Air pollution is a major global environmental health risk. It has emerged as a critical environmental issue in recent years. Microscopic air pollutants, originating from various sources such as vehicle emissions, industrial activities, and natural sources for example wildfires, possess the ability to penetrate deep into the respiratory system. The World Health Organization (WHO) reported that both prolonged and short-term exposure to airborne particulate matter (PM), specifically PM2.5 (with a diameter of less than 2.5 micrometers) at levels exceeding 100 µg/m³, and PM10 (with a diameter of less than 10 micrometers) at levels exceeding 45 µg/m³ within 24 h, and other pollutants, including nitrogen dioxide (NO2) at levels above 40 µg/m³, carbon monoxide (CO) above 4 mg/m³, sulfur dioxide (SO₂) above 40 µg/m³, and ozone (O₃) above 100 µg/m³, significantly increases cardiovascular and respiratory mortality [1,2,3,4]. Additionally, diesel exhaust particulate matter, including standard reference material (SRM), also plays a role in human health impacts [5]. In addition to air pollutants, other biological pollutants such as pollen, molds, and endotoxins could have harmful effects to health. Their effects on health have been comprehensively described elsewhere.

Cardiac ischemia-reperfusion (I/R) injury denotes the tissue damage caused when blood supply to the heart is disrupted (ischemia) and subsequently restored (reperfusion). Although restoration of blood flow is crucial for the salvaging of the ischemic myocardium, reperfusion itself can exacerbate cardiomyocyte death and tissue injury via various mechanisms such as oxidative stress, calcium overload, mitochondrial dysfunction, and inflammatory responses [6,7,8]. One potential mechanism linking exposure to air pollution to adverse cardiovascular outcomes is the exacerbation of cardiac ischemia-reperfusion Injury [9].

Emerging evidence from both experimental animal studies and epidemiological investigations has suggested that exposure to air pollutants increases the susceptibility to cardiac ischemia-reperfusion injury and worsens associated cardiovascular outcomes [10, 11]. Proposed mechanisms include the induction of systemic oxidative stress and inflammation, apoptosis, vascular dysfunction, and the direct disruption of cardiac myocyte homeostasis and mitochondrial function [9, 12,13,14]. However, the specific pathways and relative contributions of different pollutants and particulate constituents remain incompletely understood.

This review aims to elucidate the link between air pollution and myocardial ischemia-reperfusion injury, summarizing the evidence and the mechanisms involved in its impact on the exacerbation of ischemia-reperfusion injury, and highlighting potential interventions to prevent myocardial ischemia-reperfusion injury resulting from air pollution exposure. Ultimately, an enhanced understanding of this relationship may lead to increased efficacy in mitigating the cardiovascular consequences of air pollution.

Methods

This comprehensive review was performed using the PubMed database, encompassing publications from January 1991 to May 2024. This search was undertaken utilizing specific search terms such as “Ischemic–reperfusion injury*”, “I/R injury*”, “Reperfusion injury*”, “IRI*”, “air pollution*”, “particulate matter*”, and “PM2.5*”. The search yielded a total of 20 relevant original articles, all of which were subsequently incorporated into this review.

The impact of air pollutants on H9C2 cardiomyocytes subjected to hypoxia/reoxygenation injury: evidence from in vitro studies

In vitro studies have been used to investigate the impact of various air pollutants on H9C2 cardiomyocytes exposed to hypoxia/reoxygenation injury, serving as a model for ischemia-reperfusion injury. Exposure to real-ambient particulate matter (RA_PM), diesel particulate matter (DPM), and Standard Reference Material 2975 (SRM 2975) 10–100 µg/ml for 3 h was shown to decrease H9C2 cell viability following hypoxia/reoxygenation injury, with RA_PM having the most detrimental effect, followed by DPM and SRM 2975 [14]. These findings suggest that exposure to these air pollutants can directly impair cardiomyocyte survival under conditions of hypoxia/reoxygenation.

It has been shown that 200 µg/ml of PM2.5 exposure for 4 h also decreased cell viability in H9C2 cardiomyocytes subjected to hypoxia/reoxygenation injury. This effect was mediated through increased inflammation (TNF-α, IL-6), apoptosis (increased TUNEL-positive cells), and downregulation of the long non-coding RNA PEAMIR (PM2.5 Exposure Aggravated Myocardial Ischemia–Reperfusion Injury Long Non-coding RNA) and its competing endogenous RNA (ceRNA) pair, miR-29b-3p [15]. These findings indicate that PM2.5 exposure can damage cardiomyocytes during hypoxia/reoxygenation injury through multiple pathways, including inflammation, apoptosis, and dysregulation of non-coding RNAs.

