Psychosocial Stress, the Unpredictability Schema, and Cardiovascular Disease in Women

Abstract

Depression/anxiety-related disorders and psychosocial stress have been implicated as cardiovascular disease (CVD) risk factors. Women are at considerable risk for affective disorders and report greater severity from psychosocial stress, compared to men. Affective disorders and cardiovascular disease likely share underlying pathophysiological mechanisms that are potentiated among women – especially younger women. Environmental stressors that threaten the safety, security, and status of an individual are appraised by the brain, producing a cascade of evoked physiological and cognitive responses. In the short term, these processes overcome stressors, but come with long-term health implications. Chronic psychosocial stress leads to a dysregulation of the stress response systems that can lead to a heightened stress appraisal schema called the unpredictability schema, a construct that might arguably place women at heightened risk for CVD.

Main article text

Introduction

Women’s cardiovascular health is in part impacted by: (1) physiological and biological systems and (2) the societal and community demands unique to the female gender [1, 2]. Women have higher prevalence of stress-related mental disorders such as depression or anxiety than men [3–5]. It is increasingly acknowledged that the relationship between cardiovascular disease (CVD) and depression/anxiety-related disorders is highly prevalent in women, especially in younger women [6–9]. Thus, this review focuses on CVD and affective disorders (e.g., anxiety, post-traumatic stress disorder (PTSD), and depression) as end-products that potentially result from overcoming a lifetime of environmental and psychosocial stress. Stressors may serve as cues that convey key information about the condition and availability of resources in the immediate environment that are processed by the brain and conveyed to the circulatory system and the rest of the body via the autonomic nervous system, hypo-pituitary-adrenal axis, and inflammatory processes [10]. Individuals identify the level of predictability, controllability, and safety present in the environment through a cognitive perceptual and appraisal system called the unpredictability schema [11]. The influence of environmental stressors spans across physiology, development, behavior and, ultimately, health. We provide a conceptual explanation of the unpredictability schema, followed by short sections defining psychosocial stress and reviewing its impact on CVD risk in women.

The Unpredictability Schema: Affect and Cardiovascular Disease

The brain has been characterized as the “central organ of stress” [12, 13] because it perceives, appraises, and labels external environmental stimuli as either safe or threatening (see Figure 1). Contingent on the assessments of the brain appraisal system, bio-energetic resources are mobilized across physiological systems to create a coordinated stress response [10, 12–14]. For instance, the autonomic nervous system – notably the vagal nerve – is hypothesized to be an organizer for social behavior across phylogenetic time [15]. When an individual perceives themselves to be in an unsafe or threatening situation, the stressor evokes a physiological response that activates the sympathetic nervous system [15]. Sympathetic activation creates a cascade of coordinated responses within the circulatory system (among others) designed to overcome the stressor. Because the circulatory system is designed to attend to urgent threats to health (e.g., wounds, viral/bacterial infections etc.) and to mobilize and transport resources and defenses (i.e., nutrients, oxygen, hormones, cytokines) across tissues, the coordinated response includes increased heart rate, vasodilation and mobilization of oxygenated blood to the extremities with diversion of resources away from vital organs. Blood during a stress response becomes increasingly coagulated and the immune system is mobilized. These physiological responses were designed to facilitate adaptive behaviors that would quickly overcome environmental challenges in the short term.

Figure 1

Potential Life-Course Pathways of Cardiovascular Disease and Mental Psychological Stress.

The brain is the focal point of stress response in that it cognitively appraises external stimuli/stressors and situations as benign or threatening, which produces of concerted cascade of responses across different physiological systems – notably dysregulation of the Hypopituitary Adrenal/Gonadal Axes, Sympathetic Adrenal Medullary Axis, and the immune system. Over time, this results in both increased cardiovascular disease risk and reduced mental health.

