psychosocial stress and cardiovascular disease risk: the...

Psychosocial Stress and Cardiovascular Disease Risk: The Role of Physical ActivityMARK HAMER, PHD

Chronic stress and depression are associated with increased risk of cardiovascular disease and poorer prognosis, and physical(in)activity may be a key underlying biobehavioral mechanism. Physical activity has antidepressant effects, and physically fitter, moreactive individuals seem to be more biologically resilient to psychosocial stressors. This article will present data from a series ofpopulation cohort studies and laboratory-based psychophysiological studies to explore the role of physical activity as a protective factoragainst the effects of psychosocial stress on cardiovascular disease. These mechanisms may improve the treatment and prevention ofstress-related illnesses and, thus, has important implications for public health and clinical care of high-risk patients.Key words: cardiovascular disease, depression, epidemiology, physical activity, psychophysiology, stress.

CVD = cardiovascular disease; IL = interleukin; TNF-> = tumornecrosis factor >; CRP = C-reactive protein; BDNF = brain-derivedneurotrophic factor; HPA = hypothalamic-pituitary-adrenal.

INTRODUCTION

Psychosocial risk factors involve a wide range of differentvariables including mental stress, depression, anxiety,

hostility, loneliness, and social circumstances and networks.Evidence from prospective cohort studies in humans that hasemerged over the last several decades consistently demonstratesan association between various psychosocial risk factors andfuture risk of cardiovascular disease (CVD) in both initiallyhealthy samples and patients with cardiac disease (1Y4), witheffect sizes that are comparable with conventional risk factorssuch as hypertension, obesity, and smoking (5).

The issue of how to tackle factors such as chronic stress anddepression for disease prevention has been an area of consid-erable interest and intense debate in clinical and research work.For treatment to be successful, it is essential to understand thepathways that might explain the associations between psycho-social stress and disease. Our understanding of the mechanismsis evolving (see Fig. 1), and this knowledge base continues todevelop. The reasons that the underlying pathways linkingstress and CVD are incompletely understood can be partly at-tributed to methodological limitations and lack of controlledtrial data. At present, the evidence base is largely limited tofindings from observational population studies and psycho-physiological experiments. Population studies enable largenumbers of participants to be observed over time for hard clin-ical end points, although causal inferences cannot be estab-lished. Testing of acute psychophysiological stress involvesthe assessment of individual differences in biologic responsesto standardized stressors that can be related to psychosocialrisk factors, thus, is a useful technique to investigate under-lying mechanisms (6,7).

Physical activity is a potentially important mediator of the linkbetween stress and CVD. The last 50 years of epidemiologicalresearch in physical activity has provided strong evidence for the

beneficial effects of physical activity on both cardiovascular (8,9)and mental health outcomes (10,11), although the causality of theformer cardiovascular effects is much better established than thaton mental health outcomes (12,13). The aim of this article is toprovide a selective review of the evidence for physical activity asa key intermediate pathway in the association between psycho-social factors and CVD.

EPIDEMIOLOGICAL EVIDENCEIn recent years, epidemiological approaches to modeling the

relationship between stress and CVD have been refined; tradi-tionally, researchers have aimed to test if the association be-tween exposure (stress) and outcome (CVD) is maintained afteradjustments for numerous covariates. However, more contem-porary studies have started to treat covariates such as physicalactivity as mediators, thus examining the extent to which effectestimates are changed when a potential mediator is added to themodel. Such an approach is grounded in theory and mustconform to the main criteria for mediation; that is, the exposureshould be associated with the potential mediator(s), the po-tential mediator should predict the outcome, the exposurevariable should be associated with the outcome, and this asso-ciation should be significantly attenuated after adjustment forthe mediator. Evidence from contemporary studies (14Y18) hasclearly demonstrated that participants categorized as stressed/depressed report lower physical activity levels, which can ex-plain up to 30% of the association between stress/depressionand CVD (see Table 1). For example, among 6576 healthycommunity-dwelling participants, those reporting psychologicaldistress at baseline were at 50% increased risk for a CVD eventduring a 7-year follow-up (14). Subsequent adjustment forphysical inactivity in the models was associated with a 22%reduction in the strength of association between distress andCVD events, despite accounting for other covariates such as, age,sex, socioeconomic status, smoking status, and other conven-tional CVD risk factors. Similar findings were observed among1017 outpatients with stable coronary disease from the Heart andSoul study (15). In a small cohort of 909 healthy, older Europeanmen, physical inactivity explained a negligible amount of theassociation between depression and CVD mortality during a10-year follow-up (18), although depression and inactivitycombined to produce an additive risk increase of 33%. In oneof the largest behavioral intervention trials to date, consistingof 2481 patients with myocardial infarction experiencing de-pression and low perceived social support, treatment withcognitive behavior therapy had no effect on event-free survival

Psychosomatic Medicine 74:00Y00 (2012) 10033-3174/12/7409Y00Copyright * 2012 by the American Psychosomatic Society

From the Department of Epidemiology and Public Health, University Collegeof London, UK.

Address correspondence and reprint requests to Mark Hamer, PhD, Departmentof Epidemiology and Public Health, University College London, 1-19 TorringtonPlace, London, WC1E 6BT, UK. E-mail: [email protected]

The research presented in this article was made possible by funding fromthe British Heart Foundation.

