PAD, the manifestation of atherosclerosis in lower extremity arteries, is a common cardiovascular condition linked to increased risks of amputation, myocardial infarction, stroke, and death (1). PAD is an established predictor of all-cause mortality and cardiovascular death. Current epidemiological evidence demonstrates that PAD significantly raises the risk of all-cause mortality, cardiovascular death, coronary artery disease, and cerebrovascular disease (2). The global burden of PAD affects more than 200 million people, corresponding to over 3% of the world’s population (3).

The CDAI developed by Wright et al. (4) is an integrative scoring system that measures cumulative antioxidant intake (including vitamins A, C, E, selenium, zinc, and carotenoids) from dietary sources. A higher CDAI has been associated with a reduced risk of multiple chronic conditions, including diabetes, chronic obstructive pulmonary disease (COPD), low back pain, and sleep disorders (5–8). Two additional studies have, respectively, identified inverse relationships between the CDAI and the probability of cardiovascular disease in general adult populations and postmenopausal women (9, 10).

However, no studies have investigated the association between CDAI and the prevalence of PAD. Therefore, we initiated cross-sectional research to explore the relationship between CDAI and PAD using data from the 1999–2004 NHANES.

In the cross-sectional study, we enrolled 2,332 representative participants and observed the negative relationship between CDAI and PAD. This suggests that higher levels of dietary antioxidants may be linked to a lower risk of developing PAD, particularly in high-risk populations with antioxidant deficiency.

Our results suggest that CDAI may have potential clinical value in the prevention of PAD. To our knowledge, this is the first population-based study to evaluate the association between CDAI and PAD, independent of traditional cardiovascular risk factors. By analyzing the NHANES database, Teng et al. (11) demonstrated a negative association between CDAI and stroke, with the antioxidant-based nomogram model showing strong predictive capability for stroke risk. Analogously, Ma et al. (12) demonstrated that the CDAI exhibited an L-shaped inverse association with the risk of coronary heart disease (CHD), reducing it by up to 65%. A study has also found that CDAI improves Atherosclerosis, Maugeri et al. (15) using the Kardiovize Brno 2030 study found that CDAI reduced carotid intima-media thickness (cIMT) in women. Consistent with the results of the previous study, CDAI is a protective factor against cardiovascular diseases. In this study, we found a negative relationship between the CDAI and PAD, indicating that individuals with high levels of dietary antioxidants may have a lower risk of developing PAD.

Atherosclerosis is a major cause of stenosis or occlusion of the arteries lumen in the lower extremities, affecting the blood supply to the lower extremities. Oxidative stress, inflammatory response, and lipid infiltration are the primary causes of atherosclerosis formation (16). Of these, reactive oxygen species (ROS), the primary byproducts of oxidative stress, initiate atherosclerosis by inducing endothelial dysfunction, chronic inflammation, and dysregulated lipid metabolism (17). Moreover, oxidative stress critically influences PAD progression by promoting vascular inflammation and endothelial dysfunction (18, 19). Oxidative stress results from the overproduction of reactive oxygen species (ROS) combined with impaired or inadequate antioxidant defense systems (20, 21). Animal and clinical studies indicate that oxidative stress drives the initiation and progression of PAD via diverse mechanisms. In animal models, experimental hindlimb ischemia (HLI) studies have shown that the generation of ROS is closely associated with angiogenesis, endothelial dysfunction, and inflammatory responses (22). Increased muscle ROS formation was found after ligation of unilateral iliac and femoral arteries (23). Moreover, ROS interferes with vascular endothelial growth factor (VEGF) mediated angiogenesis by decreasing nitric oxide (NO) bioavailability, thereby affecting the recovery of ischemic tissues (24). In addition, animal studies of cigarette smoke exposure have demonstrated that major risk factors for PAD, such as smoking and diabetes, further exacerbate inflammation by enhancing oxidative stress and decreasing NO bioactivity (25, 26). In terms of clinical studies, a cross-sectional analysis comparing blood markers in patients with type 2 diabetes with or without PAD found higher levels of AGEs and MDA (two biomarkers closely linked to oxidative stress), and lower levels of vitamin E and total reactive antioxidant potentials (TRAPs) in patients with PAD compared to those without PAD (27). A small clinical study (n = 74,12 months duration) noted that propionyl L-carnitine improved ABI, maximum walking distance, pre-morbid walking distance, and quality of life in patients (28).

