Sex-specific effects of stress on metabolic and cardiovascular disease: are women at higher risk?

Abstract

Cardiovascular disease (CVD) has traditionally been viewed as a male disease; however, the relative risk for obesity and hypertension morbidity and mortality, major risk factors for CVD, is higher for women in the United States. Emerging epidemiological data strongly support stressful experiences as a modifiable risk factor for obesity, insulin resistance, and heart disease in women at all ages. Therefore, primary prevention of these diseases may be associated with both identifying and increasing the knowledge regarding the sex differences in emotional functioning associated with physiological responses to stress. The purpose of this review is to highlight the growing body of clinical and experimental studies showing that stress, obesity-associated metabolic disturbances, and CVD comorbidities are more prevalent in females. Overall, this review reveals the need for investigations to decipher the early origins of these comorbidities. Targeting the sources of behavioral/emotional stress through the trajectory of life has the potential to reduce the alarming projected rates for chronic disease in women.

stress can be defined as any event such as an adverse experience or perceived threat that influences the individual’s homeostasis, resulting in the activation of neuroendocrine and autonomic responses (42). Stress has well-documented adverse effects on a range of health outcomes, including hypertension, obesity, substance abuse, and smoking, all important contributors to the development of cardiovascular disease (CVD) (9). During early life, approximately one-third of the population is exposed to a wide range of emotional stress, including physical or sexual abuse, neglect, loss of a parent or caregiver, or a natural disaster. A large body of epidemiological studies provides strong evidence that “early life stress” (ELS) is an independent risk factor for chronic disease, compromising the neuroendocrine, immune, metabolic, and cardiovascular systems (17). Chronic stress is also a risk factor for depression and anxiety. The interplay between stress-related emotional disturbances and CVD comorbidities has been the focus of multiple investigations (18, 47, 71). Etiological and prognostic studies conclude that depression may be a cause or consequence of CVD, encompassing a bidirectional relationship (14). The concept of comorbidity describes the coexistence of two or more disorders; however, it is difficult to establish whether these comorbidities interact by sharing pathophysiological mechanisms. Mood disturbances induce behavioral changes, such as fatigue and physical inactivity, which in turn contribute to increased CVD risk (20). Moreover, depression and CVD may result in the activation of neurobiological pathways that are common in both diseases, such as the hypothalamic pituitary adrenal (HPA) axis, the autonomic nervous system, and the inflammatory response (22, 45).

During the lifespan, sex differences to cope with stress could play an important role underlying stress and CVD comorbidities (48). One potential cause of greater risk of stress and CVD comorbidities observed in postmenopausal women is the loss of parasympathetic tone protection, inducing a greater sympathetic control of the vascular tone. Another casual factor could be the exacerbated cortisol secretion as observed in response to laboratory stress challenges in females with chronic stress compared with males (11). Sex disparities in CVD-associated comorbidities could be based on the fact that women tend to minimize the impact of the disease and delay seeking treatment. An important observation revealed that, in the first month after myocardial infarction event, women report more evasive coping and experience lower quality of life compared with men. This behavior is related to the finding that women do not want to burden others with their health problems, most likely because of their social roles (34, 53).

The goal of this review is to discuss the potential molecular and physiological determinants for the sex differences in health disparities secondary to stress exposure through the trajectory of life. In addition, we will discuss the experimental rodent models available for the study of the sex-specific effects of stress on adiposity, insulin resistance, and blood pressure, important contributors in the pathophysiology of CVD.

Origin of Stress-Induced CVD Risk in Humans

Intrauterine life.

It is well accepted that environmental factors reducing the nutrient availability in utero enhance the risk for chronic disease later in life. Low birth weight (LBW) is an index of intrauterine growth restriction (IUGR) and a predictor of neonatal mortality. Protein restriction, gestational diabetes, and preeclampsia are common causes of IUGR linked to LBW (23, 47). Children born with LBW are at an increased risk to develop elevated adiposity during childhood, leading to obesity and insulin resistance, key components of the metabolic syndrome. For instance, The Dutch Famine Study is one of the first reports demonstrating that the correlation among prenatal malnutrition exposure, elevated adiposity, and hyperlipidemia is stronger in women than men (41, 68).