Received for publication August 8, 2012; revision received August 6, 2012.DOI: 10.1097/PSY.0b013e31827457f4

Copyright © 2012 by the American Psychosomatic Society. Unauthorized reproduction of this article is prohibited.

after a 29-month follow-up, despite significant improvementin depression and perceived social support (19). However, in asecondary analysis of the cohort in the Enhancing Recovery inCoronary Heart Disease Patients study, self-reported exercisein the 6 months after myocardial infarction was associatedwith more than a 50% reduction in the risk of subsequentdeath (20). Physical inactivity not only carries cardiovascularhealth risks but also is important in predicting the onset ofphysical decline in older adults (21) and partly explains thelink between depression and disability (22). Thus, physicaldecline, together with perceived barriers toward physical ac-tivity, such as fear and negative experiences, low self-efficacy,and lack of knowledge, may partly explain the increased riskof physical inactivity among participants with depressivesymptoms. In addition, cognitive factors such as impairedexecutive function, with reduced ability to handle, process,and retain new information, may also partly explain why de-pressed patients are less likely to adhere to treatments and life-style modification.

A clear limitation of the existing work in this area is thatmost studies are unable to provide a robust test of mediationbecause the potential mediating variables are usually measuredat the same point in time as the markers of stress exposure, thusmaking it difficult to determine the temporal nature of the as-sociation. Indeed, the association of stress with intermediaterisk factors for CVD might be bidirectional in that stress not

only causes disturbances in behavior and pathophysiologicalmarkers but also vice versa. For example, physical activityseems to be protective against the development of depressionand stress-related illness, although individuals with mental ill-ness are less likely to undertake any activity (23). These typesof issues might be resolved in the future by the use of con-temporary statistical approaches that reveal individual hetero-geneity in the direction of the effect (24). Another weakness ofthis area is the reliance on self-reported physical activity. One ofthe most significant developments in field over the last decadehas been the introduction of small solid-state accelerometerdevices that now permits physical activity to be assessed ob-jectively over several days at low cost, thus making it feasible toincorporate such measures in large-scale population studiessuch as the National Health and Nutrition Examination Survey.Physical activity epidemiologists have traditionally used self-report measures, which have the possibility of introducingreporting biases and making it more difficult to precisely definethe dose-response association between physical activity andhealth. Objective measures are able to not only assess intensityand duration of activity more effectively but also better delin-eate the duration of continuous bouts of activity and periods ofprolonged inactivity (sitting) (Fig. 2). Very few studies haveexamined associations between objectively assessed physicalactivity and mental health, and those that have reveal incon-sistent findings (25Y29). Some of these limitations inherent toepidemiological studies can be reduced by investigations thatuse experimental manipulations of physical activity levels andthose using stress reactivity paradigms.

EXERCISE AND CARDIOVASCULARSTRESS REACTIVITYPsychophysiological stress testing can be used to establish

the mechanisms and time trajectories underlying the associationbetween stress and CVD. Although acute psychophysiologicalresponses are not clinically meaningful in themselves, theyrepresent the way in which individuals respond to daily stres-sors in their normal lives and if elicited regularly might haveclinical relevance. A body of work has examined the associa-tion between psychophysiological stress reactivity and cardio-vascular risk (6), which, on balance, suggests that the effectsizes are modest but consistent after accounting for established

TABLE 1. A Summary of the Results From Epidemiological Studies Exploring the Extent to Which Physical Activity Behavior Explains the AssociationBetween Stress/Depression and CVD

Study Sample Exposure and Outcome % Explained by Physical Activity

Hamer et al. (14) Healthy general UK population (n = 6576) GHQ-12; CVD events, 7.2-y follow-up 22%

Whooley et al. (15) Patients with cardiac disease (n = 1017) PHQ-9; recurrent CVD, 4.8-y follow-up 31%

Hamer et al. (16) UK elderly population (n = 1007) GDS-15; CVD death, 9.2-y follow-up 25% (12.5% activity; 12.5% function)

Win et al. (17) Healthy general US population (n = 5888) CES-D; CVD death, 10.3-y follow-up 26%

Kamphuis et al. (18) Healthy European elderly men (n = 909) Zung Self-Rating Depression Scale;CVD death, 10-y follow-up

9%

CVD = cardiovascular disease; GHQ-12 = General Health Questionnaire; PHQ-9, Patient Health Questionnaire; GDS-15, Geriatric Depression Scale; CES-D, Centrefor Epidemiological Studies Depression scale.

Figure 1. A conceptual framework for the possible mechanisms that explainthe association between psychosocial risk factors and cardiovascular disease.HPA = hypothalamic-pituitary-adrenal; SNS = sympathetic nervous system.

M. HAMER

2 Psychosomatic Medicine 74:00Y00 (2012)


risk factors. Paradoxically, both exercise and mental stress elicitsubstantial cardiovascular reactivity, although these responsesare considered healthy in the context of exercise, whereas thesame reactivity measures are purportedly ‘‘bad’’ when exam-ined in the context of mental stress. In fact, similarities betweencentral and peripheral responses to exercise and mental stres-sors have led to the theory of ‘‘cross-stressor adaptation’’ (30),where adaptations resulting from regular exercise lead not onlyto improved physiological control during exercise but also inresponse to psychological stressors. Because exaggerated re-sponses to mental stress can have detrimental effects on health,the potential stress-buffering effects of exercise are of impor-tance. Much of the existing psychophysiological work relatingto physical activity has focused on cardiovascular responses.Several experiments have tested the impact of single bouts ofexercise, the aim of which is to examine whether stress re-activity or rate of recovery is modified after physical activity;others have made comparisons of stress responses in physicallyfit and unfit individuals; and training studies in which psycho-physiological stress responses are compared before and afterexercise training.

