By the late 1990s, considerable evidence had accumulated to identify the role that acute stress can exert in precipitating myocardial ischemia as well as to establish the role of chronic psychosocial factors that are associated with an increased risk for CVD, including depression, hostility, work stress, and social isolation.1 The epidemiologic evidence supporting the clinical importance of behavioral and psychosocial risk factors has since grown and now includes a number of meta-analyses concerning individual psychosocial risk factors. A comprehensive list of behavioral and psychosocial factors that have now been studied for their relationship to clinical heart disease is listed in Table 111–2.
TABLE 111–2.Behavioral Risk Factors Associated With Cardiovascular Disease ||Download (.pdf) TABLE 111–2. Behavioral Risk Factors Associated With Cardiovascular Disease
Physical health behaviors
Poor diet and obesity
Poor or inadequate sleep
Negative emotions and mental mindsets
Anger and hostility
Poor social support
Low socioeconomic status
Lack of life purpose
Various negative health behaviors are strongly associated with an increased risk for CVD, including poor nutrition and or weight control, physical inactivity, and smoking. Each of these behaviors is covered in other chapters of this book (see Chaps. 27, 30, 31, and 106).
Poor sleep is a newer arena that has been increasingly studied for its adverse health effects. The study of sleep has included both the examination of sleep duration and the quality of sleep. The definition of short and long sleep is arbitrary, but in most studies, short sleep has been defined as ≤ 5 to 6 hours a night and long sleep as > 8 to 9 hours a night. Repeatedly, studies have found that both short and long sleep, fragmented sleep, and insomnia have been linked to an increased risk for CVD. A meta-analysis of 15 studies found short sleep to be associated with a greater risk of either developing or dying from CVD (relative risk [RR], 1.48; 95% confidence interval [CI], 1.22-1.80), and a similar risk was associated with long sleep.2 Similarly, a meta-analysis of 13 prospective studies involving 122,501 subjects found that insomnia was associated with a risk ratio of 1.45 (95% CI, 1.29-1.63) for the development of CVD or cardiac events.3
These epidemiologic studies have been complemented by a wide variety of studies that have documented consistent pathophysiologic abnormalities in combination with poor sleep, both on an observational basis and in experimental studies that have acutely reduced sleep by various lengths of time among healthy volunteers. These abnormalities include alterations in neuroendocrine and autonomic function, elevation in levels of inflammatory proteins, and an increase in appetite and weight gain, which may be mediated in part through the reduction in the secretion of leptin, an appetite-suppressing hormone, and an increase in ghrelin, an appetite-stimulating hormone, as people get less sleep.4,5,6 Meta-analytic studies have also demonstrated an association between short sleep duration and two important mediators of CVD: hypertension7 and type 2 diabetes.8
The future study of sleep duration, however, may benefit from more investigation that relates outcomes according to the reasons for short sleep. For instance, it is yet to be distinguished how short-sleepers who restrict sleep in the pursuit of highly purposeful activity differ in health effects from those who are short-sleepers due to worry or other psychological factors.
Depression, which ranges from mild symptoms to major depressive disorder, is particularly common in cardiac populations. Major depression, which is characterized by depressed mood and/or lack of interest in nearly all activities for ≥ 2 weeks, in conjunction with at least four to five out of nine other psychological symptoms (eg, change in appetite, insomnia, fatigue, guilt), is found in approximately 15% of cardiac patients, and milder depressive symptoms also occur in another 15% of cardiac patients.9 Epidemiologic studies have consistently demonstrated the potency of depression as a risk factor for cardiac events among community cohorts without preexisting CVD; it is also a risk factor for recurrent events among patients with preexisting CVD. In a large meta-analysis of 54 studies, the adjusted risk ratio for cardiac events was increased nearly two-fold among depressed versus nondepressed subjects in both community cohorts and patients with prior CVD.10 Epidemiologic studies have also demonstrated a gradient relationship between the magnitude of depressive symptoms and the occurrence of adverse cardiac events. Notably, even mild levels of depression or of overall psychological distress have been found to be associated with an increased risk of adverse events compared to patients without symptoms, as demonstrated, for instance, in a recent large follow-up of 68,222 individuals who were assessed for psychological distress using the 12-item General Health Questionnaire (Fig. 111–1).11
Association between psychological distress as assessed by General Health Questionnaire (GHQ)-12 scores and the hazard ratios for all-cause mortality (left) and cardiovascular death (right) among 68,222 individuals. Even mild elevations in GHQ-12 scores were associated with an elevated risk for all-cause mortality and cardiac death. CI, confidence interval. Reproduced with permission from Russ TC, Stamatakis E, Hamer M, et al. Association between psychological distress and mortality: individual participant pooled analysis of 10 prospective cohort studies. BMJ. 2012 Jul 31;345:e4933.11