Sivakumar et al. also reported that exposure to DPM 100 µg./ml decreased cardiomyocyte viability in a time-dependent manner following hypoxia/reoxygenation injury, with longer exposure times (3 h) having a more pronounced effect than shorter exposures (1 h) [16]. These findings suggest that the duration of exposure to air pollutants can influence the severity of the impact on cardiomyocyte survival under hypoxia/reoxygenation conditions.

A summary of these in vitro findings is presented in Table 1. These in vitro studies provide consistent evidence that exposure to various air pollutants, including RA_PM, DPM, SRM 2975, and PM2.5, can significantly impair cardiomyocyte viability and exacerbate hypoxia/reoxygenation injury through mechanisms involving inflammation, oxidative stress, apoptosis, and dysregulation of non-coding RNAs.

Table 1 Impact of air pollutants on H9C2 cardiomyocytes with hypoxia/reoxygenation injuryThe impact of air pollutants on cardiac ischemia–reperfusion injury: current evidence from in vivo studiesUltrafine particulate matter (UFPM)

In rodent models, previous studies have reported that exposure to single dose of 100 µg ultrafine particulate matter (UFPM) increased myocardial infarct size in hearts with cardiac ischemia/reperfusion injury. In male Sprague-Dawley rats exposed to UFPM via oropharyngeal aspiration, a single dose administration was shown to increase infarct size through mechanisms involving increased mitochondrial permeability transition pore (mPTP) calcium sensitization and permeability transition. However, cardiac function parameters such as left ventricular developed pressure (LVDP), rates of pressure development (dP/dT), premature ventricular contractions (PVCs), risk of ventricular tachycardia/fibrillation, or arrhythmia scores were not altered [17]. In ICR mice exposed to single dose of UFPM 100 µg via intratracheal instillation, the increase in infarct size was associated with increased oxidative stress, as indicated by increased levels of thiobarbituric acid reactive substances (TBARS) in the myocardium [18]. Moreover, CD-1 mice exposed to a single dose of 100 µg of ultrafine particulate matter (UFPM) present in ambient particulate matter (PM) demonstrated increased infarct size and decreased cardiac hemodynamics only following UFPM exposure [19].

Interestingly, mice inhaling 100 µg of UFPM for 18 h from near-road (20 m from highway) sources showed markedly increased infarct size and worsened recovery of left ventricular developed pressure compared to mice inhaling far-road UFPM (275 m from highway) under conditions of cardiac ischemia-reperfusion injury [20]. These findings suggest that UFPM exacerbated ischemia-reperfusion injury and increased infarct size, potentially through disrupting cardiac mitochondrial function and inducing oxidative damage. Exposure to UFPM also resulted in increased cardiac injury and decreased functional recovery after ischemia-reperfusion in mice, with the smallest size fraction (< 0.1 μm) having the greatest impact in comparison to larger PM sizes [20, 21]. A summary of these reports is shown in Table 2.

Table 2 Impact of air pollutants on cardiac ischemia-reperfusion injury: current evidence from in vivo studiesParticulate matter (PM)

Various types of PM including fine PM(PM2.5), and coarse PM (PM10) have been investigated for their effects on cardiac ischemia–reperfusion in various animal models. In rats with cardiac ischemia–reperfusion injury, exposure to a single dose of 2 mg of PM2.5 was shown to increase infarct size via increased inflammation (evidenced by CK, LDH, hsCRP, IL-6, TNF-α, cTnT, P-selectin, D-dimer), oxidative stress (ROS, MDA, decreased SOD), and activation of the FXR-induced autophagy pathway [22]. Pei et al. also reported that 6 mg/kg. of PM2.5 exposure for 3 days in rats increased infarct size via apoptosis and decreased cardiac function (LVEF) during cardiac ischemia–reperfusion injury [15]. Consistent findings were reported in mice with cardiac ischemia–reperfusion injury in which chronic exposure to urban air PM2.5 (27.3 ± 7.6 µg/m3) for 3 months led to larger infarcts by inducing mitochondrial dysfunction (impaired ATP production, complex II activity, mitochondrial membrane potential) and inflammation (increased TNF-α, IL-6), along with decreased oxygen uptake and elevated left ventricular end-diastolic pressure [23].