The role of epigenetic alterations imprinted during high tissue plasticity periods is an important contribution to understanding the molecular mechanisms in developmental programming. Tobi et al. (72) demonstrated that prenatal famine leads to DNA methylation differences in a time- and sex-specific manner. Specifically, significant differences were found in methylation after famine exposure during periconception for the LEP and INSIGF genes in men only, despite reported observations of elevated body mass index (BMI) and hyperlipidemia in women. Recent work from this same group has shown that prenatal malnutrition is associated with differentially methylated regions related to growth and metabolism through a comprehensive genome-scale study, which characterized genomic regions and biological pathways (71). REVIGO analysis, a web server that performs statistical testing for high-throughput biological experiments, revealed that prenatal malnutrition affected pathways related to insulin signaling (INSR), pancreatic β cell functioning (SMAD7), fatty acid oxidation (CPT1A), and cholesterol metabolism (KLF13), suggesting that epigenetic modulation of these pathways through prenatal malnutrition may be a potential mechanism for the adverse metabolic phenotype observed later in life; however, this comprehensive study has not assessed sex differences (71).

On the other hand, maternal emotional distress symptoms, including anxiety and depression, are worse in pregnant women who display severe obesity (47). Maternal prenatal stress affecting the mother typically has a social basis and includes bullying, pressure at work, bereavement, partner abuse, limited access to a healthy alimentation and adequate health care, and low socioeconomic status. Therefore, in these circumstances, babies are exposed to unhealthy levels of stress in utero (16, 36, 70). Nonetheless, the literature analyzing the potential sex-specific outcomes in humans is limited to a handful of studies. For example, it has been reported that maternal stress may alter placental genes regulating fetal glucocorticoid exposure and placental growth. Importantly, increased maternal distress was linked with reduced mRNA levels of 11-β-dehydrogenase 2 (11β-HSD2), glucocorticoid receptor (NR3C1-α), and insulin growth factor 2 (IGF2-1), showing a subsequent secondary effect on the glucocorticoids and insulin metabolism, respectively (47). These alterations were found in placentas of female but not male offspring, suggesting a greater vulnerability of female fetuses to maternal distress with potentially greater fetal glucocorticoid exposure and excess IGF2 (47). Of note, cortisone may be reconverted to cortisol in the fetus; therefore, more studies are needed to assess the sex-specific capacity for this reconversion influencing the stress-related outcomes in the offspring.

In the long term, individuals born from mothers subjected to nutritional and/or psychosocial stress display a higher percentage of body fat, BMI, lipid profile, primary insulin resistance, and impairments in immune function and cognitive performance. Table 1 summarizes studies linking LBW and prenatal stress to several sex-specific effects on metabolic and cardiovascular risk.

Table 1.

Metabolic and CVD risk factors in individuals exposed to prenatal stress

Reference	Stressor	Number of Subjects	CVD and Metabolic Risk Factors Increased	Sex Disparity Assessment
Morrison et al. (49)	Extremely low birth weight (below 1,000 g) born between 1977 and 1982	The McMaster ELBW cohort	Adiposity, high blood pressure, diabetes, and prediabetes	No
		age- and sex-matched NBW control subjects (n = 100)
Jornayvaz et al. (31)	Low birth weight (<2.5 kg)	1,458 Middle-aged women and 1,088 men from Lausanne, Switzerland (CoLaus Study)	Fasting plasma glucose,	Yes; women with LBW had elevated HOMA, diabetes, and metabolic syndrome; nonsignificant trend seen in men
			Insulin, HOMA, adiposity, BMI, leptin
Stefan et al. (67)	Low birth weight (lowest quartile of birth weight: 2,891 ± 33 g compared with NBW, 3,657 ± 28 g)	230 Pima Indians	BMI, oral glucose tolerance test, fat biopsy, and in vitro characterization of adipocytes	Yes; acute insulin secretory response was different in both men and women with LBW compared with NBW
		n = 58 LBW
		n = 172 NBW
Lumey et al. (41)	Maternal protein restriction during Dutch Hunger Winter Families Study	359 men and women born between January 1945 and March 1946 in Amsterdam, Rotterdam, and Leiden	Serum total cholesterol, HDL cholesterol, triglycerides	Yes, females had elevated total cholesterol and triglycerides with no differences in men
		299 singletons born in same 3 cities during 1943 and 1947
		313 unexposed same-sex siblings
Entringer et al. (16)	Study of Women's Health Across the Nation (SWAN) in stressed women	Young adults	Glycemic control, BMI, percentage of body fat, leptin	No
Li et al. (36)	Maternal bereavement (loss of elder child, husband, or parent) in period 1 yr before conception until birth	Young adults	Type 2 diabetes	No
		n = 1,878,246
Tate et al. (70)	Psychological stress experienced by mothers	Meta-analysis synthesized 17 studies	BMI	No

