This population-based study aimed to investigate the association of dietary antioxidants (measured by DAI and DAQ scores) and CVD risk. According to our findings, the risk of CVDs can be minimized by boosting the amount of antioxidants in an individual’s diet.
Oxidative stress contributes to the development of a wide range of diseases, among which those related to atherosclerosis can be mentioned. Atherosclerosis is a vascular disorder that develops as a result of chronic inflammation, with oxidized low-density lipoprotein (oxLDL) and endothelium dysfunction, which have vital roles in its pathogenesis. The progression of atherosclerosis is signaled by oxLDL aggregation in the arterial wall (22). It is known that oxidative stress and inflammatory activity are associated with oxLDL accumulation and endothelial dysfunction (Li and Yang, 2018). Hence, it is plausible that by minimizing the generation of free radicals, CVDs like atherosclerosis can be prevented and treated (Lorenzon dos Santos et al., 2020).
Various nutritional antioxidants work against atherosclerosis, either by promoting endogenous antioxidant activity or directly scavenging free radicals (Lönn et al., 2012). Some examples are selenium, zinc, vitamins C and E, manganese, flavonoids, and carotenoid compounds. While most studies have looked at the health-promoting effects of these nutrients in isolation, few have investigated their combined impacts within different diets (LuuHung, 2015). When combined, dietary antioxidants may interact to provide various overall effects, which is why tools like the DAI and DAQ have been designed and implemented (Vahid et al., 2020). Some studies have assessed the relationship of the DAI with the TAC and markers of inflammation (Vahid et al., 2020, LuuHung, 2015). Notably, scores related to dietary antioxidant content as evaluated by these tools were inversely related to the levels of inflammatory factors like IL-1β and TNF-α, explaining the possible biochemical pathway through which an antioxidant-rich diet can lead to improved health outcomes like decreased mortality and CVD risk (LuuHung, 2015).
Micronutrients and cardiovascular diseases
Although it is known that selenium acts as a cofactor of antioxidative enzymes like glutathione peroxidase (GSH-Px), its cardioprotective impact remains a matter of controversy. One study observed a 24% fall in CVD risk with a 50% rise in blood selenium levels (Flores-Mateo et al., 2006). Nonetheless, selenium offers no significant protection against all-cause mortality, CVD mortality, or adverse cardiovascular events, according to meta-analyses and systematic reviews (Cammisotto et al., 2021, Rees et al., 2013, Flores-Mateo et al., 2006). Jenkins et al. concluded that the inclusion of this mineral in an antioxidative diet was important to promote cellular antioxidant activity if antioxidative supplements were to provide their health-promoting effects (Jenkins et al., 2020).
Zinc is another nutritional element that may provide antioxidative activity. The presence or absence of zinc may affect oxidative stress-related atherosclerotic processes such as disturbed NO and NF-κB-related signaling, impaired endothelial functioning, and oxidative low-density lipoprotein (LDL) modification (Choi et al., 2018). A deficiency in zinc has been cited as a contributor to atherosclerosis in some studies, with an inverse relationship being found between atherosclerosis and the serum zinc/24-h urine zinc loss ratio (Giannoglou et al., 2010). A low intake of zinc has been associated with greater carotid intima-media thickness (CIMT) in some adults(Choi et al., 2018). Another study proposed that zinc should be used as a biological marker of cardiovascular health due to its impacts on homeostasis (Knez and Glibetic, 2021). In contrast, one of the latest meta-analyses on preventive interventional trials found that zinc exerted no remarkable impact on CVD prevention (Schwingshackl et al., 2017).
Manganese is another dietary mineral that may affect the course of atherosclerosis; however, limited data are available. One study reported that normal and atherosclerotic aortic tissues were similar in terms of manganese content(Li and Yang, 2018). On the other hand, epidemiologic research indicates increased serum manganese concentrations in individuals with atherosclerosis (Rambousková et al., 2013, Ilyas and Shah, 2016). It appears that manganese is essential at trace levels, whereas excessive concentrations are toxic. In fact, some have suggested a U-shaped association of manganese with the generation of ROS, oxidative stress, and the associated diseases (Li and Yang, 2018). However, further biomolecular and population-based data are needed to confirm such theories.