Studies examining the effects of acute exercise have resultedin relatively consistent evidence, such that a single bout ofexercise is associated with buffering of blood pressure andcardiac responses to standardized behavioral challenges in thelaboratory (31). Studies that have examined psychophysiolog-ical responses in relation to physical fitness (an indicator oftraining status) and exercise training have produced moremixed results. In an early meta-analytic review of 34 studies,aerobic fitness was associated with nearly half a standard de-viation reduction in blood pressure stress reactivity (32), butmore recent updated reviews suggested both positive and in-verse associations between fitness and heart rate reactivity(33,34). Dishman and Jackson (33) reported that fitness wasrelated to greater heart rate reactivity but better recovery frommental challenge in 73 studies, although these effects werediminished when only randomized controlled exercise training

studies were included and when fitness was measured as peakoxygen uptake. In contrast, Forcier and colleagues (34) dem-onstrated an inverse association between fitness and heart ratereactivity in an analysis containing only studies with evidenceof an exercise training effect. A common problem in this area islimited sample size that can often lead to studies with insuffi-cient statistical power. This issue was, however, addressed in arecent controlled trial consisting of 149 healthy, young seden-tary participants who were randomized to a 12-week exerciseprogram, followed by a further 4 weeks of sedentary decondi-tioning (35). Participants performed various stressors beforeand after the intervention, including a public speaking task,mental arithmetic, and the Stroop Color-Word task, althoughthere was no indication of any stress-buffering effects afterexercise training. In addition, a recent trial that examined theeffects of 8-week exercise training on muscle sympatheticnervous activity measured directly from the peroneal nervefound no evidence of sympathoinhibition (36). Another studyexamined exercise training in the context of weight loss inobese children and found that weight loss through 4 months ofexercise training and diet, but not diet alone, improved vaso-dilatation responses to the Stroop mental challenge (37). Thissuggests that exercise in combination with weight loss might beimportant in attenuating cardiovascular reactivity in response tomental challenges.

One of the difficulties in interpreting data from short-term(often 8Y12 weeks) exercise trials is that individual changes infitness are usually modest, which suggests that a short period ofexercise training may not be sufficient to induce the type ofchronic adaptations required to observe stress-buffering effects.Here, a comparison of persons with a longer history of low andhigh levels of habitual physical activity may be helpful. Muchof the research in this field has relied on self-report measures ofphysical activity, and the problems with these are well known.We therefore conducted a study to examine the associationbetween objectively measured habitual physical activity levelsand psychophysiological responses in women (29). Participants

Figure 2. Data from an accelerometry device that was worn by a healthy male participant during a 24-hour period. The data emphasize the complex patterns ofactivity that can be captured by an objective measure. To view image in color, please visit: www.psychosomaticmedicine.org.

STRESS, CVD, AND PHYSICAL ACTIVITY

Psychosomatic Medicine 74:00Y00 (2012) 3


wore an accelerometer device during waking hours for 1 weekand, in addition, recorded their daily moods and took part inpsychophysiological testing. We observed robust associationsbetween objectively assessed physical activity and daily mood(Fig. 3), although no associations were found with cardiovas-cular reactivity to behavioral stressors administered in thelaboratory. Further work is required to examine if habitualphysical activity is more closely linked with physiological re-activity to naturalistic stressors. In addition, sedentary behaviormay play an important role (38), although no work has exam-ined if sedentary behavior (prolonged sitting) is related topsychophysiological responses independently of physical ac-tivity. Taken together, inconsistencies in this area may be due,in part, to small sample sizes, insufficient exercise trainingeffects, inconsistencies in methodology (i.e., design, types ofstressors, and types of stress response measures), failure toaccount for the aftereffects of a recent bout of acute exercise,and other confounding factors. Furthermore, based on the lawof initial values, it is likely that exercise will have the greatesteffects in those individuals with heightened responses from theoutset or some degree of underlying disease pathology. Forexample, exercise has been strongly associated with stress-buffering effects in participants with parental history of hy-pertension (39) and chronically stressed individuals such ascaregivers (40) compared with healthy low-risk individuals. Itshould also be noted that previous studies have generally tendedto measure blood pressure intermittently with conventional armcuffs, which may not capture the full contour of the responsethat can be obtained using beat-to-beat devices.

The potential stress-buffering benefits of regular exercisemay be largely accounted for by the fact that exercisers aremore often in the postexercise window when they encounterdaily stressors. The attenuation in blood pressure reactivityimmediately after a single bout of acute exercise is thought tobe best explained by a reduction in regional vascular resistancemediated by sympathetic nervous inhibition (41). Indeed,studies have shown that reduced noradrenaline response to abehavioral stress task was the best single predictor of the at-tenuation in postexercise blood pressure stress responses (42).Furthermore, significant increases in postexercise A1- and A2-receptor responsiveness were observed, indicating that theblood pressure response was primarily blunted by enhancing

A2-mediated vasodilatation (42). Taken together, improvementsin hemodynamic function during mental stress may be an im-portant mechanism contributing to the stress-buffering effectsof acute exercise in relation to CVD risk.

PHYSICAL ACTIVITY, STRESS, ANDINFLAMMATIONThe immune system may play an important role in psy-

chobiologic processes that link psychosocial stress with CVDand other health outcomes (43). Acute mental stress has beenshown to induce increases in circulating inflammatory markerssuch as interleukin (IL)-6 and tumor necrosis factor > (TNF->)(44), and these responses are more pronounced in participantswith enduring chronic stress and depressive symptoms (45,46),although less pronounced in physically fit participants (47).Numerous studies have also demonstrated elevated concentra-tions of various inflammatory markers at rest in differingpopulations reporting depressive symptoms (48). A large amountof interest has focused on the potential anti-inflammatory effectsof exercise. It has been argued that the increases in circulatingIL-6 that are observed after an acute bout of exercise promotean anti-inflammatory environment by increasing IL-1 receptorantagonist and IL-10 synthesis while inhibiting proinflam-matory markers such as TNF-> (49). The cytokines releasedduring exercise are thought to originate from exercising skeletalmuscle, which work in a hormone-like fashion exerting specificendocrine effects on various organs and signaling pathways.Unlike IL-6 release during acute mental stress, which seems tobe dependent on activation of the nuclear factor JB signalingpathway (50), intramuscular IL-6 expression is regulated by anetwork of signaling cascades that are likely to involve theCA2+/NFAT and glycogen/p38 MAPK pathways. This mightpartly explain why exercise-induced IL-6 release is not actingas a strong proinflammatory agent. This hypothesis is also con-sistent with data from numerous observational studies demon-strating an inverse association between regular physical activityand various proinflammatory markers (51). Results from con-trolled exercise trials have not always consistently found reduc-tions in inflammatory markers after intervention, although giventhat most health benefits from exercise are established throughchronic training adaptations, it is difficult to draw firm conclu-sions from short-term exercise trials often only lasting for

Figure 3. A, The association between physical activity and daily positive mood. B, Depressive mood measured from the Centre Epidemiological Studies Depressionscale. Physical activity groups reflect the tertile of average daily minutes actively recorded by accelerometry (e213.88, 213.89Y262.33, and Q262.34 minutes/d).