Over time, repeated exposure to stress and stress response activation results in physiological, neurological, and brain re-organization that canalize stress responses and cognitive adaptations in ways that help individuals specialize and sensitize to the features of their immediate environment [10, 14, 16–18]. Chronic stress alters brain anatomy by increasing amygdala functioning (e.g., vigilance), decreasing ventral striatal reward sensitivity (e.g., reward-seeking behavior), and decreasing executive functioning of the prefrontal cortex (e.g., impulsive behavior) [14, 17]. Pervasive and long-term activation of these brain and stress response systems from chronic stress results in dysregulation of the stress response system [12, 19] and greater vigilance and impulsive behavior [10, 20]. These adaptations, however, come with upstream costs. These adaptations manifest as decrements in mental and physical health – such as depression and CVD – through exogenous (i.e., dysregulation of the stress response systems) and endogenous pathways (i.e., increased risk-taking, decreased health-maintaining behavior, and decreased interoceptive awareness) [13, 21] (Figure 2).

Figure 2

The “Black Box” of Harsh Environments and Poor CVD Health in Adulthood.

The figure demonstrates the different levels in which harsh and unpredictable environments may influence cardiovascular health. (1) Harsh environments increase the likelihood of chronic stress exposure, which increases the dysregulation of the stress response system. (2) Dysregulation of the stress response system increases antagonistic or opportunistic socioemotional social strategies that include increased vigilance, pessimism, hostility and decreased perceived control. Over time, the combination of the up-regulated stress response systems, coupled with opportunistic/antagonistic social strategies, creates endogenous (i.e., somatic) alterations such as physiological dysregulation or allostasis; exogenous (i.e., behaviorally) alterations include increased risk-taking behavior, decreased health-maintaining behavior, and decreased interoceptive awareness.

Evidence suggests that early and repeated exposure to stressful or threatening environments can shape worldviews and perceptions in a manner that orients individuals toward perceiving society and the environment as unpredictable, unreliable, threatening, and hostile, and discounting the future [11, 16, 22]. This cognitive orientation has been called the unpredictability schema [11, 23] and includes behavioral and affective components of decreased perceptions of control, increased pessimism, hostility, and vigilance (see Table 1 for additional components of the unpredictability schema).

Table 1

Description of the Unpredictability Schema.

Unpredictability Schema Components (Adapted by Ross and Hill [11])
Self
External Locus of Control
↓ Sense of Control/Mastery
↓ Self-Efficacy
↑ Helplessness
↑ Pessimism
↑ Hopelessness
↑ Future Discounting
People
↓ Interpersonal Trust
↑ Cynical Hostility
↑ Vigilance
World
↑ Causal Uncertainty
↓ Poor Sense of Coherence
Measures of the Unpredictability Schema
Scale of Unpredictability Beliefs [23]
Unpredictability Schema Scale [24, 25]

The unpredictability schema and its components have been linked to greater anxiety and depressive symptoms, increased reward-seeking and risk-taking and poor health-maintaining behavior (e.g., over-eating) [24, 26–28]. Indeed, research documents increased drive for reward-seeking behavior, following chronic stress exposure [14, 21]. Further, brain systems calibrated by chronic stress response such as the ventral striatum are implicated in increasing health-harming, reward-seeking behaviors [14]. For example, smoking is one traditional health-harming/reward-seeking behavior both implicated in cardiovascular risk and associated with exposure to higher levels of stress [29–31]. Torres and O’Dell [30], using extensive research from animal models, propose that females are especially sensitive to nicotine, with stress heightening nicotine sensitivity in neuro-reward pathways and increasing intensity of withdrawal.

In addition to increased reward-seeking, risk-taking and decreased health-maintenance, the unpredictability schema may produce a reduction in interoceptive awareness [24]. Interoceptive awareness is the perceptual processing of internal bodily states such as pain and hunger; conversely, exteroceptive awareness is the perceptual processing of external stimuli situated outside of the body [32]. Evidence suggests that activation of one perceptual system may supersede the other [32]. Recent work on the unpredictability schema has proposed that early experiences of systemic chronic stress may orient individuals toward vigilance, which may alter perceptual systems to focus on exteroceptive awareness (external stimuli), foregoing interoceptive awareness (internal bodily sensations) [24]. As predicted, the association between a heightened unpredictability schema was associated with decreased interoceptive awareness and over-eating [24]. Thus, it is possible that increased exteroceptive awareness, as a result of hyper-vigilance and stress response, may cause people to be less aware of bodily sensations.