Interestingly, it was demonstrated that exposure 250 µg/m3 of ambient particulate matter RA_PM for 21 days was more potent than diesel PM (DPM) and standard reference material (SRM2975) in causing greater increases in infarct size, inflammation, oxidative stress, apoptosis, and impairment of hemodynamics in rats [14]. PM10 exposure was also shown to dose-dependently (5 mg/kg) increase infarct size, LDH release, oxidative stress (MDA, antioxidant depletion), and also induced arrhythmias and impaired hemodynamics in rats [24, 25]. However, CD-1 mice exposed to either 100 µg far-road fine or coarse particulate matter (PM) for 18 h did not exhibit any related changes in infarct size [20].

All these in vivo studies have demonstrated that exposure to various particulate matter (PM) pollutants, such as PM2.5, RA_PM, DPM, SRM2975, and PM10, can exacerbate cardiac ischemia–reperfusion injury in rodent models. Exposure resulted in an increase in infarct size and impaired cardiac function which were associated with heightened inflammation, oxidative stress, mitochondrial dysfunction, and apoptosis. The severity of the effects appears to be dependent on the specific type and size of the particulate matter, with ultrafine particulate matter (UFPM) and PM2.5 showing the most significant effects. These findings provide strong evidence for the role of air pollution in worsening the outcomes of cardiac ischemia–reperfusion injury. A summary of these reports is shown in Table 2.

Air pollution from diesel exhaust components

Exposure to diesel particulate matter (DPM) and diesel exhaust particles (DEP) prior to cardiac ischemia–reperfusion injury has been shown to aggravate cardiac damage in various animal models. In female Wistar rats exposed to 0.5 mg/ml of DPM, myocardial infarct size was increased in a time-dependent manner (3-hour exposure daily over 21 days compared to 1-hour exposure daily) [16]. This was mediated by mitochondrial dysfunction (evidenced by decreased electron transport chain enzymes and ATP levels), increased inflammation (elevated MPO, LDH, CK), oxidative stress (increased TBARS, depleted antioxidants like SOD, catalase, GSH/GSSG ratio), and apoptosis (increased caspase 3 activity). Prolonged DPM exposure also impaired cardiac function (decreases in heart rate, left ventricular developed pressure, and rate pressure product) and caused histological damage including edema, inflammation, and loss of myofibril organization under conditions of cardiac ischemia–reperfusion injury [16]. In adult male Wistar rats exposed to 0.5 mg DEP via intratracheal instillation for 6 h, increased infarct size and susceptibility to ischemic arrhythmias were observed, potentially via increased apoptosis (TUNEL-positive cells) and oxidative stress (elevated EPR signal) [26].

These findings suggest that exposure to diesel exhaust can potentiate the detrimental effects of cardiac ischemia–reperfusion injury on the heart through multiple pathways such as impaired mitochondrial function, oxidative stress, inflammation, apoptosis, and contractile dysfunction. The growing body of evidence linking diesel exhaust pollution to worsened cardiovascular outcomes underscores the urgent need for more effective regulations and policies to reduce emissions from diesel-powered vehicles. A summary of these reports is shown in Table 2.

Air pollution from SRM2975

SRM2975 is the Standard Reference Material produced by the National Institute of Standards and Technology (NIST), specifically it is sample of diesel particulate matter collected from an industrial diesel-powered forklift. The effects of 250 µg/m3 of SRM 2975 air pollutant exposure were investigated in female Wistar rats. Prolonged exposure to a high concentration (21 days) led to mitochondrial dysfunction as evidenced by decreasing levels of NQR, SQR, QCR, CK, LDH, COX and impaired mitochondrial respiration, mitochondrial quality control genes, and mitochondrial detoxification genes, as well as increased inflammation, shown by increased TNF-α and IL-6 levels [27, 28]. Oxidative stress was also markedly increased as indicated by decreased SOD, Catalase, GSH/GSSG, and increased NRF, Glutaredoxin 1, Peroxiredoxin 3,6, and Protein carbonyl. These deteriorating effects led to cardiac apoptosis as shown by increases in caspases 3, 7, and 9 [27, 28]. Prolonged exposure to SRM 2975 impaired cardiac function, resulting in larger infarcts and reduced cardiac function during ischemia–reperfusion events. These effects, mediated by increased oxidative stress and mitochondrial dysfunction [28], were not observed after short-term (1 day) exposure [27]. All of these findings emphasize the detrimental consequences of prolonged exposure to SRM 2975 pollutants on mitochondrial function, cardiac hemodynamics, and oxidative stress pathways in the context of cardiac ischemia–reperfusion injury. A summary of these reports is shown in Table 2.

