Editorial Comment: Hyperuricemia and Coronary Artery Disease: Marker, Mediator, or Modifiable Risk?

Abstract

Coronary artery disease (CAD) remains the leading cause of mortality worldwide despite remarkable advances in preventive strategies, diagnostic modalities, and revascularization therapies. Although conventional cardiovascular risk factors—including hypertension, diabetes mellitus, dyslipidemia, smoking, and obesity—remain the cornerstone of cardiovascular risk assessment, they do not fully account for the occurrence or severity of coronary atherosclerosis. Consequently, considerable attention has been directed toward identifying additional biomarkers that may improve risk stratification and provide insights into the underlying pathophysiology of coronary artery disease. Among these, serum uric acid has emerged as one of the most extensively investigated non-traditional biomarkers. Nevertheless, its precise role remains controversial. Whether hyperuricemia is simply a marker of adverse cardiometabolic health or an active contributor to atherosclerotic disease continues to be the subject of ongoing investigation [1,2]. In this issue of the Pakistan Heart Journal, Safi and colleagues address this important clinical question through a cross-sectional study involving 150 patients undergoing coronary angiography at a tertiary cardiac centre in Pakistan. They demonstrate that hyperuricemia is independently associated with angiographically documented CAD after adjustment for conventional cardiovascular risk factors. More importantly, elevated serum uric acid levels were associated not only with the presence of CAD but also with greater anatomical complexity, reflected by higher SYNTAX scores and a greater prevalence of multivessel coronary disease. These findings extend beyond simple disease detection and suggest that serum uric acid may serve as a marker of overall atherosclerotic burden rather than merely indicating the presence of coronary stenosis [3].  Several methodological strengths enhance the clinical relevance of this study. First, coronary angiography—the accepted reference standard for defining obstructive coronary artery disease—was used to establish disease status, thereby minimizing diagnostic uncertainty often encountered in studies relying solely on symptoms or non-invasive investigations. Second, assessment of angiographic complexity using the validated SYNTAX score provides clinically meaningful information because lesion complexity influences prognosis, treatment selection, and long-term outcomes. Third, the study contributes valuable regional evidence from South Asia, where premature coronary artery disease and metabolic disorders remain disproportionately prevalent but where data on emerging cardiovascular biomarkers remain relatively scarce. The biological mechanisms supporting these observations are biologically plausible. Experimental evidence suggests that elevated serum uric acid promotes oxidative stress through increased xanthine oxidase activity, reduces nitric oxide bioavailability, impairs endothelial function, stimulates vascular smooth muscle proliferation, activates inflammatory pathways, and enhances vascular remodeling. Collectively, these mechanisms provide a credible biological basis for an association between hyperuricemia and accelerated atherosclerosis [4]. Nevertheless, biological plausibility alone does not establish causality. Indeed, the relationship between serum uric acid and cardiovascular disease remains one of the most debated topics in preventive cardiology. Large observational cohorts and multiple meta-analyses consistently demonstrate significant associations between hyperuricemia and myocardial infarction, heart failure, stroke, and cardiovascular mortality [5-7]. However, observational studies remain susceptible to residual confounding. Hyperuricemia frequently coexists with obesity, insulin resistance, hypertension, chronic kidney disease, and systemic inflammation, making it difficult to determine whether serum uric acid independently contributes to atherosclerosis or simply reflects an adverse metabolic milieu. Current international guidelines appropriately acknowledge this uncertainty. The 2024 European Society of Cardiology Guidelines for the Management of Chronic Coronary Syndromes do not recommend routine treatment of asymptomatic hyperuricemia solely for cardiovascular prevention because convincing evidence that urate-lowering therapy reduces cardiovascular events remains lacking [8]. This distinction carries important clinical implications. Identification of an independent risk marker should not automatically be interpreted as evidence for a modifiable therapeutic target. Accordingly, the findings reported by Safi and colleagues should not be viewed as justification for initiating urate-lowering therapy solely to reduce coronary risk. Nevertheless, biomarkers need not be causal to have clinical value. Serum uric acid measurement is inexpensive, readily available, and routinely performed in clinical practice. Particularly in low- and middle-income countries, where access to advanced cardiovascular risk prediction tools may be limited, a simple laboratory parameter associated with angiographic disease burden could potentially complement existing risk assessment strategies [9]. Whether incorporation of serum uric acid into established cardiovascular risk prediction models meaningfully improves clinical decision-making remains an important question for future investigation. The findings should also be interpreted within the context of several important limitations. The cross-sectional design precludes conclusions regarding temporal sequence or causality, as exposure and outcome were assessed simultaneously. Consequently, it cannot be determined whether hyperuricemia precedes the development of coronary atherosclerosis or arises secondary to associated metabolic abnormalities. The single-centre setting and relatively modest sample size further limit generalizability. Although multivariable adjustment was performed for major cardiovascular risk factors, residual confounding related to renal function, diuretic use, dietary habits, insulin resistance, inflammatory status, and other metabolic variables cannot be completely excluded. These limitations are common to many observational studies evaluating serum uric acid and emphasize the need for cautious interpretation of the findings. Where, then, does this study fit within the existing body of evidence? Rather than resolving the longstanding debate surrounding hyperuricemia, it reinforces an increasingly consistent observation reported across diverse populations: individuals with elevated serum uric acid tend to exhibit more extensive and anatomically complex coronary artery disease. Whether serum uric acid functions as a direct mediator of atherosclerosis, an innocent bystander, or an integrated marker of adverse cardiometabolic health remains uncertain. Definitive answers will require large prospective cohort studies, Mendelian randomization analyses, and randomized clinical trials evaluating whether lowering serum uric acid translates into meaningful reductions in cardiovascular events. In conclusion, Safi and colleagues provide important evidence that hyperuricemia is independently associated with both the presence and anatomical severity of coronary artery disease in a Pakistani population. Their findings add to the growing body of literature supporting serum uric acid as a readily available marker of cardiovascular risk. At present, however, the available evidence favors interpreting hyperuricemia as an indicator of increased cardiovascular risk rather than as a proven therapeutic target. Future research should determine whether incorporation of serum uric acid into cardiovascular risk prediction models improves patient management and, more importantly, whether interventions aimed at lowering serum uric acid ultimately improve cardiovascular outcomes. References Borghi C, Agabiti-Rosei E, Johnson RJ, Kielstein JT, Lurbe E, Mancia G, et al. Hyperuricaemia and gout in cardiovascular, metabolic and kidney disease. Eur J Intern Med. 2020;80:1-11. DOI: 10.1016/j.ejim.2020.07.006 Padda J, Khalid K, Almanie AH, Al Hennawi H, Mehta KA, Wijeratne Fernando R, et al. Hyperuricemia in Patients With Coronary Artery Disease and Its Association With Disease Severity. Cureus. 2021;13(8):e17161. DOI: 10.7759/cureus.17161 Safi W, Saboor QA, Saleem S, Tufail QM, Muhammad A, Bukhari SHB. Association between Hyperuricemia and Angiographically Documented Coronary Artery Disease: A Cross-Sectional Observational Study. Pak Heart J. 2026;59(04):1041-1049. 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