyperuricemic chronic heart failure (CHF) patients to allopurinol 300 mg/day or placebo for 7 days. In the treatment group, a significant improvement was seen in endothelium dependent flow. This effect was accompanied by a significant reduction in SUA as well as a reduction in allantoin, a marker of free radical generation. Finally, another study in humans has demonstrated the ability of allopurinol therapy to reduce serum B-type natriuretic peptide (BNP). However, despite these biomarker changes allopurinol did not alter exercise capacity in chronic heart failure.
A recent study suggested that hyperuricemia may be an independent risk factor for adverse events, including decreased survival, after coronary artery bypass grafting (CABG). This study took into many clinical covariates, but it remained possible that the uric acid is associated with comorbidities which portend decreased long-term survival. Supporting the independent risk of SUA in the perioperative period are studies demonstrating that allopurinol can reduce perioperative cardiac events and improve postoperative recovery in those undergoing CABG. However, given the relatively brief duration of allopurinol therapy in these studies it is possible that the protective effect is provided by its antioxidant rather than hypouricemic impact.
The most recent interventional study by Norman et al. entailed 65 patients with angiographically demonstrated coronary artery disease, chronic stable angina, and a positive exercise stress test. These were randomized to high dose (600 mg/day) of allopurinol or placebo for 6 weeks and then crossed over to active drug or placebo. In the treatment group, allopurinol increased median time to chest pain, median exercise time, as well as time to ST depression. The authors excluded those with a history of gout, and the authors attributed the observations to other, nonhypouricemic, effects of xanthine oxidase inhibition.
There are three arguments against causality in the hyperuricemia CVD link. Most of the contrary evidence supporting these has been epidemiologic in nature.
Argument 1: Coincidence The proponents of this argument believe that there is no independent association of hyperuricemia with CVD as some studies have failed. Some studies have failed to confirm such a link. The argument goes that the relationship is coincidence or due to confounding risk factors such as obesity and hypertension. The epidemiological studies that failed to discern any independent association (leave alone causative relation) are far fewer than those that do show such a link. These entailed younger, and generally healthier, populations and may have lacked the power to identify the contribution of hyperuricemia to cardiovascular outcomes. The power needed to show a conclusive null result is much higher than that needed to show a positive link, as was the case of the two pivotal randomized controlled trials that showed that aspirin did not prevent recurrent myocardial infarction.
Argument 2: Reverse Causation This line of argument admits the existence of an independent association between hyperuricemia and cardiovascular disease but attributes it to residual confounding by other risk factors such as chronic renal failure, hyperlipidemia, and the metabolic syndrome. One study found a correlation between serum urate and carotid intima media thickness (cIMT) but this effect was lost after adjustment for relevant behavioral and biologic correlations. This conclusion is contrary to several other studies demonstrating an association of hyperuricemia with cIMT atherosclerosis even after adjustment for covariates.
Argument 3: Common-causal Genetic Variable This is the strongest argument against uric acid as a causal agent in CVD. In 2002, Ghei et al. summarized the genetic links of hyperuricemia trait with those for cardiovascular risk factors such as dyslipidemia, renal dysfunction, and impaired glucose metabolism. However, nonepidemiological interventional data are more supportive of hyperuricemia as a causal factor.
As discussed above, recent interventional study using allopurinol was the demonstration by Norman et al. in which 65 patients with angiographically demonstrated coronary artery disease, chronic stable angina, and a positive exercise stress test, were randomized to high dose (600 mg/day) of allopurinol or placebo for 6 weeks and then crossed over to active drug or placebo. In the treatment group, allopurinol increased median time to chest pain, median exercise time, as well as time to ST depression. The authors excluded those with a history of gout, and levels of SUA were not documented as relevant. The authors acknowledged that the precise mechanism of the antiischemic effect remains unclear. The discussion attributed the effect to blocking the xanthine oxidase-mediated conversion of molecular oxygen to produce mediators of oxidative stress or inhibition of xanthine oxidase-mediated breakdown of ATP to AMP, augmenting high-energy phosphates in the cardiac tissues.
