Correlation between hyperuricemia and coronary artery calcification

Abstract

This review aims to systematically explore the association between hyperuricemia and the degree of coronary artery calcification. We conducted a narrative review of scientific studies published over the past 5 years that examined the relationship between hyperuricemia and coronary artery calcification. The focus was on synthesizing evidence from epidemiological investigations, mechanistic studies, and clinical trials. Recent evidence confirms a significant epidemiological association between elevated serum uric acid levels and the prevalence and progression of coronary artery calcification. Mechanistic studies have identified multiple pathways through which uric acid promotes calcification, including inducing oxidative stress, causing endothelial dysfunction, triggering the phenotypic transformation of vascular smooth muscle cells into osteoblast-like cells, and fostering chronic inflammation. Hyperuricemia contributes to the development and progression of coronary artery calcification through a complex interplay of pathological mechanisms.

Introduction

Hyperuricemia is a common metabolic disorder worldwide. Its prevalence in China has reached 13.3% (2021 data) and is trending younger. ¹ The coronary artery wall is composed of three layers: the inner membrane, the middle membrane, and the outer membrane. The inner membrane is the innermost layer and is covered by endothelial cells. This is the smoothest layer, directly in contact with the blood, and helps prevent blood clotting. Atherosclerosis begins in the inner membrane. The middle layer is the thickest layer and is composed of smooth muscle and elastic fibers. It is responsible for the contraction and relaxation of blood vessels to regulate blood flow. The outer membrane is the outermost layer and is mainly composed of connective tissue, serving supporting and protective functions. Coronary artery calcification (CAC) is a marker of atherosclerotic plaque progression, characterized by the active deposition of calcium salts in the coronary artery wall, and is independently associated with cardiovascular events such as myocardial infarction and heart failure. ² Hyperuricemia is not only the main cause of gout but also contributes to the occurrence and development of CAC through multiple mechanisms. This article systematically summarizes the association and mechanisms between the two based on recent research. This review is guided by the Scale for the Assessment of Narrative Review Articles (SANRA). ³ We systematically searched the following databases: PubMed, Web of Science, Wiley, Springer Nature Link, Nature, Taylor & Francis, CNKI, Wanfang Data, and Embase, from 1 January 2008 to 30 August 2025. This is a narrative review. The following keywords were used in various combinations: “Hyperuricemia,” “Coronary artery calcification,” “Oxidative stress,” “Vascular smooth muscle cells,” “Inflammatory response,” “Calcium–phosphate metabolism disorder.”

Epidemiologic association

At physiological concentrations (approximately <360 μmol/L), uric acid acts as an important antioxidant, scavenging oxygen free radicals. However, when its concentration exceeds the saturation point (approximately ≥400 μmol/L), it becomes a pro-oxidant, promoting vascular damage through various mechanisms. The core process of CAC involves the phenotypic transformation of vascular smooth muscle cells (VSMCs) into osteoblast-like cells, leading to abnormal deposition of hydroxyapatite crystals in the vascular wall. Hyperuricemia may be a significant promoting factor in this pathological process. Multiple epidemiological studies have confirmed a positive correlation between hyperuricemia and the severity of CAC.^4,5

A specific study conducted in an island region (2023) ⁶ involving 273 patients with acute myocardial infarction showed that the CAC rate in patients with hyperuricemia (serum uric acid (SUA) >420 μmol/L) was significantly higher (67.9%) than in the normal group (43.2%). Hyperuricemia has been listed as the fourth major risk factor for atherosclerosis, alongside hypertension, diabetes, and hyperlipidemia. ⁷ Elevated SUA levels can contribute to the development of atherosclerosis by stimulating VSMC proliferation, impairing vascular endothelial function, and exacerbating inflammatory responses. ⁸ Increased calcification can lead to a higher risk of cardiovascular events such as heart failure, atherosclerotic cardiovascular disease, and all-cause mortality.^9,10

Hyperuricemia has a synergistic effect with other calcification markers. In patients with chronic kidney disease (CKD), elevated serum levels of carbamylated sortilin are directly associated with CAC and faster calcification progression. ¹¹ Large-scale cohort studies have shown that patients with hyperuricemia have a significantly increased risk of heart failure and all-cause mortality. ¹² In patients with CKD, the progression of CAC is faster than in the general population.^13,14

Pathological mechanisms

The mechanisms by which hyperuricemia promotes CAC are complex, involving interactions among multiple pathways, including calcium–phosphate metabolism disorder, phenotypic transdifferentiation of VSMCs, inflammation, and oxidative stress.

