Post-traumatic stress disorder: a fast track to premature cardiovascular disease?

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REVIEW ARTICLE

Post-traumatic Stress Disorder A Fast Track to Premature Cardiovascular Disease? Bailey A. Wentworth, BS,* Murray B Stein, MD, MPH,* Laura S Redwine, PhD,* Yang Xue, MD,† Pam R. Taub, MD,† Paul Clopton, MS,† Keshav R. Nayak, MD,‡ and Alan S. Maisel, MD,†

Abstract: An increasing body of evidence reported in the literature indicates a possible role for post-traumatic stress disorder (PTSD) as a cause for cardiovascular disease (CVD). However, mechanistic evidence on the progression of adverse cardiac outcomes in PTSD is lacking. In this review, we examine the potential paths by which CVD could occur in those with PTSD. Dysregulation of the hypothalamic-pituitary-adrenal axis and autonomic nervous dysfunction are commonly observed in PTSD, which in turn leads to a variety of physiological changes potentially damaging to the heart. Increased inflammation, dysfunction of the vascular endothelium, hypercoagulability, and cardiac hyperreactivity all have been noted in patients with PTSD. Altered neurochemistry, most notably increased arginine vasopressin, as well as an increased prevalence of the metabolic syndrome, may also contribute to adverse cardiac outcomes. Although the association between PTSD and physical disease is often complicated by health risk behaviors or comorbid psychiatric conditions, the evidence for a link between PTSD and CVD is substantial. In our examination, we attempt to identify potential cardiac biomarkers that may be useful in detecting increased cardiac risk in patients with PTSD. As research in this area is exceedingly limited, we hope to inspire further research, as there is great potential value in identifying prognostically useful cardiac biomarkers so as to predict and prevent the onset of CVD in patients with PTSD. Key Words: post-traumatic stress disorder, cardiovascular disease, biomarkers, MR-proADM, copeptin (Cardiology in Review 2012;00:00–00)

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lobal conflict and terrorism are prevalent in the present era, and as a result, post-traumatic stress disorder (PTSD) has increasingly become a cause of substantial disability in both civilian and military populations. Approximately 8% of the general population has had or will have PTSD at some point in their lives1 with about 7.7 million Americans suffering from the disease in a given year.2 Among returnees from the Iraq and Afghanistan wars (Operations Iraqi and Enduring Freedom), the occurrence of PTSD is estimated to be 16–17%.3 Among veterans of the Vietnam era, the lifetime incidence of PTSD is believed to be as high as 30%.1 One of the most troubling observations is that these individuals are also at increased risk for a myriad of physical illnesses. A national sample of Vietnam veterans with PTSD 20 years after service showed a higher incidence of a wide range of comorbidities, including metabolic, digestive, endocrine, nervous, respiratory, and circulatory diseases.4 Of those with PTSD, 67.5% had a chronic illness, as compared with 48.6% of veterans without PTSD. After 30 years, the same national sample showed a higher all-cause mortality rate for cardiovascular disease (CVD), cancer, and external causes of death (eg, suicide, drug overdoses, or other injury).5 © 2012 Lippincott Williams & Wilkins ISSN: 1061-5377211-0000 DOI: 10.1097/CRD.0b013e318265343b

The link between PTSD and CVD is particularly compelling. A study involving World War II prisoners of war demonstrated a significantly increased risk of chronic ischemic heart disease, hypertension, and circulatory diseases in those with PTSD.6 In a 14-year prospective study, women with five or more symptoms of PTSD were over three times more likely to develop coronary heart disease (CHD) than controls, after accounting for depression, anxiety, and cardiac risk.7 A retrospective medical record review of male veterans over an 11-year period showed a positive association between selfreported PTSD symptoms and the development of nonfatal myocardial infarction (MI) or fatal CHD.8 A diagnosis of PTSD has also been associated with electrocardiographic abnormalities, including conduction system diseases.9 The connection between PTSD and physical illness is particularly complex because PTSD often coexists with other psychiatric conditions (eg, major depression, panic disorder) and risky behaviors (eg, smoking, alcohol, and substance abuse).10 Additionally, the physiological effects of PTSD appear to be extensive, affecting multiple organ systems with intertwined health consequences including hypertension, hyperlipidemia, obesity, diabetes, endothelial dysfunction, and CHD.11–14 However, mechanistic evidence is lacking, and further research is warranted to elucidate the connection between PTSD and physical diseases in order to prevent adverse clinical outcomes. In this review, we systematically examine the current evidence of PTSD-related cardiac dysfunction and the neuroendocrine, immune, nervous, and metabolic pathways with associated biomarkers that may potentiate CVD in patients with PTSD. Figure 1 illustrates these potential relationships. In the future, patients with PTSD may benefit greatly from the identification of a set of reliable biomarkers that aid the clinician in predicting the development of early CVD, as well as the prognosis of those with PTSD.

