rozanski impact of psychological factors on the pathogenesis of cardiovascular disease and...

Impact of Psychological Factors on the Pathogenesis ofCardiovascular Disease and Implications for Therapy

Alan Rozanski, MD; James A. Blumenthal, PhD; Jay Kaplan, PhD

Abstract—Recent studies provide clear and convincing evidence that psychosocial factors contribute significantly to thepathogenesis and expression of coronary artery disease (CAD). This evidence is composed largely of data relating CADrisk to 5 specific psychosocial domains: (1) depression, (2) anxiety, (3) personality factors and character traits, (4) socialisolation, and (5) chronic life stress. Pathophysiological mechanisms underlying the relationship between these entitiesand CAD can be divided into behavioral mechanisms, whereby psychosocial conditions contribute to a higher frequencyof adverse health behaviors, such as poor diet and smoking, and direct pathophysiological mechanisms, such asneuroendocrine and platelet activation.

An extensive body of evidence from animal models (especially the cynomolgus monkey,Macaca fascicularis) revealsthat chronic psychosocial stress can lead, probably via a mechanism involving excessive sympathetic nervous systemactivation, to exacerbation of coronary artery atherosclerosis as well as to transient endothelial dysfunction and evennecrosis. Evidence from monkeys also indicates that psychosocial stress reliably induces ovarian dysfunction,hypercortisolemia, and excessive adrenergic activation in premenopausal females, leading to accelerated atherosclerosis.

Also reviewed are data relating CAD to acute stress and individual differences in sympathetic nervous systemresponsivity. New technologies and research from animal models demonstrate that acute stress triggers myocardialischemia, promotes arrhythmogenesis, stimulates platelet function, and increases blood viscosity through hemoconcen-tration. In the presence of underlying atherosclerosis (eg, in CAD patients), acute stress also causes coronaryvasoconstriction. Recent data indicate that the foregoing effects result, at least in part, from the endothelial dysfunctionand injury induced by acute stress. Hyperresponsivity of the sympathetic nervous system, manifested by exaggeratedheart rate and blood pressure responses to psychological stimuli, is an intrinsic characteristic among some individuals.Current data link sympathetic nervous system hyperresponsivity to accelerated development of carotid atherosclerosisin human subjects and to exacerbated coronary and carotid atherosclerosis in monkeys.

Thus far, intervention trials designed to reduce psychosocial stress have been limited in size and number. Specificsuggestions to improve the assessment of behavioral interventions include more complete delineation of thephysiological mechanisms by which such interventions might work; increased use of new, more convenient “alternative”end points for behavioral intervention trials; development of specifically targeted behavioral interventions (based onprofiling of patient factors); and evaluation of previously developed models of predicting behavioral change. Theimportance of maximizing the efficacy of behavioral interventions is underscored by the recognition that psychosocialstresses tend to cluster together. When they do so, the resultant risk for cardiac events is often substantially elevated,equaling that associated with previously established risk factors for CAD, such as hypertension and hypercholesterol-emia.(Circulation. 1999;99:2192-2217.)

Key Words: coronary diseasen stressn psychology

A lthough the importance of psychosocial factors in thedevelopment and expression of coronary artery disease

(CAD) has been debated, an extensive recent literature nowestablishes that psychosocial factors contribute significantlyto the pathogenesis of CAD. Furthermore, by use of newtechnologies and animal models, elucidation of the basicpathophysiology underlying the relationship between psycho-

social factors and CAD is expanding rapidly. However,because the literature relating psychosocial factors to CAD ismultidisciplinary, there may be an underappreciation of thestrength of some of the epidemiological and pathophysiolog-ical observations that have been reported. Accordingly, wewill review the relationship between psychosocial stress andCAD development, with emphasis on the following psycho-

From the Division of Cardiology, Department of Medicine, St Luke’s/Roosevelt Hospital Center, and the Department of Medicine, ColumbiaUniversity College of Physicians and Surgeons, New York, NY (A.R.); the Department of Psychiatry and Behavioral Sciences, Duke University MedicalCenter, Durham, NC (J.A.B.); and the Department of Pathology (Comparative Medicine) and Anthropology, Wake Forest University School of Medicineand Wake Forest University, Winston-Salem, NC (J.K.).

Correspondence to Alan Rozanski, MD, Division of Cardiology, St Luke’s/Roosevelt Hospital Center, 114th Street and Amsterdam Avenue, New York,NY 10025. E-mail [email protected]

© 1999 American Heart Association, Inc.

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social factors: (1) depression, (2) anxiety, (3) personalityfactors and character traits (eg, hostility), (4) social isolation,and (5) chronic and subacute life stress. Although thesedomains can overlap, epidemiological data for each domainwill be reviewed separately, emphasizing studies that haveused the “hard” cardiovascular end points of myocardialinfarction and cardiac death as outcome variables (or all-cause mortality in the case of some early studies). In someinstances, “alternative” cardiac end points will be considered,such as progression of atherosclerosis during serial carotidultrasonography. Studies that relate psychosocial factors to“soft” cardiac end points, such as angina and static findingson coronary angiography, will not be reviewed. Informationregarding the pathophysiology by which psychosocial factorspromote CAD development will be examined for each psy-chological domain. These will include (1) behavioral mech-anisms, whereby the given factor exacerbates lifestylesknown to potentiate CAD (eg, smoking), and (2) directpathophysiological effects, as delineated in experimentalanimal studies and/or investigations in humans. The patho-genic effects of 2 other phenomena, acute psychologicalstress and sympathetic nervous system hyperresponsivity,will then be reviewed. Finally, the implications of thesefindings relative to the prevention and treatment of CAD willbe discussed.

Psychosocial Factors and CADDepression and Related SyndromesEpisodes of major depression are characterized by the pres-ence of a depressed mood and markedly decreased interest inall activities, persisting for at least 2 weeks and accompaniedby at least 4 of the following additional symptoms: changes inappetite, sleep disturbance, fatigue, psychomotor retardationor agitation, feelings of guilt or worthlessness, problemsconcentrating, and suicidal thoughts. The 1-monthcommunity-based prevalence of major depression episodes is'5%.1 Among CAD patients, however, the prevalence ofmajor depression is'3-fold higher. Also, depressive symp-toms that are not sufficient in magnitude to meet the criteriafor major depression occur at least as commonly amongcardiac patients.2,3 Recent epidemiological studies evaluatingthe relationship between depression and CAD amonghealthy3–11 and CAD12–19 populations consistently demon-strate a significant prospective relationship between theoccurrence of major depression episodes and the incidence ofcardiac events (Table 1). Two additional findings are notable.First, the presence of depressive symptoms, in the absence ofdiagnosed major depression episodes, is also associated withan increased risk for cardiac events.4 Second, a number ofstudies support a gradient between the magnitude of depres-sion and future cardiac events.4,7,9 Together, these datasuggest that risk for CAD associated with depression existsalong a continuum, according to the magnitude of depressivesymptoms.

One particular aspect of depression, the absence of hope,has received particular attention. Hopelessness has beenlinked to sudden death, both in observational studies20,21 andin animal models of hopelessness.22 Recently, prospective

epidemiological studies have also reported a relationshipbetween symptoms of hopelessness and the development ofCAD.4,7 In one study, for example, a positive answer to thequestion “(During the last month) have you felt so sad,discouraged, hopeless, or had so many problems that youwondered if anything was worthwhile?” more than doubledthe risk of CAD.4 It has also been demonstrated that menexperiencing hopelessness develop significantly more carotidatherosclerosis over time.23 A related phenomenon is “vitalexhaustion.” This syndrome, measured by the 37-item Maas-tricht questionnaire,24 focuses on a triad of symptoms: fa-tigue, irritability, and demoralized feelings. The presence ofvital exhaustion has also been reported to predict future CADand/or cardiac events in healthy25 and CAD26,27 populations.

Pathophysiological MechanismsConsiderable evidence indicates that depression has bothbehavioral and direct pathophysiological effects. With respectto behavioral mechanisms, depression is associated with bothunhealthy lifestyle behaviors,28,29 such as smoking, and poorpatient compliance.29,30 Direct pathophysiological effects ofdepression involve at least 3 mechanisms. First, depression isaccompanied by hypercortisolemia.31–33 Associated findingsinclude attenuation of the adrenocorticotropin hormone re-sponse to corticotropin-releasing factor administration,32 non-suppression of cortisol secretion after dexamethosone admin-istration,34 and elevated corticotropin-releasing factorconcentrations in the cerebrospinal fluid of depressed pa-tients.35 Second, depressed individuals may develop signifi-cant impairments in platelet function, including enhancedplatelet reactivity and release of platelet products such asplatelet factor 4 andb-thromboglobulin.36,37The combinationof hypercortisolemia and enhanced platelet function estab-lishes the theoretical basis for explaining the proatherogeniceffects of depression. In addition, reduced heart rate variabil-ity38 and impaired vagal control39 have been reported amongdepressed patients. These findings suggest that depressedpatients may also be subject to enhanced arrhythmogenicpotential.

Anxiety SyndromesUntil recently, evidence linking anxiety to CAD was limitedto demonstrations of elevated mortality rates among psychi-atric patients with anxiety disorders.40 Increasing evidencenow links anxiety disorders to development of cardiac eventsin general populations (Table 2). Most notably, 3 large-scalecommunity-based studies, including one involving'34 000men, have now reported a significant relationship betweenanxiety disorders and cardiac death.41–43 Moreover, a dose-dependent relationship has been noted between anxiety levelsand the occurrence of cardiac death.42,43Anxiety has not beenassociated with myocardial infarction in these studies. Rather,the excess mortality appears to be confined to sudden (versusnonsudden) cardiac death.42,43 Notably, these community-based studies did not include women,41–43 even thoughanxiety disorders are more common among women.44

Prospective positive associations between CAD and panicdisorder45 and between CAD and “worry” (a subcategory ofgeneralized anxiety disorder)46 have also been noted in 2

Rozanski et al April 27, 1999 2193



TABLE 1. Depression and Coronary Artery Disease

Study No. of Subjects F/U, y Scales End PointsRR (95% CIs) or Other

Statistical Results

Healthy subjects

Anda et al, 1993 2832 12.4 SS of generalizedwell-beingschedule

CD, non-fatal IHD RR for depressive sx51.5(1.0–2.3)

RR for severehopelessness52.1

(1.1–3.9)

Arooma et al, 1994 5355 6.6 SS of GHQ MI RR for depressive sx53.5(1.8–6.8)

SS of PSE MI, CHF, CVA,

Vogt et al, 1994 2573 15 Investigator-tailoredscale

ACM P5NS for depressive sx

Everson et al, 1996 2428 6 SS of MMPI CD; ACM RR for severehopelessness52.3

(1.1–3.9)

Hopelessness scale RR for moderatehopelessness51.6

(1.0–2.5)

Wasserthal-Smoller et al, 1996 4736 4.5 CES-D scale ACM, CD, MI; CVA P5NS for baselinedepressive sx

