Uric acid and cardiovascular disease—recent evidence on the association and underlying mechanisms

Introduction

Cardiovascular disease (CVD) is a leading cause of mortality worldwide, accounting for 20.5 million deaths globally or approximately 1/3 of all deaths in 2021 (1). Over the decades, a number of factors that increase the risk of CVD were identified and 4 of them—arterial hypertension, hyperlipidemia, diabetes mellitus and smoking—are considered as conventional risk factors for coronary artery disease (CAD) (2). However, it has been suggested that up to 50% of patients with CAD lack conventional risk factors (3). Although this statistic has been disputed, a sizeable portion of patients with CAD has no known conventional risk factors. This led to a constant quest to identify novel cardiovascular risk factors or morbid conditions that increase the cardiovascular risk. Recently, the list of cardiovascular risk factors has been markedly expanded and includes a number of morbid conditions or risk factor candidates other than conventional risk factors, and the evidence is growing that these novel risk factors play an important role in the pathophysiology of CVD (4). Uric acid (UA) is one of these risk factor candidates for CVD that has recently been listed as a modifiable risk factor associated with CAD severity (5). Epidemiological, clinical and experimental studies show a link between elevated UA levels (or hyperuricemia) and increased risk for CVD, including arterial hypertension, CAD, atrial fibrillation (AF) and congestive heart failure (HF). A large cohort study in Asia has recently suggested that UA may predict prognosis in individuals with CAD with no or one standard modifiable cardiovascular risk factor but not in those with ≥2 of such factors (6). While participation of UA in the pathophysiology of the CVD is undisputable, the causality in the relationship between UA and CVD remains unproven and debatable. The frequent association and intricate relationship of UA with cardiovascular risk factors, such as arterial hypertension, type 2 diabetes, dyslipidemia, metabolic syndrome and chronic kidney disease (7,8) is the main reason for the ongoing debate and dilemma whether UA is a risk factor (causal relationship) or a risk marker (an associate of cardiovascular risk) for CVD. In a previous review, we have summarized evidence (up to 2018) linking elevated UA levels with the risk of CVD (9). In this narrative review, we summarized the evidence linking UA with CVD with a special emphasis on the research performed in the last 5 years. After describing UA biology, we summarized recent evidence on the association between UA and CVD by analyzing recent epidemiological, clinical, experimental, genetic (Mendelian randomization) and intervention studies with UA-lowering therapy. The pathophysiological mechanisms through which UA promotes CVD are also discussed. The association between UA and CVD in the setting of gout was outside the focus of this review.

UA biology

UA (7,9-dihydro-3H-purine-2,6,8-trione; empiric formula: C₅H₄N₄O₃; molecular weight: 168.11 Da) is a heterocyclic organic compound and a final product of purine metabolism in humans and great apes. Purine nucleotides play a central role in all organisms by serving as building blocks of nucleic acids, storage and use of chemical energy, activation of metabolites for biosyntheses, cofactors of enzymes, cellular signaling and regulators of metabolism. Purine nucleotide catabolism consists of a series of enzymatic transformations in which adenine and guanine nucleotides [adenosine triphosphate (ATP) and guanosine triphosphate (GTP)] are catabolized to UA. Since humans cannot break down the purine ring due to evolutionary loss of uricase activity, UA is the end-product of purine nucleotide catabolism. Endogenous (i.e., purine nucleotides released during nucleic acid break down) and external (dietary) purines undergo similar catabolic transformations. Purine nucleotide degradation and UA synthesis are well-characterized catabolic pathways. Adenine nucleotides at the stage of adenosine monophosphate (AMP) undergo de-amination (removal of amino group by AMP deaminase) and removal of phosphate by nucleotidase to produce inosine. Inosine is transformed into hypoxanthine by enzyme purine nucleotide phosphorylase. Guanine monophosphate (GMP) undergoes nucleotidase reaction to produce guanosine, which is transformed into guanine by purine nucleotide phosphorylase. Guanine is deaminated by guanine deaminase to produce xanthine (10). The conversion of hypoxanthine to xanthine and xanthine to UA is performed by xanthine oxidoreductase (XOR). Main aspects of UA metabolism are shown in Figure 1.

Figure 1 Main aspects of UA metabolism. ABCG2, ATP-binding cassette subfamily 2; αKG, alpha ketoglutarate; AMP, adenosine monophosphate; ATP, adenosine triphosphate; GLUT9, glucose transporter 9; GMP, guanosine monophosphate; GTP, guanosine triphosphate; IMP, inosine monophosphate; MRP4, multidrug resistance protein 4; NaDC, sodium-dependent dicarboxylate cotransporter; NPT, Na⁺/phosphate transporter; OAT, organic anion transporter; Pi, inorganic phosphate; SMCT, sodium-coupled monocarboxylate transporter; UA, uric acid; URAT, urate transporter.

XOR plays a central role in the production of UA and serves as a rate-limiting enzyme in purine catabolism. In most species, the conversion of hypoxanthine to xanthine and xanthine to UA are catalyzed by xanthine dehydrogenase activity. In mammals, these reactions are performed by XOR activity (11). Purified human XOR is a homodimer of ∼300 kDa. Each 150 kDa subunit has three domains: a N-terminal 20 kDa, a middle 40-kDa and a C-terminal 85 kDa domain. The 1st, 2nd and the 3rd domains of each subunit contain two nonidentical Fe-S centers, a flavine adenine dinucleotide (FAD) and a molybdopterin cofactor containing a molybdenum atom (Moco). The catalysis involves the sequential transfer of 2 electrons (e⁻) to the molybdenum atom (IV), Fe-S centers and FAD which is subsequently oxidized by molecular oxygen or nicotinamide adenine dinucleotide (NAD⁺) (12). XOR has a wide specificity, which allows the enzyme to reduce or oxidize diverse endogenous and exogenous substrates (including drugs) participating in their metabolism or detoxification (13). The mammalian XOR is constitutively an NAD⁺-dependent xanthine dehydrogenase, which is converted reversibly to XOR through oxidation of sulfhydryl groups of cysteine residues (to form -S-S- bridges) or irreversibly by limited proteolysis (14). Conversion of xanthine dehydrogenase to XOR is favored by low oxygen tension, tissue acidosis, hypoxic/ischemic conditions, ischemia/reperfusion cycle, glutathione deficiency and oxidizing agents like hydrogen peroxide (H₂O₂) (15-17). XOR catalyzes break down of S-nitrosothiols—a class of reactive nitrogen species—to form nitric oxide (NO), which in aerobic conditions reacts with a superoxide anion to form peroxynitrite (18). In hypoxic, acidic and inflammatory conditions, XOR shows NADH oxidase activity producing reactive oxygen species (ROS) and nitrite oxidase activity reducing nitrates to nitrites and the latter to NO (17). In aggregate, the products of XOR include UA, ROS, H₂O₂ and superoxide (O₂·⁻), NO and reduced NAD (NADH). XOR is a major producer of ROS in organism. The human gene for XOR is located on the short arm of chromosome 2 (2p23.1) and consists of 35 introns and 36 exons (spanning at least 60 kb) encoding a 1,333 amino acid residue polypeptide (19). In humans, the highest activity of XOR is found in liver and intestine with most other tissues showing only little XOR activity (20). The XOR gene expression is tightly controlled at the transcriptional and post-translational levels. The human XOR gene appears to be down-regulated in most tissues except for epithelial cells of lactating mammal glands, liver, kidney and gastrointestinal tract (21) potentially due to promoter suppression by repressor elements identified in the non-coding regions of the XOR gene (22). Subcellular location of XOR activity is a question of debate. However, XOR activity is mostly located in the cytoplasm and the outer surface of cells (23). XOR activity has also been detected in peroxisomes (24). Interestingly, XOR activity shows an asymmetric location in outer surface of cells with a higher activity observed on cell face(s) opposed by neighboring cells (20,23). The physiological consequences of asymmetrical XOR activity on the outer surface of cells are unknown. XOR activity is regulated at the substrate level by purine concentration, local pH and oxygen tension (17). In clinical setting, XOR is inhibited pharmacologically by drugs like allopurinol or febuxostat by binding to the Moco site; the NADH activity remains unaffected (25). XOR activity and UA level in serum differ according to gender and are higher in men than in women (26). UA and XOR activity show a diurnal rhythm: UA and xanthine levels in serum increase from 18:00 to 6:00 and decrease from 6:00 to 12:00, whereas XOR activity increases from 18:00 to 6:00 and from 6:00 to 12:00 (27).

UA is a weak organic acid with a pKa of 5.75 (diprotic acid with two dissociable protons with pKa1 of 5.4 and pKa2 of 10.3, respectively). Under normal physiologic conditions (37 ℃ and pH of 7.4) UA circulates in plasma and synovial fluids as monosodium urate (~99%) (28). Normal levels of UA in plasma are 1.5–6.0 mg/dL in premenopausal women and 2.5–7.0 mg/dL (208–416 µmol/L) in men. UA levels increase with age in both sexes. In postmenopausal women, UA levels increase gradually reaching values similar to those of men (29,30). Solubility of UA in water is low. However, the UA concentration in plasma may even exceed the solubility limit (6.8 mg/dL) without intravascular precipitation (crystal formation). UA solubility in plasma appears to be higher due to binding of UA to plasma proteins, particularly to albumin, which is UA main transporter and protein-bound UA has a plasma solubility that is 70% higher than free (unbound) UA (31). However, the urate-binding capacity of plasma proteins is debatable and the fact that urate is almost entirely filtered by the glomeruli in kidney suggests that the majority of UA in plasma is free (unbound to plasma proteins) (32). The body pool of UA is ~1,000 mg (~1,200 mg in men and ~600 mg in women) and the daily turnover (production and excretion) of UA is 600 to 700 mg (31). UA concentration in cerebrospinal fluid of healthy individuals is 5% to 6% of UA concentration in plasma (33). The presence of UA transporters in the blood-brain barrier and whether UA passes through the barrier in healthy individuals remain unclear (34). UA values ≥7 mg/dL for men and ≥6.0 mg/dL for women are considered as hyperuricemia.

Circulating levels of UA are maintained by a balance between UA production (~80% by liver and the remaining by intestine and other tissues) and excretion (predominantly by kidney and to a lesser degree by intestine). Evolutionary loss of hepatic uricase activity (the enzyme that catalyzes the transformation of UA to allantoin, which is 100 times more soluble than UA) in the middle of Miocene (~15 million years ago) led to higher UA levels in human predecessors and great apes than in other mammals (35). It has been suggested that the complete loss of uricase activity occurred gradually as a result of three successive mutations in the uricase gene—a nonsense mutation in codon 33 in exon 2, a nonsense mutation in codon 187 and a splice mutation in exon 3 (36,37). The gradual loss of uricase activity might have permitted adaptation to elevated UA levels and mitigated effects of hyperuricemia considering that knock-out of uricase gene in mice has devastating effects mostly related to kidney failure due to urate nephropathy (38). Although the role of evolutionary loss of uricase activity in elevation of UA levels is not disputable, other factors are important for the current-day UA levels in humans. Over the last 100 years, UA concentration in plasma has almost doubled from 3.5 to 6.5 mg/dL and the main reasons for this increase in UA levels is adaptation of Western diet consisting of increased consumption of purine-reach foods and fructose-sweetened beverages (39,40). Although fructose does not have purine ring and is metabolized through different metabolic pathways compared with purine nucleotides, fructose metabolism depletes intracellular ATP content and markedly increases availability of AMP, which is transformed into UA. Since the enzyme fructokinase is not inhibited by the product of reaction, i.e., fructose-1-phosphate, large amounts of fructose continue to be metabolized into fructose-1-phosphate with at least 2 consequences: depletion of ATP (and phosphate) and increased concentration of AMP favoring hyperuricemia and increased availability of down-stream metabolites of fructose metabolism that may serve as building blocks for lipids or cholesterol synthesis, favoring liver steatosis and metabolic syndrome (40-42). Fructose activates AMP-deaminase 2 an enzyme that initiates purine nucleotide degradation pathway and UA production. In aldolase B deficient mice, even very low amounts of fructose are sufficient to activate AMP-deaminase 2 via a phosphate trap mechanism (43). In addition, it has been suggested that dietary fructose may modify (elevate) UA level by acting at the SLC2A9 [solute carrier family 2 member 9 also known as glucose transporter 9 (GLUT9)], a renal transporter for UA, glucose and fructose (44). On the other hand, experimental studies have shown that elevated UA level in hepatocytes stimulates fructose catabolism by up-regulation of fructokinase enzyme (45). Alcohol consumption is also known as a major dietary factor for increasing UA levels (46). Ethanol and purine content appear to contribute to increased UA levels by alcoholic beverages. Ethanol increases UA levels by increasing UA production via acceleration of adenine nucleotide degradation and decreasing UA renal clearance (47). Other ingredients found in alcoholic beverages (particularly purine content) may also increase UA levels. In particular, beer consumption is associated with higher UA levels in men and women (48). Although consumption of excess amounts of purine-reach foods, fructose and alcohol contribute to UA levels and predispose to hyperuricemia, genetic factors appear to be the main determinants of UA level. A recent study has reported that summation of effects of 14 and 63 food items explained only 3.28% and 4.29% variation in UA level in general population whereas genome wide estimations of serum UA heritability explained 23.9% of variance in serum UA level (23.8% in men and 40.3% in women) (46).

