Dietary Flavonoids: Mitigating Air Pollution’s Cardiovascular Risks

Air pollution significantly impacts cardiovascular health, yet pollution reduction strategies in cardiovascular disease prevention remain limited. Dietary flavonoids show promise in protecting cardiovascular health, but their potential to mitigate air-pollution-induced risks is unexplored. This study investigates this research gap. Following PRISMA-ScR guidelines, literature from 2014–2024 was searched across MedLine/PubMed, ScienceDirect, and MDPI databases. Of 463 identified studies, 53 were eligible for analysis based on PICO criteria. Findings revealed significant impacts of air pollution on cardiovascular health, including increased disease risks and mortality. Flavonoid intake demonstrated protective effects against these risks. Flavonoid mechanisms include improved endothelial function, antioxidant and anti-inflammatory effects, blood pressure regulation, antiplatelet effects, cardioprotection, and enhanced lipid and glucose metabolism. Higher flavonoid intake was consistently associated with reduced cardiovascular risks. While reducing pollution remains crucial, promoting flavonoid-rich diets is a promising complementary strategy. Public health initiatives should raise awareness about these benefits. Further research on direct interactions between flavonoid intake and air pollution exposure is needed. Current evidence supports integrating dietary interventions into broader strategies to reduce air pollution’s cardiovascular impacts.


Introduction
Environmental pollution, particularly air pollution, has emerged as the largest cause of premature reversible death and disability worldwide, posing a significant global health concern with substantial impacts on cardiovascular health [1].In 2016 alone, ambient fine particulate matter (PM2.5)air pollution was responsible for an estimated 4.2 million deaths annually [2].Air pollution is a complex mixture of gaseous and particulate components, including nitrogen dioxide (NO 2 ), sulfur dioxide (SO 2 ), ozone (O 3 ), carbon monoxide (CO), and particulate matter of various sizes [3][4][5].Fine (PM2.5) and ultrafine (PM0.1)particulates, primarily produced through fossil fuel combustion, pose significant health risks due to their ability to penetrate deep into the lungs and enter the bloodstream [4,6].
The burden of disease attributable to air pollution is substantial, with significant economic costs to health and the environment [25,26].Vulnerable groups, such as children, elderly individuals, individuals with preexisting conditions, and individuals with lower socioeconomic status, face greater risks from the cardiovascular effects of air pollution [27].Despite its significant impact, pollution reduction has received little attention in cardiovascular disease (CVD) control programs and prevention guidelines [1].The incorporation of pollution reduction strategies for cardiovascular disease prevention could save millions of lives, highlighting the urgent need for comprehensive approaches to address this critical public health challenge.
Given these challenges, nutrition is crucial for maintaining cardiovascular health and reducing major CVD risks [28].Flavonoids have emerged as promising compounds in this context.Also known as bioflavonoids, flavonoids are a diverse group of polyphenolic secondary metabolites found in many fruits, vegetables, tea, cocoa, wine, nuts, seeds, spices, and other plant-based foods [29][30][31][32][33][34][35][36].Flavonoids are synthesized by plants as part of their defense mechanisms and contribute to the color, flavor, and nutritional value of many fruits and vegetables.Several reviews have examined their food sources and the bioavailability, metabolism, and biological activity of these compounds in humans.
Flavonoids share a common basic structure but differ in the number and arrangement of hydroxyl groups, as well as other substituents.Chemically, flavonoids have the general structure of a 15-carbon skeleton arranged in a C6-C3-C6 configuration, which consists of two phenyl rings (A and B) and a heterocyclic ring (C) containing oxygen [37].Flavonoids are classified into different families based on the degree of oxidation and pattern of substitution of the C-ring and the position of the B-ring.These chemical structures and variations allow flavonoids to exhibit a wide range of biological activities, making them important compounds in nutrition, medicine, and plant science.
Flavonoids fall into six distinct classes based on their chemical structure (Figure 1): flavones (the B-ring is attached to the C2 position of the C-ring, with a double bond between C2 and C3 and a ketone at C4), flavonols (similar to flavones but with a hydroxyl group at the C3 position), flavanones (the B-ring is attached to the C2 position of the C-ring, with a single bond between C2 and C3 and a ketone at C4), flavanols (similar to flavanones but with a hydroxyl group at the C3 position and no ketone group at C4), isoflavones (the B-ring is attached to the C3 position of the C-ring), and anthocyanidins (similar to flavonols but without a ketone at C4 and typically with a positive charge on the oxygen in the C-ring) [34,35,[38][39][40].
A healthy lifestyle, including a diet rich in these plant-based foods, is associated with the prevention of inflammatory diseases and improved cardiovascular health [41,42].Flavonoids have gained attention for their potential cardiovascular-protective benefits, as indicated by epidemiological studies from the 1990s and 2000s [28].They modulate genes related to metabolism, stress defense, and detoxification, and their molecular actions include antioxidant effects and the modulation of key enzymatic pathways [35,42].
The beneficial properties of flavonoids, such as their antioxidative, anti-inflammatory, antimutagenic, and anticarcinogenic effects, have been well documented [34,43].These compounds have shown promise in protecting against CVDs, as supported by in vitro and in vivo studies [28,36].
There are few studies centered on the mean flavonoid ingestion [44][45][46][47].A Spanish study found a median and mean of total flavonoids of 269.17 and 313.26 mg/day, respectively [46].A wider European study found a mean intake of total flavonoids of 428 ± 49 mg/day, of which 136 ± 14 mg/day was of monomeric compounds and with the lowest intakes observed in Mediterranean countries [47].A study on Australian adults found total flavonoid intake was 626 ± 579 mg/day [44] while a study on American adults found mean total flavonoid intake was 219 mg/day [45].A healthy lifestyle, including a diet rich in these plant-based foods, is associated with the prevention of inflammatory diseases and improved cardiovascular health [41,42].Flavonoids have gained attention for their potential cardiovascular-protective benefits, as indicated by epidemiological studies from the 1990s and 2000s [28].They modulate genes related to metabolism, stress defense, and detoxification, and their molecular actions include antioxidant effects and the modulation of key enzymatic pathways [35,42].
The beneficial properties of flavonoids, such as their antioxidative, anti-inflammatory, antimutagenic, and anticarcinogenic effects, have been well documented [34,43].These compounds have shown promise in protecting against CVDs, as supported by in vitro and in vivo studies [28,36] There are few studies centered on the mean flavonoid ingestion [44][45][46][47].A Spanish study found a median and mean of total flavonoids of 269.17 and 313.26 mg/day, respectively [46].A wider European study found a mean intake of total flavonoids of 428 ± 49 mg/day, of which 136 ± 14 mg/day was of monomeric compounds and with the lowest intakes observed in Mediterranean countries [47].A study on Australian adults found total flavonoid intake was 626 ± 579 mg/day [44] while a study on American adults found mean total flavonoid intake was 219 mg/day [45].Human intervention studies have explored the administration of flavonoids through whole foods, dietary supplements, or individual compounds, highlighting their role in preserving cardiovascular health and reducing the risk of major CVDs [28,38,43].Therefore, incorporating different types of flavonoids into the daily diet is highly recommended and justifiable for mitigating the risk of life-threatening diseases, such as CVD [35].
The current literature does not directly address the association between dietary flavonoid intake and the mitigation of cardiovascular health risks caused by air pollution.Through a comprehensive review of the literature published between 2014 and 2024, we summarize the existing evidence on the association between air pollution and CVD risk, examine the cardiovascular benefits of dietary flavonoids, and hypothesize that these two factors may interact.Our goal is to explore this interaction as a complementary strategy within a broader public health approach to mitigate the impact of air pollution on cardiovascular health.This research seeks to bridge the gap in current understanding and provide insights for future studies and potential interventions.