RR for increasing depressivesx51.3 (1.2–1.4)

Pratt et al, 1996 1551 13 DIS MI RR for MDE54.5 (1.7–12.4)

RR for dysphoria52.1(1.2–3.7)

Barefoot et al, 1996 730 OBD SS of MMPI CD; MI RR for depressive sx51.7(1.2–2.3) (for MI)*

Ford et al, 1998 1190 37 Tailored scale MI RR for depressive sx52.1(1.2–4.1)

Known disease

Kennedy et al, 1987 88 pts; syncope or arrhythmia 1.5 Tailored scale CD P50.01 for depressive sx

Carney et al, 1988 52; CAD on cath 1.0 DIS CD, MI, PTCA; CABG RR for MDE52.5, P,0.02†

Ahern et al, 1990 502, s/p MI and arrhythmia 1.0 BDI ACM; CD P,0.05 for depressive sx

Frasure-Smith et al, 1995 222, s/p MI 1.5 DIS; BDI CD RR for MDE53.6 (1.3–10.1)

RR for depressive sx57.8(2.4–25.3)

Barefoot et al, 1996 1250; s/p MI 15.2 Zung Self-RatingDepression scale

CD P50.002 for depressive sx

Denoillet et al, 1998 87; s/p MI & EF,50% 7.9 Million BehavioralHealth Inventory

and BDI

CD; MI RR for depressive sx54.3(1.4–13.3)

Hermann et al, 1998 273, cardiopulmonary 1.9 HADS ACM RR for depressive sx52.6(1.1–6.3)

Frasure-Smith et al, 1999 896, s/p MI 1.0 BDI CD RR for depressive sx53.2(1.7–6.3)

F/U indicates follow-up; RR, risk ratio; pts, patients; cath, catheterization; s/p, status post; MI, myocardial infarction; EF, ejection fraction; SS, subscale; GHQ,General Health Questionnaire; PSE, Present State Examination; MMPI5Minnesota Multiphasic Personality Inventory; CES-D, Center for Epidemiological Studies–Depression; DIS, Mental Health Diagnostic Interview Schedule (DSM-III diagnosis of depression); OBD, obvious depression; BDI, Beck Diagnostic Interview (measuresdepressive symptoms); HADS, Hospital Anxiety and Depression Scale; CD, cardiac death; IHD, ischemic heart disease; CHF, congestive heart failure; CVA,cerebrovascular accident; ACM, all-cause mortality; Sx, symptom; and MDE, major depression episode.

*RR for cardiac death51.62, P,0.03; †no CI reported.

2194 Psychological Factors and CAD



recent studies; however, more studies are needed to establishwhether these findings are indeed valid. The epidemiologicalinvestigation of anxiety disorders among CAD patients hasalso been quite sparse. Because 4 small studies have eachnoted a relationship between anxiety and a constellation ofhard and soft cardiac events among CAD patients (Table2),17,18,47,48more large-scale epidemiological studies amongCAD patients now appear to be warranted.

Pathophysiological MechanismThe association between anxiety and sudden death, but notmyocardial infarction, suggests that ventricular arrhythmiasmay be the mechanism for cardiac death among individualswith anxiety disorders. In support of this hypothesis, it hasbeen observed that individuals with anxiety disorders havereduced heart rate variability.49 Hence, there may be apathological alteration in cardiac autonomic tone. This alter-ation could involve either increased sympathetic stimulation,which has been linked to the occurrence of arrhythmias andsudden death,50 or impaired vagal control, which has alsobeen linked to increased cardiac mortality.51,52 With respectto the latter possibility, reduced vagal control has been linkedto impaired, vagally mediated baroreflex control of theheart.53 Such impairment appears to be a particularly impor-tant risk factor for sudden death.54,55 Along these lines, a

recent study reported reduced baroreflex cardiac control inpatients with anxiety,56 but prospective work is needed todetermine whether this is a common operative mechanism forsudden deaths among patients with anxiety syndromes.

Individuals with anxiety disorders are prone to moreunhealthy lifestyle behaviors42,43; however, the lack of corre-lation between anxiety syndromes and myocardial infarction(a sign of underlying atherosclerosis) suggests that, at leastamong initially healthy individuals, this behavioral associa-tion is not a significant pathogenic mechanism. It is conceiv-able, nonetheless, that this behavioral association could be ofimportance among CAD patients manifesting anxiety.

Personality and Character TraitsAfter the identification of the type A behavior pattern byFriedman and Rosenman in the late 1950s,57 a syndromecharacterized by competition, hostility, and exaggerated com-mitment to work, many studies have investigated whetherpersonality patterns or individual character traits promote thedevelopment of CAD. Other personality types have included“type D” personality,17 “social dominance,”58 and a “hardypersonality” construct59; these latter personality types havenot been widely studied as potential risk factors for CAD.Interest in type A behavior accelerated after the Western

TABLE 2. Anxiety Disorders

Investigator No. of Subjects F/U, yConditionStudied Scale End Points RRs

Healthy subjects

Phobic anxiety

Haines et al, 1987 1457 6 Phobic anxiety Crowne-Crisp CD 3.8 (1.6–8.6)

MI 1.3 (0.6–2.5)

Kawachi et al, 1994 33 999 2 Phobic anxiety Crowne-Crisp CD 2.5 (1.0–6.0)*

MI 0.9 (0.5–1.8)

Kawachi et al, 1994 2271 32 Anxiety Anxiety SS of theCornell Medical Index

CD 1.9 (0.7–5.4)†

MI 1.0 (0.3–3.6)

Other syndromes

Weissman, 1990 60 with panic; NR Panic disorder DIS CD NR

3778 healthy MI 4.5 (1.7–12.3)

Kubzansky et al, 1997 1759 20 Worry Worries Scale CD 0.8 (0.5–1.4)‡

MI 2.4 (1.4–4.1)‡

CAD patients

Frasure-Smith et al, 1995 222 pts, s/p MI 1 Anxiety State Trait AnxietyInventory

Combined 1 2.5 (1.6–5.6)

Moser et al, 1996 86 pts, s/p MI IHS Anxiety Brief SymptomInventory

Combined 2 4.9 (2.1–12.2)

Denoillet et al, 1998 87 pts, s/p MI 7.9 Anxiety State Anxiety Scale Combined 3 3.9 (1.2–9.6)§

Herrman et al, 1998 454 pts; 273 withcardiopulmonary disease\

1.9 Anxiety HADS ACM 2.5 (1.4–4.4)

NR indicates not reported: IHS, in-hospital study of cardiac events; 1, events include CD, MI and unstable angina. 2, events include CD, MI, acuteischemia; sustained VT or VF. 3, CD; MI; unstable angina; cardiac arrest survival. Other abbreviations as in Table 1.

*RR for sudden CD56.1 (2.4–15.7); RR compares highest- vs lowest-risk quartiles.†RR for sudden CD54.7 (0.9–21.6).‡RR for highest vs lowest terciles.§Crude RR. Adjusted RR not reported.\Other patients had other medical conditions.




Collaborative Group Study, which reported that type Abehavior was associated with a 2-fold increased risk of CADand 5-fold increased risk of recurrent MI over an 8.5-yearfollow-up.60 Although type A behavior continues to receiveattention,61 a series of studies have reported no correlationbetween type A behavior and CAD risk.62–66 This lack ofconsistency has cast doubt on the potential robustness of thetype A behavior as a clinical syndrome. Potential confoundershave been suggested. For instance, animal model studies67

and some human studies68,69 suggest that social support is apotential confounding variable. Furthermore, suspecting thatnot all components of type A behavior are pathogenic,investigators have examined the components of this behaviorpattern.

Hostility, a major attribute of the type A behavior pattern,has received considerable attention as a potential “toxic”element in this personality construct. Hostility is a broadpsychological construct, encompassing negative orientationstoward interpersonal relationships, and includes such traits asanger, cynicism, and mistrust. Table 3 lists 10 studiesassessing the relationship between hostility and CAD inhealthy subjects.70–79 The results of these prognostic studiesare mixed, with both positive and negative studies. However,the studies are of uneven quality. For instance, in one

negative study, 57% of the individuals were lost to follow-up,75 whereas the follow-up of healthy individuals in anotherstudy was only 3 years.76 Of note, 2 large studies that usedtailored scales to focus on cynical mistrust77 and anger79 haveyielded positive associations with cardiac events. In the angerstudy, a gradient was noted between anger levels and thefrequency of subsequent cardiac events.79 Thus, it is possiblethat certain components of the hostility construct are morepathogenic.

To date, there have been no large-scale epidemiologicalstudies evaluating hostility among CAD patients. Four smallepidemiological studies among CAD patients, however, havebeen positive, as noted in Table 3.76,80–82In addition, studieshave reported that CAD patients with high levels of hostilityhave a greater rate of restenosis after angioplasty,83 experi-ence more rapid atherosclerosis progression during serialcarotid ultrasonography,84,85 and manifest more ischemiaduring stress testing than other CAD patients.86

Pathophysiological MechanismsHostility may affect atherogenic activity by behavioral mech-anisms. Hostility is associated with a higher concentration ofunhealthy lifestyle behaviors, including smoking, poor diet,obesity, and alcoholism.77,79,87 Hostile individuals are alsomore likely to manifest other psychosocial factors associated

TABLE 3. Hostility and the Pathogenesis of Coronary Artery Disease

Study No. of Subjects F/U, y Scales End Points RRs or Other Statistical Results

Healthy subjects

Shekelle et al, 1983 1877 10 MMPI Ho SS CD; MI; ACM Predicted ACM (P50.02) and tended to predict CAD(P50.09)

Barefoot et al, 1983 255 MDs 25 MMPI Ho SS CD; MI; AP Ho score predicted both ACM and CAD (P,0.005)

McCranie et al, 1986 478 MDs 25 MMPI Ho SS CD; MI; angina No association

Leon et al, 1988 280 30 MMPI Ho SS CD; MI No association

Barefoot et al, 1989 118 lawyers 28 MMPI Ho SS ACM Ho score associated with mortality (P,0.01)3 subscales more predictive: cynicism, hostile affect,

and aggressive responding

Hearn et al, 1989 1399 33 MMPI Ho SS CD; ACM No association

Maruta et al, 1993 620 20 MMPI Ho SS ACM; CD No association

Koskenvuo et al, 1993 2885 3 Self-rating SS CD; CAD diagnosis No association (but P50.08 for ACM)

Everson et al, 1994 2125 9 Cynical Distrustscale

CD; MI; ACM 1.5 (0.7–3.25)\

Barefoot et al, 1995 730 27 Abbr MMPI HoSS

ACM; MI RR for MI51.6 (1.1–2.3)

Kawachi et al, 1996 1305 7 MMPI-2 angerSS

CD; MI; angina RR for chronic anger52.7 (1.3–5.6). Gradient of riskwith increasing anger (P50.008)

Patients with CAD

Hecker et al, 1988 250† 8.5 SI CD; MI; AP RR51.9 (1.3–2.8)

