Cardiovascular diseases (CVDs) remain a major health challenge globally, contributing significantly to morbidity and mortality rates worldwide. Among the various forms of CVD, atherosclerotic cardiovascular disease (ASCVD) stands out as a leading cause of myocardial infarction, stroke, and related complications. It is a complex and multifactorial condition influenced by genetic, environmental, and lifestyle factors. As the prevalence of ASCVD increases, properly understanding the intricate interplay between these factors becomes imperative for the development of effective preventive strategies.
One of the key lifestyle factors that has garnered substantial attention in recent years is dietary habits. New evidence suggests that the composition of one’s diet plays a pivotal role in ASCVD pathogenesis. In particular, dietary antioxidants, which are found abundantly in fruits, vegetables, and various other food sources, have been investigated for their potential protective effects against oxidative stress, inflammation, and atherosclerosis. Antioxidants are known to combat the damaging effects of free radicals, which are implicated in the development and progression of atherosclerotic lesions within arterial walls.
However, while numerous studies have explored the relationship between dietary antioxidants and ASCVD, the unique dietary patterns of different populations may result in varying associations between dietary antioxidants and ASCVD. Thus, there is a pressing need for region-specific investigations that shed light on the role of dietary antioxidants in the context of ASCVD.
This article delves into the intricate relationship between diet-derived antioxidants, circulation, and the risk of coronary heart disease, drawing upon a range of studies and analyses to provide a comprehensive understanding of this complex interplay.
The Multifactorial Nature of Atherosclerotic Cardiovascular Disease
The multifactorial nature of atherosclerotic cardiovascular disease (ASCVD) implicates genetic, environmental, and dietary habits. ASCVD stands out as a leading cause of myocardial infarction, stroke, and related complications. As the prevalence of ASCVD increases, properly understanding the intricate interplay between these factors becomes imperative for the development of effective preventive strategies.
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Cardiovascular disease (CVD) is among the most widely known causes of death (1), accounting for approximately one-third of the deaths around the globe. Moreover, some of the risk factors for CVD include hypertension, dyslipidemia, hyperinsulinemia, hyperglycemia, insulin resistance, and central adiposity (2). Increasing research studies demonstrate that oxidative stress and inflammatory status are closely related to CVD (3-5). Other modifiable risk factors for CVD include diet, physical inactivity, stress, and smoking.
The Role of Oxidative Stress and Antioxidants in CVD
Cardiovascular diseases are closely linked to oxidative stress, which arises when the production of reactive oxygen species (ROS) exceeds the cellular antioxidant system’s ability to neutralize them. This imbalance leads to cellular and molecular abnormalities, ultimately resulting in cardiac dysfunction4. Additionally, oxidative stress is implicated in the occurrence of arrhythmias. Reactive oxygen species can induce local electrical activity and re-entry, alter cardiac ion currents, promote myocardial fibrosis, and impair gap junction function. These changes reduce coupling between myocardial cells and facilitate re-entry, ultimately leading to the development of arrhythmias5. Oxidative stress is a key factor in the development of atherosclerosis, vascular inflammation, and endothelial dysfunction in vascular pathology 6. It contributes to the cardiovascular disease by affecting various elements of the heart and vasculature.
Oxidant stress in the cardiovascular system may occur when antioxidant capacity is insufficient to reduce reactive oxygen species and other free radicals. Oxidant stress has been linked to the pathogenesis of atherosclerosis and incident coronary artery disease. As a result of this connection, early observational studies focused on dietary antioxidants, such as β-carotene, α-tocopherol, and ascorbic acid, and demonstrated an inverse relationship between intake of these antioxidants and major adverse cardiovascular events. These findings supported a number of randomized trials of selected antioxidants as primary and secondary prevention to decrease cardiac risk; however, many of these studies reported disappointing results with little or no observed risk reduction in antioxidant treated patients. Several plausible explanations for these findings have been suggested, including incorrect antioxidant choice or dose, synthetic versus dietary antioxidant as the intervention, and patient selection, all of which will be important to consider when designing future clinical trials.
