Monosodium Urate Crystal Deposition and Its Association With Major Cardiovascular Events

Abstract

Monosodium urate (MSU) crystal deposition is a pathological hallmark of gout, not only causing joint inflammation but also potentially exerting adverse effects on the cardiovascular system. Increasing evidence indicates a significant correlation between MSU crystal deposition and major adverse cardiovascular events (MACE), including myocardial infarction, stroke, and cardiovascular death. Understanding this correlation is crucial for the comprehensive management of patients with gout.

Purines in food are building blocks of DNA and RNA, and most mammals can utilize uricase enzyme to break down purines. However, humans lack a functional uricase enzyme, and factors such as a purine-rich diet, alcohol intake, use of diuretics, and obesity in men lead to hyperuricemia [1]. MSU crystals rapidly deposit in the first metatarsophalangeal (MTP) joint. Once recognized and phagocytosed by synovial fluid macrophages, MSU crystals trigger the activation of the NLRP3 inflammasome and IL-1β [2]. IL-1β is the primary mediator of the acute inflammatory response in gout [3], acting on IL-1 receptors to promote the release of other inflammatory cytokines (TNF-α, IL-6, and IL-8) [3, 4]. IL-6 stimulates the liver to secrete CRP [3-5], thereby inducing a robust local inflammatory response. Other conditions, such as low temperature, cartilage dehydration, local edema, or avascularity in extremities, facilitate urate deposition in the pinna and distal interphalangeal joints of the fingers and toes [1].

The inflammatory and immune responses elicited by MSU crystals are key mechanisms in the pathogenesis of gout. A thorough understanding of these mechanisms aids not only in the diagnosis and treatment of gout, but also provides significant insights into related chronic inflammatory diseases.

Under ultrasound or DECT diagnosis, hyperuricemia leads to the deposition of MSU inflammatory crystals within and around joints, then triggering gout [6]. Gout has a higher prevalence in men and postmenopausal women [1, 7], with an estimated prevalence of 3.2% in the UK, 3.9% in the USA [6], and 3.8% in Taiwan [8]. Even if MSU deposits are found in the heart, they do not necessarily cause gout [1, 3-5]. Gout is associated with cardiovascular diseases and is categorized into acute gout arthritis, chronic gouty arthritis, and tophi [9, 10].

The deposition of MSU crystals is a key pathological mechanism of gout, leading to acute and chronic inflammatory responses [10], joint and soft tissue damage, and renal impairment. Understanding the mechanisms of MSU crystal deposition and associated pathological phenomena is crucial for the diagnosis, treatment, and prevention of gout.

Factors contributing to cardiovascular diseases include obesity, diabetes, hypertension, dyslipidemia, smoking, and gout patients [8]. Modern diets high in fat and salt contribute to the accumulation of high cholesterol levels, leading to arterial wall damage and lipid deposition. Excess cholesterol injures the endothelium, resulting in the accumulation of lipids and activation of the NLRP3 inflammasome, which increases levels of pro-inflammatory mediators such as IL-1β and IL-18 [11]. Chronic inflammation promotes atherosclerosis, rendering plaques unstable and prone to rupture, thereby causing thrombosis and myocardial infarction [11, 12].

MSU deposition is the only factor associated with the onset of cardio-metabolic [13]. Park found urate crystal deposition in coronary arteries [1]. Andres discovered urate deposition in coronary arteries, leading to coronary calcification [1]. When the mean serum uric acid level is above 7.4 mg/dL, urate crystal deposits are found in the aorta and coronary arteries [1].

Theoretically, MSU deposition in the heart promotes systemic inflammation, leading to thrombus formation. MSU crystals induce the activation of NLRP3 inflammasomes and IL-1β, activating endothelial macrophages to promote atherosclerosis progression, causing major cardiovascular diseases [1-3]. Inflammasomes in endothelial cells induce arteriosclerosis [2]. Studies examining cardiac valves, postsurgical carotid endarterectomy, and aortic aneurysm specimens found MSU deposition in cholesterol plaques [1]. NLRP3 inflammasomes promote plaque formation and destabilization [2]. Pagidipati found a higher risk of cardiovascular diseases with higher uric acid levels [1]. Having MSU deposition in the heart may increase the risk of major cardiovascular diseases to a fourfold [2].

Indeed, studies show that uric acid stimulates vascular smooth muscle cell proliferation, producing angiotensinogen and angiotensin II. Animal experiments have shown that hyperuricemia could stimulate renin secretion, leading to hypertension [3, 8]. High uric acid levels do not necessarily lead to gout [9]. MSU crystal deposits in blood vessels cause chronic infraclinical inflammation, leading to chronic heart failure, hypertension, and diabetes mellitus, but local exuberant inflammatory responses might not be related to CVD mortality [14]. Higher uric acid levels may not necessarily increase the risk of CVD [13, 15].