Methods
This narrative review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews guidelines [48].
A comprehensive literature search was performed up to 19 June 2024 across the Med-Line/PubMed, ScienceDirect, and MDPI databases.The search focused on the following terms: (air pollution OR air pollutants OR environmental pollutants OR particulate matter OR smog OR toxic air OR ambient air pollution) AND (dietary flavonoids OR flavonoid-rich foods OR antioxidants in diet OR polyphenols OR plant-based antioxidants OR quercetin OR catechins OR flavonols OR anthocyanins) AND (cardiovascular diseases OR heart disease prevention OR cardiovascular risk factors OR cardiovascular health outcomes OR coronary artery disease OR stroke OR hypertension OR atherosclerosis OR myocardial infarction) AND (public health interventions OR public health strategies OR nutritional epidemiology OR community health programs OR dietary guidelines OR health promotion) AND (randomized controlled trial OR case-control study OR longitudinal study).Reference lists were manually searched to find any relevant work in the reference lists of the included studies.

Study Selection
Using the PICO framework, studies were selected based on the following criteria: population (P): individuals exposed to air pollution or environmental pollutants; intervention (I): dietary intake of flavonoids and flavonoid-rich food; comparison (C): not applicable; and outcome (O): cardiovascular disease risk mitigation and improvement in cardiovascular health outcomes related to air pollution exposure.Articles were eligible if they focused on this work's main or specific objectives; were published between 2014 and 2024; were written in English; were observational, cohort, cross-sectional, a clinical trial, a narrative review, a systematic review, a meta-analysis, an umbrella analysis, or an analytical method; or were human, in vitro, or animal studies due to their crucial role in revealing the potential mechanisms of action and bioavailability of flavonoids on cardiovascular health.
Articles were excluded if they did not meet the specified criteria or were irrelevant to the research objectives, contained unpublished data, had sample sizes of less than 100 participants, were published before 2014, were duplicate publications, or were in languages other than English.The sample size criterion of 100 participants was selected to provide adequate statistical power and generalizability.Initial screening based on titles and abstracts was followed by a full-text review process conducted independently by three researchers.All discrepancies were resolved by discussion, achieving a 90% agreement rate.