M. HAMER



3 months. In the Whitehall II cohort, we recently demonstratedthat maintenance of habitual physical activity for 10 yearswas associated with lower levels of C-reactive protein (CRP)and IL-6 at follow-up and that the differences in inflamma-tory markers between active and inactive remained stable overtime (52).

Given the described link between both psychological stressand exercise with inflammatory pathways, it can be hypothe-sized that better mental well-being experienced by regularexercisers might be partly explained by an underlying inflam-matory mechanism. We conducted a study in a sample of 3609older adults from the English Longitudinal Study of Ageing, toexamine if the association between persistent depressivesymptoms and inflammatory markers during a 2-year follow-upcould be partly explained by physical activity behavior. Parti-cipants with recurrent elevated depressive symptoms at bothtime points displayed significantly elevated levels of CRP andfibrinogen at follow-up compared with nondepressed partici-pants, and this relationship was partly explained through lowerlevels of physical activity in participants with depressivesymptoms (53). The anti-inflammatory effects of exercisemight also be relevant at a neurobiological level becausealterations in neurotransmitter function involving serotonin,norepinephrine, and dopamine are known to induce depressionand are targets for currently available psychopharmacologicaltreatments. Exercise is thought to alter serotonin metabolism,release endogenous opioids, and increase central noradrenergicneurotransmission, which may all contribute to antidepressantand anxiolytic effects. The dopaminergic system is thought toplay a key role in depression, and polymorphisms of the do-pamine D2 receptor gene have also been implicated in physicalactivity behavior (54). Further research has focused on thehippocampus, where exercise-induced neurogenesis andgrowth factor expression has been proposed as potential med-iators (55). An emerging theory is that exercise enhances sev-eral growth factors such as brain-derived neurotrophic factor(BDNF) and insulin-like growth factor, which mediate theprotective and therapeutic effects of exercise on depression. Ithas been shown that an acute bout of exercise increases pe-ripheral levels of serum BDNF in an exercise intensity-dependent fashion, but resting levels of BDNF do not seem tobe affected by long-term exercise training (56), suggesting thatother compensatory mechanisms might be at play. In connec-tion to the effects of exercise on neurotrophins, the endo-cannabinoid system might represent an important mediatingsignaling pathway (57).

Another important aspect may be the interaction of the im-mune system with the hypothalamic-pituitary-adrenal (HPA)axis and autonomic nervous system. After mental stress, thesensitivity of the immune system to dexamethasone inhibition(a synthetic version of the hormone cortisol that has potent anti-inflammatory properties) is reduced, as manifest by a reductionin this hormone’s capacity to suppress the production of in-flammatory cytokines (58). In endurance-trained individuals,however, an acute bout of exercise has been shown to increasetissue sensitivity to glucocorticoids (59). HPA axis dysregula-

tion and cortisol hypersecretion have been implicated in ad-verse mental health and cardiovascular outcomes. For example,in a healthy subsample of participants from the Whitehall IIcohort, we showed that exaggerated cortisol responses to twobehavioral stress tasks were predictive of coronary artery cal-cium progression during a 3-year follow-up and incidenthypertension (60,61). Exercise may have beneficial effects onHPA functioning because some studies have shown lowerstress-induced cortisol responses in physically trained com-pared with untrained individuals (62,63). However, we failed toreplicate previous findings in our work that examined asso-ciations between objectively assessed physical activity levelsand cortisol responses to acute mental stress (29). In addition,recent data demonstrated higher levels of cortisol in the hair oftrained athletes compared with controls, suggesting greaterchronic exposure to cortisol in trained individuals (64). Someof these inconsistencies might be attributed to differences inmeasures because cortisol from hair is a reflection of chronicexposure but does not necessarily provide information aboutglucocorticoid sensitivity or acute variations, which are betterassessed through psychophysiological studies and diurnalsampling. Thus, teasing apart chronic effects from acute var-iations in daily diurnal patterns will be an interesting avenue offuture research.

In summary, the link between physical activity and stresscould be explained through several biologic processes includ-ing the inflammatory, dopaminergic, and neuroendocrine sys-tems, which might have relevance to CVD pathology and otherdiseases in which inflammatory processes play a contributingrole. However, there is a lack of experimental and longitudinalevidence to show the long-term health consequences of phys-ical activity on these biologic pathways.