Dembroski et al, 1989 192* 7.1 SI‡ CD; MI RR for total potential for hostility51.7 (P50.005)¶

Koskenvuo et al, 1993 104, CAD and HBP 3 Self-ratings§ Restenosis RR514.6 (1.4–110), for highest vs lowest quartile

DeLeon et al, 1996 149, s/p PTCA 1.5 State-TraitAnger Scale

CD; MI; CABG;PTCA; new lesions

RR52.1 (1.1–4.0)

HBP indicates high blood pressure; Ho, hostility; Abbr, abbreviated; and AP, angina pectoris. Other abbreviations as in previous tables.*Matched case-control design; patients compared with 384 controls; †500 matched controls.‡Self-rating of irritability; ease of anger-arousal; and argumentativeness.§Assessed “potential for hostility,” derived from the structured interview.\Adjusted RR for CD after adjustment for both biological and behavioral risk factors, but the crude RR was 2.7 (1.3–5.8); similar RR for MI.¶Derived from the Cook-Medley Hostility Scale.




with CAD, such as social isolation.88 An accumulating bodyof evidence also suggests multiple pathophysiological mech-anisms by which hostility may be linked to CAD. Forexample, compared with nonhostile individuals, hostile sub-jects manifest higher heart rate and blood pressure responsesto physiological stimuli, such as mental tasks,89 as well ashigher ambulatory blood pressure levels during daily-lifeactivity.90 Also, evidence suggests that hostile individuals aremore likely to exhibit hypercortisolemia and high levels ofcirculating catecholamines,91,92 as well as diminished mono-nuclear leukocyteb-adrenergic receptor function.93 Prelimi-nary data suggest that hostile individuals may also manifestdiminished vagal modulation of heart function94,95 and in-creased platelet reactivity.96,97

Social Isolation and Lack of Social SupportSince the late 1970s, a series of prospective community-basedstudies have examined the influence of social factors on thedevelopment of CAD. Initial studies focused on quantitativeaspects of social support, such as the presence of familyaffiliations, number of friends, and the extent of one’sparticipation in group and organizational activities. Thisdomain of measurement has been called one’s “social net-work.” Within this domain, some studies evaluated theinfluence of partner status (living alone, marital status, and/ormarital disruption), and others have assessed aspects of“instrumental” (ie, tangible) support, such as access to guid-ance and practical community services. Over time, however,the qualitative nature of one’s social support system (eg,amount of perceived emotional support) has also been in-creasingly subject to study. Fifteen studies examining theimpact of social factors on the future incidence of CAD ininitially healthy populations are summarized in Table 4.98–112

A relatively small network has been found, on average, to beassociated with a 2- to 3-fold increase in the incidence ofCAD over time. Similarly, low levels of perceived emotionalsupport confer an even greater increased risk for futurecardiac events.99 Table 5 lists 11 studies evaluating therelationship between social factors and prognosis in patientswith preexisting CAD.113–123Significant prognostic relation-ships are present in most of these studies, and the risk ratiosare substantial. For instance, Berkman et al119 observed anearly 3-fold increase in subsequent cardiac events inpost-MI patients reporting a low level of emotional support,and Williams et al118 observed a similar 3-fold increase inmortality over 5 years among CAD patients who wereunmarried or had no significant confidant in their life.

In addition to the consistency and magnitude of thesefindings, the cause-and-effect relationship between socialfactors and CAD development is also supported by otherevidence. First, an inverse gradient has been reported be-tween the magnitude of social support and the incidence ofCAD and/or future cardiac events, as summarized in Table6.98,100,101,103,119Moreover, acculturation independently influ-ences CAD development. For instance, in one study, 3809Japanese-Americans in California were classified accordingto the degree to which they retained a traditional Japaneseculture.124 The most traditional group of Japanese-Americanshad a CAD prevalence as low as that observed in Japan,

whereas the group that was most acculturated had a 3- to5-fold excess in CAD prevalence. Major CAD risk factors didnot account for these differences. In another study,125 tempo-ral rates of CAD development were assessed in Roseto, Pa,and an adjacent town. Initially, CAD incidence was signifi-cantly lower in Roseto, despite shared medical resources. Atthat time, Roseto was a cohesive and homogeneous commu-nity of 3-generation households, descendants of Italian im-migrants. As the distinguishing social characteristics of theRoseto community disappeared over time, its lower incidenceof CAD vanished. Finally, animal studies have also impli-cated social factors in the promotion of atherogenesis. Forinstance, Ratcliffe and Cronin126 described the potentialimportance of social disruption among animals, noting thatcrowding and social disruption were the apparent causalfactors for a 10-fold increase in atherosclerotic lesions thatoccurred among birds and mammals over a 20-year period atthe Philadelphia Zoo. Ratcliffe et al127 also studied socialsupport experimentally by deliberately assigning swine tovarious social situations (alone, pairs, groups). At postmor-tem examination, coronary arteriosclerosis was most ad-vanced in isolated females, intermediate in isolated males,and least advanced in animals sustained in groups. Morerecently, the extent of atherosclerosis was compared atautopsy among 39 cynomolgus female monkeys exposed to 2different housing conditions: 15 monkeys housed in singlecages and 24 housed in groups.128 The extent of atheroscle-rosis was 4 times greater, on average, in the females that werehoused alone than in those housed in social groups. Thisdifference occurred in the absence of significant differencesin plasma lipids. In combination, these data provide strongevidence that social factors relating to grouping and isolationcan promote atherogenesis.

Socioeconomic StatusAside from social factors, low socioeconomic status is asignificant contributor to increased risk in healthy personsand a contributor toward poor prognosis in patients withestablished CAD, in graded fashion.129 The gradient betweensocioeconomic status and cardiac outcome is observablewhether measured by education, income, or occupation. Lowsocioeconomic status is associated with increased levels ofhigh-risk behaviors130 and psychosocial risk factors.131 Inter-estingly, some evidence also suggests that low socioeconomicstatus may be an independent risk factor in its ownright,118,132,133but this possibility requires prospective valida-tion and, if true, delineation of the operative pathophysiolog-ical mechanism(s). In any case, when low socioeconomicstatus is clustered together with other psychosocial riskfactors, the risk of cardiac events is often magnified.129,134

Pathophysiological MechanismsLike other psychosocial factors, social support influences theextent to which individuals engage in such high-risk behav-iors as smoking, fatty diet intake, and excessive alcoholconsumption. In addition, social factors may exert directpathophysiological effects, including hypercortisolemia. An-imal studies have reported an association between socialisolation and hypercortisolemia135,136and reversible increasesin resting heart rates among cynomolgus monkeys, depending




on the presence or absence of social separation.137 Similarly,human studies have demonstrated an inverse relationshipbetween the quality of social relationships and urinary levelsof epinephrine138 and between the degree of social supportand resting heart rates.139 Elevated resting heart rates mayconstitute a sign of altered autonomic arousal. The presenceof social support may also attenuate blood pressure and heartrate responses to stressful stimuli in humans.140,141 In sum-mary, these data suggest that social factors promote athero-genesis through activation of the autonomic nervous system.

Chronic and Subacute Life StressWork-related stress is the most widely studied chronic lifestress relative to CAD. Although many aspects of one’s workenvironment relative to the development of CAD have been

studied, much interest has focused on models of inherent“tension” at work. One such model has been the “job strain”model, defined by Karasek et al142 as jobs with high demandbut low decision latitude. In one prospective study of 1928male workers followed up for 6 years, job strain wasassociated with a 4-fold increase in the risk of cardiovascularsystem–related death. Subsequent studies have supported therelationship between job strain and CAD risk,143,144 butnegative studies have also been reported.145,146

More recently, research has begun to focus on other formsof work-related stress. For example, one model views workstress as the outcome of high work demand and low re-ward.147 This model both predicts cardiac events146,147 andhas been correlated with progression of carotid atherosclero-sis.148 Also, low job control, per se, predicts future cardiac

TABLE 4. Social Influences and the Pathogenesis of CAD in Healthy Subjects

Study Location# of

Subjects F/U, Y Social Parameter(s) Studied End Points RR/Other Statistical Results

Berkman & Syme, 1979 Alameda County 6928 9 Network index ACM; CD 2.3†

Blazer et al, 1982 Durham, NC 339* 2.5 Roles and attachments ACM 2.0 (1.2–3.6)

Perceived social support 3.4 (1.9–6.2)

Frequency of interactions 1.9 (1.1–3.2)

House, et al, 1982 Tecumseh 2754 12 Social network variables ACM 1.9–2.8‡

Reed et al, 1983 Japanese in Hawaii 4653 6 Network scope CD; MI;AP

P,0.005

Welin et al, 1985 Gothenberg, Sweden 989 9 Number of social activities ACM P,0.0001

Number of people living at home P,0.001

Schoenbach et al, 1986 Evans County, Ga 2059 13 Network index ACM 1.5 (0.8–2.6)§

Orth-Gomer et al, 1987 Swedish Registry 17 433 6 Network scope/frequency ACM; CD 1.4 (1.1–1.7) (ACM)

0.4 (0.97–2) (MI)

Seeman, et al, 1987 Alameda County 564** 17 Social network index ACM 1.5 (1.1–2.5)

Kaplan et al, 1988 Finland 13 301 5 Social network ACM; CD 1.5 (1.2–2.0)

Hansen et al, 1989 Malmo, Sweden 500 5 Amount of emotional support ACM 2.2 (2.1–4.3)

Amount of social participation 2.5 (1.2–5.2)

Marital status 2.0 (1.0–3.8)

Pennix et al, 1992 Amsterdam 2829 2.4 Requiring instrumental support ACM 1.7 (1.1–2.7)

Positive emotional support 0.5 (0.3–0.7)

Vogt et al, 1992 HMO Members, California 2603 15 Network scope ACM 2.7 (1.8–4.0)

Network frequency 1.5 (1.1–2.0)

Network size 1.4 (1.1–1.8)

Orth-Gomer et al, 1993 Gothenberg, Sweden 736 6 Social integration CD; MI 3.8 (1.1–13.9)¶

Social attachment 3.8 (1.3–7.8)¶

Seeman et al, 1993 New Haven (NH) 2812* 5 Social ties, NH ACM 2.4 (1.4–3.1)\

(3 samples) Iowa (I), East Boston (EB) 3673* Social ties, I 1.4 (0.9–2.3)\

3809* Social ties, EB 1.0 (0.7–1.5)\

Kaplan et al, 1994 Kuopio, Finland 2503 5.9 Participation in organizations ACM 2.1 (1.3–3.7)#

Quality of relationships 1.8 (1.1–3.2)#

Divorced or separated 2.0 (1.2–3.3)

*.65 years old.†This is the RR in males; RR52.8 in females. No CIs provided.‡5Range of values for different variables in men. RR range51.1–1.9 in women. §values for men only. P5NS for women.\These are the RRs for men; the corresponding RRs for women in the 3 samples are 1.8 (1.1–3.0), 1.9 (1.1–3.0), and 1.3 (0.8–20), respectively.¶For lowest vs upper 3 quartiles; # for highest vs lowest values.**.70 years old.




events.149 Taken together, the studies regarding presence ofstress at work and subsequent CAD development have beenlargely positive, suggesting a strong causal relationship be-tween this form of chronic stress and development ofatherosclerosis.