NEUROPHYSIOLOGY OF PTSD PTSD is a mental health condition triggered by exposure to a traumatic event. Diagnostic criteria from the fourth edition of Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) includes three symptom clusters: (1) recurrent and intrusive recollections of the distressing event, (2) evidence of numbing, eg, avoidance of people, activities, or thoughts related to the trauma, and (3) persistent hyperarousal, eg, insomnia, excessive irritability, or exaggerated startle response.15 Research examining the neurophysiology of PTSD has widely indicated that a key feature of the disorder is the disrupted regulation of stress hormone release by both the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic-adrenal-medullary system.16–19 These systems have been of central focus because of their association with the aforementioned clinical characteristics distinct to PTSD of intrusive recollection, avoidance or numbing, and hyperarousal or agitation. Although a systematic review of HPA and sympathetic-adrenal-medullary alterations in PTSD is beyond the scope of this article,

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FIGURE 1.  Potential paths to cardiovascular disease in PTSD. PTSD indicates post-traumatic stress disorder; HPA, hypothalamicpituitary-adrenal; CRH, corticotropin-releasing hormone; sTF,; vWF, von Willebrand factor.

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the key traits are considered here to examine the possible neuroendocrine underpinnings in adverse cardiac outcomes in PTSD. Readers are directed to comprehensive reviews17,18 for a more thorough discussion.

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Evidence of dysregulation of the HPA axis in patients with PTSD has been observed in many studies to date. Similar to typical stress responses, PTSD is often related to elevated levels of corticotropin-releasing hormone (CRH)20 synthesized in the paraventricular nucleus of the hypothalamus. However, low levels of plasma and urinary cortisol are also commonly seen in PTSD, which contradicts the concept of usual stress-related physiology. This paradoxical finding is probably due to the increased sensitivity of the HPA axis to negative feedback. Blunted adenocorticotropin hormone (ACTH) release in response to a CRH challenge test has also been observed in females with PTSD due to abuse in childhood.21 Similarly, in response to administration of the potent glucocorticoid dethamexasone, patients with PTSD exhibit enhanced suppression of cortisol production, indicating an enhanced response to negative feedback.22 This dysfunction of the HPA axis, resulting in diminished levels of cortisol, has extensive physiological effects. Decreased cortisol can result in an enhanced immune state, dysregulation of lipid and glucose metabolism, and altered brain function, namely of mood and memory.23 The diurnal pattern of cortisol secretion also appears to be irregular in PTSD. Periodic salivary cortisol concentrations show a 2  |  www.cardiologyinreview.com

flattening of the daily cortisol slope in adults with PTSD.24 This pattern of cortisol secretion has been linked to other chronic medical conditions including CVD25 and chronic fatigue syndrome.26 Overall, these observations are strong indicators of HPA axis dysregulation; however, findings are varied and may differ with gender, age, psychiatric comorbidities, current versus lifetime PTSD, symptom severity, and trauma exposure.17,27 Although the neuropathology of PTSD needs some further clarification, there is considerable evidence to suggest reduced secretion of cortisol in patients with PTSD, especially in chronic sufferers,17 which can have far-reaching physiological effects.