Data Extraction and Synthesis
The following variables were extracted from the selected articles: air pollution and CVD, cardiovascular outcome/condition, air pollution exposure, and association, study design, and reference.For flavonoid studies: author, publication date, location, population, study design, flavonoid(s) studied, beneficial effects observed to prevent CVDs, limitations.
Then, content analysis confirmed the accuracy of the data used to identify thematic patterns [36].Consistency in reported items was ensured through consensus between researchers.The data were synthesized and tabulated based on this consensus to create a complete matrix.

Literature Retrieval Process and Basic Study Characteristics
The literature search identified 463 articles from the databases, with 134 duplicate records removed.After screening and applying the eligibility criteria, 53 studies remained and were included in this narrative review (Figure 2).Basic study characteristics will be described separately according to the study's scope to enhance clarity.

Literature Retrieval Process and Basic Study Characteristics
The literature search identified 463 articles from the databases, with 134 duplicate records removed.After screening and applying the eligibility criteria, 53 studies remained and were included in this narrative review (Figure 2).Basic study characteristics will be described separately according to the study's scope to enhance clarity.

General cardiovascular outcomes
Research has shown diverse impacts of air pollution on general cardiovascular outcomes.One study attributed increased cardiovascular diseases (CVDs) to PM2.5 and O 3 exposure [59].Moreover, PM2.5, NO 2 , O 3 , and VOC pollutants were linked to increased occurrence of CVDs; acute effects such as myocardial infarction, coronary events and endothelial injury; and chronic processes such as atherosclerosis [22], while another study also linked pollutant exposure to the early onset of CVDs, specifically hypertension (HTN) and atherosclerosis [64].A cohort study revealed that exposure to PM2.5, PM2.5 absorbance, PM10, NO 2 , and NOx is linked to the progression from pre-HTN to HTN (HR 1.105), CVD (HR 1.045), and death (HR 1.086) [23].Chronic exposure to NO 2 , O 3 , PM10, PM2.5, and SO 2 was also found to be associated with increased CVD incidence, hospitalization, disability, mortality, and costs [60].Last, an increase in the burden of noncommunicable diseases (including CVD, stroke, ischemic heart disease, and coronary heart disease) was projected under adverse scenarios, such as growing population numbers, social deprivation, and an aging population [59].
Atrial fibrillation (AF): A meta-analysis revealed associations for both short-term and long-term exposure to air pollutants.For short-term exposure, AF attacks were associated with PM2.5, SO 2 , and NO 2 .The excess risk (ER) of an AF attack per 10 µg/m 3 increase was 1.8% for PM2.5 and 1.1% for PM10.For gaseous pollutants, the ER per 10 parts per billion increase was 3.2% for NO 2 and 2.9% for SO 2 .AF incidence was linked to long-term exposure to PM2.5, PM10, SO 2 , NO 2 , and CO [54].Another meta-analysis focused on heart failure (HF) also reported associations; short-term exposure to PM2.5 (RR = 1.018) and PM10 (RR = 1.016) showed an increased risk and significant associations with NO 2 , SO 2 , and CO, while long-term exposure to various pollutants in the short-term is associated with HF [58].
For cardiac arrhythmia and other cardiac diseases, a review discussed the proarrhythmic effects of PM, lead, CO, SO 2 , and NOx, which are associated with ischemia, atrial, HF, and ventricular arrhythmias [10].Regarding major adverse cardiovascular events (MACEs), a cohort study revealed that carbon monoxide poisoning was associated with a greater risk of MACEs (HR: 2.00, 95% CI: 1.83-2.18)[51].Finally, a review reported that long-term exposure to PM10 is significantly associated with peripheral artery disease (PAD) (R 2 = 0.5) [62].Two studies confirmed that long-term exposure to PM2.5 is linked to both the development [20] and increased risk of atherosclerosis [57].
Long-term exposure to PM2.5 even below the current US standards (12 µg/m 3 ) was associated with an increased risk of CVD [24].A meta-analysis provided strong evidence of increased risk with PM2.5, SO 2 , and NO 2 [61].A cohort study revealed that long-term exposure to PM2.5 (≥54 µg/m 3 ) increases the risk of cerebrovascular disease (CeVD) [52].CO poisoning was associated with an increased risk of arrhythmia (HR: 1.83) in a cohort study, and it was also highlighted that CO-poisoned patients with comorbidities have substantially increased risks of CVD [7].A time-series study revealed that short-term exposure to ambient CO (per 1 mg/m 3 increase) is associated with increased emergency room visits (ERVs) for total CVD (RR: 1.041) [53].Table 2 summarizes the characteristics of the selected studies on the cardiovascular effects of flavonoids.Antioxidant, anti-inflammatory, and therapeutic effects through modulation of TLR4-NF-κB, PI3K-AKT, and Nrf2/HO-1 pathways.Sources include dietary flavonoids from green tea, soybeans, citrus fruits, red wine, purple grapes, etc.; specific doses are not consistently reported across human, in vitro, and animal studies.
Bioavailability and efficacy of flavonoids are not fully addressed due to variability in study designs and dosing.Flavonoids reduce the risk of atherosclerosis and atherothrombotic disease by inhibiting excessive tissue factor availability in the endothelium.They also mitigate endothelial dysfunction, reduce oxidative stress, and inhibit platelet aggregation, which are beneficial for cardiovascular health.Doses were not specified, with studies conducted on humans, rats, and in vitro.
Dose-responsive effects and bioavailability of flavonoids remain limitations.More studies needed to prove effectiveness as antithrombotic agents.

