Cardiovascular disease (CVD) represents a significant global health burden, contributing to a considerable proportion of deaths (1). Statistical data indicates that CVD is the underlying cause of one-third of all global deaths (2). Despite the long-standing focus on conventional CVD risk factors (e.g. hypertension, diabetes mellitus, high cholesterol, etc.), the incidence of both CVDs and cardiovascular deaths has continued to increase as the population continues to age, particularly in this elderly population group (3). In order to most effectively address this complex situation, investigators have progressively examined a number of previously overlooked emerging risk factors, with particular attention being paid to sarcopenia, specifically in relation to the understanding of muscle loss and frailty in patients with CVDs (4).

Sarcopenia is an age-related condition characterized by progressive and systemic musculoskeletal disorders, resulting in a loss of muscle quality and tone. It is a common occurrence in the elderly population and is associated with an increased risk of adverse outcomes (5). In addition to its effects on physical functioning and quality of life, sarcopenia is also associated with a range of meteorological abnormalities, including oxidative stress and chronic inflammation (6–8). Such anomalies are strongly linked to the onset, evolution and prognosis of a variety of chronic diseases (9, 10), particularly in light of the growing body of evidence examining their relevance to CVD health. In recent years, a substantial and continually increasing body of evidence has investigated the correlation between sarcopenia and conditions associated with CVD, including coronary heart disease, atrial fibrillation, heart failure, and stroke (11–14).

The diagnosis of sarcopenia necessitates a comprehensive evaluation encompassing muscle mass, strength, and physical performance. Conventionally employed metrics such as DXA, CT, BIA, and MRI, despite their efficacy in quantifying muscle mass, are encumbered by inherent limitations including the expense of equipment, the intricacy of operation, the challenge of dynamic monitoring, and the inability to facilitate early detection. While these metrics offer precise measurements of muscle mass, their application is hindered by factors such as the cost of equipment, the complexity of operation, the difficulty in dynamic monitoring, and the challenge in early detection (15, 16). There is an urgent requirement for the development of simple and cost-effective biomarkers for the diagnosis and surveillance of muscle loss disorders. In recent times, the creatinine-to-cystatin C ratio (CCR) has been put forth as a dependable surrogate for the evaluation of secondary muscle mass, given its accessibility and cost-effectiveness as a biomarker (17, 18). CCR is regarded as a promising predictor of sarcopenia, offering a number of advantages over traditional methods in terms of feasibility and affordability. Furthermore, studies have demonstrated a clear relationship between CCR and muscle mass (19, 20).

Despite the existence of research investigating the associations between sarcopenia and CVD, the majority of studies are based largely on cross-sectional analyses. Furthermore, there is considerable variation in the criteria used to determine sarcopenia, and the role of sarcopenia as an independent risk factor for CVD remains uncertain (12, 14, 21). With the gradual introduction of CCR as a biomarker for evaluating muscle mass and fiber, its potential in CVD disease risk evaluation ought to be investigated much further.

A plethora of prior studies have validated the standalone correlation of creatinine (Cre) and cystatin C (Cysc) with CVD. Nevertheless, there persists a dearth of substantial knowledge concerning the research on the ratio (CCR) of these two proteins. Firstly, extant literature has focused primarily on the analysis of individual markers (22, 23), neglecting to thoroughly explore the distinctive clinical significance that the CCR, as an integrative indicator, might offer. Secondly, there is a paucity of cross-sectional and longitudinal cohort studies that specifically emphasize the relationship between the CCR and CVD. The existing studies have led to an inadequate body of evidence to support causal inferences regarding its predictive value. It is imperative to note that, despite the theoretical possibility of a relationship between muscle metabolic status and CCR levels, no studies have been conducted to systematically assess the independent predictive role of CCR on CVD risk. This assessment would be based on controlling for conventional cardiovascular risk factors, including BMI, glucose, lipids, and renal impairment. The existence of these critical issues necessitates further validation of the value of CCR as a potential biomarker in clinical practice.

Consequently, the present study employs a combination of cross-sectional and longitudinal cohort studies, with full adjustment for confounders such as body mass index (BMI), triglycerides (TG), total cholesterol (TC), blood glucose (Glu), estimated glomerular filtration rate (eGFR), among others. This approach aims to comprehensively investigate the relationship between CCR and CVD. The objective is to validate the potential of CCR as an emerging biomarker for CVD prediction.

The results of this comprehensive study demonstrated a consistency between cross-sectional and longitudinal cohort studies. Baseline levels of CCR were observed to be lower in patients with CVD (p < 0.001). This study was the first to demonstrate that CCR continues to exhibit an independent association with cardiovascular risk, even after adjusted for conventional cardiovascular risk factors, particularly in those over 65 years of age. In other words, the risk of CVD increased as the level of CCR decreased, and vice versa, the risk of CVD was lower in those with higher levels of CCR. Restrictive triple spline analysis also validated this result. The present study confirmed for the first time the validity of CCR as a biomarker for assessing the prevalence of CVD. This finding has significant implications for the assessment of cardiovascular risk in the elderly population. Despite its inability to fully supplant imaging, CCR may serve as a viable primary screening instrument or a dynamic monitoring indicator, offering a novel approach to cardiovascular health management.