THE EXERCISE WITHDRAWAL PARADIGMExercise training trials are costly and require a large amount

of manpower in administering supervised exercise sessions.In addition, one of the difficulties in interpreting data fromshort-term (often 8Y12 weeks) exercise trials is that individualchanges in fitness are usually modest and some participants arenonadherent, which suggests that a short period of exercisetraining may not be sufficient to induce the type of chronicadaptations required to observe stress-buffering effects. Theexercise withdrawal paradigm therefore represents a useful,more practical alternative because mood disturbances can beelicited in habitual exercisers after a 1- to 2-week withdrawalfrom their regular training activities, which provides a model toinvestigate the links between exercise, stress, and the underlyingbiology. We and others have hypothesized that mood dis-turbances caused by withdrawal from regular exercise might actas a mild inflammatory stimulus. However, recent studies havebeen unable to confirm this hypothesis. Several studies, includ-ing one of our own that have successfully induced an increasednegative mood after several weeks of exercise withdrawal, didnot find any robust changes in a range of inflammatory markerssuch as IL-6, CRP, TNF->, fibrinogen, and soluble intracellular




adhesion molecule-1 (65,66). Similarly, 1-week withdrawal fromexercise in highly active men did not elicit any substantialchanges in CRP, IL-6, TNF->, and circulating leukocyte con-centration (67). In the same study, no changes in inflammatorymarkers were observed among sedentary participants who un-dertook 30 minutes of brisk walking each day for 1 week.Healthy men who reduced their daily step count by 85% for2 weeks developed impaired glucose tolerance, attenuation ofpostprandial lipid metabolism, and a 7% increase in intra-abdominal fat mass, although plasma cytokines and muscularexpression of TNF were not altered (68). However, another studyreported that reduced parasympathetic nervous activity as mea-sured by heart rate variability was predictive of negative moodafter exercise withdrawal (69). These findings are consistent withemerging data on underlying molecular mechanisms. For ex-ample, the expression of exercise-regulated muscle genes suchas the transcriptional coactivator PGC1>, which is thought topromote anti-inflammatory effects (70), is known to be rapidlyinduced after a single bout of acute exercise, although it quicklyreverts back to basal levels. In contrast to the transient changesafter acute exercise, greater levels of PGC1> are present inchronically trained exercised muscle than in untrained muscle.Thus, there is a clear difference between short-term and long-term adaptations, which might explain why a short 2-weekexercise withdrawal period in trained participants is insufficientto see changes. Furthermore, adherence to exercise withdrawalin regular, fit exercisers may be problematic because habitu-ally active individuals are less likely to agree to stop theirtraining regimen and perhaps compensate in other ways tomaintain a physically active life-style (e.g., taking up activecommuting for the period of exercise withdrawal). This createsother inherent limitations because removing self-chosenleisure time behaviors may in itself induce psychologicaldistress regardless of exercise cessation.

In a further study, we investigated the impact of exercisewithdrawal on psychophysiological responses to mental stressbecause this method can sometimes detect differences thatmight not otherwise be seen under resting conditions. Althoughthe effects of cytokines are often thought to be transient, theymay provoke a time-dependent sensitization so that the re-sponse to a later cytokine or stressor stimulus is enhanced,resulting in an increased vulnerability to depressed mood (71).We experimentally manipulated physical activity levels byasking a group of habitual exercisers to withdraw from theirregular training for 2 weeks (72). The adherence to exercisewithdrawal was mixed, as indicated by objective accelerometryphysical activity records, but in participants with greater mooddisturbances (assessed using the 28-item General HealthQuestionnaire) after a 2-week withdrawal, we observed sig-nificantly higher inflammatory responses to mental stresscompared with those with low or no mood disturbance. In thesame study, cortisol responses to mental stress were higher inthe exercise withdrawal phase compared with the control pe-riod, with a significant difference emerging at 20 minutespoststress. These results, although preliminary, suggest thatinflammatory and neuroendocrine factors may, in part, mediate

the protective or buffering effect of physical activity on stress-related physiological activation.

To summarize, the exercise withdrawal paradigm offers apromising way in which to elucidate some of the mechanisticpathways linking physical activity to stress and CVD risk.Future work is needed to better understand the temporal rela-tionship between exercise-induced mood disturbances andchanges in inflammatory and neuroendocrine factors.

CONCLUSIONS AND FURTHER WORKNumerous intermediate mechanisms might explain the link

between psychosocial factors and CVD and other diseases,including behavioral and biologic processes. Increasing ourknowledge about these mechanisms will contribute to more ef-fective prevention and treatment strategies and help establishpriorities for the allocation of health care and research resources.Taken together, the currently available data from epidemiologicalstudies suggest that physical activity plays an important role inexplaining the association between psychosocial factors andCVD. Interventions that reduce the magnitude of psychophysi-ological responses are also of interest because exaggeratedresponses to mental stress can have detrimental effects on health.Regular exercise is known to be an effective life-style interven-tion in the primary prevention of CVD, and this could be partlymediated through the buffering of hemodynamic, neuroendo-crine, inflammatory, and hemostatic responses to daily mentalstressors. There is reasonably strong evidence to suggest that asingle bout of acute exercise can blunt cardiovascular stressresponses, and because these effects last for 2 to 4 hours, aperson that exercises 3 times a week may be in a stress-bufferedstate up to 12 hours a week. Data from chronic training in-tervention studies on the effects beyond the aftereffects of arecent bout of acute exercise are less consistent. Incon-sistencies in this area may be due, in part, to small samplesizes, insufficient exercise training effects, inconsistencies inmethodology (i.e., design, types of stressors, and types ofstress response measures), and other confounding factors. Atpresent, there is evidence suggesting that exercise might alsomodify biologic stress responses (cortisol, inflammatorymarkers), although further experimental work is needed toextend the current findings.

Dr. Mark Hamer received the 2012 Herbert Weiner Early CareerAward of the American Psychosomatic Society. This article presents areview of the research conducted in collaboration with the author’smentor, Professor Andrew Steptoe. The author has benefited tremen-dously from his guidance and scientific support, for which he isgrateful.

REFERENCES1. Steptoe A, Kivimaki M. Stress and cardiovascular disease. Nat Rev Cardiol

2012;9:360Y70.2. Brotman DJ, Golden SH, Wittstein IS. The cardiovascular toll of stress.

Lancet 2007;370:1089Y100.3. Hamer M, Kivimaki M, Stamatakis E, Batty GD. Psychological distress as

a risk factor for cerebrovascular disease mortality: a population study in68,652 adults. CMAJ 2012;184:1461Y6.