According to a number of studies, vitamin C exerts a positive effect in minimizing CVD risk (Cammisotto et al., 2021). At doses above 500 mg/day, this vitamin was found to positively affect endothelial function, with its effect being more pronounced among individuals at greater risk of CVD (i.e., those with heart failure, diabetes mellitus, or atherosclerosis) (Ashor et al., 2014). Furthermore, cardiovascular risk factors such as cigarette use and diabetes mellitus have been associated with low blood levels of vitamin C (Toledo-Ibelles and Mas-Oliva, 2018).
Vitamin E acts as a potent antioxidant and has eight stereoisomers. One of them, α-tocopherol, shows bioactivity in the human body. Supplementation with this vitamin for preventing CVDs remains a matter of controversy. A meta-analysis of 16 clinical trials found that vitamin E supplementation markedly reduced the rate of myocardial infarction in the treated subjects compared to controls (Loffredo et al., 2015). In population-based studies, at similar blood cholesterol levels, increased dietary vitamin E has been consistently linked with greater plasma antioxidant levels and decreased CVD risk (Lönn et al., 2012). Nonetheless, a meta-analysis of 15 trials with 188,209 individuals revealed that vitamin E, β-carotene, and vitamin C supplementation revealed no protective effects against the occurrence of major cardiovascular events, myocardial infarction, cerebrovascular accidents, all-cause mortality, and cardiac mortality (Cammisotto et al., 2021).
Retinoic acid or vitamin A1 is involved in cardiogenesis signaling, with some evidence also indicating an association between this vitamin and CVDs. A study in Finland on an adult male population found that decreased levels of β-carotene, as a precursor to vitamin A, were linked with a higher rate of cardiovascular deaths, particularly in cigarette smokers (Karppi et al., 2012). Another study linked lower blood retinoic acid concentrations with a higher risk of death among coronary artery disease patients (Liu et al., 2016). In contrast, the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) long-term (five to eight years) cohort study on 23,144 male smokers found that α-tocopherol (50 mg per day) and/or β-carotene (20 mg per day) supplementation exerted no impact on the occurrence of myocardial infarction or cardiovascular-related death (Lee et al., 1999).
Dietary antioxidant indices and risk of non-communicable diseases
The DAQ and DAI contain the six most potent dietary antioxidants. These antioxidants have been investigated alone and in combination with each other and with alternative micronutrients to determine their effects on CVD, tbut few studies have made use of the mentioned antioxidant indices. Here, we will briefly discuss our results in relation to the related literature.
According to a multi-adjusted model, the DAI had a significant effect on minimizing CVD risk (Vahid et al.). Furthermore, one investigation examined the relationship of the DAQS with cardiovascular fitness and blood pressure, revealing a marked rise in maximum oxygen uptake when moving from the lower to upper DAQS tertiles with and without adjusting for confounding variables. It also showed a non-significant increase in blood pressure in the top DAQS tertile, after adjusting for confounders(Shahinfar et al., 2020a). Anotherinvestigation established a significant association between gastric neoplasms and poor dietary antioxidant indices, highlighting the need for nutritional antioxidants (Vahid et al., 2020). Furthermore, another study found that the risk of multiple sclerosis was double in individuals with low DAI values. That study found an important dose-response pattern, concluding that adequate dietary antioxidant intake might reduce the risk of developing multiple sclerosis (Abdollahpour et al., 2020). Finally, lower odds of having non-alcoholic fatty liver disease were associated with higher DAI values with and without adjustments for confounding variables (Vahid et al., 2021a). These results highlight the same pattern as that observed in our study, indicating that dietary antioxidants work together to reduce the risk of many non-communicable diseases.
One limitation of our study is the indices; we did not consider some of non-nutritive antioxidant like carotenoids or polyphenols with anti-oxidant properties and just considered some major antioxidants. Another limitation was the cross-sectional design of the study of the baseline data collection for a population-based cohort, that cannot represent causal effects of the variables.