Hyperuricemia and Cardiovascular Disease: What is Left to Prove?

Ranjith et al. report on the “Association Between Hyperuricemia and Major Adverse Cardiac Events in Patients with Acute Myocardial Infarction.” ¹ In 2683 patients presenting with acute myocardial infarction, elevated uric acid was significantly associated with hypertension, renal dysfunction, major adverse cardiovascular events, and increased risk of death. These results are not surprising given the huge literature that demonstrates an association between hyperuricemia and cardiovascular disease. Of 17 conditions that the authors evaluated as risk factors for mortality, the effect of hyperuricemia on mortality was modest with a mean odds ratio of 1.7 and a range of odds ratios of 1.0–2.8. If one searches PubMed for the terms “uric acid” and “cardiovascular disease,” 2215 citations are recognized. If one searches PubMed for the terms “uric acid,” “cardiovascular disease,” and “prospective,” 333 citations are recognized. So, “What is left to prove?”

Indeed, “What is left to prove?” The likely answer may be as follows: Randomized, double-blinded, placebo-controlled prospective trials of uric acid lowering to reduce cardiovascular disease are lacking. It is not enough to know that uric acid elevations (or even uric acid levels in the high “normal” range) are associated with cardiovascular disease, we need to know whether lowering uric acid provides true benefit. For example, we know that lowering cholesterol with statins reduces mortality with a rather low risk of developing adverse side effects. ²

Review of the homocysteine “story” is instructive. An association between elevated homocysteine levels and increased risk for cardiovascular disease was well known for decades. The ability of folic acid to lower homocysteine levels has been known for at least 30 years. ³ However, clinical trials reducing homocysteine levels through vitamin administration failed to reduce cardiovascular disease. ^4,5 Even basic science studies failed to show a benefit on vascular “health” with homocysteine reduction. ⁶ Thereafter, physicians' interest in measuring homocysteine waned because measuring homocysteine did not lead to actionable interventions that would benefit patients.

Although we desire to identify more risk factors for various diseases, we cannot ignore past research: the majority of risk factors for cardiovascular disease have been known for decades. ^7,8 Possibly our greatest challenge in preventing cardiovascular disease is treating diabetes and hypertension and reducing smoking, cholesterol, and obesity. This requires access to affordable healthcare, as well as the patient's commitment to basic interventions and preventions that are not necessarily expensive, for example, thiazide diuretics or angiotensin-converting enzyme inhibitors for hypertension and statins for cholesterol reduction.

There are guidelines for the treatment of gout that center on the reduction of uric acid levels. ^9,10

At the present time, the United States Preventive Services Task Force provides no guidelines concerning uric acid or hyperuricemia. Similarly, a search of the American Heart Association Website failed to find guidelines recommending reductions in uric acid as preventative therapy for cardiovascular disease. Should we as a society invest in a campaign to lower uric acid to prevent cardiovascular disease or treat patients with recognized cardiovascular disease? At this point, we lack sufficient data to proceed with this recommendation.