Antioxidants alleviate oxidative stress by reducing reactive oxygen species (ROS) or enhancing the effectiveness of the antioxidant defense system. Research indicates that vitamin C, due to its antioxidant properties, may provide protective benefits against cardiovascular diseases, particularly by mitigating oxidative and nitrosative stress as well as inflammation induced by doxorubicin, thereby improving cardiac structure and function. Furthermore, a dose-response meta-analysis suggests that as the intake and circulating concentrations of vitamin C increase, the risk of mortality from cardiovascular disease decreases. Additionally, α-tocopherol may have a protective effect against cardiovascular diseases.
Dietary Antioxidants and Their Potential Benefits
Antioxidants found in foods have garnered attention for their potential role in mitigating ASCVD risk by combating oxidative stress. Helping patients lower their risk of coronary artery disease remains an important task for family physicians. Typically, the focus has been on the reduction of risk factors by controlling plasma lipid levels, blood pressure and weight. However, recent advances in the understanding of atherosclerosis have suggested that dietary antioxidants may play a role in preventing primary or secondary coronary artery disease. Specifically, antioxidants may inhibit proatherogenic and prothrombotic events in the coronary arterial wall. Antioxidants derived from dietary sources, including vitamins C and E, and beta-carotene, have received the greatest attention with regard to prevention of coronary artery disease. Many food sources contain antioxidants (see the accompanying table). Foods that contain α-tocopherol (vitamin E) and beta-carotene are of particular interest, as both of these substances are carried within low-density lipoproteins.
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Including multiple dietary antioxidants such as manganese, zinc, selenium, and vitamins A and C, the Composite Dietary Antioxidant Index (CDAI) serves as a summary score for reflecting the antioxidant profile of individuals. CDAI was constructed in accordance with their aggregate anti-inflammatory impact based on markers like tumor necrosis factor-α and interleukin-1β (10). In addition, because of their critical role in most diets worldwide, interest in the health effects of dietary total antioxidant capacity (TAC) is increasing. Epidemiological and experimental studies have indicated the correlation between high individual dietary antioxidant intake and reduced cancer risk. However, the effects of combined dietary antioxidants on the risk of all-cause and cardiovascular mortality remain unclear.
The Composite Dietary Antioxidant Index (CDAI)
The composite dietary antioxidant index (CDAI) to represent dietary antioxidants. This index is a measure of individual antioxidant profiles derived from dietary combinations, developed to assess and reflect the overall impact of dietary antioxidants on health. The CDAI can reflect an individual’s profile and can indicate a person’s overall dietary antioxidant intake. It is designed based on the demonstrable anti-inflammatory efficacy of dietary antioxidants according to their ability to attenuate inflammatory factors such as tumor necrosis factor-α and interleukin-1β. The KNHANES includes zinc, beta-carotene, vitamin A, vitamin C, vitamin E, and docosahexaenoic acid as frequently consumed antioxidants.
To estimate CDAI, we standardized each of the same six dietary vitamins and minerals (vitamins A, C, and E, selenium, manganese, and zinc from food only) by subtracting the global mean and dividing by the global standard deviation.
Findings from the Korea National Health and Nutrition Examination Survey (KNHANES)
Herein, we aimed to validate the findings of previous research by conducting a large-scale cross-sectional analysis using data from the Korea National Health and Nutrition Examination Survey (KNHANES), spanning the years from 2016 to 2021. We assessed the association between the CDAI and the prevalence of ASCVD among middle-aged and older individuals in South Korea. By analyzing this extensive dataset, we aim to provide valuable insights into the potential impact of dietary antioxidant intake on the risk of ASCVD in the South Korean population.