4. Kivimaki M, Nyberg ST, Batty GD, Fransson EI, Heikkila K, Alfredsson L,

M. HAMER



Bjorner JB, Borritz M, Burr H, Casini A, Clays E, De Bacquer D, DraganoN, Ferrie JE, Geuskens GA, Goldberg M, Hamer M, Hooftman WE,Houtman IL, Joensuu M, Jokela M, Kittel F, Knutsson A, Koskenvuo M,Koskinen A, Kouvonen A, Kumari M, Madsen IE, Marmot MG, NielsenML, Nordin M, Oksanen T, Pentti J, Rugulies R, Salo P, Siegrist J, Singh-Manuox A, Suominen SB, Vaananen A, Vahtera J, Virtanen M, WesterholmPJ, Westerlund H, Zins M, Steptoe A,Theorell T. IPDWork Consortium. Jobstrain as a risk factor for future coronary heart disease: collaborative meta-analysis of 2358 events in 197,473 men and women. Lancet, published aheadof print September 13, 2012. doi: 10.1016/S0140Y6736(12)60994Y510.3389/fnhum.2010.002022012.

5. Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F, McQueen M,Budaj A, Pais P, Varigos J, Lisheng L. INTERHEART Study Investigators.Effect of potentially modifiable risk factors associated with myocardialinfarction in 52 countries (the INTERHEART study): case-control study.Lancet 2004;364:937Y52.

6. Chida Y, Steptoe A. Greater cardiovascular responses to laboratory mentalstress are associated with poor subsequent cardiovascular risk status: ameta-analysis of prospective evidence. Hypertension 2010;55:1026Y32

7. Chida Y, Hamer M. Chronic psychosocial factors and acute physiologicalresponses to laboratory-induced stress in healthy populations: a quantita-tive review of 30 years of investigations. Psychol Bull 2008;134:829Y85.

8. Hamer M, Chida Y. Walking and primary prevention: a meta-analysis ofprospective cohort studies. Br J Sports Med 2008;42:238Y43.

9. Sattelmair J, Pertman J, Ding EL, Kohl HW 3rd, Haskell W, Lee IM. Doseresponse between physical activity and risk of coronary heart disease: ameta-analysis. Circulation 2011;124:789Y95.

10. Rethorst CD, Wipfli BM, Landers DM. The antidepressive effects of ex-ercise: a meta-analysis of randomized trials. Sports Med 2009;39:491Y511.

11. Herring MP, O’Connor PJ, Dishman RK. The effect of exercise training onanxiety symptoms among patients: a systematic review. Arch Intern Med2010;170:321Y31.

12. De Moor MH, Boomsma DI, Stubbe JH, Willemsen G, de Geus EJ. Testingcausality in the association between regular exercise and symptoms ofanxiety and depression. Arch Gen Psychiatry 2008;65:897Y905.

13. Chalder M, Wiles NJ, Campbell J, Hollinghurst SP, Haase AM, Taylor AH,Fox KR, Costelloe C, Searle A, Baxter H,Winder R, Wright C, Turner KM,Calnan M, Lawlor DA, Peters TJ, Sharp DJ, Montgomery AA, Lewis G.Facilitated physical activity as a treatment for depressed adults: randomisedcontrolled trial. BMJ 2012;344:e2758.

14. Hamer M, Molloy GJ, Stamatakis E. Psychological distress as a risk factorfor CVD events: pathophysiological and behavioural mechanisms. J AmColl Cardiol 2008;52:2156Y62.

15. Whooley MA, de Jonge P, Vittinghoff E, Otte C, Moos R, Carney RM.Depressive symptoms, health behaviours, and risk of cardiovascular eventsin patients with coronary heart disease. JAMA 2008;300:2379Y88.

16. Hamer M, Bates CJ, Mishra GD. Depression, physical function, and risk ofmortality: National Diet and Nutrition Survey in adults older than 65 years.Am J Geriatr Psychiatry 2011;19:72Y8.

17. Win S, Parakh K, Eze-Nliam CM, Gottdiener JS, Kop WJ, Ziegelstein RC.Depressive symptoms, physical inactivity and risk of cardiovascular mortal-ity in older adults: the Cardiovascular Health Study. Heart 2011;97:500Y5.

18. Kamphuis MH, Geerlings MI, Tijhuis MA, Giampaoli S, Nissinen A,Grobbee DE, Kromhout D. Physical inactivity, depression, and risk ofcardiovascular mortality. Med Sci Sports Exerc 2007;39:1693Y9.

19. Berkman LF, Blumenthal J, Burg M, Carney RM, Catellier D, Cowan MJ,Czajkowski SM, DeBusk R, Hosking J, Jaffe A, Kaufmann PG, Mitchel P,Norman J, Powell LH, Raczynski JM. Enhancing Recovery in CoronaryHeart Disease Patients Investigators (ENRICHD). Effects of treating de-pression and low perceived social support on clinical events after myo-cardial infarction: the Enhancing Recovery in Coronary Heart DiseasePatients (ENRICHD) randomized trial. JAMA 2003;289:3106Y16.

20. Blumenthal JA, Babyak MA, Carney RM, Huber M, Saab PG, Burg MM,Sheps D, Powell L, Taylor CB, Kaufmann PG. Exercise, depression, andmortality after myocardial infarction in the ENRICHD trial. Med SciSports Exerc 2004;36:746Y55.

21. Lang IA, Guralnik JM, Melzer D. Physical activity in middle-aged adultsreduces risks of functional impairment independent of its effect on weight.J Am Geriatr Soc 2007;55:1836Y41.

22. Lee Y, Park K. Does physical activity moderate the association betweendepressive symptoms and disability in older adults? Int J Geriatr Psychiatry2008;23:249Y56.

