COMMENTARY

Traumatic Stress Is HeartbreakingViola Vaccarino and J. Douglas Bremner

There is growing recognition that the consequences ofposttraumatic stress disorder (PTSD) on health may reachfar beyond the neuropsychiatric sphere. For many years,

studies have documented numerous physical health problems inPTSD (1), and a possible connection between PTSD and risk ofcoronary heart disease (CHD) has received special attention.

Despite this growing interest, evidence of a link between PTSDand CHD has remained elusive, mainly because of weaknesses inthe existing literature. Until recently, much of the research in thearea of PTSD and CHD has been hindered by methodologiclimitations, including the use of cross-sectional designs, assess-ments of cardiac symptoms or diagnoses based on self-reports, orunvalidated administrative data. Research reports have oftenfailed to adjust for potential confounding factors, such assmoking, drug and alcohol abuse, and depression.

Cross-sectional designs based on self-report are especiallyproblematic in this context because of potential recall bias andpossible reverse causation, with inability to demonstrate atemporal relationship between PTSD and CHD. For instance, PTSDpatients tend to report a wide range of symptoms and medicalconditions related to almost all body systems, in addition tosymptoms of CHD (1). The implications for reverse causation arethat PTSD can be a consequence, in addition to a cause, of a heartattack (2). Although recent longitudinal studies have lent supportto a relationship between PTSD and CHD (3–5), most haveexamined PTSD symptoms in communities with a low prevalenceof PTSD and usually relied on clinical events or causes of deaththat were often not clinically confirmed.

It is only recently that data are beginning to emerge on a linkbetween a PTSD diagnosis and CHD using more objectivemeasures of CHD. These measures have included coronary arterycalcium scores as markers for plaque burden (6), accuratemeasurement of the incidence of clinical CHD events, andmyocardial perfusion imaging data (7). These studies havetypically found substantial elevations of risk of CHD in personswith PTSD, approximately a twofold increase. For example, in astudy of Vietnam-era twins, we found that twins with PTSD weretwice as likely to undergo hospitalizations or revascularizationprocedures for CHD over a median follow-up of 13 yearscompared with twins without PTSD, even after adjusting fortraditional CHD risk factors, health behaviors, depression, andother psychiatric diagnoses (7). The increased risk of CHD eventswas confirmed by quantitative measures of coronary perfusionand myocardial blood flow assessed with positron emissiontomography. The results showed that twins with PTSD had almosttwice as much compromised coronary perfusion than those

From the Department of Epidemiology, Rollins School of Public Health,Emory University, and the Department of Medicine, Division ofCardiology, Emory University School of Medicine (VV), and theDepartment of Psychiatry and Behavioral Sciences, Emory UniversitySchool of Medicine (JDB), Atlanta, Georgia.

Address correspondence to Viola Vaccarino, M.D., Ph.D., Professor,Department of Epidemiology and Professor of Medicine, EmoryUniversity, 1518 Clifton Road, Room 3011, Atlanta, GA 30322; E-mail:viola.vaccarino@emory.edu.

Received Sep 30, 2013; accepted Oct 1, 2013.

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without PTSD. These differences were only modestly reducedwhen comparing twins discordant for PTSD, who are naturallymatched for sociodemographic factors, early environment and,for the monozygotic twins, also for genetic factors. These within-pair results lent further validity to the association of PTSDwith CHD.

The study by Turner et al., in this issue of Biological Psychiatry(8), confirms these previous findings in a sample of patients fromoutpatient clinics of two Veteran Affairs Medical Centers. In thisstudy, ischemia was assessed by exercise electrocardiography(ECG). Exercise ECG testing is considered less accurate for theassessment of ischemia than stress testing in conjunction withmyocardial perfusion imaging, especially because of low specifi-city and because ST-segment changes during treadmill ECGtesting are weak markers of prevalent or incident ischemic heartdisease (9). Despite these limitations, the results are impressivelysimilar to the twin study mentioned earlier, showing about twicethe prevalence of ischemia in patients with PTSD compared withthose without the disease. Non-ECG measures of exercise tread-mill testing—in particular, exercise capacity—have emerged asstronger predictors of cardiovascular risk than ECG measures (9).It is unfortunate that exercise capacity data from the treadmilltests were not presented in this article because they would havebeen useful complementary information.

As in previous studies (6), the report by Turner et al. is basedon a clinical sample from Veteran Affairs outpatient clinics. Thereis a potential for selection bias when study participants areidentified through medical encounters because patients withPTSD may differ in their likelihood to undergo, or be referredfor, medical evaluation or treatments compared with thosewithout PTSD. That this might be true is suggested by the factthat, in this study, patients with and without PTSD did not vary insmoking behavior or socioeconomic factors, which is surprisingand inconsistent with previous studies. Thus, the need remains formore studies based on community samples or other nonselectedpopulations.