Because many observational studies have reported psycho-logical prodromata in the months preceding development ofacute MI,150 interest has also been focused on the potentialpathogenicity of “subacute” life stress (defined as an accu-mulation of stressful life events over a duration of months). Inone of the earliest attempts to quantify the relationshipbetween subacute psychological stress and CAD, Holmes andRahe151 developed a “Recent Life Change Questionnaire,”with a predetermined weighting assigned to different lifeevents, ranging from high numbers for such events as thedeath of a spouse, divorce, or loss of a job to low weightingsfor vacations and holidays. In one study, marked elevations in

Recent Life Change scores were seen for most cases of MI orsudden cardiac death during the 6-month period precedingthese events.152 Similar confirmations of increased life stressbefore cardiac events can be extended to specific cohorts,ranging from healthy middle-aged men153 to patients pre-senting with acute myocardial infarction.154

Pathophysiological MechanismsLike other psychosocial factors, chronic stress appears toexert direct pathophysiological effects, including elevation ofarterial blood pressure155,156 and neurohumoral arousal.157

Evidence of neurohumoral arousal has also been noted insituations associated with subacute stress.158,159

“Clustering” of Psychosocial VariablesAlthough psychosocial stresses have been reviewed here asindividual entities, generally, these stresses tend to cluster

TABLE 5. Social Influences and the Occurrence of Cardiac Events in CAD Patients

Study Location No. of Patients F/U, y Social Parameters Studied End PointsRRs or Other

Statistical Results

Chandra et al, 1983 Baltimore 888, s/p MI 10.0 Marital status ACM P,0.025

Ruberman et al, 1984 BHAT trial 2320, s/p MI 3.0 Social isolation CD; ACM P,0.001*

Wiklund et al, 1988 Gothenburg 201, s/p MI 5.0 Marital status ACM; MI P,0.001

Ahern et al, 1990 CAPS‡ 324, s/p MI 1.0 Marital status; No. of people at home CD No association

Case et al, 1992 New York 1234 s/p MI 2.1 Living alone CD; MI RR51.5 (1.0–2.3)

Williams et al, 1992 Duke U. 1368, CAD 9 Unmarried without confidant CD RR53.3 (1.8–6.2)

Berkman et al, 1992 New Haven 194, s/p MI 0.5 Magnitude of emotional support CD RR52.9 (1.2–6.9)

Gorkin et al, 1993 CAST-1‡ 1332, s/p MI 0.8 Magnitude of emotional supportand social functioning index

CD RR51.5, P50.01

Jenkinson et al, 1993 England 1376 s/p MI 3 Social isolation ACM RR51.5 (1.0–2.2)

Weloshin et al, 1997 Manitoba 734, s/p MI 1 Diminished perceived tangiblesupport (3 grades)

ACM RR56.5 (2.0–25.6)†

Krumholz et al, 1998 New Haven 292, CHF 1 Magnitude of emotional support CD RR52.6 (1.0–6.6)

*Approximate RR of a 2-fold increase; 95% CIs not available.†For highest of 3 grades of increasingly diminished support; mild and intermediate grade RRs51.8 (0.6–5.8) and 3.2 (1.1–9.4).‡Multicenter arrhythmia trials.

TABLE 6. Social Support and Clinical Outcome: Evidence of a Gradient Effect*

Variable Assessed(Reference) End Point Subjects

No. ofDivisions

% Experiencing End Point From Least toMost Socially Supportive Division

(15least supportive)

1 2 3 4 5 6

Emotional support (119) Death Men (n5100)† 3 59 41 23 N/A N/A N/A

Women (n594)† 3 43 32 22 N/A N/A N/A

Social integration (100) 6-year CAD incidence All patients (n5749) 3 5.7 4.5 1.5 N/A N/A N/A

Social network (98) Death Men (n52229) 4 16 12 9 6 N/A N/A

Women (n52496) 4 12 7 5 4 N/A N/A

Social activity score (103) Death Men, 1913 (n5787) 5 28 19 15 11 6 N/A

Men, 1923 (n5292) 5 14 9 7 5 3 N/A

Social relationships (101) Death Men (n51251) 6 30 24 12 11 11 8

Women (n51284) 6 7 10 9 5 6 3

N/A indicates not applicable.*Based on studies reporting percentages for each end point observed per division.†s/p MI.




together. When they do so, risk ratios for cardiac events oftenrise substantially. For example, in one study of post-MIpatients, the presence of high levels of life stress and socialisolation were each associated with an'2-fold increase insubsequent events.114 But when the 2 factors occurred to-gether, the rate of subsequent events was 4-fold higher. Asimilar synergy between these 2 factors has also beenreported among healthy individuals.160 Similarly, the combi-nation of anxiety and depression compounds cardiac risk inpost-MI patients,161 and many other examples can be foundwithin the psychosocial literature. These data indicate thatpsychological factors occurring in combination substantiallymagnify risk associated with individual psychological factors,resulting in risk elevations that are comparable to thoseassociated with hypercholesterolemia, hypertension, andother major risk factors for CAD. Furthermore, psychosocialfactors also interact synergistically with conventional CADrisk factors to heighten the risk for cardiac events. Forexample, depressed patients who smoke have a substantiallyhigher risk of cardiac events than depressed patients who donot smoke.4 These findings could provide impetus for devel-oping algorithms that integrate psychosocial factors andconventional risk factors into the Bayesian analysis of CAD,as schematized for a patient with nonanginal chest pain inTable 7.

Pathophysiological MechanismsFrom a pathophysiological point of view, the increase incardiac events associated with clustering of psychosocialstresses suggests that this clustering compounds the health-damaging effects of individual psychosocial stresses. How-ever, because psychosocial stresses and behavioral risk fac-tors in humans change over time and cluster together invariable fashion, it is difficult to study the potential mecha-nisms by which they exert their pathophysiological effects. Incontrast, adequate experimental control can be achieved inanimal models, especially monkeys. In this regard, cynomol-gus monkeys (Macaca fascicularis) provide a potentially

relevant model for studying the interaction of multiple psy-chological factors in a controlled setting. Like humans,cynomolgus monkeys develop coronary atherosclerosis whenfed fatty diets and manifest similarities to people in thedevelopment of coronary lesions and coronary vasodilatorabnormalities. Notably, cynomolgus monkeys resemble hu-man beings in both the organization and expression of theirsocial behavior. For example, dominance and nurturance aresometimes considered to be the 2 major dimensions thatdefine the content of interpersonal human behavior.162 Cyno-molgus monkeys are characterized by well-defined socialstatus hierarchies in which some animals (dominants) reliablydefeat others (subordinates) in competitive interactions, aswell as by elaborate, generation-spanning, networks of affil-iation, alliance, and mutual support. Humans and monkeysalso use similar facial expressions and postures to communi-cate an antagonistic or combative mood, and both relyextensively on visual cues to signal moods quickly andunambiguously in complex social settings. These behavioralsimilarities suggest that monkeys might be especially usefulfor modeling the human expression of anger or hostility.

In a set of investigations designed to evaluate the interac-tion between personality factors and a stressful social envi-ronment, 30 male monkeys were fed a moderately athero-genic diet while housed in 5-member social groups andassigned to 1 of 2 social conditions67: (1) an “unstable”environment in which animals were switched among groupson a regular basis so that animals periodically had toreestablish their dominance and affiliative relationships or(2) a “stable” environment in which initial group member-ships were maintained without disruption throughout a 22-month period. Repeated behavioral observations permittedidentification of individuals as relatively more dominant orsubordinate in their social groups. The index of coronaryartery atherosclerosis in this and all other cited monkeyexperiments was the average lesion extent as measured in 15cross sections of pressure-perfused coronary arteries. Fivesections each were taken from the left circumflex, leftanterior descending, and right coronary arteries for thesedeterminations. At the end of this study, quantitative evalu-ation of the coronary arteries of these animals revealed thatdominant male monkeys in an unstable environment hadsignificantly more coronary artery atherosclerosis than theother 3 subgroups (Figure 1, top). These results were inde-pendent of variations in serum lipid concentrations and bloodpressure. Thus, this animal model revealed that it was theinteraction between 2 psychosocial factors that proved patho-genic in cynomolgus monkeys: the trait of “dominance,”coupled with environmental stress.

Subsequently, to test the causal role of sympathetic acti-vation in promoting atherogenesis in these predisposed ani-mals, a number of male monkeys were housed in unstablesocial groups and fed an atherogenic diet for 26 months;however, half of the monkeys also received ab-adrenergicantagonist, propranolol, throughout the study.163 As shown inFigure 1, bottom, untreated dominant monkeys again devel-oped substantial atherosclerosis; however, pretreatment withpropranolol abolished the excess atherosclerosis that devel-ops among dominants housed in an unstable environment.

TABLE 7. Bayesian Probability of CAD in a 47-Year-Old ManWith NACP According to Risk Factors andDepressive Symptoms

ConditionCAD

Probability, %

NACP 20

NACP 1 currently smoking and HBP (systolicBP5165 mm Hg)

30

NACP 1 smoking/HBP 1 depressive symptoms 46

NACP 1 smoking/HBP 1 major depression 66

NACP indicates nonanginal chest pain; HBP, high blood pressure.Assumptions: For the purpose of this schematic example, we used the data

of Pratt et al,13 which reported RR data for both depressive symptoms in theabsence of major depression (RR52.1) and RR data for the presence of majordepression (RR54.5).

Change in initial probability (P) is calculated as follows:(1) P/(12P)3odds ratio*5odds.(2) New probability5odds/(11odds).

*Risk ratios may be used instead of odds ratios when probabilities are low,as in this example. Odds ratios should be employed when probabilities arehigh.




These data provide strong confirmatory evidence that theatherogenic effect of chronic psychological stress in thesemonkeys is dependent on concomitant sympatheticactivation.

Cynomolgus monkeys have also been used to study theinfluence of chronic psychosocial stress on coronary endo-thelial integrity. First, it was demonstrated that the stressmodel cited above induces atherosclerosis in dominant malemonkeys in the absence of hypercholesteremia, albeit withsmaller lesions than those noted for monkeys concomitantlyfed a high-cholesterol diet.164 Thus, under conditions ofchronic psychological stress, endothelial injury can occureven without dietary provocation. Subsequently, quantitativecoronary angiography was used to demonstrate that psycho-social stress in cynomolgus monkeys can also lead to impair-ment of endothelial function in the presence of underlyingcoronary atherosclerosis.165 Specifically, arterial responses innonatherosclerotic controls (which always consumed a low-cholesterol diet and were housed in stable groups) werecompared with those in monkeys that consumed a high-cho-lesterol diet for 1 year and were subsequently assigned to 1 of3 experimental conditions: (1) continued consumption of a

high-cholesterol diet plus exposure to periodic social disrup-tion, (2) consumption of a low-cholesterol diet plus exposureto periodic social disruption, and (3) consumption of alow-cholesterol diet and housed in stable social groups. Asshown in Figure 2, coronary vascular responses to acetylcho-line differed across groups in a manner consistent with theexposure to psychosocial stress. Thus, chronic psychosocialstress can impair endothelium-dependent vascular responsesin a manner that is not necessarily dependent on extent ofunderlying atherosclerosis or diet.