CVD, cardiovascular disease; NBW, normal birth weight; LBW, low birth weight; BMI, body mass index; HOMA, homeostatic model assessment.

ELS and CVD risk.

ELS involves traumatic experiences such as physical and sexual abuse, household dysfunction and neglect, witnessing a natural disaster, and parental loss or divorce (14, 17, 54, 59). In addition, socioeconomic disadvantage during childhood is recognized as a source of ELS (18). Numerous epidemiological studies have demonstrated a positive correlation between ELS and adult chronic disease with evidence of a cumulative effect (6, 14, 17). The Adverse Childhood Experiences Study and the Dunedin Multidisciplinary Health and Development Study show higher incidence of being overweight, high blood pressure, elevated cholesterol, high glycated hemoglobin, and low maximum oxygen consumption in ELS-exposed patients (14, 17). Accordingly, a report conducted in a cohort of middle-aged US adults established general associations between ELS and the adipokines leptin and irisin and the proinflammatory cytokine, C-reactive protein, with reductions in adiponectin (32).

Table 2 summarizes several studies that have reported the effect of ELS on metabolic and cardiovascular responses. Although these studies support a link between ELS and CVD risk, a limited number of them have focused and/or been designed to determine sex-specific correlations. In the last decade, more studies have incorporated this approach, reinforcing the concept of women being at higher risk. Among these reports, the Ovarian Aging Study (OVA) outcomes show that socioeconomic disadvantage appears to have a stronger impact on adulthood cardiometabolic risk when experienced during puberty in women compared with men (8). Furthermore, recent outcomes from the national longitudinal survey Americans’ Changing Lives showed for the first time that women who experienced adverse childhood experiences gain weight more rapidly throughout the 15-yr follow-up period compared with men (38). Also, the Northern Finland Birth Cohort found that stress-related eating is more prevalent among 16-yr-old girls (43%) compared with boys (15%), showing a strong association with obesity rates in females (29). Overall, sex-specific risks for comorbidities are not possible to rule out in many of the retrospective investigations because these studies were not performed with a robust experimental design to assess potential disparities. Thus the limitations in data collection performed in initial studies could lead to the underestimation of the sex-specific differences in ELS-associated risk for obesity and CVD.

Table 2.

Metabolic and CVD risk factors in individuals exposed to postnatal and childhood stressors

