The Heart of the Issue in Gout and Associated Cardiac Disease

While research and initiatives have made strides in the ensuing 58 years, cardiovascular disease (CVD) is still the leading cause of death among American men, women, and people of most racial and ethnic groups. One in every 4 deaths each year are because of CVD.²

Examining the Link Between Gout and Cardiac Disease

Gout, the most common inflammatory arthritis in adults,³ is associated with higher CV morbidity and mortality. Hypertension, smoking, diabetes mellitus, dyslipidemia, age, and obesity are risk factors for CVD, which are common comorbidities in patients with gout.⁴

In addition, inflammation has emerged as a risk factor for the development of early coronary artery disease, and possibly, acute CV events, such as myocardial infarction (MI). High uric acid that leads to chronic inflammation can potentially contribute to associated higher CV burden in gout. Evidence supports an increased CVD risk in inflammatory conditions, such as gout.^5,6

The attributable risk proportion of CVD to gout may far exceed any other rheumatic diseases. This is particularly important when considering recent data demonstrating the rising incidence and prevalence of gout.⁷

Increased serum urate (SU) levels, or hyperuricemia, are a precursor to gout. Therefore, ULT use in gout may decrease systemic inflammation, generation of oxidative species, and reverse endothelial dysfunction via hyperuricemia-dependent or -independent pathways.

In a 2019 review, Gupta and colleagues reviewed data to better understand the increased burden of CVD among patients with gout, the potential underlying mechanisms (including hyperuricemia, inflammation, endothelial dysfunction, and oxidative stress) and the effect of ULT on CVD risk reduction.⁸

Untreated gout may be associated with higher CV event and mortality risk than treated gout.⁹ Other systemic markers of inflammation are also associated with increased SU, such as increased levels of C-reactive protein (CRP), tumor necrosis factor, and interleukin (IL)-1, which, in turn, lead to a greater risk for adverse CV outcomes.^6,10 Inflammation results in increased oxidative stress, which is linked to atherogenesis.¹¹ Through this production, oxidative species are reactive in endothelial cells and activation of xanthine oxidase, which further propagates the production of harmful free radicals. These free radicals lead to increased oxidization of low-density lipoproteins in inflammatory conditions, such as gout, and have been associated with CVD. Other inflammatory conditions that bear similarity to gout with regard to chronic inflammation, such as lupus and rheumatoid arthritis, have been linked to incident CVD.

Does Gout Confer Greater Risk for Cardiac Disease? How Can Providers Address This?

The risk may be modifiable. When targeting systemic markers of inflammation, the risk for CV events has been shown to decrease, as seen in the Canakinumab Anti-Inflammatory Thrombosis Outcome Study (CANTOS; ClinicalTrials.gov Identifier: NCT01327846).⁶ Several underlying mechanisms of CVD have been hypothesized in gout, including hyperuricemia-associated endothelial dysfunction by impaired nitric oxide-mediated vasodilation, increased oxidized low-density lipoproteins, dyslipidemia, and/or acute and chronic inflammation. Use of ULT and/or colchicine (anti-inflammatory) has the potential to modify this CV risk.¹⁰

From a study that demonstrated a reduced risk for recurrent MI and a decrease in CV mortality with the use of IL-1 inhibitor canakinumab, the increased risk for fatal infections was a cause for concern.⁶ A further understanding of the risk/benefit of these medications for the improvement of cardiac outcomes in the general population and their appropriate use in gout to improve CV outcomes are needed.

While a diagnosis of hyperuricemia or gout confers a greater risk for CVD, further evidence is necessary to examine whether gout, like smoking and diabetes, is an equivalent risk factor for CVD.⁸ Patients with gout do, however, have higher incidence of CVD, therefore aggressive screening and treatment of gout should occur routinely in primary care settings. With such preventative measures, patients with gout have the potential to see improved outcomes.

