The biological, psycho-social & behavioural pathways through which ACEs ‘get under the skin’
Adverse childhood experiences (ACEs) result from exposure to abuse, neglect, or traumatic living conditions, such as parental conflict or substance abuse, occurring before the age of 18 (Felitti et al., 1998; Hughes et al., 2017). There is a vast body of literature demonstrating the pernicious effects of ACEs on physical and mental health outcomes throughout the lifecourse (Hughes et al., 2017; Soares et al., 2021), including cardiovascular health (CVH) risks and outcomes (Godoy et al., 2020; Su et al., 2015). Cardiovascular diseases (CVDs) constitute the leading cause of mortality globally (Vaduganathan et al., 2022), with a high incidence of comorbidities (Buddeke et al., 2019). This essay discusses evidence from lifecourse research showing that early-life adversities create the conditions for CVD to arise via biological, psychosocial, and behavioural mechanisms.
Biological mechanisms
While the links between ACEs and CVD incidence and mortality have been well-established (Godoy et al., 2020; Su et al., 2015a), the biological mechanisms underlying these associations have only recently begun to be explored. Findings from recent longitudinal studies suggest that adverse psychosocial experiences in childhood elevate the risks of CVD by way of cardiometabolic and immune alterations (Danese et al., 2009; Deschênes et al., 2021; Li et al., 2018; Loucks, et al., 2014; Su et al., 2015b).
Cardiobematolic dysregulation
A study of the 1958 British birth cohort revealed modest associations between childhood maltreatment and at least one of three cardiometabolic outcomes in mid-adulthood – adiposity (i.e., waist circumference, BMI), blood lipids and blood sugar levels (via HbA1c) (Li et al., 2018). Neglect and physical abuse, in particular, were seen to predict high adiposity and blood sugar profiles. While modest, the observed associations were shown to be independent of birth weight and socioeconomic position (SEP), which are known early-life health determinants. (Huxley et al. 2004; Power et al., 2013).
In addition to demonstrating primary biological pathways for the detrimental effects of ACEs on CVH in later life, findings also suggest that key lifestyle factors (e.g., smoking) may play a role in mediating some of these effects, especially amongst victims of abuse and neglect (Li et al., 2018). This indicates that biological and behavioural pathways are interlinked, as illustrated by the lifecourse epidemiology ‘accumulation of risks’ and ‘chain of risk’ models, which will be further discussed in the context of psychosocial and behavioural mechanisms (Kuh et al., 2003).
The study’s strengths include its longitudinal nature and population-based cohort, followed over five decades, and the range of cardiometabolic measures collected (Li et al., 2018). Temporality, in particular, allowed for causal mechanisms to be explored and identified (Hales et al., 2022). The study also benefited from distinguishing between forms of maltreatment (sexual/physical/emotional abuse and neglect), and collecting prospective and retrospective reports of maltreatment, thereby mitigating the risks of social desirability and recall bias (Li et al., 2018; Althubaiti, 2016). Limitations include sample attrition, and the low prevalence of sexual abuse reported, which may have been insufficient to detect any significant associations.
Inflammation
Findings from a New Zealand birth cohort study also demonstrate associations between ACEs and metabolic dysregulation, as well as immune abnormalities, which are well-established risk factors for age-related diseases such as CVD (Danese et al., 2009). As seen in Li et al., this study also sought to distinguish between different forms of adversities, and thus defined ACEs as spanning not only childhood maltreatment, but also socioeconomic adversity and social isolation. A dose-response effect was observed, whereby the risk of age-related-disease increased in accordance with the severity and number of adversities faced. Despite being too young to present with any chronic diseases at age 32, participants who had experienced maltreatment during childhood, in particular, were more likely to have elevated inflammatory markers. These findings are consistent with that of longitudinal studies concerned with exploring associations between ACEs and inflammation (Chen & Lacey, 2018; Crick et al. 2022), as well as supporting the model of biological embedding (Berens et al., 2017).
Biological embedding & allostatic load
A lifecourse epidemiology model, biological embedding posits that early-life adversities alter biological processes in enduring ways, resulting in physiological disruptions that have consequences for later life health and wellbeing (Berens et al., 2017; Hertzeman, 2012). These span neuroendocrine, immune and metabolic dysregulations that form risk factors for non-communicable diseases, such as CVD. Such lasting dysregulations appear to result from either prolonged or frequent exposures to stressors during sensitive periods (i.e., when the organism is undergoing rapid development and is highly plastic, and therefore susceptible).
Enduring exposure to stressors is also thought to result in allostatic load (McEwen, 1993). While not exclusive to ACEs, the allostatic load paradigm proposes that the lasting effects of chronic stress are characterised by insufficient or exaggerated stress responses, which, in turn, are linked to a number of pathologies (Berens et al., 2017; Danese & McEwen, 2012). Indeed, recent longitudinal evidence has linked stress sensitivity, as measured by amygdala reactivity, with CVD events (Tawakol et al., 2017). While epigenetic mechanisms are thought to underlie biological embedding and many of the physiological dysregulations resulting from allostatic load, causal evidence is needed to verify these mechanisms (Aristizabal et al., 2019).