Circulating levels and body pool of UA are regulated by an intricate and dynamic balance between UA production and excretion from the body. In humans, the liver and the intestine show abundant XOR activity. These two organs are the main producers of UA with other organs contributing to only a tiny proportion of daily UA production. Probably the most important factor of UA homeostasis is excretion of UA from the body and in 80% of cases elevated UA levels (hyperuricemia) are due to decreased excretion rather than excessive intake/production (49). The excretion of UA is a highly complex pathway that occurs almost entirely via kidney and intestinal tract (but not via biliary route). Overall, approximately 70% of UA excretion occurs via kidney and 30% via intestine (50). UA is filtered almost in its entirety during blood passage through kidney glomerulus. Interestingly and quite unusual for a waste product of metabolism, roughly 95% of filtered UA is reabsorbed in the convoluted S1 segment of proximal tubule. The next step in kidney handling of UA is an energy-dependent process of tubular secretion of roughly 50% of filtered UA load. Finally, a second phase of reabsorption follows in the segments 2 and 3 of proximal tubule with 5% to 15% of filtered UA load finally excreted in urine (51-53). However, it has to be stressed that this model of UA handling by the kidney is largely based on experimental studies. Crucial to the understanding of the UA excretion and UA homeostasis in general has been identification of a relatively large number of UA transporters that enable UA transport across cellular membrane of various cells. Commonly, these transporters are named after the code of responsible genes and their protein products (proteins acting as UA transporters). Although UA transporters are found in many cells and organs, they are mostly concentrated in kidney and intestine, i.e., in the organs with a key role in UA excretion and regulation of UA concentration in the body. Experimental studies and genome-wide association studies (GWAS) have identified a number of genes and their protein products that serve as UA transporters in the kidney: SLC22A12 [UA transporter (URAT1)], SLC2A9 (GLUT9), ABCG2 [ATP-binding cassette subfamily 2 also known as breast cancer resistance protein (BCRP)], SLC22A6 [organic anion transporter (OAT1)], SLC22A7 (OAT2), SLC22A8 (OAT3), SLC22A11 (OAT4), SLC22A13 (OAT10), SLC17A1 [Na⁺/phosphate transporter (NPT1)], SLC17A3 (NPT4), ABCC4 [multidrug resistance protein 4 (MRP4)] and PDZK1 (PZK domain containing 1 protein). Other transporters such as SLC5A [sodium-coupled monocarboxylate transporter (SMCT1)], SLC5A12 (SMCT2) and SLC13A3 (NaDC3; sodium-dependent dicarboxylate cotransporter 3) are coupled with UA transporters and transport various organic anions (such as dicarboxylate acids), which serve as a driving force for several UA transporters (54-57). On the other hand, PDZK1 protein acts as a scaffolding protein that regulates functional activity of URAT1 transporter in the proximal tubules and potentially influences the activity of ABCG2 transporter, as well (56,58). However, the main UA transporters SLC22A12 (URAT1), SLC2A9 (GLUT9), ABCG2 (BCRP) and variants of these genes account for the largest variability in the UA levels (59). These transporters enable reabsorption or secretion of UA in the nephron tubules. They are located in the apical or basolateral sides of the epithelial tubular cells and their content differs across various segments of proximal and distal tubules. Details of renal UA transporters and their specific location across various segments of nephron tubules are found in the excellent review by Halperin Kuhns and Woodward (54). Cellular localization of UA transporters is shown in Figure 1.

The intestine plays a crucial role in the regulation of UA level and is a major extra-renal organ that contributes to roughly 30% of UA excretion. The main UA transporters expressed in the intestine are GLUT9 and ABCG2 transporters (60). The GLUT9 is located on the basolateral side of enterocytes and its function is to transport UA from extracellular place into the cells, which later is secreted in the intestinal lumen via ABCG2 transporters located on the brush border of enterocytes. ABCG2 is a high-volume UA transporter that plays an important role in the excretion of UA, regulation of UA in physiological conditions and development of hyperuricemia and gout in pathophysiological conditions associated with its dysfunction. The use of ABCG2 UA transporter inhibitor elacridar in mouse (61), gene mutations associated with reduced ABCG2 transporter function (Q141K; rs2231142 variant) or loss of function (Q126X; rs72552713 variant) (62,63) and GWAS (64) have shown that decreased UA excretion via intestinal route due to functional deficit of intestinal ABCG2 UA transporter causes hyperuricemia and gout. The reduced or loss of function of intestinal UA transporters increases the burden on the kidney to excrete more UA which may accentuate kidney damage and/or favor urinary stone formation (65). Intestinal excretion of UA could be particularly important in patients with renal failure and genetic variants of the ABCG2 (single nucleotide polymorphisms) might particularly influence UA levels in patients with renal disease (66).

Consistent with the liver as the main producer of UA, several UA transporters, such as ABCG2, SLC2A9, SLC22A7, SLC22A11, SLC2A12 (Glut12) and MRP4 are expressed in hepatocytes and involved in the transport of UA in the extracellular space and (overwhelmingly) in blood (67-71). The expression of NPT1 and NPT4 in hepatocytes is questionable (55). A recent study showed that UA produced in hepatocytes is excreted directly in blood via UA transporters GLUT9 and MRP4 with a minimum excretion in the bile (72). Although ABCG2 is expressed on the bile canalicular side (membrane) of the hepatocytes (61,67), suggesting that UA may be excreted into the bile, biliary excretion of UA is considered to be negligible (61). Another recent study in the GLUT12 knockout in mice suggested that GLUT12 may be involved in UA transport from the blood into the hepatocytes, as well (71).

The complex regulation of UA production and excretion and existence of UA transporters in many organs and tissues have fueled the hypothesis that UA has physiological roles beyond being a waste product of purine and nitrogen metabolism. However, most of the postulated UA roles remain hypothetical. The most widely accepted physiological function of UA is its antioxidant effect, via which UA protects tissues from deleterious effects of various oxidants, primarily ROS and modulates numerous metabolic and cellular responses. In fact, UA is the most abundant endogenous antioxidant in organism accounting for 35% to 65% of total antioxidant capacity of plasma surpassing antioxidant capacity of plasma proteins (10% to 50%) and exogenous antioxidants, such as ascorbate (up to 24%) and vitamin E (5% to 10%) (73). Some authors have hypothesized that evolutionary loss of uricase with consequent increase in UA levels was advantageous because it preserved antioxidant power of plasma following loss of ability of ascorbate synthesis in human predecessors (35). However, the time gap between inactivation of L-gulono-lactone oxidase gene and endogenous synthesis of ascorbic acid (vitamin C) occurring some 61 million years ago (74) and inactivation of uricase gene occurring 15 million years ago (35) in human ancestors appears to contradict this hypothesis since human ancestors survived for more than 40 million years without protection by elevated UA levels. Nevertheless, UA offers important antioxidant protection by serving as an active scavenger of reactive radicals generated by autoxidation of hemoglobin and of peroxide generated by macrophages (35,75). Due to its ability to provide electrons and act as a reducing agent, UA actively scavenges singlet oxygen, peroxyl and hydroxyl radicals and peroxynitrite (ONOO⁻). Plasma UA protects erythrocyte membrane and plasma lipids from lipid peroxidation, which appears to depend on the presence of ascorbate (35), whereas neutralization of peroxynitrite by UA requires the presence of ascorbate and thiol groups (76). UA may stimulate superoxide dismutase, which appears to be inactivated in atherosclerotic ApoE^−/− mice, thus helping in scavenging ROS (77). However, the ROS scavenging ability of serum UA has been questioned. A recent human study involving 192 participants showed an association between UA and derivative of ROS [derivative of reactive oxygen metabolites (d-ROMs) in serum] independent of XOR activity, which was more prominent in women. However, there was no association between UA level and biological antioxidant potential (BAP). The study suggested that UA may increase oxidative stress by increasing ROS production independent of XOR activity without effect on ROS scavenging (78). In addition, it is increasingly being recognized that UA increases oxidative stress by disrupting mitochondrial physiology, impairing efficiency of ATP, increasing ROS production and accentuating oxidative stress (79). UA exerts anti-aging and neuroprotective effects mostly due to protection from ROS and oxidative stress. Experimental studies in mice have shown that UA prolongs lifespan of female mice via the antioxidant action, which led to lower levels of oxidative protein nitration and lipid peroxidation in muscle and brain tissues (80). In addition, UA prolongs the lifespan of Caenorhabditis elegans (a free-living nematode) via the antioxidant activity, which regulates insulin/IGF-1 signaling and the function of transcription factors DAF-16 (DAuer Formation 16), HSF-1 (heat shock factor 1) and SKN-1 (protein skinhead-1) (81). Consistent with the role of oxidative stress in the pathophysiology of neuro-degenerative disease, it has been hypothesized that UA has neuroprotective properties mostly via its antioxidant action. The hypothesis was further supported by finding low levels of UA in patients with multiple sclerosis (82), Alzheimer’s disease (83) and Parkinson’s disease (84). The fact that blood-brain barrier is almost impermeable to UA and that brain per se produces only tiny amounts of UA (33) appears to contradict this hypothesis. However, it has been suggested that UA may reach central nervous system from circulation via increased permeability of blood-brain barrier that occurs in the setting of various pathological conditions that affect blood-brain barrier permeability (85). The neuroprotective effects of UA in patients with neurodegenerative diseases have been recently reviewed (55). Low levels of UA have been reported in a number of autoimmune diseases likely suggesting an involvement of increased oxidative stress or deficient antioxidant protection by UA in these diseases (86). UA has been implicated in the maintenance of blood pressure, particularly under conditions of low salt diets. One experimental study in rats showed a gradual decrease in blood pressure following low-salt diet, which was prevented by UA supplementation. Although, the underlying mechanisms of blood pressure maintenance by UA are unknown, UA may increase blood pressure by promoting sodium reabsorption and stimulating renin-angiotensin system (87) as well as increasing the mRNA levels for angiotensinogen, angiotensin-converting enzyme and angiotensin 2 receptors (88). Evidence available suggests that UA is an enhancer of immune system. UA released from the damaged somatic cells may serve as an enhancer of immunity stimulating dendritic and antigen-presenting cells and cytotoxic T lymphocytes (32). UA at physiological concentrations may inhibit CD38 (cluster of differentiation 38)—an important receptor (a glycoprotein receptor found on the membranes of many immune cells) and multifunctional enzyme that catalyzes the synthesis of adenosine diphosphate ribose from NAD⁺ and degrades NAD⁺. Thus, UA is suggested to limit NAD⁺ degradation and increase NAD⁺ availability (55). On the other hand, hyperuricemia causes dysregulation of immune cells, such as monocytes, macrophages and T cells leading to cytokine expression, alterations in chemotaxis and differentiation and a strong inflammatory response (89). On the other hand, monosodium urate crystals activate CD38 and contribute to inflammation in human and murine macrophages (90). UA has been implicated in tissue healing and repair via its ability to initiate an inflammatory response, scavenge ROS and mobilize progenitor endothelial cells (91). Demonstration of endothelial dysfunction in patients with severe depletion of UA caused by loss-of-function mutations in the SLC22A12 (URAT1) transporter has suggested that UA may have a role in preserving endothelial function in physiological conditions (92). However, this issue remains controversial and, as we will see later in this review, elevated UA levels cause endothelial dysfunction. UA may also serve as a modulator of fructose, glucose and lipid metabolism (93) and participate in the transport of organic anions across the cellular membranes in kidney and other organs (54).

Recent evidence on the association between UA and CVD

Elevated UA level and hyperuricemia have been implicated as a causal or pathogenic risk factor in several diseases including CVD. The association between gout and CVD has been shown almost 150 years ago. In 1879, Mahomed (94) suggested a link between gout and atheroma or arterial hypertension in the setting of Bright’s disease. Ten years later, Haig (95) described a relationship between blood pressure and circulating UA levels. In 1897, Davies (96) described a number of cardiovascular alterations associated with gout and implicated UA in the genesis of elevated blood pressure, thickened and rigid arterial walls, arteriosclerosis and atheroma, left ventricular hypertrophy and cardiac fatigue, a term synonymous with HF. In 1951, Gertler et al. (97) showed that UA levels were higher in patients with premature CAD compared with healthy subjects and suggested to consider UA as a risk factor for CAD. Subsequently, UA was included in the protocols of the Framingham study to be assessed as a potential risk factor for CVD (98). In 1967, Kannel et al. (99) reported the results of the Framingham study (a cohort of 5,127 subjects), which showed that elevated UA was associated with a higher 12-year incidence of CAD in men 30 to 59 years of age alongside elevated cholesterol. The Health Professionals Follow-up Study (n=51,297 men) showed a 38% higher adjusted risk for cardiovascular deaths, a 59% higher adjusted risk for myocardial infarction and a 55% higher adjusted risk for CAD-related death in men with a history of gout over a 12-year period (100). In recent years, numerous prospective longitudinal studies, observational clinical and mechanistic studies, meta-analyses, Mendelian randomization studies and intervention trials with UA-lowering therapies have further strengthen the evidence linking elevated UA level with CVD and CVD-related mortality, albeit without offering enough evidence to support a causal relationship. In the following material, we summarized recent evidence linking UA with the risk of arterial hypertension, CAD, AF and HF. The impact of UA-lowering therapy on the association between UA and CVD and the putative mechanisms of the association between UA and CVD are also discussed.