A growing body of evidence from numerous studies has demonstrated a correlation between sarcopenia and CVD, particularly in the elderly population (28, 29). Furthermore, sarcopenia has been identified as a risk factor for the progression of CVD (30). A population-based study of middle-aged and older Chinese adults with sarcopenia, defined as low levels of strength, mass and fitness, identified a strong link with an increased risk of CVD, including heart disease and stroke (21). However, the majority of studies have concentrated on either muscle mass or a single factor of muscular function, with no suitable metrics available for clinical assessment. In comparison, we introduced the CCR as a complex indicator that assesses the impact of muscular health on CVD risk in a more holistic manner. Thus, our study has provided a new rationale for further exploration in this area. As measurements of Cre and Cysc were clinically inexpensive and accessible, the CCR may be a prospective and time-efficient marker for identification of cardiovascular risk in individuals.

Cre, a metabolic by-product of muscle tissue, is typically eliminated by the kidneys through urine. Given its status as a by-product of muscle metabolism, the Cre concentrate is closely correlated with muscle mass. Cysc is a protein produced by nucleated cells and is primarily used as a marker of glomerular filtration rate (GFR), which is minimally affected by mass metabolism (31–35). Given the greater reliance of Cre levels on muscle mass than Cysc levels, the computation of the ratio of Cre to Cysc, which allows for a degree of correction for errors in a single marker due to aberrant renal function or changes in muscle mass, represents a more stable and reliable method for the evaluation of muscle mass (36).

In addition to reflecting bone and muscle mass, CCR may also serve as an indicator of an inflammatory state. In instances of chronic infection, the formation of Cre may be suppressed. Consequently, reduced levels of Cre are frequently associated with an inflammatory response (15). An elevated Cysc level is associated with an exacerbation of the inflammatory state. In addition to its role as a sensitive marker of renal function, Cysc is also a reliable indicator of the body’s overall inflammatory burden (37). Furthermore, CCR is indicative of chronic inflammation, with elevated CCR values correlating with heightened inflammatory negativity (38). Furthermore, inflammation has been demonstrated to be a pivotal factor in the development and progression of CVD, particularly in conditions such as atherosclerosis, coronary artery disease, and heart failure (39–42). Thus, fluctuations in CCR levels, particularly elevated Cysc, may indicate that the organization is in a state of chronic inflammation and that this may be associated with the onset and progression of CVDs.

While the present study focused on the cardiovascular predictive value of CCR, the potential impact of chronic kidney disease (CKD) as an important confounder is acknowledged. CKD has been identified as a risk factor for CVD (43), occupying a significant position within the complex network of pathophysiological processes associated with inflammation and CVD (44). Renal hypoplasia has been demonstrated to result in the accumulation of uremic retention molecules within the body (45), thereby inducing oxidative stress. Oxidative stress, in turn, has been shown to promote inflammatory cell recruitment through the activation of the NF-κB pathway (46). Concurrently, renal hypoplasia has been observed to induce vascular calcification and thickening of the aortic wall (47). These phenomena have been demonstrated to result in endothelial cell dysfunction and vascular smooth muscle cell dysfunction, thereby accelerating the pathogenesis of cardiovascular disease (45). This CKD-inflammation-CVD triad may partially explain the association between CCR and CVD in this study: Cystatin C, a GFR marker, exhibits elevated levels that directly reflect renal impairment (48); CKD-related muscle atrophy affects creatinine metabolism, thereby interfering with the interpretation of CCR (49). However, after adjusting for CRE-based eGFR, CCR maintained an independent association with CVD risk (OR=0.78, 95%CI:0.68-0.90), a robustness that suggests that the predictive value of CCR is not exclusively mediated by renal function and that muscle metabolism may influence CVD risk through pathways other than renal function (e.g., anti-inflammatory effects). This finding has the potential to generate novel concepts for the development of personalized cardiovascular risk assessment strategies for diverse renal function states.

The present study has several notable strengths. First and foremost, our findings indicated that CCR may offer a novel approach to the surveillance of CVD, particularly in the elderly population. To the best of our knowledge, this was the inaugural study to examine the correlation between CCR and CVD. Subsequently, we adjusted for a multitude of potential confounding variables to ensure robust results. Thirdly, the integration of cross-sectional data to establish correlations at a specific point in time and the incorporation of longitudinal data to elucidate the causal relationships served to reinforce the compelling nature of the findings. Nevertheless, it was imperative to recognize that our study was not without its inherent limitations. (i)Population limitations: As the study population was limited to Chinese older adults, the findings may not be applicable to other populations. (ii)Self-reporting bias: CVD diagnosis relied on self-reporting, and the absence of medical records may have affected the accuracy of the results. (iii) Selection bias: Subjects with missing Cre and Cysc data and incomplete CVD data were eliminated, which may cause bias in selection and restrict the application of the findings. It would be prudent to consider that such limitations may influence the prevalence and precision of the research results, and that additional research may be required to confirm them.

The results demonstrated that a relatively high CCR was associated with a reduced risk of CVD in middle-aged and elderly Chinese individuals. Given the extensive clinical utilization of Cre and Cysc, the CCR, as a cost-effective marker, may prove effective in identifying individuals at risk of CVD, thereby facilitating early intervention to slow the progression of CVD. However, further verification of these results and assessment of their suitability for use in a wider population are necessary.