Other air pollutants: DCB230, C60 fullerene, CO and multipollutant mixtures

DCB230 is another air pollutant found in derived-environmentally persistent free radicals (EPFRs). Exposure to 1 day 230 µg of DCB230 in male Sprague-Dawley rats has been shown to decrease cardiac function without changing the infarct size, even with prolonged exposure in conditions of cardiac ischemia–reperfusion injury [29]. A single dose of ultrafine DCB230 exposure (8 mg/kg) in Brown Norway rats led to decreased ventricular function and increased oxidative stress (increased 8-isoprostane at 60-minute exposure) and inflammation without any change in infarct size under conditions of cardiac ischemia–reperfusion injury [30]. The lack of a significant increase in infarct size following exposure to DCB230 could be due to the effects of the short-time nature of the exposure and the mimicking pollutant properties of DCB230.

In Sprague-Dawley rats, exposure to intratracheal and intravenous 28 µg of C60 fullerene for 24 h increased cardiac infarct size in female rats during cardiac ischemia–reperfusion injury following increased inflammation (increased IL-6 and MCP-1 levels) [31]. Prolonged CO exposure (30–100 ppm) for in Wistar rats also led to increased infarct size via oxidative stress and impaired Ca2+ handling [32]. In contrast, inhalation of multi-pollutant mixtures by mice resulted in a decrease in infarct size in cardiac ischemia–reperfusion injury [33]. The decrease in infarct size following multipollutant mixture exposure had no evident responsible mechanism but the pollutant involved fewer components of particulate matter [33].

It is important to note that the effects of air pollutants on cardiac ischemia–reperfusion injury could vary depending on the specific pollutant, exposure duration, and animal model used. While some pollutants, such as DCB230 and multi-pollutant mixtures, did not result in an increase in infarct size, they still had detrimental effects on cardiac function, oxidative stress, and inflammation. The increase in infarct size observed in association with C60 fullerene and CO exposure highlights the potential for certain pollutants to directly exacerbate myocardial damage during ischemia–reperfusion injury. The sex-specific effects of C60 fullerene exposure on the infarct size in female rats underscore the importance of considering gender differences in the cardiovascular effects of air pollutants.

A comprehensive summary of the findings of the in vivo studies investigating the impact of air pollutants on cardiac ischemia–reperfusion injury is presented in Table 2. These studies provide compelling evidence that exposure to various air pollutants, including PM2.5, RA_PM, DPM, SRM 2975, PM10, DCB230, C60 fullerene, CO, and multi-pollutant mixtures, can aggravate myocardial damage and impair cardiac function in the context of ischemia–reperfusion injury.

Based on current evidence, the reperfusion phase appears to have a more pronounced effect, primarily due to the activation of mitochondrial permeability transition pores (mPTP), calcium overload, and oxidative stress, which are hallmark features of reperfusion injury. Additionally, chronic or high-dose pollutant exposures, such as PM2.5 and diesel particulate matter (DPM), can prime the myocardium by inducing systemic inflammation (e.g., elevated TNF-α and IL-6 levels) and vascular dysfunction, thereby increasing susceptibility to injury during the ischemic phase. However, it is important to note that the majority of studies measured parameters after the completion of the ischemia/reperfusion (I/R) injury cycle, which limited the ability to distinguish the specific contributions of each phase.

Exploring potential intervention against detrimental effects of air pollutants on cardiac ischemia–reperfusion Injury

In the past decades, several in vivo studies have investigated the effects of potential interventions on cardiac ischemia–reperfusion injury induced by air pollutants. A summary of these reports is shown in Table 3. Those interventions include treatment with Cyclosporin A, a β1 adrenoreceptor selective antagonist (metoprolol), a TRPV1 antagonist (AMG 9810), vanillic acid, SB216763 (a GSK-3β inhibitor), and indomethacin.