Conceptualization of Psychosocial Stress and Stressors

An extensive literature exists that describes the conceptualization and measurement of stress and stressors [33, 34]. A stressor is conceptualized as an environmental stimulus or event that threatens the security, autonomy, status, and, survival of an organism. Broadly, there exists three domains of stressors [33]: (1) negative life events, discrete events that individuals experience such as losing a job or death of a loved one, (2) chronic difficulties, sustained and long-term stressful situations, such as caring for a loved one or living in a disadvantaged neighborhood, and (3) cumulative stress exposure (lifetime stress) which is also known as the sum-total or culmination of chronic and acute life stressors across the lifespan. Stressors are further distinguished across development, whereby stressors experienced prenatally or in childhood/adolescence are categorized as early adversity and stressors following those developmental stages are adult stressors.

Harshness – defined as “external sources of disability and death” that are independent of age and health [16] – and unpredictability – defined as “spatial variation in harshness” [16] – have been suggested as relevant dimensions of environmental risk (i.e., life stressors) that convey key information about the safety, security, and controllability about the immediate environment and the reliability and trustworthiness of individuals present in the environment. Indeed, harshness and unpredictability help inform and link the disparate literature between mood disorders and CVD risk in women.

Women CVD and Psychosocial Stressors in Women

Psychosocial stress and its underlying components negatively impact cardiovascular health and mortality [35] (see Figure 1). The INTERHEART study showed that psychosocial factors were as potent to CVD risk (Odds Ratio (OR): 2.67, 95% Confidence Intervals (CI): 2.21–3.22) as smoking (OR: 2.87, 95% CI: 2.58–3.19) as other traditional risk factors, like Type II diabetes (OR: 2.37, 95% CI: 2.07–2.71) [36]. Disaggregation of psychosocial stress in INTERHEART revealed that, compared to age- and sex-matched controls, patients with reported myocardial infarction had elevated psychosocial stress from different measured stress domains, including home and work stress, financial stress, stressful life events, and depression [37]. Additionally, patients had lowered perceived locus of control. A series of meta-analytic and pooled-analyses work continues to find support for an association between psychosocial stress and CVD, including hypertension [38], stroke (with greater risk in women) [39], coronary heart disease [40], and CVD death [41].

The examination of the relationship between assorted domains of life stress (e.g., work, relationship, health, jobs) among middle-aged and older adults (45–84 years old) on markers of endothelial dysfunction, a precursor to CVD, found that reporting two or more stressful life events compared to no life events were associated with greater endothelial dysfunction, as evidenced by decreased flow-mediated dilation and higher levels of I-CAM1 [42]. The sequelae of work stress have been an extensively studied stress domain. Meta-analyses have found an association between work stress and CVD [43], including stroke risk [44]. Specifically focusing on women, prospective work in the Women’s Health Study (WHS) highlighted the significance of psychosocial stress [45], by examining the effects of job strain on incident CVD risk [46]. Both high strain, characterized by a combination of low control and high demands, and active strain, characterized by high control and high demands, were associated with greater risk of acute cardiovascular events [46]. Caregiver burden has also been implicated in CVD risk. Current [HR: 1.35, 95% CI: 1.06–1.68] and long-term care of a spouse [HR: 1.95, 95% CI: 1.19–3.18] have found strong associations between caregiving and CVD risk [47]. Caring for an ill spouse at ≥9 hours a week (RR: 1.82, 95% CI: 1.08–3.05) compared to 0 hours a week was associated with greater CVD risk in the Nurse’s Health Study [48].