Support also derives from electronic medical record-based study of 9924 hyperuricemic veterans in whom urate-lowering therapy reduced mortality even after adjustments for other prognostic factors (HR 0.77; CI 0.65–0.91). Furthermore, several human and animal studies have prospectively applied urate-lowering therapies to the treatment of direct CVD risk factors including hypertension and more directly to, cardiomyopathy and coronary artery bypass grafting.
There are several striking similarities between SUA and C-reactive protein (CRP) as markers of coronary risk. CRP is a liver-produced protein that is up-regulated in many clinical situations. Significant numbers of observational studies showed that a high level of CRP is an independent risk factor for CVD. In some interventional studies, reduction of CRP was associated with improved cardiovascular risk although a recent systematic review concluded that the case was weak. Biological mechanisms linking CRP to CAD have been elucidated. Some have argued that CRP is in the causal pathway for coronary artery disease, but others dispute this assertion. A consensus is evolving in the cardiology community that CRP can be useful in the prediction of coronary artery disease.
The recent JUPITER study has demonstrated that in those with elevated CRP, even in the setting of normal levels of LDL, initiation of HMG-CoA reductase inhibitor (Statins), reduced risk of cardiovascular events including myocardial infarction, stroke, need for cardiac revascularization as well as all-cause mortality. Though a clear causal role for CRP in the initiation or propagation of CVD is uncertain, use of this marker has identified both those at risk for CVD, as well as those who may benefit from risk reduction interventions. It is possible to envisage a similar use of serum urate therapies. The use of CRP is also being followed as a biomarker of therapies. Whether nonhypouricemic cardiovascular risk modifications will impact on serum uric acid in a similar fashion has not been studied. The metabolic syndrome and serum insulin levels can influence serum urate levels and it is therefore conceivable that serum urate could serve as a barometer for metabolic and cardiovascular status.
Abstract and Introduction
Abstract
Purpose of review To review and interpret the recently published data on hyperuricemia and cardiovascular disease to present an opinion on the nature of link between serum uric acid concentration and the risk for cardiovascular outcomes, and to comment on its implications for clinical practice.
Recent findings Evidence has accumulated in prospective observational studies that link hyperuricemia among younger adults with the risk of subsequent hypertension. Such associations have been observed with respect to insulin resistance, diabetes, and other cardiovascular risk factors. Newer data confirm the link between hyperuricemia and cardiovascular mortality. The use of allopurinol has been shown to be associated with reduced mortality risk in longer term observational studies and with reduced blood pressure in short-term randomized controlled trials. None of these findings is confounded by traditional risk factors.
Summary The available evidence has established a link between hyperuricemia and cardiovascular disease and this may be causal. Without waiting for the resolution of causality arguments, one can start using serum uric acid concentration as an inexpensive cardiovascular risk marker.
Introduction
Elevated levels of serum uric acid (SUA) have been associated in population studies with an increased risk of cardiovascular disease (CVD). What remains unclear is the causality of this relationship, namely does SUA contribute independently to the pathophysiology of CVD or is it simply an epiphenomenon due to the presence of concurrent-related conditions such as hypertension, kidney disease, or the metabolic syndrome? This article will provide an overview of the current evidence linking hyperuricemia and CVD and address potential mechanisms which could implicate it directly with CVD or its risk factors, especially hypertension. Finally, we will use evidence provided by observational and early prospective studies of CVD risk reduction by urate-lowering therapy.
Individual levels of SUA vary according to genetic background, renal function, diet, and metabolic factors. From an epidemiological perspective, a large number of prospective observational studies and case–control studies have linked elevated serum uric acid concentration with adverse outcomes such as acute myocardial infarction, hypertension, heart failure, peripheral vascular disease, stroke, and the metabolic syndrome.
Fortunate is he, who is able to know the causes of things [Virgil 29 BC, Georgica (II, v. 490)].
