Environmental Exposome and Atrial Fibrillation: Emerging Evidence and Future Directions

There has been increased awareness of the linkage between environmental exposures and cardiovascular health and disease. Atrial fibrillation is the most common sustained cardiac arrhythmia, affecting millions of people worldwide and contributing to substantial morbidity and mortality. Although numerous studies have explored the role of genetic and lifestyle factors in the development and progression of atrial fibrillation, the potential impact of environmental determinants on this prevalent condition has received comparatively less attention. This review aims to provide a comprehensive overview of the current evidence on environmental determinants of atrial fibrillation, encompassing factors such as air pollution, temperature, humidity, and other meteorologic conditions, noise pollution, greenspace, and the social environment. We discuss the existing evidence from epidemiological and mechanistic studies, critically evaluating the strengths and limitations of these investigations and the potential underlying biological mechanisms through which environmental exposures may affect atrial fibrillation risk. Furthermore, we address the potential implications of these findings for public health and clinical practice and identify knowledge gaps and future research directions in this emerging field.

framework for capturing an individual's lifetime environmental exposures.It complements our understanding of the genome by acknowledging the intricate interplay between genetics and a myriad of factors in the background environment in shaping human health and disease. 3The exposome encompasses the entirety of environmental factors that an individual encounters, including physical, chemical, and biological agents, as well as lifestyle and social factors. 4This holistic approach allows for a more nuanced investigation into the complex relationship between nature and nurture, elucidating their collective impact on health outcomes.
A central tenet of the exposome paradigm is that conditions can only be understood in the context of their environment and inherent underlying susceptibility.In this framework, the response of the biological system is the product of their interactions, not the sum of the individual components as many factors may have opposing or modifying results.The effect in an exposomic framework is iterative, not linear, and often unpredictable; understanding patterns and trends over time is a part of the natural dynamics of the system.Thus, the exposomic framework is identical to a systems framework, in which one may need to take a relatively agnostic view on the exclusive importance of single factors and acknowledge the simultaneous interaction of multiple interconnected exposures in shaping response over time.These exposures can include ambient air pollution, toxic chemicals, infectious agents, dietary patterns, socioeconomic factors, psychosocial stressors, and many others.By capturing this comprehensive array of external and internal factors, the exposome concept enables a more holistic assessment of environmental influences on health.
Understanding the exposome's impact on health outcomes requires the integration of various research disciplines, including epidemiology, toxicology, genomics, social sciences, and increasingly data science approaches.By leveraging advancements in technology and data collection methods, such as wearable sensors, biomonitoring, and high-throughput omics technologies, researchers can generate detailed exposure profiles and gain insights

AF
atrial fibrillation CVD cardiovascular disease NOX2 NADPH oxidase 2 PM 2. 5  fine particulate matter SO 2  sulfur dioxide TRPC3 transient receptor potential channel 3 VOC volatile organic compound WHO World Health Organization Some mechanisms have been identified but many remain to be investigated.The personal exposome and the external exposome interact with components of the biologic responses and drivers (such as epigenetics, inflammation, autonomic dysfunction) to increase the risk of atrial fibrillation (AF) either via traditional risk factors (eg, hypertension, obesity) or via direct impact on cardiac myocytes.The traditional risk factors may also increase the risk of AF directly, or via intermediary cardiovascular events (eg, heart failure; Illustration credit: Ben Smith).Exposome and Atrial Fibrillation into how specific environmental factors interact with an individual's biology over time. 5Ultimately, a deeper understanding of the exposome may better inform targeted interventions, regulatory policy decisions, and personalized medicine approaches, contributing to improved health outcomes and disease prevention strategies.

SOCIAL ENVIRONMENT
Social determinants of health have received significant attention as drivers of cardiovascular disease.Given the importance of the individual and community social factors, a recent National Heart, Lung and Blood Institute workshop called for transforming future AF research within the context of the social determinants of health. 6[8][9][10] The social environment is the broader physical, social, and cultural context in which people live that influences human behavior, relationships, development, and quality of life.It includes factors like institutions, culture, technology, demographics, socioeconomics, geography, politics, and media, and overlaps with natural and built environments.The social environment is difficult to quantify, but some surrogate factors have been examined in the context of health outcomes.Emerging evidence suggests that neighborhood social environment factors are associated with AF risks.For example, a study in Sweden showed that neighborhood deprivation was independently associated with AF hospitalization rate in women, independently of individual-level social factors and demographics, but the association was not seen in men. 11Another study of 5.6 million individuals in the United Kingdom showed that neighborhood deprivation was linked with incident AF and AF fatality. 12Similar findings were also noted in a study from Sweden. 13Neighborhood deprivation has also been linked with reduced overall anticoagulation and direct oral anticoagulants in patients with new-onset AF. 14 In Canada, a country with universal health care and prescription medication coverage, neighborhood deprivation was associated with a lower likelihood of cardiologist visit, and rhythm control interventions in patients with AF, despite having a higher cardiovascular disease burden. 15Other factors of the broader community and social context, such as social cohesion and network, community engagement, social support and discrimination have been linked with various aspects of cardiovascular disease in general, but have not been studied in AF specifically.Taken together, while individual-level social determinants of health are important drivers of AF, the broader social environment and neighborhood context also independently contribute to AF risks, outcomes, and disparities.More research is needed to further elucidate the complex relationships between social environmental factors, and their intersection with natural and built environment, with AF.