Women hospitalized for Takotsubo or stress-induced cardiomyopathy, a diagnosis more prevalent in women, were more likely to report experiencing greater negative life events than unexposed women [49]. Other work in middle-aged adult men and women with stable coronary heart disease demonstrates that women (particularly younger women, e.g., ≤50 years old), compared to men, are at greater risk for mental stress-induced myocardial ischemia [50]. In this study, women experienced higher levels of myocardial ischemia in response to mentally-induced stress compared to men (OR: 2.06, 95% CI: 1.12–3.79). These findings were more potent in younger women (e.g., ≤50 years old) where women had a 4-fold higher likelihood of mentally-induced stress ischemia compared to their male counterparts. This work may have relevance for the observed phenomenon in women afflicted with chest pain and without epicardial coronary artery disease. Additional work suggests that mental health status may moderate the association between life stressors and cardiovascular health. In a sample of 28,583 US men and women (mean age = 44.8; female = 57.6%), the association between negative life events and CVD incidence was stronger in participants who reported a history of depression [51], suggesting that psychological status may amplify the effects of negative life events. Furthermore, early adversity has been implicated in the progression of CVD risk [52]. Some research suggests that the effects of early adversity may be more potent in women, as well as heightened in women with stressful life experiences in adulthood [53]. Table 2 outlines studies of psychological status with a focus on stress and CVD in women.

Table 2

Selected Summary of Psychosocial Status Papers with a Focus on Stress and Cardiovascular Disease Risk.

Authors	n	Female	Study Design	Psychological Factor	Outcome	Parameter Estimate	95% CI
Garad et al. [53]	4408	50.8%	Prospective	1–2 Child Adversity events	Incident CVD	1.96*	1.26–3.06
Garad et al. [53]	4408	50.8%	Prospective	3+Child Adversity events	Incident CVD	3.02*	1.87–4.88
May-Ling et al. [54]	3392	100%	Prospective	History of Trauma Exposure	CHD	1.54	1.29–1.83
Sumner et al. [8]	49,978	100%	Prospective	Trauma Exposure/0 PTSD Symptoms	Incident CVD	1.38	1.09–1.75
Hendrickson et al. [55]	1021	18%	Prospective	Traumatic Events (4th Quartile)	Incident CVD	1.38	1.06–1.81
Yusuf et al. [36]	12,461†	24.1%†	Case-Control	Psychosocial Factors (Composite)	Myocardial Infarction	3.49*	2.41–5.04
Liu et al. [38]	5696	n/a	Meta-analysis	Psychosocial Stress	Hypertension	2.40	1.65–3.49
Booth et al. [39]	154,938	n/a	Meta-analysis	Psychosocial Stress	Stroke	1.90*	1.40–2.56
Russ et al. [41]	68,222	55.9%	Pooled-analysis	Psychosocial Distress (GHQ-12 Score)	CVD Death	1.17	1.12–1.22
Richardson et al. [40]	118,696	n/a	Meta-analysis	Perceived Stress	CHD	1.27	1.12–1.45
Gallo et al. [56]	5313	62.1%	Cross-Sectional	Chronic Stress	Prevalent CHD	1.22	1.10–1.36
Rosengren et al. [37]	11,119†	n/a	Case-Control	Stressful Life Events (1 Event)	MI	1.30*	1.11–1.52
Rosengren et al. [37]	11,119†	n/a	Case-Control	Stressful Life Events (2+Events)	MI	1.37*	1.12–1.68
Bernston et al. [51]	28,583	57.6%	Prospective	Stressful Life Events (Past Year)	Incident CVD	1.15	1.11–1.19
Mathews et al. [57]	9056	74%	Cross-Sectional	Stress	ICH (6–7 components)	0.65*	0.54–0.79
Mathews et al. [57]	9056	74%	Cross-Sectional	Low Life Satisfaction	ICH (6–7 components)	0.66*	0.45–0.97
Mathews et al. [57]	9056	74%	Cross-Sectional	Anxiety	ICH (6–7 components)	0.65*	0.45–0.95
Rosengren et al. [37]	11,119†	n/a	Case-Control	Feeling Depressed (Last 2 Weeks)	MI	1.60*	1.37–1.88
Whooley et al. [7]	7518	100%	Prospective	Depression	CVD Death	1.80	1.2–2.50
May-Ling et al. [54]	3392	100%	Prospective	Depression	CHD	1.56	1.20–2.04
May-Ling et al. [54]	3392	100%	Prospective	Depression and Anxiety	CHD	1.79	1.38–2.32
Capistrant et al. [47]	8472	52.3%	Prospective	Current Spousal Caregiving (≥14 h/week)	Incident CVD	1.35	1.06–1.68
Capistrant et al. [47]	8472	52.3%	Prospective	Long-term Spousal Caregiving (≥14 h/week – 2 years)	Incident CVD	1.95	1.19–3.18
Lee et al. [48]	54,412	100%	Prospective	Spousal Caregiving (≥9 h/week)	CHD	1.82	1.08–3.02
Rosengren et al. [37]	11,119†	n/a	Case-Control	Home Stress (Several Periods)	MI	1.53*	1.23–1.90
Rosengren et al. [37]	11,119†	n/a	Case-Control	Home Stress (Permanent)	MI	1.88*	1.31–2.69
Rosengren et al. [37]	11,119†	n/a	Case-Control	Financial Stress (Moderate)	MI	1.22*	1.05–1.41
Rosengren et al. [37]	11,119†	n/a	Case-Control	Financial Stress (Severe)	MI	1.33*	1.08–1.64
Slopen et al. [46]	22,086	100%	Prospective	Active Job Strain (High Demand/High Control)	Incident CVD	1.38	1.07–1.77
Slopen et al. [46]	22,086	100%	Prospective	High Job Strain (High Demand/Low Control)	Incident CVD	1.38	1.08–1.77