Sympathetic-Adrenal-Medullary Dysfunction Consistent with the clinical presentation of “persistent hyperarousal”, patients with PTSD exhibit perturbations in autonomic nervous activity, namely enhanced sympathetic and diminished parasympathetic function. Sympathetic activation in patients with PTSD has been identified via elevated catecholamine levels in 24-hour urine samples, most notably of norepinephrine and dopamine, which have been positively correlated with PTSD symptom severity.28 Persistently elevated catecholamine levels may be at least partially responsible for the increased heart rate (HR) and hypertension commonly seen in PTSD. Several studies have reported that patients with PTSD have an elevated heart rate at baseline and a more distinctive increase in HR in response to stressors.29,30 The effects of heightened sympathetic arousal have a direct impact on CV electrophysiology. Patients with anxiety disorders © 2012 Lippincott Williams & Wilkins

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were examined for autonomic nervous function by measuring heart rate variability, respiratory sinus arrhythmia, and electrodermal activity. Patients with PTSD had significantly decreased respiratory sinus arrhythmia and heart rate variability at baseline after controlling for respiratory variations, which indicated diminution of parasympathetic activity. Electrodermal activity, which is largely controlled by sympathetic innervation, was also noted to be higher in patients with PTSD upon stressor cues.19 Other studies have demonstrated similar results,31–33 including blunted parasympathetic response to trauma cues. Reduced heart rate variability has been associated with a wide range of illnesses, including diabetes and CVD, and has also been shown to be an independent predictor of mortality in patients after MI.34 One marker of increased sympathetic activation, adrenomedullin, may be of prognostic value when assessing cardiac risk in patients with PTSD. Originally discovered in pheochryomo-cytoma tissue, adrenomedullin is a natriuretic peptide released from the adrenal gland, heart, kidney, lung, brain, and vascular endothelium.35 Increased adremedullin secretion occurs in patients with congestive heart failure.35 In recent research, the stable adrenomedullin fragment mid-regional proadrenomedullin (MR-proADM) has been shown to be predictive of adverse outcomes in patients with acute heart failure. In the 15-center prospective Biomarkers in Acute Heart Failure study,36 MR-proADM was found to be more accurate than B-type natriuretic peptide in predicting mortality in patients with acute heart failure at 90 days. Recent data from our group indicate that MR-proADM, in addition to B-type natriuretic peptide and the endothelial marker CT-proET-1, is useful in predicting CV mortality in patients with PTSD.37 This imbalance in autonomic activity resulting in increased catecholamines, elevated resting heart rate, high blood pressure, and reduced cardiac vagal tone, can increase the risk for CVD. Increased resting heart rate and hypertension are known to be predictors of mortality in patients with CVD.38 Furthermore, chronically increased catecholamine release resulting in persistent stimulation of cardiac β-adrenergic receptors is known to be damaging to the heart and can also impair endothelial function, increasing the risk for atherosclerosis and vascular disease.13,39 The significance of reduced heart rate variability is still under debate, but is also a predictor of mortality in patients with heart failure as well as adverse events in patients after MI.34 In patients with PTSD, MR-proADM may be prognostically useful in detecting adverse effects of enhanced sympathetic activity on the heart, though further research is needed. Recently, it was shown that the use of β-adrenergic blocker could reduce the incidence of PTSD, suggesting the importance of autonomic imbalance in PTSD and a potential treatment.40

Neurochemical Dysregulation The frequent coincidence of CVD with obesity, metabolic syndrome, and depressive disorders has led recent research to explore possible common neural origins of these diseases. Although the precise relationships are still largely unknown, certain neurobiological similarities may be of interest in further probing a link between PTSD and somatic disease. Szczepanska-Sadowska and colleagues present a complete review.41 Arginine vasopressin (AVP) is a hypothalamic hormone known for its role in fluid balance and regulation of blood pressure. Similar to CRH, it is synthesized in the paraventricular nucleus of the hypothalamus and its release is potentiated by CRH. As high levels of CRH are often seen in PTSD, it is reasonable to expect that AVP would also be elevated. Indeed, recent research has suggested that high levels of AVP are associated with various affective disorders, including anxiety and depressive disorders.42 Among war veterans with trauma exposure, those with a PTSD diagnosis had higher plasma levels of © 2012 Lippincott Williams & Wilkins