BUILT ENVIRONMENT
The built environment encompasses human-made surroundings, such as land use patterns, utilities, public spaces, and buildings.As such, the built environment includes a myriad of factors that influence human health, especially with the increasing urbanization.7][18][19] It is crucial to acknowledge that environmental hazards, such as increased fine particulate matter (PM 2.5 ) emissions from traffic roads, are often intertwined with built environments.However, it is equally vital to recognize the built environment as a distinct component of the exposome, given its unique and significant potential impacts on human health.The relationship between the built environment and AF specifically has not been well studied, but extrapolations can be made from relationships to overall CVD and its risk factors.Greenspace can modulate the impact of temperature and pollution as plants sequester pollutants and can reduce heat exposure.Greenspace has been shown to have various health benefits, including improved mental health, increased physical activity, and reduced exposure to air pollution, which could indirectly influence AF risk.In a study conducted by Wang et al, 20 it was observed that among Medicare beneficiaries in Miami-Dade, United States, those in the highest tertile of greenness had 6% reduced odds of AF compared with those in the lowest tertile of greenness.However, unlike other cardiac conditions such as myocardial infarction, ischemic heart disease, and heart failure, AF did not exhibit a clear linear relationship with greenness in terms of odds of the disease. 20One study has also shown that the availability of healthy food options in the environment is associated with a lower risk of incident AF. 21These data highlight the connection between food deserts, which are areas lacking access to healthy food options, and an increased risk of obesity and subsequent risk of AF.Further research is needed to examine the impact of the built environment on AF risk and outcomes.

AMBIENT ENVIRONMENT Air Pollution
The link between air pollution and AF has been under increased scrutiny in recent years given the central importance of air quality as an important risk factor for the incidence and exacerbation of CVD.A multitude of studies have put forward the possibility of an association between exposure to air pollution, notably particulate Circulation Research.2024;134:1029-1045.DOI: 10.1161/CIRCRESAHA.123.323477

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Exposome and Atrial Fibrillation matter and gaseous pollutants, and the incidence of new-onset AF. [22][23][24] (Figure 2).A comprehensive systematic review and meta-analysis were recently conducted to evaluate the short-term and long-term impacts of ambient air pollution on AF, encompassing 18 studies.The review revealed that short-term exposure to certain pollutants escalated the risk of AF.Furthermore, long-term exposure to air pollution, excluding ozone (O 3 ), was also significantly linked to the occurrence of AF in an otherwise healthy population.It was noted that these short-term effects fluctuated based on factors such as region, age, sex, and specific outcomes. 25nvironmental pollution, particularly air pollution, was found to have a significant impact on AF outcomes such as stroke.A study by Rhinehart et al 26 established a link between high levels of PM 2.5 in the air and increased risk of stroke in patients with AF, in patients from Allegheny County, Pennsylvania.Similarly, a study from Singapore by Tan et al 27 discovered a complex relationship between air pollutants and stroke risk in patients with AF, with increased concentrations of O 3 and carbon monoxide heightening the risk of acute ischemic strokes, whereas higher levels of sulfur dioxide (SO 2 ) appeared to mitigate it.
Fine particulate matter PM 2.5 , which represents fine particulate matter with a diameter of 2.5 micrometers or smaller, is the most studied air pollutant with respect to health hazards.Satellite-derived data suggest that attributable sources and composition of PM 2.5 vary across different regions and countries. 28,29Annual and daily PM 2.5 concentrations can vary greatly around the world.For example, in India, annual average PM 2.5 levels in cities like Delhi often exceed 100 μg/m 3 , which is >10× higher than the World Health Organization guideline of 5 μg/m 3 .Meanwhile, cities in the United States and Europe typically have annual averages between 5 and 15 μg/m 3 .Daily PM 2.5 levels in heavily polluted cities like Beijing, China can spike above 500 μg/m 3 on severely polluted days, while staying below 20 μg/m 3 on cleaner days.During major wildfires, PM 2.5

Figure 2. Exposure-response relationship curves between fine particulate matter (PM 2.5 ) concentrations and atrial fibrillation.
The associations were presented as the odds ratio of atrial fibrillation associated with each unit increase in PM 2.5 concentrations at lag 18 to 24 hours.The black lines were mean estimates and the shaded areas were 95% CIs.Reprinted from Liu et al 47  Exposome and Atrial Fibrillation levels can spike as high as 500 μg/m 3 over extended periods of time in downwind communities. 30tudies examining the relationship between PM 2.5 exposure and AF have produced mixed findings, likely due to differences in geographic location, patient characteristics, exposure duration, composition, and assessment methods.A significant portion of PM 2.5 is anthropogenic, that is, related to human activity.Initial studies have reported a significant association between increased PM 2.5 levels and an elevated risk of AF, particularly among older adults and patients with implantable cardioverter-defibrillators (ICDs). 31,32In a cohort study of patients followed in a medical center in Boston, MA, investigators noted that short-term exposure to PM 2.5 acts as an acute trigger for AF, with a 26% increased risk observed for every 6.0 μg/m³ increase in PM 2.5 levels in the 2 hours preceding an AF event. 31However, not all studies have consistently demonstrated a positive correlation between long-term PM 2.5 exposure and AF risk.Some investigations, including a case-crossover study and a retrospective analysis, found no significant associations between short-term or long-term PM 2.5 exposure and AF incidence. 33,34Similarly, a study in South Korea indicated that PM 2.5 may function as an acute trigger for AF but showed no correlation with long-term exposure risk. 35In contrast, another study employing machine learning techniques identified long-term PM 2.5 exposure as a critical predictor of incident AF in the South Korean population. 36Other studies have reported potential effects of long-term PM 2.5 exposure on AF risk.For example, a time-stratified case-crossover study observed an increased risk of AF episodes with PM 2.5 levels. 37A Chinese study found a 3.1% increased odds ratio of AF for every 10 μg/m³ increase in long-term PM 2.5 exposure. 38Additionally, a Taiwanese report revealed a positive association between elevated PM 2.5 levels and the emergence of new AF cases. 39 study from China observed seasonal variations in PM 2.5 concentrations, with higher levels reported during winter and lower levels in summer. 40The effects of PM 2.5 seemed to be heightened in settings of intense solar geomagnetic activity 41 and monsoon climates. 42his highlights the intricate relationship between meteorologic conditions and air pollution in influencing AF presentation.Moreover, secondary compounds such as NO 3 − , SO 4 2− , and NH 4 + , which constitute a significant portion of atmospheric PM 2.5 also exhibit seasonal fluctuations, 40 and likely carry a significant role.The association between PM 2.5 and incident AF seems to be independent of genetic determinants of AF.In a large study of >400 000 individuals enrolled in the UK biobank, PM 2.5 was associated with increased risk for AF independently of an AF polygenic risk score. 43n summary, while PM 2.5 exposure has been identified as a potential factor influencing AF incidence, further research is necessary to consolidate these findings and elucidate the specific conditions under which PM 2.5 poses an increased risk.The impact of underlying risk factors and confounding factors in the environment such as geographic location, and exposure duration must be taken into consideration, when evaluating the correlation between PM 2.5 exposure and AF.

