Uric Acid & Heart Disease

First, I should point out that the offending article was referring to the 2005 report “Serum uric acid and cardiovascular disease: Recent developments, and where do they leave us?” by Joshua F Baker and colleagues. The full report costs an arm and a leg aorta and ventricle, but the free abstract reads:

The relationship between serum uric acid (SUA) and cardiovascular disease has been controversial. Here we review recent literature assessing whether hyperuricemia is an independent risk factor for adverse cardiovascular outcomes. Studies from the past 6 years evaluating the association of SUA with cardiovascular disease were identified through MEDLINE, EMBASE, and Cochrane library searches, bibliography cross-referencing, and review articles. Twenty-one cohort studies in healthy and high-risk patients with cardiovascular disease were identified and reviewed. In studies of high-risk patients, in which more overall events were recorded, 10 of 11 studies were supportive of an independent association. In 10 studies of healthy patients, 6 suggested an independent association of SUA with adverse cardiovascular outcomes. Increasing SUA is likely an independent risk factor for cardiovascular disease in high-risk individuals. However, the magnitude of excess risk attributable to high SUA is likely to be small in healthy individuals. Trials of SUA-lowering therapy in hyperuricemic patients evaluating the effect on cardiovascular outcomes are justified in high-risk patients.

So, if you are at high risk of heart disease, high uric acid will increase your risk, but probably not if you are healthy. Further trials are justified, which brings us to the offending article that is giving us some insight on subsequent trials. The article is actually a letter from Joel A Simon MD, titled “Clinical Trials of Uric Acid Lowering for Coronary Heart Disease Risk Reduction”. (My bold is simply to refer back to the sentence that started all this)

To the Editor:Baker et al. reviewed the scientific literature on the relation of serum uric acid to cardiovascular disease published since 1998.¹ In concluding, they note that “there is sufficient evidence ? to justify a large-scale controlled trial (of uric acid lowering) in high-risk individuals.”Three secondary coronary heart disease (CHD) prevention trials have been published in which patients were randomly allocated to uric acid-lowering treatment. The Anturane Reinfarction Trial ^{2, 3} and the Anturan Reinfarction Italian Study4 both reported large statistically significant decreases in the risk for sudden cardiac death among patients with myocardial infarction who were treated with sulfinpyrazone, an antiplatelet uricosuric agent. Although serum uric acid levels were measured, they were not reported in the Anturane Reinfarction Trial except to note that participants taking sulfinpyrazone had consistent lowering of serum uric acid levels.² The results of the Anturane Reinfarction Trial were questioned but were subsequently affirmed by an independent committee of adjudicators.⁵ The Anturan Reinfarction Italian Study, another secondary CHD prevention trial, reported that treatment with sulfinpyrazone resulted in a marked reduction in fatal and nonfatal myocardial infarctions.⁴ Serum uric acid levels were measured as a means of assessing pill compliance, and on-study serum uric acid levels were reported as 2.8 mg/dL in the sulfinpyrazone group, compared with 5.5 mg/dL in the placebo group. In contrast with these 2 positive studies, a Canadian trial using sulfinpyrazone in patients hospitalized for unstable angina reported no benefit on the risk for cardiac death and nonfatal myocardial infarction.⁶ Although each of these studies examined sulfinpyrazone as an antiplatelet agent, they effectively tested whether lowering serum uric acid levels with a uricosuric agent decreases CHD events.References :1. Baker JF , Krishnan E , Chen L , Schumacher HR . Serum uric acid and cardiovascular disease (recent developments, where do they leave us?) . Am J Med . 2005;118:816?826 . 2. Sulfinpyrazone in the prevention of cardiac death after myocardial infarction. The Anturane Reinfarction Study . N Engl J Med M . 1978;298:289?295 .3. The Anturane Trial Research Group . Sulfinpyrazone in the prevention of sudden death after myocardial infarction . N Engl J Med . 1980;302:250?256 . 4. Sulphinpyrazone in post-myocardial infarction. Report from the Anturan Reinfarction Italian Study . Lancet . 1982;1(8266):237?242 .5. The Anturane Reinfarction Trial. reevaluation of outcome . N Engl J Med . 1982;306:1005?1008 .6. Cairns JA , Gent M , Singer J , et al. ? Aspirin, sulfinpyrazone, or both in unstable angina. Results of a Canadian multicenter trial . N Engl J Med . 1985;313:1369?1375