• Reduction in cardiovascular disease risk and mortality
Recent research has consistently demonstrated the beneficial effects of flavonoid intake on cardiovascular health.A higher intake of flavonoid-rich foods and beverages was found to be associated with a lower risk of cardiovascular mortality in a cohort of 55,786 females and 29,800 males [71].Similarly, a cohort of 369,827 older adults reported that increased total flavonoid, flavonol, anthocyanidin, and flavone consumption was linked to reduced risks of death from CVD (HR 0.90-0.93),IHD (HR 0.89-0.94),CeVD (HR 0.84-0.89),and PAD (HR 0.79-0.81)[68].Earlier cohort studies supported these findings, showing that moderate habitual flavonoid intake (~500 mg/d) [73] was inversely associated with CV mortality and CVD incidence.Furthermore, two studies highlighted the protective effects of quercetin and myricetin [70], as well as total flavonoids [69], on CVD-specific mortality.An inverse association between the intake of flavonoids, flavan-3-ols, anthocyanidins, and flavanones and cardiovascular risk, nonfatal events, and all-cause mortality was also observed [76].Similarly, a cohort of 84,158 adults revealed a strong inverse association between CVD and the intake of every 10 mg/d of anthocyanins (HR 0.98), catechins (HR 0.98), and flavonols (HR 0.94) [75].

Mechanisms of Action and Evidence
The selected articles provided mechanistic insights into the impact of flavonoids on cardiovascular health.

• Endothelial function and vascular health
A randomized controlled trial with 174 adults at risk of CVD demonstrated significant improvements.A high-flavonoid fruit and vegetable diet (>15 mg/100 g of total flavonoids) improved endothelium-dependent microvascular reactivity (p = 0.017) in men with the addition of +2 portions/day after 6 weeks [87].Additionally, flavanol-rich cocoa improved flow-mediated dilation and reduced blood pressure [88], while notable improvements in vascular function and blood pressure regulation were found [82].The administration of hesperidin to humans and animals also restored endothelial function [93].Moreover, a high-flavonoid diet with an increase of +4 portions per day after 12 weeks significantly increased plasma nitric oxide (NO) levels (p = 0.0243) in the whole study group [87].Maalik et al. highlighted that flavonoids such as quercetin, kaempferol, epicatechin, daidzein, and hesperetin increase nitric oxide (NO) levels.They achieve this by directly stimulating endothelial nitric oxide synthase (eNOS), activating the PI3K/Akt pathway to enhance eNOS activity through phosphorylation, and increasing intracellular calcium levels, which promote NO synthesis [86].The role of anthocyanins and hesperetin in vasodilation through the modulation of K + and Ca 2+ ion channels has also been emphasized [83].