Nitrogen Dioxide
Nitrogen dioxide (NO 2 ) is a highly reactive gas that plays a multifaceted role in our environment.In addition to being a key pollutant itself, NO 2 is used as a surrogate marker for a number of nitrogen oxide (NO x ) compounds that contribute to the formation of other gaseous pollutants. 44UV light in sunlight triggers photochemical reactions to form nitric oxide (NO), O 3 , and other volatile organic compounds, as well as nitric acid (HNO 3 ) and nitrous acid (HNO 2 ) that produce acid rain. 44NO x is largely generated from human activity, although a small amount is produced from natural sources such as forest fires, lightning, trees, grasses, and yeast.The environmental protective agency reports that about 50% comes from automobile/mobile sources and 20% from electrical power plants. 44An association between NO 2 exposure and increased risk of AF has been noted.Studies conducted in different geographic regions have reported this relationship, highlighting the global relevance of NO 2 as a risk marker for AF.
In Iceland, each 10 μg/m³ increase in NO 2 was associated with a 3% increase in AF-related emergency room visits, with a stronger effect observed in younger females. 45The Women's Health Initiative Cohort study also found that postmenopausal women residing closer to roads and experiencing long-term exposure to higher NO 2 levels had a greater risk of AF. 46 Similarly, a Chinese study observed a positive association between NO 2 levels and AF outpatient visits, particularly during cooler months.A 10 μg/m³ increase in NO 2 was associated with a 5.59% rise in daily outpatient visits for AF. 46nother study in China revealed that an interquartile range increase in NO 2 levels was linked to increased risk of AF, with stronger associations found in females, older individuals, and during cold seasons. 47he relationship between NO 2 and AF, however, is not universally consistent.A study conducted in Denmark, involving a large cohort of female nurses, did not observe a significant association between NO 2 exposure and AF incidence, even after adjustments for other factors. 48ene by environment interactions seems to play a role in a heightened risk of AF associated with NO 2 .Ma et al. recently showed a positive interaction between NO 2 exposure with AF polygenic risk score with respect to incident AF, with 35% of the AF risk being attributed to interactive effects between NO 2 and polygenic risk. 43here is substantial evidence supporting the association between NO 2 exposure and increased risk of AF.However, variations in study populations, exposure Circulation Research.2024;134:1029-1045.DOI: 10.1161/CIRCRESAHA.123.323477

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Exposome and Atrial Fibrillation durations, and adjustment factors may contribute to inconsistent findings.It may also be that NO 2 itself may not mediate these relationships, 23 as NO 2 levels are used as a surrogate marker for a multitude of NO x compounds, as described previously.Further research is needed to better understand the specific conditions and populations in which NO 2 exposure poses a significant risk for AF.

Ozone (O 3 )
Good O 3 occurs in the stratosphere (the upper layer atmosphere) to protect humans from the sun's UV light.This is in contrast with tropospheric (lowest major layer of the atmosphere) O 3 , which is formed through reactions with NO x and volatile organic compounds , 49 as previously described, and is a major component of air pollution and smog.O 3 acts as a generator of hydroxyl radicals, and through cascading reactions, forms additional oxidizing species in the atmosphere. 49O 3 has been linked to adverse respiratory outcomes and total mortality. 3,24,50Although numerous studies have reported significant associations between other pollutants and AF, the link between O 3 levels and AF has not always been as clear. 38,45A systematic review identified a statistically significant association between AF development and O 3 exposure, noting a population-attributable risk of 1.09 (95% CI, 0.20-1.86). 22Rich et al conducted a study focusing on patients living in the Boston, Massachusetts, metropolitan area, who had ICDs implanted between June 1995 and December 1999 (n=203), followed until July 2002.The researchers found a statistically significant positive correlation between episodes of paroxysmal AF and an increase in O 3 concentration (22 parts per billion) in the hour before the arrhythmia, reporting an odds ratio of 2.08 ([95% CI, 1.22-3.54];P=0.001). 51urthermore, Dahlquist et al 37 detected an association between O 3 levels and episodes of AF, in patients from Danderyd Hospital in Stockholm, Sweden, particularly during warmer seasons, consistent with findings of higher O 3 levels in high-pressure systems that limit vertical mixing, and during higher temperatures which are associated with increased photochemical activities. 49

NOISE POLLUTION
Noise pollution, specifically from sources such as traffic, aircraft, railways, and industrial/construction activities, has been associated with various negative health outcomes, including CVD like AF.Several studies have investigated the relationship between noise exposure and AF incidence.Song et al conducted a systematic review and found a significant association between noise exposure and the risk of AF (Figure 3).The pooled analysis of seven estimates indicated that the highest noise level was associated with a statistically significant increased risk of AF.Additionally, each 10 dB(A) increment in noise exposure was associated with a higher risk of AF. 52 Another study involving German population-based cohorts examined the association between noise annoyance from multiple sources and AF.The analysis revealed consistent and positive associations between noise annoyance and prevalent incident AF in men, while the association was weaker in women, particularly for incident AF. 53 A Danish study involving female nurses investigated the relationship between road traffic noise, air pollution, and AF incidence.The findings indicated that long-term exposure to higher levels of road traffic noise was associated with an increased risk of AF.However, the associations with air pollution were not significant. 48urthermore, a study analyzing a cohort of middle-aged individuals found that exposure to residential road traffic  Exposome and Atrial Fibrillation noise was associated with a higher risk of AF.The association remained consistent even after adjusting for air pollution. 54Noise is also associated with circadian disruption.Several studies have demonstrated an important impact of noise in disrupting the sleep cycle and circadian circuits. 55,56n summary, these studies suggest a potential association between noise pollution, including traffic-related noise, and increased risk of AF but these links are currently weak and require better-designed experiments that also focus on the noise exposome, which undoubtedly reflects other exposures including air pollution and psychological stress.