Calcium–phosphate metabolism disorder

Hyperuricemia can indirectly interfere with calcium–phosphate metabolism by affecting parathyroid hormone (PTH) and CKD. Hyperuricemia directly damages the kidneys, leading to decreased renal function, which in turn causes disorders in calcium–phosphate metabolism, resulting in hypocalcemia and hyperphosphatemia. This further indirectly affects PTH secretion by the parathyroid glands, leading to increased bone calcium release. As renal function gradually declines to late-stage CKD, more uric acid is retained in the body, and phosphate excretion further decreases, raising plasma phosphate concentrations and promoting the Ca×P product. ¹⁵ Impaired excretion of Ca²⁺ and phosphate can lead to hypocalcemia and hyperphosphatemia, both of which can affect the synthesis and secretion of PTH. ¹⁶

The PTH signaling pathway in the proximal tubule increases the expression of 1α-hydroxylase (CYP27B1), which catalyzes the 1α-hydroxylation of 25-hydroxyvitamin D (25(OH)D₃) to generate 1,25-(OH)₂D₃. 1,25-(OH)₂D₃ acts on the intestines, kidneys, and bones, stimulating the absorption, reabsorption, and resorption of calcium and phosphate. ¹⁷ PTH has both anabolic and catabolic effects on bone. Receptor activator of nuclear factor-κ B ligand (RANKL) binds to the receptor activator of nuclear factor kappa-B (RANK) on immature osteoclasts and promotes their differentiation into mature osteoclasts. PTH can also inhibit osteoblast secretion of osteoprotegerin (OPG), which normally inhibits the binding of RANKL to RANK; thus, PTH indirectly promotes osteoclastogenesis. ¹⁸ Normal VSMCs are primarily of the contractile type. High-phosphate conditions can induce VSMCs to increase BMP-2 expression and calcium deposition, promoting their differentiation into an osteogenic phenotype (Figure 1).

Figure 1.

Mechanism of calcium–phosphate metabolism disorder. (Hyperuricemia can damage the kidneys. Impaired renal function disrupts phosphorus metabolism and interferes with the synthesis of active vitamin D (1,25-(OH)₂D₃). This leads to decreased serum calcium (Ca²⁺) levels and increased serum phosphorus (HPO₄²⁻) levels. Disruption of calcium and phosphorus metabolism stimulates the parathyroid glands to secrete excessive amounts of PTH, which in turn triggers a cascade of abnormalities in bone metabolism, renal damage, and vascular calcification. This ultimately creates a vicious cycle of multisystem pathological damage.)

Inflammatory response

High concentrations of uric acid (>420 μmol/L) can activate nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, induce reactive oxygen species (ROS) generation, and damage vascular endothelial function. Simultaneously, uric acid crystals can directly stimulate monocytes to secrete inflammatory cytokines such as IL-6 and TNF-α, exacerbating the vascular wall inflammatory response and promoting plaque calcification. Excessively high uric acid levels promote the deposition of monosodium urate (MSU) crystals. MSU crystals are recognized and bound by Toll-like receptors (TLR2/4) on the monocyte–macrophage cell membrane. ¹⁹ This leads to the recruitment of apoptosis-associated speck-like protein containing a CARD (ASC) and its interaction with the effector protein pro-caspase-1 and the NLRP3 protein complex, forming the NLRP3 inflammasome. ²⁰ Upon activation of the NLRP3 inflammasome, pro-caspase-1 is cleaved into caspase-1, which processes inactive pro-IL-1β and pro-IL-18 within macrophages into active IL-1β and IL-18, which are then secreted extracellularly. ²¹ IL-1β binds to the IL-1 receptor (IL-1R) on target cells. The adaptor protein MyD88 binds to IL-1R and transduces the signal, activating NF-κB, ²² which induces VSMCs to secrete osteopontin (OPN).^23,24 OPN is an extracellular matrix protein that inhibits abnormal matrix mineralization under normal physiological conditions. ²⁵ The mechanism by which OPN promotes hydroxyapatite (HAp) crystal deposition is not fully understood; however, in specific pathological states, OPN overexpression can promote HAp crystal deposition. ²⁶