^*Parameter estimate disaggregated by women. ^†Cases only.

CVD, cardiovascular disease; PTSD, post-traumatic disease; CHD, coronary heart disease; ICH, ideal cardiovascular health.

Psychological Status and CVD Risk: Intersection of Sex and Race/Ethnicity

As reviewed by Mehta and colleagues [1], women of color, including Hispanic/Latinas and black women, experience more severe physical and mental comorbidities and greater cardiovascular complications at younger ages than other women. Although not only limited to U.S. women belonging to racial/ethnic minority groups, earlier progression of CVD in women is more pronounced in women with depression or anxiety disorders [1, 58]. Further, because racial/ethnic minority women are more likely to reside in harsh, unpredictable, and uncontrollable environments, they are more likely to encounter chronic stress exposure across the lifespan, potentially making ethnic and racial minority women more susceptible to CVD as a result of their life experiences. Additionally, nativity status is another important CVD factor to consider among racial/ethnic minorities. For example, foreign-born Hispanics/Latinos have greater risk of CVD death than US-born Hispanic/Latinos, the risk is highest among Cubans, then Puerto Ricans, and Mexicans [59].

Exposure to adversity among racial/ethnic minorities begins early in life. Racial/ethnic minorities, and economically-disadvantaged children have been reported to experience more adversity than white and economically-privileged children [60]. Evidence suggests that a dose-effect of early adversity on adult cardiovascular health exists. Men and women who reported 3 or more early adverse (ACE) events compared to no events had greater CVD risk (OR: 2.14, 95% CI: 1.56–2.94) and the effect was most potent in individuals who reported 2 or more adult life events (OR: 3.00, 95% CI: 1.74–5.20) [53]. When stratified by sex, the association was only significant among women [53]. This trend continues into later adulthood and may be partially attributed to socioeconomic status.

Data from the Women’s Health Study (WHS) showed that markers of economic prestige (higher education and income) were protective against prospective cardiovascular events over 10 years, even after control for traditional cardiovascular risk factors and novel CVD surrogate biomarkers markers such as C-reactive protein [61]. Emerging work from WHS demonstrates that cumulative psychosocial stress, a composited measure consisting of acute negative life events and chronic stressors was significantly higher among Blacks, Hispanics, and Asians when compared to White women, even when after accounting for SES and depression/anxiety [62]. Other work in a sample of over 9000 men and women similarly finds that poorer psychological quality is related with decrease likelihood of attaining ideal or intermediate cardiovascular health status [57]. Trauma exposure [54, 55] and PTSD symptoms arising from trauma [8] are also substantial CVD risk factors [8, 63].