• Antioxidant effects
Flavonoids, including catechins, epicatechins, procyanidins, and herbal monomers such as baicalin, quercetin, luteolin, and naringin, exhibit antioxidant properties through multiple mechanisms [84,90].These compounds act as electron donors, neutralizing reactive oxygen species (ROS), such as peroxynitrite, hydroxyl, and peroxyl radicals [83].They modulate and enhance antioxidant defense systems, preventing oxidative stress and reducing oxidative damage [84].Flavonoids interact with enzymes involved in ROS production, including glutathione S-transferase, NADH oxidase, microsomal monooxygenase, and mitochondrial succinoxidase [83].Quercetin can chelate free metal ions, reducing free radical formation [83], and has been shown to increase glutathione levels and superoxide dismutase activity [83,90], which could directly counteract the oxidative effects of pollutants.The antioxidant effects of flavonoids include direct ROS scavenging, metal ion chelation, lipid peroxidation reduction, and enhancement of antioxidant systems by modulating the Nrf2/HO-1 pathway [85,90].This modulation increases mitochondrial enzyme activity and upregulates antioxidant enzymes [90].Hesperidin supplementation has been shown to increase total antioxidant capacity compared to that in placebo groups [93].
• Anti-inflammatory effects A high-flavonoid fruits and vegetables diet with +2 portions/day after 6 weeks reduced C-reactive protein (p = 0.001) and E-selectin (p =0.0005) in men [87].A total of 320 mg/d twice a day for six months in hypercholesterolemic individuals decreased C-reactive protein, soluble vascular cell adhesion molecule-1, and plasma IL-1β [92].Hesperidin led to notable decreases in the levels of TNF-α and IL-6 in type 2 diabetes patients, while a hesperidin-derived metabolite suppressed endothelial cell inflammation [93].Red wine flavonoids have been demonstrated to inhibit the biosynthesis of eicosanoids, particularly cyclooxygenases and 5-lipoxygenase enzymes.These enzymes metabolize free arachidonic acid to produce proinflammatory compounds, which are known to initiate the inflammatory cascade [84].Wine flavonoids can activate the NF-kB pathway, reducing the release of proinflammatory cytokines [84].A study revealed that increased flavonoid intake was associated with decreased methylation of the TLR2 gene, a principal player in the inflammatory response [96].Additionally, several flavonoids inhibit the TLR4-NF-kB and PI3K-AKT pathways to reduce inflammatory cytokine production [85,90].The main flavonoid subgroups show anti-inflammatory potential by modulating eicosanoid and prostaglandin synthesis, inhibiting neutrophil degranulation, reducing the concentration of arachidonic acid, and inhibiting phosphodiesterase.

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Blood pressure regulation Flavonoids indirectly contribute to blood pressure (BP) regulation by improving endothelial function and modulating the renin-angiotensin-aldosterone system [92].Specifically, catechins from cocoa have been associated with lower systolic (SBP) and diastolic (DBP) blood pressure in both human and animal studies.Additionally, epicatechin has demonstrated a mean reduction of 4.1 and 2.0 mmHg in SBP and DBP, respectively [86].Catechin-rich green tea decreased SBP and DBP [93].For hypertension, it is well documented that hesperetin and naringin have antihypertensive effects; likewise, the antihypertensive effect of anthocyanins is more pronounced in subjects with higher BP [86].Rutin and quercetin also demonstrated antihypertensive effects after retarding the effects of a high-salt diet in rats [93].Finally, various in vitro and rat studies have shown the antihypertensive capacity of kaempferol, quercetin, naringenin, and epicatechin [83].The consumption of flavonoid-rich cocoa (450-900 mg/day over one week to one month) resulted in a reduction in BP, particularly in individuals with compromised vascular health [88].

• Antiplatelet and antithrombotic effects
Evidence shows that flavonoids have antiplatelet and antithrombotic effects through multiple mechanisms.Wine flavonoids, for instance, inhibit platelet aggregation by altering membrane fluidity, ligand-receptor affinity, and intracellular signaling pathways and even mediating antiplatelet effects through antioxidant and NO pathways [84].Various flavonoids, including quercetin, kaempferol, proanthocyanidins, naringenin, formononetin, nobiletin, anthocyanins, vitexin, and calycosin, demonstrate these effects.They act by reducing collagen-induced aggregation, inhibiting thromboxane A2 production, regulating lipid metabolism, reducing inflammation, enhancing antioxidant activity, promoting autophagy [85], and reducing the progression of atheroma plaques [83].Notably, 500 mg/day of quercetin attenuates atherosclerosis, while 50 or 100 mg/kg/day of kaempferol in mice decreases the atherosclerotic lesion area and improves vasorelaxation [92].Furthermore, flavonoids reduce the risk of atherosclerosis and atherothrombotic disease by inhibiting excessive tissue factor availability in the endothelium [89].

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Cardioprotective effects Two studies underscore the effect of flavonoids in modulating the PI3K-AKT pathway, which is known to improve endothelial function and vasodilation and reduce oxidative stress, thereby aiding cardiovascular health [85,86].Additionally, flavonoids influence the TLR4-NF-κB pathway [85], which can mitigate inflammation and protect against cardiovascular damage.Flavonoids modulate inflammation, reducing cardiomyocyte death and minimizing postischemic infarct size in rats [78].Low concentrations of epigallocatechin-3gallate in green tea increased the survival of myocytes [93].