This study includes data from 2016 to 2021. The CDAI was calculated based on nutrition intake, including zinc, beta-carotene, vitamin A, vitamin C, vitamin E, and docosahexaenoic acid. This cross-sectional analysis explored the relationship between the CDAI and ASCVD after adjusting for relevant covariates. Logistic regression models were employed, and subgroup analyses by sex were conducted to discern sex-specific effects.
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A total of 19,818 individuals were analyzed, with 7.0% of them diagnosed with ASCVD. CDAI distribution and antioxidant analyses revealed higher CDAI levels in non-ASCVD individuals. Standardized antioxidant values increased across CDAI quartiles. Initially, a significant association (odds ratio [95% confidence interval]: 0.96 [0.94-0.99]) was found between the CDAI and ASCVD, which was attenuated after adjusting for covariates (1.0 [0.98-1.02]). Subgroup analyses by sex showed nuanced associations, with the CDAI potentially reducing the risk of ASCVD in men (0.71 [0.53-0.94]) while increasing it in women (1.4 [1.01-1.95]).
Mendelian Randomization Studies: Examining Causal Relationships
Current research on the effects of circulatory antioxidants on cardiovascular diseases presents contradictory and inconsistent results. Nevertheless, most existing studies are observational and prone to various confounding factors, leading to unclear causal relationships. This study employs Mendelian randomization(MR), a genetic approach, to evaluate the causal effects of five circulatory antioxidants-vitamin A, beta-carotene, vitamin C, α-tocopherol, and lycopene-on cardiovascular diseases. This methodology mitigates the influence of confounding variables, thereby clarifying causal relationships. This research aims to establish a foundational understanding of the causal effects of antioxidants on the cardiovascular system, with the goal of inform the development of more effective cardiovascular disease .Materials and methodsStudy design overviewThis study employs a two-sample Mendelian randomization analysis of summary-level genome-wide association data to investigate potential causal links between dietary antioxidants (α- and γ-tocopherols, ascorbic acid, retinol, β-carotene, and lycopene) and five cardiovascular diseases: (arrhythmia, cardiomyopathy, heart failure, myocardial infarction, pericarditis, angina pectoris and coronary atherosclerosis). We analyze absolute levels of dietary antioxidants in the bloodstream and the relative concentrations of circulating antioxidant metabolites in plasma or serum, representing two distinct phenotypes.
Our analysis indicates that genetically elevated absolute retinol levels may be associated with an increased risk of cardiomyopathy (OR: 6.38; 95% CI: 1.23-33.20; P = 0.028, Fig. 1.b) heart failure (OR: 2.26; 95% CI: 1.01-5.07; P = 0.047, Fig. 1.c) We also found that elevated genetic levels of absolute retinol may be associated with an increased risk of angina pectoris (OR: 1.34; 95% CI: 0.82-2.21; P = 0.244, Fig. 1.f) and coronary atherosclerosis (OR: 1.32; 95% CI: 0.81-2.15; P = 0.257, Fig. 1.g) .within the UK Biobank cohort. Following Bonferroni correction, the FinnGen study revealed that genetically elevated absolute α-tocopherol levels significantly correlate with a heightened risk of myocardial infarction (OR: 5.10; 95% CI: 2.92-8.91, P < 0.001, Fig. 1.b)、cardiac arrhythmias (OR: 1.94, 95% CI 1.34-2.83; P = 0.001, Fig. 1.a), angina pectoris(OR:5.42; 95% CI: 2.23-13.17; P < 0.001, Fig. 1.f), and coronary atherosclerosis(OR: 6.13; 95% CI: 2.83-12.98; P < 0.001, Fig. 1.g). A meta-analysis of the UK Biobank and FinnGen studies demonstrated that absolute α-carotene significantly contributes to the risk of cardiac arrhythmias (OR; 2.00; 95% CI; 1.39-2.86; P < 0.001, Fig. 1.a) and myocardial infarction (OR; 4.81; 95% CI; 2.84-8.15; P < 0.001, Fig. 1.d). Additionally, our meta-analysis identified a suggestive pathogenic effect of retinol on cardiomyopathy (OR, 3.49; 95% CI, 1.25-9.77; P = 0.017, Fig. 1.b), α-tocopherol is significantly associated with angina pectoris (OR: 4.33; 95% CI: 2.07-9.09; P < 0.001, Fig. 1.f) and coronary atherosclerosis (OR: 5.34; 95% CI: 2.81-10.12; P < 0.001, Fig. 1.g).
