Cardiovascular Disease and Gout
The prevalence of cardiovascular disease continues to rise and is among the leading cause of mortality in the world. Inflammatory conditions such as Rheumatoid Arthritis and Gout are often associated with a higher risk and earlier onset of this disease. Research links gout to an increased risk of several types of cardiovascular disease, including heart attack, heart failure, and atrial fibrillation, or an irregular heartbeat. Epidemiological, experimental, and clinical data show that patients with hyperuricemia SUA are at increased risk of cardiac, renal, and vascular damage and CV events.
A 2018 Arthritis Care & Research study, for example, found that adults 65 and older have at least a two-fold risk of heart attack compared with those without gout. Gout also ups risks for stroke and peripheral vascular disease. A study presented at the 2021 European Renal Association-European Dialysis and Transplant Association details findings that hyperuricemia is a risk factor for cardiovascular disease and all-cause mortality, as well as an increase in parallel with a reduction in kidney function. 21,963 patients participated in the Uric Acid Right Heart Health (URRAH) project and yielded a total of 1582 cardiovascular events with 3130 deaths that occurred during over 9 years of follow-up tracing.
Investigator Elisa Russo, MD of the University of Genoa reported a 21% and 10% increased risk for cardiovascular mortality and all-cause mortality, respectively, per 1/mg/dl increase in uric acid levels. This is a clear and significant association. Additionally, patients with kidney function/blood filtration challenges showed significant risk factor increases for both cardiovascular mortality and all-cause mortality. Cardiovascular mortality was significantly more likely among patients with both hyperuricemia and stages of kidney disease than those who had neither risk factor.
Both Cardiovascular and Gout risks are lower in women during the pre-menopausal years due to the protective effect of estrogen. However, this protection against heart-disease is lost in the post-menopausal years and essentially matches the risks for both when comparing to men. Men and women both share the same risk factors including smoking, diabetes, hypertension, hyperlipidemia, and family history of heart disease. Studies are still needed to explore the sex-based differences in the pathogenesis of gout-associated heart disease.
Gout is associated with systemic inflammation and other studies have linked systemic inflammation to the risk of heart disease and other chronic inflammatory conditions. Below is a model detailing the mechanisms of cardiovascular disease.
Potential pathogenic pathways for higher risk of cardiovascular disease in patients with gout. Solid lines indicate current evidence supporting the mechanism/pathway and dotted lines indicate potential mechanism/pathway, for which more evidence is needed. Several links from gout to the intermediate event (endothelial dysfunction, etc.) may be through (mediated by) hyperuricemia or non-hyperuricemia pathways (eg, systemic inflammation).
The molecular mechanisms of high UA activating NLRP3-inflammasomes and promoting macrophage M1/M2 polarization. AMPK, AMP-activated protein kinase; HIF-1α, hypoxia-inducible factor-1α; IL-1β, interleukin-1β; MAPK, mitogen activated protein kinases; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor κB; NLRP3, nod-like receptor protein 3; TLR, Toll-like receptors; UA, uric acid.
The possible molecular mechanisms of high UA promote the occurrence and development of cardiovascular diseases. High UA regulates numerous molecular signals such as inflammation, oxidative stress, insulin resistance, and endothelial dysfunction, thus affects the progression and prognosis of cardiovascular diseases including hypertension (A), atherosclerosis (B), atrial fibrillation (C) and heart failure (D). AMPK, AMP-activated protein kinase; mROS, mitochondrial ROS; mTOR, mammalian target of rapamycin; NLRP3, nod-like receptor protein 3; RAS, renin-angiotensin system; UA, uric acid.
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