Psychosocial mechanisms
As well as being at higher risk of CVD, individuals with a history of ACEs are more likely to present with psychosocial challenges and affective disorders in later life (Felitti et al., 1998; Sahle et al., 2021). Evidence from a number of longitudinal studies exploring the multifaceted, and often interlinked, physical and mental impacts of ACEs suggests that early-life exposures can heighten experiences of stress in adulthood (Matthews et al., 2022; Mosley-Johnson et al., 2021; Pulkki-Råback et al., 2015; Westerlund et al., 2012), as well as compounding the likelihood of mental illness (Deschênes et al., 2021; Lehman et al., 2009). Elevated stress levels and poor mental health outcomes are, in turn, positively associated with poor CVH and CVD mortality (Liu et al., 2022; Malik et al., 2020; Rugulius, 2002).
Stress
Two recent prospective studies, which utilised data from the Midlife in the US (MIDUS) population-cohort, shed light on the far-reaching, nuanced effects of ACEs in predicting and modulating stress. One study explored the impact of ACEs on stress arising from day-to-day tasks and responsibilities, and self-reported physical health (Mosley-Johnson et al., 2021). Findings suggest a graded relationship between ACEs and the incidence of daily stressors, stress severity, as well as physical symptoms, irrespective of sociodemographic and economic differences. Abuse, in particular, was associated with an increased volume and frequency of stressors. Causality, however, cannot be inferred, as data for ACEs and stress were collected at the same point in time.
A more recent study examined the relationships between ACEs, adulthood psychosocial disadvantages (APDs), such as job strain and social isolation, and hypertension (Matthews et al., 2022). It found that, while ACEs were not directly associated with blood pressure (BP) profiles, where present, ACEs tended to strengthen the association between APDs and risk of hypertension. As per the findings from Mosley-Johnson et al., this suggests that ACEs appear to magnify perceived day-to-day stress; cohort studies from Finland and Sweden support these findings (Pulkki-Råback et al., 2015; Westerlund et al., 2012). The mechanisms through which psychosocial stress, in turn, heightens CVD risk are well known, and include autonomic dysregulations that span neuroendocrine and cardiometabolic changes (Kivimäki & Steptoe, 2017).
While displaying many strengths, namely large sample sizes and longitudinal designs, the two studies discussed are limited by a retrospective, self-reported ascertainment of ACEs. Furthermore, findings stemming from the MIDUS dataset, more broadly, cannot be generalised to non-white, non-middle-aged individuals with lower levels of education (Matthews et al., 2022).
The observed effects of ACEs on individuals’ experience of stress supports the diathesis-stress, or vulnerability-stress, model, which first arose in the field of psychology (Kalamatianos & Canellopoulos, 2019). It posits that early-life exposures to chronic stress lower the threshold for stress reactivity in ways that endure and come to bear on psychological wellbeing later in life. This is in line with lifecourse understandings of sensitive periods as having lasting and latent effects on both mental and physical health outcomes (Gilman & McCormick, 2010). It also lends support to the ‘accumulation of risk’ model (Kuh et al., 2003), such that subsequent and repeated distress resulting from heightened stress sensitivity may present a cumulative, detrimental effect over the lifecourse via allostatic load (Wiley et al., 2017).
Mental illness
Longitudinal studies have investigated the co-occurence of CVD or CVD risk factors and depression, and their association to ACEs. An analysis of the Whitehall II cohort study found that depression and anxiety largely mediated the relationship between ACEs and coronary heart disease (CHD), appearing to have a stronger effect than health behaviours, such as smoking (Deschênes et al., 2021). A study of the US CARDIA (Coronary Artery Risk Development in Young Adults) sample found that, while only low SEP in childhood contributed to high BP, a combination of low SEP and a harsh family environment was associated with higher levels of depression, anxiety, and internalised anger in adulthood (Lehman et al., 2009).
This further illustrates the ways early-life exposures produce adaptive behaviours that become maladaptive over time, and which have lasting effects on an individual’s capacity to self-regulate (McEwen, 2017). Biopsychosocial mechanisms are thought to underlie the relationship between ACEs and mental illness, including stress sensitivity and inflammation (Sheffler et al., 2020), which initial research suggests may derive from epigenetic alterations leading to cellular ageing (Lindqvist et al., 2015). The heightened CVD risk associated with mental illness, particularly depression, seems to be rooted in a combination of physiological disturbances and unhealthy behaviours that are often observed in depressed individuals (Penninx, 2017).