NATURAL ENVIRONMENT
Studies investigated the association between meteorologic conditions such as extreme temperatures and changes in humidity and air pressure, and AF.

Temperature
With the changing climates around the globe, it is critical to understand the impact of temperature effects on AF.It is estimated that >1 million global deaths are attributed to high and low ambient temperatures annually. 57esearch efforts have increasingly focused on exploring the connection between weather patterns, particularly temperature variations, and the incidence of AF.
9][60][61][62] The likelihood of emergency department visits due to AF escalates during these periods. 63,64When temperature plummets, the risk of AF onset tends to climb, with the elevated risk materializing 1 day postexposure and lingering for up to 5 days.In comparison to a reference temperature of 31.5 °C, extreme cold (−9.3 °C) significantly amplifies the risk of AF onset by 25% 65 (Figure 4).Further dissecting the influence of geography and demographics, the temperature impact on AF risk has been more acutely felt in the southern regions of China, where the effect tapered off at lower temperatures. 65cute AF episodes associated with nonoptimum temperatures accounted for around 7.59%, with southern region residents, males, and those under 65 years of age being most affected. 65However, there exist findings that challenge this observed pattern.An examination of data from the Get With The Guidelines-AFib registry, a nationwide initiative spanning 141 US-based hospitals, revealed no apparent seasonal variation in AF admissions. 66This study, as acknowledged by the authors did not account for other meteorologic factors outside of the season, and hospitals participating in the registry were heavily in academic urban areas of the United States.These findings echo the conclusions drawn from a study of 899 acute ischemic stroke patients from the Argentinean Stroke Registry.This research found that the occurrence of AF exhibited a seasonal variation and a nonuniform distribution across air temperatures.AF peaked in cold seasons and on stroke onset days marked by low temperatures. 67eyond AF incidence, multiple studies have also probed into the impact of different weather conditions on the stroke rate in patients with AF.A study leveraging data from Taiwan's National Health Insurance Research Database found that the incidence of ischemic stroke among patients with AF exhibited a seasonal variation.Specifically, stroke incidence peaked during winter and rose by 19% in comparison to summer.On average, days with temperatures below 20 °C were associated with a higher stroke risk compared with days with average temperatures of 30 °C.The risk elevation was also observed over longer durations with consistently lower temperatures.This suggests that AF-related stroke occurrences might also be modulated by environmental factors, such as temperature. 68Collectively, the existing body of research largely concurs on the correlation between temperature variations and AF incidence, noting a marked increase during periods of low temperatures and extreme weather conditions.This interplay also extends to AF-related stroke occurrences.Nevertheless, as some studies have reported no seasonal variation in AF or related hospital admissions, this affirms the need for further research to refine our understanding of this relationship and its implications for the management of AF.

Humidity and Atmospheric Pressure
The exploration into the interplay between humidity, atmospheric pressure, and AF remains in its nascent stages, with only a few studies shedding light on this complex relationship.One such prospective study in Boston, MA, which monitored 200 patients equipped with dual-chamber ICDs showed a strong correlation between lower absolute humidity (indicative of drier air) and increased likelihood of AF.Notably, a 0.5 g/m 3 decrease in absolute humidity over 24 hours increased the odds of AF by 4%, and even more startling, this likelihood spiked to 5% when exposure occurred within the previous 2 hours. 69he relationship between these factors demonstrates the intricate dynamics involved and emphasizes the significance of further exploration.However, contrasting evidence from a study conducted in northern Italy, which found no significant correlation between daily humidity and acute emergency department visits for AF, underscores the current inconclusiveness in the relationship between humidity and AF. 63Another 3-year investigation cataloged 1492 AF episodes, revealing a seasonal pattern in AF, unaffected by relative humidity levels, but linked to outdoor temperature and atmospheric pressure. 64dding to the body of evidence, a 10-year retrospective analysis from Israel found that weather conditions, inclusive of air humidity and atmospheric pressure, were significantly associated with the occurrence of paroxysmal AF.This correlation was especially pronounced in 87% of patients who had co-existing coronary heart disease, hypertension, or were of older age. 64 systematic review, surveying 15 studies, discovered a seasonal pattern in the occurrence of AF paroxysms, with peaks in winter and troughs in summer.Interestingly, the study identified an inverse correlation between temperatures and atmospheric pressure with the occurrence of AF paroxysms, suggesting a potential link between increased atmospheric pressure and heightened AF risk.However, the study also found a positive correlation with the duration of daylight, highlighting the intricate interplay of various environmental factors in AF onset.61 Given the limited evidence and the complexity of the relationship, more research is needed to better understand the association of humidity and atmospheric pressure on the incidence and outcomes of AF.While these studies hint at potential links the findings are far from uniform.The heterogeneity further underscores the importance of expanding our understanding of the intricate interplay between weather conditions and cardiac health.