Despite these issues, the study by Turner et al. provideswelcome new evidence of a link between PTSD and CHD. Themechanisms behind this relationship, however, still need to beunderstood. Clearly, maladaptive behaviors, such as smoking andsubstance abuse, which are almost invariably more common inpersons with PTSD, may be implicated. Lower propensity to seekmedical care and poor functioning could translate to reducedself-care or reduced access to health care. In addition tobehavioral and lifestyle factors, however, it has long beensuggested that neurobiological features characteristic of PTSDcould have potential damaging effects on the cardiovascularsystem (Figure 1).

PTSD is characterized by chronic dysregulation of neurohor-monal systems involved in the stress response. Dysregulation ofthe hypothalamic-pituitary-adrenal axis in PTSD is evidenced byincreased corticotrophin releasing factor levels and decreasedperipheral cortisol concentrations at rest, in addition to increasedcortisol release with psychological stressors, particularly remin-ders of the trauma. In addition, there is increased activation of thesympathetic nervous system during psychological stressors, againparticularly with trauma-reminiscent events (10). Indeed, combat

BIOL PSYCHIATRY 2013;74:790–792& 2013 Society of Biological Psychiatry

Figure 1. Schematic representation of potential mechanisms linkingposttraumatic stress disorder to coronary heart disease. HPA, hypothalamic-pituitary-adrenal; SNS, sympathetic nervous system.

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veterans with PTSD, compared with control subjects, exhibit anincrease in heart rate and other physiologic parameters inresponse to auditory reminders of trauma (such as tapes of thesound of gunfire), combat slides, or scripts of the individual’straumatic experiences. They also evidence an increase in heartrate, blood pressure, and PTSD symptoms with pharmacologicstimulation of the noradrenergic system, as well as altered brainfunction (decreased frontal lobe function) compared with sub-jects without PTSD (10). No similar responses are observed inconjunction with neutral stressors such as mental arithmetic.

Hemodynamic and neuroendocrine hyperreactivity duringpsychological stress have been linked to future adverse cardio-vascular health status. However, the specific mechanisms for sucheffects are not clear. A commonly endorsed risk pathway ischronic disruption of neuroendocrine and immune functionsystems involved in physiologic homeostasis, leading to repeatedand eventually sustained elevations in blood pressure, heart rate,plasma glucose, insulin resistance, and dyslipidemia. However, itseems unlikely that these risk factors entirely account for therelationship between PTSD and CHD risk because when they wereadjusted for statistically in previous studies, the relationshipremained. In addition, although some studies found an associa-tion between PTSD and these metabolic risk factors, many othersdid not. In our twin study, PTSD was unrelated to metabolic riskfactors measured at follow-up, such as glucose levels, bloodpressure, dyslipidemia, and obesity (7). Thus, pathways other thantraditional cardiovascular risk factors must be involved in therelationship between PTSD and CHD.

Elevated catecholamine response to trauma-reminiscent cuesmay have direct effects on the myocardium, the vascularendothelium, plaque stability, inflammation, and platelet func-tion, which could affect cardiovascular risk independent oftraditional risk factors and even independent of coronary plaqueburden. For example, catecholamine-induced peripheral vaso-constriction during psychologic stress may increase cardiacafterload, which could predispose to myocardial ischemia. Inaddition, neuroendocrine and hemodynamic hyperreactivitycould have long-term effects on vessel function, includingcoronary microvascular function, an established early marker ofischemic heart disease. Repeated sympathetic system responsesto trauma reminders could also affect myocardial electricalstability and the risk for cardiac arrhythmias, as suggested bythe observation that heart rate variability and baroreflex func-tion, important risk factors for cardiac events, arrhythmias andmortality, are reduced in subjects with PTSD. Finally, epigeneticprocesses are emerging as a potential connection betweenpsychosocial stress, psychiatric disorders including PTSD, andcardiovascular disease, and provide a biological mechanismthrough which environmental exposures, such as psychologicaltrauma, can modulate gene expression.

Much has been learned about the connection between PTSDand CHD, but much more needs to be discovered, particularlyin relation to underlying mechanisms. Furthermore, moreneeds to be learned about PTSD-related factors that maymodulate CHD risk. These include, for example, the time courseof PTSD (i.e., age of onset, duration, treatment response, andremission); the type and severity of PTSD symptoms; the role ofpsychiatric comorbidity, such as depression and substanceabuse; the type of trauma and developmental epoch in whichit occurs; the potential effects of treatment drugs, such asantipsychotics; and the role of buffering factors such as socialconnections and emotional support. These data would provideimportant information related to vulnerability or resiliencetoward CHD risk in persons with PTSD. In addition to being adebilitating and prevalent psychiatric condition, PTSD repre-sents a useful model for how psychological stress can get“under the skin,” and thus the implications of this research willbe broad.

VV is supported by National Institutes of Health Grant Nos. 2K24HL077506, R01 HL109413, 2R01 HL68630, R01 AG026255, and P01HL101398. JDB is supported by grants K24 MH076955, R01MH056120, R01 HL088726, and P01 HL101398.

The authors reported no biomedical financial interests orpotential conflicts of interest.

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