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Lipid metabolism The administration of rutin and quercetin increased lipid peroxidation, retarding the increase in triglyceride, LDL, and total cholesterol serum levels induced by a high-salt diet, while catechin-rich green tea produced an overall restoration to normal levels in the lipid profile, specifically an important decrease in LDL cholesterol [93].Raman et al. reported that flavan-3-ols significantly decreased TGs (net change: −0.03 mmol/L), LDL (net change: −0.07 mmol/L), and total cholesterol (net change: −0.14 mmol/L) while significantly increasing HDL (net change: 0.03 mmol/L) [82].Daily oral intake of 450 mg of naringin for 90 days had effects on obese patients with hypercholesterolemia, reduced body weight, and reduced lipid profiles [91].Similarly, the administration of 270 mg of flavonoid-rich citrus fruit reduced cholesterol (20-30%) and LDL (19-27%) within four weeks [92].

Air Pollution and Cardiovascular Risks
The evidence presented in this work demonstrates the significant and wide-ranging impacts of air pollution on cardiovascular health.Consistent associations have been observed between various air pollutants, particularly PM2.5, PM10, NO 2 , O 3 , and SO 2 , and increased risks of CVDs or associated risk factors.These include endothelial injury and systemic inflammation, HTN, stroke, MI, AF, and HF [18,22,59,64].
Short-term exposure to air pollutants has been linked to acute cardiovascular events and mortality [5,22,54,57].Meanwhile, long-term exposure to air pollutants has been consistently associated with the development and progression of chronic cardiovascular conditions.Studies have demonstrated links between PM2.5 exposure and increased risks of hypertension, cardiovascular disease, and mortality [23].Causal relationships have been established between PM2.5 exposure and both coronary artery disease and hypertension using Mendelian randomization techniques [56].These findings are corroborated by earlier research indicating that long-term PM2.5 exposure significantly exacerbates cardiovascular risk and reduces life expectancy [6].
The evidence suggests that air pollution contributes to the development of atherosclerosis, endothelial dysfunction, and systemic inflammation, which are major pathophysiological mechanisms in cardiovascular diseases [18,20,57].These processes may explain the observed increases in both acute events and chronic disease progression.
Moreover, multiple studies indicate that exposure to air pollutants increases the risk of inflammatory response, oxidative stress, cardiovascular mortality, and disability, even at levels below current regulatory standards in some countries [20,21,24].This underscores the importance of reducing air pollution levels as much as possible to protect public health, noting that short-term elevations in PM2.5 have been shown to increase the relative risk of acute cardiovascular events by 1% to 3%, while long-term exposures increase this risk by approximately 10% [21].
Notably, the effects of air pollution on cardiovascular health may be compounded by other environmental and lifestyle factors.Carbon monoxide poisoning has been associated with a greater risk of major adverse cardiovascular events [51], highlighting the potential for synergistic effects between different types of environmental exposure.Furthermore, coexposure to air and noise pollution, which are prevalent in modern urban societies, may contribute to the development of hypertension and diabetes mellitus [97].
Given the significant cardiovascular risks posed by air pollution, there is a pressing need for strategies to mitigate these effects.While reducing air pollution levels remains the primary goal, complementary approaches to protect cardiovascular health are also crucial.Dietary interventions, particularly those rich in bioactive compounds such as flavonoids, have emerged as a promising area of research.The following section explores the cardiovascular benefits of flavonoids and their potential to counteract the harmful effects of air pollution.

Cardiovascular Benefits of Dietary Flavonoids
Research on flavonoids has shown significant benefits for cardiovascular health, ranging from a reduced risk of CVD to improvements in specific conditions [68,71,73,77].Specific flavonoids such as quercetin, myricetin, and kaempferol have been highlighted for their protective effects against CVD-specific mortality [69,70,81].
Different subclasses of flavonoids offer various cardiovascular benefits.Anthocyanins and flavan-3-ols have been linked to a reduced risk of hypertension [67,72] and a lower incidence of coronary heart disease (CHD) [65,82].In contrast, flavonols have shown promise in reducing overall CVD [95] and stroke [66] risk.Proanthocyanidins have also demonstrated significant benefits, such as lower incidence of CHD [65].
The cardiovascular benefits of flavonoids are supported by multiple mechanisms of action.They have been shown to improve endothelial function by enhancing endotheliumdependent microvascular reactivity and increasing NO levels [86,87].Flavonoids also exhibit potent antioxidant effects, neutralizing reactive oxygen species and boosting antioxidant defense systems [83,84,90] by modulating the Nrf2/HO-1 pathway [85,90].The anti-inflammatory properties of these compounds include their ability to modulate the TLR4-NF-κB and PI3K-AKT pathways [85,90], reduce inflammatory cytokine production, and subsequently decrease inflammatory markers such as C-reactive protein and E-selectin [87,92].
Furthermore, flavonoids play a crucial role in blood pressure regulation.Catechins and epicatechin, in particular, have demonstrated antihypertensive effects [86,93].The antiplatelet and antithrombotic effects of flavonoids, including their ability to inhibit platelet aggregation and reduce the risk of atherosclerosis, have been well documented [84,85,89].
Last, flavonoids not only positively influence lipid metabolism by improving lipid profiles, such as reducing LDL cholesterol and triglycerides while increasing HDL cholesterol [82,93], but also exert beneficial effects on glucose and insulin metabolism.For instance, flavan-3-ols have been shown to significantly decrease hemoglobin A1c levels and improve insulin resistance [82].
Strong evidence supports the ability of flavonoids to positively impact multiple aspects of cardiovascular health through various mechanisms, underscoring their potential as a valuable dietary component in the prevention and management of cardiovascular diseases.
Direct comparisons among these flavonoid subclasses suggest that while all offer cardiovascular benefits, their effects may vary significantly.For instance, flavonols and proanthocyanidins appear particularly effective in reducing CVD and stroke risk, respectively, compared to other flavonoids.Catechins and epicatechins also show notable benefits for blood pressure regulation and endothelial function.However, more direct comparisons between the effects of different types of flavonoids on cardiovascular health are needed.Further research in this area could provide more clarity on their relative benefits and help refine dietary recommendations.