OTHER ENVIRONMENTAL CHEMICALS
The number of chemicals that might come into contact with a human being is staggering with the European Chemical Agency recognizing over 130 000 molecules.Per-and polyfluoroalkyl substances, a class of forever chemicals, last in the environment for long periods.They are critical to the production of everything including smartphones, firefighters' suits, aircraft and electric vehicles, and especially microchips.Increasingly, per-and polyfluoroalkyl substances have been linked to CVDs. 3 Currently, there is limited knowledge on the role of chemicals on toxic metals on AF.The best-studied chemical in the context of AF is alcohol, which has been linked with incidence of AF, especially when it is consumed in large quantities as has been documented in other reviews on this topic 70,71

THE COMPLEX INTERACTION OF DIFFERENT ENVIRONMENTS IN THE EXPOSOME
Different parts of the exposome interact in complex, and not well understood, manner.For example, socioeconomic factors play a significant role in the exposure to environmental factors, and vice versa.Environmental justice studies have shown that individuals living in socially deprived regions are also at higher risk for adverse environmental hazards. 72A study by Klompmaker et  Exposome and Atrial Fibrillation between higher socioeconomic status and increased green spaces, as indicated by the higher Normalized Different Vegetation Index, NatureScore, park cover, and the likelihood of containing blue space.Specifically, urban areas with higher median household incomes had significantly greener and park cover compared with those in the lower income quintile.The study also noted racial and ethnic disparities, with areas having lower percentages of non-Hispanic White individuals and higher percentages of Hispanic individuals correlating with decreased green spaces.In urban areas, a weak positive association was observed between the percentage of non-Hispanic Black individuals and increased green spaces, while no clear associations were found for the percentage of Hispanic individuals. 73Similar findings of socioeconomic inequalities and access to greenspace have also been reported from Europe. 74ocioeconomic inequalities have also been associated with inequalities in environmental noise exposure. 75 study of noise pollution in the Greater Accra Metropolitan Area in Ghana, a rising environmental health concern in sub-Saharan African cities.By measuring environmental noise at 146 locations, the study utilized highresolution land use regression models to predict annual average noise levels.The findings unveiled that road traffic and vegetation majorly influenced noise variations.Predicted noise levels were highest in the city center and near major roads, with almost the entire population in the Accra Metropolis living in areas where noise levels exceeded World Health Organization guidelines for road traffic noise.Remarkably, poorer areas faced significantly higher median noise levels compared with wealthier areas, presenting a disparity of about 5 dBA.76 A review of socioeconomic inequalities in the World Health Organization European Region on ambient air pollution found strong evidence that areas with higher deprivation and lower economic status often face higher levels of pollutants like particulate matter (PM 2.5 , PM 10 ) and nitrogen oxides (NO 2 , NO x ).The review found that ethnic minorities have varied exposure, sometimes higher or lower compared with the majority population, depending on the specific minority group.The conclusion was that different social groups disproportionately bear the burden of higher pollutants across the World Health Organization European Region.77 Another study presented a model estimating personal PM 2.5 exposure for about 1.3 million children (aged, 4-16 years) in Greater London across different income groups.It combined data on time-activity patterns, outdoor and indoor air pollution concentrations, and building characteristics to account for variations in exposure.Results revealed disparities in personal exposure across socioeconomic groups.Children from the lowest income quintile experienced a median daily exposure of 17.2 μg/m³, whereas those from the highest income quintile had an exposure of 14.5 μg/m³.78 A study explored the issue of residential segregation in China, particularly focusing on the association between socioeconomic status, built environment, and health risks.The research, conducted on a 1 km×1 km grid scale, reveals that central areas with high housing prices generally have better-built environments, lower PM 2.5 concentrations, and lower mortality rates.In contrast, suburban areas with lower housing prices face poorer built environments, higher PM 2.5 levels, and increased mortality rates.The built environment's impact on health is found to be moderated and mediated by PM 2.5 levels and housing prices, offering crucial insights for mitigating health inequalities through informed urban planning in China.79 In Africa as well, similar trends are seen-A study addressed the lack of long-term air pollution exposure data in growing sub-Saharan African cities by developing high-resolution spatiotemporal land use regression models to map PM 2.5 and black carbon concentrations in the Greater Accra Metropolitan Area.The 1-year measurement campaign at 146 sites informed the models, revealing that 48% to 69% and 63% to 71% of the variance in PM 2.5 and black carbon concentrations, respectively, could be explained by factors related to road traffic, vegetation, and temporal variables.The entire population is exposed to PM 2.5 levels exceeding the World Health Organization guideline, with the poorest neighborhoods experiencing the highest exposures.80 Pasetto et al composed a review, of studies from 2010 to 2017 on justice in industrially contaminated sites in the World Health Organization European Region.81 Out of 14 articles identified, most showed an overburden of socioeconomic deprivation or vulnerability in areas assessed for environmental inequalities.81 In summary, global socioeconomic factors significantly influence environmental conditions, such as access to green areas, and levels of noise and air pollution, among other environmental health hazards.81 Recognizing the cycle of poverty in which poor health, impoverishment, and limited education continually feed into each other, 82 it is crucial now to include the built and natural environmental exposures and inequality in the cycle.82