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AVP than those without exposure to trauma.43 In rats, those with a gene alteration resulting in overexpression of AVP exhibited highanxiety behavior, and conversely, those with decreased AVP function showed reduced anxiety and depressive-like behavior. One reviewer suggests utilization of AVP receptor antagonists as a future avenue of treatment for PTSD.44 Elevated AVP is also associated with adverse CV outcomes, in particular, heart failure.45 In transgenic mice, overexpression of the primary cardiac AVP receptor, V1A, resulted in left ventricular dysfunction, hypertrophy, and dilatation.46 In other studies, enhanced stimulation of vasopressinergic neurons in rats was associated with left ventricular hypertrophy and postinfarct heart failure.47 Copeptin, the c-terminal segment of pre-pro-vasopressin, is a reliable surrogate marker of AVP48 and has been shown to be a strong prognostic biomarker in patients with heart failure after acute MI.49 In another multicenter study of patients with acute heart failure, elevated copeptin levels were associated with significantly increased 90-day mortality, heart failure–related readmissions, and emergency department visits.50 Additionally, a redistribution of neurotransmitter receptors is seen in patients with PTSD. In a retrospective analysis of in vivo imaging on patients with various anxiety disorders including PTSD, there was a significant reduction of serotonin transporter receptors in the mesencephalon, serotonin receptors in the cingulate and mesencephalon, and dopamine receptors in the striatum, as well as a widespread reduction of GABAA receptors in the frontal, temporal, occipital lobes, and cingulate.51 This altered composition indicates that the action of serotonin, dopamine, and GABA may be key players in the pathophysiology of anxiety disorders including PTSD. Reduced GABA signaling, which normally acts antagonistically to dopamine, would result in an increased effect of dopaminergic neurotransmission and overall excitability,51 which is consistent with the observation of elevated dopamine and norepinephrine levels in 24-hour urine samples in patients with PTSD.28 Disinhibition of dopaminergic signaling may be partially responsible for sympathetic activation and increased CV reactivity.

HEIGHTENED IMMUNE ACTIVITY Individuals with PTSD may also be at increased CV risk due to the apparent disinhibition of immune activity and greater incidence of inflammatory conditions observed. Increased inflammatory activity is associated with vascular endothelial injury and CV remodeling.52 In a nationwide sample of 2490 Vietnam veterans, those with chronic PTSD were found to have a higher prevalence of autoimmune diseases, including thyroid disease, rheumatoid arthritis, psoriasis, and type I diabetes. They were also more likely to have higher T-lymphocyte counts and enhanced in vivo immune responses to antigen-placed delayed type hypersensitivity test.53 In a study of women with PTSD due to childhood abuse, similar changes in immune function were also observed, including a faster skin barrier recovery time.54 These observations contrast with the reactivity of a patient with chronic stress, in which immune function as described by the antigen-placed delayed type hypersensitivity test and skin recovery time is expected to be lower.55 Lymphocyte count and activity also indicate a disinhibited immune state in PTSD, although the data are mixed. Some studies show increased numbers of leukocytes55 and T lymphocytes,53,55,56 whereas others have found no change.54,57 It may be important to consider the activation of T cells: in a study involving maltreated women, those exhibiting more severe PTSD symptoms were found to have a higher percent of T lymphocytes expressing an early activation marker (CD45RA).58 www.cardiologyinreview.com  |  3

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Cytokine production in patients with PTSD appears to support increased inflammation. Inflammatory cytokines appear to be higher in patients with PTSD, whereas some antiinflammatory cytokines are lower. Baseline levels of interleukin (IL)-1β are higher in patients with PTSD as compared with controls,59 and have been positively correlated with duration of PTSD symptoms.60 TNF-α levels are also higher in patients with PTSD in studies of maltreated women and in veterans.56,61 Another inflammatory cytokine, IL-6, has been found to be elevated at baseline in patients with PTSD,56 and may be positively correlated with anxiety and depression.62 Higher levels of IL-6 in the mornings and low cortisol levels in the evening in the 24-hour period after a motor vehicle accident were also shown to predict PTSD development in children at 6 months.63 Some studies have also shown positive correlation between C-reactive protein and PTSD;64,65 however, the evidence is conflicting.61 Furthermore, levels of antiinflammatory cytokines are attenuated in PTSD. In a sample of earthquake survivors, those with PTSD showed lower plasma levels of IL-8 and IL-2, though plasma IL-2 levels correlated with the experience of traumatic stress and was not necessarily a PTSD diagnosis.62 Levels of IL-4 have also been inversely associated with PTSD symptom strength.57,61 Lymphocyte glucocorticoid receptor density and sensitivity also appear to be altered, though the results are mixed.17,66 These conflicting results in levels of inflammatory cytokines may be due to the varied time course after the initial trauma when they were measured. Dysregulation at the HPA axis, resulting in decreased cortisol secretion, could be a major contributor to the immune dysfunction in patients with PTSD, as reduction in the inhibitory effects of cortisol can result in abnormally heightened immune function.56 Autonomic dysfunction, resulting in chronically elevated catecholamines, can also increase cytokine production via increased stimulation of β-adrenergic receptors on immune cells.67 Traumatic stress may also lead to epigenetic changes, in which altered gene expression favors increased immune activity.68 These changes are probably responsible for the increased prevalence of autoimmune disorders in patients with PTSD and may have more far-reaching effects, such as the accelerated injury of vascular endothelium and ultimately the development of CVD.