23. Azevedo Da Silva M, Singh-Manoux A, Brunner EJ, Kaffashian S, ShipleyMJ, Kivimaki M, Nabi H. Bidirectional association between physical ac-

tivity and symptoms of anxiety and depression: the Whitehall II study. EurJ Epidemiol 2012;27:537Y46.

24. Rosmalen JG, Wenting AM, Roest AM, de Jonge P, Bos EH. Revealingcausal heterogeneity using time series analysis of ambulatory assessments:application to the association between depression and physical activityafter myocardial infarction. Psychosom Med 2012;74:377Y86.

25. Yoshiuchi K, Nakahara R, Kumano H, Kuboki T, Togo F, Watanabe E,Yasunaga A, Park H, Shephard RJ, Aoyagi Y. Year-long physical activityand depressive symptoms in older Japanese adults: cross-sectional datafrom the Nakanojo study. Am J Geriatr Psychiatry 2006;14:621Y4.

26. Mendlowicz MV, Jean-Louis G, von Gizycki H, Zizi F, Nunes J. Acti-graphic predictors of depressed mood in a cohort of non-psychiatric adults.Aust N Z J Psychiatry 1999;33:553Y8.

27. Janney CA, Richardson CR, Holleman RG, Glasheen C, Strath SJ,Conroy MB, Kriska AM. Gender, mental health service use and objec-tively measured physical activity: data from the National Health andNutrition Examination Survey (NHANES 2003Y2004). Ment Health PhysAct 2008;1:9Y16.

28. Hamer M, Stamatakis E. Objectively assessed physical activity, fitness andsubjective wellbeing. Ment Health Phys Act 2010;3:67Y71.

29. Poole L, Steptoe A, Wawrzyniak AJ, Bostock S, Mitchell ES, Hamer M.Associations of objectively measured physical activity with daily moodratings and psychophysiological stress responses in women. Psychophys-iology 2011;48:1165Y72.

30. Sothmann MS, Buckworth J, Claytor RP, Cox RH, White-Welkley JE,Dishman RK. Exercise training and the cross-stressor adaptation hypothesis.Exerc Sport Sci Rev 1996;24:267Y87.

31. Hamer M, Taylor A, Steptoe A. The effect of acute aerobic exercise onstress related blood pressure responses: a systematic review and meta-analysis. Biol Psychol 2006;71:183Y90.

32. Crews DJ, Landers DM. A meta-analytic review of aerobic fitness and re-activity to psychosocial stressors. Med Sci Sports Exerc 1987;19:S114Y20.

33. Dishman RK, Jackson EM. Cardiorespiratory fitness and laboratory stress:a meta-regression analysis. Psychophysiol 2006;43:57Y72.

34. Forcier K, Stroud LR, Papandonatos GD, Hitsman B, Reiches M,Krishnamoorthy J, Niaura R. Links between physical fitness and car-diovascular reactivity and recovery to psychological stressors: a meta-analysis. Health Psychol 2006;25:723Y39.

35. Sloan RP, Shapiro PA, Demeersman RE, Bagiella E, Brondolo EN,McKinley PS, Crowley O, Zhao Y, Schwartz JE, Myers MM. Impact ofaerobic training on cardiovascular reactivity to and recovery from chal-lenge. Psychosom Med 2011;73:134Y41.

36. Ray CA, Carter JR. Effects of aerobic exercise training on sympathetic andrenal responses to mental stress in humans. Am J Physiol Heart CircPhysiol 2010;298:H229Y34.

37. Ribeiro MM, Silva AG, Santos NS, Guazzelle I, Matos LN, Trombetta IC,Halpern A, Negrao CE, Villares SM. Diet and exercise training restoreblood pressure and vasodilatory responses during physiological maneuversin obese children. Circulation 2005;111:1915Y23.

38. Hamer M, Stamatakis E, Mishra G. Television- and screen-based activityand mental well-being in adults. Am J Prev Med 2010;38:375Y80.

39. Hamer M, Jones J, Boutcher SH. Acute exercise reduces vascular reactivityto mental challenge in offspring of hypertensive families. J Hypertens 2006;24:315Y20.

40. King AC, Baumann K, O’Sullivan P, Wilcox S, Castro C. Effects ofmoderate-intensity exercise on physiological, behavioral, and emotionalresponses to family caregiving: a randomized controlled trial. J Gerontol ABiol Sci Med Sci 2002;57:M26Y36.

41. Halliwill JR. Mechanisms and clinical implications of post-exercise hy-potension in humans. Exerc Sport Sci Rev 2001;29:65Y70.

42. Brownley KA, Hinderlitter AL, West SG, Girdler SS, Sherwood A, LightKA. Sympathoadrenergic mechanisms in reduced hemodynamic stressresponses after exercise. Med Sci Sports Exerc 2003;35:978Y86.

43. Vaccarino V, Johnson BD, Sheps DS, Reis SE, Kelsey SF, Bittner V,Rutledge T, Shaw LJ, Sopko G, Bairey Merz CN. National Heart, Lung,and Blood Institute. Depression, inflammation, and incident cardiovasculardisease in women with suspected coronary ischemia: the National Heart,Lung, and Blood Institute-sponsoredWISE study. J Am Coll Cardiol 2007;50:2044Y50.

44. Steptoe A, Hamer M, Chida Y. The effects of acute psychological stress oncirculating inflammatory factors in humans: a review and meta-analysis.Brain Behav Immun 2007;21:901Y12.

45. Hamer M, Williams E, Vuonovirta R, Giacobazzi P, Gibson EL, Steptoe A.




The effects of effort-reward imbalance on inflammatory and cardiovascularresponses to mental stress. Psychosom Med 2006;68:408Y13.

