Proteomics in cardiology: research and practice.

Application of multi-omics analysis in atherosclerosis

Atherosclerosis is a leading global cause of disability and mortality, with a rising trend of early onset across populations. Its pathogenesis is multifactorial, encompassing multiple interconnected pathways including dyslipidemia, inflammation, and immune dysregulation. Current therapeutic strategies targeting lipoproteins are insufficient to address disease progression, and there remains an urgent unmet clinical need to further elucidate its pathogenic mechanisms, refine diagnostic approaches, and identify novel therapeutic targets. In recent years, the vigorous development of omics technology has provided help for in-depth investigation of the pathogenesis of diseases and search for new diagnosis and treatment targets. The application of multi-omics analysis has elevated atherosclerotic research to a new tier, yielding high-quality findings that further unravel atherogenic molecular mechanisms. These findings provide critical theoretical and translational groundwork for developing novel diagnostics, targeted therapies, and robust early risk stratification tools. In this review, we summarize integrated multi-omics applications in atherosclerosis, and outline novel perspectives for prospective therapeutic strategies. 

MASLD and Cardiovascular Risk: Mechanisms and Implications for Clinical Practice

Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly recognized as a systemic cardiometabolic disease. This review summarizes recent advances in epidemiology, pathophysiology, biomarkers, and treatment relevant to cardiovascular risk assessment and management. Fibrosis stage is the strongest independent predictor of cardiovascular outcomes in MASLD, conferring up to a 2.5-fold increase in events beyond traditional risk factors. Noninvasive tools, including Fibrosis-4 (FIB-4) and liver stiffness measurement, also predict cardiovascular mortality. Semaglutide and resmetirom offer dual hepatic and cardiometabolic benefits. MASLD affects 38% of adults globally, and cardiovascular disease (CVD) is the leading cause of death across disease stages. Fibrosis-based risk stratification remains absent from standard cardiovascular risk models despite its prognostic value. Therapies with combined liver and cardiovascular benefits are promising, but whether improving liver disease reduces cardiovascular events remains uncertain.

Dyslipidaemia: Pathophysiology, Epidemiology, Diagnostic Advances, and Emerging Therapeutic Strategies

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

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. DOI: 10.47144/phj.v59i4.3741 Ndrepepa G. Uric acid and cardiovascular disease. Clin Chim Acta. 2018 Sep;484:150-163. DOI: 10.1016/j.cca.2018.05.046 Kuwabara M, Bjornstad P, Hisatome I, Niwa K, Roncal-Jimenez CA, Andres-Hernando A, et al. Elevated Serum Uric Acid Level Predicts Rapid Decline in Kidney Function. Am J Nephrol. 2017;45(4):330-7. DOI: 10.1159/000464260 Cui K, Song Y, Yin D, Song W, Wang H, Zhu C, et al. Uric acid levels, number of standard modifiable cardiovascular risk factors, and prognosis in patients with coronary artery disease: a large cohort study in Asia. J Am Heart Assoc. 2023;12:e030625. DOI: 10.1161/JAHA.123.030625 Yu J, Han J, Mao J, Guo L, Gao W. Association between serum uric acid level and the severity of coronary artery disease in patients with obstructive coronary artery disease. Chin Med J (Engl). 2014;127(6):1039-45. Vrints C, Andreotti F, Koskinas KC, Rossello X, Adamo M, Ainslie J, et al. 2024 ESC Guidelines for the management of chronic coronary syndromes. Eur Heart J. 2024;45(36):3415-537. DOI: 10.1093/eurheartj/ehae177 Goodarzynejad H, Anvari MS, Boroumand MA, Karimi A, Abbasi SH, Davoodi G. Hyperuricemia and the presence and severity of coronary artery disease. Lab Med. 2010;41(1):40-45. DOI: 10.1309/LMKDB9PBKZGUS20T

Beyond Traditional Risk Factors: The MAINER Approach to Atherosclerotic Cardiovascular Disease

Recent studies have increasingly shown that cardiovascular risk cannot be adequately explained by isolated biomarkers alone. Among emerging metabolic markers, the triglyceride-glucose (TyG) index and its anthropometric derivatives have demonstrated promising associations with coronary slow flow phenomenon, highlighting the importance of metabolic dysfunction in cardiovascular disease. 1 Atherosclerotic cardiovascular disease results from the interaction of insulin resistance, central adiposity, systemic inflammation, endocrine dysfunction, and nutritional status rather than from isolated metabolic abnormalities. 2,3 This complexity has stimulated the development of composite indices that integrate biomarkers from different biological domains, although most currently focus on only a limited number of pathways. Furthermore, the TyG index has recently been shown to independently predict major adverse cardiovascular and cerebrovascular events in a large prospective cohort of nondiabetic individuals, reinforcing its role as a clinically relevant metabolic risk marker. 4 Similarly, in our study of patients with decompensated heart failure admitted to the coronary intensive care unit, the C-reactive protein (CRP)-TyG index (CTI) was identified as a predictor of in-hospital mortality. 5 These findings suggest that a single biochemical or clinical index may not adequately capture the complexity of cardiovascular disease. In addition to these parameters, incorporating body shape-related characteristics may further improve patient evaluation. Composite indices that simultaneously assess inflammatory burden, metabolic status, anthropometric characteristics, and endocrine balance may

Obesity, lipids, inflammation, and healthy aging.

Cardiovascular disease (CVD) is the leading cause of death and disability globally. Thus, prevention efforts aimed at reducing CVD events allow for greater functional independence and wellbeing over the course of life. Low-density lipoprotein-cholesterol is causally associated with atherosclerosis and is the primary target for atherosclerotic CVD (ASCVD) prevention. More recently, low-grade systemic inflammation has been recognized for its role in atherosclerotic disease initiation and progression. Additionally, there is compelling evidence for combined assessments of lipid and inflammatory biomarkers to predict long-term CVD events and guide prevention efforts early in life. In the context of CVD prevention, there have also been population shifts in CVD risk factor prevalence. Obesity prevalence has increased drastically over the last three decades, contributing to disability, lower life expectancy, and higher risk of CVD through multiple mechanisms. Specifically, obesity leads to a more atherogenic lipid profile and higher levels of systemic inflammation. The purpose of this review is to synthesize available literature on the interplay between obesity, dyslipidemia, and inflammation with CVD and how optimization of these risk factors is critical for healthy aging and longevity.