Association of early life adversity with cardiovascular disease and its potential mechanisms: a narrative review

Strong epidemiological evidence has shown that early life adversity (ELA) has a profound negative impact on health in adulthood, including an increased risk of cardiovascular disease, the leading cause of death worldwide. Here, we review cohort studies on the effects of ELA on cardiovascular outcomes and the possible underlying mechanisms. In addition, we summarize relevant studies in rodent models of ELA. This review reveals that the prevalence of ELA varies between regions, time periods, and sexes. ELA increases cardiovascular health risk behaviors, susceptibility to mental illnesses, and neuroendocrine and immune system dysfunction in humans. Rodent models of ELA have been developed and show similar cardiovascular outcomes to those in humans but cannot fully replicate all ELA subtypes. Therefore, combining cohort and rodent studies to further investigate the mechanisms underlying the association between ELA and cardiovascular diseases may be a feasible future research strategy.


Introduction
Since Felitti et al. conducted the Adverse Childhood Experiences Study in 1998, the relationship between Early Life Adversity (ELA) and negative long-term health outcomes has attracted much research attention (1).Also called adverse childhood experiences in human studies, ELA is defined as potentially traumatic events that occur before adulthood, including threats to the child's bodily, familial, or social safety and security, and ranges from broad categories of abuse, neglect, and household dysfunction to more specific experiences of bullying, exposure to crime, victimization, and economic hardship (1)(2)(3)(4).ELA is highly prevalent, with regional variations occur.According to data from the Behavioral Risk Factor Surveillance System, 61.55% of adults in the United States have experienced ELA (2); in European countries, this figure ranges from 20.4 to 69.4% (5).In Chinese middle-aged or older adults it can be up to 80.9%, according to data from the China Health and Retirement Longitudinal Study (6).Societal changes over time affect the prevalence of specific adverse experiences.For example, during the first 15-18 years of the 21st century, parental illness, sibling death, exposure to domestic violence, childhood poverty, parental divorce, serious childhood illness, physical abuse, sexual abuse, physical and emotional bullying, and exposure to community violence declined; however, parental alcohol and drug abuse increased (7).ELA exposure has been strongly associated with the development of various health conditions in later life, including cardiovascular disease, which is the leading cause of death worldwide.Cohort studies indicate that ELA increases the odds of cardiovascular health risk behaviors, such as smoking and alcoholism, as well as having longterm effects on the stress response system, leading to autonomic, vascular, and inflammatory dysfunction, and contributing to the onset and development of cardiovascular disease (4).Rodent models such as maternal separation have been developed to study the underlying mechanisms of cardiovascular effects of ELA.Consistent with human cohort studies, negative cardiovascular outcomes were observed (8).
This review provides an overview of the epidemiological evidence linking ELA to the development of cardiovascular disease and the mechanisms underlying the effects of ELA on the cardiovascular system.In addition, we summarize the rodent models that have been developed to mimic ELA and mechanistic studies performed using these models.Finally, we discuss the direction of future research.

ELA and cardiovascular outcomes in humans
An increasing number of cohort studies have shown ELA to be strongly associated with negative cardiovascular outcomes (Table 1).Different types of adversities have been carefully classified, and their effects studied.Abuse, neglect, and household dysfunction are the three most common types of adversity; all of these have been shown to increase the risk of cardiovascular events in adulthood, including ischemic heart disease, myocardial infarction, coronary heart disease, stroke, and heart failure (9, 11, 13-15, 18, 19, 21).These correlations were dose-dependent, the more types of adversities experienced, the higher the risk (9,13,18).Exposure to a single adversity type has been associated with a 1.3-to 1.7-fold increase in the risk of ischemic heart disease compared with that of individuals not exposed to adversity (9).The risk of developing myocardial infarction was increased in individuals who experienced ELA compared with those who did not, while the risk of developing coronary heart disease and stroke was increased in individuals exposed to more than four types of ELA compared with those who experienced fewer types (13).The risk of developing heart failure doubled following exposure to three to five types of ELA (18).
Certain specific types of ELA have also been associated with cardiovascular events.The risk of hypertension was increased in males who have witnessed violence with a weapon and female victims of violence (12).Fetal exposure to famine increased the risk of diabetes (16), while famine experienced in early life increased the risk of total cardiovascular disease, myocardial infarction, stroke, and coronary heart disease (17).In addition, early exposure to air pollution increased the lifetime burden on the cardiovascular system, contributing to the development of cardiovascular disease (22).
Sex differences are observed in the incidence and effects of ELA.Within the same racial and ethnic population, females are more likely than males to experience ELA (23).The risk of cardiovascular disease increased in women who were exposed to financial difficulties, interpersonal conflicts, and chronic illness in a relative.For men, an increased risk was observed only following chronic illness in a relative (10).Stoke was most strongly associated with physical abuse in women and household incarceration in men (20).
ELA increases the risk of both cigarette and e-cigarette smoking (25, 26,31,35), with exposed individuals more likely to start smoking by 16 years of age and smoke for a lifetime (36).Physical abuse was associated with smoking in both males and females; sexual and verbal abuse were associated with smoking in females but not males (27).This correlation has intergenerational effects, maternal exposure to childhood physical abuse was associated with an increased risk of both smoking during pregnancy and the child smoking (29).
ELA is also associated with high-intensity binge drinking (32).Heavy and binge drinking was more common in men who lived with a drug abuser as a child than in those who did not, and verbal abuse was correlated with binge drinking in both men and women (30).The greater the total number of adversities experienced, the higher the probability of binge drinking (28,37).Although some studies suggest that moderate drinking may be beneficial for cardiovascular health, large cohort studies have shown that all levels of alcohol consumption are associated with an increased cardiovascular risk (45-47).
A meta-analysis showed that physical inactivity increased among children and adolescents exposed to bullying (33).A separate metaanalysis of 10 observational studies showed that the risk of obesity in adulthood increased 46% following ELA (34).Physical inactivity and obesity have been closely associated with high blood lipid, glucose, and blood pressure levels, which are major contributors to cardiovascular disease (48,49).
A systematic review and meta-analysis indicated that ELA has a considerable impact on long-term sleep health: the greater the exposure, the higher the risk of sleep disorders (38).ELA exposure was associated with both short and long sleep duration: victims of childhood sexual abuse were 146% more likely to short sleep and 99% more likely to long sleep; reporting more than four types of adversities raised these risks to 3.10 and 2.13 times, respectively (39).Both short and long sleep duration and poor sleep quality are associated with an increased risk of all-cause mortality and cardiovascular events (50, 51).