However, higher uric acid levels (> 6.8 mg/dL) [6] in conjunction with metabolic syndrome (hypertension, obesity, hyperlipidemia) increase the risk of gout [9]. Research indicates that both serum uric acid and metabolic syndrome activate the sympathetic nervous system, the renin–angiotensin system, and increase the levels of pro-inflammatory adipokines and cytokines, leading to an accelerated heart rate, altered blood flow circulation, and increased vascular resistance [1, 8]. Gout patients are prone to hypertension [4, 5, 10, 13, 16], and studies have shown a potentially increased incidence of hypertension in rheumatology outpatient clinics [8]. Hypertension predisposes individuals to cardiovascular diseases (MI, stroke) [8]. Tophi, accompanying high uric acid levels, increases the risk of coronary artery and cerebrovascular diseases [8, 13]. Tophaceous gout patients with high serum urate levels have an increased mortality risk [13]. Gout, being an early metabolic abnormality, is prone to cause MI [8]. Cardiac and vascular MSU deposits are related to peripheral MSU deposits [2]. Peripheral joint inflammation leads to systemic inflammation, increasing the prevalence of cardiovascular diseases [8].

During acute gout attacks, patients mostly experience inflammation and pain in the knee, feet, and 1st MTP joints, affecting walking and regular exercise. Prolonged immobility can lead to a high coagulation status, poor venous return, and an increased risk of deep vein thrombosis (DVT) [8]. Reduced physical activity due to lower limb pain increases the risk of cardiovascular diseases. Cipolletta indicated that a gout flare can trigger atherothrombosis, leading to cardiovascular diseases (unstable angina, MI, ischemic stroke) [5]. Case–control studies have associated acute gout attacks with MI and stroke [5].

Allopurinol and febuxostat, as inhibitors of xanthine oxidase, act to reduce the conversion of purines to urate, thereby decreasing the deposition of urate crystals in joint fluid [10, 17]. This reduction in crystal deposition reduces the secretion of inflammatory cytokines by monocytes and macrophages, mitigating local inflammation in soft tissues and joints [8] and preventing acute gout attacks [4]. There is potential for these therapies to reduce the risk of cardiovascular diseases [3, 4].

Allopurinol administration under conditions of high uric acid levels has been associated with reduced mortality from major cardiovascular diseases [8]. Randomized controlled trials (RCTs) have shown that allopurinol therapy in hospitalized patients with chronic kidney disease reduces cardiovascular diseases [8]. A 2020 Taiwanese study demonstrated that urate-lowering therapy reduces the risk of cardiovascular disease and stroke [3].

Conversely, a 2014 Taiwanese study found no cardiovascular benefit of allopurinol therapy in gout patients [8, 18]. Several important risk factors for cardiovascular disease, such as smoking, alcohol consumption, body mass index, and blood pressure, were not accounted for, and issues with compliance and adherence to treatment were noted [18]. In a 2019 RCT, urate-lowering therapy was found to be unrelated to reducing MSU crystal deposition and cardiovascular mortality [13, 19]. However, the study was limited by incomplete participation and a small sample size [19].

When renal function is impaired, we can take oral administration of Febuxostat, which can rapidly lower serum uric acid levels (< 6 mg/dL) [4, 20]. Side effects include abnormal liver function and arthralgias [20]. Cardiovascular thromboembolic events (MI, stroke, death) may occur slightly more frequently with Febuxostat compared to allopurinol [17, 20].

Elevated CRP is a risk factor for cardiovascular diseases, and anti-inflammatory treatments reduce the risk of subsequent myocardial infarction in patients with heart disease [2]. Treatment with aspirin and colchicine for gout flares reduces the risk of cardiovascular diseases (MI, stroke) [5]. Studies have indicated that using IL-1 inhibitors (such as rilonacept) and IL-18 inhibitors can suppress NLRP inflammasomes, reducing the risk of cardiovascular diseases [5].

The inflammation and immune response triggered by MSU crystal deposition are key mechanisms in the pathogenesis of gout and are significantly correlated with MACE. Urate-lowering therapy may be one effective means of improving cardiovascular outcomes in patients with MSU crystal deposition, along with a low-fat, low-salt diet [5], diabetic and blood pressure control [5], and active regular exercise and smoking cessation [5]. Future research could focus on the impact of urate-lowering therapy on the risk of cardiovascular events and cardiovascular function.

S.-T.S., Y.-H.L., W.-T.P., and J.C.-C.W. had full access to the study data and verified the underlying study data. J.C.-C.W. led the conception. S.-T.S. wrote the original draft of this paper. S.-T.S., Y.-H.L., W.-T.P., and J.C.-C.W. contributed to the conception and writing with review and editing of this paper. All authors had final responsibility for the decision to submit for publication.

Dr. James Wei is the chief editor of IJRD and a co-author of this article. To minimize bias, he was excluded from all editorial decision-making related to the acceptance of this article for publication.