Current research has shown that hyperuricemia (HUA) can precipitate saturated MSU crystals that activate NADPH oxidase, producing excessive ROS and promoting inflammation. ²⁷ High concentrations of ROS can oxidize thioredoxin-1 (Trx-1) and promote its dissociation from apoptosis signal-regulating kinase 1 (ASK1). ²⁸ Phosphorylated ASK1 activates the downstream p38 MAPK pathway, ²⁹ subsequently upregulating the expression of inflammatory factors such as IL-1β, interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α). These inflammatory factors can disrupt vascular endothelial function, increase vascular permeability, promote adhesion molecule expression, and reduce nitric oxide (NO) bioavailability. Activation of the p38 MAPK pathway can upregulate the expression of key components of the NLRP3 inflammasome, thereby mediating cell apoptosis and oxidative stress. ³⁰ When large amounts of inflammatory factors such as IL-1β, IL-6, and TNF-α act on target cells and generate inflammatory signals, they promote activation of NF-κB, a key regulator of the cellular inflammatory response, which rapidly enters the nucleus to regulate the expression of various genes, including inducible nitric oxide synthase (NOS2) and cyclooxygenase-2 (COX-2). NOS2 can continuously produce large amounts of NO·, which reacts with O₂⁻· to form ONOO·. COX-2 catalyzes arachidonic acid to produce prostaglandin E2 (PGE2), promoting inflammation. NF-κB can also inhibit the expression of antioxidant enzymes, weakening the cell’s antioxidant capacity. ³¹

MSU is recognized and bound by Toll-like receptors (mainly TLR2/4) on the monocyte–macrophage cell surface, activating NF-κB to promote NLRP3 and IL-1β expression. The NLRP3 inflammasome directly promotes the secretion of inflammatory cytokines IL-1β and IL-18. MSU damages the cell membrane, leading to dysregulation of intracellular ion levels, specifically decreased intracellular potassium and calcium, providing signals for inflammasome activation and promoting NLRP3 inflammasome assembly. ³² The NLRP3 inflammasome promotes plaque formation and instability. ³³ IL-1β acts on IL-1R, promoting the release of other inflammatory cytokines such as IL-6, IL-8, and TNF-α. Among these, IL-6 stimulates the liver to secrete C-reactive protein (CRP), inducing a strong local inflammatory response and exacerbating vascular wall inflammation (Figure 2). ³⁴

Figure 2.

Mechanism of inflammatory response. (MSU crystals formed in hyperuricemia may activate signaling pathways within macrophages, such as TLR/NF-κB, the NLRP3 inflammasome, and ASK1–p38 MAPK. This leads to the release of large quantities of inflammatory cytokines, which stimulate the liver to synthesize C-reactive protein (CRP), thereby further amplifying systemic inflammation and creating a local–systemic inflammatory cycle. Ultimately, this may trigger an inflammatory response in the vascular wall, promoting the progression of vascular calcification and atherosclerosis.) MSU: monosodium urate; TLR: Toll-like receptors.

Oxidative stress response

Oxidative stress stimulates endothelial cells to release BMP-2, promoting VSMC differentiation into osteoblast-like cells. During the phenotypic transition to osteoblast-like cells, VSMCs cease expressing smooth muscle phenotype markers such as smooth muscle α-actin (α-SMA) and SM22, and instead express osteogenic-related molecules such as ALP, OPN, osteocalcin, and runt-related transcription factor 2 (Runx2). ³⁵

Uric acid is the final product of purine metabolism in the human body and has a dual role as both an antioxidant and a pro-oxidant. Its antioxidant function protects the cardiovascular system, whereas excessive retention of uric acid can induce oxidative stress and promote the generation of ROS. ROS can damage cellular structures, promote apoptosis, and thereby accelerate atherosclerosis. ³⁶ Uric acid combines with sodium ions in the blood to form monosodium urate (MSU) crystals, which deposit in renal tissue, causing inflammation and obstruction. Uric acid can also exacerbate vascular damage by affecting the renin–angiotensin system (RAS).