ENDOTHELIAL DYSFUNCTION Patients with PTSD may be more susceptible to vascular endothelial damage. In a study of police officers with varying PTSD symptoms, brachial reactivity was measured using flow-mediated dilation; those with severe PTSD symptoms had half the brachial reactivity than those with lesser symptoms.69 Levels of coronary artery calcium, a measure of atherosclerotic risk, in a population without known CHD were also positively correlated with PTSD symptoms.70 Another study assessed the levels of soluble tissue factor and von Willebrand factor which are markers of inflammation and tissue injury, and found increased levels of both markers in association with psychological distress. Although soluble tissue factor was not exclusive to a PTSD diagnosis, von Willebrand factor correlated well with the diagnosis and PTSD symptom severity.71 Levels of blood coagulants can also indicate endothelial dysfunction. A study in which resting plasma levels of clotting factors were measured in patients with PTSD, both fibrinogen and factor VIII:C were found to be linked to PTSD symptom severity and level of hyperarousal, but were not independently associated with the diagnosis.72 Similarly, a flow-cytometry analysis in veterans showed correlation between increased platelet reactivity and PTSD.73 This hypercoagulation seen in patients with PTSD could confer an increased risk for vascular wall damage, atherogenic processes, and acute coronary syndrome.74 4  |  www.cardiologyinreview.com

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Elevated levels of soluble cell adhesion molecules (CAMs) may also connect PTSD with CV risk. A sample of patients those who developed PTSD after MI had higher levels of soluble vascular CAMs and soluble intercellular CAMs, both at rest and after a trauma-specific interview.75 Damage to the endothelial lining of blood vessels appears to be accelerated by traumatic stress. Hypercoagulibility, high levels of inflammatory cytokines, and low brachial reactivity, can all contribute to the progression of atherosclerosis and the development of CVD.