Anxiety is another negative emotion that is common in medical practice. Anxiety symptoms may range from mild symptoms to severe psychiatric conditions, including phobias, panic disorder, generalized anxiety disorder, and post-traumatic stress disorder (PTSD). The presence of anxiety symptoms was found to be associated with an increased incidence of CVD in a meta-analysis of 20 studies (hazard ratio, 1.48; 95% CI, 1.15-1.38), but the analysis was notable for considerable variability in results among individual studies, with only 50% of the studies manifesting a significant adjusted association between anxiety and CVD.12 Another meta-analysis of 12 studies involving 5750 post–myocardial infarction (MI) patients found a 36% increased risk in overall mortality for those with anxiety symptoms.13
Anxiety syndromes requiring psychiatric help are consistently associated with substantial cardiac risk. For instance, in a 10-year follow-up of 438 acute post-MI patients, Roest et al14 noted an approximately two-fold adjusted risk for adverse outcomes among patients with generalized anxiety disorder, and comparable risk was reported in the Heart and Soul Study.15 A meta-analysis of 12 studies reported an adjusted hazard ratio of 1.49 (95% CI, 1.24-1.74) for CVD among individuals with panic disorders,16 and a meta-analysis of six community cohort studies found a hazard ratio of 1.55 (95% CI, 1.34-1.79) for CVD among those with PTSD.17 The risk associated with PTSD is further highlighted by a study of 562 twins who were followed for a mean of 13 years.18 The presence of PTSD was associated with a 2.2-fold increase in CVD and greater abnormalities on myocardial perfusion imaging for twins who had PTSD compared to their counterpart twins without a history of PTSD.
Hostility is a negative cognitive state that has been widely studied with respect to its potential link to CVD. Hostility is a broad construct that encompasses the traits of anger, cynicism, and mistrust. Interest in this construct was an outgrowth of original work regarding “type A behavior pattern,” a triad of hostility, impatience/time urgency, and a highly competitive drive that is no longer studied as a result of inconsistent findings regarding this proposed behavioral construct. A variety of studies have linked hostility/anger to various pathophysiologic determinants of CVD and to progression of atherosclerosis,9 but epidemiologic study in this arena has been inconsistent. A meta-analysis of 25 studies found a modestly increased risk for cardiac events in association with anger/hostility among healthy population (RR, 1.19; 95% CI, 1.05-1.03), and a similar increase in a meta-analysis of 19 studies involving patients with known CVD was noted (RR, 1.24; 95% CI, 1.08-1.42).19 Both a tendency toward some degree of self-denial or lack of self-awareness among patients with hostility and anger and potential limitations in the questionnaires that have been used to assess this psychosocial construct represent challenges in studying this domain.20
The role of optimism versus pessimism has attracted increasing attention as a risk factor for cardiac events. Pessimism is commonly characterized as a general personality disposition toward expecting negative outcomes in the future; optimists tend toward expecting positive outcomes. Prior study has also assessed optimism versus pessimism according to one’s “explanatory style.” Pessimists have an explanatory style of invoking self-blame for negative events, as well as a tendency to view negative events as persistent and affecting many aspects of their lives. Optimists, in contrast, tend to avoid self-blame, and view negative events as transitioning and limited in scope. Both dispositional and explanatory pessimism have been linked to negative health outcomes. An increasing number of studies have established a consistent relationship between pessimism and reduced longevity and increased risk of cardiovascular events and stroke.21 As with most psychosocial risk factors, a dose-response relationship has been noted between the level of pessimism/optimism and the occurrence of cardiac events.
Chronic stress can be studied objectively through exposure of experimental animals to stress under controlled circumstances. A particularly useful model in this regard has been the study of chronic stress in cynomolgus monkeys (Macaca fascicularis), since these animals both exhibit social behaviors that can be well quantified and develop atherosclerosis in a manner that is similar to humans. When male monkeys are placed into social groups, they fight among each other until they establish a pecking order from the most dominant to submissive monkeys.22 Fighting then subsides. However, by periodically rearranging the distribution of monkeys within groups, a condition of chronic fighting is established. Among male monkeys who were subjected to the experimental condition of changing groups, dominant male monkeys (who tend to do the most fighting) developed considerably greater atherosclerosis compared to dominant monkeys in stable social groups or to submissive monkeys (Fig. 111–2).