MECHANISTIC INSIGHTS LINKING THE EXPOSOME AND AF
The mechanisms by which the exposome impacts AF risk remain understudied, but mechanistic insights can be extrapolated from studying the impacts on AF risk factors.Generally, the exposome effects are likely to be mediated through their effects on risk factors (eg, air pollution leading to inflammation, low neighborhood walkability increased obesity).Particulate matter air pollution is the most widely studied environmental risk factor for cardiovascular disease, and multiple studies have examined the pathophysiologic and molecular pathways involved.There is lack of studies that investigated the mechanisms of multiple simultaneous exposures.The underlying mechanisms are likely multifaceted, with both direct and indirect pathways influencing cellular and physiological processes, which act partly through known traditional and nontraditional AF risk factors, such as adipose dysfunction, fibrosis, and inflammation.For instance, walkability and access to healthy food resources in the built environment can directly encourage an active lifestyle and a healthier diet, influencing activity levels and mitigating obesity, a risk factor for AF.Greenspaces, by potentially improving air quality and fostering physical activity, also contribute to lower AF risk by reducing exposure to air pollutants.
Air pollutants are inhaled and can result in target organ effect via multiple pathways, including localized inflammation at the inhalation site (lungs), which results in systemic signaling and various downstream effects.Among air pollutants, the mechanisms of health effects of PM 2.5 exposure are the most studied (Figure 5).At the cellular level, cardiac inflammation, often worsened by air pollution, can lead to cardiac fibrosis, 24 a key factor in cardiac remodeling associated with AF. [83][84][85] Prior evidence with long-term exposure to PM 2.5 in mice suggests marked increases in myocardial fibrosis, left ventricular hypertrophy, and diastolic dysfunction with expression of a fetal gene expression program. 86PM 2.5 exposure is also associated with endothelial dysfunction in the coronary arteries with attenuation of coronary flow reserve suggesting an important impact of sustained PM 2.5 exposure on vascular function that could then initiate alterations in contractile function. 87Experiments involving mice have shown a dose-dependent relationship between PM 2.5 exposure and myocardial fibrosis severity with involvement of the renin-angiotensin system via activating the expression of Ang II, ERK1/2, and TGF-β1 in cardiac tissues induced by PM 2.5 . 88,89Human umbilical vein endothelial cells treated with PM 2.5 exhibit activation of the NLRP3 inflammasome pathway, 90,91 inducing TGF-beta1 production, collagen deposition, and fibrosis. 89,90,92ltered NLRP3 inflammasome activity has also been shown to be increased in cardiomyocytes and lysates of atrial whole tissue of patients with AF. 93 Pollutants like PM 2.5 , NO 2 , have been associated with increased levels of systemic inflammation as evidenced by elevated levels of circulating biomarkers like C-reactive protein 94,95 and interleukin-6. 95,96][99] Acute PM 2.5 exposure significantly disturbs atrial depolarization, as evidenced by P-wave complexity and PR duration. 100In human-induced pluripotent stem cell-derived cardiomyocytes, a concentration-dependent reduction in calcium transient amplitude was observed, along with increased early after depolarizations with increasing levels of PM 2.5 exposure. 101This exposure notably shortened action potential duration and reduced L-type calcium peak current density in a dosage-dependent manner. 101The data also suggest that PM 2.5 preferentially affects gene expression related to calcium signaling, with significant upregulation of transient receptor potential channel 3 (TRPC3), a phenomenon mitigated by pretreatment with pyr3, a TRPC3 inhibitor. 101The observed decline in mRNA levels of L-type calcium channels and Ca 2+ ATPase in patients with AF 86 may underlie the cellular mechanism through which PM 2.5 contributes to AF. 101 At a physiological level, PM 2.5 can result in autonomic dysfunction, blood pressure changes, myocardial fibrosis, and systemic inflammation that can all predispose to AF risk.5][106] A study reported autonomic imbalance in healthy individuals exposed to air pollution for over 15 years, characterized by lower parasympathetic modulation and overall heart rate variability. 107Another study of healthy elderly adults aged 60 years to 80 showed a notable decrease in heart rate variability following 2-hour exposure to concentrated ambient air pollution particles. 108He et al 109 further substantiated the acute adverse impact of PM 2.5 on cardiac autonomic modulation, highlighting significant effects within 6 hours and the most substantial between 3 and 6 hours postexposure.1][112] A study by Rankin et al 113 controlled diesel exhaust particle exposures that caused significant elevations within 30 minutes in several muscle sympathetic nerve activity metrics, compared with filtered air.Heart rate significantly increased, while there were trends for elevations in systolic and diastolic BP, likely hemodynamic consequences of SNS activation. 113In another study, comparing ultrafine carbon particles with or without concomitant ozone in a randomized, crossover, double-blind fashion did not result in sympathetic activation. 114In this study, norepinephrine was modestly increased, while the ratio between plasma dihydroxyphenylglycol and norepinephrine levels, a marker for norepinephrine clearance, was reduced with ultrafine carbon and O 3 .In a post hoc analysis of the Multi-Ethnic Study of Atherosclerosis cohort, a 17 ppb higher annual NO x concentration was associated with a 6.3% higher mean urinary epinephrine level; a 2 μg/m 3 higher annual ambient PM 2.5 concentration was associated with a 9.1% higher mean epinephrine and 4.4% higher dopamine levels. 115Thus, the totality of evidence supports peripheral autonomic dysfunction in response to air pollution exposure that could potentially serve as a trigger for AF in predisposed individuals.Some shared mechanisms are also noted with other environmental exposures.For example, exposure to loud noise and noise annoyance act as stressors, activating the autonomic nervous system and triggering the release of stress hormones, leading to physiological changes that can trigger AF in susceptible individuals. 116n studies involving healthy individuals and patients with CVD, short-term exposure to simulated aircraft and railway noise has been found to impair sleep quality and increase stress hormone levels, blood pressure, endothelial dysfunction, and oxidative stress, 116,117 all of which have been linked with AF risk.
Circadian disruption, associated with sleep fragmentation and reduced sleep quality, has been associated with an increased risk of AF. 118 Hypertension, which is an established risk factor for AF, has also been linked to both PM 2.5 and noise pollution. 118,119Recent animal and human studies provide additional insights.Exposure to noise and PM 2.5 may act at the amygdalar level, promoting autonomic imbalance and release of stress hormones with consequent oxidative stress, inflammation, metabolic abnormalities, altered gene expression, and endothelial dysfunction, both in healthy individuals and in subjects with preexisting CVD. 120An important interaction of noise and PM 2.5 in disrupting circadian rhythm in a manner similar to light at night exposure highlights the fact that stressors including light, noise, and air pollution may entrain common cardiovascular pathways of increased risk such as inflammation and oxidant stress. 55,56Experimental studies in animals have shown that noise-induced stress can increase blood pressure, stress hormone levels, endothelial dysfunction, oxidative stress, NOX2 (NADPH oxidase 2) activity, and vascular inflammation.These effects can be prevented by NOX2 deficiency. 118It is likely though unproven that, circadian disruption by noise and PM 2.5 exposure may indeed also induce susceptibility to AF.
The mechanisms governing the relationship between meteorologic conditions and AF are not fully elucidated; yet, despite several proposed hypotheses.One proposition revolves around the common pathways with noise and PM 2.5 , involving the autonomic nervous system.Meteorologic changes such as fluctuations in temperature, atmospheric pressure, and humidity may influence the autonomic nervous system which could potentially trigger AF in predisposed individuals.Another hypothesis centers around vasoconstriction and blood pressure.Cold climates and alterations in atmospheric pressure may induce peripheral vasoconstriction, leading to elevated blood pressure and increased heart strain.This heightened workload may provoke AF episodes. 121,122Inflammation is also considered a potential link.Shifts in temperature and other weather-related elements may cause variations in inflammatory markers such as C-reactive protein.Given that inflammation is believed to play a pivotal role in the onset and persistence of AF, weatherinduced inflammation could be a key factor.Another postulation is related to blood viscosity and coagulation.Particularly, cold weather conditions can elevate blood viscosity and induce a hypercoagulable state, potentially increasing the risk of thromboembolic events and consequently triggering AF. 121 Last, according to studies by Ahn et al 59 and Knezovic et al, 123 weather changes may affect the concentration levels of air pollutants.Thus, meteorologic changes might indirectly influence AF by altering air pollutant compositions.
A recent dual-risk model suggested that genetic predisposition to AF may become apparent when cellular stressors surpass the adaptive response capacity. 124The exposome, therefore, may modulate the stressors that interact with genetic susceptibility to influence AF occurrence.Overall, these hypotheses illustrate the potential multifaceted interactions between weather conditions and AF, emphasizing the need for continued research to fully unravel this complex relationship. 75