METABOLIC DISORDERS Patients with PTSD appear to be at increased risk for the metabolic syndrome. Several studies have shown that PTSD is associated with hyperlipidemia, obesity, and altered adipokines.76–79 In a study of combat-exposed Croatian veterans, those with PTSD had higher cholesterol, elevated triglycerides, a higher low-/high-density lipoprotein ratio, and an overall higher atherosclerotic index.80 Among New York police officers, those in the severe PTSD symptom group were three times more likely than the low symptom group to have the metabolic syndrome as characterized by hyperlipidemia, hypertension, obesity, low high-density lipoprotein, or impaired glucose tolerance.81 A sample of veterans with chronic PTSD also showed increased rates of the metabolic syndrome with a positive correlation to PTSD symptom severity.82 Obesity may also be associated with PTSD. In a national sample of veterans, those with PTSD had a significantly higher average body mass index (BMI).83 In a sample of women, a higher BMI and a higher waist-hip ratio was found in those with PTSD.84 However, this finding has not been universally replicated. In another study, BMI was correlated only with depression.85 A few studies have revealed an imbalance in adipocytokine activity is imbalanced in patients with PTSD. Among earthquake survivors in Taiwan, elevated leptin levels were observed in those with PTSD and were positively correlated with symptom severity.86 In patients after MI, higher levels of leptin were seen in patients with depression and PTSD.87 Baseline levels of neuropeptide Y, which generally causes increased hunger via its action on the hypothalamic satiety center, has been shown to be lower in plasma and cerebrospinal fluid of patients with PTSD.88–90 Similarly, plasma and cerebrospinal fluid levels of orexin-A are lower in those with PTSD and are inversely correlated with symptom severity.91 The role of adiponectin has not been assessed in PTSD, but it has been shown to inversely correlate with anxiety, which is a common symptom of PTSD.92 These findings of elevated leptin, low neuropeptide Y, and low orexin levels are particularly unusual because each of these changes would act to decrease appetite; yet, increased rates of obesity are often seen in PTSD. Altered adipokines, including elevated leptin in patients with PTSD, may reflect regulatory dysfunction including leptin resistance. Interestingly, leptin may also contribute to sympathetic activation and hypertension.92 A handful of studies suggest that PTSD may also be related to developing insulin resistance and type II diabetes. Individuals with PTSD resulting from deportation to Siberia in childhood showed a greater incidence of diabetes, CHD, higher fasting glucose, elevated triglycerides, and hypertension.93 Other reports indicate a higher prevalence of diabetes in a nationwide sample of veterans with PTSD53 and among traumatized refugees.94 In an animal model examining the effects of stress on metabolism, sensitization of the HPA axis induced by persistent stress resulted in hyperglycemic and hyperinsulemic mice.95 This may be due to increased adrenergic receptor activation at the pancreas, resulting in increased glucagon and insulin, with the net effect being hyperglycemia.41 © 2012 Lippincott Williams & Wilkins

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Post-traumatic Stress Disorder

TABLE 1.  Summary of Potential Cardiac Biomarkers in Post-traumatic Stress Disorder System

Physiologic Changes

Potential Cardiac Biomarkers

Immune

Proinflammation: Enhanced DHT test reactivity Increased T-lymphs, activated T-lymphs Increased inflammatory cytokines Increased catecholamines Elevated heart rate, blood pressure Decreased heart rate variability and respiratory sinus arrhythmia Increased CRH Decreased cortisol Flattened diurnal cortisol rhythm Hypercoagulability Decreased brachial reactivity by flow-mediated dilation

Tumor necrosis factor-α IL-1β IL-6

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Autonomic nervous Neuroendocrine Vascular Endothelium

Metabolism

Adipokine imbalances Possible insulin resistance, predisposition for diabetes

MR-proADM Copeptin B-type natriuretic peptide CRH ACTH cortisol Soluble intercellular CAM Soluble vascular CAM von Willebrand factor Soluble tissue factor Fibrinogen Factor VIII:C Coronary artery calcium Leptin Neuropeptide Y Orexin Adiponectin

CRH indicates corticotropin-releasing hormone; ACTH, adenocorticotropin hormone; CAM, cell adhesion molecules; IL, interleukin; MR-proADM, mid-regional proadrenomedullin

Although there is some evidence of adverse effects of PTSD on metabolic function, the research in this area is limited, and further research is necessary to clarify the relationships. However, the observations of hyperlipidemia and obesity in patients with PTSD are relatively consistent, and confer an increased risk of developing CVD, particularly when combined with accelerated endothelial damage and heightened immune function.

POTENTIAL FOR CARDIOVASCULAR RISK Compounding the mental health burden of PTSD, the increased physical illness evident in the PTSD population is cause for great concern. Summarized in Figure 1, the aforementioned effects of PTSD on neuroendocrine function, sympathetic arousal, immune activity, and metabolism together indicate a high risk for CVD. Until recently, mechanisms linking CV risk with PTSD have been explained through indirect pathways, based on the alterations of the HPA axis and autonomic function resulting in high catecholamines and inflammation, pituitary neurohormonal imbalance, and increased risk for metabolic syndrome. More recent evidence suggests that the neuropathology of PTSD may directly increase CV risk by neurophysiological signaling processes. This is an area worth further investigation. Complicating the relationship, individuals with PTSD often have comorbid psychiatric diagnoses, including major depression, hostility, or antisocial behavior. They may also engage in behavioral health risks associated with CVD, such as smoking, alcoholism, or physical inactivity. When investigating neurophysiological mechanisms linking CVD with PTSD, such factors must be considered.