Hypertension
Animal studies offer the opportunity for interventions well beyond those that can be applied in human studies. Animals, unlike humans, possess the uricase enzyme which breaks down uric acid to easily excretable allantoin. Thus lower animals cannot spontaneously develop hyperuricemia. However, in murine models of hyperuricemia, hypertension has been observed which, on treatment with allopurinol, lowered blood pressure concurrent with a fall in SUA while the antihypertensive agent hydrochlorothiazide had no antihypertensive effect.
Small-scale human studies have observed a similar antihypertensive effect of urate-lowering therapy. In a 12-week study, allopurinol reduced both systolic and diastolic blood pressure in a cohort of 21 hyperuricemic patients. Similarly an antihypertensive effect was demonstrated in obese adolescent males with hypertension and the same investigations have more recently presented evidence in abstract form in which they demonstrate the ability of allopurinol to lower blood pressure and demonstrate that this effect is greater than that seen with the uricosuric/antihypertensive agent losartan.
Cardiomyopathy
Regardless of the cause, the presence of dilated cardiomyopathy is associated with left ventricular strain, impaired myocardial oxygen consumption, and endothelial dysfunction. Observational and interventional studies in animals and humans have demonstrated the ability of allopurinol to improve these effects. One study performed in dogs demonstrated that intravenous allopurinol improved myocardial efficiency in animals with dilated cardiomyopathy. Given the four-fold increase of xanthine oxidase activity in the failing heart and therapy limited to a single dose of allopurinol it is possible that this effect was independent of SUA reduction. Similar studies in humans have demonstrated the ability of intracoronary allopurinol to increase myocardial energy metabolism. Upregulation of myocardial xanthine oxidase in this context may indicate that allopurinol is effective via xanthine oxidase inhibition. Doehner et al. demonstrated the ability of allopurinol to improve peripheral vasodilator capacity by randomizing hyperuricemic chronic heart failure (CHF) patients to allopurinol 300 mg/day or placebo for 7 days. In the treatment group, a significant improvement was seen in endothelium dependent flow. This effect was accompanied by a significant reduction in SUA as well as a reduction in allantoin, a marker of free radical generation. Finally, another study in humans has demonstrated the ability of allopurinol therapy to reduce serum B-type natriuretic peptide (BNP). However, despite these biomarker changes allopurinol did not alter exercise capacity in chronic heart failure.
Coronary Artery Bypass Grafting
A recent study suggested that hyperuricemia may be an independent risk factor for adverse events, including decreased survival, after coronary artery bypass grafting (CABG). This study took into many clinical covariates, but it remained possible that the uric acid is associated with comorbidities which portend decreased long-term survival. Supporting the independent risk of SUA in the perioperative period are studies demonstrating that allopurinol can reduce perioperative cardiac events and improve postoperative recovery in those undergoing CABG. However, given the relatively brief duration of allopurinol therapy in these studies it is possible that the protective effect is provided by its antioxidant rather than hypouricemic impact.
Angina
The most recent interventional study by Norman et al. entailed 65 patients with angiographically demonstrated coronary artery disease, chronic stable angina, and a positive exercise stress test. These were randomized to high dose (600 mg/day) of allopurinol or placebo for 6 weeks and then crossed over to active drug or placebo. In the treatment group, allopurinol increased median time to chest pain, median exercise time, as well as time to ST depression. The authors excluded those with a history of gout, and the authors attributed the observations to other, nonhypouricemic, effects of xanthine oxidase inhibition.
The Case against and for Hyperuricemia as a Causal Link
There are three arguments against causality in the hyperuricemia CVD link. Most of the contrary evidence supporting these has been epidemiologic in nature.