Mental factors
ELA is associated with the development of mental illnesses in adulthood, including anxiety, depression, post-traumatic stress  (19).
The number of adversity types experienced was a nonlinear predictor of depression (55).A meta-analysis including over 200,000 participants showed that individuals maltreated in childhood had an increased risk of depression and cardiometabolic disease, and were three times more likely to have comorbid depression and cardiometabolic disease (56).A systematic review and meta-analysis associated childhood trauma with the severity of hallucinations and delusions in individuals with psychotic disorders (57).In addition, patients with schizophrenia report more exposure to ELA than healthy controls (58).
Mental illness increases the burden on the cardiovascular system through biological pathways such as elevated cortisol, oxidative stress, inflammation, and autonomic nervous system dysfunction, as reviewed in detail by Treur et al. (59).Patients with severe mental illness have twice the cardiovascular mortality rate of the general population (60,61).Both anxiety and depression are associated with an increased risk of mortality owing to cardiovascular events (62,63).Schizophrenia reduces life expectancy by 15-20 years, with 40-50% of deaths due to cardiovascular disease (64).Thus, ELA may predispose individuals to cardiovascular diseases later in life through their susceptibility to mental illnesses.

Biological pathways
ELA disturbs the neuroendocrine and immune systems in adulthood; this dysregulation has been associated with cardiovascular diseases.Hypothalamic-pituitary-adrenal (HPA) axis dysfunction has been observed in individuals exposed to ELA (65-68).A meta-analysis indicated that cortisol levels affected by ELA (67).Bullying, emotional abuse, and cumulative exposure to adversity have been associated with low daytime salivary cortisol levels in adolescents (66).Increased levels of hair cortisone were detected among middle-aged and older individuals exposed to ELA (65, 68).Meta analyses have indicated that ELA increases levels of inflammatory mediators such as C-reactive protein, interleukin-6, and tumor necrosis factor-α (69,70).These effects persist into late adulthood (71).Dysregulated inflammation and cortisol levels may contribute to the development of mental illnesses such as depression (72-74), increasing the risk of cardiovascular disease.
ELA has been reported to directly increase circulating endothelin-1 levels in young adulthood, with greater numbers of adversity types faced further increasing endothelin-1 levels (75).Endothelin-1 is a peptide produced by the vascular endothelium in response to stress (76, 77) and is implicated in the pathogenesis of cardiovascular diseases (78).Physical exercise decreases endothelin-1 levels among women exposed to ELA and improves cardiovascular psychophysiological outcomes; endothelin-1 may therefore be a potential therapeutic target for the treatment of cardiovascular diseases following ELA (79).
4 Impact of ELA on the cardiovascular system in rodents 4.1 Rodent models of ELA In humans, ELA primarily involves abuse, neglect, and household dysfunction.To mimic these adversities, several types of rodent models have been developed: (1) Maternal separation, in which pups are removed from their mother for several hours per day (at different times each day) during the postnatal period (2).Social deprivation, in which pups are separated from both their mother and littermates for several hours per day (at different times each day) during the postnatal period (3).Limited bedding and nesting, in which the mother and pups have limited access to nesting material during the postnatal period (4).Early weaning, in which pups are weaned before postnatal day 21, usually on postnatal day 17.Of these, maternal separation is the most widely used.To simulate multiple ELA exposures, these models are used in combination, such as maternal separation combined with limited bedding and nesting and maternal separation combined with early weaning (80, 81).These rodent models effectively simulate the negative outcomes of ELA, behavioral experiments have shown that rodents exposed to ELA elicit negative psychopathological outcomes in adulthood.Mice exposed to maternal separation and limited nesting were more susceptible to depression-like behaviors after social defeat (82).Social deprivation during postnatal days 1-14 increased the risk of social dysfunction later in life (83).