UA and arterial hypertension

The association between elevated UA level and arterial hypertension is complex and hyperuricemia and high blood pressure commonly coexist. Elevated UA levels are reported in 25% to 60% of patients with untreated arterial hypertension and in nearly 90% of adolescents with essential arterial hypertension of new onset (39). It has been hypothesized that elevated UA levels following uricase gene loss in human ancestors had an evolutionary advantage due increased ability to maintain blood pressure especially in conditions of low-salt ingestion (101). However, it is widely accepted that in the current-day humans elevated UA levels appear to have at least a pathogenic role in promoting the development of arterial hypertension. Experimental studies in rats using an irreversible competitive uricase inhibitor showed a 10 mmHg increase in blood pressure for each 0.5 mg/dL UA increase. Of note, the use of XOR inhibitors or uricosuric agents (both therapeutic strategies lower UA levels) abolished hypertensive response in these animals (102). Human studies also support an association between elevated UA levels and the risk of arterial hypertension. Hyperuricemia has been identified as an independent risk factor for progression from prehypertension to hypertension (103). Studies in children and adolescents may be particularly appropriate to assess the role of UA in pathophysiology of arterial hypertension. Feig and Johnson (104) performed a study on the association between elevated UA levels and arterial hypertension in children and adolescents 6 to 18 years of age and normal renal function. The study included 63 subjects with primary hypertension, 40 subjects with secondary hypertension, 22 subjects with white coat hypertension and 40 controls of similar age. UA levels were significantly higher in children with primary (6.7±1.3 mg/dL) and secondary hypertension (4.3±1.4 mg/dL) but not in children with white coat hypertension (3.6±0.7 mg/dL) compared with controls (3.6±0.8 mg/dL). There were strong correlations between UA level and systolic (r=0.80) and diastolic (r=0.66) blood pressure in controls and children with primary hypertension, which were independent of renal function. The study strongly suggested that UA might have a role in the development of early primary hypertension (104). A cross-sectional analysis of 2009–2020 of the National Health and Nutrition Examination Survey (NHANES) data in which patients with metabolic syndrome, gout or an age <20 years were excluded showed that hyperuricemia was associated with arterial hypertension with an adjusted odds ratio (OR) of 2.21, 95% confidence interval (CI): 1.71 to 2.85. The association was observed in men and women. Elevated C-reactive protein levels were not associated with arterial hypertension. The study emphasized an independent association between elevated UA and prevalent arterial hypertension (105). A 2011 meta-analysis suggested an association between elevated UA levels and incident arterial hypertension with an adjusted risk ratio of 1.41 or a risk ratio of 1.13 for each 1 mg/dL increase in the UA levels with a stronger association in younger subjects and women (106). Along the same lines, a 2014 meta-analysis of 25 studies with 97,874 participants showed an association and a dose-response relationship between hyperuricemia and incident arterial hypertension. The risk for incident arterial hypertension increased by 48% [relative risk (RR) =1.48 (95% CI: 1.33–1.65)] by hyperuricemia and by 15% [RR =1.15 (95% CI: 1.06–1.26)] for each 1 mg/dL increment in the UA level. The meta-analysis confirmed a dose-response relationship between UA and the risk of incident arterial hypertension. The association was consistent across subgroups according to sex, ethnicity (Asian or non-Asian), follow-up duration (<5 or ≥5 years) and sample size (<3,000 or ≥3,000 participants) (107). A recent Mendelian randomization analysis that employed inverse variance weighting showed that genetically predicted serum UA was associated with a higher risk of arterial hypertension [OR =1.318 (95% CI: 1.184–1.466)] (108). The 2023 European Society of Hypertension guidelines include UA measurement in the setting of screening of patients with arterial hypertension (109).

UA levels correlate with the increased risk of mortality in patients with arterial hypertension. The Uric Acid Right for Heart Health (URRAH) study—a multicenter population-based longitudinal study of 22,714 patients recruited in hypertension clinics across Italy—identified UA levels as an independent correlate of all-cause and cardiovascular mortality over a 20-year follow-up and UA improved risk prediction for mortality when included in the risk prediction models for mortality. For each 1 mg/dL increase in the UA level the adjusted risk for all-cause and cardiovascular mortality increased by 53% [adjusted hazard ratio (HR) =1.53, 95% CI: 1.21–1.93] and 208% [adjusted HR =2.08 (95% CI: 1.15–2.97)], respectively. The UA values of 4.7 and 5.6 mg/dL were best UA cutoffs with respect to discrimination for all-cause and cardiovascular mortality, respectively (110). Another analysis from the URRAH study showed an independent association of UA with fatal myocardial infarction, with a 38% higher adjusted risk for fatal myocardial infarction for each 1 mg/dL increase in UA level over a mean follow-up of 122.3 months. The association was significant in women but not in men. The best UA cut-off for discrimination for fatal myocardial infarction was 5.7 mg/dL (110). A recent publication from the URRAH study showed that elevated UA predicts all-cause and cardiovascular mortality in cardiometabolic patients without established CVD, independent of triglyceride levels (111).

UA-induced high blood pressure may be a mediator of increased risk of mortality in patients with hyperuricemia. A recent study consisting of a Mendelian randomization analysis using data from the UK Biobank, Million Veterans Program and GWAS study consortia, and a meta-analysis of randomized controlled trials assessed the impact UA-mediated arterial hypertension on the association between UA and CVD. The Mendelian randomization analysis showed that for each standard deviation increase in the genetically predicted serum UA level, the risk for CAD, peripheral arterial disease and stroke increased by 19%, 12% and 11%, respectively. The analysis also showed that high blood pressure mediated approximately 1/3 of increased risk for CVD associated with hyperuricemia. The meta-analysis of randomized controlled trials showed that UA-lowering therapy had a favorable effect on reducing systolic blood pressure and major adverse cardiovascular events (MACE) in patients with CVD but not in all individuals. The study supported an effect of elevated UA on increasing blood pressure, which in turn may mediate an increased risk for CVD associated with elevated UA levels (112). Antihypertensive drug therapy may reduce cardiovascular risk associated with elevated UA levels. An observational phenome-wide association study (Obs-PheWAS) and polygenic risk score PheWAS (PRS-PheWAS) that included a total of 385,917 unrelated European individuals identified a total of 41 overlapping disease outcomes associated with UA. UA-lowering drugs reduced the risk of coronary atherosclerosis, congestive HF, occlusion of cerebral arteries and peripheral vascular disease. Combination of UA-lowering drugs with antihypertensive therapy exerted additive effects and was associated with a 6%, 8%, 8%, 10% reduction in the risk of coronary atherosclerosis, HF, occlusion of cerebral arteries and peripheral vascular disease, respectively (113). A 2021 meta-analysis of 49,800 hypertensive patients showed that patients with the highest UA level had a higher risk for all-cause [HR =1.51 (95% CI: 1.12–2.02)] and cardiovascular [HR =1.68 (95% CI: 1.28–2.20)] mortality and MACE events [HR =1.48 (95% CI: 1.28–1.70)] compared with reference lower UA levels. However, there was no association between UA and the risk of incident stroke (114).

With respect to the mechanism(s) of the association between UA and arterial hypertension, Feig et al. (115) discern two phases: an initial phase of elevated blood pressure due to vasoconstriction induced by activation of renin-angiotensin system and reduced NO, which can be reversed by UA-lowering drugs and a subsequent phase induced by proliferation of vascular smooth muscle cells leading to secondary arteriosclerosis, impaired pressure natriuresis and sodium-sensitive arterial hypertension, which cannot be reversed by lowering of UA levels (115). Hyperuricemia may cause vascular alterations leading to arterial stiffness—a condition characterized by decreased arterial distensibility caused by arterial structural alterations consisting of elastin degradation and an increase in stiff collagen—which is involved in the pathophysiology of arterial hypertension and CVD (116). The increased arterial stiffness associated with hyperuricemia has been explained by UA-induced harmful effects such as endothelial dysfunction, increased oxidative stress, stimulation of vascular inflammation, elastin degradation and fibrosis (116). In a large cross-sectional study in Korean population, elevated UA was associated with arterial stiffness assessed by brachial ankle pulse wave velocity with a linear relationship in men and women (117). Another study has shown an association between UA and arterial stiffness in patients with essential hypertension and metabolic disorders (118). The detailed mechanisms of the association between elevated UA levels and arterial hypertension are discussed later in this review.

In aggregate, recent epidemiological, clinical and Mendelian randomization studies and meta-analyses expand the existing evidence with respect to the association between elevated UA levels and the risk of arterial hypertension. However, the causality in the relationship between elevated UA and arterial hypertension remains unproven.

UA and CAD

The association between elevated UA and the risk of CAD has been extensively investigated. However, the debate is still going on whether the association between elevated UA and the risk of CAD is causal or epiphenomenal. Recent studies have reported higher UA levels in patients with established CAD, higher rates of incident CAD in patients with prolonged exposure to elevated UA levels as well as a correlation between UA level and CAD severity. UA and XOR activity were detected in atherosclerotic plaques and found to correlate with plaque burden and markers of plaque instability. Of note, recent studies consistently reported poor outcomes in patients with CAD and elevated UA levels. Recent studies also offered additional support for an association between elevated UA and the risk of CAD, albeit without a definitive answer to the dilemma of causality.

Several studies have shown that hyperuricemia is highly prevalent among subjects with established cardiovascular risk factors, such as older age, male sex, insulin resistance, type 2 diabetes, dyslipidemia, arterial hypertension, obesity and insulin resistance (7,8,119,120). Elevated UA levels or hyperuricemia are commonly associated with chronic kidney disease (121), metabolic syndrome (122), nonalcoholic fatty liver disease (122) and elevated homocysteine levels (123). The latter conditions increase cardiometabolic risk and predispose to atherosclerosis and CAD and are listed as nonconventional cardiovascular risk factors. A study based on the 2001–2018 NHANES data that included 11,219 individuals, 12–18 years of age, showed that elevated UA levels were associated with higher odds of various cardiometabolic risk factors in American adolescents. UA levels were associated positively with total cholesterol and triglycerides, low-density lipoprotein (LDL)-cholesterol, non-high-density lipoprotein (non-HDL)-cholesterol, insulin and systolic and diastolic blood pressure and negatively with HDL-cholesterol and single point insulin sensitivity estimator. After adjustment, UA was independently associated with high total cholesterol and triglycerides, high non-HDL-cholesterol and low HDL-cholesterol. In females, UA was independently associated with elevated blood pressure and high total cholesterol (124).

Observational and cohort studies have confirmed an association between elevated UA and CAD. Elevated UA levels were associated with the risk of CAD in 2,287 patients with essential arterial hypertension. The high UA level (UA > median value of 5.2 mg/dL) was associated with 21.6% higher adjusted risk for CAD over a mean follow-up of 8 years (125). A recent Korean study that included 17,492 participants without CVD at baseline showed that elevated UA levels predicted incident CAD in patients with chronic kidney disease of new onset and both conditions, i.e., elevated UA level and chronic kidney disease were associated with 65% higher risk of incident CAD after adjusting for potential confounders over a 4-year period (126). However, in the REason for Geographic And Racial Differences in Stroke (REGARDS) study, elevated UA was not associated with the incident CAD but with the risk of sudden cardiac death [adjusted HR =1.19 (95% CI: 1.03–1.37) for sudden cardiac death and HR =1.05 (95% CI: 0.96–1.15) for incident CAD for each 1 mg/mL increase in UA level] (127). In the longitudinal Brazilian study that included 4,096 participants, the highest UA quintile was independently associated with subclinical atherosclerosis assessed by carotid intima-media thickness in women and men but not with the coronary artery calcium (128). Conversely, in the Swedish CArdioPulmonary bioImage Study (SCAPIS) study, higher UA levels were associated with the presence of coronary artery calcium in men but not in women, whereas UA was not associated with common carotid intima-media thickness or carotid plaques in men or women (129). A meta-analysis of 11 studies with 11,108 subjects showed that higher UA levels were associated with a 1.806-fold higher risk of developing coronary calcium or 31% higher risk of coronary calcium progression for each 1.0 mg/dL higher serum UA (130). In a recent cohort study that included 11,222 healthy subjects with no carotid plaques at baseline, 25.94% of subjects (1,071 women and 1,840 men) developed carotid artery plaques over 10 years. After adjustment, the association between UA and the risk of carotid artery plaques remained significant in women but not in men (131). A recent study in China that enrolled 25,284 participants, free CVD and CVD risk factors and normal (3–6 mg/dL) UA levels in serum at baseline reported 1,007 cases of CVD over a median follow-up of 12.97 years. The risk of incident CVD increased by 12% and 28% in subgroups with UA level 4–5 and 5–6 mg/dL, respectively, compared with the subgroup with UA level 3–4 mg/dL. The relationship between UA in serum and the risk for CVD was J-shaped. The study suggested that elevated UA levels may promote CVD even in the absence of CVD risk factors (132). Elevated UA levels were associated with CAD in postmenopausal women (133) and patients with type 1 diabetes who were candidates for pancreas transplant (134). In patients with CAD, higher UA levels correlated with the presence of carotid plaques (135) potentially suggesting an association of elevated UA with the presence of atherosclerosis in multiple vascular beds. One study has shown that elevated UA was associated with the risk of in-stent restenosis after drug-eluting stent implantation in diabetic patients together with increased very low LDL-cholesterol, higher SYNTAX (Synergy between Percutaneous Coronary Intervention with TAXus and Cardiac Surgery) score and previous percutaneous coronary intervention (PCI) (136). In 216 patients with in-stent restenosis after coronary stent implantation who underwent optical coherence tomography of stented lesions, higher serum UA levels (≥7.0 mg/dL) were associated with a higher incidence of neoatherosclerosis (63% vs. 43%; P=0.004). Lipid plaques and thin-cap fibroatheroma were more frequent among patients with higher UA levels. After adjustment, higher UA levels correlated independently with the occurrence of neoatherosclerosis in patients with in-stent restenosis (137). Variation in serum UA levels over time appear to be associated with higher risk of CVD regardless of the direction of variation and the harmful effects of UA variation were induced by excessive inflammation and elevated blood pressure (138). Another recent two-step Mendelian randomization analysis that used genetic and clinical data assessed the impact of body mass index on the association between UA and various CVD. UA was genetically correlated with body mass index and showed a positive causal relationship with AF, CAD and essential hypertension. Body mass index mediated the effect on AF by 42.2%, CAD by 76.3% and essential hypertension by 10%. The study supported a causal effect of UA on AF, CAD and arterial hypertension mediated at least partially by an impact of UA on the body fat potentially stimulating the secretion from the fat tissue of inflammatory and endocrine factors with a pathophysiological role in CVD (139).