The key antioxidants included in the CDAI—such as carotenoids, vitamins A, C, E, and essential trace metals (e.g., Zn, Se)—exert protective effects against oxidative stress through diverse mechanisms. Vitamin C is a water-soluble compound generated through glucose metabolism (29, 30). It synthesizes the reducing agents needed for collagen fibers, and it also protects the body from free radicals. Moreover, Vitamin C has been demonstrated to ameliorate oxidative stress through the modulation of key signaling pathways (31). Carotenoids are structurally similar to vitamin A (32). They may be involved in antioxidant protection against oxidative free radical attack (33). Some studies indicate that vitamin A and carotenoids are potent antioxidants that may inhibit the development of cardiovascular diseases and enhance visual health (34, 35). They can impact both free radicals and peroxyl radicals. Vitamin E, as an essential nutrient that can only be ingested exogenously, is a fat-soluble vitamin group present in high concentrations throughout the body, including cell membranes and cytoplasmic proteins, and is involved in regulating the body’s redox balance (36). Numerous studies have demonstrated that Vitamin E exhibits anti-atherosclerotic and anti-cardiovascular effects (37, 38). The trace element selenium (Se) is regarded as a beneficial dietary supplement due to its significant antioxidant capabilities and function of enhancing health (39). Amino acids, peptides, and enzymes are selenium-containing compounds, also playing crucial biological roles in the human body (40). Selenium and its derivatives, especially selenoproteins containing selenocysteine form selenium, have been shown to have antioxidant properties (41). Zn(II), Cu(I), and iron, the metal thiolate groups, also function as redox switches (42), serving as crucial and irreplaceable elements in the reaction pathway.

However, the US Preventive Services Task Force (USPSTF) found through a systematic review of RCTs that current evidence is insufficient to evaluate the balance of benefits and risks of using single or combined nutritional supplements for the prevention of certain diseases (43). Findings from retrospective research also support similar conclusions (44, 45).

Although the effects of single nutrients are not significant or insufficiently supported by evidence, some studies have found that the Mediterranean diet, rich in antioxidant components, is linked to a lower risk of cardiovascular disease and PAD (46). The Mediterranean Diet is predominantly plant-based, particularly in fruits, vegetables, legumes, and nuts, which are abundant in antioxidants such as vitamin A, C, E, polyphenols and others (47). The Mediterranean diet has been used for the prevention of cardiovascular diseases, including peripheral arterial disease and ischemic stroke. The Mediterranean diet was found to be superior to a low-fat diet in the prevention of cardiovascular events, including peripheral arterial disease, myocardial infarction, and ischemic stroke, in a 1,000-person RCT, supporting the secondary prevention of cardiovascular disease through the Mediterranean diet (48). Additionally, an exploratory, non-prespecified analysis of a large-scale randomized controlled trial revealed that the Mediterranean diet, characterized by an unrestricted energy intake and rich in antioxidants, significantly reduces the prevalence of PAD, underscoring its value in cardiovascular disease prevention (49, 50).

Interestingly, as depicted in Figure 4, our study revealed a potential differential benefit of antioxidant dietary intake across sex and age groups. Specifically, female participants and individuals under 65 years of age exhibited a more pronounced reduction in PAD risk with increasing CDAI levels. Accumulating evidence indicates that female sex hormones, particularly estrogen, exert multifaceted atheroprotective effects (51). A prospective study on oxidative balance scores and hypertension also observed similar sex-specific differences and demonstrated that it may be mediated by oxidative stress mechanisms (52). In elderly individuals, advanced age drives vascular aging process. It includes oxidative stress, endothelial dysfunction, and progressive arterial stiffening, which collectively may compromise the efficacy of antioxidant interventions (53). Therefore, this may raise different guidelines for the prevention of PAD in people of different genders and ages. For instance, premenopausal women or middle-aged people at risk of PAD might benefit from a diet plan that emphasizes foods high in antioxidants, while older populations may require adjunct therapies to overcome age-related declines in antioxidant absorption or utilization.

This study has several advantages. Firstly, this study is grounded in data extracted from the NHANES, which employs a randomized and scientifically rigorous sampling methodology. This approach ensures that the selected cohort reflects the demographic diversity of the US population, providing a robust representation of the US population’s health and nutritional status. Additionally, this study benefits from a substantial sample size, enhancing statistical precision and reliability. Additionally, we also adjusted for a large number of covariates to make the results more independent and more credible. Nevertheless, the limitations of this study must be acknowledged. Firstly, due to the cross-sectional study design, the authors were unable to establish clear causal relationships. Secondly, dietary information was self-reported, which may introduce inaccuracies due to recall bias. Moreover, due to the NHANES study protocol, which excluded individuals aged below 40 years from screening for these variables, the association between CDAI and PAD could not be comprehensively evaluated across a broader demographic spectrum.

In conclusion, our study demonstrates that CDAI is inversely associated with PAD in U. S. adults aged ≥40 years. Moreover, this association remained consistent across all subgroups, supporting the potential role of antioxidant-rich diets (reflected by higher CDAI scores) in PAD prevention in the general population. However, further comprehensive research and prospective cohort studies are needed to explore causal relationships and validate these findings.