Sex DifferencesThe relative sparing of premenopausal women in relation tomen of similar age is a prominent feature of CAD, ischemicstroke, and atherosclerosis.166 Although this phenomenon issometimes referred to as “female protection,” it is moreaccurately characterized as a delay in disease onset, with theincidence curve for women lagging behind that of men by'10 years.167 The various effects of estrogen are believed toaccount for most of this sex difference, at least with respect toCAD incidence and atherosclerosis.168 Not only are premeno-pausal women “protected” from atherosclerosis, but theprovision of estrogen replacement to initially healthy post-menopausal women is associated with a significant reductionin CAD risk.168,169 Nevertheless, because atherosclerosisprogresses over decades, it is likely that the clinical eventsoccurring in postmenopausal women have their beginnings inthe premenopausal years. This conclusion is supported by arecent study showing the presence of relatively extensivefocal atherosclerosis in premenopausal women.170 Ovarianabnormalities or failure, by reducing the amount of endoge-nous estrogen, could accelerate atherogenesis in premeno-pausal women, thereby predisposing these individuals toCAD (and possibly ischemic stroke) in later years.

Notably, studies in premenopausal monkeys suggest thatpsychosocial stress reliably induces ovarian impairment inthe half of socially housed females that occupy subordinatestatus in their social groups.171,172Subordinate monkeys haveestradiol concentrations of'60 pg/mL, contrasting signifi-cantly with dominants at 130 pg/mL.173 Furthermore, thesesubordinate, ovary-impaired females, compared with theirdominant counterparts, develop exacerbated atherosclerosisand abnormalities in coronary reactivity.171,173,174Such fe-males are also typically hypercortisolemic and have exagger-ated heart responses to stress, characteristics that are them-selves risk factors for atherosclerosis in both humans andmonkeys.

These animal findings establish the possibility that behav-ioral stressors influence the development of CAD in womenduring the premenopausal period, through effects on estro-genic and neuroendocrine activity. In fact, several lines ofevidence are consistent with the suggestion that ovarianimpairment, possibly stress-induced, potentiates atherogene-sis before menopause in women. First, 2 studies have linkeda lifelong history of menstrual irregularity with a significantlyincreased risk for acute myocardial infarction.175,176 A thirdstudy has shown that irregularly menstruating women, incomparison with normally cycling control women, have

Figure 1. A, Measurements of coronary artery intimal extent(6SEM) among dominant and subordinate monkeys living inunstable (left) or stable (right) groups. Atherosclerosis was sig-nificantly more extensive in dominant, unstable animals com-pared with monkeys in other 3 conditions. B, Coronary arteryatherosclerosis extent in dominant and subordinate monkeys, allhoused in unstable groups and either untreated (left) or treatedwith propranolol HCl (right). Exacerbated atherosclerosis ofdominant animals living in unstable groups was completelyinhibited by b-adrenergic blockade. A was adapted from Refer-ence 67; B, from Reference 163.




elevated plasma fibrinogen concentrations (a risk factor forCAD) and a thickened arterial intima.177 The possibility thatthese observations might reflect the reduced concentrations ofendogenous estrogen characteristic of ovary-impaired womenis supported by the finding that premenopausal women withangiographically confirmed CAD have significantly lowerplasma estradiol concentrations than do control subjects andthat such levels resemble those observed in subordinatefemale monkeys.173,178

Notably, many premenopausal women may experienceovarian compromise at some time during their reproductiveyears.179 The general term for this compromise is functionalhypothalamic hypogonadism, the manifestations of whichrange from subclinical luteal-phase defects with regularmenstrual intervals to irregular cycles to amenorrhea.179,180

Psychogenic stress is often linked to functional hypothalamichypogonadism in women.172,181–183One particular expressionof this syndrome, functional hypothalamic amenorrhea, isassociated with abnormal luteinizing hormone pulse genera-tor activity and is accompanied by hypercortisolemia andother neuroendocrine and behavioral indicators ofstress.184,185Furthermore, recent data suggest that subclinicalovarian abnormalities sufficient to cause premenopausal boneloss may affect a substantial number of women.179,186 Forexample, disturbed luteal phase function characterized 29%of the menstrual cycles recorded from a sample of 66premenopausal women thought to be cycling normally; de-creases in spinal density at both 1 and 5 years after measure-

ment were significantly associated with this degree of abnor-mality.179 If ovarian hormones are indeed cardioprotective,women with functional hypothalamic hypogonadism andsubclinical ovarian dysfunction could share with subordinatemonkeys a predilection for accelerated atherosclerosis and anincreased risk of CAD, especially because a relatively modestimpairment of ovarian function is sufficient to cause markedexacerbation of atherosclerosis in monkeys.172

Ovarian impairment probably has eluded detection as a riskfactor for CAD because it is often occult and becausepremenopausal women have a low incidence of CAD.174

Nonetheless, surrogate measures (eg, a history of menstrualirregularity) are associated with premature CAD or elevatedCAD risk factors.176,177 Hence, the percentage of premeno-pausal women who experience accelerated atherosclerosismay be much larger than the number diagnosed as amenor-rheic or otherwise ovary-impaired. At present, however,atherosclerosis progression has not been studied prospec-tively in premenopausal women in conjunction with ovarianfunction.

Acute Life StressAnecdotal reports and case studies187–189have long reported arelationship between acute stress and the development ofcardiac disease. In addition, the effects of acute stress on heartdisease are well supported by epidemiological studies regard-ing natural life stressors. An acute stressor associated withincreased rates of cardiac events is bereavement.190,191 For

Figure 2. Mean coronary vascular responses during intracoronary infusion of acetylcholine (individual values and means) measured aspercent change in diameter from control (y axis, left). Left bar represents vascular response in 6 monkeys consuming a low-cholesterol(CHOL) monkey chow and sustained in a nonstressed environment for full 36 months; this group served as control for this study. Other3 groups of monkeys were experimental groups, all fed a high-cholesterol diet for first 18 months of experiment and then subjected tothe following interventions for duration of experiment: (1) 9 monkeys continued on atherogenic diet and were housed in unstable socialconditions (HI CHOL/UNSTABLE); (2) 8 monkeys consumed cholesterol-lowering diet and were housed in unstable psychosocial envi-ronment (LOW CHOL/UNSTABLE); and (3) 10 monkeys were fed cholesterol-lowering diet and placed into stable psychosocial environ-ment (LOW CHOL/STABLE). Vascular responses to infusion of acetylcholine (mean6SEM) are represented by solid bars: vasodilatoryresponses are represented by increases above middle horizontal line and vasoconstrictor responses by decreases below this line. Aver-age plaque sizes in 3 experimental groups are shown in gray bars. Notably, the 2 experimental groups in unstable social environment(2 middle bars) had similar coronary vasoconstrictor responses, despite different cholesterol diets and differing magnitudes of underly-ing atherosclerosis. By contrast, the 2 experimental groups fed a cholesterol-lowering diet for second half of experiment (last two bars)had opposite coronary vascular responses to acetylcholine infusion, despite similar diets and similar magnitude of coronary atheroscle-rosis. Thus, presence or absence of ongoing psychosocial stress in this study modulated endothelial function.




example, in one study of 95 647 individuals followed up for4 to 5 years, the highest relative mortality occurred immedi-ately after bereavement, with a.2-fold higher risk for menand 3-fold higher risk for women.190 After the first month,mortality rates returned to normal population levels. Cardiacevent rates also increased in the immediate aftermath of otheracute life stressors, such as earthquakes and terrorist activi-ties. For instance, during the massive Los Angeles earthquakeof 1994, the number of sudden cardiac deaths due to CADrose sharply, from a daily average of 4.6 in the precedingweek to 24 on the day of the earthquake.192 Similarly, therewas also a sharp increase in the number of deaths on the firstday of missile strikes on Israeli cities during the Gulf War of1991.193 Finally, a retrospective interview format has beenused to examine the effect of anger as an acute trigger ofmyocardial infarction among 1623 post-MI patients.194 A7-point self-report anger scale (15calm, 75enraged) wasused, with anger episodes defined as scores$5. After anepisode of anger, the relative risk of myocardial infarctionwas increased.2-fold.

Pathophysiological MechanismsIn contrast to chronic stress, acute stress is easier to modeland can be studied under controlled laboratory conditions inboth humans and animals. In recent years, as increasinglysophisticated techniques, such as radionuclide imaging tech-niques and the measurement of coronary endothelial function,have been applied to the laboratory study of acute stress, anunderstanding has emerged as to how such acute stress causesdeleterious effects in CAD patients, as schematized in Figure3 and elucidated below.

Induction of Myocardial IschemiaThe ability of acute psychological stress to induce myocardialischemia has been assessed in the laboratory with modeledforms of stress (eg, mental arithmetic and speaking tasks) andsensitive imaging techniques able to detect the extent andseverity of mental stress–induced myocardial ischemia. Thesetechniques include those used to measure left ventricularfunction (radionuclide ventriculography195–199 [Figure 4],echocardiography,200 assessment of left ventricular changesby either a stationary probe201 and ambulatory VEST202) and

Figure 3. Schematic of pathophysiological effects of acute psychosocial stress. Sympathetic nervous system (SNS) stimulation emanat-ing from acute stress leads to a variety of effects, ranging from heart rate and blood pressure stimulation to direct effects on coronaryvascular endothelium. Clinical consequences of these effects include development of myocardial ischemia, cardiac arrhythmias, andfostering of more vulnerable coronary plaques and hemostatic changes. These changes form substrate for development of acute myo-cardial infarction and sudden cardiac death.