So, this promotes the view that lowering uric acid reduces heart disease risk, but the authors of the original report advise caution. They reply:

We thank Dr. Simon for his comments. He cites several studies evaluating the uricosuric antiplatelet agent, sulfinpyrazone, in the prevention of reinfarction in patients with myocardial infarction (MI).^{1, 2, 3, 4} He notes that these studies demonstrate that patients treated with sulfinpyrazone had significantly lower serum uric acid (SUA) levels, as well as fewer subsequent coronary events. We agree that these studies are of interest, but we have concerns about attributing this effect specifically to uric acid lowering.There are several other studies taking a similar approach to the question of SUA lowering for coronary heart disease risk reduction. For example, a recent study by Hoieggen et al suggests that losartan may be superior to atenolol for prevention of adverse cardiovascular outcomes in high-risk patients in the losartan intervention for endpoint-reduction in hypertension (LIFE) study due to its SUA lowering properties.⁵The data from these studies may be misleading. Antiplatelet agents^{6, 7} and angiotensin receptor blockers⁸ have both been shown to prevent adverse cardiovascular events in patients at high risk, including patients with recent MI. In both of these cases it is difficult to determine what benefit, if any, SUA lowering may have had on preventing adverse cardiovascular outcomes with the confounding other potential benefits of each therapy. Even xanthine oxidase inhibition might have benefits in cardiovascular disease prevention, independent of its ability to lower SUA levels.^{9, 10, 11, 12}The question of whether SUA lowering itself is beneficial in high-risk patients may be difficult to answer definitively.References:1. Sulfinpyrazone in the prevention of cardiac death after myocardial infarction. The Anturane Reinfarction Study . N Engl J Med . 1978;298:289?295 .2. The Anturane Trial Research Group . Sulfinpyrazone in the prevention of sudden death after myocardial infarction . N Engl J Med . 1980;302:250?256 .3. Sulphinpyrazone in post-myocardial infarction. Report from the Anturan Reinfarction Italian Study . Lancet . 1982;1(8266):237?242 .4. The Anturane Reinfarction Trial (reevaluation of outcome) . N Engl J Med . 1982;306:1005?1008 .5. Hoieggen AAM , Kjeldsen SE , Julius S , et al. ? The impact of serum uric acid on cardiovascular outcomes in the LIFE study . Kidney International . 2004;65:1041?1049 .6. Fox KA , Mehta SR , Peters R , et al. ? Clopidogrel in unstable angina to prevent recurrent ischemic events trial. Benefits and risks of the combination of clopidogrel and aspirin in patients undergoing surgical revascularization for non-ST-elevation acute coronary syndrome: the cClopidogrel in unstable angina to prevent recurrent ischemic events (CURE) trial . Circulation . 2004;110(10):1202?1208 Sep 7; Epub 2004 Aug 16 .7. Hung J . Medical Issues Committee of the National Heart Foundation of Australia. Aspirin for cardiovascular disease prevention . Med J Aust . 2003;179(3):147?152 Aug 4 .8. Weir R , McMurray JJ . Treatments that improve outcome in the patient with heart failure, left ventricular systolic dysfunction, or both after acute myocardial infarction . Heart . 2005;91(Suppl 2):ii17?ii20 May; discussion ii31, ii43-8. Review .9. Kinugasa Y , Ogino K , Furuse Y , et al. ? Allopurinol improves cardiac dysfunction after ischemia-reperfusion via reduction of oxidative stress in isolated perfused rat hearts . Circ J . 2003;67(9):781?787 Sep .10. Desco MC , Asensi M , Marquez R , et al. ? Xanthine oxidase is involved in free radical production in type 1 diabetes (protection by allopurinol) . Diabetes . 2002;51(4):1118?1124 Apr .11. Cappola TPKD , Nelson GS , Berger RD , et al. ? Allopurinol improves myocardial efficiency in patients with idiopathic dilated cardiomyopathy . Circulation . 2001;104:2407?2411 .12. Struthers ADDP , Lindsay P , McNaughton D , Broomhall J , Macdonald TM . Effect of allopurinol on mortality and hospitalizations in congestive heart failure (a retrospecctive cohort study) . Heart . 2002;87:229?234 .

Now, perhaps, it’s my turn to scream. All that info, and the question may be difficult to answer definitively.OK, I for one will get off the fence, and offer an opinion. Get your heart checked regularly. If your uric acid is high, lower it.