Soluble uric acid (sUA) can promote ROS production in human aortic smooth muscle cells via URAT1-mediated p-ERK1/2 activation. ³⁷ ROS comprise a group of chemically reactive free radicals and nonradicals. Free radicals include superoxide anion (O₂⁻·), hydroxyl radical (HO·), nitric oxide (NO·), and lipid radicals. Nonradicals include singlet oxygen (¹O₂), hydrogen peroxide (H₂O₂), hypochlorous acid (HOCl), and peroxynitrite (ONOO·). These species can act directly or interact and transform into each other, forming more destructive products. Among them, ONOO· is formed by the reaction of NO· and O₂⁻·, promoting oxidative stress and causing cellular damage (Figure 3 and Table 1).^38,39

Figure 3.

Mechanism of oxidative stress response (MSU crystals stimulate activation of the RAAS and the URAT1/ERK pathway, triggering a cascade of events involving oxidative stress, ROS production, and cell apoptosis. This may ultimately lead to kidney damage, atherosclerosis, and vascular calcification.). MSU: monosodium urate; ROS: reactive oxygen species.

Table 1.

Molecular mechanisms and intervention targets of hyperuricemia-promoted CAC.

Mechanism category	Key molecules/pathways	Pathological effects	Potential intervention strategies	References
Calcium–phosphate metabolism disorder	PTH, CYP27B1, 1,25-(OH)2D3, NF-κB, OPG, and Calcium–phosphate metabolism	Hypercalcemia, hyperphosphatemia, and accelerated vascular calcification	Phosphate binders and calcimimetics	15–18
VSMC phenotypic transdifferentiation	BMP-2, NF-κB, ALP, OPN, Runx2, ASC, and NLRP3	VSMC osteogenic transformation and calcium salt deposition	DLTM compound and Runx2 inhibitors	20,22,26,35
Inflammatory response	ROS, ASK1, NF-κB, NOS2, COX-2, NLRP3, TNF-α, IL-1β, IL-6, IL-8, IL-18, and p38MAPK pathway	Chronic vascular inflammation and pro-calcification microenvironment	Colchicine and IL-1β antagonists	27–32,34
Oxidative stress and endothelial dysfunction	ROS, URAT1, p-ERK1/2, HO•, NO•, O2−•, and ONOO•	Endothelial injury, increased vascular permeability, and foam cell formation	Allopurinol and SGLT2 inhibitors	36–39

The table summarizes the molecular mechanisms by which hyperuricemia promotes CAC, the associated pathological effects, potential intervention strategies, and the references.

CAC: coronary artery calcification; VSMC: vascular smooth muscle cell.

Advances in clinical research

Value of imaging assessment

Coronary computed tomography angiography (CCTA) is a noninvasive gold standard for assessing CAC, and its calcium score (CACS) can independently predict cardiovascular events. ⁴⁰ In a prospective study by Sørensen et al. ⁴¹ multidetector computed tomography (MDCT) was used to detect vascular calcification in the coronary, carotid, thoracic aortic, abdominal aortic, and iliac arteries of 580 patients with CKD.

Intravascular ultrasound (IVUS) and optical coherence tomography (OCT) can more accurately assess the depth, arc, and plaque stability of calcification. Yap et al. ⁴² used near-infrared spectroscopy intravascular ultrasound (NIRS-IVUS) as a reference standard to explore the impact of calcification (Ca) on the efficacy of CCTA in assessing plaque burden and composition. Cao et al. ⁴³ retrospectively compared 188 plaques and 84 normal segments from 40 consecutive cases evaluated for chest pain using CCTA and OCT. Furthermore, a study by Fangmeng et al. ⁴⁴ involving 258 patients with acute coronary syndrome with calcified culprit plaques who underwent OCT-guided stent implantation showed differences compared with superficial calcified sheets and calcified protrusions.

Prognostic association between hyperuricemia and CAC

In a 2022 study by Wang et al. ⁴⁵ on the relationship between SUA levels and coronary artery calcium deposition in a middle-aged and elderly Chinese population, the mRNA expression of IL-6 and CXCL8 was significantly higher in the HUA group and the HUA with CAC (HUA–CAC) group than in the normal control group and the CAC group. A high SUA level (p < 0.001) was an independent risk factor for CACS, and elevated SUA levels increased the risk of CAC. A 10-years cohort study in a Middle Eastern population published by Sarebanhassanabadi M in 2024 ⁴⁶ showed that patients with SUA ≥5.2 mg/dL (309 μmol/L) had a 2.3 times higher proportion of CACS ≥400 compared with patients with SUA <3.5 mg/dL (208 μmol/L).