Mendelian randomization is an epidemiological method that uses genetically determined variation to address causal questions (distinguish correlation from causation in the relationship) about how modifiable exposures influence different outcomes (140). Mendelian randomization was used to assess whether there is a causal relationship between UA and CAD, and the results are not consistent. Two Mendelian randomization studies performed in 2016 did not support causal effects of genetically determined UA on the risk for CAD (141,142), particularly after accounting for the pleiotropy (142). A GWAS in 2,153 Mexican children and adults used a Mendelian randomization approach to assess whether genetic variants that modify serum UA level were associated with premature CAD. Only two loci were associated with elevated serum UA levels (SLC2A9 for lead single nucleotide polymorphism rs7678287 and ABCG2 for lead single nucleotide polymorphism rs2231142). Serum UA levels were associated with premature CAD, metabolic syndrome and decreased glomerular filtration rate (GFR). However, Mendelian randomization approach using the lead single nucleotide polymorphisms (SLC2A9 and ABCG2) associated with serum UA levels showed no causal effect between elevated UA and premature CAD (143). A 2021 study that used a two-sample Mendelian randomization approach that assessed 28 single nucleotide polymorphisms related to serum UA in 15,666 patients with type 2 diabetes did not support a causal effect of genetically determined serum UA levels on the risk of CAD in patients with type 2 diabetes (144). A 2024 two-sample Mendelian randomization study investigated whether there is a causal link between serum UA and six CVD in a large number of cases and controls from the European population (343,836 participants with 19,041,286 single nucleotide polymorphisms). The CAD data set included 42,096 cases and 361 controls. The study showed that a genetic predisposition to elevated serum UA levels significantly increased the risk of CAD [OR =1.227 (95% CI: 1.107–1.360)], arterial hypertension (OR =1.318), myocardial infarction (OR =1.184), HF (OR =1.158), angina (OR =1.150) and coronary heart disease (OR =1.170). The study offered robust evidence supporting a causal relationship between genetically elevated serum UA and CVD including CAD (108). Another recent Mendelian randomization study and GWAS obtained from the Global Urate Genetics Consortium comprising 110,347 individuals assessed whether there is causality between genetically predicted UA and CAD, cerebrovascular disease and AF/flutter. The study suggested that genetically predicted elevated UA levels exert a causal effect on the risk for CAD [OR =1.118 (95% CI: 1.044–1.197), cerebrovascular disease [OR =1.002 (95% CI: 1.000–1.003)], and AF/flutter [OR =1.141 (95% CI: 1.037–1.256)] (145). A large GWAS study that included 457,690 individuals (121,289 individuals with CAD and 63,495 individuals with myocardial infarction) showed that genetically determined elevated serum UA level was associated with the increased risk of CAD [OR =1.10 (95% CI: 1.06–1.15)] and myocardial infarction [OR =1.12 (95% CI: 1.07–1.18)]. In individuals of European ancestry, elevated serum UA levels were associated with the risk of CAD and myocardial infarction in men but not in women; in East Asian individuals (Biobank Japan), the causal effect of serum UA on CAD was observed in both sexes (146). A recent cross-sectional analysis of 23,080 individuals included in the 2009–2018 NHANES database showed that subjects with the severe elevation of UA levels (UA ≥700 µmol/L in men and ≥600 µmol/L in women) had a significantly higher risk of myocardial infarction after controlling for potential confounders [OR =2.843 (95% CI: 1.296–6.237)]. In the two-step Mendelian randomization analysis incorporated in the same study and performed to test the causality in the UA-myocardial infarction relationship, UA was associated with the risk of myocardial infarction [OR =1.333 (95% CI: 1.079–1.647)]. However, the inverse variance-weighted analysis indicated no causal relationship between genetic susceptibility to myocardial infarction and UA levels [OR =1.001 (95% CI: 0.989–1.012)] (147). In summary, Mendelian randomization studies gave conflicting results with respect to the causal association between serum UA and the risk of CAD. One factor that may explain conflicting results in Mendelian randomization studies is pleiotropy (a scenario in which variation in a gene associates with multiple phenotypes). The important impact of pleiotropy is illustrated in a recent large GWAS analysis in which, genetic loci predicting higher UA levels did not associate with gout. The counterintuitive phenomenon was explained by pleiotropic effects suggesting that UA-increasing allele(s) also affects the expression of gene(s) that associate with reduced risk of gout (148).

Patients with established CAD have higher UA levels compared with subjects without CAD (149) and hyperuricemia is frequent in patients with CAD being reported in 14.2% of patients with severe disease (150). In patients with confirmed CAD, UA correlates with CAD severity assessed by Gensini score (151) or SYNTAX score (152), coronary calcium in patients with early chronic kidney disease (153) and asymptomatic subjects (154), markers of vulnerable plaques assessed by optical coherence tomography (155), noncalcified plaques by coronary computed tomography angiography in asymptomatic population (156) and cardiac allograft vasculopathy after heart transplantation (157). UA levels correlate with multivessel disease, nonculprit lesion occlusion and Gensini score (158) and extent of coronary lesions and C-reactive protein in patients with acute coronary syndromes (159). One optical coherence tomography study reported more prevalent plaque rupture in patients with acute coronary syndrome and UA level >8 mg/dL (160). A recent study that used dual-energy computed tomography showed that patients with a history of hyperuricemia or gout had a higher likelihood of monosodium urate deposition in the atherosclerotic coronary plaques (161). Another study that included 1,242 patients referred to coronary computed tomography angiography showed that high-risk plaque features were more frequent among patients with hyperuricemia (defined as UA >6.5 mg/dL). In addition, low attenuation plaques, higher plaque burden and coronary artery calcium score were more frequent in patients with hyperuricemia. However, after adjustment, low attenuation plaques, stenosis severity, plaque types and G score but not UA were associated with a higher risk of MACE at a 8.32-year mean follow-up (162). UA has been detected in the carotid atherosclerotic plaques collected during carotid endarterectomy. Interestingly, UA was more commonly detected (86.9% vs. 22.2%; P=0.001) and its concentration was higher [25.1±9.5 vs. 17.9±3.8 µg/g; P=0.021] in symptomatic compared with asymptomatic plaques. Serum UA level was higher in patients with symptomatic plaques than asymptomatic plaques and UA in serum correlated positively with UA concentration in carotid plaques. The authors concluded that UA may be involved in the pathogenesis of carotid plaques, provides mechanistic explanation for plaque instability and subsequent ischemic cerebrovascular events and may serve as a systemic biomarker for carotid artery plaques (163). In patients with carotid artery atherosclerosis, elevated UA levels have been reported to correlate with intraplaque neorevascularization, which may promote plaque vulnerability (164). A recent experimental study using an atherosclerotic ApoE^−/− mouse model showed that high UA levels promoted atherosclerosis, exacerbated plaque vulnerability by increasing macrophage infiltration, lipid accumulation, enlarging necrotic cores and decreasing collagen fibers. High UA levels increased foam cell apoptosis and inhibited autophagy in atherosclerotic plaques (165).

In aggregate, recent studies offered additional evidence on the association between elevated UA and CAD. However, the causal relationship between elevated UA levels and the risk of CAD remains unproven.

UA and outcome in patients with CVD

Elevated UA levels have consistently been reported to be associated with a higher risk of mortality across various CVDs. A 2016 meta-analysis of 14 studies with 341,389 participants showed that hyperuricemia was associated with a higher risk of CAD mortality [RR =1.14 (95% CI: 1.06–1.23)] and all-cause mortality [RR =1.20 (95% CI: 1.13–1.28)]. For each 1 mg/dL higher UA level, the risk for CAD-related and all-cause mortality increased by 20% and 9%, respectively. The association with all-cause mortality was stronger in women (166). A recent report from the 1999–2008 NHANES data that included 4,308 individuals reported a significant nonlinear relationship between UA and all-cause and cardiovascular mortality over a median follow-up of 80 months. Individuals with UA levels ≥6.127 mg/dL had an adjusted HR of 1.146 (95% CI: 1.078–1.217) for all-cause mortality whereas individuals with UA levels ≥5.938 mg/dL had an adjusted HR of 1.123 (95% CI: 1.03–1.225) for cardiovascular mortality (167). In 8,124 patients with no established CVD or uncontrolled metabolic disease recruited in the URRAH study and followed for over 20 years, higher UA levels (defined at a cut-off of 4.7 mg/dL for all-cause mortality and 5.6 mg/dL for cardiovascular mortality) predicted all-cause [HR =1.25 (95% CI: 1.12–1.40)] and cardiovascular mortality [HR =1.31 (95% CI: 1.11–1.74)]. The association was consistent in subjects with normotriglyceridemia and hypertriglyceridemia (111). In a longitudinal cohort study of 92,454 participants, 7,670 (8.3%) cardiovascular events or cardiovascular deaths occurred over a median follow-up of 4.7 years. Overall, for each 1 mg/dL increase in the UA level, the composite endpoint of adverse events increased by 6% after adjustment in the multivariable Cox model. In patient groups with UA 5.0 to <6.0, 6.0 to <7.0 and >7.0 mg/dL, the adjusted risk for composite endpoints (CVD and cardiovascular death) increased by 10%, 20% and 36%, respectively compared with the patient group with UA 4.0 to <5.0 mg/dL. UA was associated with a similar higher risk of CVD and mortality (168). A cohort study of 3,977 patients with CVD showed a significantly higher risk of all-cause [adjusted HR =1.38 (95% CI: 1.16–1.64)] and cardiovascular [adjusted HR =1.39 (95% CI: 1.04–1.86)] mortality associated with higher UA levels over a median follow-up of 68 months, with both risk estimates calculated for 4th vs. 1st quartile of UA level. The association between UA and mortality was U-shaped (169). UA predicted the risk of major adverse cardiac and cerebrovascular events in 428 patients with intermediate coronary lesions undergoing PCI guided by fractional flow reserve. The high UA group had a significantly higher risk of major adverse cardiac and cerebrovascular events over a median follow-up of 5.8 years (170). Another study that included 3,202 patients with CAD undergoing PCI showed that patients with UA in the upper quartile had a higher risk of MACE, myocardial infarction, cardiovascular death, HF-related hospitalization or total major cardiovascular events compared with patients with UA in the lowest quartile over a mean follow-up of 65.06±32.1 months (171). Our group assessed the association between elevated UA and 10-year outcomes after PCI in 3,998 patients with CAD. Elevated UA level was associated with a higher risk of 10-year mortality with an adjusted risk of all-cause and cardiac mortality of 22% and 24%, respectively for each 1 mg/dL higher UA level. UA was not associated with progression of atherosclerosis in nontreated lesions or intimal hyperplasia (restenosis) in stented lesions (172). High UA levels were associated with a higher risk of 3-year mortality in patients with chronic total occlusions treated with PCI (173). Another recent study showed a U-shaped relationship between serum UA levels and 12-month incidence of major adverse cardiac and cerebrovascular events in men but not in women (174). A cohort study of 33,034 patients with CAD showed a U-shaped relationship between UA and all-cause mortality over a median follow-up of 4.91 years (175). UA predicted 4-year mortality in 1,068 patients presenting with acute coronary syndromes treated by PCI (176) and in elderly patients after a median of 519 days after elective PCI (177). Elevated UA was associated with severity of CAD and 1-year incidence of MACE in patients with acute coronary syndrome and arterial hypertension after PCI (158) and patients with non-obstructive CAD over a median follow-up of 26 months (178). In a study of 165 patients with chronic total occlusions undergoing PCI with drug-eluting stents, elevated UA was associated with the risk of target lesion revascularization after successful recanalization over a median follow-up of 34 months (179). Elevated UA levels were associated with higher risk of all-cause mortality in patients on hemodialysis over a mean follow-up of 32.9 months (180). A large study that included 27,707 patients with chronic kidney disease, free of CVD at baseline reported a higher risk of myocardial infarction, congestive HF, stroke or all-cause mortality in patients with high UA levels over a median follow-up of 12 years (181). In a 1999–2018 NHANES cohort study that included 7,101 patients with type 2 diabetes, elevated UA predicted the risk of all-cause and cardiovascular mortality during 57,926 person-years follow-up (182). A 2019 meta-analysis that included 32 studies with 1,134,073 participants showed a significant positive non-linear association between UA levels and the risk of CVD mortality [HR =1.45 (95% CI: 1.33–1.58)], albeit with significant heterogeneity. The association was non-linear and stronger in women than in men (183). The strong association between progressive elevation of UA in serum and UA levels of ≥6 mg/dL could be considered an alarm signal for cardiovascular risk (184).