Potential Interactions between Flavonoid Intake and Air Pollution Exposure
Based on the evidence reviewed, we hypothesize that dietary flavonoids could mitigate and prevent the adverse cardiovascular effects of air pollution exposure through several mechanisms.Although not explicitly discussed in our review of air pollution and cardiovascular health, oxidative stress is a key underlying mechanism of air pollution-induced cardiovascular damage.
We propose the following specific mechanisms by which flavonoids may mitigate the cardiovascular effects of air pollution:

Improvement in Endothelial Function Impaired by Pollutants
Endothelial dysfunction, a critical factor in cardiovascular risk, is a well-documented consequence of exposure to airborne particulate matter [6,18,22].Flavonoids enhance NO levels by stimulating eNOS and activating the PI3K/Akt pathway, along with increasing intracellular calcium levels [86].These mechanisms improve endothelium-dependent vasodilation and may counteract pollution-induced endothelial dysfunction [83,87,93].

Antiplatelet and Antithrombotic Effects Mitigating Pollution-Induced Thrombosis Risk
Long-term exposure to high levels of air pollution, especially particulate matter, increases platelet activation and thrombotic risk [20,21,61].Flavonoids demonstrate significant antiplatelet and antithrombotic effects by inhibiting platelet aggregation, suppressing phospholipase C and protein kinase C phosphorylation, and modulating calcium mobilization [85,89].They also reduce tissue factor expression and attenuate atherosclerosis development by decreasing oxidized LDL levels [83,85].
Although direct studies examining these interactions are limited, the established cardiovascular benefits of flavonoids and their ability to counteract the underlying mechanisms of pollution-induced damage provide a strong rationale for the hypothesis that flavonoid intake may help mitigate the cardiovascular risks associated with air pollution exposure.Further research directly examining this interaction is warranted.Other studies have shown how flavonoids protect reproductive health and counteract cancer [98], and due to similar mechanisms, air pollutants, triggering cardiovascular health protection from air pollution-induced risks.

Public Health Implications
Complementary public health measures are essential considering the widespread exposure to air pollution and the challenges in rapidly reducing emissions.Flavonoids have significant potential to mitigate air pollution-induced cardiovascular risks, making dietary interventions a promising strategy for protecting cardiovascular health.
Several strategies to mitigate the cardiovascular effects of air pollution, including personal, local, public health policy, and research-based interventions [21,99], must be used for a better approach.Based on our aims and scope, we will focus on the strategies most relevant to promoting dietary flavonoids as a complementary approach while also briefly mentioning common strategies to reduce air pollution.
These interventions include encouraging and facilitating research to explore flavonoid bioavailability, mechanisms of action [35,85,86,[89][90][91][92], and complementary strategies, including dietary interventions, to mitigate the cardiovascular impacts of air pollution [98,[100][101][102].Additionally, increasing public awareness about the health risks of air pollution [103,104] and the benefits of dietary interventions to reduce the negative health impacts of air pollution [105][106][107][108][109] is essential.Promoting the consumption of flavonoid-rich diets and considering supplementation, when necessary, while ensuring accessibility regardless of socioeconomic status or geographic location [106,110] is also important.Common strategies for reducing air pollution include transitioning to cleaner and renewable energy sources, implementing land use assessments, relocating major traffic sources, promoting low-emission and zero-emission vehicles, encouraging active transport, and adopting sustainable agricultural practices [108,111].
However, it is crucial to emphasize that while dietary interventions, such as increased flavonoid intake, can offer additional protection, they should not replace efforts to reduce air pollution.Instead, they should be seen as a complementary strategy to protect public health, while broader and sustainable efforts to improve air quality are pursued [112].The primary focus must remain on reducing air pollution levels through stricter regulations and cleaner technologies [113].By implementing these actions, we can potentially offer an additional layer of protection for cardiovascular health while still addressing the core cause of air pollution.