Comparison of the amount of atherosclerosis at necropsy (vertical axis) among male cynomolgus monkeys that were experimentally divided into “stable” groups (no regrouping) versus “unstable” groups (period regrouping, to ensure continual fighting among monkeys). All monkeys were fed the same atherogenic diet. Dominant males in the unstable group had substantially more atherosclerosis.
Among individuals, chronic stress has most commonly been studied in relationship to work stress. One of the earliest models of work stress that continues to be studied is that of “job strain.” The model posits that job strain is present when individuals demonstrate a high sense of job demand with little job latitude. Studies have consistently shown an increased risk for CVD among those individuals reporting job strain, but the relationship has been relatively modest. For instance, a recent meta-analysis found only a 1.23-fold increase in the incident risk of CVD in association with measurement of job strain.23 Various other factors may be important to consider when assessing work stress, including the chronicity of the stress. In the INTERHEART study (Effect of Potentially Modifiable Risk Factors Associated With Myocardial Infarction in 52 Countries), the odds ratio for developing MI was 1.38 (95% CI, 1.19-1.61) for those experiencing intermittent work stress, but 2.14 (95% CI, 1.73-2.64) for those experiencing chronic work stress.24
Another common stressor is marital stress. Research in this regard has focused on both marital status and strain within marriages. A large meta-analysis of 104 studies that examined data concerning the risk of death associated with marital dissolution found that the risk of death among those who divorced or separated, compared to married individuals, was age dependent, with risk being highest among younger men who experienced divorce or separation (Fig. 111–3).25 Study into the cardiovascular health effects of psychological stress within marriages, however, has been quite limited. A few epidemiologic studies, primarily in women, have found that measures of marital stress were associated with an increased frequency of cardiac events, but more consistent study is needed to better evaluate this common stressor.
Mean hazard ratio (HR) for all-cause mortality by mean age in men and women experiencing divorce or separation, based on a meta-analysis of 104 studies. The HR was highest among young men, with the difference among men and women decreasing with increasing age. Reproduced with permission from Shor E, Roelfs DJ, Bugyi P, Schwartz JE. Meta-analysis of marital dissolution and mortality: reevaluating the intersection of gender and age. Soc Sci Med. 2012 Jul;75(1):46-59.25
A third stressor is the enduring effects of childhood abuse or trauma. A meta-analysis of 24 studies has linked childhood abuse to an increased risk of CVD and other adverse medical outcomes in adulthood.26 In a particularly large study, the Nurses’ Health Study 2,27 which involved a 16-year follow-up of 66,798 women, a history of childhood abuse was common, having occurred in approximately one-fifth of the women, and within this subgroup, it was associated with an approximately 1.5-fold increase in the onset of cardiovascular events by middle age. Adult risk factors such as smoking, diabetes, and body mass index, as well as psychosocial factors, such as depression, accounted for the majority of this risk. Childhood abuse can also induce persistent neuroendocrine and immune dysfunction in adulthood.28,29
Acute and chronic illness can also produce stress. For instance, Edmondson et al30 recently reported a 12% prevalence of PTSD among acute coronary syndrome (ACS) patients in a meta-analysis of 24 studies; in three of these studies, subsequent outcome data indicated a doubling of subsequent risk of death among ACS patients who had PTSD.
Future study regarding situational stressors may further evaluate how individual differences in perceived stress may affect clinical outcomes. Individuals vary widely in their perceived sense of stress in response to a given life situation, depending on personality, resilient resources, and other factors. One of the interesting aspects regarding stress, in this regard, is an apparent U-shaped relationship between the degree of life adversity and an individual’s sense of satisfaction (Fig. 111–4).31 A likely reason for this U-shaped relationship may be a basic human need to seek growth and meaning, as described by Ryff.32 That is, people are driven to seek goal-oriented activities and challenges, which provide a source of purpose, life satisfaction, and self-esteem. In the absence of challenge, humans may develop boredom and dissatisfaction, which may lead to negative downstream health effects.