Figure 4. Comparative still-frames of left anterior oblique scinti-grams in patient who underwent radionuclide ventriculographyat rest and then during a mental stress task involving a speechtask given in imaging laboratory. Patient had worsening of leftventricular segmental wall motion while speaking about feelingsof personal stress concerning his problems in caring for hisfamily. Images shown for rest are on top and those for thespeaking task on bottom. Shown are end-diastolic (ED) images(left), end-systolic (ES) images (middle), and superimposed EDand ES edges (right). During speech, frank dyskinesis (abnormaloutward motion during systole) developed in septum. From Ref-erence 195.




those used to assess myocardial perfusion (positron emissiontomography203 and 99mTc-sestamibi myocardial perfusion to-mography204). Approximately half of CAD patients withexercise-induced myocardial ischemia also manifest induc-ible ischemia during mental stress testing in the laboratory, asidentified by these techniques. Mental stress–induced ische-mia, however, is not common among CAD patients withoutexercise-induced ischemia. Mental stress–induced ischemia isusually electrocardiographically and clinically “silent” andgenerally occurs at relatively low heart rate elevations com-pared with exercise testing. In addition, the frequency andmagnitude of mental stress–induced ischemia varies accord-ing to the type of mental stressor. Specifically, stress that ismore emotionally laden and/or personally relevant, such as aspeaking assignment concerning personal faults, results in asignificantly greater frequency and magnitude of inducibleleft ventricular wall motion abnormalities than does morenonspecific mental stress, such as the performance of mentalarithmetic or the Stroop Color-Word task.195 Because themean heart rate increases of'15 to 20 bpm duringlaboratory-modeled public speaking201 are far less than thoseof real-life speaking experiences,205,206this and similar tasksmay underestimate the potential potency of mental stress incertain real-life situations. Recall of angry events is also alaboratory trigger of myocardial ischemia,196 which supportsthe epidemiological study of anger by Mittleman et al.194

These laboratory studies are complemented by ambulatoryECG studies that demonstrate an association between psy-chological stress and/or negative emotions and the occurrence

of myocardial ischemia during daily-life circumstances (Fig-ure 5).207–209 Like ischemia induced during mental stresstesting in the laboratory, transient ischemic episodes out ofhospital are overwhelmingly silent and occur at relatively lowheart rate elevations.210 Furthermore, patients who manifestmyocardial ischemia during laboratory mental stress are alsomore likely to manifest myocardial ischemia during ambula-tory ECG monitoring of daily-life activity.200,209,211Just asCAD patients who demonstrate myocardial ischemia duringdaily-life activity manifest a significantly increased likeli-hood of subsequent cardiac events,212 recent studies alsosuggest that mental stress–induced ischemia in the laboratorysetting also predicts cardiac events (Figure 6).197,198

Mechanisms for mental stress–induced myocardial ische-mia.Even though heart rate elevations during laboratory-induced mental stress are relatively small, blood pressureelevations during mental stress are substantial, parallelingthose noted with exercise.195,200 Thus, oxygen demand isincreased during mental stress testing. However, because thedouble product threshold for the induction of ischemia duringmental stress testing is substantially lower than that associ-ated with exercise testing, other mechanisms must also beinvolved. One mechanism is mental stress–induced coronaryvasoconstriction.213,214During mental stress, significant cor-onary vasoconstriction may occur in CAD patients at sitesmanifesting vasoconstriction during acetylcholine infu-sion.213 Because acetylcholine is used to test for endotheli-um-dependent coronary vasoconstriction, these findings sug-

Figure 5. A, On x-axis, feelings of two positiveemotional states, being in control (far left) andhappiness, and 3 negative emotional states arerepresented. y-axis represents percent of hourswith ischemia during 2760 hours of monitoringamong 58 patients with CAD. Low levels of eachstate are represented by gray bars and high levelsby solid bars. Percentage of ischemic hoursincreased during negative emotional states. Rela-tive risk ratios for ischemia during high vs low lev-els of tension, frustration, and sadness, respec-tively (after adjustment for time of day andphysical activity level) were as follows: 2.2 (1.1–4.5), 2.2 (0.7–6.4), and 2.2 (1.1–4.3). Control hoursare all nonischemic hours during 48 hours of mon-itoring. Adapted from Reference 209. B, Linearrelationship between magnitude of sadness andduration of myocardial ischemia during ambulatoryECG monitoring was also noted. Relative risk(95% CI) for ischemia by level of sadness was asfollows: 1.8 (1.0–3.4) for level 1; 2.3 (1.0–5.3) forlevel 2; 3.4 (1.0–11.7) for level 3; and 2.4(0.3–16.6) for level 4.




gest that neurohumoral stimulation during mental stressinduces coronary vasoconstriction through an endothelium-dependent mechanism. In addition, it has been reported thatthe coronary microcirculation fails to dilate during mentalstress.215 However, significant coronary vasoconstriction alsooccurs during exercise in CAD patients216 through the sameendothelium-dependent mechanism as noted for mentalstress. Thus, other mechanisms must be considered to explainwhy mental stress ischemia is induced at relatively lowdouble-product thresholds compared with exercise testthresholds for ischemia. One potential factor may relate tothe presentation of stress. Mental stress testing in the labora-tory is a “sudden” stressor, presenting without warm-up.Maximal heart rate and blood pressure responses are gener-ally observed at the near onset of mental stress, and ischemicabnormalities are induced relatively rapidly during laboratorymental stress.201 By contrast, laboratory exercise is alwayspresented to patients in a graded fashion. However, whenhealthy individuals were exercised to a high workload with-out warm-up, ST-segment depression was induced in asignificant number of subjects.217 Similarly, Eschar et al218

compared 6 CAD patients during graded versus suddenexercise stress; during the graded stress protocol, 3 patientshad the indication of chest pain, and only 1 patient developedexercise-induced ST-segment depression of$1 mm. Bycontrast, during sudden stress, all 6 patients both had theinduction of chest pain and developed.2 mm of ST-segmentdepression. Because CAD patients may commonly experi-ence short bursts of strenuous physical and mental stresswithout warm-up during daily life, further study of this issueis warranted.

Autonomic factors may also be operative in regulatingmyocardial ischemia. For instance, myocardial ischemia dur-

ing daily life shows a characteristic circadian rhythm.219 Eventhough exogenous factors (ie, the amount of physical andmental activity) trigger episodes of myocardial ische-mia,208,209,219Krantz et al219 demonstrated that the circadianrhythm of myocardial ischemia also appears to have anendogenous component, as demonstrated in Figure 7. Under-standing the factors driving this apparent endogenous com-ponent could help further elucidate the pathophysiology ofmental stress–induced ischemia.

Other factors that may potentially help regulate myocardialischemia may be elucidated by the evolving study of factorsthat modify hemodynamic responses to exercise and mentalstress. This includes the study of systems modulating sys-temic vascular tone, such as the endothelial system. In thePsychophysiological Investigations of Myocardial Ischemia(PIMI) Study, systemic vascular resistance increased duringmental stress and decreased during exercise testing amongCAD patients.199 In that study, increased systemic vascularresistance during mental stress testing was reported to be themost significant hemodynamic feature associated with mentalstress–induced myocardial ischemia. Interestingly, in a sub-sequent recent study, increases in systemic vascular resis-tance during mental stress were directly related to compro-mised peripheral endothelial function in a group of 40 healthymen and women.220 These data raise the possibility thatexcessive systemic vascular resistance responses to mentalstress may be a potential marker of peripheral endothelialdysfunction. However, prospective work is clearly indicatedto determine the reproducibility and validity of these newobservations and their potential pathophysiological import.

Promotion of ArrhythmogenesisInvestigators have consistently noted an interrelationshipbetween behavioral factors and arrhythmogenesis in hu-mans.50,221–224According to Lown et al,221 3 sets of condi-tions contribute to the occurrence of such arrhythmias:(1) myocardial electrical instability, most often due to CAD;(2) an acute triggering event, frequently related to mentalstress; and (3) a chronic, pervasive, and intense psychologicalstate, often including depression and hopelessness. To studythe pathophysiological interrelationship between behavioralfactors and ventricular fibrillation, Verrier et al225 assessedmyocardial electrical instability in conscious, freely movingdogs by placing a catheter in the right ventricular apex,scanning the ECG, and delivering repeated electrical stimu-lation during the vulnerable part of the cardiac cycle. Theamount of electrical stimulation required to produce repeti-tive extrasystoles (REs) was used to define the ventricularfibrillatory threshold. Inasmuch as the animal does notperceive this stimulation, investigators can more directlystudy the effects of experimentally produced behavioral stateson the ventricular fibrillatory threshold. In an initial series ofstudies, dogs were exposed to either an undisturbed environ-ment or one in which the animal was held in a sling and givenperiodic transthoracic shocks over 3 successive days.50 Be-haviorally, the animals seemed relaxed in the undisturbedenvironment and agitated and autonomically aroused in thesling. The RE threshold was reduced by.40% when animalswere moved from the benign to the stressed environment.

Figure 6. After performance of mental tasks during radionuclideventriculography, patients were followed up over time (x-axis).Probability of event-free survival is plotted as a function of men-tal stress–induced EF change plotted at 2 prototypical values, 1SD below (EF change5212.40%) and 1 SD above (EFchange511.05%) mean of entire sample (EF change526.73%). Curves are adjusted for baseline EF, history of myo-cardial infarction, and age. Relative risk associated with lowercurve compared with higher curve is 2.40 (P50.024). From Ref-erence 197.




Similarly, a natural emotion, an anger-like state provoked bydenial of access to food, similarly reduced the REthreshold.225

Taken together, these studies show that behavioral stress,whether produced by aversive conditioning or a more natu-ralistic conflict, significantly decreases the electrical stabilityof the heart. Furthermore,b-adrenergic blockade prevents theeffects of either aversive conditioning or induced anger on theRE threshold, suggesting that these effects are mediated, inpart, by sympathetic arousal.226Other work demonstrated thatwhen dogs were first predisposed to arrhythmia by acutemyocardial ischemia (a 10-minute period of coronary arteryocclusion followed by reperfusion), exposure to the stress ofan aversive sling environment significantly increased theincidence of ventricular fibrillation.225 In general, stimuli thatelicit anger-like responses are especially likely to provokeabnormalities in rhythm.225 Researchers have also relatedbehavioral factors to arrhythmia in other experimental ani-mals.227 Thus, the data relating behavioral factors to arrhyth-mias are impressive in reliability of the effects and in theidentification of excessive sympathetic activation as a majorprecipitating factor.