Limitations and Strengths
Despite the evidence suggesting promising ways for dietary flavonoids to mitigate cardiovascular disease risks associated with air pollution exposure, several limitations are worthy of consideration.
First, the variability in bioavailability among different flavonoids presents a significant challenge in assessing their health effects.Many studies rely on in vitro experiments that use doses higher than those typically bioavailable in humans, complicating the translation of these findings into real-world efficacy.This discrepancy, coupled with inconsistencies in bioavailability influenced by factors such as age, metabolism, and the complexity of flavonoid chemistry, obscures the true impact of flavonoids on health.
Another important issue related to flavonoid intake is the fact that there is no consensus on what is considered a moderate or high intake, and inconsistent values appear throughout the reviewed studies.Furthermore, dietary flavonoid intake is often assessed only at baseline, which may not accurately reflect subsequent dietary changes and could introduce recall bias.Self-reported dietary intake methods, commonly used in studies, are prone to inaccuracies and recall bias, potentially skewing the results.Thus, while in vitro studies offer valuable insights, further research is crucial to bridge the gap between laboratory findings and actual physiological responses and to refine dietary recommendations.
Second, the study designs predominantly utilized in the reviewed articles limit causal inference.Observational designs and meta-analyses cannot definitively establish cause-andeffect relationships, and potential residual confounding factors, such as unadjusted total energy intake or lifestyle changes postdiagnosis, may have influenced the outcomes.The heterogeneity in dietary assessment methods and the variability in flavonoid composition between different foods and beverages further complicate the interpretation of the results.Additionally, some studies did not stratify for hypertension severity or account for changes in dietary data over extended periods, affecting the detection of associations and limiting generalizability.
Despite these limitations, this narrative review has several strengths.This study provides a comprehensive synthesis of the literature on the intersection of dietary flavonoids and cardiovascular health in the context of air pollution exposure, highlighting a novel and underexplored area of public health research.By gathering evidence from diverse studies, this review underscores the potential of flavonoids to counteract the underlying mechanisms of pollution-induced cardiovascular damage, providing a strong rationale for further investigation.
Finally, we emphasize the importance of dietary interventions as a complementary strategy to broaden efforts aimed at reducing the impact of air pollution on human health.By integrating findings from both clinical trials and epidemiological studies, this study presents a balanced perspective on the feasibility and potential impact of promoting flavonoid-rich diets.This approach supports ongoing research and advocates for public health initiatives to raise awareness and encourage the consumption of flavonoid-rich foods as part of a holistic strategy to protect cardiovascular health.

Conclusions
The evidence highlights the significant cardiovascular risks posed by air pollution and the potential use of dietary flavonoids to mitigate these effects.Air pollutants such as PM2.5, PM10, NO 2 , O 3 , and SO 2 are linked to increased risks of hypertension, stroke, myocardial infarction, atrial fibrillation, and heart failure.Flavonoids, with their antioxidant, anti-inflammatory, and endothelial-function-improving properties, could counteract the cardiovascular damage caused by these pollutants.
Although reducing air pollution remains the primary goal, promoting flavonoid-rich diets is a promising complementary strategy to protect cardiovascular health.Public health initiatives should focus on raising awareness about the benefits of flavonoids and encouraging their consumption as part of an integral approach to mitigate the cardiovascular impacts of air pollution.
Further research is needed to explore the direct interactions between flavonoid intake and air pollution exposure.However, the current evidence supports the integration of dietary interventions into broader public health strategies to reduce the health impacts of air pollution on cardiovascular health.

Figure 2 .
Figure 2. PRISMA flow diagram for the study selection and article eligibility process [49].

Figure 2 .
Figure 2. PRISMA flow diagram for the study selection and article eligibility process [49]. .

4. 3 . 4 .
Blood Pressure Regulation to Offset the Hypertensive Effects of Pollution

Table 1 .
Summarized findings on the association between air pollution exposure and cardiovascular outcomes.

Table 2 .
Summarized findings of flavonoid effects on cardiovascular health.
Sources include red wine, tea, fruits, and citrus fruits, and dietary supplementation.Specific doses are not reported.Effects observed across various studies including human, in vitro, and animal research.

Table 2 .
Cont.Hesperidin improves endothelial function and reduces blood pressure (10-50 mg/kg of glucosyl hesperidin in animals; 500 mg/day for 6 days of hesperidin capsules in humans).Rutin and quercetin regulate and restore elevated blood pressure, promote antioxidant defense, and reduce lipid peroxidation in rats.Catechin-rich green tea decreases systolic and diastolic blood pressure and LDL cholesterol in humans.Doses and sources for rutin, quercetin, and catechin were not specified.