FUTURE DIRECTIONS FOR RESEARCH T1

Although the evidence for an association between PTSD and CV risk factors is strong, the mechanisms involved are still unclear. This is an area ripe for exploration, as research is limited. Table 1 summarizes the potential biomarkers that may elucidate the mechanistic underpinnings in PTSD and aid in identifying a cohort in which targeted interventions are effective. Investigation into these and other © 2012 Lippincott Williams & Wilkins

emerging CV biomarkers will probably paint a more complete picture of the pathophysiology. Surrogates of the neurohormones AVP (copeptin) and adrenomedullin (MR-proADM) might be of unique value, as well as inflammatory cytokines and endothelial factors, which have all been implicated in cardiac disease, including heart failure.96,97 Future goals include the development of a multimarker panel which aids in the CV risk stratification in those with PTSD. However, for now, targeted research on biomarkers in PTSD and heart disease is a necessary next step in clarifying the role of PTSD in the accelerated development of CVD and heart failure. REFERENCES 1. Carlstedt RA. Handbook of Integrative Clinical Psychology, Psychiatry, and Behavioral Medicine: Perspectives, Practices, and Research. New York, NY: Springer, 2010. 2. “NIH Fact Sheets - Post-Traumatic Stress Disorder (PTSD).” NIH Research Portfolio Online Reporting Tools (RePORT). National Institute of Mental Health. Available at: http://report.nih.gov/NIHfactsheets/ViewFactSheet. aspx?csid=58. 3. Litz BT, Schlenger WE. PTSD in service members and new veterans of the Iraq and Afghanistan wars: a bibliography and critique. PTSD Research Quarterly. 2009; 20:1–3. 4. Boscarino JA. Diseases among men 20 years after exposure to severe stress: implications for clinical research and medical care. Psychosom Med. 1997;59:605–614. 5. Boscarino JA. External-cause mortality after psychologic trauma: the effects of stress exposure and predisposition. Compr Psychiatry. 2006;47:503–514. 6. Kang HK, Bullman TA, Taylor JW. Risk of selected cardiovascular diseases and posttraumatic stress disorder among former World War II prisoners of war. Ann Epidemiol. 2006;16:381–386. 7. Kubzansky LD, Koenen KC, Jones C, et al. A prospective study of posttraumatic stress disorder symptoms and coronary heart disease in women. Health Psychol. 2009;28:125–130. 8. Kubzansky LD, Koenen KC, Spiro A 3rd, et al. Prospective study of posttraumatic stress disorder symptoms and coronary heart disease in the Normative Aging Study. Arch Gen Psychiatry. 2007;64:109–116. 9. Boscarino JA, Chang J. Electrocardiogram abnormalities among men with stress-related psychiatric disorders: implications for coronary heart disease and clinical research. Ann Behav Med. 1999;21:227–234. 10. Kibler JL. Posttraumatic stress and cardiovascular disease risk. J Trauma Dissociation. 2009;10:135–150.