Deleterious Endothelial EffectsIn animal model studies, acute stress also causes coronaryendothelial abnormalities, which range from endothelial dys-function to frank endothelial injury and necrosis. For exam-ple, borderline hypertensive rats exposed to air-jet stress inthe face (2 h/d for 10 days) display impaired arterial dilationin response to acetylcholine.228 Furthermore, the stressedanimals also have a reduced sensitivity to nitroprusside,indicating an attenuated response to exogenous nitric oxide.The authors concluded that behavioral stress impairs endo-thelium-independent and nitric oxide–mediated coronary re-laxation, but without causing visible endothelial damage (asevaluated by scanning electron microscopy). With respect toendothelial injury, investigators have directly tested thehypothesis that sympathetic stimulation alters endothelialintegrity by exposing rabbits to chloralose anesthesia, amanipulation that produces persistent and reproducible in-creases in heart rate, blood pressure, and plasma norepineph-rine concentrations (all indicators of sympathetic activa-tion).229,230 Compared with conscious controls, chloralose-treated animals developed marked endothelial injury (asindicated by IgG incorporation) at both unbranched andcircumostial aorta. In contrast, pretreatment with ab-blocking agent attenuated heart rate and blood pressureincreases, and endothelial injury was completely inhibited.Finally, male monkeys exposed to a clear-cut acute psycho-logical stressor, 72 hour introduction to social strangers, hada significantly higher frequency of IgG-positive (injured)endothelial cells in the circumostial areas of the descendingthoracic aorta than did control animals not exposed to thisstressor.231 Again, pretreatment withb-adrenergic blockingagents prevented this stress-induced arterial damage (Figure8). Importantly, the animals in this study consumed a low-cholesterol diet, indicating that the endothelial response tobehavioral stimulation and adrenergic blockade was indepen-dent of dietary stimulation. Studies such as these clearly link

Figure 7 A, Hour-by-hour circadian variation of myocardial ische-mia in 63 CAD patients manifesting myocardial ischemia duringambulatory ECG monitoring. Left, Total ischemic time (minutes) ineach hour of day; right, number of ischemic episodes in each hour.There was a morning peak in ischemic time/hour between 6 and11 AM, with a secondary rise between 2 and 6 PM, before taperingof ischemia in evening. ANOVAs revealed a significant overall tem-poral variation in ischemic time during course of day. A similar pat-tern was noted for number of ischemic episodes. B, To assesscontribution of an endogenous component to diurnal variation ofischemia, hourly duration of ischemia was controlled for concomi-tant activities, according to a statistical formula that regressedmaximal physical and mental activity levels for each hour on corre-sponding ischemic time. This yielded “activity-adjusted residualscores,” which reflect measurements of ischemia not accountedfor by activity. Shown are 3 separate curves for adjusted measure-ments of predicted ischemic time per hour of day, including thoseadjusted for (1) physical activity, (2) mental activity, and (3) heartrate. Adjusted ischemic times .0 on y axis indicate ischemic timesthat were longer than expected on the basis of concurrent activitylevels or heart rate. Conversely, values ,0 indicate ischemic timesthat were shorter than expected. Thus, if there had been no ische-mic effect independent of activity, flat curves would be present.Rather, analyses showed a significant diurnal variation for all 3curves (P,0.01), proving presence of a circadian rhythm that isendogenous in nature. Further statistical analysis of hour-by-hourchanges in ischemic time revealed that for each curve, there was asignificant increase in ischemic time at 6 AM vs 5 AM. Afternoonpeak in ischemia noted in A, however, is now abolished, suggest-ing that this afternoon rise in ischemia is of an exogenous nature,driven by physical and mental activity levels. From Reference 220.




behavioral factors and neuroendocrine activation to disrup-tion of endothelial integrity and thus the earliest stages ofatherosclerosis. On the basis of these animal data, it isreasonable to ask whether acute or subacute psychologicalstressors might similarly induce transient endothelial dys-function in human beings as well. If so, it could help explainwhy prodromal psychological symptoms frequently precedethe occurrence of acute myocardial infarction.

Coagulation EffectsThe ability of emotional stress to induce coagulation abnor-malities in human beings has been known for manyyears.232,233Recently, the effects of acute psychological stresson indices of coagulation have been studied during laboratorymental stress tasks234,235and during various naturalistic stres-sors.236,237 In both situations, significant, but not alwaysconsistent, platelet abnormalities have been observed. Acutelaboratory mental stress also causes hemoconcentrationthrough stress-induced decreases in plasma volume, as ob-served in various studies.238,239This latter finding is signifi-cant in light of recent observations linking blood viscosity tocardiac events.240 Animal studies further confirm the abilityof acute stress to induce coagulation abnormalities.241

The duration of coagulation abnormalities induced byacute natural stresses is not yet known. However, becauseblood samples were fortuitously obtained in 42 hypertensivepatients before the large Hanshin-Awaji earthquake, investi-gators obtained repeat blood samples 7 to 14 days afterwardto assess the effects of this acute stressor on coagulationparameters.236 The earthquake induced transient increases inblood pressure; blood viscosity determinants, such as hemat-ocrit and fibrinogen levels; and various hemostatic factors,including fibrin turnover and plasmin-a2–plasmin inhibitorcomplex, an activation marker of fibrinolysis. These param-eters returned to normal levels by 4 to 6 months after theearthquake. These findings suggest that coagulation abnor-

malities may persist for weeks after a single stressful event. Amore chronic hypercoagulable profile has also been reportedamong individuals subjected to forms of subacute stress.242,243

It is not yet clear whether mental stress–induced hemocon-centration and mental stress–induced platelet activation arethe result of the same or different mechanisms. A recentlaboratory study, however, suggests that different mecha-nisms may be operative,244 because platelet activation in thisparticular study correlated only with changes in serum cate-cholamine levels during mental stress, whereas mental stress–induced hemoconcentration correlated only with changes inmean arterial blood pressure, but not serum catecholaminelevels, during mental stress.

Sympathetic NervousSystem Hyperresponsivity

Sympathetic nervous system hyperreactivity (also called car-diovascular reactivity) has been defined as a dispositionaltendency to exhibit exaggerated heart rate and blood pressureresponses when encountering behavioral stimuli experiencedas engaging, challenging, or aversive. On a theoretical basis,it has been postulated that individuals manifesting moreelevated heart rate and blood pressure responses to suchphysiological challenge (ie, “hot reactors”) may experiencemore substantial sympathetic nervous system responses overtime than “cold reactors” and that this may in turn promotethe development of atherosclerosis. The first findings tosupport this hypothesis were reported by Keys et al,245 whoevaluated 20 clinical variables in 275 men followed up for 20years. Among these clinical variables, the diastolic bloodpressure response to cold pressor stimulation was the mostpredictive variable for future CAD development. Subse-quently, however, negative prognostic studies were alsoreported.116,246In a recent development, the potential athero-genic effect of sympathetic hyperresponsivity has been as-sessed in 4 studies that used serial carotid Doppler measure-ments.247–250 In each study, progression of carotidatherosclerosis was more rapid among individuals manifest-ing more pronounced heart rate and blood pressure responsesto physiological challenge.

Cynomolgus monkeys consistently display significant in-dividual differences in heart rate response during a threat ofcapture and during exposure to a benign manipulation involv-ing the mere appearance of the experimenter in the monkeyhousing area. Because these monkeys can thus be reliablyidentified as hot versus cold reactors, they establish anexcellent animal model for the study of sympathetic nervoussystem hypersensitivity. Moreover, among cynomolgus mon-keys fed the same high-fat diet, the atherosclerotic lesions ofhot-reactor monkeys is twice as large as those of theirlow-reactive counterparts.251 This reactivity-atherosclerosisassociation is seen in both male and female monkeys and inboth the coronary and carotid arteries.252,253

Inasmuch as sympathetic nervous system hyperresponsiv-ity is not concentrated in dominant male monkeys, thereappear to be 2 mechanisms by which psychological factorspromote atherogenesis in males of this species. First, somemonkeys (ie, hot reactors) may be susceptible to developmentof atherosclerosis because of an intrinsic sympathoadrenal

Figure 8. Frequency of injured endothelial cells in circumostialareas of descending thoracic aorta (y axis). Percentage of IgG-positive cells on Hautchen preparations was taken as index ofarterial injury. Psychosocial stress (72-hour exposure of malemonkeys to social strangers) caused a significant (P,0.02)increase in number of injured cells in unmedicated animal group(controls) (left bars). b-Blockade, either with metoprolol (lipophil-ic) or atenolol (hydrophilic) (right bars) significantly (P,0.01)inhibited injurious effect of stress. 95% CIs are in parentheses.Adapted from Reference 231.




hyperresponsivity to behavioral stimuli. Other monkeys (ie,dominant individuals in unstable social environments), con-versely, may be at increased risk because of frequent elicita-tion of heart rate (and presumably blood pressure) responsesin stressful environments.252 Sympathoadrenal activation,provoked in either of 2 ways, could thus provide a commonpathway by which atherosclerosis is mediated. Among fe-males, social subordination, ovarian impairment, hypercorti-solemia, and exaggerated heart rate responses to stress seemto occur concurrently, dramatically accelerating atherogene-sis in affected individuals.172 Other studies have linkedsympathetic hyperresponsivity to the induction of ischemiaduring exercise254 and mental stress,255 and to the develop-ment of hypertension.256–258Combined, these recent animaland human studies raise the possibility that sympathetichyperresponsivity may constitute a risk factor for the devel-opment or progression of CAD.

Therapeutic ImplicationsAs we have summarized, a confluence of pathophysiologicaland epidemiological studies establish that both acute andchronic forms of psychosocial stress contribute to the patho-genesis of coronary atherosclerosis. These data establish animperative for enhancing behavioral interventions amongCAD-prone individuals. Because acute forms of psychosocialstress are ubiquitous and frequently unavoidable, it could beargued that the best general protection from their deleteriouseffects is the underlying prevention and treatment of coronaryartery disease. However, because chronic forms of psycho-social stress are subject to clinical modification, their contri-bution to the underlying development of coronary diseasemight potentially be reduced by interventions designed totreat these factors. Evidence to support this hypothesis hasbeen limited by a lack of adequate clinical investigation. Inour opinion, the issue of studying and integrating psychoso-cial interventions into clinical practice would benefit from thefollowing measures.

1. Physicians need to emphasize the role of psychosocialrisk factors in counseling their patients.

Patients often know that their lifestyle and psychosocialproblems may affect their health, but when physicians do nottake these problems seriously, patients are likely to concludethat such problems are not important. Conversely, whenphysicians engage patients in the identification of psychoso-cial issues, alteration of the psychosocial risk factors is morelikely. Thus, more physicians need to be made aware of therecent developments that establish key psychosocial variablesas risk factors for the development of CAD and as contrib-uting factors to the expression of disease activity.

2. The effectiveness of behavioral interventions for cardiacpatients needs to be evaluated and implemented in clinicalsettings.

Among some physicians, there is a perception that psycho-social factors do not merit much attention. Reasons for thismay be multifold. First, many physicians are not aware of thestrength of association between psychosocial risk factors andCAD development. Second, the lack of consensus regardingthe measurement of some psychosocial risk factors may beconfusing to clinical practitioners. Third, physicians who

regard psychosocial factors as potentially important maynonetheless lack expertise to assist patients in modifyingthese factors. Perhaps with the exception of risk factors thatmay be altered pharmacologically (eg, as in the treatment ofdepression), many physicians lack training in behavioralintervention techniques. Fourth, even when physician moti-vation and training are present, such interventions are oftentime-consuming and labor-intensive. Also, reimbursement forsuch services is often limited. Finally, available evidenceshowing the effectiveness of psychosocial interventions oftensuffers from methodological limitations, such as “soft” clin-ical end points, and inconsistent results. Regarding this lastpoint, a recent meta-analysis, in fact, demonstrates significanthealth benefits when psychosocial interventions are added toroutine medical management of patients with CAD.259 At thesame time, there are discordant results among 14 publishedbehavioral intervention trials that have assessed the impact ofpsychosocial interventions on the frequency of major cardiacevents, such as cardiac death and myocardial infarction (seeTable 8).260–273These trials are also notable for their limita-tions in size and number. Most notably, however, no reduc-tion in psychological distress was observed in most of thenegative trials noted in Table 8. This includes the 2 largetrials recently conducted by Jones and West271 and Frasure-Smith et al.273 Thus, one of the potential reasons for thediscordance among these behavioral intervention studiesappears to be the use of ineffective behavioral interventions.In our view, future improvements in this area require work inthe following 2 areas:

A. The efficacy of psychosocial interventions may beimproved by development of “patient-specific” treatmentplans, based on the “profiling” of the major psychosocial riskfactors in individual patients.