Table 3 Potential interventions and their effects on cardiac ischemia–reperfusion injury induced by air pollutants: current evidence from in vivo studies

Use of a 10 mg/kg i.p of β1 adrenoreceptor antagonist was shown to decrease cardiac infarct size, oxidative stress, and apoptosis which occurred as a result of exposure to diesel exhaust particles (DEP). However, its effects may be less potent in cases of high-dose acute pollutant exposure or in patients with β1-adrenoreceptor downregulation. Additionally, the required duration of treatment remains a limitation in some contexts [26]. It was more effective than the use of 30 mg/kg of sensory TRPV1 antagonist in treatment of cardiac ischemia–reperfusion injury in adult male Wistar rats with Langendorff models. Although it is effective for acute pollutant exposures, its efficacy in chronic exposure models is less studied, and it may not adequately address systemic inflammatory effects [26].

In rats exposed to high doses of PM10 during cardiac ischemia–reperfusion injury, 10 mg/kg vanillic acid for 10 days was shown to decrease cardiac infarct size and oxidative stress while improving hemodynamic function, as evidenced by ± dp/dt, LVSP, and LVDP. However, its benefits are limited in scenarios involving high single-dose PM10 exposure, reducing its applicability in more severe or sustained exposure conditions [25]. Vanillic acid was also shown to increase the expression of antioxidant enzymes and decrease the levels of reactive oxygen species (ROS), indicating protection against cardiac ischemia–reperfusion injury following exposure to high doses of PM10 [24].

In female Wistar rats, treatment with 0.7 mg/kg SB216763 (a GSK-3β inhibitor) effectively decreased cardiac infarct size and improved cardiac function after a single day of exposure to SRM2975, with levels of inflammatory and apoptotic markers being unchanged during cardiac ischemia–reperfusion injury [27]. However, treatment with SB216763 did not improve mitochondrial function in cases of prolonged exposure to SRM2975. Furthermore, its benefits are primarily demonstrated in short-term air pollutant exposure models, and its applicability in chronic exposure settings is limited [27].

In Sprague–Dawley rats with cardiac ischemia–reperfusion injury exposed to C60 fullerene, indomethacin (10 mcg/kg) was shown to decrease endothelin-1-induced coronary artery contraction [31]. This suggests that indomethacin mitigated the proinflammatory and vasoconstrictive effects caused by exposure to C60 fullerene in cardiac ischemia–reperfusion injury. However, it has no significant effect on reducing the infarct size, which limits its utility as a direct intervention for I/R injury [31].

A comprehensive summary of the findings from these in vivo studies investigating potential interventions and their effects on cardiac ischemia–reperfusion injury induced by air pollutants is presented in Table 3. There are still limited in vivo reports regarding the investigation of potential interventions to mitigate the adverse effects of air pollutants on cardiac ischemia–reperfusion injury. While some interventions, such as Cyclosporin A, β1 adrenoreceptors antagonist, and vanillic acid, showed promising results in reducing infarct size and improving cardiac function, the efficacy of others, like SB216763 and Indomethacin, varied depending on the pollutant and duration of exposure. These findings emphasize the complex nature of air pollution-induced cardiac injury and the need for targeted, pollutant-specific interventions. As air pollution continues to pose a significant threat to cardiovascular health worldwide, it is crucial that future research focuses on the unraveling of the intricate mechanisms underlying the relationship between pollutants and cardiac ischemia–reperfusion injury. Figure 1 illustrates the detrimental impact of air pollution and potential interventions on cardiac ischemia-reperfusion injury induced by air pollutants.

Fig. 1

Summary of detrimental impact of air pollution and potential interventions and their effects on cardiac ischemia–reperfusion injury induced by air pollutants. Exposure to air pollution aggravates infarct size under cardiac ischemia–reperfusion injury via increased mitochondrial dysfunction, inflammation, oxidative stress, apoptosis, and changes in pathology and genetics. Reports have shown that treatments with cyclosporin A, vanillic acid, GSK-3β, metoprolol, and a TRPV1 antagonist were able to decrease infarct size under conditions of cardiac ischemia–reperfusion injury. This figure was made with Biorender