UA and AF

AF is most common sustainable arrhythmia in humans that is associated this significant morbidity and mortality. The most important risk factors for nonvalvular AF are structural heart disease including congestive HF and arterial hypertension, acute coronary events, advanced age and surgical procedures. Cardiometabolic factors are increasingly being recognized as predisposing factors for AF. Evidence available strongly supports an association between elevated UA levels and the risk for AF and an involvement of UA in the pathophysiology of this arrhythmia.

Numerous studies have suggested an association between elevated UA levels and the risk of AF. The prevalence of AF is higher in subjects with gout compared with subjects without gout (185). Recent retrospective analyses (186,187), cross-sectional population-based (188-190) and case-control (191) studies have demonstrated a higher prevalence of AF in subjects with higher UA levels. However, due to a suboptimal design these studies offer no strong evidence with respect to the association between UA and AF risk. Longitudinal population-based studies offered strong evidence with respect to the association between elevated UA levels and the risk for AF (192-194). A recent analysis from the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study showed that in-treatment serum UA levels were a strong predictor for AF of new onset in hypertensive patients, independent of antihypertensive treatment, age, sex, and left ventricular hypertrophy (195). A recent study in patients with acute myocardial infarction suggested that incorporation of UA in the CHA₂DS₂-VASc [congestive heart failure, hypertension, age ≥75 years (doubled), diabetes mellitus, prior stroke or transient ischemic attack (doubled), vascular disease, age 65–74 years, female] score markedly improved the discrimination by the score with respect to prediction of AF of new onset (196). Preoperative UA levels have been associated with a higher risk of postoperative AF after coronary artery bypass surgery (197).

The recently published Swedish AMORIS (Apolipoprotein-Mortality Risk) cohort study offers probably the strongest evidence with respect to the association between elevated UA level and the risk of AF. The study included 339,604 individuals, 30 to 60 years of age and free from CVD at baseline. Overall, 46,516 incident AF episodes occurred over a mean follow-up of 25.9 years. In subjects with UA in the 2nd, 3rd and 4th quartile, the adjusted risk for AF increased by 9%, 19% and 45%, respectively, compared with subjects with UA in the 1st quartile. The strength of association did not differ in subgroups with and without incident arterial hypertension, type 2 diabetes, HF or CAD. There was a dose-response relationship between UA and AF (198). In a recent publication from the AMORIS study that included 308,509 individuals followed over a mean follow-up of 9.4 years, UA largely accounted for the relationship between impaired renal function [assessed by estimated GFR (eGFR)] and AF. In this analysis, reduced eGFR was associated with a higher 10-year incidence of AF [adjusted HR =1.72 (95% CI: 1.29–2.30) for eGFR <30 mL/min/1.73 m² and adjusted HR =1.10 (95% CI: 1.03–1.18) for eGFR 30 to <59 mL/min/1.73 m², both compared with eGFR 60 to 89 mL/min/1.73 m²]. After the inclusion of UA in the multivariable model, the association between eGFR and the risk for AF was abolished. Interestingly, after stratification for hyperuricemia (UA >420 µmol/L in men and >360 µmol/L in women) patients with eGFR <30 mL/min/1.73 m² without hyperuricemia showed a higher risk of AF [HR =2.58 (95% CI: 1.64–4.07)] (199). A recent GWAS study that included >140,000 European individuals and 109,029 East Asian individuals and 25 single nucleotide polymorphisms associated with UA-AF relationship and two single nucleotide polymorphisms associated with gout-AF relationship failed to evidence a causal relationship between UA levels or gout and the risk of AF (200).

Recent meta-analyses have consistently reported a higher risk of AF associated with elevated UA levels or gout (201-203). A 2021 meta-analysis that included 31 studies with 504,958 participants showed that UA levels were associated with a higher risk of AF of new onset, paroxysmal AF and persistent AF. In eight cohort studies, UA was associated with higher incidence of AF [RR =1.92 (95% CI: 1.68–2.20)] (201). A 2022 meta-analysis that included 11 studies with 608,810 participants showed that patients with hyperuricemia were more likely to have AF than patients without hyperuricemia [RR =2.42 (95% CI: 1.24–3.03)] (202). Another 2022 meta-analysis that included 12 studies showed that hyperuricemia [8 studies: RR =1.83 (95% CI: 1.35–2.47)] and gout [4 studies: RR =1.33 (95% CI: 1.04–1.71)] were associated with a higher incidence of AF. However, in hyperuricemia studies, the association was significant in studies from China and cross-sectional studies but not in studies from Japan or cohort studies (203). A recent meta-analysis that included 14 studies with 2,046 patients showed that UA levels of patients who had AF recurrence after ablation were significantly higher than in patients who did not have AF recurrence. The recurrence rate of AF following radiofrequency ablation was significantly higher in patients with high UA level compared with patients with low UA level [OR =2.21 (95% CI: 1.73–2.83)] (204). In patients with AF, hyperuricemia was associated with higher risk of mortality and hospitalization for HF over a mean follow-up of 3.7 years (205).

The underlying mechanisms of the association between elevated UA level and the risk of AF are unknown. However, experimental and clinical studies suggest that UA may predispose to AF either indirectly as a correlate of other factors that increase the risk for AF or directly via electrophysiological effects of UA. A number of putative mechanisms through which UA may increase the risk of AF have been proposed. First, UA is closely associated with cardiovascular risk factors, which increase the risk of AF, particularly by causing structural alterations or metabolic heart dysfunction. On one hand, UA may serve as a bridge linking cardiovascular risk factors with CVD, i.e., mediating the effects of cardiovascular risk factors on the heart and blood vessels. In particular, UA and arterial hypertension—known to be a predisposing factor for AF—may have a synergistic action in promoting AF and the association of arterial hypertension with AF may be in part mediated by UA (206). On the other hand, as discussed earlier in this review, the association of UA with CVD (including AF) is mediated largely by arterial hypertension (112) and obesity (139). Second, elevated UA level and hyperuricemia promote AF via through inflammation and oxidative stress, which are the widely accepted mechanisms of UA involvement in the pathophysiology of CVD (206). UA stimulates the synthesis of a number of proinflammatory cytokines (Figure 2) and inflammation appears to be involved in the pathophysiology of AF (207). Population-based studies (208) and analyses from randomized trials (209) have shown an association of C-reactive protein with the risk of AF. Increased oxidative stress and increased cellular and tissue content of ROS associated with elevated UA levels promote the formation of a substrate that facilitates initiation and maintenance of AF. ROS cause electrical (by altering the activity of various cellular currents and Ca²⁺-handling), structural (myocyte necrosis, apoptosis, myolysis and interstitial fibrosis that impair impulse propagation) and autonomic nervous system (further altering cellular electrophysiology) remodeling. Mechanisms of the association of ROS with AF are found in the excellent review by Pfenniger et al. (210). Third, UA stimulates the synthesis of angiotensin-2 (211) and endothelin-1 (212) promoting smooth muscle cell proliferation (211,213), increases arterial stiffness (214), reduces NO availability (215) and causes endothelial dysfunction (216) and all these alterations may predispose to AF. Fourth, apart from alteration of cellular currents in atrial cardiomyocytes caused by ROS, UA appears to have direct electrophysiological effects that promote AF (217,218). As recently shown, at least 4 UA transporters—URATv1/GLUT9, ABCG2, MRP4 and MCT9—are expressed in mouse atrial myocytes (219). UA enters the cells via URATv1 transporter and activates nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase to increase intracellular content of ROS, which activate the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling pathway leading to expression and stabilization of Kv1.5 channel protein increasing the ultra-rapid delayed-rectifier current (I_Kur) resulting in shortening of action potential of atrial myocytes (219). Intracellular UA may also lead to stabilization of Kv1.5 channel protein and enhancement of the ultra-rapid delayed-rectifier current (I_Kur) via activation of heat shock protein 70 (Hsp70) (220). Higher UA levels were found to be associated with pathological left atrial substrate (low-voltage areas) at electro-anatomical mapping (221).

Figure 2 Putative mechanisms of participation of uric acid in the pathophysiology of cardiovascular disease. Minus sign means inhibition. AMP, adenosine monophosphate; AMPK, AMP-activated protein kinase; Cox2, cyclooxygenase-2; CRP, C-reactive protein; EC, endothelial cells; ERK, extracellular signal-regulated kinase; IL, interleukin; eNOS, endothelial nitric oxide synthase; LDL, low-density lipoprotein; MAPK, mitogen-activated protein kinase; MCP-1, monocyte chemoattractant protein-1; MMP, matrix metalloproteinases; MSU, monosodium urate; NADP, nicotinamide adenine dinucleotide phosphate; NF-κB, nuclear factor kappa B; NLRP3, nucleotide-binding oligomerization domain-like receptor protein 3; NO, nitric oxide; OxLDL, oxidized LDL; ROS, reactive oxygen species; SMC, smooth muscle cells; TGF-β1, transforming growth factor beta-1; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor; VSMC, vascular smooth muscle cell.

In aggregate, recent epidemiological and clinical studies added new evidence regarding the association between elevated UA level and the risk of AF and recent mechanistic studies have further clarified the role of UA in the AF pathophysiology. However, recent studies failed to prove a causal relationship between UA and AF.

UA and HF

HF represents an end-stage of most CVD with arterial hypertension and CAD being the most frequent etiological factors. HF induces a powerful neuro-endocrine activation and causes numerous metabolic alterations that may alter UA production/excretion balance predisposing to hyperuricemia, which may be further aggravated by renal alterations and diuretic use.

Serum UA is associated with prevalence and severity of HF. The prevalence of gout is reported to be approximately 10% in patients with HF (222). Experimental and clinical studies have shown an increased expression and activity of XOR in failing myocardium, which may lead to increased UA production and hyperuricemia in patients with HF (223). Elevated serum UA was found to be independently associated with subclinical left ventricular dysfunction in general population (224), progression to left ventricular diastolic dysfunction in apparently healthy subjects (225), HF prevalence in patients with acute (226) and chronic (227) coronary syndromes, reduced left ventricular ejection fraction in patients with CVD (228) and left ventricular hypertrophy in middle-aged women and men without CVD risk (229). UA strongly correlates with N-terminal pro-brain natriuretic peptide in patients with CAD without overt HF (230), central hemodynamic parameters (pulmonary capillary wedge pressure and cardiac index) in patients with advanced HF with very low left ventricular ejection fraction (231) and right ventricular dysfunction in patients with HF and preserved left ventricular ejection fraction (232). A recent systematic review concluded that hyperuricemia is associated with severity and complications of HF (233). Plasma XOR activity has been reported to be extremely high in patients severely decompensated acute HF (234) and higher in patients with HF and AF compared with patients with HF and sinus rhythm. Elevated UA has been suggested to aggravate HF through UA-induced upregulation of fatty acid synthase via SREBP1 (sterol regulatory element-binding protein 1) signaling pathway leading to fatty acid accumulation and impairment of energetic metabolism (235). Hyperuricemia may aggravate HF by energetic alterations related to increased oxidative stress leading to NAD⁺ depletion, suppression of sirtuin-1 and mitochondrial dysfunction (223).