U-shaped relationship between the magnitude of cumulative adversity and four measures of well-being: global distress, functional impairment, life satisfaction, and posttraumatic stress (PTS) symptoms as assessed among 2398 individuals reporting lifetime exposure to negative events. The presence of some versus no exposure to stress predicted lower global distress, functional impairment, and PTS symptoms and higher life satisfaction scores. Adapted with permission from Seery MD, Holman EA, Silver RC. Whatever does not kill us: cumulative lifetime adversity, vulnerability, and resilience. J Pers Soc Psychol. 2010;99:1025-41.31
In addition, the meaning that is invested within a given life situation may be a potential modifier of perceived stress and clinical outcomes. For instance, caregiving is a stress that has not been uniformly found to be associated with an increased frequency of clinical events. Potentially, the amount of meaning associated with the caregiving experience could be an important modifying factor,33 but this postulate requires prospective study.
A further aspect regarding perceived stress is the self-beliefs or concerns that patients may have regarding the potential toxicity of stress. This issue was recently studied by Keller et al.34 They assessed mortality in a representative US sample of 28,753 individuals, who rated both their level of perceived stress and their perception as to whether their stress was impacting their health. Among those who reported a high level of stress, increased mortality occurred only among those who also self-appraised their stress as harmful to their health. Pending more prospective study, this finding suggests that modifying patients’ self-beliefs regarding the toxicity of stress might be a potentially useful behavioral intervention.
Social Isolation and Poor Social Support
As with chronic stress, the pathophysiologic effects of social isolation can be studied experimentally in social animal species. As summarized by Capiocci et al,35 placing social animals into isolation has been shown to produce adverse physiologic effects. A direct effect of social isolation upon atherosclerosis has been assessed quantitatively in female cynomolgus monkeys. Compared with dominant female monkeys, female monkeys who are submissive are more prone to atherosclerosis when fed a high-cholesterol diet, but placing monkeys in a single cage results in substantially greater amounts of atherosclerosis compared to monkeys housed in social groups (Fig. 111–5).36
Comparison of the amount of atherosclerosis at necropsy among female cynomolgus monkeys in social groups and in monkeys that were housed in single cages, all fed the same atherogenic diet. Among the social groups, female monkeys that were submissive had more atherosclerosis, but the single-caged monkeys had substantially greater atherosclerosis than the monkeys who were in groups. Data from Shively CA, Clarkson TB, Kaplan JR. Social deprivation and coronary artery atherosclerosis in female cynomolgus monkeys. Atherosclerosis. 1989 May;77(1):69-76.36
The role of social factors upon human health has been repeatedly demonstrated. The classic Alameda County study was the first to link risk of death to the size of one’s social network in a large epidemiologic study.37 This study demonstrated a strong inverse gradient relationship between the size of one’s social network and subsequent risk of death (Fig. 111–6). The study of social health has subsequently expanded to include many aspects of social life, including the size, structure, and frequency of contact within social networks, and various aspects of functional support, including informational and emotional support. Both structural and functional support are important mediators of health outcomes. A recent meta-analysis of 148 studies indicated a large effect size regarding the health buffering provided by strong social support.38 An index of social integration was associated with an approximately two-fold increase in survival in this meta-analysis.
Age-adjusted mortality among men and women during a 9-year follow-up of Alameda County residents divided according to the size of their social network.
Socioeconomic status (SES) is generally characterized as a composite of factors, such as education, occupational status, economic resources, and social status. Longitudinal studies have consistently demonstrated a strong inverse gradient between various measures of SES and adverse cardiac events,39 including recent novel data based on tax and Social Security records, which demonstrate a marked gradient between income and life expectancy in the United States.40 Among children, low SES status also augurs for a greater risk of adult CVD risk factors and adverse cardiac outcomes.41 Low SES has the capacity to serve as a composite chronic stressor because of the various factors that make stressful experiences more likely in low SES environments, including a greater likelihood of more financial strain, less job security and latitude, poorer housing conditions, more impoverished neighborhoods, and/or a diminished sense of public safety. Several mechanisms appear to account for the increased risk associated with low SES. First, low SES is associated with a higher frequency of poor health habits, such as poor nutrition and overeating, smoking, and physical inactivity.42 Second, the stress associated with low SES (eg, economic hardship, job insecurity) increases the prevalence of depression and other mental status parameters that may in turn increase CVD.43 In addition, pathophysiologic mechanisms that can promote CVD are also more prevalent in low SES populations, such as more autonomic and metabolic dysfunction.44,45
Synergy Among Psychosocial Risk Factors
Although epidemiologic study tends to assess individual psychosocial risk factors in isolation, these factors have a high tendency to cluster in real life. Various lines of evidence indicate that clustering of psychosocial risk factors increases the risk of clinical events. For instance, poor social support can augment the health impact of life stress. In an early study in this regard, Ruberman et al46 found that high levels of life stress or social isolation each doubled the risk of all-cause death compared to patients with low levels of each risk factor among 2230 post-MI patients followed for 3 years. However, when both risk factors were present, death risk was substantially increased compared to the presence of one risk factor alone (Fig. 111–7).