Our analysis of the UK Biobank data reveals significant evidence that genetically elevated ascorbate metabolite levels correlate with an increased risk of cardiomyopathy (OR, 1.31; 95% CI, 1.09-1.57; P = 0.004, Fig. 2.b). Moreover, In the FinnGen study, γ-tocopherol was significantly associated with an increased risk of angina pectoris(OR: 1.29; 95% CI: 1.09-1.52; P = 0.003,Fig. 2.f), However no significant association was found in the UK Biobank or in the meta-analysis.
This study employed the UK Biobank and FinnGen databases to explore the genetic links between antioxidant metabolites and cardiovascular diseases. Our findings indicate that elevated genetically influenced retinol levels correlate with an incresed risk of cardiomyopathy and heart failure. The FinnGen study revealed that genetically elevated absolute α-tocopherol levels, after Bonferroni correction, are significantly associated with a higher risk of myocardial infarction, cardiac arrhythmias, angina pectoris and coronary atherosclerosis. A meta-analysis of UK Biobank and FinnGen data demonstrated that absolute α-carotene definitively contributes to the pathogenesis of cardiac arrhythmias and myocardial infarction. And α-tocopherol is significantly associated with angina pectoris and coronary atherosclerosis.
Limitations and Considerations
The present research has certain limitations. It is an observational study that did not have data that highlighted the use of any dietary supplements and behavioral (physical activity and sleep) changes. The diagnosis of CVD based on the self-reports from participants, this may lead to discrepancies from the actual situation.
Although these epidemiological studies generated excitement regarding the protective benefit of antioxidants, when considered together it is clear that they have a number of limitations that may have influenced the outcomes.
During aging, different levels of cell injury can be caused as a result of oxidative reactions, thus mediating the pathogenesis of chronic diseases, such as CVD, atherosclerosis, and cancer. As an external contributor, diet can regulate the plasma redox state and protect against reactive oxygen and nitrogen species. Dietary TAC has an impact on the population with a cardiometabolic risk profile (17-19). An evaluation of the link between dietary TAC and CVD risk factors based on a systematic review of observational studies revealed inverse relationships for fasting blood sugar, blood pressure, C-reactive protein, and waist circumference and positive relationships for high-density lipoprotein cholesterol (20).
Conflicting Evidence and the Need for Further Research
However, some studies have not found vitamin E to exhibit a preventive effect on cardiovascular diseases11, and Gilbert et al.12 reported that beta-carotene and vitamin A, which are common antioxidants, neither reduced the risk of cardiovascular disease nor prevented potential adverse effects.
The somewhat encouraging findings from observational studies were used as the basis to support a number of randomized primary and secondary prevention clinical trials. The primary prevention Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) study examined cardiovascular disease as a secondary outcome in 29,133 male smokers randomized to α-tocopherol, β-carotene, a combination of the two, or placebo. At 8 years follow-up, neither antioxidant was found to decrease cardiovascular disease [23-25]. Similarly, the Beta-Carotene and Retinol Efficacy Trial (CARET) was terminated early after finding that β-carotene and retinol (vitamin A) had no effect on incident cardiovascular disease [26,27]. Similarly, negative findings were also reported in the Vitamin E Atherosclerosis Prevention Study (VEAPS). This study randomized 353 participants with elevated LDL cholesterol levels (>130 mg/dL) to α-tocopherol or placebo and examined intima-media thickness every 3 months for up to 3 years.
tags: #diet #derived #antioxidants #circulation #and #coronary