Reference	Stressor	Number of Subjects	CVD and Metabolic Risk Factors Increased	Sex Disparity Assessment
Danese et al. (14)	Socioeconomic disadvantage, maltreatment, social isolation-assessed at ages 3, 5, 7, 9, 11, 13,15,18, 21, 26, and 32 yr	1,037 (52% male) in Dunedin Multidisciplinary Health and Development Study within New Zealand	CRP, obesity, high blood pressure, high total cholesterol, low HDL, glycated hemoglobin	No
Bercovich et al. (6)	Israeli subjects born in Europe during 1940–1945 with definitive self-reported exposure to the Holocaust	70 European Jews born under Nazi rule (exposed group); 230 Israeli-born (control group)	BMI, hypertension, diabetes, dyslipidemia, congestive heart failure, anxiety/depression	No
Felitti et al. (17)	Questionnaire completed by adults about adverse childhood experiences, such as childhood abuse and household dysfunction	8,056 Americans at Kaiser Permanente’s San Diego Health Appraisal Clinic	Ischemic heart disease, stroke, obesity, diabetes, liver disease	No
Joung et al. (32)	Early life adversity and psychosocial measurements obtained via validated interview and questionnaires	95 adults from Boston, MA aged 35–56 yr	BMI, waist circumference, leptin, reduction in adiponectin	No
Winning et al. (75)	Childhood psychological stress assessed at ages 7, 11, and 16; adult psychological stress assessed at ages 23, 33, and 42 yr	1958 British Birth Cohort, n = 6,714	cardiometabolic risk, inflammation, total cholesterol, triglycerides, glycosylated hemoglobin, resting heart rate, systolic and diastolic blood pressure	No
Liu et al. (39)	Childhood stress occurring before ages of 16 including socioeconomic status, parental loss/divorce, alcoholism of parent, parental instability	2,259 women, 1,358 men from American’s Changing Lives Survey	Elevated BMI	Higher in women
Mason et al. (44)	Physical, sexual, and emotional abuse before the age of 11	4,377 women in Growing Up Today Study (GUTS)	Women reporting abuse had elevated BMI and binge eating	No
Appleton et al. (4)	Child emotional functioning at age 7 to assess childhood distress proneness	219 women, 158 men from Collaborative Perinatal Project	BMI, CVD risk through Framingham, total and HDL cholesterol	Women had 31% CVD increase; men 17% increased risk
Takizawa et al. (69)	Exposure to bullying at ages 7 and 11 assessed by parental interviews	7,102 participants from the National Child Development Study in the 1958 British Birth Cohort Study	Adiposity (BMI and waist:hip), CRP	Women had higher BMI and risk for obesity
Jaaskelainen et al. (29)	Maternal health behaviors assessed via questionnaire by the mother and birth weight records; stress-related eating behavior and health behaviors in adolescents.	3,598 girls, 3,347 boys from Northern Finland Birth Cohort 1986	Obesity via BMI and waist circumference	Increased stress eating and obesity in girls compared with boys

CRP, C-reactive protein.

Adult life, stress, and CVD risk.

Diabetes, a risk factor for stroke and coronary heart disease, is 44% greater in adult women than men (3, 60). Smoking, high cholesterol, obesity, and hypertension have been shown to contribute to women’s CVD risk more than men’s; however, these traditional risk factors only account for 40% of the variance of CVD (3). Beginning in puberty, psychological stress appears to increase the risk for obesity, particularly in women (2). The hypothesized underlying mechanisms for this health disparity are sex differences in lean muscle mass, glucose metabolism, body fat distribution, adipocyte size and function, hormonal regulation of body weight, adiposity influence of menopause transition, and altered susceptibility to peripheral insulin resistance (57). Later in life, ovarian senescence contributes to increased neuropsychiatric disease risk. The transition to reproductive senescence occurs during the aging process and is much more pronounced, with erratic fluctuations, in women compared with men (48). Because sex hormones affect the HPA axis function, it is not surprising that women are two to three times more likely to experience depression, schizophrenia, and other psychotic disorders during the perimenopausal period compared with men of a similar age (48).

To date, there are few studies assessing depression and CVD comorbidities in sex-balanced study designs. For instance, the Pittsburgh Healthy Women Study showed that middle-aged women who reported life events as extremely stressful, including divorce and widowhood, had an increased risk for developing metabolic syndrome over a 15-yr follow-up period (21). The Stockholm Women’s Intervention Trial for Coronary Artery Disease (SWITCHD) utilized a group-based psychosocial intervention program for women with coronary disease and demonstrated a threefold improvement in rates of survival after 7 yr compared with those women receiving usual care (53). The success of these rates was based in sessions that emphasized methods for reducing and coping with marital and work-related stress. Moreover, Xu et al. (76) have shown that women perceive greater psychological stress than men at baseline, which was largely accounted for in sex differences of comorbidities, mental health status, family conflict, caregiving demand, and financial struggles. In this context, it is well established that coronary microvascular disease affects more women (young women in particular) than men (30, 76). Also, these factors somewhat explain a worse postacute myocardial infarction (AMI) recovery in women compared with age-matched men (76). Furthermore, angina-like pain, ECG changes during stress, and angiographically normal coronary arteriogram (defined as Syndrome X) are more prevalent in women (30).