Longitudinal population-based studies have shown an increased risk of incident HF in subjects with elevated UA level. In the Framingham Offspring cohort study that included young general community dwellers (n=4,912; mean age, 36 years), the incidence rates of HF were approximately 6 times higher in subjects with UA in the 4th quartile (UA >6.3 mg/dL) versus those with UA in the 1st quartile (UA <3.4 mg/dL) over a median follow-up of 29 years (236). A 2014 meta-analysis that included 28 studies showed that elevated UA level was associated with a higher risk of incident HF and adverse outcomes in patients with established HF. In five studies that have assessed incident HF, for each 1 mg/dL higher UA level the risk of incident HF was increased by 19% and there was a dose-effect relationship between UA and incident HF (237). In 1,009 adults with left ventricular hypertrophy and suspected left ventricular diastolic dysfunction, subjects with UA in the highest tertile had a higher risk of new-onset HF with preserved ejection fraction over a median follow-up of 7.2 years (238). In subjects of older age (70.9±6.0 years) free of comorbidities, asymptomatic hyperuricemia was associated with higher risk of incident HF [6.5% vs. 3.1%; adjusted HR =2.34 (95% CI: 1.50–3.63)] over a mean follow-up of 47.4±3.6 months (239). A recent study that included 18,438 adults with established CVD but free of HF at baseline showed a higher risk of incident HF with a HR of 1.50 (95% CI: 1.30–1.73) for 3rd vs. 1st UA tertile over a 6.1-year median follow-up (240).

Recent randomized trials that tested the efficacy of novel drugs in patients with HF provided important information on the association between UA and HF or prognosis as well as the impact of novel drugs on UA level. In the Prospective Comparison of ARNI (angiotensin receptor-neprilysin inhibitor) with ARB (angiotensin-receptor blockers) Global Outcomes in HF with Preserved Ejection Fraction (PARAGON-HF) trial, hyperuricemia was found in 26% of the patients. Hyperuricemia was associated with older age, higher New York Heart Association (NYHA) class, shorter duration of HF, lower Kansas City Cardiomyopathy Questionnaire Overall Summary Score, lower blood pressure, higher body mass index, lower GFR, higher N-terminal pro-brain natriuretic peptide level and higher proportions of patients with AF, diabetes mellitus and diuretic use. Hyperuricemia was associated with increased risk of primary outcome [rate ratio =1.61 (95% CI: 1.37–1.90)]. Sacubitril-valsartan drugs reduced serum UA level compared with valsartan at 4 months and UA-lowering effect was greater in patients with elevated UA level (241). In the Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and a Reduced Ejection Fraction (EMPEROR-Reduced) trial, the prevalence of hyperuricemia was 53% with no difference according to gender and elevated UA levels correlated with severity of HF. The sodium-glucose cotransporter-2 (SGLT-2) inhibitor empagliflozin caused a rapid and sustained decrease in the UA level and improved clinical events related to hyperuricemia (242). A post hoc analysis from the EMPEROR Preserved trial showed that hyperuricemia (UA >5.7 mg/dL in women and >7.0 mg/dL in men) was prevalent in 49% of patients with HF and preserved left ventricular systolic function. As in patients with reduced left ventricular function (242), UA levels correlated with severity of HF and empagliflozin reduced UA level and the rate of events related to hyperuricemia (243).

Mendelian randomization studies gave conflicting results with respect to a causal relationship between elevated UA and the risk of HF. Earlier studies (141) and a recent analysis of 5,723 patients with type 2 diabetes included in the 1999–2018 NHANES study and a Mendelian randomization study that included 47,309 HF cases and 930,014 controls incorporated in the same study found no causality relationship between UA levels and congestive HF (244). Conversely, a recent Mendelian randomization study reported an increased risk of HF [OR =1.09 (95% CI: 1.01–1.17)] associated with genetically predicted elevated UA level and suggested a causal relationship between elevated UA and the risk of HF (245). Another recent large genetic study that used summary statistics of HF from HERMES consortium, FinnGen and UKBiobank studies showed that genetically determined serum UA was associated with the risk of HF [OR =1.07 (95% CI: 1.03–1.10)]. The study provided consistent evidence with respect to the causal effect of genetically predicted serum UA level on HF. However, no consistent evidence was found regarding a causal effect of HF on serum UA levels (246). More recent Mendelian randomization studies have offered additional evidence supporting a causal association between elevated UA and the risk of HF (108,247).

Recent studies have provided consistent evidence on the association of hyperuricemia with adverse outcomes, primarily with the increased risk of mortality in patients with HF. The Chronic Heart Failure Registry and Analysis in the Tohoku District-2 (CHART-2) study that included 4,652 patients followed up over a median of 6.3 years showed an increase in mortality with increasing UA levels. In patients with UA levels <3.8, 3.8–7.1, 7.2–9.2 and >9.2 mg/dL, mortality rates were 35%, 29%, 36% and 55%, respectively; hospitalizations for HF were 25%, 24%, 29% and 46%, respectively. After adjustment, the association between UA and mortality and readmission for HF remained significant. Elevated UA levels were positively correlated with serum creatinine, diuretic use, dyslipidemia, arterial hypertension, HF admission, AF, smoking, brain natriuretic peptide and body mass index and negatively with female sex, age, statin use, type 2 diabetes and left ventricular diastolic dimension (248). These correlates of elevated UA level are important for understanding the increased risk of death or admission for HF associated with hyperuricemia in patients with HF. In the Dapagliflozin and Prevention of Adverse-outcomes in Heart Failure (DAPA-HF) trial, the risk of HF hospitalization and cardiovascular death increased by 7% and 6%, respectively, per 1 mg/dL higher UA level and the increase in the risk for these outcomes was linear for UA values >7.09 mg/dL. Dapagliflozin reduced UA by 0.84 mg/dL over 12 months (249). A post hoc analysis from the 1999–2016 NHANES database showed that elevated UA was associated with all-cause and cardiovascular mortality in men but not in women over a median of 127 months (250). A recent study in elderly with chronic HF showed that elevated UA was associated with the risk of cardiovascular death in patients with reduced and preserved ejection fraction over a median follow-up of 18 months (251). A large NHANES-based study showed that subjects with hyperuricemia or gout were 2.46 and 2.35 times more likely to develop HF and 1.37 and 1.45 times more likely to experience all-cause death compared with subjects without these conditions at long-term follow-up (252). Elevated UA levels were also associated with the risk of readmission in patients with HF (253,254). A number of recent meta-analyses supported an association between elevated UA levels or hyperuricemia and adverse outcomes in patients with acute HF (255-257). A 2019 meta-analysis that included 10 studies with 12,854 patients with acute HF showed that patients with highest UA levels had a 43% and 68% higher adjusted risk for all-cause death or composite end-point of death or readmission for HF (255). A 2021 meta-analysis that included 18 publications showed that high UA level was associated with the risk of all-cause mortality (HR =2.24), cardiovascular mortality (HR =1.14) and composite of death or cardiac events (HR =1.26) (256). Along the same lines, a 2024 meta-analysis that included 12 studies showed that high UA level was associated with the risk of all-cause mortality (RR =1.21) and cardiovascular mortality (RR =1.71) in patients with HF and preserved ejection fraction (257). Meta-analyses of UA-lowering studies and trials did not evidence an improvement of mortality or other cardiovascular outcomes with UA-lowering therapy in patients with HF (258,259). One recent meta-analysis suggested that UA-lowering therapy may even increase all-cause mortality [RR =1.15 (95% CI: 1.05–1.25)], even though higher UA levels per se were associated with increased risk of HF, all-cause mortality, cardiac mortality and rehospitalization for HF (260).

UA-lowering therapy and CVD

Based on the strong association between elevated UA or hyperuricemia and the risk of CVD, it was hoped that pharmacological UA-lowering interventions may improve the outcomes of patients with CVD. Since UA-lowering therapies induce sustainable reduction in UA levels, it was expected that interventional studies in analogy with the Mendelian randomization studies, will help in clarification of the causal relationship between UA and CVD. Currently, UA-lowering therapies consist of three classes of drugs: XOR inhibitors (allopurinol, febuxostat and topiroxostat), URAT1 transporter inhibitors (probenecid, benzbromarone and dotinurad) and recombinant uricase (pegloticase); these drugs reduce UA synthesis, increase UA urinary excretion or degrade purine ring of UA.

Allopurinol, a drug approved for therapy of gout in 1966, was used to improve cardiovascular outcomes. A study from the United Kingdom Clinical Practice Datalink that used a propensity-matched design (2,032 pairs) to reduce the impact of confounding showed that allopurinol-exposed patients had 39% lower risk of cardiac events and 50% lower risk of stroke over a 10-year period in adults with arterial hypertension (261). However, these favorable results were not replicated in the subsequent randomized trials. The Allopurinol versus usual care in UK patients with ischemic heart disease (ALL-HEART) study randomized 5,937 subjects with CAD to receive allopurinol or usual care. The primary endpoint was a composite of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death. There were no differences in the rates of primary endpoint (11.0% vs. 11.3%; P=0.65) or death of any cause (10.1% vs. 10.6%; P=0.77) between allopurinol and usual care arms over a 4.8-year mean follow-up. The study did not support the use of allopurinol to reduce cardiovascular risk in patients with CAD without gout (262). A recent analysis from the ALL-HEART trial showed that allopurinol (600 mg daily) did not improve cardiovascular outcomes compared with usual care in patients with CAD and no gout and suggested that the drug should not be used for secondary prevention in these patients (263). In addition, no evidence of plaque stabilization by allopurinol was observed in patients with acute coronary syndrome (264).

Febuxostat—a nonpurine highly selective inhibitor of oxidized and reduced forms of XOR—has been used as a UA-lowering agent in patients with gout. Since earlier studies provided signals that febuxostat may increase the risk for cardiovascular events, the Cardiovascular Safety of Febuxostat and Allopurinol in Patients with Gout and Cardiovascular Morbidities (CARES) trial was conducted as a Food and Drug Administration requirement to assess the safety of the drug. The trial randomized 6,190 patients and the primary endpoint was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke or unstable angina requiring urgent revascularization. The primary endpoint occurred in 10.8% of patients assigned to febuxostat and 10.4% of patients assigned to allopurinol (P=0.66) over a median of 32 months of follow-up. All-cause (7.8% vs. 6.4%; P=0.04) and cardiovascular death (4.3% vs. 3.2%; P=0.03) were higher in patients assigned to febuxostat. However, therapy was discontinued in 56.6% of the patients. The study showed noninferiority of febuxostat versus allopurinol in patients gout with respect to the composite endpoint but a higher rate of all-cause and cardiovascular mortality in patients assigned to febuxostat (265). The Febuxostat versus Allopurinol Streamlined (FAST) trial randomized 6,128 patients with gout to receive febuxostat or allopurinol. The primary endpoint was a composite of hospitalization for nonfatal myocardial infarction or biomarker positive acute coronary syndrome, nonfatal stroke or cardiovascular death. Febuxostat was noninferior to allopurinol with respect to the primary endpoint (5.6% vs. 7.9%), all-cause death (3.5% vs. 5.7%) or cardiovascular death (2.5% vs. 2.7%) over a median of 1,467 days. The study did not raise safety concerns related to febuxostat versus allopurinol and all-cause mortality was even lower with febuxostat (266). The Febuxostat for Cerebral and CARdiorenovascular Events PrEvEntion StuDy (FREED) assigned 1,070 elderly patients with hyperuricemia to receive febuxostat or not (no febuxostat arm). The primary endpoint included cerebral, cardiovascular, renal and all-cause deaths over 36 months. The primary endpoint occurred less often in patients assigned to febuxostat (23.3% vs. 28.7%; P=0.017). Renal impairment occurred less often with febuxostat (16.2% vs. 20.5%; P=0.041) (267). A subgroup analysis from the FREED trial that included patients with CVD at baseline (n=234) showed that febuxostat reduced the primary outcome consistent with the source trial and cardiovascular mortality (2.6% vs. 14.3%; P=0.004) with a significant febuxostat-by-CVD interaction (P=0.007) (268).

Uricosuric drugs were tested in small studies using surrogate endpoints. An experimental study of myocardial ischemia in mice showed that probenecid exerts an inotropic effect through its effect on Ca²⁺ influx without exacerbating reperfusion injury (269). In a small number of patients with univentricular congenital heart disease who have undergone Fontan procedure and have impaired ventricular systolic function (n=8), probenecid improved ventricular systolic and diastolic function via augmenting cardiomyocyte calcium hemostasis (270). In two randomized, placebo-controlled studies incorporated in a single publication, allopurinol (600 mg/day) improved endothelial function assessed by forearm blood flow to acetylcholine, whereas probenecid at a dose to cause the same UA lowering (1,000 mg/day) showed no any measurable effect on endothelial function (271). A small randomized study of 21 hyperuricemic patients undergoing coronary stenting showed no difference between febuxostat and benzbromarone in coronary endothelial function (272). Another small randomized study of 30 patients with hyperuricemia showed that reactive hyperemia indices and high-molecular weight adiponectin levels were significantly higher in patients treated with benzbromarone than febuxostat (273). Although benzbromarone is a potent uricosuric agent, it did not receive Food and Drug Administration approval due to concerns about hepatotoxicity. A recent review article has suggested that highly selective inhibition of URAT1 transporter by dotinurad may be beneficial for metabolic syndrome, chronic kidney disease and CVD (274). Another URAT1 transporter inhibitor, lesinurad has been withdrawn from US and European markets due to the risk of acute kidney injury by the drug. There is no evidence on the effects UA-lowering agents topiroxostat or pegloticase on cardiovascular outcomes in subjects or patients with elevated UA levels or gout. Some experts see benefits of XOR inhibition with respect to improvement of cardiovascular outcomes in patients with CVD (275). However, other experts see benefits of XOR inhibition in improving surrogate endpoints like blood pressure, endothelial function, proteinuria and carotid intima-media thickness but not in hard clinical outcomes such as mortality (276).