Clinical intervention and management strategies

Controversies in urate-lowering drug therapy

Urate-lowering therapy primarily falls into two categories: xanthine oxidase inhibitors and uricosuric agents. Recent studies have found that modulating the gut microbiota may also become a new approach to treating hyperuricemia. Allopurinol, as a first-generation (purine analog) drug, can delay the progression of CKD by reducing uric acid levels and may indirectly inhibit CAC. Febuxostat, as a second-generation (nonpurine analog) drug, is primarily metabolized by the liver. It has a stronger urate-lowering effect and is more advantageous for patients with renal insufficiency.

Sodium–glucose cotransporter-2 inhibitors (SGLT2i) exhibit pleiotropic effects beyond traditional urate-lowering drugs. Their mechanisms for lowering uric acid may include: (a) increasing uric acid excretion by blocking renal tubular uric acid transporters (e.g. URAT1); (b) inhibiting URAT1-mediated uric acid reabsorption by reducing serum insulin levels; (c) inhibiting intracellular glucose entry into proximal tubular cells, restoring sirtuin-1 production, and thereby inhibiting xanthine oxidase activity; and (d) inhibiting inflammasome activation, including IL-1β and NLRP3 production, thereby alleviating gout symptoms. Benzbromarone has shown good efficacy in rapidly reducing SUA levels and inhibiting inflammation in patients with hyperuricemia and gout. Notably, compared with febuxostat and allopurinol, benzbromarone has a lower risk of cardiovascular events, although this difference did not reach statistical significance.

Modulating the gut microbiota has emerged as a new strategy for treating hyperuricemia. Targeting the gut microbiota can lower SUA levels by promoting purine decomposition, reducing uric acid production, and increasing uric acid excretion.

Based on current research, there is a lack of relevant evidence on whether urate-lowering drugs can alleviate CAC. Further studies are needed to confirm whether urate-lowering therapy can reduce CAC.

Lifestyle interventions

Dietary control (low purine, low fructose), weight management (BMI <24 kg/m²), smoking cessation, and alcohol limitation can significantly reduce SUA levels while improving metabolic indicators such as blood lipids and blood glucose, thereby delaying the progression of CAC. Patients with hyperuricemia are advised to limit intake of fried foods, alcohol, and high-purine foods; increase dairy and soy products; ensure adequate sleep; and actively improve liver and kidney function. ⁴⁷

Combination therapy

For patients with refractory hyperuricemia and CAC, combination therapy with uricosuric agents (e.g. benzbromarone) and uric acid production inhibitors may be considered. However, urine pH should be monitored (target 6.2–6.9) to prevent kidney stones.

Summary and outlook

Hyperuricemia (HUA) has a close epidemiological and pathological association with CAC. HUA may promote the progression of CAC through multiple pathways such as inducing oxidative stress, chronic inflammation, and the transdifferentiation of VSMCs into osteoblast-like cells. HUA is also exacerbated by calcium–phosphate metabolism disorders, especially in patients with CKD, where this effect is more pronounced.

Current strategies for lowering uric acid have shown conflicting effects on delaying the progression of CAC. The cardiovascular risks of febuxostat still require careful evaluation. Emerging approaches such as lifestyle interventions and modulation of the gut microbiota show promise.

Future research should focus on identifying the direct molecular targets of uric acid in CAC, such as BMP-2 and the NLRP3 inflammasome as well as other signaling pathways, and on conducting multicenter, large-sample clinical studies to verify the long-term effects of urate-lowering therapy on CAC. Combined with precise assessment strategies using imaging and biomarkers (such as osteopontin and carboxy-selective protein), this may provide new directions for individualized treatment and primary prevention of cardiovascular events.

The novelty of this review lies in its detailed description of the pathogenesis of CAC promoted by hyperuricemia. It involves multiple pathways, including calcium–phosphate metabolism disorders, phenotypic transdifferentiation of VSMCs, inflammation, and oxidative stress. However, the connections among these pathways are not fully established and lack sufficient experimental evidence. Further research is needed to clarify their interaction mechanisms.