Unique Global Environmental Threats Faced by Women

Across the globe, women encounter distinct life experiences that may amplify the risk of mental illness and cardiovascular disease. At birth and infancy, some groups experience a greater “loss” of female babies than is expected [64]. Additionally, young girls in select cultures and environments may experience reduced access to health care, increasing risk of child mortality [65]. Early stressful experiences marked by sexual, emotional and physical abuse are more likely to be reported by women and individuals from disadvantaged economic backgrounds [66]. Women are also disproportionately at risk for increased poverty than men [67, 68]. As such, greater poverty increases the likelihood that women will be exposed to or reside in harsh and unpredictable neighborhoods [69, 70] or will report more negative life events [71], with U.S minority women and their offspring experiencing higher levels of poverty than white women [68]. For example, in 2015, Black women had the highest levels of poverty (23.1%), followed by Native American (22.7%), Hispanic/Latinas (20.9%), and Asian women (11.7%) [68]. Furthermore, women will be more likely to sustain households with minimal resources [72, 73]. Overall, thus, women, across their life span, may potentially encounter adverse environments and experience negative life events that may impact mental and cardiovascular health.

Sex, Environmental Appraisal, and Processing

In addition to unique lived experiences of some women, evidence suggests potential differential processing of environmental information by sex; differences that may emerge at puberty [74]. Humans have an evolutionary history of cooperation and reliance on others for security, resources and survival [75]. For this reason, humans, among other social animals, have an intense drive for connection and need to belong [76], which emerges early in life through the attachment to caregivers and persists in adulthood through romantic relationships and familial/friendship bonds. As such, any stressor that deprives an individual of social connection, threatens an individual’s status, and/or ostracizes an individual from a group, can result in marked negative physiological responses [77–79]. Perceptions of stress are also influenced by social connections. Individuals who report depression, lower social support, a recent relationship dissolution, or family conflict report higher levels of perceived stress [71]. The impact of psychological stress on health may be contingent on the appraised level of social support available to the individual in their immediate environment. In particular toxic stress [80], defined by adverse experiences without social support and unhealthy brain architecture results in illness compared to both positive or tolerable stress which are both associated with good social support and healthy brain architecture [81]. Indeed, evidence shows heightened diastolic blood pressure reactivity to acute stress in lonelier individuals, with the effect particularly more potent in women [82]. Loneliness has been linked with lower quality support networks (i.e., smaller support networks, less emotional and practical support) [82]. Indeed, a study by Steptoe et al. found that social isolation/loneliness contributes to increased stroke and coronary artery disease risk, as well as all-cause mortality among 6500 participants of the English Longitudinal Study of Ageing (ELSA) [83].

Some research suggests that differences in estrogen and oxytocin levels by sex may differentially modulate the stress response [84–86]. Elevated levels of sustained inflammation, as measured by surrogate inflammatory biomarkers like C-reactive protein, may be the result of a dysregulated glucocorticoid stress response and reduction in anti-inflammatory effects [87].

Finally, the relationship between stressful life experiences and CVD progression may also be implicated by telomere attrition. Telomeres are nucleoprotein sequences that serve as protective caps that conserve the cellular integrity of chromosomes and have been demonstrated to be shorter in women with elevated psychosocial stress and in individuals with recent stressful life events [88, 89]. Furthermore, individuals afflicted with affective disorders had significantly shorter telomeres when compared to age-matched controls [90], and other evidence suggests that chronicity of affective disorders is also linked with shorter telomeres [91]. In totality, emerging evidence suggests an interplay between psychosocial stressors, the unpredictability schema and chronic diseases such as cardiovascular disease.

Conflict of Interest

The authors declare no conflict of interest.

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