46. Pace TW, Mletzko TC, Alagbe O, Musselman DL, Nemeroff CB, MillerAH, Heim CM. Increased stress-induced inflammatory responses in malepatients with major depression and increased early life stress. Am JPsychiatry 2006;163:1630Y3.

47. HamerM,SteptoeA.The association between physical fitness, parasympatheticcontrol, and pro-inflammatory responses to mental stress. PsychosomMed2007;69:660Y6.

48. Howren MB, Lamkin DM, Suls J. Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis. Psychosom Med 2009;71:171Y86.

49. Pedersen BK. Exercise-induced myokines and their role in chronic dis-eases. Brain Behav Immun 2011;25:811Y6.

50. Bierhaus A, Wolf J, Andrassy M, Rohleder N, Humpert PM, Petrov D,Ferstl R, von Eynatten M, Wendt T, Rudofsky G, Joswig M, Morcos M,Schwaninger M, McEwen, B, Kirschbaum C, Nawroth PP. A mechanismconverting psychosocial stress into mononuclear cell activation. Proc NatlAcad Sci U S A 2003;100:1920Y5.

51. Hamer M. The relative influences of fitness and fatness on inflammatoryfactors. Prev Med 2007;44:3Y11.

52. Hamer M, Sabia S, Batty GD, Shipley MJ, Tabak AJ, Singh-Manoux A,Kivimaki M. Physical activity and inflammatory markers over 10 yearsfollow up in men and women from the Whitehall II cohort study. Circu-lation. 2012;126:928Y33.

53. Hamer M, Molloy GJ, de Oliveira C, Demakakos P. Persistent depressivesymptomatology and inflammation: to what extent do health behavioursand weight control mediate this relationship? Brain Behav Immun2009;23:413Y8.

54. Simonen RL, Rankinen T, Perusse L, Leon AS, Skinner JS, Wilmore JH,Rao DC, Bouchard C. A dopamine D2 receptor gene polymorphism andphysical activity in two family studies. Physiol Behav 2003;78:751Y7.

55. Cotman CW, Berchtold NC, Christie LA. Exercise builds brain health: keyroles of growth factor cascades and inflammation. Trends Neurosci2007;30:464Y72.

56. Knaepen K, Goekint M, Heyman EM, Meeusen R. NeuroplasticityVexercise-induced response of peripheral brain-derived neurotrophic factor:a systematic review of experimental studies in human subjects. SportsMed 2010;40:765Y801.

57. Heyman E, Gamelin FX, Goekint M, Piscitelli F, Roelands B, Leclair E, DiMarzo V, Meeusen R. Intense exercise increases circulating endocanna-binoid and BDNF levels in humansVpossible implications for reward anddepression. Psychoneuroendocrinology 2012;37:844Y51.

58. Rohleder N, Schommer NC, Hellhammer DH, Engel R, Kirschbaum C.

Sex differences in glucocorticoid sensitivity of proinflammatory cytokineproduction after psychosocial stress. Psychosom Med 2001;63:966Y72.

59. Duclos M, Gouarne C, Bonnemaison D. Acute and chronic effects ofexercise on tissue sensitivity to glucocorticoids. J Appl Physiol 2003;94:869Y75.

60. Hamer M, Endrighi R, Venuraju SM, Lahiri A, Steptoe A. Cortisolresponses to mental stress and the progression of coronary artery calcifi-cation in healthy men and women. PLoS One 2012;7:e31356.

61. Hamer M, Steptoe A. Cortisol responses to mental stress and incidenthypertension in healthy men and women. J Clin Endocrinol Metab2012;97:E29Y34.

62. Rimmele U, Seiler R, Marti B, Wirtz PH, Ehlert U, Heinrichs M. The levelof physical activity affects adrenal and cardiovascular reactivity to psy-chosocial stress. Psychoneuroendocrinology 2009;34:190Y8.

63. Traustadottir T, Bosch PR, Matt KS. The HPA axis response to stress inwomen: effects of aging and fitness. Psychoneuroendocrinology 2005;30:392Y402.

64. Skoluda N, Dettenborn L, Stalder T, Kirschbaum C. Elevated hair cortisolconcentrations in endurance athletes. Psychoneuroendocrinology 2012;37:611Y7.

65. Poole L, Hamer M, Wawrzyniak AJ, Steptoe A. The effects of exercisewithdrawal on mood and inflammatory cytokine responses in humans.Stress 2011;14:439Y47.

66. Kop WJ, Weinstein AA, Deuster PA, Whittaker KS, Tracy RP. Inflam-matory markers and negative mood symptoms following exercise with-drawal. Brain Behav Immun 2008;22:1190Y6.

67. Lund AJ, Hurst TL, Tyrrell RM, Thompson D. Markers of chronic in-flammation with short-term changes in physical activity. Med Sci SportsExerc 2011;43:578Y83.

68. Krogh-Madsen R, Thyfault JP, Broholm C, Mortensen OH, Olsen RH,Mounier R, Plomgaard P, van Hall G, Booth FW, Pedersen BK. A 2-wkreduction of ambulatory activity attenuates peripheral insulin sensitivity. JAppl Physiol 2010;108:1034Y40.

69. Weinstein AA, Deuster PA, Kop WJ. Heart rate variability as a predictor ofnegative mood symptoms induced by exercise withdrawal. Med Sci SportsExerc 2007;39:735Y41.

70. Handschin C, Spiegelman BM. The role of exercise and PGC1alpha ininflammation and chronic disease. Nature 2008;454:463Y9.

71. Anisman H, Merali Z. Cytokines, stress and depressive illness: brain-immune interactions. Ann Med 2003;35:2Y11.

72. Endrighi R, Steptoe A, Hamer M. Mood disturbance following exercisewithdrawal is associated with greater inflammatory responses to stress.Psychosom Med 2011;73:A110.

M. HAMER



psychosocial stress and cardiovascular disease risk: the...

Documents