Cumulative mortality curves among post–myocardial infarction patients followed for 36 months, according to baseline levels of education, life stress, and social isolation. When both life stress and social isolation were considered together, there was a substantially larger gradient of risk compared to consideration of either factor alone. Reproduced with permission from Ruberman W, Weinblatt E, Goldberg JD. et al: Psychosocial influences on mortality after myocardial infarction. N Engl J Med. 1984 Aug 30;311(9):552-559.46
Similarly, psychological stressors are also potentiated when occurring among individuals with low SES.47,48 Depression and anxiety are highly comorbid, and when both are present, the likelihood for future clinical event rates is elevated compared to the presence of either emotion alone.49 The prognosis associated with psychosocial stress may also be potentiated by the presence of poor health habits, such as physical inactivity (Fig. 111–8).50
Cumulative incidence of cardiovascular death in the Cardiovascular Health Study. Both depression and physical inactivity each individually increased the risk of cardiovascular death, but when both were present, there was greater mortality than the presence of either risk factor alone. Reproduced with permission from Win S, Parakh K, Eze-Nliam CM, et al. Depressive symptoms, physical inactivity and risk of cardiovascular mortality in older adults: the Cardiovascular Health Study. Heart. 2011 Mar;97(6):500-505.50
Pathophysiology Of Negative Psychosocial Stressors
The pathophysiologic mechanisms by which psychosocial risk factors promote atherosclerosis and increase the risk for cardiac events has been extensively studied, both in human studies and in experimental animal studies. Psychosocial risk factors exert their deleterious effects by two basic pathways: a wide variety of direct pathophysiologic effects and negative impact on health behaviors (Fig. 111–9).9,21 When psychosocial stress is chronic, such as in depression, it can result in persistent activation of the hypothalamic-pituitary-adrenal axis and dysregulation of the sympathetic nervous system, leading to a rise in serum cortisol levels and elevated norepinephrine levels. The result is widespread systemic effects, which vary in presentation according to the type and magnitude of stress. In depression, these effects include autonomic dysfunction; a variety of endocrine-related abnormalities, including central obesity, insulin resistance, and a three-fold increase in the risk for diabetes; increased risk for ovarian dysfunction and osteoporosis; endothelial dysfunction; a variety of platelet abnormalities; and unfavorable alterations in brain plasticity, including enlargement of the amygdala (the brain’s fear center) and reduction in the size of the hippocampus and prefrontal cortex.1,9 Other pathophysiologic effects of chronic stressors may include increased risk of arrhythmias, hypertension, and enhanced cardiovascular reactivity (ie, the tendency to manifest increased heart rate and blood pressure responses to physiologic stimuli with prolonged time to recovery to baseline measurements). Cardiovascular reactivity has been linked to a higher frequency of subsequent hypertension and carotid intima-medial thickness according to a meta-analysis of 36 studies.51
Psychosocial risk factors promote coronary disease risk through two basic mechanisms: direct pathophysiologic effects, which may vary according to the type and intensity of psychosocial stress, and behavioral effects, including a greater propensity toward unhealthy behaviors when psychosocial stress is present and a decreased likelihood of adhering to behavioral recommendations. ANS, autonomic nervous system; BP, blood pressure; HR, heart rate.
There are two principal behavioral mechanisms by which psychosocial risk factors also exert their pathogenic effects. First, extensive study has repeatedly demonstrated that unhealthy behaviors, such as overeating, poor nutritional choices, physical inactivity, and smoking, are more common among patients with psychosocial risk factors such as depression, anxiety, pessimism, loneliness, and chronic stress. Second, these same psychosocial factors tend to impede the ability of patients to comply with behavioral changes recommended by their physicians. For instance, a meta-analysis of 122 studies found that various aspects of social support each had a significant negative effect upon patient adherence to medical regimens.52 Similarly, another meta-analysis found a three-fold increase in poor patient adherence among depressed versus nondepressed patients.53