GAPS IN KNOWLEDGE AND FUTURE DIRECTIONS
Several gaps in knowledge and future research directions have emerged in understanding the comprehensive impact of the environment on the risk and outcomes of AF.First, while numerous epidemiological studies have explored the association between environmental factors and AF risk, there is a need for more longitudinal studies that can establish causality and elucidate the temporal relationship between exposure and incidence and progression of AF.Additionally, the underlying biological mechanisms linking environmental exposures to AF remain incompletely understood and with inconsistent findings at times, warranting further investigation into the molecular and cellular pathways involved.
Furthermore, the impact of cumulative and chronic exposure to multiple environmental risk factors on AF development requires comprehensive assessment.Integrating data from diverse environmental domains, such as air pollution, noise pollution, green space, and social environment, will provide a more holistic understanding of the environmental exposome and its influence on AF.In parallel, advancements in technology and remote sensing can enable high-resolution exposure assessment (such as through airnow.gov),facilitating the identification of specific exposure metrics and thresholds that may be particularly relevant to AF.
Global shifts in climate have resulted in increasing frequency and intensity of natural disasters such as hurricanes, floods, and heatwaves.An increase in the prevalence of AF following an earthquake in Japan has been reported. 125,126Subsequent follow-up studies of the same population noted a continued increase in rates of AF for up to 3 years following the disaster. 127This surge was attributed to a concurrent rise in poor lifestyle, increased Exposome and Atrial Fibrillation inflammation, and heightened psychological stress following the disaster.Given that stress is a known trigger for AF, it's imperative to investigate further how the escalating frequency and severity of natural disasters, stemming from climate change, might influence its incidence.
Following a large earthquake in Japan, an increase in obesity and alcohol intake was noted, along with heightened inflammation, which was attributed to the heightened psychological stress experienced after the major natural disaster. 125Natural disasters can lead to acute stress, physical exertion, disruption in medical care, and other physiological changes that could precipitate or exacerbate AF episodes.Furthermore, the psychological strain associated with climate change events could be a triggering factor for AF in vulnerable populations.Exploring the relationship between environmental stressors and AF can provide a comprehensive understanding of its triggers and potential preventative measures, ensuring better cardiovascular care in an age marked by escalating environmental challenges.
Integrative and agnostic models that combine multiple tiers of information at the genomic, epigenomic, transcriptomic, and epi-transcriptomic pathways are needed to provide an integrative narrative on AF.Understanding the interactions between genetic predisposition and environmental factors will help further tailor prevention and intervention strategies to effectively mitigate the burden of AF.Additional studies are also needed to examine the relationship between the progression of AF, its severity, the incidence of stroke, and its links to the exposome.
Finally, a glaring issue within exposome and AF research is the alarming deficiency of data involving key demographic groups. 6This shortfall in data is particularly concerning for individuals from underrepresented racial and ethnic groups, who may exhibit unique risk factors or disease trajectories, which are currently underexplored.Additionally, further research is needed on people with high-risk occupations, such as those with high noise or chemical exposures.The issue is compounded for those of lower socioeconomic status, where the interplay between economic factors and health outcomes remains inadequately examined.Furthermore, individuals with low health literacy-an important demographic often overlooked-represent another area where our understanding remains limited.These research gaps present significant hurdles in achieving a truly comprehensive understanding of the impacts of the environment on risk and outcomes in AF, hence highlighting the urgent need for a more inclusive research approach.