Mechanisms underlying the effect of ELA on the cardiovascular system in rodents
Consistent with results from human studies, ELA in rodents negatively affects the cardiovascular system (Table 3).Neuroendocrine, immune system and vascular dysfunction have been identified following ELA in rodents.Dysfunction in the HPA axis and reninangiotensin-aldosterone system were detected in rats and mice following maternal separation, as evidenced by increased levels of corticotropin-releasing hormone, adrenocorticotropic hormone, corticosterone, and angiotensin II (84,86,92).Circulating endothelin-1 levels were significantly increased in rats following maternal separation (85).In a mouse model of maternal separation, acute mixing stress induced lower blood pressure and heart rate responses (87).Maternal separation in rats resulted in misprogramming of resistance artery smooth muscle, increased vasoconstriction and blood pressure (88), and blood-brain barrier dysfunction (84, 95).ELA also increased oxidative stress and inflammation.Levels of the reactive oxygen species nicotinamide adenine dinucleotide phosphate oxidases 2 and 4 (89, 90) and the inflammatory protein interleukin-1β and Toll-link receptor 4 (93,95) were increased in rodents following ELA.ELA may be linked to oxytocin signaling, cardiac oxytocin receptors decreased following maternal separation on postnatal days 1-21, but increased following maternal separation on postnatal days 12-16 (91).Maternal separation and early weaning increased adiposity in female mice, which may be the mechanism underlying the development of obesity and diabetes following ELA (94).
Frontiers in Public Health 06 frontiersin.org5 Discussion and future directions Despite the progress in community and family support, ELA remains highly prevalent and contributes to the morbidity and mortality of cardiovascular diseases worldwide.The prevalence of ELA varies between countries and regions, and between sexes.Over time, the prevalence of different subtypes of ELA changes.This means that the adoption of rigorous sampling strategies is required to dynamically surveil the prevalence of subtypes of ELA and minimize data bias (7).It also means that policymakers need to be flexible in the use of prevention strategies to reduce the incidence of ELA.Numerous cohort studies have revealed the association between ELA and cardiovascular disease, with the risk increasing with greater ELA exposure.However, the frequency, intensity, exposure duration, and exposure timing of each subtype of ELA, which may also have an impact on cardiovascular outcomes, have not been fully assessed (96).Each individual's childhood experience is unique and may experience some specific subtypes of ELA.Therefore, how to accurately evaluate the effect of ELA on an individual's cardiovascular system requires further investigation.
Mechanistic studies in humans have shown that ELA increases cardiovascular health risk behaviors, susceptibility to mental illnesses, and neuroendocrine and immune system dysfunction.But whether ELA directly affects the development of cardiovascular disease or whether the association between ELA and cardiovascular disease is fully mediated through risk behaviors remains to be determined.Rodent models have been developed to study the mechanisms underlying the effects of ELA on cardiovascular outcomes and result in cardiovascular dysfunction similar to that observed in humans.Rodents exposed to ELA showed similar behavioral tendencies to humans exposed to ELA, such as alcohol consumption (97), drug addiction (98), and depression-like behavior (82).However, whether these behavioral effects contribute to cardiovascular outcomes remains largely unknown.Rodent models provide an important research tool as they allow the association between ELA and cardiovascular disease to be analyzed in a homogenous population under controlled conditions.However, these models cannot fully replicate all of ELA subtypes.Therefore, combining cohort and rodent studies to analyze the association between ELA and cardiovascular diseases may be a feasible future research strategy.

TABLE 1
Large cohort studies on the correlation of ELA with cardiovascular outcomes.
Material deprivation (family poverty, parental long-term unemployment), Loss or threat of loss in the family (parental and sibling somatic illness and death), Family dynamics (foster care placements, parental and sibling psychiatric illness, parental alcohol and drug abuse,

TABLE 2
Correlation of ELA with cardiovascular risk behaviors.PTSD), and schizophrenia.Cohort studies have shown that ELA increases the incidence of anxiety, depression, and PTSD (52-54).ELA exposure has been associated with both the onset and severity of depression and cardiovascular disease n = 108,330, participants from 5 high-income countries Sleep deficiency and poor sleep quality Yu et al. (38) Physical abuse, Sexual abuse, Verbal abuse, Mental illness, Substance abuse, Separation/divorce, Violence in adults, Incarceration 2020 Behavioral Risk Factor Database participants n = 42,786, 55.8% female, aged ≥65 years Short and long sleep duration Cheng et al. (39)

TABLE 3
Molecular and/or structural alteration following ELA on cardiovascular system in rodent.