In the last few years, numerous medications, other than those mentioned earlier, have been tested in patients with hyperuricemia or gout aiming either to reduce UA level or ameliorate deleterious effect of elevated UA levels such as increased oxidative stress, inflammation and endothelial dysfunction. However, few drugs have shown a consistent clinical benefit. Losartan, particularly at high dose, appears to reduce UA levels in patients with hyperuricemia (277,278) through uricosuric effects related to inhibition of URAT1 transporter. Losartan and dapagliflozin combination therapy led to lower UA levels compared with monotherapy in patients with HF (279). Recent research has shown that SGLT-2 inhibitors effectively reduce UA levels in patients with or without HF. As already shown, empagliflozin and dapagliflozin markedly reduce UA levels and events related to hyperuricemia in patients with HF (243,249). Meta-analyses of randomized trials have also shown that SGLT-2 inhibitors reduce UA levels in various clinical scenarios (222,280-283). Although the exact mechanisms of UA-lowering effects of SGLT-2 inhibitors are not entirely clear, these agents may reduce UA levels via inhibition of UA production and/or increasing UA excretion. Detailed molecular mechanisms of SGLT-2-induced reduction of UA levels have recently been reviewed (284).

Meta-analyses that have summarized the effects of UA-lowering therapy gave mixed results but in general, they did not confirm a benefit of UA lowering with XOR inhibitors. A 2019 meta-analysis that included ten randomized trials in which febuxostat (n=8,602) was compared with allopurinol (n=5,118) or placebo (n=643) showed no effect of febuxostat on MACE, defined as nonfatal myocardial infarction, angina pectoris, HF, CAD or cardiovascular death [pooled RR =0.9 (95% CI: 0.6–1.5)] However, the risk for cardiovascular death was higher with febuxostat [pooled RR =1.29 (95% CI: 1.01–1.66)] (285). Another meta-analysis of 28 trials did not show a benefit of UA-lowering therapy (predominantly allopurinol or febuxostat) on MACE defined as a cardiovascular death, myocardial infarction, ischemic stroke or HF [risk ratio =0.93 (95% CI: 0.74–1.18)], all-cause mortality [risk ratio =1.04 (95% CI: 0.78–1.39)] or kidney failure [risk ratio =0.97 (95% CI: 0.61–1.54)]. The authors concluded that there is no sufficient evidence to support UA-lowering therapy with XOR inhibitors to improve cardiovascular or renal outcomes (286). A 2024 meta-analysis with 47 studies (28 studies comparing XOR inhibitors vs. placebo, 17 studies comparing allopurinol vs. febuxostat, and 2 studies comparing XOR inhibitors vs. uricosuric agents) showed no difference between various comparisons with respect to cardiovascular death, myocardial infarction, ischemic stroke HF or composite endpoint of MACE. The risk of HF, assessed in three randomized controlled trials was lower with febuxostat compared with allopurinol [OR =0.66 (95% CI: 0.50–0.89)]. The meta-analysis discouraged the routine use of UA-lowering therapies to reduce cardiovascular events in the setting of primary or secondary prevention (287).

UA and other cardiovascular morbid conditions

Elevated UA levels have been implicated in the pathophysiology of idiopathic pulmonary hypertension and may predict an increased risk of mortality in these patients. A recent study that included 207 patients with idiopathic pulmonary arterial hypertension showed that hyperuricemia conferred a 2.6-fold higher risk of 5-year mortality. Female patients, patients 30 years or younger and those with a higher UA variability had a particularly higher risk of mortality (288). A meta-analysis of 26 studies showed that patients with pulmonary arterial hypertension had higher UA levels than patients without the disease. Patients with hyperuricemia had 2.32 higher odds for the development of pulmonary arterial hypertension and 19% higher hazards of death (289). One recent Mendelian randomization study even suggested that there may be a causal link between UA and idiopathic arterial pulmonary hypertension and that UA may be used as a biomarker and therapeutic target for idiopathic arterial pulmonary hypertension (290). It has been suggested that elevated UA may increase the risk of ventricular arrhythmias in patients with left ventricular hypertrophy (291), reperfusion ventricular arrhythmias in patients with acute myocardial infarction (292) and other diseases (293). Elevated UA levels are associated with the risk of left atrial thrombus or spontaneous echo contrast in the left atrium (294). Hyperuricemia aggravated myocardial ischemia-reperfusion injury in a mouse model via the ROS/NLRP3 (nucleotide-binding oligomerization domain-like receptor protein 3) inflammasome pyroptosis pathway whereas inflammasome inhibitors and ROS scavengers partly reversed the injury (295). Elevated UA level was associated with higher risk of slow flow/no-reflow after primary PCI in patients with ST-segment elevation myocardial infarction (296).

Pathophysiological mechanisms of the association between UA and CVD

Recent experimental and clinical studies have suggested a number of pathophysiological mechanisms through which UA may promote CVD. Pathophysiological mechanisms of UA involvement in the pathophysiology of CVD have been recently reviewed (32,276,297-300) and as with almost all other aspects of the association between UA and CVD, most of these mechanisms currently remain at the stage of hypothesis. However, four putative mechanisms may underlie the association between elevated UA and the risk of CVD: association with cardiovascular risk factors, increased oxidative stress, increased inflammatory burden and a direct effect of UA on cellular processes leading to cellular (cardiac) dysfunction and injury. At cellular level, endothelial dysfunction is the most widely accepted effect of hyperuricemia with an impact on CVD. The main pathophysiological mechanisms linking elevated UA with atherosclerosis and CVD are shown in Figure 2. Despite ample evidence gathered from recent experimental and clinical studies, it remains hotly debated whether UA is a risk marker or risk factor for atherosclerosis and CVD.

Elevated UA level commonly coexists with cardiometabolic risk factors (7,8,119,120) and is considered as a correlate of increased cardiometabolic risk and a marker of increased cardiometabolic stress on myocardium and blood vessels. The relationship between UA and cardiometabolic risk factors goes beyond the merely coexistence. Cardiovascular risk factors and comorbidities (like metabolic syndrome or chronic kidney disease) may lead to hyperuricemia, which in turn, may further aggravate them and/or accentuate their effects on the heart and vessels. Elevated UA levels commonly co-exist with obesity and correlate with hyperinsulinemia and insulin resistance (301). On the other hand, excessive body fat may favor hyperuricemia by increasing production and impairing excretion of UA (302), whereas hyperuricemia per se may accelerate fat production by liver and peripheral fat tissue (303). A similar relationship exists between UA and arterial hypertension. Hyperuricemia, when present, may potentiate effects of cardiometabolic risk factors or even serve and a means through which these factors exert at least a part of their effects on myocardium and blood vessels. Conversely, hyperuricemia may exert its deleterious cardiovascular effects via risk factors like arterial hypertension (112) and obesity (139). This intricate and mutual relationship and dependence between UA and cardiometabolic risk factors are the main reasons for the ongoing debate whether UA is simply a correlate of increased cardiovascular risk or it is directly involved in the pathophysiology of CVD.

Increased oxidative stress due to hyperuricemia-induced overproduction of ROS and related reactive species is the critical factor in promoting atherosclerosis and CVD by UA. At physiological amounts, ROS participate in cellular signaling pathways and protect against infection and at physiological conditions cells are protected by effective antioxidant systems. However, the oxidant/antioxidant balance appears to be broken by hyperuricemia. Although, UA in plasma exerts powerful antioxidant effects, in the hydrophobic and acidic milieu and in cytoplasm of the cells UA at supra-physiological amounts acts as a pro-oxidant and promotes oxidative stress, both in soluble and crystalized forms. At supra-physiological amounts, UA may enhance peroxynitrite-mediated oxidation of LDL and liposomes and the aminocarbonyl that results from the reaction may cause tissue damage. UA at supraphysiological amounts activates NADPH oxidase (NOX), which is a major producer of ROS (55). The increased oxidative stress occurring in the setting of hyperuricemia has three main sources: increased XOR activity, increased expression and/or activity of NOX and dysfunctional mitochondria (298). Since the ROS are products of XOR reaction (the final step in UA synthesis) the increased expression and/or activity XOR leads to ROS generation and increase in their cellular content. Another important source of ROS is NOX—a cell membrane-bound enzyme that protects against infection. Four forms of NOX (NOX1, NOX2, NOX4 and NOX5) are found in vascular wall including smooth muscle cells, endothelial cells, fibroblasts and perivascular fat cells (298). Soluble UA stimulates NOX activity and ROS production in mouse adipocytes, which resulted in activation of MAPK p38 and ERK1/2, a decrease in NO availability, an increase in protein nitrosylation and lipid oxidation (304). Elevated UA levels cause mitochondrial injury resulting in mitochondrial dysfunction and increased production of ROS. Incubation of human aortic endothelial cells with UA for 48 hours led to increased generation of ROS and 200% increase in intracellular oxidative stress, decreased ATP content and endothelial nitric oxide synthase (eNOS)-mediated NO synthesis (305). Although the exact mechanisms of UA-mediated mitochondrial dysfunction remain to be elucidated, ROS, UA-mediated suppression of AMP-activated protein kinase (AMPK) or activation of Rho kinase have been suggested as potential mechanisms (298). UA may increase oxidative stress via urate radical formation. UA may undergo one electron oxidation to produce UA radical (UA·), which (if not reduced by ascorbate) may react with superoxide to produce urate hydroperoxide. Oxidized UA reacts with amino acids to form adducts with proteins and enzymes (oxidative uratylation) altering their function. The adduct formation with albumin in healthy individuals is increased during inflammation (306). This is an important concept that opens new perspectives on the participation of UA in inflammation and disease via a direct pro-oxidant action. UA reacts with peroxynitrite to produce the aminocarbonyl radical further propagating oxidative reactions (307). UA may serve as a substrate for myeloperoxidase leading to UA radical formation and exacerbation of oxidative stress and enhancing NO consumption by myeloperoxidase (308). Estrogen hormone may counteract UA-induced endothelial damage by limiting UA accumulation in blood vessels, promoting NO release, attenuating ROS production and reducing chronic inflammation (309). URAT1 is expressed in mouse cardiomyocytes and functions as an UA transporter. The expression of URAT1 protein is upregulated by palmitic acid, whose levels are elevated in metabolic syndrome (310). Thus, in dysmetabolic states, UA may mediate adverse metabolic effects on myocardium via URAT1 transporter.

Regardless of source, ROS at supraphysiological concentrations interfere with numerous cellular signaling pathways, attack almost all known cellular components and cause cellular injury. One of the most important cellular effect of UA-mediated elevation of ROS content is reduced NO availability, which may result from reduced production and/or increased degradation. Since NO plays a crucial role in endothelial integrity and function, reduced NO availability is the main factor of hyperuricemia-related endothelial dysfunction, in which cellular endothelium is transformed into a pro-inflammatory and pro-thrombotic cellular platform. Incubation of human umbilical vein endothelial cells (HUVECs) with UA, was associated with reduced eNOS activity and NO production, higher rates of apoptosis (assessed by annexin V staining) and increased endoplasmic reticulum stress (311)—all of them contributing to endothelial dysfunction. UA inhibits basal and vascular endothelial growth factor (VEGF)-induced NO production in bovine aortic endothelial cells (312) and insulin-induced eNOS phosphorylation and NO production in endothelial cells mediated by phosphatidylinositol 3 kinase/protein kinase (PI3K/Akt) pathways (313). ROS act directly with NO reducing NO content and producing peroxynitrite (ONOO⁻) which is a powerful reactive species responsible for DNA damage, cell death and lipid peroxidation (299). Peroxynitrite oxidizes tetrahydrobiopterin—a cofactor of eNOS—leading to eNOS decoupling (decoupling of oxygen reduction from NO generation) transforming the enzyme from a NO producer to a ROS producer further reducing NO availability (314). UA increases arginase activity (an enzyme that degrades arginine—a precursor of NO) decreasing NO production in pulmonary artery endothelial cells (315). UA may lead to NO depletion by reacting directly with NO in a rapid irreversible reaction resulting in formation of 6-aminouracil (215). UA-mediated ROS cause glycocalyx shedding (316), further contributing to endothelial dysfunction by increasing endothelial permeability, inflammation and exposure of adhesion molecules promoting leukocyte and platelet adhesion to dysfunctional endothelium (317). Hyperuricemia induces insulin resistance in cardiomyocytes by increasing phosphorylation of insulin receptor substrate 1 (IRS1) and subsequent inhibition of phosphorylation of protein kinase B (Akt) contributing to endothelial dysfunction (318). UA increases expression of aldose reductase and enhances ROS production via NADPH oxidase contributing further to endothelial dysfunction (319). As already mentioned, UA stimulates expression of angiotensin-2 (211) and endothelin-1 (212), which worsen endothelial function. Studies using HUVECs have shown that UA induces a localized renin-angiotensin system in endothelial cells, leading to increased production of angiotensin-2 and expression of angiotensin-2 AT1 and AT2 receptors (88). By reducing NO availability and increasing expression of angiotensin-2 and endothelin-1, hyperuricemia shifts the balance between vasodilator and vasoconstrictor stimuli toward vasoconstrictor stimuli increasing the risk for arterial hypertension, endothelial dysfunction, atherosclerosis and vascular adverse events. Elevated UA levels induce cardiomyocyte apoptosis, interstitial fibrosis and diastolic dysfunction in rat hearts through calpain-1 activation and increased endoplasmic reticulum stress (320).