Both longitudinal studies discussed benefited from large cohort samples with no previous incidence of CVD at baseline, and multiple iterations of data collection spanning 38 and 15 years, respectively. While the Whitehall II sample is not representative of the wider population, consisting of mostly white men (Deschênes et al., 2021), the CARDIA study sample was more diverse, having sought a balance of Whites and African-Americans, and men and women (Lehman et al., 2009).
Behavioural mechanisms
ACEs have been found to significantly increase the risk of unhealthy behaviours, whereby individuals with a history of ACEs are up to three times more likely to smoke, and six times more likely to drink excessively (Hughes et al., 2017). CVD is among a number of non-communicable diseases, including cancer and diabetes, that are in part precipitated by modifiable health behaviours (Peters et al., 2019). Few longitudinal studies have investigated the intermediary role of lifestyle factors in the association between ACEs and CVH outcomes, of which two have already been discussed (Deschênes et al., 2021; Li et al., 2018). Findings from these are mixed, suggesting that health behaviours differentially mediate the risk of CVD following ACEs.
Smoking
Another MIDUS population-cohort study from the US found that smoking significantly elevated the risks of heart attack in individuals with a history of ACEs, exceeding the effects of obesity (Morton et al., 2015). A Finnish longitudinal cohort study showed that a combination of ACEs and adulthood disadvantage, for which neighbourhood deprivation levels served as a proxy, contributed towards both behavioural ands cardiometabolic CVD risks factors, including smoking, obesity, and diabetes (Halonen et al., 2015). Strengths of this particular study include a vast sample (n=37,699) that was followed over a 9-year period. Its generalisability is limited, however, by Finland’s status as a welfare nation, which entitles individuals to far greater financial support than most other countries, and the predominantly white, female make-up of the study sample. Moreover, the aggregation of childhood and adulthood adversities renders it difficult to isolate the independent effects of ACEs on health behaviours and CVH, as well as clouding the ‘chain of risk’ pathways linking ACEs and later life socioeconomic outcomes (Metzler et al., 2017).
Research exploring broader associations between ACEs and health behaviours indicate that women may be disproportionately affected, with evidence for smoking cessation being less likely amongst females with a history of ACEs (Saddleson et al., 2015; Strine et al., 2012). An analysis of the longitudinal Nurses Health Study II cohort showed that the odds of young women initiating smoking in mid-late adolescence increased in proportion to the timing, severity and accumulation of abuse experienced during childhood (Jun et al., 2008). A similar dose-response effect was observed in an Australian longitudinal study, which showed that four or more ACEs predicted a more than two-fold increase in smoking prevalence (Loxton et al., 2021). Crucially, smoking tends to be established as a habit early in life (Barrington-Trimis et al., 2020),often adopted as a coping mechanism, which might serve an adaptive purpose in the short-term, but confers long-term, detrimental health risks that are by the presence of ACEs.
These findings demonstrate the varying, interconnected pathways through which ACEs may come to bear on CVH. As well as altering brain structures and autonomic processes during sensitive periods (Berens et al., 2017), ACEs tend to be highly interrelated (Dong et al., 2003), resulting in an accumulation of multiple negative exposures, which in turn set off a ‘chain’ of risks (e.g., smoking), thereby compounding any existing health risks (Cable, 2014).
The biological, psychosocial, and behavioural pathways through which ACEs ‘get under the skin’, exerting deleterious effects on all aspects of health, including cardiovascular outcomes, attest to the complex, interdependent, and highly susceptible nature of the human mind and body. A lifecourse approach helps shed light on the long-lasting, otherwise overlooked and invisible, consequences of early-life exposures. As well as uncovering the degree to which ACEs can influence health outcomes for the worst, lifecourse research also has a role in identifying the protective factors that may dampen the damage done by ACEs, and thereby contribute towards lessening health inequalities (Crouch et al., 2019).
While there is rich longitudinal data on ACEs and CVD risk factors, more prospective research linking ACEs and CVD incidence and mortality, as well as exploring underlying mechanisms, is required. Future longitudinal analyses must also reflect more diverse populations, among whom differing cultural norms and values, as well as socioeconomic circumstances, are likely to influence the nature and subsequent effects of ACEs. Indeed, initial evidence from Chinese studies suggests that cultural as well as generational disparities in ACEs may underlie health inequalities observed within and across nations (Liu et al., 2022).
Although interventions in adolescence and adulthood can mitigate the risks and harms resulting from ACEs, more must be done to understand and prevent the conditions that give rise to them in the first place. The interrelated nature of socioeconomic hardship and early-life psychosocial adversities (Walsh et al., 2019), alongside emerging evidence for the intergenerational dimensions of trauma (Zhang et al., 2022), suggest that ACEs do not occur in a vacuum. An intersectional, interdisciplinary approach to future research, practice, and policy is required to implement interventions aimed at not just lessening the latent and enduring harms of ACEs, but tackling their root causes.