Numerous studies demonstrate that the interindividual correlation among total peripheral resistance, cardiac output, and muscle sympathetic nerve activity (MSNA) observed in young men does not exist in young women. Consequently, blood pressure regulation appears different between men and women, possibly because of influences of female sex hormones on the cardiovascular function (25). These differences in blood pressure regulation may explain why young women (premenopausal) display a high prevalence of orthostatic intolerance and older women (postmenopausal) show high levels of MSNA and increased blood pressure. Mechanistically, the assessment of sex differences in stress reactivity requires the measurement of physiological responses to acute stressors in laboratory settings. This includes activities of the HPA axis (e.g., cortisol) and sympathetic nervous system [e.g., heart rate (HR) and blood pressure]. Although greater acute autonomic responses have been found in adult men, women display an increased sensitivity of the adrenal cortex (64). Overall, further investigation of pathophysiological mechanisms and therapeutic interventions of coronary arterial dysfunction considering stress response in women is needed. The effects of stress during postnatal life and childhood are summarized in Table 2.

Stress and Risk for Metabolic and Cardiovascular Dysfunction: Models in Rodents

Intrauterine life.

Many models developed in rodents have successfully mirrored LBW and perinatal programming of CVD (15, 52). Experimental studies have shown that maternal malnutrition produces metabolic and cardiovascular alternations in the offspring similar to those observed in epidemiological studies described above. Therefore, bilateral uterine artery ligation to induce IUGR has been a very essential model to investigate the molecular mechanisms linked to LBW-induced cardiovascular programming. This procedure increased adiposity and induced hypertension at 1 yr of age in female rats (52). Also, glucose intolerance is developed at 6 mo of age before cessation of the estrous cycle in female IUGR rats; however, these rats exhibit persistent estrus and a significant increase in adiposity, fasting glucose, and testosterone at 1 yr of age (52).

Behavioral stress during pregnancy is studied using the restraint stress model during gestation to examine the susceptibility to chronic disease in the offspring (5, 10, 28). Dams exposed to prenatal stress have elevated adrenal weights and reduction in corticosterone clearance, increasing circulating glucocorticoids that cross the placenta, directly linked to impaired peripheral glucose and insulin metabolism (24). Male offspring from stressed mothers exhibit hyperinsulinemia with no differences in control offspring when fed a high-fat diet for 1 week; however, this study did not determine effects in female offspring (5). Prenatal social stress model (PNS) includes placing a pregnant intruder rat with another pregnant rat (10). The PNS exposure resulted in sex-specific differences in the offspring in relation to glucose disposal and glucocorticoid metabolism. Female offspring exposed to PNS have lower birth weights with catch-up weight at postnatal day 10, hyperinsulinemia, and decreased expression of phosphoenolpyruvate carboxykinase (PEPCK), which could mobilize more free fatty acids and promote insulin resistance. Conversely, PNS-exposed male offspring did not exhibit differences in insulin or glucose tolerance but had elevations in plasma triglycerides and downregulation of the glucocorticoid receptor in liver and skeletal muscle as well as hepatic levels of peroxisome proliferator-activated receptor-α (PPARα) (10). Also, female offspring from stressed dams have increased visceral and retroperitoneal fat depots after 10 wk of a high-sucrose diet compared with nonstressed dams; mRNA expression in white adipose tissue demonstrated an upregulation of several obesity-related genes, including Fasn, Scd1, Adpn, and Ppargc1a in stressed dams (55).

Postnatal life.