Elevated UA levels induce a strong inflammatory response, which contributes to endothelial dysfunction and increased cardiovascular risk. Increased amounts of ROS and other reactive species induced by UA at supra-physiological amounts promote a pro-inflammatory state by initiating various pro-inflammatory pathways. In addition, elevated UA levels may promote inflammation via a (more) direct participation in cellular inflammatory pathways. The activation of the NLRP3 by soluble UA (321) and monosodium urate crystals (322) is one of the most studied mechanisms of UA-induced inflammation. UA has been classified as a damage-associated molecular pattern (DAMP) signal that is released from ischemic or dying cells and following crystallization and internalization by immune cells and macrophages activates NLRP3 inflammasome. Monosodium urate crystals also bind to toll-like receptor 4 (TLR-4) (with participation of adaptor molecule MyD88) and activate a signaling cascade involving nuclear transcription factor (NF-κB) initiating transcription of inflammatory genes for interleukin (IL)-1 and IL-18 (323). In addition, monosodium urate crystals may cause cellular injury by damaging plasma membranes of the surrounding cells. In mice, soluble UA promotes NLRP3 inflammasome-dependent secretion of IL-1β through activation of hypoxia-inducible factor-1α (HIF-1α) and mitochondrial ROS with the involvement of mammalian target of rapamycin (mTOR)-AMPK pathway (324). UA-activated NLRP3 inflammasome induces caspase-1 maturation, which activates pro-IL-1β and pro-IL-18 into mature IL-1β and IL-18, respectively, and the latter are secreted from the cell. Activated caspase-1 also cleaves gasdermin D (GSDMD) which forms a pore in the cell membrane triggering pyroptosis, an inflammatory form of lytic programmed cell death (325). Caspase-1, inflammatory ILs and pyroptosis amplify the inflammatory response to hyperuricemia and promote atherosclerosis and atherosclerotic plaque instability (325). The role of inflammasomes in promoting CVD including atherosclerosis, myocardial infarction and HF has been recently reviewed (325). Experimental studies have also shown that UA upregulated C-reactive protein expression in human vascular smooth muscle cells and HUVECs (326). A recent 15-year cohort study suggested that a combination of elevated UA and C-reactive protein levels increased the risk for CVD (327). In vascular smooth muscle cells, UA induces expression of tumor necrosis factor-α (TNF-α) via the ROS-MAPK-NF-κB pathway (328) and monocyte chemoattractant protein-1 (MCP-1) via MAPK and cyclooxygenase-2 (329). In patients with gout, circulating levels of UA, C-reactive protein, tumor necrosis factor α, and IL-6 are reported to be significantly higher than in controls (330). IL-6 has been implicated in the monosodium urate crystal mediated NLRP3 inflammasome activation and release of IL-1β by neutrophils (331). Subjects with hyperuricemia have higher levels of transforming growth factor beta-1 (TGF-β1), a pro-fibrotic cytokine, and TGF-β1 signaling has been implicated in the UA-induced pro-inflammatory phenotype of human monocytes (332). Studies with HUVECs have demonstrated that UA upregulated prorenin receptors in endothelial cells and exposure of endothelial cells to UA leads to heightened cytokine production, vascular inflammation and monocyte adhesion (333). In experimental studies in HUVECs, UA induces expression, acetylation and nuclear-cytoplasmic translocation of high mobility group box chromosomal protein-1 (a DNA binding protein), which is considered as a powerful proinflammatory cytokine (334). UA-induced high mobility group box protein-1 interacts with the receptor for advanced glycation end products (RAGE) increasing oxidative stress and inflammatory response promoting endothelial dysfunction (216). These inflammatory mediators and processes are key players in the pathophysiology of atherosclerosis and CVD.

UA promotes a prothrombotic state and vascular thrombosis (335) via various mechanisms including increased oxidative stress, inflammation and endothelial dysfunction (336), glycocalyx shedding and exposure of adhesion molecules (316), platelet activation and decreased platelet inhibition by thienopyridines (337). In cultured endothelial cells, UA induced phosphatidylserine externalization and endothelial microparticle shedding through TMEM16F expression and activation promoting a hypercoagulable state (338). Apart from phenotypic transformation of endothelial cells into a prothrombotic platform, UA appears to promote vascular thrombosis via effects on coagulation cascade, as well. Incubation of HUVECs with UA at various concentrations led to increased gene expression, protein levels and surface exposure of tissue factor as well as a significant reduction of the tissue factor pathway inhibitor potentially via NF-κB pathway (339).

Numerous studies have detected UA in atherosclerotic plaques and have implicated it in the plaque build-up and destabilization. In patients with symptomatic atherosclerotic carotid plaques XOR activity and the percentage of macrophages that expressed XOR activity were significantly higher than in asymptomatic patients and XOR activity correlated with serum UA levels (340). In the ApoE^−/− model of atherosclerosis in mice, HUVECs and human atherosclerotic arterial samples, hyperuricemia aggravates atherosclerotic plaque load and promotes atherosclerosis via NLRP3 inflammasome-mediated pyroptosis of endothelial cells regulated by cellular ROS (341) and promotes plaque instability through apoptosis targeted autophagy (165). Another study in ApoE^−/− model of atherosclerosis in mice found that UA promotes atherosclerosis via downregulation of nuclear factor-erythroid 2-related factor2 (NRF2)/SLC7A11/glutathione peroxidase 4 (GPX4) signaling pathway leading to autophagy dysfunction and pyroptosis of macrophages (342). In patients with CAD, serum UA levels correlate inversely with fibrous cap thickness and positively with the length of calcification estimated by optical coherence tomography (155) and with echogenic features of carotid plaque vulnerability in elderly patients with atherosclerotic disease (343). UA induces proliferation and migration of vascular smooth muscle cells transforming these cells from a contractility phenotype to a proliferative/migratory phenotype (344).

Despite ample evidence regarding the presence of UA in atherosclerotic plaques, the underlying mechanisms through which intra-plaque UA promotes atherosclerosis remain partially known. However, increased oxidative stress (due to UA-induced ROS production from endothelial cells, vascular smooth muscle cells, macrophages and blood-born cells, like monocytes) and pro-inflammatory state induced by the presence of UA within the atherosclerotic plaques promote atherosclerotic plaque propagation and instability. Increased amounts of ROS oxidize LDL, which are trapped in the subendothelial space. Dysfunctional endothelial cells produce cytokines such as MCP-1, which attracts circulating monocytes (but also other classes of leukocytes) and upregulates the expression of adhesion molecules [intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1)] enabling monocyte adhesion and migration into the atherosclerotic plaque (345). Under the impact of cytokines and mitogens present in atherosclerotic plaques, monocytes differentiate into macrophages, which engulf oxidized-LDL facilitated by ROS and p38MAPK signaling pathway and further differentiate into foam cells (345,346). UA within the atherosclerotic plaque induces apoptosis of endothelial cells, vascular smooth muscle cells and foam cells contributing to necrotic core formation and expansion (345,347,348). In addition, vascular smooth muscle cell apoptosis reduces the number of these cells in the fibroatheroma cap leading to thin-cap fibroatheroma, which is prone to rupture and vascular arterial thrombosis, particularly in inflamed and rapidly expanding atherosclerotic plaques (Figure 2). ROS activates matrix metalloproteinases, which participate in almost all stages of atherosclerosis and via proteolytic degradation of fibrous (collagen and elastin) components of atherosclerotic plaque cap contribute to cap thinning and plaque instability increasing the risk of plaque rupture (349) and subsequent adverse clinical events. Monosodium urate deposits in atherosclerotic plaques are reported to be associated with coronary calcium score (161,350) and a higher risk of subsequent MACE (351). In analogy with cholesterol crystals (352), sharp-edged monosodium crystals may damage (mechanically) the plaque cap and promote plaque rupture/erosion, particularly when pressed towards the cap by rapidly expanding inflamed plaque. Finally, regardless of origin, increased amounts of ROS (345) and inflammatory cytokines (353) within the atherosclerotic plaque lead to plaque inflammation promoting rapid plaque expansion and rupture.

Elevated UA levels and hyperuricemia promote a dysmetabolic state. The effects of UA in fructose metabolism and potential deleterious metabolic effects have been earlier discussed (45,319). UA promotes insulin resistance in multiple organs, such as pancreas, skeletal muscle, adipose tissue, liver, heart, endothelial cells and macrophages via a multitude of mechanisms, which have been recently reviewed (354). Since the insulin resistance is the underlying pathophysiological mechanism of metabolic syndrome, hyperuricemia may promote numerous metabolic alterations via this mechanism. UA may reduce glucose uptake by cardiomyocytes via activation of IRS1 phosphorylation, inhibition of Akt phosphorylation and translocation of glucose transporter type 4 (GLUT4) (355). Elevated UA may also interfere with energy metabolism promoting mitochondria dysfunction via suppression of AMPK activity (298) which may disrupt cardiomyocyte energy metabolism and impair antioxidant systems with negative consequences for myocardium (300).

Conclusions

Recent research has offered new evidence that have further confirmed the association between elevated UA level and the risk for CVD including the risk for arterial hypertension, CAD, AF and HF and the risk for poor outcomes (notably reduced survival) in subjects/patients with CVD. In addition, recent research has markedly increased our knowledge with respect to the mechanisms through which elevated UA levels increase cardiovascular risk and promote CVD. Elevated UA level or hyperuricemia is intrinsically related to cardiovascular risk factors and hyperuricemia and cardiovascular risk factors appear to be interdependent in terms of the impact on cardiovascular health and disease. Specifically, cardiovascular risk factors may mediate at least a part of their effects on the heart and blood vessels via hyperuricemia and the latter may exert their deleterious effects on cardiac and vascular structures via cardiovascular risk factors (notably arterial hypertension). Elevated UA levels promote a pro-oxidative and pro-inflammatory state with both conditions playing a crucial role in the pathophysiology and development of CVD. Elevated UA levels promote endothelial dysfunction and transform the vascular endothelium into a pro-inflammatory, pro-atherogenic and pro-thrombotic platform. The key (but not the only) mechanism through which the elevated UA causes endothelial dysfunction is reduced NO availability via reduced synthesis and/or increased breakdown of this molecule. Hyperuricemia shifts the balance between vasodilator and vasoconstrictor stimuli toward vasoconstrictor stimuli increasing the risk for arterial hypertension, endothelial dysfunction, atherosclerosis and vascular adverse events. Elevated UA level causes (or gives weight to) various metabolic alterations including the impairment of energetic metabolism promoting a worse cardiometabolic risk profile and may be a component of dysmetabolic heart syndrome. While recent research has markedly enriched our understanding regarding the association between elevated UA and the risk of CVD and the underlying mechanisms of the association, so far it failed to offer a clear answer to the causality in the relationship between UA and CVD. Mendelian randomization and intervention studies with UA-lowering therapy were hoped to provide information on the UA-CVD causality considering that these studies allow to assess whether cardiovascular risk and CVD differ in conditions of prolonged exposures to low or high(er) UA levels. However, Mendelian randomization studies gave inconsistent results whereas intervention-studies with UA-lowering therapies, particularly with XOR inhibitors, were disappointing in terms of reduction of incident CVD or CVD-related outcomes even though these therapies consistently reduced UA level. Notably, another class of drugs, i.e., the SGLT-2 inhibitors caused a rapid and sustained decrease in the UA level and improved clinical events related to hyperuricemia in patients with HF.

Several aspects of the association between UA and CVD need further research. First well-designed epidemiological studies need to be performed to assess the causality including inverse causality in the UA-CVD relationship. Second, since the majority of research on the pathophysiological role of UA in CVD was obtained from experimental studies, which were extrapolated to humans, more human studies should be performed to delineate the underlying mechanisms of the UA involvement in the pathophysiology of CVD. Notably, most available research shows an indirect effect of UA in the increase of cardiovascular risk via promoting pro-oxidative and pro-inflammatory states. Thus, a direct effect of UA in the pathophysiology of CVD requires further research. Third, randomized and well-powered clinical studies with UA-lowering drugs including novel XOR inhibitors and, particularly other classes of UA-lowering drugs are required. Fourth, since the increased risk of incident CVD and adverse outcomes related to elevated UA levels appear to involve UA levels that are in the upper part of reference range of UA level, a reappraisal of reference range of UA by authoritative bodies is required to determine truly physiological concentrations of circulating UA. The interest in the assessment of UA involvement in the pathophysiology of CVD has resurrected and likely, it will remain high at the least for the near future.

Acknowledgments

None.

Footnote

Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://jlpm.amegroups.com/article/view/10.21037/jlpm-25-8/coif). G.N. serves as an unpaid Editorial Board Member of Journal of Laboratory and Precision Medicine from August 2024 to December 2026. The author has no other conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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