Because multiple psychosocial factors contribute to thedevelopment of CAD, patient-specific targeted interventionsmay be appropriate. To date, however, few psychosocialintervention trials have tailored their intervention to specificpsychosocial risk factors. This approach requires that indi-vidual difference characteristics be identified (eg, clinicaldepression, social isolation, job stress). On the basis of suchprofiling, patient-specific interventions could target specificpsychosocial risk factors. For instance, individuals lacking insocial support might be preferentially targeted for therapiesincorporating group support or the development of moreadequate social skills. Of note, recent trials are beginning tofocus on the potential utility of targeting individual psycho-social factors. For instance, in the NHLBI-sponsored Enhanc-ing Recovery in Coronary Heart Disease (ENRICHD) trial,more than 3000 patients with major depressive disorderand/or social isolation are randomized to either a cognitivetherapy stress reduction program or usual care. In theindustry-sponsored Sertraline and Depression in Heart AttackStudy (SADHART), post–acute MI patients with majordepressive disorder are randomized to antidepressant therapy(ie, sertraline, a selective serotonin receptor inhibitor) orplacebo.

B. Because the problem of lifestyle factors (eg, smoking,alcohol use) and psychosocial stress frequently cluster to-gether, treatment of patients who are noncompliant with




lifestyle changes may benefit from consideration of concom-itant psychosocial stresses.

As schematized in Figure 9, in addition to directly promot-ing the pathogenesis of atherosclerosis, psychosocial factorsalso promote the pathogenesis of atherosclerosis in 2 otherbasic ways: (1) the maintenance of lifestyle behaviors thatpromote atherosclerosis and (2) the discouragement of theirmodification. Conversely, amelioration of behavioral riskfactors may also promote psychosocial well-being. For ex-ample, exercise training not only improves functional capac-ity but also may reduce symptoms of depression.274 Thus, theproblem of psychosocial stress and patient noncompliancewith behavioral risk factors should be considered togetherfrom the perspective of use of economic resources anddevelopment of cost-effective behavioral interventionstrategies.

This overall problem is best tackled by further acknowl-edgment that the modification of lifestyle habits and certainforms of psychosocial stress are often difficult to achieve. Forthis reason, considerable attention has been given to study of

the predictors of successful and unsuccessful behavioralchanges among individuals. A variety of models of behav-ioral change have been introduced and in some instancesstudied among patients with CAD or CAD risk factors.275,276

Furthermore, psychological theories related to the issue ofmotivation have increasingly been used to provide incentiveto employees and promote productivity in the corporateworld. The application of these approaches is also warrantedto determine their incremental value for treating psychosocialproblems in CAD patients.

3. The pathophysiological mechanisms by which behaviortherapies reduce cardiac events need to be identified.

To date, the mechanism(s) by which behavioral interven-tions might reduce the incidence of cardiac events has not yetbeen well delineated. In this regard, 2 recent animal stud-ies165,272have uncovered a potentially important ameliorativemechanism: improvement in coronary endothelial function.For instance, investigators compared vascular responses inthe iliac arteries of 3 groups of male monkeys exposed to anatherogenic diet for 2 years277: (1) a group of “no-stress”

TABLE 8. Impact of Psychosocial Intervention Trials on Cardiac Events

StudyType ofPatients

No. of Patients

F/U, y Type of Intervention

Reduction inPsychosocial

Factors?Cardiac End

Points Reduction in Events?ControlGroup

InterventionGroup

Rahe et al, 1979 s/p MI 22 39 3 Group education and support Yes (for overwork;time urgency)

CD/MI Yes (P,0.05)

Stern et al, 1983 s/p MI 20 35 1 Group counseling Yes (for depression) ACM; MI No

Friedman et al,1984

s/p MI 270 592 4.5 TABP modification and groupcounseling

Yes (for TABP) CD/MI Yes (P,0.005)

Horlick et al, 1984 s/p MI 33 83 0.5 Hospital-based educationprogram (6 wk)

No (for anxiety;depression)

CD No

Patel et al, 1985 $2 RF 93 99 4 Breathing, muscle relaxation,meditation

Not assessed Angina;MI-1; CD

Small sample

Maeland et al,1987

s/p MI 1115 137 3.3 Educational program No (for anxiety;depression)

ACM No*

Dixhoorn et al,1987

s/p MI 46 42 2.5 Physiological relaxation (eg,breathing, exercised)

Not assessed CD; MI; UAP;CABG

Yes (P50.05)

Frasure Smith et al,1989

s/p MI 229 232 5 Home-based nursingintervention

Yes (for GHQ) MI; CD Yes (P50.04 for MI†)

Thompson et al,1990

60 s/p MI 30 30 0.5 Group counseling Yes (for anxiety anddepression)

ACM Small sample

Nelson et al, 1994 s/p MI 20 20 0.5 Physiologic stressmanagement (eg, breathing)

Yes (for ability tohandle “stress”)

MI; ACM Small sample

Burell et al, 1994 s/p MI 24 23 2 TABP modification Yes (for TABP) CD/MI Small sample

Jones et al, 1996 s/p MI 1155 1159 1 Group sessions 37 wks forstress management and

counseling


ACM; CD No

Blumenthal et al,1997

CAD withEII

40 33 5 Structured group instructionwith multiple stress

reduction components

Yes (for GHQ scoresand hostility)

CD, MI,PTCA, CABG

Yes RR50.26(0.07–0.90)

Frasure Smith et al,1997

s/p MI 684 692 1 Home-based nursingintervention, to decrease

transient increase in distress


CD No

RF indicates risk factors; EII, exercise-induced ischemia; TABP, type A behavior pattern; MI-1, undocumented myocardial infarction; and UAP, unstable anginapectoris.

*At 6 months of follow-up, short-term lower anxiety and death rate (P,0.05) in intervention group.†At 1 year (length of intervention), P50.07 for CD reduction in intervention group.




animals housed in stable social groups; (2) an “early-stress”group of animals, housed in unstable groups for the first halfof the experiment and thereafter in stable groups (ie, theequivalent of a stress reduction group); and (3) a “current-stress” group of animals, housed in stable social groups forthe first half of the experiment, and thereafter in disruptedgroups. In comparison to the current-stress group, the early-stress animals had less endothelial dysfunction, despite in-gestion of the same diet (Figure 10). These data indicate thatwhereas exposure to chronic stress impairs endothelium-mediated dilation of atherosclerotic iliac arteries, its removaltends to reverse this process. On the basis of such data, aprospective trial to test the possibility that stress reductionimproves endothelial dysfunction may be indicated inhumans

Although both acute and chronic forms of psychosocialfactors may induce coronary endothelial dysfunc-tion,165,228,231,277the mechanisms by which this occurs arecurrently unknown. Increasingly, however, the inflammatorynature of coronary disease as it relates to coronary endothelialfunction is being delineated.278 For instance, both biome-chanical factors associated with pulsatile blood flow (eg,shear stress and cyclic strain) and biochemical factors (eg,cytokines and growth factors) appear to promote inflamma-

tory inducers of atherosclerosis, such as vascular cell adhe-sion molecules.279 Prospective studies are needed to deter-mine whether and how psychosocial factors adverselypromote this molecular pathobiology or, in the case ofbiobehavioral interventions, favorably modify it.

4. The relevance and design of future behavioral interven-tion trials need to be improved.

In the real world, biobehavioral interventions are notundertaken in the absence of other medical regimens. Thus, auseful practical design for future studies is one that incorpo-rates effective medical treatment (eg, lipid-lowering therapy)and conventional lifestyle modifications (eg, dietary recom-mendations) in all patients and then looks at the added riskreduction associated with the incorporation of effective psy-chosocial stress interventions in a subgroup of the patients.However, because large-scale epidemiological studies arecostly and require years of evaluation, potential alternativeend points are also needed to permit the early and rapidassessment of the efficacy of specific behavioral interven-tions. Current potential end points might include noninvasivemeasurements of endothelial function, the magnitude ofatherosclerosis progression on carotid ultrasound, and themagnitude of inducible myocardial ischemia during stresstesting. For instance, using myocardial ischemic end points,Blumenthal et al272 were able to assess the efficacy of astress-reduction intervention by using a small sample of'100 patients (Figure 11). Once a behavioral interventionlooks promising with respect to its effect on such alternativeend points, more large-scale epidemiological investigationscould then be designed based on the garnered practicalexperience.

5. Organizational support is needed to spur interdiscipli-nary scientific collaboration among scientists interested inbiobehavioral medicine.

Figure 9. According to scheme portrayed here, psychosocialfactors may contribute to development and promotion of CAD in3 basic ways: (1) they directly promote pathogenesis of athero-sclerosis: (2) they contribute to maintenance of unhealthy life-style behaviors, such as smoking and a poor diet; and (3) afterdevelopment of clinical disease, when targeted reduction of allunhealthy lifestyle behaviors becomes increasingly paramount,coexisting psychosocial stresses form an important barrier tosuccessful modification of these lifestyle behaviors.

Figure 10. Effect of treatment with acetylcholine, in a vesselbath preparation, on percent dilation of iliac arteries in cynomol-gus monkeys from 3 experimental groups: unstressed controls;“early stress,” which was then withdrawn; and “late stress”.Analysis revealed that arteries from monkeys in “late stress”group had impaired endothelium-mediated dilation (shifteddose-response curve down and to right) vs other 2 groups(P,0.05). Thus, later withdrawal of stress in “early stress” groupwas associated with less resultant endothelial dysfunction overtime. From Reference 277.




Scientists from a wide variety of backgrounds have con-tributed to the observations noted in this article. The Amer-ican Heart Association and American College of Cardiologyhave tremendous potential for spurring more formal commu-nication and cooperation of an interdisciplinary nature. Byencouraging research and collaboration that span acrossdisciplines, the future development of interventions for psy-chosocial risk factors could derive the synergistic benefitrepresented by the maxim “the whole is greater than the sumof its parts.”

AcknowledgmentsThis work was supported, in part, by grants HL-43028, MH-49679,and HL-49572 from the National Institutes of Health. We appreciatethe able assistance provided by Drs Ehtasham Qureshi, AbrahamBornstein, and Siu-Sun Yao and the inspiration and support providedby the late Dr Jules Rozanski.

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Alan Rozanski, James A. Blumenthal and Jay KaplanImplications for Therapy

Impact of Psychological Factors on the Pathogenesis of Cardiovascular Disease and

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