During the postnatal period, there are few mechanisms to protect the offspring from excessive glucocorticoid exposure and HPA axis overactivation during the hyporesponsive period, which is a stage of resilience to mild stressors (42, 74). This is a key event in the origin of long-term hypersensitivity to secondary stressors. Several studies have demonstrated increased metabolic and cardiovascular risk secondary to increased synthetic glucocorticoid administration (39). Maternal separation is a unique chronic behavioral stress model, well known to modulate the adult life HPA axis sensitivity and behavioral stress responses in a sex-dependent manner (27, 35, 37). Maternal separation has become an essential tool to mimic the long-term effects on the cardiovascular system as a consequence of ELS exposure (40, 63, 73). In addition, maternal separation exerts profound effects on metabolic responses. For instance, maternally separated male rats consuming an omega-3-deficient diet have elevated food intake and body weight gain, increased plasma insulin and leptin, impaired glucose tolerance, and elevated hepatic levels of PEPCK (7). When female maternally separated rats are fed a high-sucrose diet for 10 wk, they undergo significant increases in visceral fat, elevated insulin, and leptin levels, as well as impairments in a homeostatic model assessment of insulin resistance (56). Furthermore, our laboratory has recently reported that female rats exposed to maternal separation are particularly susceptible to body weight gain and metabolic derangements compared with male rats (51). However, body weight gain was similar between male maternally separated and control rats fed a high-fat diet. The evidence of the involvement of stress hormones during postnatal life as a major insult affecting the plasticity of metabolically active tissues is supported by the fact that the pharmacological inhibition of the corticosterone synthase blunted the stress response induced by maternal separation, abrogating the effects of diet-induced obesity in female rats (51).

Furthermore, there are a number of factors that have been suggested as a link between maternal separation model and greater cardiovascular risk, as we have recently reviewed (50), including the activation of neuroendocrine systems increasing NF-κB, brain-derived neurotropic factor, nerve growth factor-1A, and neurotrophin 3-4 during postnatal life and circulating glucocorticoids, angiotensin II, endothelin-1, and IL-6 during adult life. In addition, epigenetic alterations play an important role in the axis involving the brain, adrenal glands, and target organs, which can lead to changes in feeding behavior at the level of the paraventricular nucleus of the hypothalamus and also alter the release of hormones such as leptin, insulin, and ghrelin to increase feeding behavior, as extensively reviewed by Sominsky and Spencer (66).

Adult life.

Cardiovascular adaptive responses during acute stress include increases in blood pressure, HR, and cardiac output; however, their prolonged activation can result in the development of chronic disease. Chronic stress can lead to enduring cardiovascular changes in blood pressure, HR, cardiac function, autonomic activity, and inflammation, which are not resolved after the stressor ceases (46). There are several animal models of chronic stressors, including repeated restraint stress, chronic variable stress, repeated social defeat stress, and chronic social isolation. These chronic stressors are proposed to be linked to the development of hypertension (13). Khurana et al. (33) examined whether repeated mild restraint stress would alter neuronal activity in a sex-specific manner in rats. Significant increases in Fos immunoreactivity, a marker for neuronal activation, were found in both sexes across multiple brain regions in response to repeated mild stress. Fos induction was dramatically higher in the amygdala and the piriform cortex only in intact females following repeated stress compared with a single restraint stress exposure. By contrast, the frontal cortex of intact and ovariectomized females showed habituation to the repeated stressor (33). Males displayed modest sensitization in the frontal cortex with no changes in other brain areas (33). Exposure to a mild repeated stress results in sex differences in synaptic adaptations and patterns of brain activation that likely contribute to observed sex differences in stress-induced behaviors.

Psychological stress can affect reproduction in females at the level of the oocyte (19). In a series of experiments to investigate the cumulative effect of restraint stress on follicular development, it was demonstrated that chronic stress impairs the developmental potential of oocytes primarily in antral follicles with significant increases in glucocorticoids and corticotropin-releasing hormone (19), thus providing evidence that chronic stress can impair reproduction potential in females. Of note, the nonhuman primate nervous system is more similar to human than rodent nervous system in several aspects, including serotonergic system organization and function. Therefore, female cynomolgus monkeys have been shown as a unique model to investigate the comorbidity of depression and coronary heart disease risk in women (65).