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11. Cohen BE, Marmar C, Ren L, et al. Association of cardiovascular risk factors with mental health diagnoses in Iraq and Afghanistan war veterans using VA health care. JAMA. 2009;302:489–492. 12. Schnurr PP, Spiro A 3rd, Paris AH. Physician-diagnosed medical disorders in relation to PTSD symptoms in older male military veterans. Health Psychol. 2000;19:91–97. 13. McFarlane AC. The long-term costs of traumatic stress: intertwined physical and psychological consequences. World Psychiatry. 2010;9:3–10. 14. Dedert EA, Calhoun PS, Watkins LL, et al. Posttraumatic stress disorder, cardiovascular, and metabolic disease: a review of the evidence. Ann Behav Med. 2010;39:61–78. 15. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. 2000. 16. Tsigos C, Chrousos GP. Hypothalamic-pituitary-adrenal axis, neuroendocrine factors and stress. J Psychosom Res. 2002;53:865–871. 17. Yehuda R. Advances in understanding neuroendocrine alterations in PTSD and their therapeutic implications. Ann N Y Acad Sci. 2006;1071:137–166. 18. de Kloet CS, Vermetten E, Geuze E, et al. Assessment of HPA-axis function in posttraumatic stress disorder: pharmacological and non-pharmacological challenge tests, a review. J Psychiatr Res. 2006;40:550–567. 19. Blechert J, Michael T, Grossman P, et al. Autonomic and respiratory characteristics of posttraumatic stress disorder and panic disorder. Psychosom Med. 2007;69:935–943. 20. Baker DG, West SA, Nicholson WE, et al. Serial CSF corticotropin-releasing hormone levels and adrenocortical activity in combat veterans with posttraumatic stress disorder. Am J Psychiatry. 1999;156:585–588. 21. Bremner JD, Vythilingam M, Anderson G, et al. Assessment of the hypothalamic-pituitary-adrenal axis over a 24-hour diurnal period and in response to neuroendocrine challenges in women with and without childhood sexual abuse and posttraumatic stress disorder. Biol Psychiatry. 2003;54:710–718. 22. Yehuda R, Southwick SM, Krystal JH, et al. Enhanced suppression of cortisol following dexamethasone administration in posttraumatic stress disorder. Am J Psychiatry. 1993;150:83–86. 23. Fries E: Hypercortisolemic disorders. In: Hellhammer DH, Hellhammer J, eds. Stress: The Brain-Body Connection.(Key Issues in Mental Health), vol. 174. Basel, Switzerland: Karger; 2008:60–77. 24. Yehuda R, Golier JA, Kaufman S. Circadian rhythm of salivary corti sol in Holocaust survivors with and without PTSD. Am J Psychiatry. 2005;162:998–1000. 25. Vreeburg SA, Kruijtzer BP, van Pelt J, et al. Associations between sociodemographic, sampling and health factors and various salivary cortisol indicators in a large sample without psychopathology. Psychoneuroendocrinology. 2009;34:1109–1120. 26. Nater UM, Youngblood LS, Jones JF, et al. Alterations in diurnal salivary cortisol rhythm in a population-based sample of cases with chronic fatigue syndrome. Psychosom Med. 2008;70:298–305. 27. Heim C, Nemeroff CB. Neurobiology of posttraumatic stress disorder. CNS Spectr. 2009;14(1 Suppl 1):13–24. 28. Yehuda R, Southwick S, Giller EL, et al. Urinary catecholamine excretion and severity of PTSD symptoms in Vietnam combat veterans. J Nerv Ment Dis. 1992;180:321–325. 29. Buckley TC, Kaloupek DG. A meta-analytic examination of basal car diovascular activity in posttraumatic stress disorder. Psychosom Med. 2001;63:585–594. 30. Orr SP, Metzger LJ, Lasko NB, et al.; Harvard/Veterans Affairs Post-traumatic Stress Disorder Twin Study Investigators. Physiologic responses to sudden, loud tones in monozygotic twins discordant for combat exposure: association with posttraumatic stress disorder. Arch Gen Psychiatry. 2003;60:283–288. 31. Thayer JF, Yamamoto SS, Brosschot JF. The relationship of autonomic imbalance, heart rate variability and cardiovascular disease risk factors. Int J Cardiol. 2010;141:122–131. 32. Sack M, Hopper JW, Lamprecht F. Low respiratory sinus arrhythmia and prolonged psychophysiological arousal in posttraumatic stress disorder: heart rate dynamics and individual differences in arousal regulation. Biol Psychiatry. 2004;55:284–290. 33. Cohen H, Benjamin J. Power spectrum analysis and cardiovascular morbidity in anxiety disorders. Auton Neurosci. 2006;128:1–8. 34. Sahar T, Shalev AY, Porges SW. Vagal modulation of responses to mental challenge in posttraumatic stress disorder. Biol Psychiatry. 2001;49: 637–643. 35. Gardner DG, Shoback DM, Greenspan FS. Greenspan’s Basic & Clinical Endocrinology. New York, NY: McGraw-Hill Medical; 2007.

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AUTHOR QUERIES AUTHOR PLEASE ANSWER ALL QUERIES AQ1—Please confirm the running head. AQ2—Please provide expansion for sTF. AQ3—Please provide expansion for HR. AQ4—Please provide expansion for CV. AQ5—Please provide expansion for GABA. AQ6—Please provide expansion for DHT. AQ7—Please provide publisher details for American Psychiatric Association. 2000