CONCLUSIONS
Given the crucial role of natural, built, and social environments in influencing the occurrence of AF, it is essential to transition to systems approaches capable of mitigating the AF disease burden.The impact of broad exposomic changes on AF risk urgently requires extensive research.These exposomic shifts, driven by environmental modifications, have the potential to both amplify and mitigate AF risk.It is crucial to acknowledge that not all environmental changes enhance risk; some can indeed be beneficial, diminishing the likelihood of AF.Future research should delve into this dual aspect by exploring these relationships in diverse populations.It should also consider potential effect modifiers and scrutinize the underlying mechanisms through which the environment alternately heightens or lessens AF risk through exposomic variations.
Our understanding of the impact of various air pollution components on AF is still incomplete.The United States environmental protective agency identifies 6 major air pollutants-ground-level ozone, particulate matter, carbon monoxide, lead, sulfur dioxide, and nitrogen dioxide-as potentially harmful to the environment and health.However, detailed literature on their individual effects on AF for many of these pollutants is limited, highlighting the need for further studies.The relationship between the social environment, exposure to pollutants and climate events, and built environments and their subsequent effect on AF is highly intricate.This complex interaction involves multiple factors and dimensions that intersect and influence one another in various ways.The social environment can significantly impact individuals' exposure to pollutants and climate change, which, in turn, can affect the incidence and progression of AF.Despite the recognized interconnections, substantial gaps in understanding remain.Further investigation is essential to comprehensively elucidate the multifaceted interactions and impacts concerning the socioeconomic environment, pollutants, and climate change, and AF, ultimately enabling more effective prevention and management strategies for AF in diverse populations and contexts.
The rapid increase in urbanization across the globe has led to denser cities with significant challenges.These challenges include an increase in poverty, as economic disparities are exacerbated by the rising cost of living and inadequate infrastructure to support the growing urban populations.This situation is compounded by the continued reliance on fossil fuels and increasing energy consumption, which in turn contributes to environmental degradation and climate change.The intertwined effects of these factors have a direct and measurable impact on both mental and physical health.We must acknowledge the vicious cycle of poor health, lack of financial resources, and limited access to education which create an interdependent self-perpetuating loop.To this cycle, we must now add the dimensions of built and natural environmental exposures, which disproportionately affect minoritized communities resulting in an additional dimension of inequality: environmental inequality, and as a result disparities in AF-associated morbidity and mortality.These elements interlock to form a complex web that affects health outcomes, emphasizing the need for Circulation Research.2024;134:1029-1045.DOI: 10.1161/CIRCRESAHA.123.323477

Wass et al
Exposome and Atrial Fibrillation holistic approaches to urban planning and health care that address these interconnected issues.Understanding the association between the exposome and AF has significant implications for public health, clinical practice, and the formulation and execution of healthprotective environmental policies.This understanding emphasizes the need for clinicians to recognize broad environmental exposures as potentially modifiable risk factors for AF, guiding them in offering practical lifestyle recommendations to patients.A comprehensive understanding of these connections will also facilitate the development and implementation of integrated policy solutions.These solutions, aimed at reducing a wide array of environmental exposures, would naturally encompass initiatives in urban planning.Thoughtful urban planning strategies, such as zoning for green space and promoting renewable energy transitions, can contribute significantly to mitigating exposures implicated in AF, thereby lowering the global burden of this condition.Furthermore, this understanding underscores the crucial role of health care professionals as advocates for a healthier environment.Physicians and other health care workers are positioned to lead in championing environmental policies and urban planning efforts that prioritize public health and contribute meaningfully to the reduction of AF and other environmentally influenced conditions.The collaborative efforts of health care professionals and policymakers can significantly advance public health, demonstrating a unified commitment to safeguarding both the environment and the health of individuals worldwide.

Figure 1 .
Figure 1.A conceptual framework linking the exposome and atrial fibrillation.Some mechanisms have been identified but many remain to be investigated.The personal exposome and the external exposome interact with components of the biologic responses and drivers (such as epigenetics, inflammation, autonomic dysfunction) to increase the risk of atrial fibrillation (AF) either via traditional risk factors (eg, hypertension, obesity) or via direct impact on cardiac myocytes.The traditional risk factors may also increase the risk of AF directly, or via intermediary cardiovascular events (eg, heart failure; Illustration credit: Ben Smith).

Figure 3 .
Figure 3. Noise and atrial fibrillation.Association between noise exposure and the risk of atrial fibrillation in a meta-analysis of cohort studies.Relative risks (RRs) for the highest noise level are noted on the x axis (Redrawn from data from Song et al 52 with permission.Copyright ©2022, Environmental Science Pollution Research International).

Figure 4 .
Figure 4. Ambient temperature and atrial fibrillation risk.Findings are from a national study in 322 cities in China.A, National exposure-response curves for the associations between ambient temperature (°C) and acute onset of atrial fibrillation episodes cumulated over 0 to 7 days.B, National and region-specific lag structures for the associations of atrial fibrillation episodes onset with extremely low temperature.The associations were presented as relative risks comparing the extremely low temperatures to the referent temperatures (31.5 °C).The solid black lines are the mean estimates for the relative risks of atrial fibrillation episodes onset, and the gray areas are their 95% Cis (Reprinted from Zhu et al 65 with permission.Copyright ©2023, The Science of the Total Environment).

Figure 5 .
Figure 5. Mechanisms of air pollution, noise, and ambient temperature on risk of atrial fibrillation (AF).Cellular responses include eNOS (endothelial nitric oxide synthase) uncoupling, oxidative stress, and vascular inflammation, while systemic effects involve autonomic imbalance, hypothalamic pituitary adrenal (HPA) axis activation, immune activation, and circadian disruption.These processes collectively result in a cascade of events, including obesity, insulin resistance, hypertension, inflammation, myocardial fibrosis, hemodynamic stress, and atrial remodeling, all contributing to the pathogenesis of AF.The red boxes show intermediate pathways that have been traditionally been linked with AF and can be exacerbated by the shown environmental exposures.Understanding these complex interactions is vital for developing targeted interventions aimed at mitigating the impact of environmental factors on AF susceptibility (Illustration credit: Ben Smith).PM 2.5 indicates fine particulate matter.