The biological factors influencing the sex-specific risk for CVD are associated with the protective and harmful effects of the gonadal hormones, especially estrogens and androgens. Sexual dimorphism in blood pressure regulation has been extensively reviewed (3, 43). For instance, treatment with testosterone for 5 wk in ovariectomized female SHR rats increases blood pressure in a dose-dependent manner, providing evidence that male hormones contribute to hypertension (61). On the other hand, ovariectomy in Dahl salt-sensitive rats accelerates hypertension with aging and upregulates angiotensin II type 1 receptors, which is attenuated with estrogen replacement therapy (26). Recently, sexual dimorphism has been described at the level of sex chromosome genes in a transgenic mouse model, showing a deleterious effect of the second X chromosome in females linked to greater risk for abdominal aortic aneurism in a mouse model (1).

Advancement on Sex Differences in Stress-Related Comorbidities

Our past reliance on male animals in drug testing and development may justify the fact that women report more adverse drug reactions compared with men as a result of being underdiagnosed, undertreated, and neglected in cardiovascular research (62). Historically, the hesitation for use of female animals in preclinical research has been related to the complexities of the female estrus cycle; however, the data collected from female animals are no more variable than those from males (mean coefficient of variation is 0.67 ± 0.8 compared with 0.66 ± 0.8, P = 0.919) and include behavioral, morphological, physiological, and molecular traits from 293 studies (58). Despite the scientific basis supporting similar data variability between sexes, the male bias in animal research has persisted. A recent literature search to determine the number of publications investigating the incidence of comorbidities was conducted at the National Center for Biotechnology Information (NCBI) library using keywords such as gender, sex, CVD, and women. This search shows 2,576 publications from years 1990–2000, 6,176 publications from years 2000–2010, and 6,054 publications only from years 2010–2017. All of this clinical and preclinical evidence for sex-specific health disparities serves as a foundation for a policy revealed by the National Institutes of Health in May 2014, which announced that sex must be considered as a biological variable in all NIH-funded preclinical research and mandated the inclusion of women in clinical research (12). Thus more comparative data between sexes will be forthcoming to elucidate sex-specific mechanisms in the prevention and treatment of CVD morbidity and mortality.

In summary, this overview supports the notion that the association between psychosocial/emotional stress and cardiovascular risk is stronger in females from prenatal to adult life. One important contributor to this response is the sex-specific effect of perceived stress combined with the physiological activation of the HPA axis (Fig. 1). On the basis of the rising number of studies considering the sex-specific effects on the interplay between environmental stressors and CVD, there is a hopeful trend to incorporate this matter into future research. Long-lasting effects of emotional stress could serve as a silent causal factor for the uncontrolled epidemic rates for obesity and CVD. More preclinical and clinical studies supporting an increased stress-related risk for metabolic and cardiovascular diseases in females are needed.

Fig. 1.

Origins of greater metabolic and cardiovascular diseases through the lifespan in women. BMI, body mass index; CRP, C reactive protein; SBP, systolic blood pressure; IR, insulin resistance; CAD, coronary artery disease; AMI, acute myocardial ischemic disease.

Perspectives and Significance

Despite the paucity of studies investigating the stress-related comorbidities though the trajectory of life focused on women’s physiological responses to stress, there is substantial evidence pointing to several psychosocial disadvantages affecting predominantly young women. Therefore, women at high risk may include single mothers with low socioeconomic status, working mothers, and older women living alone with limited social support. Most importantly, this condition will most likely affect the metabolic and cardiovascular risk in the next generation. Sex-specific predispositions should be factored in the detection of mental health and CVD comorbidities as well as in treatment and rehabilitation programs to meet the specific needs of men and women to improve patient outcomes and survival. A role for sex hormones, and potentially sex chromosomes, as a biological variable provides a promising tool to elucidate the molecular mechanisms behind this phenomenon.

GRANTS

This study was supported by the National Heart Lung and Blood Institute Grant R00 HL111354 to A. S. Loria.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

M.O.M. and A.S.L. performed experiments; M.O.M. and A.S.L. analyzed data; M.O.M. and A.S.L. interpreted results of experiments; M.O.M. and A.S.L. prepared figures; M.O.M. and A.S.L. drafted manuscript; M.O.M. and A.S.L. edited and revised manuscript; A.S.L. approved final version of manuscript.