Argument 1: Coincidence The proponents of this argument believe that there is no independent association of hyperuricemia with CVD as some studies have failed. Some studies have failed to confirm such a link. The argument goes that the relationship is coincidence or due to confounding risk factors such as obesity and hypertension. The epidemiological studies that failed to discern any independent association (leave alone causative relation) are far fewer than those that do show such a link. These entailed younger, and generally healthier, populations and may have lacked the power to identify the contribution of hyperuricemia to cardiovascular outcomes. The power needed to show a conclusive null result is much higher than that needed to show a positive link, as was the case of the two pivotal randomized controlled trials that showed that aspirin did not prevent recurrent myocardial infarction.
Argument 2: Reverse Causation This line of argument admits the existence of an independent association between hyperuricemia and cardiovascular disease but attributes it to residual confounding by other risk factors such as chronic renal failure, hyperlipidemia, and the metabolic syndrome. One study found a correlation between serum urate and carotid intima media thickness (cIMT) but this effect was lost after adjustment for relevant behavioral and biologic correlations. This conclusion is contrary to several other studies demonstrating an association of hyperuricemia with cIMT atherosclerosis even after adjustment for covariates.
Argument 3: Common-causal Genetic Variable This is the strongest argument against uric acid as a causal agent in CVD. In 2002, Ghei et al. summarized the genetic links of hyperuricemia trait with those for cardiovascular risk factors such as dyslipidemia, renal dysfunction, and impaired glucose metabolism. However, nonepidemiological interventional data are more supportive of hyperuricemia as a causal factor.
As discussed above, recent interventional study using allopurinol was the demonstration by Norman et al. in which 65 patients with angiographically demonstrated coronary artery disease, chronic stable angina, and a positive exercise stress test, were randomized to high dose (600 mg/day) of allopurinol or placebo for 6 weeks and then crossed over to active drug or placebo. In the treatment group, allopurinol increased median time to chest pain, median exercise time, as well as time to ST depression. The authors excluded those with a history of gout, and levels of SUA were not documented as relevant. The authors acknowledged that the precise mechanism of the antiischemic effect remains unclear. The discussion attributed the effect to blocking the xanthine oxidase-mediated conversion of molecular oxygen to produce mediators of oxidative stress or inhibition of xanthine oxidase-mediated breakdown of ATP to AMP, augmenting high-energy phosphates in the cardiac tissues.
Support also derives from electronic medical record-based study of 9924 hyperuricemic veterans in whom urate-lowering therapy reduced mortality even after adjustments for other prognostic factors (HR 0.77; CI 0.65–0.91). Furthermore, several human and animal studies have prospectively applied urate-lowering therapies to the treatment of direct CVD risk factors including hypertension and more directly to, cardiomyopathy and coronary artery bypass grafting.
The C-reactive Protein Analogy
There are several striking similarities between SUA and C-reactive protein (CRP) as markers of coronary risk. CRP is a liver-produced protein that is up-regulated in many clinical situations. Significant numbers of observational studies showed that a high level of CRP is an independent risk factor for CVD. In some interventional studies, reduction of CRP was associated with improved cardiovascular risk although a recent systematic review concluded that the case was weak. Biological mechanisms linking CRP to CAD have been elucidated. Some have argued that CRP is in the causal pathway for coronary artery disease, but others dispute this assertion. A consensus is evolving in the cardiology community that CRP can be useful in the prediction of coronary artery disease.
The recent JUPITER study has demonstrated that in those with elevated CRP, even in the setting of normal levels of LDL, initiation of HMG-CoA reductase inhibitor (Statins), reduced risk of cardiovascular events including myocardial infarction, stroke, need for cardiac revascularization as well as all-cause mortality. Though a clear causal role for CRP in the initiation or propagation of CVD is uncertain, use of this marker has identified both those at risk for CVD, as well as those who may benefit from risk reduction interventions. It is possible to envisage a similar use of serum urate therapies. The use of CRP is also being followed as a biomarker of therapies. Whether nonhypouricemic cardiovascular risk modifications will impact on serum uric acid in a similar fashion has not been studied. The metabolic syndrome and serum insulin levels can influence serum urate levels and it is therefore conceivable that serum urate could serve as a barometer for metabolic and cardiovascular status.