Treating gout with allopurinol can include cardioprotective benefits such as potential reduction in the risk for MI, stroke, atrial fibrillation, and other CVDs, as seen in observational studies in select populations. These studies have shown that a longer duration of ULT use (≥2 years) may be needed to decrease CVD-specific morbidity.^12,13 However, randomized controlled trials (RCTs) are required to validate findings of observational studies and determine which subgroup populations of gout are most likely to benefit from appropriate long-term urate lowering with ULTs.

In conclusion, comorbidities associated with gout, chronic and recurrent acute inflammation, as well as oxidative stress, are all likely to contribute to the pathogenesis of CVD. Anti-inflammatory agents may decrease CVD not only in the general population, but also in people with chronic inflammatory conditions.

Once a diagnosis of gout is conferred, care providers should commence gout treatment quickly as inflammation plays an important role in cardiac disease. Well-designed RCTs are needed to test these hypotheses generated from observational studies regarding the higher risk of CV disease in gout.

References

1. Harold JG. The evolution of American Heart Month. American College of Cardiology. Published February 23, 2017. Accessed February 10, 2022. https://www.acc.org/latest-in-cardiology/articles/2017/02/21/12/42/the-evolution-of-american-heart-month
2. Centers for Disease Control and Prevention. Underlying cause of death, 1999-2018. CDC WONDER Online Database. Atlanta, GA. Published online 2018. Accessed February 10, 2022.
3. Bardin T, Richette P. Impact of comorbidities on gout and hyperuricaemia: an update on prevalence and treatment options. BMC Med. 2017;15:123. doi:10.1186/s12916-017-0890-9
4. Choi HK, Curhan G. Independent impact of gout on mortality and risk for coronary heart disease. Circulation. 2007;116:894-900. doi:10.1161/CIRCULATIONAHA.107.703389
5. Krishnan E, Baker JF, Furst DE, Schumacher HR. Gout and the risk of acute myocardial infarction. Arthritis Rheumatol. 2006;54:2688-2696. doi:10.1002/art.22014
6. Ridker PM, Everett BM, Thuren T, et al. Anti-inflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017;377:1119-1131. doi:10.1056/NEJMoa1707914
7. Zhu Y, Pandya BJ, Choi HK. Prevalence of gout and hyperuricemia in the US general population: the National Health and Nutrition Examination Survey 2007-2008. Arthritis Rheumatol. 2011;63:3136-3141. doi:10.1002/art.30520
8. Gupta MK, Singh JA. Cardiovascular disease in gout and the protective effect of treatments including urate-lowering therapy. Drugs. 2019;79:531-541. doi:10.1007/s40265-019-01081-5
9. Pérez Ruiz F, Richette P, Stack AG, et al. Failure to reach uric acid target of <0.36 mmol/L in hyperuricaemia of gout is associated with elevated total and cardiovascular mortality. RMD Open. 2019;5. doi:10.1136/rmdopen-2019-001015
10. Jalal DI, Jablonski KL, McFann K, Chonchol MB, Seals DR. Vascular endothelial function is not related to serum uric acid in healthy adults. Am J Hypertens. 2012;25:407-413. doi:10.1038/ajh.2011.237
11. Kotur-Stevuljevic J, Memon L, Stefanovic A, et al. Correlation of oxidative stress parameters and inflammatory markers in coronary artery disease patients. Clin Biochem. 2007;40:181-187. doi:10.1016/j.clinbiochem.2006.09.007
12. Singh JA, Cleveland J. Allopurinol and the risk of incident peripheral arterial disease in the elderly: a US Medicare claims data study. Rheumatology (Oxford). 2018;57(3):451-461. doi:10.1093/rheumatology/kex232
13. Singh JA, Yu S. Allopurinol and the risk of atrial fibrillation in the elderly: a study using Medicare data. Ann Rheum Dis. 2017;76(1):72-78. doi:10.1136/annrheumdis-2015-209008

This article originally appeared on Rheumatology Advisor